WO2002006245A1 - Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof - Google Patents

Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof Download PDF

Info

Publication number
WO2002006245A1
WO2002006245A1 PCT/US2001/021286 US0121286W WO0206245A1 WO 2002006245 A1 WO2002006245 A1 WO 2002006245A1 US 0121286 W US0121286 W US 0121286W WO 0206245 A1 WO0206245 A1 WO 0206245A1
Authority
WO
WIPO (PCT)
Prior art keywords
branched
straight chained
compound
cycloalkyl
alkyl
Prior art date
Application number
PCT/US2001/021286
Other languages
French (fr)
Inventor
Bharat Lagu
John Wetzel
Mohammad R. Marzabadi
John E. Deleon
Charles Gluchowski
Stewart Noble
Dhanapalan Nagarathnam
George Chiu
Original Assignee
Synaptic Pharmarceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synaptic Pharmarceutical Corporation filed Critical Synaptic Pharmarceutical Corporation
Priority to JP2002512149A priority Critical patent/JP2004504303A/en
Priority to EP01952440A priority patent/EP1299362A4/en
Priority to CA002384041A priority patent/CA2384041A1/en
Priority to AU73192/01A priority patent/AU783403B2/en
Publication of WO2002006245A1 publication Critical patent/WO2002006245A1/en
Priority to AU2006200052A priority patent/AU2006200052A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/79—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • MCH Melanin-concentrating hormone
  • MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996) . Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with o /+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles
  • MCH mRNA levels
  • the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells.
  • mouse melanoma B16-F1, G4F, and G4F-7
  • PC12 PC12
  • COS cells C12 cells
  • the K D O.ll ⁇ nM
  • MCH methylcellulose
  • lateral hypothalamus a brain area implicated in the regulation of thirst and hunger
  • orexins A and B which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al . , 1998).
  • MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Ba jaoui-Bouhaddi et al . , 1994) . Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al . , 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al .
  • MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al . , 1998) .
  • the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al . , 1992) . In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value 'to consider the involvement of this MCH system in movement disorders, such as Parkinson' s disease and Huntingdon' s Chorea in which extrapyramidal circuits are known to be involved.
  • MCH may regulate reproductive functions in male and female rats .
  • MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al . , 1996).
  • MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al . , 1996) .
  • MCH stimulated luteinizing hormone
  • anti-MCH antiserum inhibited LH release
  • the zona incerta which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al . , 1984).
  • MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin.
  • MCH analogues may also be useful in treating epilepsy.
  • MCH has also been observed to affect behavioral correlates of cognitive functions .
  • MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al . , 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention.
  • a possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers.
  • MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996) . Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals .
  • the term "antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
  • agonist refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
  • the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCHl) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vi tro assays is disclosed.
  • MCHl melanin-concentrating hormone-1
  • the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa) , sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCHl receptor may be beneficial.
  • feeding disorders ovalbumina, bulimia and bulimia nervosa
  • sexual/reproductive disorders depression, anxiety, depression and anxiety
  • epileptic seizure hypertension
  • cerebral hemorrhage congestive heart failure
  • sleep disturbances or any condition in which antagonism of an MCHl receptor may be beneficial.
  • the compounds of the present invention may be used to reduce the body mass of a subject.
  • This invention provides a compound having the structure
  • each of Y ⁇ , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C ⁇ C- ? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y ⁇ / Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a ethylenedioxy group;
  • each X is independently S; 0; or NR 3 ; wherein R x is -H; -N0 2 ; -CN; straight chained or branched C- L -C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or -C0 2 (CH 2 ) n V;
  • R 2 is -H; straight • chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ⁇ - C i0 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3
  • each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 4 is (i)
  • dashed line represents a single bond or a double bond
  • each R is independently -H; -F; straight chained or branched C x ⁇ C- ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CON(R 3 ) 2 ;
  • each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R 5 is -H; -N0 2 ; -N 3 ;
  • R 6 is -H; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ;
  • -CON(R 3 ) 2 aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 7 is H; F; CI; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N ( R 3 ) 2 ;
  • R 8 is independently straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) g OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 inclusive;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • r is an integer from 0 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive;
  • This invention further provides a compound having the structure :
  • each R is independently -H; -F; straight chained or branched C x -C ⁇ j alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -SR 3 ; -C0 2 R 3 ; or
  • each R x is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 ) 0R 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ;
  • each R 2 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 )
  • each R 3 is independently -H; straight chained or branched C; ⁇ _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; ⁇ SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • X is (CH 2 ) n , 0, S or NR 3 ;
  • aryl or heteroaryl optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C- ; alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C alkynyl; C 3 -C 7 cycloalkyl;
  • m is an integer from 0 to 4 inclusive;
  • n is an integer from 0 to 6 inclusive
  • p is an integer from 1 to 4 inclusive
  • q is an integer from 1 to 3 inclusive
  • This invention also provides a compound having the structure :
  • each R is independently -H; -F; straight chained or branched C ⁇ C- ? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -C0N(R 3 ) 2 ;
  • each R x is independently -H; F; Cl; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -C0R 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ;
  • C 1 -C 7 alkyl monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ;
  • V is H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • aryl or heteroaryl optionally substituted with one or more F; CI ; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ -C ⁇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is an integer from 0 to 2 inclusive;
  • t is an integer from 2 to 6 inclusive
  • each of Y ⁇ r Y 2 , Y 3 , Y and Y 5 is independently -H; straight chained or branched C ] _-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I;
  • any two of Y , Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each X is independently S; 0; or NR 3 ;
  • R x is -H; -N0 2 ; -CN; straight chained or branched C ⁇ -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
  • R 2 is -H; straight chained or branched C ] _-C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-Cx-Cx Q -monofluoroalkyl or C 3 -C 10 cycloalkyl-C 1 - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
  • each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R is independently -H; -F; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
  • B is N or CY 4 ;
  • each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS; wherein each ⁇ is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C- y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or
  • V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
  • W is CR 5 ; CR 6 or N;
  • Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
  • each R 5 is -H; -N0 ; -N 3 ; -CN; straight chained or branched C x -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ;
  • each R 6 is independently -H; straight chained or branched C x -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
  • R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; -XCOR 8 ; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 8 is -H; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) )
  • b is 1 or 2;
  • d is an integer from 0 to 2 inclusive;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 constitu ive ;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • t is an integer from 2 to 6 ' inclusive;
  • each of Y , Y 2 , Y 3 , Y and Y 5 is independently -H; straight chained or branched C ⁇ ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
  • any two of Y ⁇ r Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each X is independently S; 0; or NR 3 ; wherein R- L is -H; -N0 2 ; -CN; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -C0N(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
  • R 2 is -H; straight chained or branched C ⁇ -C- 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ] ⁇ - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
  • each R 3 is independently -H; straight chained or branched C -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
  • B is N or CY 4 ;
  • each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycl
  • V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
  • W is CR 5 ; CR 5 or N;
  • Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
  • each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3
  • each R 6 is independently -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
  • R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; -XC0R 8 ; straight chained or branched C ⁇ C ⁇ y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 8 is -H; straight chained or branched Ci-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 )
  • b is 1 or 2;
  • d is an integer from 0 to 2 inclusive;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 inclusive ;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • t is an integer from 2 to 6 inclusive
  • the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
  • This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amounr. of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
  • This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • This invention further provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • This invention provides a compound having the structure
  • each of Y x , Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -C0R 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y x , Y 2 ,
  • Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group
  • each X is independently S; 0; or NR 3 ;
  • R x is -H; -N0 2 ; -CN; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or -C0 2 (CH 2 ) n V;
  • R 2 is -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C L - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n NHR 3 , -(
  • each R 3 is independently -H; straight chained or branched C j ⁇ -C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • dashed line represents a single bond or a double bond
  • each R is independently -H; -F; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -CON(R 3 ) 2 ;
  • each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C- L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ;
  • R 6 is -H; straight chained or branched C x -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ;
  • -CON(R 3 ) 2 aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 7 is H; F; CI; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p 0R 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
  • R 8 is independently straight chained or branched C- L -C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -
  • n is independently an integer from 0 to 5 inclusive;
  • each p is independently an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive;
  • r is an integer from 0 to 3 inclusive;
  • t is an integer from 2 to 6 inclusive
  • the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound has the structure:
  • the compound has the structure
  • the compound has the structure:
  • A is
  • the compound has the structure :
  • the compound has the structure:
  • the compound has the structure
  • the compound has the structure :
  • the compound has the structure :
  • the compound has the structure
  • the compound has the structure :
  • the compound has the structure
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the compound has the structure
  • the compound has the structure:
  • the compound has the structure :
  • the compound has the structure:
  • A is
  • the compound has the structure
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is ( - ) -1, 2 , 3 , 6-tetra-hydro-l- ⁇ n- [4- (3 , -acet-amido) -phenyl- piperidin-1-yl] ropyl ⁇ carboxamido-4-methoxymethyl-6- (3,4- difluoro-phenyl) -2-oxopyrimidine-5-carboxylic acid methyl ester.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound has the structure
  • each R is independently -H; -F; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or j polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -SR 3 ; -C0 2 R 3 ; or
  • each R x is independently -H; straight cha'ined or branched C--C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
  • each R 2 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C j ⁇ -C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 )
  • each R 3 is independently -H; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C 1 -C alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • X is (CH 2 ) n , O, S or NR 3 ;
  • aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C;L-C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
  • n is an integer from 0 to 6 inclusive
  • p is an integer from 1 to 4 inclusive
  • q is an integer from 1 to 3 inclusive
  • the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
  • the compound has the structure:
  • W is phenyl optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; or (CH 2 ) q SR 3 .
  • the compound has the structure
  • the compound has the structure
  • each R is independently -H; -F; straight chained or branched C 1 -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CON(R 3 ) 2 ;
  • each R x is independently -H; F; Cl; Br; I; -N0 2 ; -N 3 ; -CN; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN
  • each R 3 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ] _-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; -C0N(R 3 ) 2 ; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 ) 2 ; CN; -N
  • V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ;
  • (CH 2 ) q SR 3 straight chained or branched C- L -C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C x -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is an integer from 0 to 2 inclusive;
  • p is an integer from 1 to 7 inclusive
  • q is an integer from 1 to 3 inclusive
  • t is an integer from 2 to 6 inclusive
  • the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
  • the compound has the structure :
  • the compound has the structure
  • W is phenyl optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; or straight chained or branched C 1 -C 7 alkyl groups .
  • the compound has the structure
  • aryl includes phenyl and naphthyl and the term “heteroaryl” is used to include five and six membered unsaturated rings that may contain one or more heteroatoms such as oxygen, sulfur, and nitrogen.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl , indazolyl, benzimidazolyl , benzthiazolyl , purinyl, imidazo [2 , 1-jb] thiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3- benzothiazolyl .
  • the salts include but are not limited to the acids and bases listed herein.
  • the salts include, but are not limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the salts include, but are not limited to the inorganic base, ammonia.
  • the salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethyla ine, morpholine, piperazine and guanidine .
  • This invention further provides for the hydrates and polymorphs of all of the compounds described herein .
  • the present invention includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
  • the term "administering" shall emcompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention further includes metabolites of the compounds of the present invention.
  • Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is an amount from about 0.01 mg to about 800 mg .
  • the amount of the compound is an amount from about 0.01 mg to about 500 mg .
  • the amount of the compound is an amount from about 0.01 mg to about 250 mg .
  • the amount of the compound is an amount from about 0.1 mg to about 60 mg .
  • the amount of the co pound is an amount from about 1 mg to about 20 mg .
  • the carrier is a liquid and the composition is a solution.
  • the carrier is a solid and the composition is a tablet.
  • the carrier is a gel and the composition is a suppository.
  • This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable carrier” is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions .
  • the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet.
  • the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins .
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators .
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent .
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate sorbitan monoleate
  • polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • the present invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure:
  • each of Y X l Y 2 , Y 3 , Y 4 and Y 5 is independently -H; straight chained or branched C;-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 3 , -OCOR 3 , -COR 3 , -CON(R 3 ) 2 , or -COOR 3 ; or any two of Y ⁇ r Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each X is independently S; 0; or NR 3 ;
  • R x is -H; -N0 2 ; -CN; straight chained or branched Ci-C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
  • R 2 is -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C; L -C 10 -alkyl, C 3 -C 10 cycloalkyl-C; L -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-C ; - C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 )
  • each R 3 is independently -H; straight chained or branched C ; -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R is independently -H; -F; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -0R 3 ; or -CN(R 3 ) 2 ;
  • B is N or CY ;
  • each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS;
  • each ⁇ is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C- L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
  • Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
  • each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; or -C0N(R 3 ) 2 ; -XC0R 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -C0N(R 3 )
  • each R 6 is independently -H; straight chained or branched C j ⁇ -C-y alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ;
  • R is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ;
  • R 8 is -H; straight chained or branched C x -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR
  • b is 1 or 2;
  • d is an integer from 0 to 2 inclusive;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 inclusive;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • t is an integer from 2 to 6 inclusive
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • At least one R 5 group is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -XCOR 8 ; or straight chained or branched C- L -C 7 alkyl.
  • A is :
  • the compound is selected from the group consisting of:
  • the compound has the structure
  • the compound has the structure
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; -XCOR 3 ; or straight chained or branched C- L -C 7 alkyl.
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • A is
  • the compound is selected from the group consisting of
  • the compound has the structure
  • the compound has the structure
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • the compound has the structure
  • each of Y x , Y 2 , Y 3 ,. Y 4 and Y 5 is independently -H; straight chained or branched C J ⁇ -C- J alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
  • any two of Y x , Y 2 , Y 3 , Y 4 and Y 5 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each X is independently S; 0; or NR 3 ; wherein R x is -H; -N0 2 ; -CN; straight chained or branched Ci L -C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; ⁇ OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; -CON(R 3 ) 2 ; or C0 2 (CH 2 ) n V;
  • R 2 is -H; straight chained or branched C- L -C 7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or .alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C 3 -C 10 cycloalkyl-C 1 -C 10 -alkyl, C 3 -C 10 cycloalkyl-C 1 -C 10 -monofluoroalkyl or C 3 -C 10 cycloalkyl-Ci- C 10 -polyfluoroalkyl; -CN; -CH 2 XR 3 , -CH 2 X (CH 2 ) p NHR 3 , -(CH 2 ) n
  • each R 3 is independently -H; straight chained or branched C;-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R is independently -H; -F; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OR 3 ; or -CN(R 3 ) 2 ;
  • B is N or CY ;
  • each D is independently C(R 3 ) 2 ; 0; S; NR 3 ; CO; or CS;
  • each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -0R 3 ; -SR 3 ; (CH 2 ) q OR 3 ; (CH 2 ) q SR 3 ; straight chained or branched C; L -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • V is C(R 5 ) 2 ; CR 5 R 6 ; NR 5 or NR 6 ;
  • W is CR 5 ; CR 6 or N;
  • Z is S; 0; C(R 3 ) 2 ; or NR 3 ;
  • each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; -XCOR 8 ; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN
  • each R 6 is independently -H; straight chained or branched C 1 -C 7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • R 7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ;
  • R 8 is -H; straight chained or branched L -C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ; or -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q OR
  • b is 1 or 2;
  • d is an integer from 0 to 2 inclusive;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 inclusive;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • t is an integer from 2 to 6 inclusive
  • the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
  • This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
  • This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
  • This invention also provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
  • the feeding disorder is bulimia, obesity or bulimia nervosa.
  • the subject is a vertebrate, a mammal , a human or a canine .
  • the compound is administered in combination with food.
  • a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • compositions which need not be pharmaceutical as that term is understood in the art.
  • Such compositions comprise a compound in accordance with the subject invention in an amount effective to antagonize an MCHl receptor and a suitable carrier.
  • the invention provides a method of agonizing and/or antagonizing an MCHl receptor which comprises contacting the receptor, e.g. in vitro or in in vivo, with an amount of a compound of this invention effective to agonize and/or antagonize the receptor.
  • PYRIMIDINE To a stirring solution of 5- (benzyloxycarbonyl) -1, 6-dihydro-2- methoxy-4-ethyl-6- (3 , 4-difluorophenyl) pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH 2 C1 2 (200 mL) was added 4-nitrophenyl chloroformate as a powder (11.5 g, 57.1 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo .
  • the organic layer was dried over Na 2 S0 4 , filtered and solvent was removed in vacuo.
  • the resulting mixture of diastereomers was separated by column chromatography (petroleum ether/ether, 9/1 to 4/1) .
  • the first major product to elute was (+) -5- (benzyloxycarbonyl) -4-ethyl- 1, 6-dihydro-l- ⁇ N- [1- phenyl) -ethyl] ⁇ carboxamido-2- methoxy-6- (3, -difluorophenyl) pyrimidine .
  • 5-METHYLBENZFUROXAN 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated methanolic sodium hydroxide solution (1.50 L) . This suspension was cooled (5 °C) and aqueous sodium hypochlorite until the red color disappeared. The resulting fluffy yellow precipitate was filtered, washed with cold water and recrystallized from ethanol, giving 5-methylbenzfuroxan (88.2 g, 89 % yield) as a pale yellow solid: H NMR d 2.39 (s, 3 H) , 6.90-7.40 (br m. 3 H) .
  • 5-METHYLBENZOFURAZAN To 5-Methylbenzfuroxan (88.2 g, 0.590 mol) in refluxing EtOH (75 mL) was added dropwise P(OEt) 3 (150 mL) . Heating was continued at reflux temperature for 1 h. The solvent was removed in vacuo and the residue was shaken with water (200 mL) and allowed to stand overnight at (0-5 °C) . The resulting brown solid was filtered, washed with water.
  • 5-DIBROMOMETHYLBENZOFURAZAN An anhydrous solution of 5-methylbenzofurazan (70.0 g, 0.520 mol), N-bromosuccinamide (325 g) , and benzoyl peroxide (0.50 g) in carbon tetrachloride (1.5 L) was heated at reflux temperature with stirring for 30 h. The reaction mixture was washed with water (2 X 500 mL) , dried (NaS0 4 ) , and the solvent was removed in vacuo .
  • 6- (3, 4-DIFLUOROPHENYL) -1,2,3, 6-TETRAHYDRO-2-OXO-5-METHOXY CARBON-YL-4-METHYL-l- ( 4-NITROPHENOXY) CARBONYLPYRIMIDINE : Aqueous 6 N hydrochloric acid (10 mL) was added to a stirring solution of 6- (3, 4-difluorophenyl) -1, 6- dihydro- 2-methoxy-5-methoxycarbonyl- 4-methyl-1-
  • reaction mixture was cooled to -78 °C and tert- butyl 4-oxo-l-piperidinecarboxylate (40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes.
  • Tf 2 NPh (15.0 g, 42.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and the mixture was stirred at 0 °C overnight.
  • the reaction mixture was concentrated in vacuo, re-dissolved in hexanes/EtOAc (9/1), passed through a plug of alumina and washed with hexanes/EtOAc (9/1) .
  • TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-l,2,3, 6- TETRAHYDRO-1- PYRIDINECARBOXYLATE A mixture of saturated of aqueous Na 2 C0 3 solution (25 mL) , tert-butyl 4- ⁇ [ (trifluoromethyl) sulfonyl] oxy ⁇ - 1,2,3,6- tetrahydro-1-pyridine-carboxylate (20 mmol) , 3-acet- amidophenylboronic acid (30 mmol) and tetrakis- triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight.
  • PIPERIDINECARBOXYLATE A mixture tert-butyl 4- [3- (acetylamino) phenyl] -1,2,3, 6-tetra-hydro-l- pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg) . : H NMR ⁇ 7.80 (s, 1 H) , 7.41-7.20 (m, 3
  • 1-BENZYL-4-METHYL-4-PHENYLPIPERIDINE l-Benzyl-4-methyl- piperidin-4-ol (4.81 g, 23.4 mmol) was added to a suspension of A1C1 3 (15.62 g, 117 mmol) in benzene (100 mL) at room temperature under argon. The mixture was stirred at reflux for 24 hours, then cooled and poured cautiously into ice water (100 g of ice, 50 mL of water) . The aqueous phase was adjusted to pH 11-12 by addition of 6 N aqueous NaOH at 0 °C, and extracted with EtOAc (3 x 100 mL) .
  • the aqueous phase was adjusted to pH 11 by addition of 1 N aqueous NaOH.
  • the organic phase was separated, dried over magnesium sulfate and concentrated.
  • the residual oil was purified by flash chromatography (CHCl 3 /MeOH/2 N NH 3 in MeOH 100/4/0 to 100/20/10), giving l-benzyl-4- methyl-4- phenylpiperidine (1.20 g) and 1.10 g (51%, 82% based on consumed starting material) of 4-methyl-4-phenylpiperidine :
  • the solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h.
  • the crude product was dissolved in 50 mL of chloroform, stirred for 1 h, and filtered. The white solid was washed with additional chloroform (20 mL) , the solvent was evaporated from the combined filtrates to leave the crude product as an oil .
  • the oil was purified by column chromatography (dichloromethane / methanol / 2 M ammonia in methanol, 10/3/1), giving the desired product (2.70 g, 93%).
  • TETRAHYDRO-1-PYRIDINECARBOXYLATE n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL,
  • 1,2, 3, 6-TETRAHYDRO-4- (3-NITROPHENYL) PYRIDINE Into a stirred solution of 5.00 -g (16.0 mmol) of tert-butyl 1,2,3, 6-tetrahydro-4- (3-nitrophenyl) pyridine-1- carboxylate in 100 ml of 1,4-dioxane at 0°C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets.
  • TERT-BUTYL 3- (4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIDINYL) PROPYLCARBAMATE : A mixture of 2.80 g (14.0 mmol) of 1, 2, 3, 6-tetrahydro-4- (3-nitrophenyl) pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3- bromopropyl) carbamate, 11.6 g (84.0 mmol) of K 2 C0 3 , 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4- dioxane was heated at reflux temperature for 14 hours.
  • TETRAHYDRO-5-PYRIMIDINECARBOXYLATE A mixture of 3.02 g (6.33 mmol) 5-methyl 1- ( 4-nitrophenyl) (6S)-6-(3,4- difluorophenyl) -4- (methoxymethyl) -2-oxo-3, 6-dihydro- 1, 5 ( 2H) -pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3- (4- (3-nitrophenyl) -3, 6-dihydro-l (2H) -pyridinyl) -1- propanamine, 7.94 g (75.5 mmol) of K 2 C0 3 and 1.00 L of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour.
  • the reaction mixture was filtered and concentrated in vacuo .
  • the residue was dissolved in 100 L of ethyl acetate and washed 3 X 50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgS0 4 ) and concentrated in vacuo .
  • the residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours.
  • the reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgS0 4 ) and concentrated in vacuo .
  • reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 °C for 3 hrs. After cooling to room 'temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3x20 mL) and the combined organic extracts were washed with sat NH 4 C1 (20 mL) and brine (20 mL) , dried over MgS0 4 and concentrated under reduced pressure.
  • 4- (4-Nitrophenyl) -1,2,3, 6 tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-W- [3- ( 4- piperidinyl) phenyl] propanamide using HCl gas and tert- Butyl 4- (4-Nitrophenyl) -3, 6-dihydro-l ⁇ 2H) - pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction mixture was concentrated in va cuo to give the crude product (69.8 mg) that used in the next reaction without further purification.
  • BENZYL 6- (3 , 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1 , 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE.
  • (+) -BENZYL 6- (3, 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1, 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE.
  • (+) -benzyl 6- (3, 4-difluorophenyl) -4-ethyl-2-methoxy- 1- ( ⁇ [ (li?) -1-phenylethyl] amino ⁇ carbonyl) -1, 6-dihydro-5- pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH 2 C1 2 was added 1, 8-diazabicyclo [5, 4 , 0] -undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature.
  • (+) -benzyl 6- (3, 4- difluorophenyl) -4-ethyl-2-methoxy-l, 6-dihydro-5- pyrimidinecarboxylate 6. 4 g, 16.0 mmol
  • pyridine 1.5 mL
  • 4-nitrophenyl chloroformate (3.41 g, 19.2 mmol) at room temperature.
  • PYRIMIDINEDICARBOXYLATE Into a well-stirred solution of 6- (3, 4-Difluorophenyl) -1, 6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-l- [ (4- nitrophenyloxy) carbonyl] pyrimidine (1.5 mmol, 0.66 g) in 5 L of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0 °C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHC1 3 (20 mL) and washed with brine.
  • TERT-BUTYL N-(4-[ ( 1-NAPHTHYLCARBONYL) AMINO] - CYCLOHEXYLMETHYL) -CARBAMATE A mixture of 1-naphthoic acid (1.00 mmol, 0.172 g) , DMAP (2.00 mmol, 0.250 g) and ECD (0.383 g, 2.00 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 0.5 h followed by the addition of tert-butyl (4-amino) cyclohexyl) ethylcarbamate amine (1.09 mmol, 0.250 g) .
  • 4-ACETYL-l- (3-AMINOPROPYL) -4-PHENYLPIPERIDINE A solution of 4-Acetyl-4-phenylpiperidine (7, 1.53 g, 7.50 mmol), 3-bromo-propylamine hydrobromide (1.64 g, 7.50 mmol) and potassium carbonate (1.24 g, 9.00 mmol) was stirred in refluxing 1,4-dioxane (50 mL) for 12 h. After removal of dioxane, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH 2 C1 2 (100 L + 3 x 50 mL) .
  • the reaction mixture was stirred at room temperature for 12 h.
  • the reaction mixture was quenched with aqueous 6 N HCl .
  • the reaction mixture was concentrated to a small volume, partitioned between dichloromethane and water (100 mL each) , the mixture was adjusted to pH 8 by addition of Na 2 C0 3 , the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 30 mL) .
  • the combined organic extracts were dried (Na 2 S0 4 ) and the product was chromatographed, giving the desired product.
  • the HCl salt was prepared by the addition of 1 N HCl in ether to a solution of the product in CH 2 C1 2 .
  • Example 8 6- (BENZOFURAZAN-5-YL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBONY L-4- METHYL-2-OXO-l- ⁇ N- [3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] ⁇ CARBOXAMIDO-PYRIMIDINE: A solution of 6- (benzofurazan- 5-yl) -1, 6-dihydro-2- methoxy-5-methoxycarbonyl- 4 -methyl-1- ⁇ N- [3- (4-phenylpiperidin-l- yl) propyl] ⁇ carboxamidopyrimidine in MeOH was treated with 6 N HCl at 0 °C .
  • Example 9 4- (3-METHOXY) -PHENYL PIPERIDINE: HCl salt; mp 150-154 °C; l R NMR52.04 (s, br, 2H) , 2.25 (s, br, 2H) , 2.80 (s, br, IH) , 3.09 (s, br, 2H) , 3.66 (s, 2H) , 3.78 (s, 3H) , 6.79 (s, br, 3H) , 7.23 (s, IH) , 9.41 (s, br, IH) .
  • the compound of Example 10 may also be prepared via hydrogenation of the compoun of example 2 (H 2 balloon method, methanol, Pd/C, overnight) .
  • a synthetic path analogous to the latter route (Scheme 11) was used in the preparation of the tritiated analog, which in turn, was used as a radioligand in the MCH pharmacological assays.
  • 3- (4-PHENYLPIPERIDIN-l-YL) PROPYLAMINE A solution of BH 3 in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a stirring solution of 3- (4-phenylpiperidin-l-yl) - propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20 mL) under argon at room temperature. The mixture was heated at reflux temperature for 4.5 hours and then cooled to room temperature. Aqueous 6 N HCl (130 mL) was added and stirring was continued for 2 hours at 50-70 °C .
  • the mixture was basified to pH 9 by addition of aqueous 6 N NaOH and extracted with EtOAc (100 mL) and CH 2 C1 2 (3 x 100 L) .
  • the combined organic extracts were dried over magnesium sulfate and concentrated.
  • the residue was dissolved in CH 2 C1 2 (20 mL) and treated with HCl in ether (1.0 M, 50 mL) .
  • the solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water ⁇ 60 mL) was added to the resulting white solid, 1 N NaOH was added until pH 10-11 was reached, and then the aqueous phase was extracted with CH 2 C1 2 (3 X 50 mL) .
  • the combined extracts were dried over magnesium sulfate and the solvents were evaporated, giving the desired product (4.50 g, 87%) .
  • 6-(3,4-DIFLOUROPHENYL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBON YL-4- METHYL-2-OXO-l- ⁇ N-[3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] ⁇ CARBOXAMIDO-PYRIMIDINE: A solution of 6- (3, 4- difluorophenyl) -1, 6-dihydro- 2-methoxy-5-methoxy carbonyl-4-methyl-l- ⁇ N- [3- (4-phenyl-piperidin- 1-yl) propyl] ⁇ carboxamidopyrimidine (100 mg, 0.185 mmol, mp 43-45 °C) in MeOH (5 mL) was treated with aqueous 6 N HCl (1.5 mL) at 0 °C .
  • HYDROBROMIDE A solution. of 2 , 4 ' -dipyridyl (25.0 g, 160 mmol) and 3-bromopropyl-amine hydrobromide (35.0 g, 160 mmol) in DMF (60 mL) was heated at 90-95 °C for 10 h.
  • 3-AMINOPROPYL-4- (2-PYRIDYL) PIPERIDINE A suspension of 3- (3 ' , 6 ' -dihydro-2 ' -H- [2, 4 ' ' ] bipyridinyl-1 ' -yl) -propylamin e (3.48 g crude, 15.9 mmol) and Pearlman's catalyst (1.0 g) in MeOH (40 mL) was hydrogenated under 120 psi for 10 h, after which the reaction mixture was filtered through a pad of Celite and the solvent was removed.
  • the HCl salt was prepared by treatment of a solution of the free base in ether with 1 N HCl in ether.
  • the white powder was dried under reduced pressure: 1 H NMR ⁇ 2.05-2.20 (m, 4H) , 2.77-2.88 (m, 2H) , 3.00-3.20 ( , 4H) , 3.35-3.47 (m, 2H) , 3.47 (s, 3H) , 3.64-3.70 (m, 2H) , 3.71 (s, 3H) , 4.05 (br t, IH) , 4.67 (s, 2H) , 6.59 (s, IH) , 7.05-7.20 (m, 3H) , 7.79 (t, IH) , 8.00 (d, IH) , 8.43 (dt, IH) , 8.96 (br t, IH, NH) , 12.4 (br s, IH) . m.p. 188-191
  • PROPYLAMINE N- ( tert-utoxycarbonyl) -3-bromopropylamine (0.772 g, 3.27 mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added to a stirring solution of the amine (0.566 g, 3.27 mmol) in dioxane ( 20 mL) and the reaction mixture was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL) .
  • Trifluoroacetic acid (1 ml) was added to 1-tert- butoxycarbonyl-3- (4-spiro [isobenzo-furan-1 (3H) , 4 ' - piperidine] ) propylamine ( 0.180 g, 0.52 mmol) in dichloromethane (5 ml) and the resulting solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into dichloromethane (25 ml) . The organic layer was dried over sodium sulfate, filtered and concentrated, giving propylamine (0.156 g, 100%) which was used in the subsequent step without further purification .
  • reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
  • the combined organic extracts were dried over sodium sulfate, filtered and concentrated.
  • Example 22 (+) -1,2, 3, 6-TETRAHYDRO-l- (N- [4- (BENZO-4' ,5' (H) FURAN) PIPER IDIN-1- YL] PROPYL ⁇ CARBOXAMIDO-4-ETHYL- 6- (3, 4- DIFLUOROPHENYL) -2-OXO- PYRIMIDINE-5-CARBOXAMIDE HYDROCHLORIDE: DMAP • ECD (0.250 mmol, 0.050 g) was added to a stirred mixture of (+) -1, 2, 3, 6-tetra-hydro-l- ⁇ N- [4- (benzo-4 ' , 5 ' (h) furan) piperidin-1-yl] propyl ⁇ carbox- amido-4-ethyl-6- (3, 4-difluorophenyl) -2-oxo-pyrimidine-5-c arboxyl-ic acid hydrochloride (0.100 mmol, 0.055 g
  • Example 23 (1) -1,2,3, 6-TETRAHYDRO-l- ⁇ N-[4- ( 3 , 4-DIHYDRO-2-OXOSPIRO- NAPHTHALENE-1 (2H) ) -PIPERIDINE-1-YL] PROPYL ⁇ CARBOXAMIDO-5- METHOXYCARBONYL-2- 0X0-6- ( 3 , 4-BENZOFURAZAN) -4- METHYLPYRIMIDINE HYDROCHLORIDE
  • Step B 1- (3-AMINOPROPYL) SPIRO [ISOCHROMAN-3 , 4 ' PIPERIDIN] -1-ONE : To 1- (3-tert-Butoxycarbonylaminopropyl) spiro [isochroman-3, 4 ' -piperidin] -1-one (0.144 g, 0.375 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid , was added and the solution stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.110 g (100%) of the product which was used as such for the subsequent step.
  • reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
  • the organic layer was dried over sodium sulfate, filtered and concentrated.
  • reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl.
  • the organic layer was dried over sodium sulfate, filtered and concentrated.
  • Example 42 The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ( ⁇ [3- (4- ⁇ 3- [ (3, 3-dimethylbutanoyl) amino] phenyl ⁇ -l- piperidinyl) propyl] mino ⁇ carbonyl) -6- (methoxymethyl ) -2- oxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylate .

Abstract

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. In an embodiment of the invention, the feeding disorder is bulimia, bulimia nervosa or obesity.

Description

SELECTIVE MELANIN CONCENTRATING HO MONE-1 (MCHl) RECEPTOR ANTAGONISTS AND USES THEREOF
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al . , 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of α-MSH. Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996) . Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with o /+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles
(Rossi et al., 1997). MCH also has been reported to functionally antagonize the behavioral effects of α-MSH
(Miller et al . , 1993; Gonzalez et al, 1996; Sanchez et al . , 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH
(ppMCH) mRNA levels (Presse et al . , 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al . , 1996) .
Although the biological effects of MCH are believed, to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand ( [3H] -MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bma were determined (Drozdz and Eberle, 1995) . Radioiodination of the tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe13, Tyr19] -MCH was successful (Drozdz et al . , 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the KD = O.llδnM and the Bmax -1100 sites/cell. Importantly, the binding was not inhibited by a-MSH but was weakly inhibited by rat ANF (Ki = 116 nM vs. 12 nM for native MCH)
(Drozdz et al . , 1995) . More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al . ,
1997) and melanoma cells (Drozdz et al . , 1998), where photo-crosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH receptor localization using this ligand have been reported as yet.
The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger (Grillon et al . , 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al . , 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Ba jaoui-Bouhaddi et al . , 1994) . Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al . , 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al . , 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998) . MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al . , 1998) . Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders. In all species studied to. date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al . , 1992) . In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value 'to consider the involvement of this MCH system in movement disorders, such as Parkinson' s disease and Huntingdon' s Chorea in which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5ql2-13) (Pedeutour et al . , 1994) . Locus 12q23-24 coincides with a locus to which autoso al dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al . , 1992; Twells et al . , 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy. Furthermore, the gene for
Darier's disease, has been mapped to locus 12q23-24
(Craddock et al . , 1993). Dariers' disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier's disease. Interestingly, diseases with high social impact have been mapped to this locus. Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5ql2-13 using genetic linkage analysis (Melki et al . , 1990; estbrook et al . , 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5qll.2-13.3 (Sherrington et al . , 1988; Bassett et al . , 1988; Gilliam et al . , 1989) . The above studies suggest that MCH may play a role in neurodegenerative diseases and disorders of emotion .
Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats . MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al . , 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al . , 1996) . In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al . , 1997) . The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al . , 1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and Wagner, 1997) . MCH has also been observed to affect behavioral correlates of cognitive functions . MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al . , 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996) . Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals .
As used in this invention, the term "antagonist" refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis. Conversely, the term "agonist" refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCHl) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vi tro assays is disclosed. The in vitro receptor binding and activation assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa) , sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCHl receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject.
Summary Of The Invention
This invention provides a compound having the structure
Figure imgf000009_0001
wherein A is
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
wherein each of Yα, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C^C-? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yχ / Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a ethylenedioxy group;
wherein each X is independently S; 0; or NR3; wherein Rx is -H; -N02; -CN; straight chained or branched C-L-C-7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; or -C02(CH2)nV;
wherein R2 is -H; straight • chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-Cχ- Ci0-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3, -CH2X(CH2)pNHCXR7 ; or -OR3; or wherein Rx and R2 together may form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is (i)
Figure imgf000011_0001
Figure imgf000012_0001
(iii;
Figure imgf000012_0002
Figure imgf000012_0003
; vii)
Figure imgf000012_0004
, l l ,
Figure imgf000013_0001
wherein the dashed line represents a single bond or a double bond;
wherein each R is independently -H; -F; straight chained or branched Cx~C-ι alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CON(R3)2;
wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; -C0N(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -C0N(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Ci-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is -H; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C]_-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R7 is H; F; CI; Br; I; -N02; -N3; -CN; straight chained or branched C]_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -C0R3; -C02R3; or -C0N ( R3 ) 2 ;
wherein R8 is independently straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; C0R3; C02R3; -C0N(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)gOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive; wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof,
This invention further provides a compound having the structure :
Figure imgf000016_0001
wherein each R is independently -H; -F; straight chained or branched Cx-C~j alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -SR3; -C02R3; or
-OR 3'
wherein each Rx is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH2) 0R3; -C0R3; -C02R3; or -C0N(R3)2;
wherein each R2 is -H; -N02; -N3; -CN; straight chained or branched C -Cη alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; or -C0N(R3)2; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, onofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched C;ι_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -C0N(R3)2; CN; -N02; -N(R3)2; -OR3; ~SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2)n, 0, S or NR3;
wherein is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cj^-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C^C-; alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C alkynyl; C3-C7 cycloalkyl;
wherein m is an integer from 0 to 4 inclusive;
wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof .
This invention also provides a compound having the structure :
Figure imgf000018_0001
wherein each R is independently -H; -F; straight chained or branched C^C-? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -0R3; or -C0N(R3)2;
wherein each Rx is independently -H; F; Cl; Br; I; -N02; -N3; -CN; straight chained or branched C^C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)p0R3; -C0R3; -C02R3; -CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; ~SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched
C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 is -H; -N02; -N3; -CN; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -C0R3; -C02R3; -CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; ~OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C-L-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; C02R3; - CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; CI ; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^-C^ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof .
This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure:
Figure imgf000022_0001
Figure imgf000022_0002
wherein A is
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
wherein each of Yχ r Y2, Y3, Y and Y5 is independently -H; straight chained or branched C]_-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I;
-N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Y , Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
wherein Rx is -H; -N02; -CN; straight chained or branched Cχ-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; or C02(CH2)nV;
wherein R2 is -H; straight chained or branched C]_-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-Cx-CxQ-monofluoroalkyl or C3-C10 cycloalkyl-C1- C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3,
-CH2X (CH2)pNHCXR5 ; -0R3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein RΔ is
Figure imgf000025_0001
(v)
Y
Figure imgf000025_0002
!vii )
Figure imgf000026_0001
I viii)
Figure imgf000026_0002
Figure imgf000026_0003
wherein each R is independently -H; -F; straight chained or branched C]_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS; wherein each ϋ is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N0 ; -N3; -CN; straight chained or branched Cx-Cη alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C]_-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7.alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; or -CON(R3)2;
wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C]_-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C]_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C]i-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclus ive ;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6' inclusive;
or a pharmaceutically acceptable salt thereof.
This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure :
Figure imgf000030_0001
wherein A is
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
wherein each of Y , Y2, Y3, Y and Y5 is independently -H; straight chained or branched C^^-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
-N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yχ r Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3; wherein R-L is -H; -N02; -CN; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -C0N(R3)2; or C02(CH2)nV;
wherein R2 is -H; straight chained or branched Cχ-C-7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C]^- C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3,
-CH2X (CH2)pNHCXR5 ; -0R3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C -Cη alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R. is
Figure imgf000032_0001
R-
Figure imgf000033_0001
(iv)
Figure imgf000033_0002
,v
Y,
Figure imgf000033_0003
(vi;
Figure imgf000033_0004
(vii ;
Iviii )
Figure imgf000034_0001
Figure imgf000034_0002
wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS; wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR5 or N;
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^^-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)p0R3; -COR3; -C02R3; or -CON(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C^^-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)q0R3; (CH2)qSR3; -XC0R8; straight chained or branched C^C^y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched Ci-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; or -C0N(R3)2; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive ;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety.
This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amounr. of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000039_0001
This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
This invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
This invention further provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
Detailed Description Of The Invention
This invention provides a compound having the structure
Figure imgf000040_0001
Figure imgf000040_0002
wherein A is
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000041_0003
wherein each of Yx , Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C^C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -CI, -Br, or -I; -N02; -N3; -CN; -OR3, -OCOR3, -C0R3, -CON(R3)2, or -COOR3; or any two of Yx , Y2,
Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
wherein Rx is -H; -N02; -CN; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)p0R3; -COR3; -C02R3; -CON(R3)2; or -C02(CH2)nV;
wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-CL- C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3,
-CH2X (CH2)pNHCXR7 ; -OR3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched Cj^-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is
Figure imgf000043_0001
v
Figure imgf000043_0002
(vi)
Figure imgf000043_0003
( ii)
Figure imgf000044_0001
wherein the dashed line represents a single bond or a double bond;
wherein each R is independently -H; -F; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -0R3; or -CON(R3)2;
wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C-L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)p0R3; -COR3; -C02R3; -CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched cι~c 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is -H; straight chained or branched Cx-Cη alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3;
-CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R7 is H; F; CI; Br; I; -N02; -N3; -CN; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)p0R3; -COR3; -C02R3; or -CON(R3)2;
wherein R8 is independently straight chained or branched C-L-C-7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive; wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
one embodiment, the compound has the structure:
Figure imgf000048_0001
Figure imgf000048_0002
In another embodiment, the compound has the structure:
Figure imgf000049_0001
Figure imgf000049_0002
In a further embodiment, the compound has the structure:
Figure imgf000049_0003
Figure imgf000049_0004
In yet another embodiment of the present invention variable A is
Figure imgf000050_0001
In an embodiment of the present invention, the compound is
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000050_0004
Figure imgf000051_0001
Figure imgf000051_0002
In another embodiment, the compound has the structure:
Figure imgf000051_0003
In further embodiments, the compound has the structure
Figure imgf000051_0004
In an embodiment, the compound has the structure:
Figure imgf000052_0001
In other embodiments , A is
Figure imgf000052_0002
In an embodiment of the invention, the compound has the structure :
Figure imgf000052_0003
In other embodiments, the compound has the structure:
Figure imgf000052_0004
In additional embodiments, the compound has the structure
Figure imgf000053_0001
In one embodiment of the present invention, the compound has the structure :
Figure imgf000053_0002
In another embodiment of the instant invention, A is
Figure imgf000053_0003
In other embodiments of the invention, the compound has the structure :
Figure imgf000053_0004
In an embodiment, the compound has the structure
Figure imgf000054_0001
In another embodiment , the compound has the structure :
Figure imgf000054_0002
In yet another embodiment, the compound has the structure
Figure imgf000054_0003
In an embodiment, A is
Figure imgf000054_0004
In a further embodiment, the compound has the structure
Figure imgf000055_0001
In another embodiment, the compound has the structure:
Figure imgf000055_0002
In yet another embodiment , the compound has the structure :
Figure imgf000055_0003
In an additional embodiment, the compound has the structure:
Figure imgf000055_0004
In other embodiments , A is
Figure imgf000056_0001
In an embodiment, the compound has the structure
Figure imgf000056_0002
In yet another embodiment, the compound is
(+) -1, 2 , 3 , 6-tetra-hydro-l- {n- [4- (3 , -acetamido) -phenyl- piperidin-1-yl] ropyl}carboxamido-4-methoxymethyl-6- (3,4- difluoro-phenyl) -2-oxopyrimidine-5-carboxylic acid methyl ester. In a further embodiment, the compound is ( - ) -1, 2 , 3 , 6-tetra-hydro-l- {n- [4- (3 , -acet-amido) -phenyl- piperidin-1-yl] ropyl}carboxamido-4-methoxymethyl-6- (3,4- difluoro-phenyl) -2-oxopyrimidine-5-carboxylic acid methyl ester.
In a further embodiment, the compound is
Figure imgf000056_0003
In a further embodiment, the compound has the structure
Figure imgf000057_0001
wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or j polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -SR3; -C02R3; or
-OR 3'
wherein each Rx is independently -H; straight cha'ined or branched C--C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein each R2 is -H; -N02; -N3; -CN; straight chained or branched Cj^-C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; or aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; ~OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or' carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted with one or more F; CI; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2)n, O, S or NR3;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C; -C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein m is an integer from 0 to 4 inclusive; wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
In an embodiment, the compound has the structure:
Figure imgf000059_0001
In a further embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02 ; -N(R3)2; -OR3; -SR3; (CH2)qOR3; or (CH2)qSR3.
In another embodiment, the compound has the structure
Figure imgf000059_0002
In one embodiment, the compound has the structure
Figure imgf000060_0001
wherein each R is independently -H; -F; straight chained or branched C1-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CON(R3)2;
wherein each Rx is independently -H; F; Cl; Br; I; -N02; -N3; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 is -H; -N02; -N3; -CN; straight chained or branched C]_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -C0R3; -C02R3; -C0N(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -C0N(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3;
(CH2)qSR3; straight chained or branched C-L-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C -C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein W is
( a ) C3-C7 cycloalkyl , monofluorocycloalkyl , polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3 ; C02R3 ; -CON (R3) 2 ; CN; -N02 ; -N (R3) 2 ; -OR3 ; -SR3 ; (CH2) qOR3 ; (CH2 ) qSR3 ; straight chained or branched Cx-C-j alkyl , monofluoroalkyl , polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (-) enantiomer.
In an additional embodiment, the compound has the structure :
Figure imgf000063_0001
In a further embodiment, the compound has the structure
Figure imgf000063_0002
In yet another embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02 ; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; or straight chained or branched C1-C7 alkyl groups .
In yet another embodiment, the compound has the structure
Figure imgf000063_0003
In the present invention, the term "aryl" includes phenyl and naphthyl and the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more heteroatoms such as oxygen, sulfur, and nitrogen. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl , indazolyl, benzimidazolyl , benzthiazolyl , purinyl, imidazo [2 , 1-jb] thiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3- benzothiazolyl .
Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the acids and bases listed herein. The salts include, but are not limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The salts include, but are not limited to the inorganic base, ammonia. The salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethyla ine, morpholine, piperazine and guanidine . This invention further provides for the hydrates and polymorphs of all of the compounds described herein .
The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term "administering" shall emcompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is an amount from about 0.01 mg to about 800 mg . In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg . In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg . In another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg . In another embodiment, the amount of the co pound is an amount from about 1 mg to about 20 mg . In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet. In a further embodiment, the carrier is a gel and the composition is a suppository.
This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions .
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins .
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators . Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils
(e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent .
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. The present invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure:
Figure imgf000069_0001
Figure imgf000069_0002
wherein A is
Figure imgf000070_0001
Y
,Y
Yr AiLrX AN Li/ /J ,
Figure imgf000070_0002
Figure imgf000070_0003
wherein each of YX l Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C;-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yχ r Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
wherein Rx is -H; -N02; -CN; straight chained or branched Ci-C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; or C02(CH2)nV;
wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C;L-C10-alkyl, C3-C10 cycloalkyl-C;L-C10-monofluoroalkyl or C3-C10 cycloalkyl-C;- C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3,
-CH2X (CH2)pNHCXR5 ; -OR3; or Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C;-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is
Figure imgf000071_0001
R. Ai)
Figure imgf000072_0001
Figure imgf000072_0002
Y
Figure imgf000072_0003
(vi)
Figure imgf000073_0001
, ll,
Figure imgf000073_0002
! viii)
R5
Figure imgf000073_0003
R7
Figure imgf000073_0004
Figure imgf000073_0005
wherein each R is independently -H; -F; straight chained or branched Cα-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -0R3; or -CN(R3)2;
wherein B is N or CY ;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS;
wherein each ϋ is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C-L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein is CR5; CR5 or N;
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C~C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; or -C0N(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -C0N(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched Cj^-C-y alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein R is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3;
-CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3;
(CH2)qSR3; -XCOR8; straight chained or branched Cj-C- alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl;
C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched Cx-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound has the structure
Figure imgf000076_0001
Figure imgf000076_0002
In a further embodiment, the compound has the structure
Figure imgf000077_0001
In an additional embodiment, the compound has the structure
Figure imgf000077_0002
Figure imgf000077_0003
In a further embodiment, at least one R5 group is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; -N02; -N(R3)2; -OR3; -XCOR8; or straight chained or branched C-L-C7 alkyl. In another embodiment , A is :
Figure imgf000078_0001
In further embodiments, the compound is selected from the group consisting of:
(b;
Figure imgf000078_0002
(c)
Figure imgf000078_0003
-71
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000079_0003
In other embodiments, the compound has the structure
Figure imgf000079_0004
In a further embodiment, the compound has the structure
Figure imgf000080_0001
In additional embodiments, A is
Figure imgf000080_0002
and R7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR3 ; or straight chained or branched C-L-C7 alkyl.
In one embodiment, the compound has the structure
Figure imgf000080_0003
In an embodiment of the present invention, the compound has the structure
Figure imgf000081_0001
In yet another embodiment, the compound has the structure
Figure imgf000081_0002
In further embodiments , A is
Figure imgf000081_0003
and Z is 0 or CH- In an additional embodiment, the compound is selected from the group consisting of
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000082_0003
In one embodiment, the compound has the structure
Figure imgf000083_0001
In a further embodiment, the compound has the structure
Figure imgf000083_0002
In another embodiment, A is
Figure imgf000083_0003
In yet another embodiment, the compound is
Figure imgf000084_0001
Figure imgf000084_0002
In a further embodiment, the compound has the structure
Figure imgf000084_0003
In another embodiment, the compound has the structure
Figure imgf000084_0004
In yet another embodiment, the compound has the structure
Figure imgf000085_0001
In one embodiment, the compound has the structure
Figure imgf000085_0002
In another embodiment, the compound has the structure
Figure imgf000085_0003
In another embodiment, the compound has the structure
Figure imgf000085_0004
This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure :
Figure imgf000086_0001
Figure imgf000086_0002
wherein A is
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
wherein each of Yx, Y2, Y3,. Y4 and Y5 is independently -H; straight chained or branched CJ^-C-J alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I;
-N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yx, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3; wherein Rx is -H; -N02; -CN; straight chained or branched CiL-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; ~OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; or C02(CH2)nV;
wherein R2 is -H; straight chained or branched C-L-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or .alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-Ci- C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3,
-CH2X(CH2)pNHCXR5 ; -OR3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C;-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is
Figure imgf000088_0001
R7
Figure imgf000088_0002
Figure imgf000089_0001
iv
Figure imgf000089_0002
V
Yc
Figure imgf000089_0003
19-
(vi)
(vii)
Figure imgf000090_0001
Figure imgf000090_0002
, Vlll,
Figure imgf000090_0003
IX
Figure imgf000090_0004
Figure imgf000090_0005
wherein each R is independently -H; -F; straight chained or branched C;L-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CN(R3)2;
wherein B is N or CY ;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; -XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
-N(R3)2; "OR3; -(CH2)pOR3; -COR3; -C02R3; or
-CON(R3)2;
wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3;
-CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; -XCOR8; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl;
C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched L-C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;L-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject's depression and/or anxiety. This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000094_0004
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000095_0003
This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
This invention also provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the feeding disorder is bulimia, obesity or bulimia nervosa. In a further embodiment, the subject is a vertebrate, a mammal , a human or a canine . In yet another embodiment , the compound is administered in combination with food. In the subject invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating the above noted disorders-.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
This invention further provides compositions which need not be pharmaceutical as that term is understood in the art. Such compositions comprise a compound in accordance with the subject invention in an amount effective to antagonize an MCHl receptor and a suitable carrier.
Still further, the invention provides a method of agonizing and/or antagonizing an MCHl receptor which comprises contacting the receptor, e.g. in vitro or in in vivo, with an amount of a compound of this invention effective to agonize and/or antagonize the receptor.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Section
I . Synthetic Methods for Examples
General Methods: All reactions (except for those done by parallel synthesis reaction arrays) were performed under an Argon atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques. The parallel synthesis reaction arrays were performed in vials (without an inert atmosphere) using J-KEM heating shakers (Saint Louis, MO) . Anhydrous solvents were 'purchased from Aldrich Chemical Company and used as received. The examples described in the patent (1-37) were named using ACD/Name program (version 2.51, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada) . Unless otherwise noted, the 1H and 1C NMR spectra were recorded at 300 and 75 MHz (QE Plus) with CDC13 as solvent and tetra ethylsilane as internal standard, s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; sextet; septet; br = broad; m = multiplet. Elemental analyses were performed by Robertson
Microlit Laboratories, Inc. Unless otherwise noted, mass spectra were obtained using low-resolution electrospray
(ESMS) and MH+ is reported. Thin-layer chromatography (TLC) was carried out on glass plates precoated with silica gel 60 F254 (0.25 mm, EM Separations Tech.). Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech) . Flash column chromatography was performed on Merck silica gel 60
(230 - 400 mesh). Melting points (mp) were determined in open capillary tubes on a Mel-Temp apparatus and are uncorrected.
Procedures for the Synthesis of the Dihydropyrimidine Intermediates 5-METHOXYCARBONYL-4-METHOXYMETHYL-1, 2, 3, 6-TETRAHYDRO-2- OXO-6- (3, 4-DIFLUOROPHENYL) -PYRIMIDINE: To a stirring mixture of methyl 4-methoxyacetoacetate (50.0 g, 0.342 mol), 3, 4-difluorobenz-aldehyde (51.4 g, 0.362 mol), and urea (31.6 g, 0.527 mole) in THF (300 mL) at room temperature were added copper (I) oxide (5.06 g, 0.035 mole) and acetic acid (2.05 mL) , sequentially, followed by dropwise addition of boron trifluoride diethyl etherate (56.0 mL, 0.442 mole). The mixture was stirred and refluxed for 8 h, whereupon TLC (1/1 EtOAc/hexanes ) analysis indicated completion of the reaction. The reaction mixture was cooled and poured into a mixture of ice and sodium bicarbonate (100 g) and the resulting mixture was filtered through Celite. The Celite pad was washed with dichloromethane (400 mL) . The organic layer was separated from the filtrate and the aqueous layer was extracted with more dichloromethane (3 X.300 mL) . The combined organic extracts were dried (sodium sulfate) and the solvent evaporated. The crude product was purified by flash column (ethyl acetate/hexanes, 1/1; then ethyl acetate), giving the product as pale yellow foam, which on trituration with hexane became white powder (103 g, 97%). 1H NMR d 3.48 (s, 3H), 3.65 (s, 3H) , 4.65 (s, 2H) , 5.39 (s, IH) , 6.60 (br s, IH, NH) , 7.00 - 7.20 (m, 3H) , 7.72 (br s, IH, NH) .
( +) -5-METHOXYCARBONYL-4-METHOXYMETHYL-1 , 2,3, 6-TETRAHYDRO-2- 0X0-6- (3, 4-DIFLUOROPHENYL) -PYRIMIDINE: The racemic intermediate 5-methoxycarbonyl-4-methoxymethyl-l, 2,3,6- tetrahydro-2-oxo-6- (3, 4-difluorophenyl) pyrimidine was resolved by chiral HPLC. [Chiralcel OD 20 X 250 mm #369-703-30604; lambda 254 nm; hexanes/ethanol 90/10; 85 mg per injection; retention time of the desired enantiomer: 16.94 min., the first enantiomer peak to elute], giving ( + ) - 5 - m e t h o x y c a r b o n y l - 4 - m e t h o x y m e t h y l - 1,2,3, 6-tetrahydro-2oxo-6- (3, 4-difluorophenyl) -pyrimidine (40-42 wt% isolation of the desired enantiomer from the racemate) ; [α]D = + 83.8 (c = 0.5, chloroform). The (-) -isomer was also isolated as the later eluting fraction from the chiral chromatography column.
( + ) -5-METHOXYCARBONYL-4-METHOXYMETHYL-1, 2, 3, 6-TETRAHYDRO- 2-OXO- 6- (3, 4-DIFLUOROPHENYL) -1- [ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: To a solution of ( + ) -5-methoxycarbonyl-4-methoxymethyl-l, 2, 3, 6 - tetrahydro-2-oxo-6- (3, 4- difluorophenyl) -pyrimidine (1.98 g, 6.34 mmol) in anhydrous THF (20 L) at -78 °C under argon atmosphere, a solution of lithium hexamethyldisilazide in THF (IM, 18.0 mL, 18.0 mmol) was added over 2-3 min. and the mixture was stirred for 10 min. This solution was added over 6 min., via a cannula, to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at -78 °C . Stirring was continued for 10 min. and the mixture was poured onto ice (50 g) and extracted with chloroform (2 X 50 mL) . The combined extracts were dried
(sodium sulfate) and the solvent was evaporated. The residue was purified by flash column chromatography
(hexanes/ethyl acetate, 4/1 to 3.5/1) as the eluent. The product was obtained as yellow syrup which upon trituration with hexanes became a white powder (2.40 g, 79%): XH NMR d 3.52 (s, 3H) , 3.74 (s, 3H) , 4.65-4.80 (q, J=16.5 Hz, 2H) , 6.32 (s, IH) , 7.10-7.30 (m, 4H) , 7.36 (d, J=9 Hz, 2H) , 8.27 (d, J=9 Hz, 2H) .
BENZYL 3-[ (3, -DIFLUOROPHENYL) METHYLENE] -4-OXOPENTANOATE :
A solution of benzyl propionylacetate (36.3 g, 176 mmol),
3,4- difluorobenzaldehyde (25.0 g, 176 mmol), piperidine
(0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) was refluxed with removal of water using a Dean-Stark apparatus for 5 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The reaction mixture was washed with water (100 mL) , followed by brine (100 mL) and dried over anhydrous Na2S04. The solvent was evaporated, giving a pale yellow syrup (60.2 g) . The product was used in the next step without further purification.
5- (BENZYLOXYCARBONYL) -1, 6-DIHYDRO-2-METHOXY-4-ETHYL-6- (3, 4-DI-FLUOROPHENYL) PYRIMIDINE: A suspension of benzyl 3- [ (3, 4-di-fluorophenyl) methylene] -4-oxopentanoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.7 g, 97.0 mmol) and NaHC03 (16.3 g, 130 mmol) in DMF (190 mL) was stirred at 70 °C for 20 h. After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4X100 mL) , brine (200 mL) and dried over Na2S04. After removal of solvent, the residue was purified by column chromatography (EtOAc/Hexane, 1/9 to 3/7), giving the title compound as a colorless oil (10.6 g, 58%) . The NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
5- (BENZYLOXYCARBONYL) -4-ETHYL-l, 6-DIHYDRO-2-METHOXY-6- (3, 4-DI-FLUOROPHENYL) -1- [ ( 4-NITROPHENYLOXY) CARBONYL]
PYRIMIDINE: To a stirring solution of 5- (benzyloxycarbonyl) -1, 6-dihydro-2- methoxy-4-ethyl-6- (3 , 4-difluorophenyl) pyrimidine (17.0 g, 44.0 mmol) and 4-dimethylaminopyridine (7.00 g, 57.3 mmol) in CH2C12 (200 mL) was added 4-nitrophenyl chloroformate as a powder (11.5 g, 57.1 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo . The residue was purified by chromatography (EtOAc/Hexane, 1 / 9 t o 3 / 7 ) , g i v i n g 5- (benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-2- methoxy- 6- (3, 4-difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine as a colorless viscous oil (12.6 g, 50%). XH NMR d 1.24 (t, J=7.2 Hz, 3H) , 2.81-2.98 (m, 3H) , 3.97 (s, 3H) , 5.14 (ABq, A=5.08, B= 5.20, J= 12.3 Hz, 2H) , 6.28 (s, 3H) , 7.03-7.29 (m, 8H) , 7.35 (d, J=9.2 Hz, 2H) , 8.26 (d, J=9.2 Hz, 2H) .
5- (BENZYLOXYCARBONYL) -4-ETHYL-l, 6-DIHYDRO-l- {N- [1-PHENYL) ETHYL] }-CARBOXAMIDO-2-METHOXY-6- (3 , 4-DIFLUOROPHENYL) PYRIMIDINE: To a stirred mixture of
5- (benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-2- methoxy-6- (3, 4-difluorophenyl) -1- [ (4-nitrophenyloxy) carbo nyl] pyr-imidine (12.6 g, 22.9 mmol) in THF (150 mL) was added a solution of R- (+) -α-methyl benzylamine (3.53 mL, 27.1 mmol) at room temperature. The stirring was continued for 12 h and the solvent was removed in vacuo. The yellow residue was dissolved in chloroform (200 mL) and was washed with 10% K2C03 solution (2x30 mL) . The organic layer was dried over Na2S04, filtered and solvent was removed in vacuo. The resulting mixture of diastereomers was separated by column chromatography (petroleum ether/ether, 9/1 to 4/1) . The first major product to elute was (+) -5- (benzyloxycarbonyl) -4-ethyl- 1, 6-dihydro-l- {N- [1- phenyl) -ethyl] } carboxamido-2- methoxy-6- (3, -difluorophenyl) pyrimidine . Colorless oil; Rf= 0.31 (petroleum ether/ether, 4/1); yield: 3.8 g (31%); [α]D = +267.05 (c = 0.76, CHC13) ; XH NMR d 1.22 (t, J=7.5 Hz, 3H) , 1.52 (d, J=6.9 Hz, 3H) , 2.88 (q, J=6.0 Hz, 2H) , 3.99 (s, 3H) , 4.99 (m, IH) , 5.09 (ABq, A=5.00, B= 5.19, J= 12.6 Hz, 2H) , 6.66 (s, IH) , 6.99-7.36 (m, 13H) . The second m a j o r p r o d u c t t o e l u t e w a s
(-) -5- (benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-l- {N-
[2-phenyl) ethyl] } carboxamido-2-methoxy-6- (3, 4-dif luorophe nyl) pyr-imidine . Colorless oil; Rf= 0.22 (petroleum ether/ether, 4/1); yield: 3.20 g (26%); [α]D = -146.89 (c = 0.38, CHC13 ); H NMR δ 1.22 (t, J=7.2 Hz, 3H) , 1.49 (d, J=6.6 Hz, 3H),2.88 (q, J=6.0 Hz, 2H) , 3.94 (s, 3H) , 5.03 (m, IH) , 5.11 (ABq, A=5.02, B= 5.19, J= 12.6 Hz, 2H) , 6.68 (s, IH) , 6.91-7.34 (m, 13H) .
(+) -5- (BENZYLOXYCARBONYL) -1, 6-DIHYDRO-2-METHOXY-4-ETHYL-6 - (3, 4-DI-FLUOROPHENYL) PYRIMIDINE: To a stirred solution of (+) -5- (benz-yloxycarbonyl) -4-ethyl-l, 6-dihydro-l- {N- [2-phenyl) ethyl] } carbox-amido-2-methoxy-6-
(3, 4-difluorophenyl) pyrimidine (1.00 g, 1.83 mmol) in toluene (10 mL) was added 1, 8-diazabicyclo [5, 4 , 0] -undec- 7-ene (0.120 L, 0.810 mmol) at room temperature and the resulting solution was heated at reflux temperature for 5 h and then stirred for 12 h at room temperature. The solvent was evaporated and the residue was purified by flash column (EtOAc/Hexanes , 1/3), giving (+) -5- (benzyloxycarbonyl) -1, 6- dihydro-2-methoxy-4-ethyl -6- (3, -difluorophenyl) pyrimidine (0.560 g, 77%).
(+) -5- (BENZYLOXYCARBONYL) -4-ETHYL-l, 6-DIHYDRO-2-METHOXY-6 - (3, 4-DI-FLUOROPHENYL) -1- [ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: To a stirring solution of ( + ) -5- (benzyloxycarbonyl) -1, 6-dihydro-2- methoxy-4-ethyl-6- (3, 4-difluorophen-yl) pyrimidine (17.0 g,
44.0 mmol) and 4-dimethylaminopyridine (6.99 g, 57.3 mmol) in CH2C12 (200 mL) was added 4-nitrophenyl chloroformate
(11.6 g, 57.3 mmol) at room temperature. The reaction mixture was stirred for 12 h and then the solvent was removed in vacuo . The residue was purified by chromatography (EtOAc/Hexane, 1/9 to 3/7), giving (+) -5- (benzyloxycarbonyl) -4-ethyl-l, 6-dihydro-2-methoxy-6 -(3,4- difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine as a viscous colorless oil (19.3 g, 7 6% ) .
5-METHYLBENZFUROXAN: 4-Methyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated methanolic sodium hydroxide solution (1.50 L) . This suspension was cooled (5 °C) and aqueous sodium hypochlorite until the red color disappeared. The resulting fluffy yellow precipitate was filtered, washed with cold water and recrystallized from ethanol, giving 5-methylbenzfuroxan (88.2 g, 89 % yield) as a pale yellow solid: H NMR d 2.39 (s, 3 H) , 6.90-7.40 (br m. 3 H) .
5-METHYLBENZOFURAZAN: To 5-Methylbenzfuroxan (88.2 g, 0.590 mol) in refluxing EtOH (75 mL) was added dropwise P(OEt)3 (150 mL) . Heating was continued at reflux temperature for 1 h. The solvent was removed in vacuo and the residue was shaken with water (200 mL) and allowed to stand overnight at (0-5 °C) . The resulting brown solid was filtered, washed with water. The crude product was purified by flash chromatography, giving 5-methylbenzofurazan (70.0 g, 87 %) as white needles; XH NMR δ 2.41 (s, 1 H) , 7.19 (dd, J=9.3, 1.1 Hz, 1 H) , 7.48 (d, J=l .1 Hz, 1 H) , 7.66 (d, J=9.3 Hz, 1 H) .
5-DIBROMOMETHYLBENZOFURAZAN: An anhydrous solution of 5-methylbenzofurazan (70.0 g, 0.520 mol), N-bromosuccinamide (325 g) , and benzoyl peroxide (0.50 g) in carbon tetrachloride (1.5 L) was heated at reflux temperature with stirring for 30 h. The reaction mixture was washed with water (2 X 500 mL) , dried (NaS04) , and the solvent was removed in vacuo . The residue was chromatograghed (EtOAc/hexane, 1/150) , giving 122 g (80%) of the title compound as a white solid: 1H NMR d 6.69 (s, 1 H), 7.69 (d, J=9.6 Hz, 1 H) , 7.77 (s, 1 H) , 7.89 (d, J=9.6 Hz, 1 H) . 5-FORMYLBENZOFURAZAN: AgNQ3 (163 g) in 2 L of water was added to a refluxing mixture of dibromomethylbenzofurazan
(122 g, 418 mmol) in EtOH (1 L) . Heating at reflux temperature was continued for 2 h. The mixture was cooled, the precipitated AgBr was removed by filtration through
Celite, and the solvent was concentrated. The resulting solution was extracted with toluene (10 X 100 mL) , dried over magnesium sulfate, and the solvent was removed in vacuo . The residue was chromatograghed (EtOAc/hexane, 1/125), giving the title aldehyde (48.2 g, 78%) as a white solid: H NMR δ 7.92 (m, 2H) , 8.39 (s, 1 H) , 10.10 (s, 1 H) .
METHYL 2- { (BENZOFURAN-5-YL) METHYLENE } -3-OXOBUTYRATE : A mixture of 5-formylbenzofurazan (0.60 g, 4.1 mmol), methyl acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.23 mmol), and acetic acid (0.014 g, 0.23 mmol) in benzene (30 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. Benzene was evaporated in vacuo, the residue was dissolved in ethyl acetate (80 mL) and washed with brine (50 L) , saturated potassium bisulfate solution (50 mL) , and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over magnesium sulfate, the solvent removed under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane, 1/9 to 3/20) . The desired product was obtained as oil (0.98 g, 98%) and was used in the next step without any further characterization.
6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYLPYRIMIDINE: A mixture of methyl 2- { (benzofuran-5-yl) -methylene} -3-oxobutyrate (1.02 g, 4.10 mmol), O-methylisourea hydrogen sulfate (1.06 g, 6.20 mmol) , and NaHC03 (1.30 g, 16.4 mmol) in DMF (15 L) was stirred and heated at 70 °C for 16 h. The mixture was cooled, diluted with EtOAc (50 mL) and washed with water (5X 50 mL) , brine (50 mL) and dried over magnesium sulfate. The solvent was evaporated and the crude product was purified by flash chromatography (EtOAc/hexane, 1/9 to 1/5), giving the desired product as an oil (0.520 g, 43%) :
^HNMR δ 2.38 and 2.42 (2 s, 3 H) , 3.60 and 3.66 (2 s, 3 H) , 3.74 and 3.82 (2 s, 3 H) , 5.53 and 5.68 (2 s, 1 H) , 6.31 and 6.32 (br s, 1 H) , 7.0-7.8 (m, 3 H) .
6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYL-l-[ ( 4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE : To a solution of 6- (benzofuran-5-yl) -1, 6-dihydro-
2-methoxy-5-methoxycarbonyl-4- methylpyrimidine (0.485 g, 1.6 mmol) and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in CH2C12 (20 mL) at 0-5 °C was added 4-nitrophenyl chloroformate (0.307 g, 1.52 mmol) . The mixture was then allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by
' flash chromatography (EtOAc/hexane, 1/9 to 3/20) , giving the desired product as white crystals (0.665 g, 89%); mp
180-183 °C; λE NMR δ 2.54 (s, 3 H) , 3.75 (s, 3 H) , 3.98 (s, 3 H) , 6.37 (s, 1 H) , 7.40 (d, J=9.3 Hz, 2 H) , 7.52 (d, J=9.0 Hz, 1 H) , 7.68 (s, 1 H) , 7.84 (d, J=9.0 Hz, 1 H) , 8.32 (d, J=9.3 Hz, 2 H) .
(+) and (-) -6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-METHOXY-5- METH0XYCARB0NYL-1-[N-(S) -1- ( 1-PHENYLETHYL) ] -4-METHYLPYRIM IDINE: A solution of 6- (benzofurazan-5- yl) -1, 6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl- 1- (4-nitrophenoxy) carbonylpyrimidine (800 mg, 1.71 mmol) and (S) - (-) -a-methylbenzylamine (269 mg, 2.22 mmol) in THF (50 mL) was stirred at room temperature for 12 h. The THF was removed in vacuo and the residue was dissolved in EtOAc (100 mL) , washed by 10% aqueous K2C03 solution (3x50 mL) , brine (50 mL) and dried (Na2S04) .
After removal of the solvent, the residue was purified by chromatography (EtOAc/hexane, 1/20 to 3/20) , separating the two diastereomers. The isomers of 6- (benzofurazan-5-yl) -1, 6-dihydro-2-methoxy-5-methoxycarb onyl-1- [N- (S) -1- (1-phenylethyl) ] - 4-methylpyrimidine were obtained as colorless oils. 1st Isomer (367 mg, 47.7%) : [α]D= +278 (c=0.50, CHC13) ; lH NMR δ 1.54 (d, J=6.9 Hz, 3H) , 2.45 (s, 3H) , 3.68 (s, 3H) , 3.99 (s, 3H) , 5.02 (quintet, J=6.9 Hz, IH) , 6.71 (s, IH) , 6.89 (d, J=6.6 Hz, IH) , 7.2-7.9 ( , 8H) . '2nd Isomer (205 mg, 26.6%) : [α] D
=-81 (c=0.43, CHC13) ; λE NMRδl.52 (d, J=6.6 Hz, 3H) , 2.48 (s, 3H) , 3.71 (s, 3H) , 3.96 (s, 3H) , 5.00 (quintet, J=6.6 Hz, IH) , 6.74 (s, IH) , 6.90 (d, J=6.5 Hz, IH) , 7.2-7.9 (m, 8H) .
6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCARB ONYL-4- METHYLPYRIMIDNE: A solution of the 1st isomer of 6- (benzofura-zan-5-yl) -1, 6-dihydro-2-methoxy- 5-methoxycarbon-yl-l- [N- (S) -1- (1-phenylethyl) ] -4-methylpy rimidine (960 mg, 2.14 mmol) and 1, 8-diazabicyclo
[5, 4, 0]undec-7-ene (107 mg, 0.705 mmol) in toluene (50 mL) was stirred at 100 °C for 5 h. After cooling to room temperature, toluene was removed in vacuo and the residue was purified by chromatography (EtOAc/hexane, 1/9 to 3/7). 6- (Benzofurazan-5- yl) -1, 6-dihydro-2-methoxy-
5-methoxycarbonyl- 4-methylpyrimidine was obtained as a colorless oil (635 mg, 98.3%). XH NMRδ2.38 (s, 3H) , 3.66 (s, 3H) , 3.74 (s, 3H) , 5.68 (s, IH) , 6.32 (br s, IH) , 7.0-7.8 (m, 3H) . 6- (BENZOFURAZAN-5-YL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCARB
ONYL-4-METHYL-1- ( 4-NITROPHENOXY) CARBONYLPYRIMIDINE : T o a solution of 6- (benzofuran-5-yl) -1, 6-dihydro-2-methoxy-
5-methoxycarbonyl- 4-methylpyrimidine (0.485 g, 1.60 mmol) and 4-dimethylamino-pyridine (0.200 g, 1.60 mmol) in CH2C12
(20 mL) , at 0-5 °C, was added 4-nitrophenyl chloroformate
(0.307 g, 1.52 mmol). After addition, the mixture was allowed to warm to room temperature. After 12 hours, the solvent was evaporated and the residue was purified by flash column chromatography (EtOAc/hexane, 1/9 to 3/20) , giving the desired product as white crystals (0.665 g,
89%): mp 180-183 °C; lH NMRδ2.54 (s, 3 H) , 3.75 (s, 3 H) ,
3.98 (s, 3 H) , 6.37 (s, 1 H) , 7.40 (d, J = 9.3 Hz, 2 H) ,
7.52 (d, J = 9.0 Hz, 1 H) , 7.68 (s, 1 H) , 7.84 (d, J = 9.0 Hz, 1 H) , 8.32 (d, J = 9.3 Hz, 2 H) ; [α]D = +266 (c=2.70, CH,C12) .
METHYL 2- { (3,4-DIFLUOROPHENYL) METHYLENE } -3-OXOBUTYRATE : A mixture of 3, 4-difluorobenzaldehyde (14.2 g, 0.100 mol), methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol) in benzene (150 L) was stirred and heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated and the residue was dissolved in ethyl acetate (200 mL) . The resulting solution was washed with brine (50 mL) , saturated potassium bisulfate solution (50 mL) , and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (EtOAc/hexane, 1/9 to 3/20), giving the desired product as a yellow oil (9.80 g, 41%) which was used in the subsequent step without any further characterization. 6- (3, 4-DIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCAR BONYL-4-METHYLPYRIMIDINE: • A mixture of methyl 2-{(3,4- difluorophenyl) -methylene} -3-oxobutyrate (8.80 g, 36.3 mmol), O-methylisourea hydrogen sulfate (9.40 g, 546 mmol), and NaHC03 (12.3 g, 146 mol) in DMF (30 mL) was heated at 70 °C with stirring for 16 h. The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5 X 300 mL) , brine (300 mL) , and dried over magnesium sulfate. The solvent was evaporated and the crude product was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/7) as the gradient eluent, giving the desired product as an oil (3.82 g, 35%) .
6- (3, 4-DIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-METHOXYCAR BONYL-4-METHYL-1- [ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: 4-Nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added to a solution of 6- (3, 4-difluorophenyl) -1, 6-dihydro- 2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.46 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH2C12 (50 mL) , at 0-5 °C and the mixture was then allowed to warm to room temperature. After 12 h, the solvent was. evaporated and the residue was purified by flash chromatography (EtOAc/hexane, 1/9 to 3/20) , giving the desired product as white crystals (3.72, 85%): mp 172-174 °C.
6- (3, 4-DIFLUOROPHENYL) -1,2,3, 6-TETRAHYDRO-2-OXO-5-METHOXY CARBON-YL-4-METHYL-l- ( 4-NITROPHENOXY) CARBONYLPYRIMIDINE : Aqueous 6 N hydrochloric acid (10 mL) was added to a stirring solution of 6- (3, 4-difluorophenyl) -1, 6- dihydro- 2-methoxy-5-methoxycarbonyl- 4-methyl-1-
(4-nitrophenoxy) carbonylpyrimidine (10.0 g) in THF (200 mL) at room temperature. The stirring was continued for 3 h. The solvent was evaporated and the residue was dried under vacuum, giving the desired product as a white powder (9.70 g, 100%) : mp 185-186 °C .
( +) -1- (3-BROMO-PROPYLCARBAMOYL) -6- (3, 4-DIFLUOROPHENYL) -4- METHYL- 2-OXO-l, 6-DIHYDRO-PYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: A solution of 10% aqueous HCl (5 L) was added to a stirring solution of (+)-6-(3,4- difluorophenyl) -1, 6-dihydro- 2-methoxy-5-methoxycarbonyl- 4-methyl-l- [ (4-nitrophenyloxy) -carbonyl] pyrim-idine (4.10 g, 9.10 mmol) in THF (20 mL) at room temperature and the resulting solution was stirred overnight. The THF was removed in vacuo and the . resulting residue was extracted with EtOAc (3 X 20 mL) , washed with brine (10 mL) and then dried over Na2S04. The solvent was removed in vacuo, giving (+) -6- (3, 4-di-fluorophenyl) -1, 6-dihydro-2- oxo-5- methoxycarbonyl-4-methyl-l- [ (4-nitrophenyloxy) carbonyl] pyrimidine as a viscous oil (3.8 g, 8.5 mmol) . The oil was dissolved in THF (20 mL) and 3-bromo-propylamine hydrobromide (2.33 g, 10.8 mmol) and NaHC03 (1.81 g, 21.5 mmol) were added. The resulting suspension was stirred at room temperature overnight. The THF was removed in vacuo and the resulting residue was dissolved in water (10 mL) and then extracted with EtOAc (3 X 20 mL) . The EtOAc extracts were combined, dried over Na2S04, filtered and the solvent was removed , giving (+) -1- (3-bromo- propylcarba oyl) -6- (3, 4-difluorophenyl) - 4-methyl-2-oxo-l, 6-dihydropyrimidine-5-carboxylic acid methyl ester (3.28 g, 83%): τR NMRδ 2.05-2.15 (m, 2 H) , 2.43
(s, 3 H) , 3.40-3.56 (m, 4 H) , 3.72 (s, 3 H) , 6.69 (s, 1 H) ,
7.08-7.27 (m, 3 H) , 7.57 (br s, 1 H) , 8.84 (br t, 1 H) . Anal. Calcd for C17H18N304 F2Br: C, 45.76; H, 4.07; N, 9.42.
Found: C, 45.70; H, 3.99; N, 9.16.
3-{ (3,4,5-TRIFLU0R0PHENYL)METHYLENE}-2,4-PENTANEDI0NE: A stirring mixture of 3, 4 , 5-trif luorobenzaldehyde (4.20 g, 26.2 mmol), 2, 4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated and the yellow oily residue, 2- { (3, 4 , 5-trifluorophenyl) ethylene} -
2, 4-pentanedione, was used in the next step without further purification.
6- (3, ,5-TRIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-ACETYL- 4-METHYLPYRIMIDINE: A mixture of 2-{ (3,4,5- trifluorophenyl) methylene } - 2 , 4-pentanedione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHC03 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 °C for 6 h. The mixture was filtered and the solid residue was .washed with ethanol (100 mL) . The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography (EtOAc/hexane, 1/9 to 1/4), giving the desired product as an oil (2.80 g, 36%) .
6- (3, 4,5-TRIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-ACETYL- 4-METH-YL-l-[ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: 4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 6- (3, 4 , 5-trifluorophenyl) -1, 6- dihydro-2-methoxy-5-acetyl-4-meth-ylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2C12 (200 mL) at 0-5 °C, and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by - flash chromatography (dichloro-methane/EtOAc, 1/9 to 3/20), giving the desired product as a white powder (4.00 g, 92%) .
6- (3, 4,5-TRIFLUOROPHENYL) -1,2,3, 6-TETRAHYDRO-2-OXO-5-ACET
YL-4- METHYL-l-[ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: A solution of 6 N aqueous HCl (4 mL) was added to a stirring -Ill- solution of 6- (3, 4 , 5-trifluorophenyl) -1, 6- dihydro-2-methoxy-5-acetyl-4-methyl- l-[ (4- nitrophenyloxy) carbonyl] pyrimidine (4.00 g, 8.63 mmol) in THF (100 mL) at 0-5 °C, and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and used in the next step without any further purification (3.88 g, 100%).
Procedures for the Synthesis of the Piperidine Intermediates
(reference for the general procedure for Pd coupling of vinyl triflate and boronic acids or tributyl tin reagents: See, uston, Wise Synthesis (1991), 993)
TERT-BUTYL 4-{ [ (TRIFLUOROMETHYL) SULFONYL] OXY} - 1,2,3, 6-TETRA-HYDRO-l-PYRIDINECARBOXYLATE : n-Butyllithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of dry THF at 0 °C and stirred for 20 minutes. The reaction mixture was cooled to -78 °C and tert- butyl 4-oxo-l-piperidinecarboxylate (40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf2NPh (15.0 g, 42.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and the mixture was stirred at 0 °C overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes/EtOAc (9/1), passed through a plug of alumina and washed with hexanes/EtOAc (9/1) . The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with a small amount of Tf2 Nph. XH NMR δ 5.77 (s, 1 H) , 4.05 (dm, 2 H, J=3.0 Hz), 3.63 (t, 2 H, J=5.7 Hz), 2.45 (m, 2 H) , 1.47 (s, 9 H) . TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-l,2,3, 6- TETRAHYDRO-1- PYRIDINECARBOXYLATE : A mixture of saturated of aqueous Na2C03 solution (25 mL) , tert-butyl 4- { [ (trifluoromethyl) sulfonyl] oxy}- 1,2,3,6- tetrahydro-1-pyridine-carboxylate (20 mmol) , 3-acet- amidophenylboronic acid (30 mmol) and tetrakis- triphenylphosphine palladium (0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3X) . The combined organic extracts were dried and concentrated in vacuo . The crude product was chromatograghed, giving the desired product 1H NMR δ 8.11
(br s, 1 H) , 7.57 (br s, 1 H) , 7.41 (brδ, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H," J=7.8 Hz), 7.08 (br d, 1 H, J=7.8
Hz), 5.99 (b s, 1 H) , 4.03 (br m, 2 H, J=2.7 Hz), 3.59 (t,
2 H, J=5.7 Hz), 2.46 ( , 2. H, ) , 2.16 (s, 3 H) , 1.49 (s, 9
H) .
NI- [3- (1,2, 3, 6-TETRAHYDRO-4-PYRIDINYL) PHENYL] CETAMIDE: A solution of 4 M HCl in dioxane (10 mL) was added to tert-butyl 4- [3- (acetylamino) phenyl] -1,2,3,6- tetrahydro-1-pyridinecarboxyl-ate (8.25 mmol) in dichloromethane (30 mL) . The reaction mixture was stirred at room temperature overnight, concentrated in va cuo, giving the desired product as the hydrochloride salt (2.1 g) . XH NMR δ 7.41-7.00 ( , 4 H) , 6.10 (br, 1 H) , 3.55 (m, 2 H) , 3.16 (t, 2 H, J = 5.7 Hz), 2.44 (m, 2 H) , 2.19 (s, 3 H) .
TERT-BUTYL N-(3-BROMOPROPYL) CARBAMATE: Prepared from 3-bromopropylamine hydrobromide and BOC20 in the presence of base in dichloromethane: λH NMR δ 5.07 (br, 1 H) , 3.31 (t, 2 'H, J=6.6 Hz), 3.12 (apparent br q, 2 H, J=6.0 Hz), 1.92 ( p , 2 H , J=6 . 6 Hz ) , 1 . 30 ( s , 9H ) .
REACTION OF NI- [3- ( 1, 2, 3, 6-TETRAHYDRO-4-PYRIDINYL) PHENYL] ACETAMIDE WITH TERT-BUTYL N- (3-BROMOPROPYL) CARBAMATE
TERT-BUTYL N- (3-{4- [3- (ACETYLAMINO) PHENYL] -
1,2,3, 6-TETRAHYDRO- 1-PYRIDINYL} PROPYL) CARBAMATE : A solution of NI- [3- (1, 2, 3, 6- tetrahydro-4-pyridinyl) phenyl] acetamide hydrochloride (8.24 mmol), tert-butyl N- (3-bromopropyl) carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight. The solids were removed by filtration, the solution was concentrated in vacuo and the product was chromatographed, giving the desired product (110 mg) . H NMRδ7.65 (s, 1 H) , 6.98 (s, 1 H) , 7.45 (d, 1 H, J=7.8 Hz), 7.16 (apparent t, 1 H, J=7.8 Hz), 7.10 (d, 1 H, J=7.8 Hz), 6.02 (s, 1 H) , 5.23 (b, 1 H) , 3.40 (b, 2 H) , 3.30-1.80 (m, 10 H) , 2.18 (s, 3 H) , 1.45 (s, 9 H) .
Deprotection of BOC :
Nl-{3- [1- (3-AMINOPROPYL) -1, 2, 3, 6-TETRAHYDRO-4-PYRIDINYL] P HENYL}ACETAMIDE: A 1:1 solution of TFA:CH2C12 (5 mL) was added to tert-butyl N- (3- { 4- [3- (acetylamino) phenyl] - 1 , 2, 3, 6-tetrahydro-l- pyridinyl }propel) carbamate in dichloromethane (5 mL) . The resulting solution was stirred at room temperature for 1-3 days, saturated NaHC03 was added until pH > 6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg) : 1H NMR δ 7.68 (br, 1 H) , 7.35 (dm, 1 H, J=7.8 Hz), 7.25 (apparent t, 1 H, J=7.8 Hz), 7.15 (dm, 1 H, J=7.8 Hz), 6.12 (m, 1 H) , 3.22 (m, 2 H) , 3.03 (t, 2 H, J=7.3 Hz), 2.78 (t, 2 H, J=5.5 Hz), 2.70-2.50 (m, 4 H) , 2.10 (s, 3 H) , 1.87 (p, 2 H, J=7.3 Hz) . TERT-BUTYL 4- [3- (ACETYLAMINO) PHENYL] -1-
PIPERIDINECARBOXYLATE: A mixture tert-butyl 4- [3- (acetylamino) phenyl] -1,2,3, 6-tetra-hydro-l- pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg) . :H NMR δ 7.80 (s, 1 H) , 7.41-7.20 (m, 3
H) , 6.94 (d, 1 H, J=7.5 Hz)., 4.21 (m, 2 H) , 2.75 (m, 2 H) ,
2.62 (m, 1 H) , 2.16 (s, 3 H) , 1.78 (m, 2 H) , 1.56 (m, 2 H) , 1.48 (s, 9 H) .
NI- [3- (4-PIPERIDYL) PHENYL] ACETAMIDE: A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4- [3- (acetylamino) -phenyl] -1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL) . The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product (550 mg) : mp 102-104 °C; lh NMR δ 2.02 (d, J=13.2 Hz, 2H) , 2.11-2.45 (m, 5H) , 2.67-2.77 (m, IH) , 3.00-3.10 (m, 2H) , 3.51 (d, J=10.5 Hz, 2H) , 6.94 (d, J=7.5 Hz, IH) , 7.20-7.46 (m, 3H) , 7.60 (s, IH) .
TERT-BUTYL N- (3- { 4- [3- (ACETYLAMINO) PHENYL]
PIPERIDINOJPROPYL) -CARBAMATE: A solution of
NI- [3- (4-piperidyl) phenyl] acetamide (550 mg, 0.210 mmol), tert-butyl N- (3-bromopropyl) -carbamate (550 mg, 0.230 mmol), K2C03 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days . The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg) . aH NMR δ 8.15 (s, 1 H) , 7.47-7.44 (m, 2 H) , 7.22 (t, 1 H, J=7.8 Hz), 6.94 (d, 1 H, J=7.8 Hz), 5.53 (b, 1 H) , 3.23 (b, 6 H) , 2.80-1.60 (m, 9 H) , 2.20 (s, 3 H) , 1.45 (s, 9 H) .
Nl-{3-[l- (3-AMINOPROPYL) -4-PIPERIDYL] PHENYL}ACETAMIDE : TFA (1.0 L) was added to a solution of tert-butyl N- (3- { - [3- (acetyl-amino) phenyl] piperidino} propyl) carbamate (340 mg) in dry dichloromethane (10 mL) and stirred at room temperature for 5 h. A 10% aqueous solution of KOH was added to the reaction mixture until pH > 6 and then the dichloromethane was removed in vacuo . The aqueous layer was frozen and lyophilized, giving a solid which was then extracted with methanol. Removal of methanol gave the desired product (120 mg) as an oil. 1H
NMR δ 8.56 - 8.46 (s, IH), 7.43 - 7.30 (m, 2H), 7.23 - 7.16
(apparent t, IH, J=7.5 Hz), 6.95 - 6.92 (m, IH) , 3.03 -
2.99 (m, 2H), 2.77 - 2.73 (t, 2H, J = 6.6 Hz), 2.50-1.60 (m, 10 H) , 2.13 (s, 3 H) .
1-BENZYL-4-HYDROXY-4- ( 4-FLUORO-2-METHYLPHENYL) PIPERIDINE: XH NMR δ 7.40-7.26 (M, 5 H) , 6.91-6.76 (m, 3 H) , 3.57 (s, 2 H) , 2.83- 2.72 (m, 2 H) , 2.61 (s, 3 H) , 2.58-2.43 (m, 2 H) , 2.23-2.12 (m, 2 H) .
l-BENZYL-4- ( 4-FLUORO-2-METHYLPHENYL) -1,2,3, 6-TETRAHYDROPY RIDINE: H NMR δ 7.41-7.26 (m, 5 H) , 7.05 (dd, 1 H, J=6.0, 8.1 Hz), 6.87-6.80 (m, 2 H) , 5.52-5.50 ( , 2 H) , 3.65 (s, 2 H) , 3.13 (q, 2 H, J=3.3 Hz), 2.69-2.66 (t, 2 H, J=5.1 Hz), 2.35-2.31 (m, 2 H) , 2.27 (s, 3 H) .
4- (4-FLUORO-2-METHYLPHENYL) PIPERIDINE: XH NMR δ 7.17 (t, 1 H, J=7.2 Hz) , 6.83-6.80 (m, 2 H) , 3.22 (m, 2 H) , 2.81-2.73 (m, 2 H) , 2.66 (br s, 1 H) , 2.33 (s, 3 H) , 1.80-1.60 (m, 4 H) .
l-BENZYL-4- (3, 4 , 5-TRIFLUOROPHENYL) -1,2,3, 6-TETRAHYDR0PYRI
DINE: XH NMR δ 7.50-7.20 (m, 7 H) , 5.67 (m, 1 H) , 3.69 (s, 2 H) , 3.19 (apparent q, 2 H, J=2.7 Hz), 2.75 (t, 2 H, J=5.7 Hz) , 2.34 (m, 2 H) .
4- (3, 4,5-TRIFLUOROPHENYL) PIPERIDINE: mp 197-199 °C; XH NMR δ 2.05 (d, J=13.2 Hz, 2H) , ) , 2.33 (dd, J=25.5 Hz, J=12.9
Hz, 2H) , 3.06-3.23 (m, 3H) , 3.73 (d, J=12.0 Hz, 2H) , 6.94-7.04 (m, 2H) .
4- (3, 4,5-TRIFLUOROPHENYL) PIPERIDINE: XH NMR δ 7.20-6.80 (m,
2 H) , 3.73 (m, 2 H) , 3.14 (m, 3 H) , 2.33 ( , 2 H) , 2.05 (m, 2 H) .
TERT-BUTYL N-3-[4- (3, 4 , 5-TRIFLUOROPHENYL) PIPERIDINO] PROPYL-CARBAMATE : XH NMR δ 6.91 (m, 2 H) , 5.62 (b, 1 H) ,
4.31 (t, 2 H, J=5.4 Hz) , 3.63 (m, 2 H) , 3.39 (dt, 2 H, J= 2.1, 6.0 Hz) , 3.40-2.70 (m, 7 H) , 2.46 (t, 2 H, J=6.9 Hz) , 2.10-1.60 (m, 4 H) , 1.45 (s, 9 H) .
3- [4- (3, 4, 5-TRIFLUOROPHENYL) PIPERIDINO] -1-PROPANAMINE: XH
NMR δ6.93 (m, 2 H) , 4.30 (b, 1 H) , 3.36 (b, 1 H) , 3.06 (m, 2 H) , 2.77 (m, 2 H) , 2.43 (m, 2 H) , 2.20-1.40 (m, 9 H) .
l-BENZYL-4- (5-FLUORO-2-METHOXYPHENYL) -4-PIPERIDINOL: XH NMR δ7.40-6.80 (m, 8 H) , 3.94 and 3.85 (s, 3 H) , 3.61 and 3.58
(s, 2 H) , 2.80-1.90 (m, 8 H) .
l-BENZYL-4- (5-FLUORO-2-METHOXYPHENYL) -1,2,3, 6-TETRAHYDROP YRIDINE: XH NMR δ 7.40-6.70 (m, 8 H) , 5.84 (m, 1 H) , 3.77 (s, 3 H) , 3.64 (s, 2 H) , 3.17 (m, 2 H) , 2.68 (t, 2 H, J=5.7 Hz) , 2.54 (m, 2 H) .
4- (5-FLUORO-2-METHOXY) PHENYL PIPERIDINE: mp 254-258 nC; 2H
NMR δl.53-1.68 (m, 2H) , 1.79 (d, J=11.7 Hz, 2H) , 2.12 (dt, J=2.1 Hz, J=11.7 Hz, IH) , 2.77 (dt, J=l .8 Hz, J=12.3 Hz, IH) , 2.90-3.05 (m, IH) , 3,10-3.22 (m, 2H) , 3.68 (s, IH) , 3.79 (s, 3H) , 6.72-6.93 (m, 3H) . Anal. Calcd. For C12H17N0FC1 + 0.14 CH2C12: C, 56.60; H, 6.76; N, 5.44.
Found: C, 56.60; H, 6.92; N, 5.28.
TERT-BUTYL N-3- [4- (5-FLUORO-2-METHOXYPHENYL) PIPERIDINO] PROPYL-CARBAMATE : lR NMR δ 6.90-6.70 (m, 3 H) , 5.76 (b, 1 H) , 3.80 (s, 3 H) , 3.68 (m, 1 H) , 3.40-2.90 (m, 4 H) , 2.45
(t, 2 H, J=6.6 Hz), 2.20-1.60 (m, 9 H) , 1.45 (s, 9 H) .
3- [4- (5-FLUORO-2-METHOXYPHENYL) PIPERIDINO] -1-PROPANAMINE : XH NMR 57.00-6.80 (m, 3 H) , 3.80 (s, 3 H) , 3.05 (d, 2 H, J=11.4 Hz) , 2.76 (t, 2 H, J=6.9 Hz), 2.43 (dd, 2 H, J=7.8
Hz) , 2.05 (dt, 2 H, J=2.4 , 11.7 Hz), 1.90-1.20 (m, 10 H) .
TERT-BUTYL 4- (1-NAPHTHYL) -1,2,3, 6-TETRAHYDRO-l- PYRIDINECARBOXYL-ATE: Η NMR δ 8.00-7.80 (m, 2 H) , 7.76 (d, 1 H, J=8.1 Hz) , 7.50-7.44 (m, 2 H) , 7.42 (d, 1 H, J=8.1
Hz) , 7.27 (d, 1 H, J=8.1 Hz) , 5.76 (br, 1 H) , 4.14 (m, 2 H) , 4 or 3.29 (t, 2 H, J=5.7 Hz) , 2.52 (br , 2 H) , 1.53 (s, 9H) .
4- (1-NAPHTHYL) PIPERIDINE: HCl salt; mp 330-332 °C; XH NMR δ 1.66-1.70 (m, 2H) , 2.20-2.26 (m, 2H) , 2.30-2.43 ( , 2H) , 2.72-2.84 (m, IH) , 3.15-3.26 (m, 2H) , 7.42-7.56 (m, 4H) , 7.78 (d, J=8.1 Hz, IH) , 7.90 ( d, J=8.1 Hz, IH) , 8.04 (d, J=8.1 Hz, IH) . Anal. Calcd. For C15H18N0C1 + 0.20 CH2C12 : C, 68.96; H, 7.00; N, 5.29. Found: C, 68.64; H, 7.04; N, 5.24.
TERT-BUTYL N-3- [4- ( 1-NAPHTHYL) PIPERIDINO] PROPYLCARBAMATE :
2H NMRδ8.09 (d, 1 H, J=8.4 Hz), 7.86 (dd, 1 H, J=1.8, 7.5 Hz) , 7.71 (dd, 1 H, J=2.4 , 6.9 Hz) , 7.60-7.30 (m, 4 H) , 6.31 (br, 1 H) , 5.75 (br, 1 H) , 4.26 (t, 1 H, J=5.4 Hz) , 3.40-3.00 (m, 6 H) , 2.54 (t, 2 H, J=6.9 Hz) , 2.24 (dt, 2 H, J= 3.0, 11.4 Hz), 2.00-1.60 ( , 6 H) , 1.45 (s, 9 H) .
4-(3-METHYL-2-PYRIDYL)-4-PIPERIDIN0L: xH MRδ8.21 (dd, I H, J=1.2, 4.5 Hz), 7.36 (dd, 1 H, J=6.6, 7.8 Hz) , 7.02 (dd, 1 H, J=4.8, 7.5 Hz) , 3.07 (dt, 2 H, J=2.7, 12.3 Hz), 2.89 (m, 2 H) , 2.46 (s, 3 H) , 2'.22 (dt, 2 H, J=4.8, 12.3 Hz), 1.39
(dm, 2 H, J=12.3 Hz) .
TERT-BUTYL 4- (3-METHYL-2-PYRIDYL) -1,2,3, 6-TETRAHYDRO- 1-PYRIDINE-CARBOXYLATE: XH NMR δ 8.16 (dd, 1 H, J=1.2, 3.3 Hz) , 7.51 (dm, 1 H, J=7.5 Hz), 7.15 (dd, 1 H, J=4.8, 7.5
Hz) , 5.73 (br, 1 H) , 4.01 (m, 2 H) , 3.59 (t, 2 H, J=5.7 Hz) , 2.40 (m, 2 H) , 1.44 (s, 9 H) .
T E R T - B U T Y L N-3- [4- (3-METHYL-2-PYRIDYL) PIPERIDINO] PROPYLCARBAMATE: lti
NMRδ 8.37 (dd, 1 H, J=4.2, 4.8 Hz), 7.51 (dd, 1 H, J=7.2, 7.5 Hz) , 7.20 (dd, 1 H, J=4.5, 7.5 Hz) , 6.73 (br, 1 H) , 3.26 (m, 4 H) , 3.05 (d, 2 H, J=12.0 Hz) , 2.80-2.40 ( , 4 H) , 2.61 (s, 3 H) , 1.82 (p, 2 H, J=6.3 Hz) , 1.54 (d, 2 H, J= 12.0 Hz) .
T E R T - B U T Y L '4- (3-METHOXYPHENYL) -1,2,3, 6-TETRAHYDRO-l-PYRIDINECARB- OXYLATE: XH NMR δ 7.23 (t, 1 H, J= 8.1 Hz) , 6.96 (d, 1 H, J=7.5 Hz) , 6.89 (d, 1 H, J=l .8 Hz) , 6.80 (dd, 1 H, J=2.4 , 8.1 Hz), 6.02 (br, 1 H) , 4.20-4.00 (m, 3 H) , 3.80 (s, 3 H) , 3.62 (t, 2 H, J=5.7 Hz) , 2.51 (br, 2 H) , 1.49 (s, 9 H) .
1-BENZYL-4-METHYL-PIPERIDIN-4-OL: Methyllithium (1.4 M in Et_.0, 54.0 mL) was added to a solution of 1-benzyl- 4-piperidone (5.00 mL, 27.0 mmol) in anhydrous ether at -78 °C under argon. Stirring was continued at -78 °C for 1.5 hours. Ether (200 mL) and water (40 mL) were added, and the two phases were separated. The aqueous solution was extracted with Et20 (3 x 50 mL) . The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was chromatographed (EtOAc to EtOAc-MeOH 9/1), giving 4.81 g (87%) of the desired product as a colorless oil: XH NMR δ 1.21 (s, 3 H) , 1.56 (dt, J = 13, 3 Hz, 2 H) , 1.65 (td, J = 10, 4 Hz, 2 H) , 2.35 (td, J = 10, 3 Hz, 2 H) , 2.53 (m, 2 H) , 7.24 (m, 1 H) , 7.29 (m, 4 H) ; 13C NMR δ 30.44, 39.37, 50.39, 63.80, 68.50, 127.56, 128.80, 129.80, 139.17.
1-BENZYL-4-METHYL-4-PHENYLPIPERIDINE : l-Benzyl-4-methyl- piperidin-4-ol (4.81 g, 23.4 mmol) was added to a suspension of A1C13 (15.62 g, 117 mmol) in benzene (100 mL) at room temperature under argon. The mixture was stirred at reflux for 24 hours, then cooled and poured cautiously into ice water (100 g of ice, 50 mL of water) . The aqueous phase was adjusted to pH 11-12 by addition of 6 N aqueous NaOH at 0 °C, and extracted with EtOAc (3 x 100 mL) . The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was chromatographed (hexane- Et20 19/1 to 9/1, followed by hexane-EtOAc 3/1), giving the desired product (3.23 g, 52%) as a brown oil: XH NMRδl.25 (s, 3 H) , 1.80 (m, 2 H) , 2.17 (m, 2 H) , 2.44 (m, 2 H) , 2.55 (m, 2 H) , 3.50 (s, 2 H) , 7.25 (m, 1 H) , 7.35 (m, 4 H) ; 13C NMRδ36.82, 37.65, 50.95, 54.93, 64.08, 126.19, 126.51, 127.59, 128.83, 128.95, 129.05, 129.89, 139.24.
4-METHYL-4-PHENYLPIPERIDINE: Freshly prepared methanolic formic acid solution (4.4% by weight, 70 mL) was added to l-benzyl-4-methyl-4-phenylpiperidine (3.23 g, 12.2 mmol). To the resulting solution was added 10% palladium on carbon (2.00 g) . The mixture was stirred at room temperature for 24 hours. The solid was filtered out and washed with MeOH (30 mL) , H20 (15 mL) , CH2Cl2 (30 mL) and MeOH (15 mL) . The combined filtrate and washings were concentrated, and the residue was dissolved in CH2C12 (50 mL) and H20 (10 mL) . The aqueous phase was adjusted to pH 11 by addition of 1 N aqueous NaOH. The organic phase was separated, dried over magnesium sulfate and concentrated. The residual oil was purified by flash chromatography (CHCl3/MeOH/2 N NH3 in MeOH 100/4/0 to 100/20/10), giving l-benzyl-4- methyl-4- phenylpiperidine (1.20 g) and 1.10 g (51%, 82% based on consumed starting material) of 4-methyl-4-phenylpiperidine :
XH NMRδl.24 (s, 3 H) , 1.71 (m, 2 H) , 2.06 (m, 2 H) , 2.82
(m, 3 H) , 2.94 (m, 2 H) , 7.19 (m, 1 H) , 7.32 (m, 4 H) ; 13C
NMR 537.22, 38.54, 43.44, 47.74, 126.31, 127.43, 129.01, 149.73.
3-AMINOPROPYL-4-METHYL-4-PHENYLPIPERIDINE: A solution of 4-methyl-4-phenylpiperidine (1.00 g, 5.70 mmol), 3-bromo- propylamine hydrobromide (1.87 g, 8.55 mmol) and potassium carbonate (1.97 g, 14.2 mmol) in refluxing dioxane (20 mL) was stirred for 36 hours. After removal of the solvent, water (50 mL) was added and the pH adjusted to 11-12 by the addition of 1 N aqueous NaOH. The mixture was extracted with CH2C12 (150 mL + 3 x 100 mL) . The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (CHCl3/MeOH/2 N NH3 in MeOH 100/20/10), giving the desired product as a colorless oil (241 mg, 18%): λti NMRδl.18 (s, 3 H) , 1.61 (p, J = 7 Hz, 2 H) , 1.75 (m, 2 H) , 2.10 (m, 2 H) , 2.33 (t, J = 7 Hz, 2 H) , 2.40 (m, 2 H) , 2.45 (m, 2 H) , 2.72 (t, J = 6 Hz, 2 H) , 3.02 (br s, 2 H) , 7.14 (m, 1 H) , 7.3.0 (m, 4 H) ; 13C NMR530.28, 36.78, 37.64, 41.51, 50.96, 57.51, 126.16, 126.40, 128.91, 149.20.
Preparation of
3- [ 4- (4-Fluorophenyl) piperidin-1-yl] propylamine
4- (4-FLUOROPHENYL) PIPERIDINE HYDROCHLORIDE: To a solution of 4- (4-fluorophenyl) -1,2,3, 6-tetrahydropyridine hydrochloride (10 g) in methanol (200 mL) was added 10% palladium on charcoal (0.5 g) and the mixture was hydrogenated at 50 psi for 3 h. The catalyst was removed by filtration and solvent was evaporated, leaving the product (10.0 g) as a white powder, which was used in the next step without purification. The product appeared to be pure based on XH NMR and TLC analysis. XH NMR δ 1.95-2.03 (br d, 2H) , 2.14-2.29 (m, 2H) , 2.70-2.80 (m, IH) , 2.91-3.07 (br q, 2H) , 3.60-3.64 (br d, 2H) ,
6.96-7.03 (m, 2H) , 7.19-7.22 (m, 2H) , 9.60 (br s, IH) , 9.71 (br s, IH) .
4- (4-FLUOROPHENYL) PIPERIDINE: mp °C; IH NMR 51.51-1.66 (m, 2H) , 1.80 (d, J=7.2 Hz, 2H) , 2.53-2.64 (m, IH) , 2.67-2.77
(m, 2H) , 3.17 (d, J=12.0 Hz, 2H) , 6.94-7.03 (m, 2H) , 7.13-7.21 (m, 2H) .
Anal. Calcd. For CUH14NF + C4H404 : C, 58.70; H, 5.83; N, 4.18. Found : C , 58 . 72 ; H , 5 . 84 ; N , 3 . 98 .
3- [4- (4-FLUOROPHENYL) PIPERIDIN-1-YL] PROPYLPHTHALIMIDE : A mixture of 4- (4-fluorophenyl) piperidine hydrochloride (5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassium carbonate (15 g) in DMF (100 mL) was stirred at 95-100 °C for 12 h. About 80% of the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with brine (3 X 100 mL) and dried (Na2S04) . The solvent was evaporated from the ethyl acetate solution and the residue was purified by column chromatography (1/1 hexane-ethyl acetate to 100% ethyl acetate), giving crude product (7.50 g, 88%) . This crude product was crystallized from isopropanol, giving a white crystalline solid (4.50 g, 1st crop) . This material was used in the next step. Concentration of the mother liquor and cooling gave the second crop of desired product (1.0 g) . 1H NMR 5 1.43-1.52 (m, 2H) , 1.67-1.75 (m, 2H) , 1.80-1.96 (m, 4H) , 2.33-2.46 (m, 3H) , 2.94-2.99 (br d, 2H) , 3.78 (t, J=7 Hz, 2H) , 6.90-7.04 (m, 4H) , 7.70-7.74 (m, 2H) , 7.84-7.87 (m, 2H) .
3- [4- (4-FLUOROPHENYL) PIPERIDIN-1-YL] PROPYLAMINE: Hydrazine (4 mL) was added to a solution of 3- [4-
( 4-fluorophenyl) piperidin- 1-yl] propylphthalimide (4.50 g, 12.3 mmol) in methanol '(200 mL) , and the mixture was stirred at reflux for 8 h. The solution was cooled to room temperature, and the resulting white solid which formed was filtered and washed with methanol (20 mL) .
The solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h. The crude product was dissolved in 50 mL of chloroform, stirred for 1 h, and filtered. The white solid was washed with additional chloroform (20 mL) , the solvent was evaporated from the combined filtrates to leave the crude product as an oil . The oil was purified by column chromatography (dichloromethane / methanol / 2 M ammonia in methanol, 10/3/1), giving the desired product (2.70 g, 93%). λH NMR δ 1.60-1.83 (m, 6H) , 1.96-2.07 (m, 4H) , 2.40-2.55 (m, 3H) , 2.70-2.85 (br t, 2H) , 3.03-3.07 (br d, 2H) , 6.93-7.00 (m, 2H) , 7.14-7.20 (m, 2H) .
4- (4-METHYL-4-(3,5-DIMETHYLPHENYL) PIPERIDINE: hygroscopic; ^ NMRδl^O (s, 3H) , 1.74-1.80 (m, 2H) , 2.08-2.16 (m, 2H) , 2.30 (s, 6H) , 2.50-2.56 (m, 2H) , 2.64-2.68 (m, 2H) , 2.97-3.04 (m, IH) , 6.87 (s, IH) , 6.94 (s, 2H) .
Piperidine Side Chain Intermediates
TERT-BUTYL 4- { [ (TRIFLUOROMETHYL) SULFONYL] OXY} -1 ,2,3,6-
TETRAHYDRO-1-PYRIDINECARBOXYLATE : n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL,
44.2 mmol) in 40 mL of dry THF at 0 °C and stirred for 20
'minutes. The reaction mixture was cooled to -78 °C and tert-butyl 4-oxo-l-piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf2NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at °C overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes : EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes : EtOAc (9:1). The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf2NPh. XH NMR (400 MHz, CDC13) δ 5.77 (s, 1 H) , 4.05 (dm, 2 H, J=3.0 Hz), 3.63 (t, 2 H, -J=5.7 Hz), 2.45 (m, 2 H) , 1.47 (s, 9 H) .
TEKT-BUTYL 4- [3- (AMINO) PHENYL] -1,2,3, 6-TETRAHYDRO-l- PYRIDINECARBOXYLATE :
A mixture of 2 M aqueous Na2C03 solution (4.2 mL) , tert- butyl 4- { [ (trifluoromethyl) sulfonyl] oxy}-l, 2,3,6- tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours, under an inert atmosphere (an initial degassing of the mixture is recommended to prevent the formation of triphenylphosphine oxide) . The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3X) . The combined organic extracts were dried and concentrated in vacuo . The crude product was chromatograghed (silica, hexanes : EtOAc : dichloromethane (6:1:1) with 1% added isopropylamine to protect the BOC group from hydrolysis) to give 0.330 g of the desired product in 81% yield:
XH NMR (400 MHz, CDC13) δ 7.12 (t, IH, J= 7.60 Hz), 6.78 (d, IH, J= 8.4 Hz), 6.69 (t, IH, J= 2.0 Hz), 6.59 (dd, IH, J= 2.2, 8.0 Hz), 6.01 (m, IH) , 4.10-4.01 (d, 2H, J= 2.40 Hz), 3.61 (t, 2H, J= 5.6 Hz), 2.52-2.46 (m, 2H) , 1.49 (s, 9H) ; ESMS m/e : 275.2 (M + H)+.
Anal. Calc. for Cι6H24N202: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92
TERT-BUTYL 4- [3- (AMINO) PHENYL] -1-PIPERIDINECARBOXYLATE
A mixture of 3.10 g of tert-butyl 4- (3-aminophenyl) - 1, 2, 3, 6-tetrahydropyridine-l-carboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 L of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane: methanol 95:5 with 1% isopropylamine added to protect the BOC group from hydrolysis) to give 2.63 g of the desired product (84%) . TERT-BUTYL 4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIDINECARBOXYLATE
αH NMR ( 400 MHz , CHC13 ) δ 8 . 23 ( s , IH ) , 8 . 11 ( d, IH, J=8 . 0 Hz ) , 7 . 69 (d, IH, J=8 . 0 Hz ) , 7 . 51 ( t , IH , J=8 . 0
Hz), 6.20 (m, IH) , 4.17-4.08 (m, 2H) , 3.67 (t, 2H, J=5.6 Hz), 2.61-2.52 (m, 2H) , 1.50 (s, 9H) ; ESMS m/e : 249.1 (M + H - C4H8) + .
1,2, 3, 6-TETRAHYDRO-4- (3-NITROPHENYL) PYRIDINE: Into a stirred solution of 5.00 -g (16.0 mmol) of tert-butyl 1,2,3, 6-tetrahydro-4- (3-nitrophenyl) pyridine-1- carboxylate in 100 ml of 1,4-dioxane at 0°C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3 X 80 mL of dichloromethane and the combined organic extracts were dried (MgS04) , filtered and concentrated in va cuo . The residue was purified by column chromatography (silica, 9 : 1 , dichloromethane : methanol + 1% isopropyl amine) to afford 2.85 g (87.5% yield) of the desired product: XH NMR (400 MHz, CDC13) δ 8.24 (s, IH) , 8.09 (d, IH, J=8.4 Hz), 7.71 (d, IH, J=8.0 Hz), 7.49 (t, IH, J=8.0 Hz), 6.35-6.25 (m, IH) , 3.58 (apparent q, 2H, J=3.'0 Hz), 3.14 (t, 2H, J=5.6 Hz), 2.54-2.46 (m, 2H) .
TERT-BUTYL 3- (4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIDINYL) PROPYLCARBAMATE : A mixture of 2.80 g (14.0 mmol) of 1, 2, 3, 6-tetrahydro-4- (3-nitrophenyl) pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3- bromopropyl) carbamate, 11.6 g (84.0 mmol) of K2C03, 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4- dioxane was heated at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was dried (MgS04) , concentrated in vacuo and the residue was purified by column chromatography (silica, 9:1, dichloromethane: methanol + 1% isopropyl amine) to afford 4.35 g (85.7% yield) of the desired product: 1H
NMR (400 MHz, CDC13) 5 8.24 (t, IH, J=l .9 Hz), 8.09 (dd, IH, J=1.9, 8.0 Hz), 7.70 (apparent d, IH, J=8.0 Hz), 7.49 (t, IH, J=8.0 Hz), 6.23 (m, IH) , 3.29-3.18 (m, 4H) , 2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H) , 1.82-1.70 (m, 2H) , 1.44 (s, 9H) ; ESMS m/e : 362.2 (M + H)+.
3- (4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) -PYRIDINYL) -1- PROPANAMINE: Into a stirred solution of 4.35 (12.0 mmol) of tert-butyl 3- (4- (3-nitrophenyl) -3, 6-dihydro-l (2H) - pyridinyl) propylcarbamate in 100 ml of 1,4-dioxane at 0°C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3 X 80 mL of dichloromethane, the combined organic extracts were dried (MgS04) , filtered and concentrated in vacuo . The residue was purified by column chromatography (silica, 9 : 1 , dichloromethane : methanol + 1% isopropyl amine) to afford 3.05 g (97.0% yield) of the desired product: XH NMR (400 MHz, CDC13) δ 8.24 (t, IH, J=1.8 Hz), 8.09 (dd, IH, J=1.8, 8.2 Hz), 7.69 (dd, IH, J=1.8, 8.2 Hz), 7.48 (t, IH, J=8.2 Hz), 6.24 (m, IH) , 3.21 (d, 2H, J=3.6 Hz), 2.84 (t, 2H, J=6.6 Hz), 2.75 (t, 2H, J=5.8 Hz), 2.64-2.54 (m, 4H) , 1.76 (m, 2H); ESMS m/e : 262.2 (M + H)+; Anal . Calc. for C14HιN302 (0.06 CHC13) : C, 62.90; H, 7.16; N, 15.65. Found: C, 63.20; H, 7.16; N, 15.65.
METHYL (4S)-3-[ ( {3- [4- (3-AMINOPHENYL) -1- IPERIDI YL] ROPYL}AMINO) CARBONYL] -4- (3 , 4- DIFLUOROPHENYL)-6-(METHOXYMETHYL) -2-0X0-1,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: A mixture of 3.02 g (6.33 mmol) 5-methyl 1- ( 4-nitrophenyl) (6S)-6-(3,4- difluorophenyl) -4- (methoxymethyl) -2-oxo-3, 6-dihydro- 1, 5 ( 2H) -pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3- (4- (3-nitrophenyl) -3, 6-dihydro-l (2H) -pyridinyl) -1- propanamine, 7.94 g (75.5 mmol) of K2C03 and 1.00 L of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo . The residue was dissolved in 100 L of ethyl acetate and washed 3 X 50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgS04) and concentrated in vacuo . The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgS04) and concentrated in vacuo . The residue was purified by column chromatography (silica, 9.5 : 0.5 , dichloromethane : methanol + 1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product. TERT-BUTYL 4- [3- (ISOBUTYRYLAMINO) PHENYL] -3, 6-DIHYDRO- l(2H)-PYRIDINECARBOXYLATE: Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4- (3-aminophenyl) -3, 6-dihydro- 1 (2H) -pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgS04) , and concentrated in vacuo . The residue was purified by column chromatography (silica, 50 : 46 : 3 : 1, hexanes : dichloromethane : methanol : isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: XH NMR (400 MHz, CDC13) o 7.69 (s, 1 H) , 7.34 (d, 1 H, J=7.8 Hz), 7.27 (t, IH, J=7.8 Hz), 7.11 (d, IH, J=7.8 Hz), 6.04 (s, IH), 4.05 (s,.2H), 3.62 (apparent t, 2, H, J=4.9 Hz), 2.51.(m, 3H) , 1.49 (s, 9H) , 1.25 (d, 6H, J=7.4 Hz); ESMS /e : 345.5 (M + H)+. Anal. Calc. for C2oH28N203+0.175 CHC13: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88
Γ.ERΓ-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-l- PIPERIDINECARBOXYLATE: A mixture of 2.90 g (8.40 mmol) of tert-butyl 4- [3- (isobutyrylamino) phenyl] -3, 6-dihydro- 1 (2H) -pyridinecarboxylate and 0.80 g of 10% yield Pd/C in 100 mL of ethanol was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, the filtrate was dried (MgS04) and concentrated in vacuo . The residue was purified by column chromatography (silica, 9.5 : 0.5 , dichloromethane : methanol + 1% isopropyl amine) to afford 2.40 g (84.0% yield) of the desired product: XH NMR (400 MHz, CDC13) δ 7.49-7.44 (m, 2H), 7.24 (t, IH, J=7.6 Hz), 6.93 (d, IH, J=7.6 Hz), 4.20-4.10 (m, 2H) , 2.86-2.45 (m, 4H) , 1.86-1.75 (m, 4H) , 1.48 (s, 9H) , 1.24 (d, 6H? J=6.8 Hz); ESMS m/e : 345.2 (M + H)+; Anal. Calc. for C20H30N2O3+0.3H20: C, 68.27; H, 8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84.
2-METHYL-.2V- [3- (4-PIPERIDINYL) PHENYL] PROPANAMIDE: Into a stirred solution of 2.20 (6.50 mmol) of tert-butyl 4- [3- ι (isobutyrylamino) phenyl] -1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0 °C was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3 X 80 mL of dichloromethane, the combined organic extracts were dried (MgS0 ) , filtered and concentrated in vacuo . The residue was purified by column chromatography (silica, 9 : 1 , dichloromethane : methanol + 1% isopropyl amine) to afford 0.700 g (46.0% yield) of the desired product: XH NMR (400 MHz, CDC13) δ 7.47 (s, IH) , 7.40 (d, IH, J=7.8 Hz), 7.24 (t, IH, J=7.8 Hz), 7.00 (d, IH, J=7.8 Hz), 3.23-3.14 (m, 5H) , 2.82-2.57 (m, 4H) , 1.20 (d, 6H, J=6.8 Hz); ESMS m/e : 247.2 (M + H)+; The hydrochloride salt was used for the combustion analysis: Anal. Calc. for Cι5H22N2O+HCl+0.15 CHC13: C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N,
3- (4-PIPERIDINYL)ANILINE: XH NMR (400 MHz, CDC13) δ 7.01 (t, IH, J=7.6 Hz), 6.62-6.54 (m, 3H) , 3.16 (br d, 2H, J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, IH, J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, J=4.0, 12.3 Hz); ESMS m/e : 177.2 (M + H)+.
raJJRT-BUTYL 4- (4-NITROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIDINECARBOXYLATE: To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4- { [ (trifluoromethyl) sulfonyl] oxy} -3, 6-dihydro-l [ 2H) - pyridinecarboxylate (1.0 g) , 4-nitrophenylboronic acid (0.71 g) , sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g) , tetrakis ( triphenylphosphine) - palladium (0) (0.173 g) and ethylene glycol dimethyl ether (10 mL) . The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 °C for 3 hrs. After cooling to room 'temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3x20 mL) and the combined organic extracts were washed with sat NH4C1 (20 mL) and brine (20 mL) , dried over MgS04 and concentrated under reduced pressure. The residue was purified by chromatography ( 6 : l=hexane : ethyl acetate with 1% NH3) to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as prompt as practical: XH NMR (400 MHz, CDC13) δ 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, IH) , 4.13 (m, 2H) , 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H) , 1.49 (s, 9H) .
4- (4-NITROPHENYL) -1,2,3, 6-TETRAHYDROPYRIDINE :
4- (4-Nitrophenyl) -1,2,3, 6 tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-W- [3- ( 4- piperidinyl) phenyl] propanamide using HCl gas and tert- Butyl 4- (4-Nitrophenyl) -3, 6-dihydro-l {2H) - pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction mixture was concentrated in va cuo to give the crude product (69.8 mg) that used in the next reaction without further purification.
Dihydropyrimidine Intermediates
3- (3 , 4 , 5-TRIFLUOROBENZYLIDENE) -2 , 4-PENTANEDIONE : A stirring mixture of 3, , 5-trifluorobenzaldehyde (4.20 g, 26.2 mmol), 2, 4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5.00 mmol) in benzene (150 mL) was heated at reflux temperature in a Dean-Stark apparatus for 8 h. The benzene was evaporated and the yellow oily residue was used in the next step without further purification.
1- [2-METHOXY-4-METHYL-6- (3,4, 5-TRIFLUOROPHENYL) -1 , 6- DIHYDRO-5-PYRIMIDINYL] ETHANONE : A mixture 3- ( 3 , 4 , 5- trifluorobenzylidene) -2, 4-pentanedione (26.2 mmol), 0- methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHC03 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 °C for 6 h. The mixture was filtered and the solid filter cake was washed with ethanol (100 mL) . The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography (EtOAc/hexane, 1/9 to 1/4), to afford the desired product as an oil (2.80 g, 36%). 4-NITROPHENYL 5-ACETYL-2-METHOXY-4-METHYL-6- (3, 4,5- TRIFLUOROPHENYL) -1 (6H) -PYRIMIDINECARBOXYLATE :
4-Nitrophenyl chloroformate (1.89 g, 9.38 mmol) was added to a solution of 1- [2-methoxy-4-methyl-6- (3, , 5- trifluorophenyl) -1, 6-dihydro-5-pyrimidinyl] ethanone
(2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2C12 (200 mL) at 0-5 °C, and the resulting mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (dichloromethane/EtOAc, 1/9 to 3/20) , to give the desired product as a white powder (4.00 g, 92%) .
4-NITROPHENYL 5-ACETYL-4-METHYL-2-OXO-6- (3,4,5- TRIFLUOROPHENYL) -3 , 6-DIHYDRO-l (2H) - PYRIMIDINECARBOXYLATE :
A solution of 6 N aqueous HCl (4 mL) was added to a well-stirred solution of 4-nitrophenyl 5-acetyl-2- methoxy-4-methyl-6- (3,4, 5-trifluorophenyl) -1 (6H) - pyrimidinecarboxylate (4.00 g, 8.63 mmol) in THF (100 mL) at 0-5 °C, and the mixture was allowed to warm to room temperature. After 2 h, solvent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and used in the next step without further purification (3.88 g, 100%).
: XH NMR (DMSO) δ 10.29 (s, IH) , 8.23 (d, 2H, J=9.1 Hz), 7.51 (d, 2H, J=9.1 Hz), 7.15-7.07 (m, 2H) , 6.18 (s, IH) , 2.30 (s, 3H) , 2.28 (s, 3H) ; ESMS m/e: 450.2 (M + H)+; Anal. Calc. for C2oHι4F3N3θ6: C, 53.46; H, 3.14; N, 9.35. Found: C, 53.26; H, 3.21; N, 9.35. BENZYL 2-PROPIONYL-3- (3,4, 5-TRIFLUOROPHENYL) -2- PROPENOATE. A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3, 4-difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) were heated at reflux temperature with removal of water using a Dean-Stark apparatus for 5h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried over anhydrous Na2S04. The solvent was evaporated to afford a pale yellow syrup (60.2 g) , which was used in the next step without further purification.
BENZYL 6- (3 , 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1 , 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE. A suspension of benzyl 2-propionyl-3- (3,4, 5-trifluorophenyl) -2-propenoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHC03 (16.3 g, 130.2 mmol) in DMF (190 mL) was stirred at 70 °C for 20h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4X100 mL) , brine (200 mL) and dried over Na2S04. After removal of solvent, the residue was purified by column chromatography (Si02, EtOAc/Hexane, 10%-30%) to afford benzyl 6- (3, 4-difluorophenyl) -4- ethyl-2-methoxy-l, 6-dihydro-5-pyrimidinecarboxylate as a colorless oil (10.6 g, 58% yield). The product was directly used in the next step after 1H NMR spectroscopy which showed it to be a mixture of amine/imine tautomers.
5-BENZYL 1- (4-NITROPHENYL) 6- (3 , 4-DIFLUOROPHENYL) -4- ETHYL-2-METHOXY-l ,5 (6H) -PYRIMIDINEDICARBOXYLATE . Into a well-stirred solution of benzyl 6- (3, 4- difluorophenyl) -4-ethyl-2-methoxy-l, 6-dihydro-5- pyrimidinecarboxylate (27.5 g, 68.75 mmol) and pyridine (9.2 mL) in CH2C12 (300 L) was added 4-nitrophenyl chloroformate (14.49 g, 82.5 mmol) at room temperature. The reaction mixture was stirred for 4 h and then washed with 10% aqueous KOH solution (2 X 150 mL) . The organic layer was separated and dried over Na2S04. The solvent was removed in vacuo and the residue was used in the next step without further purification: αH NMR (CDC13) 5 1.24 (t, J=7.2 Hz, 3H) , 2.81-2.98 (m, 3H) , 3.97 (s, 3H) , 5.14 (ABq, 2H) , 6.28 (s, 3H) , 7.03-7.29 (m, 8H) , 7.35 (d, J=9.2 Hz, 2H) , 8.26 (d, J=9.2 Hz, 2H) .
BENZYL 6- (3 , 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1-
( { [ (1R) -1-PHENYLETHYL]AMINO}CARBONYL) -1 , 6-DIHYDRO-5- PYRIMIDINECARBOXYLATE .
Into a stirred mixture of 5-benzyl 1- (4-nitrophenyl) 6- (3, 4-difluorophenyl) -4-ethyl-2-methoxy-l, 5 (6H) - pyrimidinedicarboxylate (12.6 g, 22.86 mmol) in THF (150 mL) was added a solution of R- (+) -α-methyl benzylamine (3.53 mL, 27.44 mmol) at room temperature. The stirring was continued for 12 h and the solvent was removed in vacuo. The yellow residue was dissolved in chloroform (200 mL) and was washed with 10% K2C03 solution (2 x 30 mL) . The organic layer was dried over Na2S04, filtered and the solvent was removed in vacuo . The resulting mixture of diastereomers was separated by column chromatography over silica gel with 9:1 pet. ether: ether to 4:1 pet. ether:ether. First major product to elute was (+) -benzyl 6- (3, 4-difluorophenyl) -4-ethyl-2-methoxy- 1- ( { [ (li?) -1-phenylethyl] amino} carbonyl) -1, 6-dihydro-5- pyrimidinecarboxylate: Colorless oil, Rf= 0.31(4:1 pet ether:ether) ; wt.= 3.8 g (60% yield); [α] D = +267.05 (c = 0.76, CHC13); 1H NMR (CDC13) δ 1.22 (t, J=7.5 Hz, 3H) , 1.52 (d, J=6.9 Hz, 3H) , 2.88 (q, J=6.0 Hz, 2H) , 3.99 (s, 3H), 4.99 (m, IH) , 5.09 (ABq, 2H) , 6.66 (s, IH) , 6.99- 7.36 (m, 13H) ; The second major product to elute was (- ) -benzyl 6- (3, -difluorophenyl) -4-ethyl-2-methoxy-l- ( { [ (If?) -1-phenylethyl] amino} carbonyl) -1, 6-dihydro-5- pyrimidinecarboxylate: Colorless oil; Rf= 0.22 (4:1 pet ether:ether) ; wt . = 3.2 g (51.2% yield); [α]D = -146.89 (c = 0.38, CHC13); λ NMR (CDCI3) δ 1.22 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.6 Hz, 3H) , 2.88 (q, J=6.0 Hz, 2H) , 3.94 (s, 3H) , 5.03 (m, IH) , 5.11 (ABq/ 2H) , 6.68 (s, IH) , 6.91-7.34 (m, 13H) .
(+) -BENZYL 6- (3, 4-DIFLUOROPHENYL) -4-ETHYL-2-METHOXY-1, 6- DIHYDRO-5-PYRIMIDINECARBOXYLATE. Into a stirred solution of (+) -benzyl 6- (3, 4-difluorophenyl) -4-ethyl-2-methoxy- 1- ( { [ (li?) -1-phenylethyl] amino} carbonyl) -1, 6-dihydro-5- pyrimidinecarboxylate (17.1 mmol, 9.35 g) in CH2C12 was added 1, 8-diazabicyclo [5, 4 , 0] -undec-7-ene (17.1 mmol, 2.56 mL) and stirring was continued for 16 h at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 5.27 g of the (+) -benzyl 6- (3, 4-difluorophenyl) -4-ethyl-2- methoxy-1, 6-dihydro-5-pyrimidinecarboxylate was obtained (77% yield) .
(+) -5-BENZYL 1- (4-NITROPHENYL) 6- (3 , 4-DIFLUOROPHENYL) -4- ETHYL-2-METHOXY-l,5(6H)-PYRIMIDINEDICARBOXYLATE. Into a well-stirred solution of (+) -benzyl 6- (3, 4- difluorophenyl) -4-ethyl-2-methoxy-l, 6-dihydro-5- pyrimidinecarboxylate ( 6. 4 g, 16.0 mmol) and pyridine (1.5 mL) in CH2C12 (150 mL) was added 4-nitrophenyl chloroformate (3.41 g, 19.2 mmol) at room temperature. The reaction mixture was stirred for 4 h and then it was washed with 10% aqueous KOH solution (2 X 100 mL) . The organic layer was separated and dried over Na2S04. The solvent was removed in va cuo . The residue of (+)-5- benzyl 1- (4-nitrophenyl) 6- (3, 4-difluorophenyl) -4-ethyl- 2-methoxy-l, 5 (6ϋ) -pyri idinedicarboxylate was used in the next step without further purification.
a. 2- (4-METHOXYBENZYL) -2-THIOPSEUDOUREA HYDROCHLORIDE.
Into a well-stirred suspension of thiourea (7.6 g, 0.1 mol) in THF (50 mL) at 0 °C, 4-methoxybenzyl chloride (16 g, 0.1 mol) was added in 10 min and the reaction mixture was allowed to warm to room temperature. After 2 hours the reaction mixture was heated to 65 °C and kept at that temperature for 5 hours . The reaction mixture was cooled to room temperature and diluted with diethyl ether (200 mL) . The white precipitate that formed was filtered and dried (22.5 g, 96% yield); m. p. 161-163 °C .
b. METHYL 2- { (4-NITROPHENYL) ETHYLENE} -3-OXOBUTYRATE .
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g, 0.11 mol), piperidine
(0.41 g, 4.80 mmol), and acetic acid (0.288 g, 4.8 mmol) in 2-propanol (400 L) was stirred at room temperature for 48 hours. The resulting white solid, methyl 2-{(4- nitrophenyl) methylene } -3-oxobutyrate was filtered, washed with 2-propanol (2 X 50 mL) and dried (21.8 g, 93% yield) . c .
1 , 6-DIHYDRO-5-METHOXYCARBONYL-2- [ { (4-METHOXYPHENYL) METHY L}THIO] -4-METHYL-6- (4-NITROPHENYL) PYRIMIDINE.
A mixture of methyl 2- {( 4-nitrophenyl) ethylene} -3- oxobutyrate (8.96 g, 0.04 mol), 2- (4-methoxybenzyl) -2- thiopseudourea hydrochloride (9.28 g, 0.04 mol), and NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and heated at 70-75 °C for 4.5 hours. The reaction mixture was cooled to room temperature, poured into ice-water (300 mL) and extracted with EtOAc (2 X 400 L) . The combined EtOAc extracts were washed with 10% NaHC03 solution (2 X 60 L) , brine (100 mL) , and then dried (MgS04) . The solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10% through 30% EtOAc in hexane as the gradient eluent. The desired product was obtained as an oil, which on trituration • ith EtOAc/hexane became a yellow solid (11.4 g, 66.7% yield) which was shown by 1H NMR to be a mixture of tautomers : m.p. 138-139 °C; XH NMR (CDC13) δ 2.15 (s, 3 H), 3.62 (s, 3 H) , 3.72 (s, 3 H) , 4.05 and 5.78 (s and d, J=3 Hz, 1 H) , 4.08, 4.20 (AB q, J=12.5 Hz, 2 H) , 4.21 and 6.40 (s and d, J=3 Hz, 1 H) , 6.66 (2 d, J=8.5 Hz, 2 H) , 7.08 (2 d, J=8.5 Hz, 2 H) , 7.37 (2 d, J=8.8 Hz, 2 H) , 8.7 (2 d, J=8.8 Hz, 2 H) ; Anal. Calcd. for C21H21N305S: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.02; H, 4.93; N, 9.77.
d. 1 , 6-DIHYDRO-5-METHOXYCARBONYL-2- [ { (4-METHOXYPHENYL) METHYL} HIO] -4-METHYL-6- (4-NITROPHENYL) -1- [ (4-NITROPHENY LOXY) CARBONYL] YRIMIDINE .
Into a well-stirred mixture of 1, 6-dihydro-5-methoxy carbonyl-2- [ { (4-methoxyphenyl) methyl } thio] -4-methyl-6- (4 -nitrophenyl) pyrimidine (4.50 g, 10.5 mmol), NaHC03 (3.69 g, 0.044 mol), CH2C12 (200 L) , and water (50 mL) at 0-5 °C, 4-nitrophenyl chloroformate (2.40 g, 12.0 mmol) was added over a 5 min period and the reaction mixture was allowed to warm to room temperature. After 10 hours, the TLC analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, 0.0032 mol) was added and the stirring was continued for an additional 4 hours. The two layers were separated, the CH2C12 layer was washed with saturated aqueous NaHC03 solution (3 X 50 mL) , dried (MgS0 ) , and the solvent evaporated. The residue was recrystallized from CH2Clr and hexane to give the product as white crystals (5.50 g, 88.4% yield): m.p. 156-157 °C; ^-NMR (CDC13) δ 2.53 (s, 3 H) , 3.70 (s, 3 H) , 3.81 (s, 3 H) , 4.06, 4.36 (ABq, J=13.5 Hz, 2 H) , 6.30 (s, 1 H) , 6.78 (d, J=8.6 Hz, 2 H) , 7.17 (d, J=8.6 Hz, 2 H) , 7.20 (d, =8.8 Hz, 2 H) , 7.32 (d, J=8.8 Hz, 2 H) , 7.97 (d, J=8.8 Hz, 2 H) , 8.25 (d, J=8.8 Hz, 2 H) ; Anal. Calcd. for C28H24N409S : C, 56.75; H, 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.
a . 6- (BENZOFURAZAN-5-YL) -1 , 6-DIHYDRO-2-OXO-5- METHOXYCARBONYL-4-BROMOMETHYL-l- [ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE . Into a well-stirred solution of 6- (benzofurazan-5-yl) - 1, 6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-l- [ (4- nitrophenyl-oxy) carbonyl] pyrimidine (0.310 mmol, 0.140 g) in 1.5 mL of chloroform was added a solution of bromine (0.310 mmol, 0.020 L) in 1.5 mL of chloroform at 0 °C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in va cuo and the residue was again dissolved in CHCI3 (10 mL) and washed with brine. The organic layer was separated, dried over Na2S04, filtered and the solvent was removed in vacuo to obtain 0.15 g (88% yield) of 6- (benzofurazan-5-yl) -1, 6-dihydro-2-oxo-5-methoxycarbonyl- 4-bromomethyl-l- [ (4-nitrophenyl-oxy) carbonyl] pyrimidine as a yellow foam. The crude product was used in the next step without purification. 1H NMR (CDCI3) δ 3.79 (s, 3 H) , 4.72 (ABq, 2 H) , 6.47 (s, 1 H) , 7.37 (d, J=9.1 Hz, 2 H) , 7.51 (d, J=7.8 Hz, 1 H) , 7.80 (s, 1 H) , 7.92 (d, J=9.1 Hz, 1 H) , 8.30 (d, J=9.1 Hz, 2 H) .
c . 4-NITROPHENYL 4- (2 , 1 , 3-BENZOXADIAZOL-5-YL) -2 , 5-DIOXO- 1,2,5, 7-TETRAHYDROFURO[3 , 4-D] PYRIMIDINE-3 (4H) - CARBOXYLATE . 6- (3, 4-Benzofurazan-5-yl) -1, 6-dihydro-2-oxo-5-methoxy- carbonyl-4-bromomethyl-l- [ (4- nitrophenyloxy) carbonyl] pyrimidine (0.27 mmol, 0.15 g) was heated in oil bath for 3 h (bath temperature 130 °C . The brownish-yellow residue thus obtained was washed with CHCI3 and 4-nitrophenyl 4- (2, 1, 3-benzoxadiazol-5- yl) -2, 5-dioxo-l, 2,5, 7-tetrahydrofuro [3, 4-d] pyrimidine- 3 (4H) -carboxylate was obtained as an off-white solid which was used in the next step without further purification (crude wt . 0.11 g, 93% yield): XH NMR (DMSO- de) δ 8.38-7.56 (m, 7H) , 6.33 (s, IH) , 5.02 (s, 2H) ; Anal. Calc. for Cι9HιιN508+2.3H20: C, 47.85; H, 3.28; N, 14.63. Found: C, 47.73; H, 2.51; N, 14.77.
5-METHYL 1- (4-NITROPHENYL) 4- (BROMOMETHYL) -6- (3 , 4- DIFLUOROPHENYL) -2-OXO-3 , 6-DIHYDRO-l , 5 (2H) -
PYRIMIDINEDICARBOXYLATE: Into a well-stirred solution of 6- (3, 4-Difluorophenyl) -1, 6-dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-l- [ (4- nitrophenyloxy) carbonyl] pyrimidine (1.5 mmol, 0.66 g) in 5 L of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0 °C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHC13 (20 mL) and washed with brine. The organic layer was separated, dried over Na2S0 , 1 filtered and the solvent was removed in vacuo to afford the desired product as a yellow foam, which was used in the next step without purification. 1H NMR δ 3.75 (s, 3 H), 4.67 (ABq, 2 H) , 6.35 (s, 1 H) , 7.09-7.19 ( , 4 H) , 7.37 (d, J=9.0 Hz, 2 H) , 8.27 (d, J=9.0 Hz, 2 H) .
4-NITROPHENYL 4- (3 , 4-DIFLUOROPHENYL) -2 , 5-DIOXO-l ,2,5,7- TETRAHYDROFURO [3 , 4-D] PYRIMIDINE-3 (4ff) -CARBOXYLATE .
5-methyl 1- (4-nitrophenyl) 4- (bromomethyl) -6- (3, 4- difluorophenyl) -2-oxo-3, 6-dihydro-l, 5 (2if) - pyrimidinedicarboxylate (1.5 mmol, 0.81 g) was heated in an oil bath for 3 h (bath temperature 130 °C) . The brown residue thus obtained was washed with CHCI3 and the desired product was obtained as a pale brown solid which was used in the next step without further purification (crude wt . 0.51 g) : XH NMR (DMSO-d6) δ 4.94 (br s, 2 H) , 6.08 (s, 1 H), 7.20-7.43 (m, 4 H) , 8.35 (d, J=10.2 Hz, 2 H) .
4-NITROPHENYL 4- (1 , 3-BENZODIOXOL-5-YL) -2 , 5- DIOXOHEXAHYDROFURO [3 , 4-D] PYRIMIDINE-3 (4H) -CARBOXYLATE : XH
NMR (DMSO) δ 11.35- (s, IH) , 8.16 (d, 2H, J=9.5 Hz)', 7.32 „ _(.d ._2H J=8.9._Hz) ,._6.81-6.65 (m, 3H) , 5.88 (s,. lH.)-,__4-._8-5-
(ABq, 2H) ; ESMS m/e : 440.1 (M + H)+; Anal. Calc. for C20H15N3O9+I.5H2O: C, 51.29; H, 3.87; N, 8.97. Found: C, 51.38; H, 2.85; N, 8.73. 5-METHYL 1- (4-NITROPHENYL) (6S) -6- (3 , 4-D I FLUOROPHENYL) - 4-METHYL-2-OXO-3 , 6-DIHYDRO-l , 5 (2H) -
PYRIMIDINEDICARBOXYLATE: XH NMR (400 MHz, CDC13) δ 8.29 (d, 2H, J=9.1 Hz), 7.36 (d, 2H, J=8.9 Hz) , 7.25-7.11 (m, 3H) , 6.37 (s, IH), 3.75 (s, 3H) , 2.46 (s, 3H) ; ESMS m/e: 448.1 (M + H)+; Anal. Calc. for C20H15F2N3O7 : C, 53.70; H, 3.38; N, 9.39. Found: C, 53.35; H, 3.36; N, 9.27.
BENZYL
4-{ [ (TERT-BUTOXYCARBONYL) MINO] METHYL } CYCLOHEXYLCARBAMATE : Oxalyl chloride (1.1 equivalents) was added dropwise to a mixture of 4- [ [ (tert-butoxycarbonyl) -amino] ethyl] - cyclohexanecarboxylic acid (1 equivalent, Maybridge) in toluene. The reaction mixture was stirred at room temperature for 2-6 h. The solvent was removed in vacuo, the residue was dissolved in acetone and the resulting mixture was added dropwise to an aqueous solution of sodium azide (1.2 equivalents) at a rate such as to maintain a temperature of 10-15 °C . After the completion of the reaction, the reaction mixture was extracted with ethyl acetate, the combined extracts were dried and concentrated in vacuo. The residue was dissolved in acetone and added slowly to warm (60 °C) benzene. After the completion of the reaction, benzyl alcohol was added to the reaction mixture, stirred for 2 days and the desired product was isolated (For Typical References, See: G. Schroeter Ber . 1909, 42, 3356; and Allen, C.F.H.; Bell, A. Org. Syn. Coll. Vol. 3 (1955) 846.).
A solution of benzyl 4-{ [ (tert-butoxycarbonyl) amino] methyl }-cyclohexyl carbamate in MeOH containing 10% Pd/C was hydrogenated at 50 psi overnight. The reaction mixture was filtered through Celite 545 and the Celite 545 was washed with methanol. The combined methanol extracts were concentrated. in vacuo, giving trans- tert-butyl 4-aminocyclohexylmethylcarbamate (95 %).
9H-9-FLUORENYLMETHYL N- [4- (AMINOMETHYL) CYCLOHEXYL] CARBAMATE: : XH NMR δ 8.02 (br, 1 H) , 7.33 ( , 5 H) , 5.07 (s, 2 H) , 3.71 (s, 1 H) , 3.40 (br m, 1 H) , 2.80 (br m, 2 H) , 1.94 (ABq, 4 H) , 1.68 (br, 1 H) , 1.30-1.00 (m, 5 H) . Nl-[4-(AMINOMETHYL)CYCLOHEXYL]-l-NAPHTHAMIDE: HCl in dioxane (10 mL, 4 N) was added to a solution of tert- butyl [4- (1-naphthoyl-amino) cyclohexyl] methylcarbamate (0.350 g) in dichloromethane (20 L) , stirred overnight, concentrated in vacuo, giving the desired product: 1H NMR 58.24 (dd, 1 H, J=1.2, 8.7 Hz), 7.85 (dt, 2 H, J=2.7, 9.7 Hz), 7.60-7.30 (m, 4 H) , 5.98 (m, 1 H) , 4.02 (m, 1 H) , 3.80-3.40 (m, 4 H) , 2.53 (d, 2 H, J=6.0 Hz), 2.02 (ABq, 4 H) , 1.41-1.90 (m, 4 H) .
TERT-BUTYL N-(4-[ ( 1-NAPHTHYLCARBONYL) AMINO] - CYCLOHEXYLMETHYL) -CARBAMATE: A mixture of 1-naphthoic acid (1.00 mmol, 0.172 g) , DMAP (2.00 mmol, 0.250 g) and ECD (0.383 g, 2.00 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 0.5 h followed by the addition of tert-butyl (4-amino) cyclohexyl) ethylcarbamate amine (1.09 mmol, 0.250 g) . The reaction mixture was stirred at room temperature overnight and purified by flash chromatography, giving the desired product as a white solid (0.160 g) : lR NMR58.29 (dd, 1 H, J=1.8, 9.1 Hz), 7.89 ( , 2 H) , 7.60-7.40 (m, 4 H) , 5.85 (br d, 1 H, J=6.3 Hz), 4.65 (m, 1 H) , 4.04 (m, 1 H) , 3.02 (t, 1 H, J=6.3 Hz), 2.05 (ABq, 4 H) , 1.62 (m, 2 H) , 1.46 (s, 9 H), 1.40-1.10 (m, 4 H) .
4-ACETYL-l- (3-AMINOPROPYL) -4-PHENYLPIPERIDINE: A solution of 4-Acetyl-4-phenylpiperidine (7, 1.53 g, 7.50 mmol), 3-bromo-propylamine hydrobromide (1.64 g, 7.50 mmol) and potassium carbonate (1.24 g, 9.00 mmol) was stirred in refluxing 1,4-dioxane (50 mL) for 12 h. After removal of dioxane, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2C12 (100 L + 3 x 50 mL) . The combined organic solutions were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (EtOAc-MeOH-Et3N 100/40/20), giving the desired product as a colorless oil (780 mg, 40%) : XH
NMRδl.56 (p, J = 7 Hz, 2 H) , 1.84 (s, 3 H) , 1.98 (m, 2 H) , 2.15 (br t, J = 12 Hz, 2 H) , 2.29 (t, J = 7 Hz, 2 H) , 2.41 (br d, J = 12 Hz, 2 H) , 2.66 (t, J = 7 Hz, 4 H) ,
7.18 - 7.30 ( , 5 H) ; 13C NMR 5 26.28, 31.11, 33.43, 41.47, 51.62, 55.31, 57.19, 77.32, 77.74, 78.17, 126.95, 127.69, 129.44, 142.25, 210.15.
For the preparation of benzo-4 ' , 5 ' [H] furanpiperidine refer to W.E.Parham et al , J. Org . Chem . (1976) 41, 2268.
TERT-BUTOXY{ [3- (BENZO-4' ,5' [H] FURANPIPERIDIN-1-YL) PROPYL] AMINO}METHANOL: To a stirred solution of the N-[4-(benzo- ' , 5 ' [H] furanpiperidine (0.566 g, 3.27 mmol) in dioxane (20 mL) , N- (tert-butoxycarbonyl) -3-bromopropylamine (0.772 g, 3.27 mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added and the solution was refluxed for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5), giving the desired product as a colorless oil (0.856 g, 79 %) ; 1H NMR (1.45 (s, 9 H) , 1.63-2.04 (m, 6 H) , 2.33-2.52 (m, 4 H) , 2.87 (d, J=11.0 Hz, 2 H) , 3.2 (br s, 2 H) , 5.07 (s, 2 H) , 5.6 (br s, 1 H) , 7.13-7.28 (m, 4 H) .
3- (4-METHYL-4-PHENYL-1-PIPERDINYL) PROPYLAMINE: Trifluoroacetic acid (1 mL) was added to tert-butoxy{ [3- (4-methyl-4-phenyl-l-piperdinyl) propyl] -amino}methanol (0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted with dichloromethane (25 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.340 g (98%) of 3- (4-methyl-4- phenyl-1-piperdinyl) propylamine which was used without further purification in the subsequent step.
Procedures for the Reaction of the Amine Side Chains with the p-Nitrophenylcarbamate Intermediates:
General Procedure:
An equimolar solution of an amine side chain such as 3- ( 4-methyl-4-phenyl-l-piperdinyl) propylamine and a p-nitrophenylcarbamate intermediate such as 5-methoxycarbonyl-4-methoxymethyl- 1,2,3,6- tetrahydro-2-oxo-6- (3, -difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine and 1-2 equivalents of a base such as diisopropylethylamine in dichloromethane were stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography, giving the desired product. In case of 2-methoxy intermediates, conversion to the oxo derivatives was accomplished by treatment of the 2-methoxy product with HCl. in dioxane.
2-OXO-3-{SPIRO[lH-INDANE-l, ' -PIPERIDINE] PROPYLAMINE (0.03 19 g, 0.123 mmol) was added to (+)-6-(3,4 -difluorophenyl) -1, 6-dihydro- 2-methoxy-5- methoxycarbonyl-4-ethyl-l- (4-nitrophenoxy) carbonyl- pyrimidine (0.052 g, 0.112 mmol) in dry dichloromethane (10 mL) and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 6 N HCl (2 mL) . After neutralization with aqueous 10% KOH solution, the reaction mixture was extracted into dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving of the desired product (0.040 g) as a syrup.
1 N HCl in ether (5 mL) was added to the free base (0.040 g, 0.072 mmol) in dichloromethane (4 mL) and the solution was concentrated under reduced pressure. The crude product was recrystallized from ether, giving the desired compound (0.042 g, 99 %) as a pale yellow solid; mp 178-182 °C; Anal. Calcd. for C29H34F2N405C12 + 0.6 H20 : C, 57.87; H,5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95.
General Procedure for the reaction of the piperidines and piperazines with 1- (3-bromo-propylcarbamoyl) -6- (3 , - difluoro-phenyl) -4-methyl-2-oxo-l, 6-dihydro-pyrimidine- 5-carboxylic acid methyl ester:
The amine (0.15 mmol) was added to a solution of
1- (3-bromo- propylcarbamoyl) -6- (3, 4-difluorophenyl) -4- methyl-2-oxo-l, 6-di-hydropyrimidine-5-carboxylic acid methyl ester (43.0 mg, 0.100 mmol) in anhydrous acetone (10 mL), followed by NaHC03 (41 mg, 0.3 mmol) and KI (16 mg, 0.1 mmol) . The resulting suspension was heated to reflux for 10 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography (EtOAc, followed by EtOAc/MeOH, 9/1) . The product was then dissolved in 2 mL of chloroform, acetone or EtOAc and HCl in EtΞ0 (1 M, 0.5 mL) was added at room temperature. The solvent was removed in vacuo, giving the desired compound as an HCl salt . Ξxample 1
( -) -1 , 2 , 3 , 6-TETRAHYDRO-l- {N- [ 4- ( 3 , -ACETAMIDO) -PHENYL- PIPERIDIN-1- YL] PROPYL}CARBOXAMIDO-4-METHOXYMETHYL-6- (3,4- DIFLUORO-PHENYD-2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: ESMS, 612.25 (M+l); XH NMR δ 1.76-1.87 ( ,
6H) , 2.03-2.13 (m, 2H) , 2.18 (s, 3H) , 2.49 (t, J=6.9 Hz, 3H), 3.10 (d, J=ll.l Hz, 2H) , 3.30-3.42 (m, 2H) , 3.45 (s, 3H) , 3.71 (s, 3H) , 4.68 (s, 2H) , 6.68 (s, IH) , 6.96 (d, J=7.5 Hz, IH) , 7.04-7.11 (m, 2H) , 7.16-7.26 (m, 2H) , 7.34 (d, J=6.3 Hz, IH) , 7.45 (s, IH) , 7.94 (s, IH) , 8.98 (t, J=5.4 Hz, IH) .
Example 2 METHYL 3-[ (3-4- [3- (ACETYLAMINO) PHENYL] -1, 2 , 3 , 6-
TETRAHYDRO-1-PYR-IDINYLPROPYL) AMINO] CARBONYL-4- (3,4- DIFLUOROPHENYL) -6- (METHOXY-METHYL) -2-OXO-l, 2, 3, 4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: ^ NMRδδ.θO (t, 1 H, J=3.6 Hz), 7.75 (s, 1 H) , 7.50-7.00 ( , 8 H) , '6.68 (s, 1 H) , 6.03 (br s, 1 H) , 4.67 (s, 2 H) , 3.71 (s, 3 H) , 3.47 (s, 3 H) , 3.38 (ABrn, 2 H) , 3.16 (m, 2 H) , 2.71 (t, 2 H, J =5.4 Hz), 2.56 (m, 4 H) , 2.35-1.90 (br, 2 H) , 2.17 (s, 3 H) , 1.82 (p, 2 H, J=7.2 Hz); ESMS, 612.25 (M+l).
Example 3
(1) -1,2, 3, 6-TETRAHYDRO-l- {N- [3- (4-O-ACETYL) -4-PHENYLPIPER IDIN-1- YL] PROPYL}CARBOXAMIDO-5-METHOXYCARBONYL- 4-METHOXYMETHYL-6- (3, 4- DIFLUOROPHENYL) -2-OXOPYRIMIDINE : 4-Acetyl-l- (3-aminopropyl) - 4-phenylpiperidine (190 mg, 0.687 mmol) was added to a stirring solution of 5-methoxy carbonyl-4-methoxymethyl- 1,2,3, 6-tetra-hydro-2-oxo- 6- (3, 4-difluorophenyl) -1- [ -(4-nitrophenyloxy) carbonyl] pyrimidine (281 mg, 0.573 mmol) in dry dichloromethane (3 mL) and THF (4 mL) . The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with aqueous 6 N HCl . The reaction mixture was concentrated to a small volume, partitioned between dichloromethane and water (100 mL each) , the mixture was adjusted to pH 8 by addition of Na2C03, the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 30 mL) . The combined organic extracts were dried (Na2S04) and the product was chromatographed, giving the desired product. The HCl salt was prepared by the addition of 1 N HCl in ether to a solution of the product in CH2C12. The precipitated salt was filtered, washed with ether and dried in vacuo, giving (1) -1, 2, 3, 6-tetrahydro-l-{N- [3- (4-0-acetyl) -4- phenylpiperidin-1-yl] propyl } carboxamido-5-methoxycarbonyl-4- methoxymethyl-6-
( 3 , -dif luorophenyl ) -2-oxopyrimidine ( 170 mg, 47 % ) as the hydrochloride salt : ( C31H36N4F207 + HCl + 0 . 6 CH2C12 ) ; mp 82 - 84 °C .
Example 4
Benzyl ester precursor to the product of Example 4 : ( +)-l,2,3, 6-TETRAHYDR0-l-{N- [4- (BENZO-4' ,5' (H) FURAN) PIPER IDIN-1- YL] PROPYL} -CARBOXAMIDO-4-ETHYL-6- (3, 4- DIFLUOROPHENYL) -2-OXO- PYRIMIDINE-5- CARBOXYLIC ACID PHENYLMETHYL ESTER: 1H NMR δ 7.60-7.00 (m, 12 H) , 6.85 (br, 1 H) , 6.62 (s, 1 H) , 5.10 (ABq, 2 H) , 5.67 (s, 2 H) , 4.03 (br, 1 H) , 4.01 (s, 3 H) , 3.40 (apparent q, 2 H, J=6.8 Hz), 3.20-1.60 (m, 12 H) , 2.86 (q, 2 H, J=2.5 Hz), 1.19 (t, 3 H, J=7.5 Hz) .
(+)-l,2,3, 6-TETRAHYDRO-l- {N- [4- (BENZO-4' ,5' (H) FURAN) PIPER
IDIN-1-YL] PROPYL}-CARBOXAMIDO-4-ETHYL-6- (3, 4-
DIFLUOROPHENYL) -2-OXO- PYRIMIDINE-5 CARBOXYLIC ACID
HYDROCHLORIDE: XH NMR δ 8.95 (br s, 1 H) , 8.22 (br s, 1 H) , 7.40-6.95 (m, 7 H) , 6.95 (s, 1 H) , 6.63 (s, 1 H) , 5.10-4.95 (m, 2 H) , 3.40-3.20 (m, 4 H) , 3.10-2.80 (m, 4 H) , 2.55-2.20 (m, 1 H) , 2.15 (m, 1 H) , 1.85 (m, 2 H) , 1.55-1.30 (m, 4 H) , 1.20 (t, 3 H, J=7.6 Hz) ; Anal. Calc. For C29H32N405F2 + HCl + 1.5 H20: C, 56.36; H, 5.87; N,
8.06. Found: C, 56.72; H, 6.11; N, 7.61.
Example 5
1,2,3, 4-TETRAHYDRO-1-OXO-2-NAPHTHACETIC ACID METHYL ESTER: Under argon, α-tetralone (5.00 g, 34.2 mmol) in dry THF (300 mL) was treated with LDA in THF (2 M, 18.8 mL) at -78 °C . The solution was stirred at -78 °C for 1 h. Methyl bromoacetate (15.7 g, 0.103 mole) was then added to the solution, the mixture was stirred overnight and allowed to warm to room temperature . The solvent was evaporated and the residue was dissolved into CHC13 (300 L) , washed with water and saturated brine, and then dried over Na2S04. After filtration and removal of solvent, the residue was vacuum distilled. The product, a colorless oil (7.21 g, 96.5%) was collected at 180 °C/1 mm Hg; XH NMR ( 400 Mhz) δ 1.98 (m, IH) , 2.25 ( , IH) , 2.44 (m, IH) , 2.90-3.20 (m, 4H) , 3.73 (s, 3H) , 7.10-8.10 ( , 4H) ; El mass spectrum M+ at m/z 218.
l-HYDROXY-2- (2-HYDROXYETHYL) -1,2,3, 4-TETRAHYDRONAPHTHALEN E: A solution of 1, 2 , 3, 4-tetrahydro-l-oxo-naphthacetic acid methyl ester (6.15 g, 28.2 mmol) in THF (150 mL) was treated with LiAlH4 (2.82 g, 70.5 mmol) and then the reaction mixture was heated at reflux temperature for 5 h. The suspension was cooled to 0 °C and quenched by addition of solid Na2SO4-10 H20, The mixture was stirred at room temperature for 4 hrs . The solid was removed by filtration and concentration of the filtrate in vacuo gave a yellow oil (5.33 g, 98.3%); XH NMR indicated the formation of an isomeric mixture. El mass spectrum M+ at m/z 192. The mixture was directly used in next reaction without further purification.
2- ( 2-HYDROXYETHYL) -1 , 2 , 3 , 4-TETRAHYDRO-1-OXO-NAPHTHALENE : A solution of isomeric mixture of l-hydroxyl-2- (2-hydroxyethyl) - 1, 2, 3, 4-tetrahydronaphthalene (3.00 g, 15.6 mmol) in CH2C12 (100 mL) was treated with Mn02 (20.4 g, 0.234 mole) . The suspension was stirred at room temperature for 16 h and the solids were removed by filtration. Concentration of the filtrate in vacuo gave a brown oil, which was further purified by flash chromatography (MeOH/ CHC13 , 5/95), giving a yellow oil (2.00 g, 67.4%): XH NMR δ 1.76 ( , IH) , 1.98 (m, IH) , 2.21 (m, 2H) , 2.57 (br, IH) , 2.70 (m, 2H) , 3.20 (m, 2H) , 3.81 (m, 2H) , 7.00-8.20 (m, 4H) ; CI mass spectrum (M+l)+ at m/z 191.
2- (2-BROMOETHYL) -1 , 2 , 3 , 4-TETRAHYDRO-l-OXONAPHTHALENE : A solution of 2- (2-hydroxethyl) -1, 2 , 3, 4-tetrahydro-
1-oxo-naphthalene (2.00 g, 10.5 mmol) in CH2C12 (100 mL) was treated with PBr3 (948 mg, 3.50 mmol) at 0 °C. The mixture was stirred at room temperature for 72 h and then poured onto 100 g of ice. The organic layer was separated, washed with aqueous 10% K2C03 solution, H20, saturated NaCl and dried over Na,S04. After filtration and removal of the solvent, the residue was purified by chromatography (EtOAc/hexane, 1/10), giving a yellow oil
(1.18 g, 44.4%); NMRδl.49 (m, 2 H) , 2.24 (m, IH) , 2.60 (m, IH) , 2.75 (m, IH) , 3.03 (m, 2H) , 3.64 (m, 2H) , 7.10-8.10 (m, 4H) ; EIMS M+ m/z 223, M/M+2=l : 1.
2- [2- (4-BENZAMINO-l-PIPERIDYL) ETHYL] -1 , 2 , 3 , 4-TETRAHYDRO-l -OXO- NAPHTHALENE: A mixture of 2- (2-bromoethyl) - 1, 2 , 3, 4-tetrahydro-l-oxonaphthalene (1.18 g, 4.66 mmol), 4-benzamidopiperidine (952 mg, 4.66 mmol) and K2C03 (1.29 g, 9.32 mmol) in acetone (200 mL) was stirred at room temperature for 48 h. The solids were removed by filtration. Concentration of filtrate in vacuo gave a yellow solid which was purified by chromatography (MeOH: CHC13, 5/95) . The product was recrystallized from an EtOAc/hexane mixture, giving a white powder (268 mg,
15.3%); mp 158-159 °C; XH NMR δ 1.53 (m, 2H) , 1.67 (m, IH) , 1.91 (m, IH) , 2.02 (m, 2H) , 2.21 (m, 4H) , 2.50 (m, 3H) ,
2.95 (m, 4H), 4.01 (m, IH) , 5.95 (d, J=8.0 Hz, IH) ,
7.20-8.10 (m, 9H) ; CI MS (M+l) +m/z 377; Anal. Calcd for
C24H28N202 : C , 7 6 . 55 ; H . 7 . 51 ; N , 7 . 44 . Found : C , 7 6 . 28 ; H ,
7.46; N, 7.37.
Example 6
METHYL
4- (2,l,3-BENZOXADIAZOL-5-YL) -3- [ ( 1- [4- (DIBUTYLAMINO) -
BENZYL] -4-PIPERIDYLMETHYL) MINO] CARBONYL-6-METHYL-2-OXO-1 ,2,3,4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: XH NMR δ 7.72 (dd, 1 H, J=0.6, 9.6 Hz), 7.70-7.50 ( , 2 H) , 7.11 (d, 2
H, J=8.7 Hz), 6.59 (d, 2 H, J=8.7 Hz), 5.90 (s, 1 H) ,
3.94 (s, 3 H) , 3.63 (s, 2h) , 3.24 (t, 4 H, J=7.8 Hz), 2.80 (m, 2 H) , 2.49 (d, 2 H, J=6.3 Hz), 2.38 (s, 3 H) , 2.90-1.00 (m, 5 H) , 1.54 (p, 4 H, J= 7.8 Hz), 1.35 (sextet, 4 H, J=7.8 Hz), 0.94 (t, 6 H, J=7.8 Hz).
Example 7
(+) -1,2, 3, 6-TETRAHYDRO-l- {N- [4- (N' -ETHYL) -N-BENZIMIDAZOLY L- PIPERIDIN-lYL]PROPYL}CARBOXAMIDO-4-METHYL-6-(3,4-
DIFLUOROPHENYL) - 2-OXOPYRIMIDINE HYDROCHLORIDE: 1H NMR 5
8.95 (t, 1 H, J=3.6 Hz), 7.61 (b, 1 H) , 7.60-6.95 (m, 7 H) , 6 . 69 (s, 1 H) , 4.36 (m, 1 H) , 3.94 (q, 2 H, J=7.2 Hz), 3.72 (s, 3 H) , 3.42 (ABm, 4 H) , 3.30 (m , 2 H, 4.76 (m, 4 H) , 2.43 (s, 3 H) , 2.13 (m, 2 H) , 1.77 (m, 4 H) , 1.33 (t, 3 H, J=7.2 Hz) .
Example 8 6- (BENZOFURAZAN-5-YL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBONY L-4- METHYL-2-OXO-l-{N- [3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] }CARBOXAMIDO-PYRIMIDINE: A solution of 6- (benzofurazan- 5-yl) -1, 6-dihydro-2- methoxy-5-methoxycarbonyl- 4 -methyl-1- {N- [3- (4-phenylpiperidin-l- yl) propyl] } carboxamidopyrimidine in MeOH was treated with 6 N HCl at 0 °C . The solution was stirred at room temperature for 2 h and the MeOH was removed in vacuo. 6- (Benzofurazan-5-yl) - 1,2,3, 6-tetrahydro- 5-methoxycarbonyl-4-methyl-2-oxo-1- {N- [3- (4- phenylpiperidin-1-yl) propyl] } carboxamidopyrimidine hydrochloride was obtained as a white powder: mp 134-137 °C.
Example 9 4- (3-METHOXY) -PHENYL PIPERIDINE: HCl salt; mp 150-154 °C; lR NMR52.04 (s, br, 2H) , 2.25 (s, br, 2H) , 2.80 (s, br, IH) , 3.09 (s, br, 2H) , 3.66 (s, 2H) , 3.78 (s, 3H) , 6.79 (s, br, 3H) , 7.23 (s, IH) , 9.41 (s, br, IH) . Anal. Calcd. For C12H18N0C1 + 0.30 CH,C12 : C, 58.34; H, 7.40; N, 5.53. Found: C, 58.30; H, 7.71; N, 5.35.
(+) -1, 2, 3, 6-TETRAHYDRO-l-N- [4- (3-METHOXY) -PHENYL} -PIPERID IN-1- YL]-PROPYL-CARBOXAMIDO-4- METHOXYMETHYL-6- (3,4- DIFLUOROPHENYL) - 2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 80-84 °C; [α]D = +94.7, (c = 0.25, MeOH); XH NMR
51.74-1.84 (m, 6H) , 1.99-2.09 (m, 2H) , 2.38-2.51 (m, 3H) , 3.03 (d, J=ll.l Hz, 2H) , 3.24-3.43 (m, 2H) , 3.48 (s, 3H) , 3.71 (s, 3H) , 3.80 (s, 3H) , 4.72 (s, 2H) , 6.68 (s, IH) , 6.72-6.84 (m, 3H) , 7.05-7.11 (m, 2H) , 7.15-7.27 (m, 2H) , 7.72 (s, IH) , 8.84 (t, J=5.4 Hz, IH) . Anal. Calcd. For C30H37N4O6F,Cl : C, 57.8; H, 6.0; N, 9.0. Found: C,
57.61; H, 6.57; N, 6.97.
Example 10
(+) -1, 2, 3, 6-TETRAHYDRO-l- {N- [4- (3, -ACETAMIDO) -PHENYL-PIPE RIDIN-1-YL] PROPYL } CARBOXAMIDO-4-METHOXYMETHYL-6- (3, 4-DIFL UORO-PHENYL) -2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 135-138 °C; [α]D = +105.5, (c = 0.11, MeOH); ESMS, 614.25 (M+l); λR NMR δ 1.76-1.87 (m, 6H) , 2.03-2.13 ( , 2H) , 2.18 (s, 3H) , 2.49 (t, J=6.9 Hz, 3H) , 3.10 (d, J=ll.l Hz, 2H) , 3.30-3.42 .(m, 2H) , 3.46 (s, 3H) , 3.71 (s, 3H) , 4.68 (s, 2H) , 6.68 (s, IH) , 6.96 (d, J=7.5 Hz, IH) , 7.04-7.11 (m, 2H) , 7.16-7.26 (m, 2H) , 7.34 (d, J=6.3 Hz, IH) , 7.45 (s, IH) , 7.94 (s, IH) , 8.97 (t, J=5.4 Hz, IH) ; ESMS, M+l 614.25
The compound of Example 10 may also be prepared via hydrogenation of the compoun of example 2 (H2 balloon method, methanol, Pd/C, overnight) . A synthetic path analogous to the latter route (Scheme 11) was used in the preparation of the tritiated analog, which in turn, was used as a radioligand in the MCH pharmacological assays.
Example 11
3- ( 4-PHENYLPIPERIDIN-l-YL) PROPIONITRILE : Acrylonitrile (3.1 L, 44 mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.00 g, 18.0 mmol) in EtOH (40 mL) and the mixture was stirred at room temperature for 1.5 h. The volatiles were removed, giving 3.80 g of the desired product (brown oil, 99%) .
3- (4-PHENYLPIPERIDIN-l-YL) PROPYLAMINE: A solution of BH3 in THF (1.0 M, 83.0 mL, 83.0 mmol, 3.5 eq) was added to a stirring solution of 3- (4-phenylpiperidin-l-yl) - propionitrile (5.10 g, 24.0 mmol) in anhydrous THF (20 mL) under argon at room temperature. The mixture was heated at reflux temperature for 4.5 hours and then cooled to room temperature. Aqueous 6 N HCl (130 mL) was added and stirring was continued for 2 hours at 50-70 °C . The mixture was basified to pH 9 by addition of aqueous 6 N NaOH and extracted with EtOAc (100 mL) and CH2C12 (3 x 100 L) . The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was dissolved in CH2C12 (20 mL) and treated with HCl in ether (1.0 M, 50 mL) . The solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water { 60 mL) was added to the resulting white solid, 1 N NaOH was added until pH 10-11 was reached, and then the aqueous phase was extracted with CH2C12 (3 X 50 mL) . The combined extracts were dried over magnesium sulfate and the solvents were evaporated, giving the desired product (4.50 g, 87%) .
6-(3,4-DIFLOUROPHENYL) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBON YL-4- METHYL-2-OXO-l-{N-[3- (4-PHENYLPIPERIDIN-l-YL) PROPYL] }CARBOXAMIDO-PYRIMIDINE: A solution of 6- (3, 4- difluorophenyl) -1, 6-dihydro- 2-methoxy-5-methoxy carbonyl-4-methyl-l- {N- [3- (4-phenyl-piperidin- 1-yl) propyl] } carboxamidopyrimidine (100 mg, 0.185 mmol, mp = 43-45 °C) in MeOH (5 mL) was treated with aqueous 6 N HCl (1.5 mL) at 0 °C . The solution was stirred at room temperature for 2 hrs and MeOH was removed in vacuo . 6- (3, 4-Diflourophenyl) - 1, 2, 3, 6-tetrahydro- 5-methoxycarbonyl-4-methyl-2-oxo-l- {N- [3- (4- phenylpiperidin-1-yl ) propyl] } carboxamidopyrimidine hydrochloride was obtained as a white powder (89 mg, 86%) . p 133-136 °C . Example 12
3-{ (3, 4, 5-TRIFLUOROPHENYL) METHYLENE} -2, 4-PENTANEDIONE: A stirring mixture of 3, 4 , 5-trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2, -pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol) in benzene (150 mL) was heated at reflux temperature (equipped with a Dean-Stark trap) for 8 h. The benzene was evaporated, the yellow oily residue, 2- { (3, 4 , 5-trifluorophenyl) -methylene} -2 , 4- pentanedione, was used in the next step without further purification.
6- (3, 4, 5-TRIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-ACETYL- 4- METHYLPYRIMIDINE: A stirring mixture of 2-{ (3,4,5- trifluoro-phenyl) methylene} -2 , 4-pentanedione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHC03 (6.60 g, 78.6 mmol) in EtOH (400 mL) was heated at 95-100 °C for 6 h. The mixture was filtered, the solid residue was washed with ethanol (100 mL) . The solvent was evaporated from the combined filtrates and the crude product was purified by flash column chromatography
(EtOAc/hexane, 9/1 to 4/1), giving the desired product as an oil (2.80 g, 36%) .
6- (3, 4,5-TRIFLUOROPHENYL) -1, 6-DIHYDRO-2-METHOXY-5-ACETYL- 4- METHYL-l-[ (4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE: 4-Nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added to a solution of 6- (3, 4 , 5-trifluorophenyl) - 1, 6-dihydro-2-methoxy-5-acetyl-4- methylpyrimidine (2.80 g, 9.38 mmol) and pyridine (10 mL) in CH2C12 (200 mL) at 0-5 °C and then the mixture was allowed to warm to room temperature. After 12 h, the solvent was evaporated and the residue was purified by flash chromatography (CH2Cl,/EtOAc, 9/1 to 20/3) , giving the desired product as a white powder (4.0 g, 92%). 6- (3, 4,5-TRIFLUOROPHENYL) -1,2,3, 6-TETRAHYDRO-2-OXO-5-ACET YL-4- METHYL-l-[ ( 4-NITROPHENYLOXY) CARBONYL] PYRIMIDINE : Aqueous 6 N aqueous HCl (4 mL) was added to a stirring solution of 6- (3, 4 , 5-trifluorophenyl) -1, 6-dihydro- 2-methoxy-5-acetyl-4- methyl-1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (4.0 g, 8.63 mmol) in THF (100 L) at 0-5 °C, and the mixture was allowed to warm to room temperature. After 2 h, the solvent was evaporated and the product was dried under vacuum, giving the desired product as a pure single component which was used in the next step without further purification (3.88 g, 100%).
(+)- 1,2,3,6- TETRA HYDRO-1- {N- [4- ( 4-FLUOROPHENYL) - PIPERIDINE- 1-YL] - PROPYL} CARBOXAMIDO- 5- ACETYL- 2- OXO-6- ( 3,4 ,5-TRI FLUORO PHENYL)- 4- METHYL PYRIMIDINE HYDROCHLORIDE: XH NMR δ 7.20-6.86 (m, 6 H) , 6.64 (s, 1 H) , 5.56 (s, 1 H) , 3.70-3.80 (m, 2 H) , 3.43-3.35 (m, 2 H) , 3.19-2.98 (m, 2 H) , 2.40 (s, 3 H) , 2.28 (s, 3 H) , 2.50-1.60 (m, 8 H) .
Example 13
Nl-[4- ( [4- (DIBUTYLAMINO) BENZYL] AMINOMETHYL) CYCLOHEXYL] -1- NAPHTH-AMIDE: lR NMR δ 8.26 (dd, 1 H, J=2.1, 7.2 Hz), 7.87 (m, 2 H) , 7.51 (m, 2 H) , 7.40 (apparent t, 1 H, J=7.8 Hz), 7.17 (d, 1 H, J=8.7 Hz), 6.61 (d, 2 H, J=8.7 Hz), 5.94 (d, 1 H, J=8,l Hz), 4.04 (m, 1 H) , 3.76 (m, 1 H) , 3.63 ( , 2 H) , 3.21 (t, 4 H, J=7.6 Hz average), 2.53 (d, 2 H, J=6.7 Hz), 2.10, ABm, 4 H) , 1.55 (p, 4 H, J=7.7 Hz average), 1.34 (sept, 4 H, J=7.6 Hz average), 1.17 ( , 4 H) , 0.95 (t, 6 H, J=7.6 Hz average).
Example 14
(+) -1,2,3, 6-TETRAHYDRO-l-{N-[4- (1-NAPHTHYL) -PIPERIDIN-1-Y L] PROP-YL} CARBOXAMIDO-4- METHOXYMETHYL-6- (3,4- DIFLUOROPHENYD-2-OXO-PYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 168-172 °C; [α]D = +94.7, (c = 0.25, MeOH) ; λE
NMRδ 1.75-1.84 ( , 2H) , 1.87-2.01 (m, 4H) , 2.14-2.28 ( , 2H) , 2.47 (t, J=7.2 Hz, 2H) , 3.10 (d, J=ll.l Hz, 2H) , 3.28-3.45 (m, 3H) , 3.48 (s, 3H) , 3.71 (s, 3H) , 4.68 (s, 2H) , 6.70 (s, IH) , 7.05-7.12 (m, 2H) , 7.16-7.24 (m, IH) , 7.42-7.54 (m, 4H) , 7.69-7.75 (m, 2H) , 7.85 (d, J=11.4 Hz, IH) , 8.09 (d, J=ll.l Hz, IH) , 8.91 (t, J=5.4 Hz, IH) .
Example 15
4- (5-FLUORO-2-METHOXY) PHENYL PIPERIDINE: mp 254-258 °C; λR NMRδ 1.53-1.68 (m, 2H) , 1.79 (d, J=11.7 Hz, 2H) , 2.12 (dt, J=2.1 Hz, J=11.7 Hz, IH) , 2.77 (dt, J=l .8 Hz, J=12.3 Hz, IH) , 2.90-3.05 (m, IH) , 3.10-3.22 (m, 2H) , 3.68 (s, IH) , 3.79 (s, 3H) , 6.72-6.93 (m, 3H) . Anal. Calcd. For
Cj.2H17NOFCl + 0.14 CH2C12: C, 56.60; H, 6.76; N, 5.44. Found: C, 56.60; H, 6.92; N, 5.28.
(+) -1,2,3, 6-TETRAHYDRO-l- {N- [4- (5-FLUORO-2-METHOXY) PHENYL PIPERI-DIN-l-YL]PROPYL}CARBOXAMIDO-4- METHOXYMETHYL-6-
(3, 4-DIFLUORO-PHENYL) -2-OXOPYRIMIDINE-5-CARBOXYLIC ACID
METHYL ESTER: lR NMRδ 8.93 (t, 1 H, J=5.4 Hz) , 7.76 (br, 1 H) , 7.30-6.69 (m, 7 H) , 4.69 (s, 2 H) , 3.79 (s, 3 H) , 3.71 (s, 3 H) , 3.48 (s, 3 H) , 3.38 (m, 2 H) , 3.10-2.80 (m, 3 H) , 2.42 (t, 2 H, J=7.2 Hz) , 2.07 (dt, 2 H, J=3.0,
8.4 Hz) , 2.00-1.60 (m, 6 H) .
Example 16
(+)-l,2,3, 6-TETRAHYDRO-l- {N- [ 4-HYDROXY-4- (2-PYRIDYL) -PIPE RIDIN-1-YL] PROPYL } CARBOXAMIDO- - METHOXYMETHYL-6-
(3, 4-DIFLUOROPHENYL) -2- OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp 132-135 °C; [ ]D = +94.7, (c = 0.25, MeOH); λR NMRδl.47 (d, J=11.7 Hz, 2H) , 1.74-1.85 (m, 2H) , 2.43-2.63 (m, 9H) , 2.87 (d, J=10.2 Hz, 2H) , 3.30-3.47 (m, 2H) , 3.49 (s, 3H) , 3.71 (s, 3H) , 4.69 (s, 2H) , 6.69 (s, IH) , 7.04-7.21 (m, 4H) , 7.49 (dd, J=0.6 Hz, J=6.9 Hz, IH) , 7.72 (s, br, IH) , 8.36 (dd, J=1.2, 4.8 Hz, IH) , 8.89 (t, J=5.4 Hz, IH) .
Example 17
1- (3-AMINOPROPYL) -4- [2-PYRIDYL] PYRIDINIUM BROMIDE
HYDROBROMIDE: A solution. of 2 , 4 ' -dipyridyl (25.0 g, 160 mmol) and 3-bromopropyl-amine hydrobromide (35.0 g, 160 mmol) in DMF (60 mL) was heated at 90-95 °C for 10 h.
After cooling to room temperature, anhydrous ether (500 mL) was added to the mixture, the resulting white solid was filtered, washed with Et20 and dried, giving 1- (3-aminopropyl) -4- [2-pyridyl] pyridinium bromide hydrobromide (60 g, 100%)). ^ NMR (DMSO-d6) δ 2.35-2.44 (m, 2 H) , 3.08-3.13 (m, 2 H) , 4.76-4.81 (m, 2 H) , 7.58 (dd, J=4.8 Hz, J=7.5 Hz, 1 H) , 8.03 (dt, J=l .8 Hz, J=7.8
Hz, 1 H) , 8.32 (d, J=7.8 Hz, 1 H) , 8.77-8.81 (m, 3 H) , 9.12 (d, J=6.3 Hz, 2 H) . Anal. Calcd. for C13H16N3Br + HBr
+ 0.5 H20: C, 40.65; H, 4.72; N, 10.94. Found: C, 40.83;
H, 4.37; N, 11.05.
3- (3 ' , 6'-DIHYDR0-2'-H- [2, ' ] BIPYRIDINYL-1 ' -YL) -PROPYLAMIN E: NaBH4 (2 g, 53 mmol) in small portions was added to a solution of 1- (3-aminopropyl) -4- [2-pyridyl] pyridinium bromide hydrobromide (6 g, 16 mmol) in MeOH (150 mL) at 0-5 °C over a period of 2 h. The reaction mixture was stirred overnight at room temperature and then the solvent was evaporated. The residue was suspended in ether (200 mL) and treated' ith aqueous 50% NaOH solution (100 mL) . The ether layer was separated and the aqueous layer was extracted with additional ether (2 X 50 mL) . The combined ether extracts were dried over potassium carbonate and the solvent was removed, giving 3- (3' , 6 ' -dihydro-2' -H- [2, 4' ] bipyridinyl-1 ' -yl) - propylamine (3.48 g) as an oil. The crude product was used in the next step immediately without further purification.
3-AMINOPROPYL-4- (2-PYRIDYL) PIPERIDINE: A suspension of 3- (3 ' , 6 ' -dihydro-2 ' -H- [2, 4 '' ] bipyridinyl-1 ' -yl) -propylamin e (3.48 g crude, 15.9 mmol) and Pearlman's catalyst (1.0 g) in MeOH (40 mL) was hydrogenated under 120 psi for 10 h, after which the reaction mixture was filtered through a pad of Celite and the solvent was removed. The residue was purified by column chromatography over silica gel (30 g) [Note: If a large excess of silica gel is used the recovery of the product will be very low] (CH2Cl2/methanol/2M NH3 in MeOH, 90/8/4 to 90/40/40) . The product was obtained as a pale yellow oil (3.21 g, 91%) . λR NMRδ (CD3OD) 1.50-1.99 ( , 10 H) , 2.02-2.06 (m, 2 H) , 2.37-2.75 (m, 3 H) , 3.02-3.06 (br m, 2 H) , 7.05-7.09 (m, 4 H) , 7.16 (dt, J=0.9 Hz, J=8.7 Hz, 1 H) , 8.48 (dd, J=0.9 Hz, J=4.2 Hz, 1 H) .
Part II
(+) -6- (3, 4-DIFLUOROPHENYL) -1-[N- [4- (2-PYRIDYL) PIPERIDIN-1 -YL]- PROPYL] }CARBOXAMIDO-5-METHOXYCARBONYL-4-METHOXYMETHYL-2-0 XO- 1,2,3, 6-TETRAHYDR0PYRIM1DINE DIHYDROCHLORIDE
5-METHOXYCARBONYL-4-METHOXYMETHYL-1, 2, 3, 6-TETRAHYDRO-2-OX 0-6- (3, 4-DIFLUOROPHENYL) -PYRIMIDINE: Copper (I) oxide (5.06 g, 0.035 mole) and acetic acid (2.05 mL) were added sequentially to a stirring solution of methyl 4-methoxyacetoacetate (50.0 g, 0.351 mol), 3 , 4-difluorobenzaldehyde (51.4 g, 0.351 mmol), and urea (31.6 g, 0.527 mole) in THF (300 mL) at room temperature, followed by dropwise addition of boron trifluoride diethyl etherate (56.0 L, 0.456 mole). The mixture was stirred at reflux temperature for 8 h, whereupon TLC (1/1 EtOAc/hexanes) indicated completion of the reaction. The reaction mixture was cooled and poured into a mixture of ice and sodium bicarbonate (100 g) and the resulting mixture was filtered through Celite. The Celite pad was washed with dichloromethane (400 mL) . The organic layer was separated from the filtrate and the aqueous layer was extracted with more dichloromethane (3 X 300 mL) . The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes, l/l;then ethyl acetate), giving the desired product as a pale yellow foam. The foam was triturated with hexanes, giving a white powder (103.3 g, 94%). XH NMRδ3.476 (s,
3H) , 3.651 (s, 3H), 4.653 (s, 2H) , 5.39 (s, IH) , 6.60 (br s, IH, NH) , 7.00-7.20 (m, 3H) , 7.72 (br s, IH, NH) .
( +) -5-METHOXYCARBONYL-4-METHOXYMETHYL-1 , 2,3, 6-TETRAHYDRO- 2-0X0-6- (3, 4-DIFLUOROPHENYL) -PYRIMIDINE: The racemic intermediate 5-methoxycarbonyl- -methoxymethyl- 1,2,3, 6-tetrahydro-2-oxo-6- (3, 4-difluorophenyl) pyrimidine was resolved by chiral HPLC [Chiralcel OD 20 X 250 mm #369-703-30604; lambda 254 nm; hexanes/ethanol 90/10 ; 85 mg per injection; retention time of the desired enantiomer: 16.94 min., the first enantiomer peak to elute], giving (+) -5-methoxycarbonyl-4- methoxymethyl-1, 2,3,6- tetrahydro-2-oxo-6- (3,4- difluorophenyl) -pyrimidine (40-42 wt% isolation of the desired enantiomer from the racemate) ; [ ]D = +83.8 (c = 0.5, chloroform).
(+)-5-METHOXYCARBONYL-4-METHOXYMETHYL-l,2,3, 6-TETRAHYDRO- 2-0X0-6- (3, 4-DIFLUOROPHENYL) -1- [ (4-NITROPHENYLOXY) CARBONY L] PYRIMIDINE : A solution of lithium hexamethyldisilazide in THF (IM, 18.0 mL, 18.0 mmol) was added over 2-3 min. to a solution of (+) -5-methoxycarbonyl-4-methoxymethyl- 1,2,3, 6-tetrahydro-2-oxo-6- (3, 4-difluorophenyl) -pyrimidin 5 e (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at -78 °C under argon atmosphere and the mixture was stirred for 10 min. The resulting solution was added over 6 min., via a cannula, to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at -78
10 °C . The mixture was stirred for an additional 10 min. and the mixture was poured onto ice (50 g) and extracted with chloroform (2 X 50 mL) . The combined extracts were dried (sodium sulfate) and the solvent evaporated. The residue was purified by flash chromatography (hexanes/ethyl
15 acetate, 4/1 to 3.5/1), giving the product as a yellow syrup, which on trituration with hexanes became a white powder (2.40 g, 79%). iH NMRδ3.52 (s, 3H) , 3.74 (s, 3H) , 4.65-4.80 (q, J=16.5 Hz, 2H) , 6.32 (s, IH) , 7.10-7.30 (m, 4H) , 7.36 (d, J=9 Hz, 2H) , 8.27 (d, J=9 Hz, 2H) .
20
(+) -6- (3, 4-DIFLUOROPHENYL) -1-{N- [4- (2-PYRIDYL) PIPERIDIN-1 -YL] -PROPYL] } CARBOXAMIDO-5-METHOXYCARBONYL-4- METHOXYMETHYL-2-OXO- 1,2,3, 6-TETRAHYDROPYRIMIDINE DIHYDROCHLORIDE: A solution of (+) -5-methoxycarbonyl-
25 4-methoxymethyl-l, 2,3, 6-tetrahydro-2-oxo-6- (3, 4-difluorop henyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (2.38 g, 5 mmol), 3-aminopropyl-4- (2-pyridyl) piperidine (1.21 g, 5.5 mmol) in THF (20 mL) was stirred at room temperature for 12 h. The solvent was evaporated and the residue was
30. re-dissolved in ethyl acetate (100 mL) . The resulting solution was washed with ice-cold 1 N NaOH (4 X 50 mL) , brine (2 X 50 mL) and dried over potassium carbonate. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (dichloromethane/MeOH/2
35 M ammonia in MeOH, 980/10/10 to 940/30/30 ) , giving a clean fraction of the desired product (2.45 g, 88%) as a foam and a slightly impure fraction (0.30 g, 10%) . 1H NMR 51.60-2.00 (m, 6H) , 2.05-2.15 (m, 2H) , 2.38-2.43 (br t, 2H) , 2.65-2.80 (m, IH) , 3.05-3.06 (br d, 2H) , 3.30-3.45 (m, 2H) , 3.48 (s, 3H) , 3.704 (s, 3H) , 4.68 (s, 2H) , 6.68 (s, IH) , 7.05-7.20 (m, 5H) , 7.58-7.63 (dt, IH) , 7.70 (s, IH, NH) , 8.50-8.52 (dd, IH) , 8.88 (br t, IH) .
The HCl salt was prepared by treatment of a solution of the free base in ether with 1 N HCl in ether. The white powder was dried under reduced pressure: 1H NMRδ 2.05-2.20 (m, 4H) , 2.77-2.88 (m, 2H) , 3.00-3.20 ( , 4H) , 3.35-3.47 (m, 2H) , 3.47 (s, 3H) , 3.64-3.70 (m, 2H) , 3.71 (s, 3H) , 4.05 (br t, IH) , 4.67 (s, 2H) , 6.59 (s, IH) , 7.05-7.20 (m, 3H) , 7.79 (t, IH) , 8.00 (d, IH) , 8.43 (dt, IH) , 8.96 (br t, IH, NH) , 12.4 (br s, IH) . m.p. 188-191
°C; [ ]D = +141.13 (c = 0.265, MeOH); Anal. Calcd. for C28H34N505F2C1 + 0.6 H20:C, 52.36; H, 5.84; N, 10.90. Found: C, 52.24; H, 5.96; N, 10.80. (Note: NMR analysis of this product did not show the presence of any water. However, it was noted by the lab that performed the elemental analysis that this sample gains weight during handling by absorbing water from the atmosphere) .
Example 18
( 1 ) -1 , 2 , 3 , 6-TETRAHYDRO-l- {N- [ 4- ( ISOBENZOFURAN) PIPERIDINE-
1-YL] -PROPYL} CARBOXAMIDO-5-METHOXYCARBONYL-2-OXO-
6- (3, 4-BENZOFURAZAN)- 4-METHYLPYRIMIDINE HYDROCHLORIDE
4- (3, 4-BENZOFURAZAN) -6-METHYL-2-OXO-3- { [3- ( 4-SPIRO [ISOBEN ZO-FURAN-1 (3H) , 4 ' -PIPERIDINE] PROPYL} -1, 2 , 3, 4- TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER : 1- (3-Aminopropyl) -4- spiro [iso-benzofuran-1 (3H),4'- piperidine] (0.028 g, 0.110 mmol) was added to (+) -6- (benzofurazan) -1, 6-dihydro-2-methoxy- 5-methoxycarbonyl-4-methyl-l- (4-nitrophenoxy) carbonylpyri midine (0.047 g, 0.100 mmol) in dry dichloromethane (10 L) and the solution was stirred at room temperature for 24 h. Aquesous 6 N HCl (2 mL) was added to the reaction mixture which was stirred for another 1 h. The reaction mixture was basified with aqueous 10% KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving the desired product (41.0 mg, 73 %) as a syrup: λR NMR δ 1.76-1.81 (m, 7 H) , 1.94-2.04 (m, 6 H) , 2.32-2.48 (m, 1 H) , 2.83 (d, J=10.6 Hz, 2 H) , 3.36-3.43 (m, 2 H) , 3.75 (s, 3 H) , 5.05 (s, 2 H) , 6.83 (s, 1 H) , 7.07-7.27 (m, 4 H) , 7.54 (d, J=9.5 Hz, 1 H) , 7.69 (s, 1 H) , 7.78 (d, J=9.5 Hz, 1 H) , 8.85 (d, J=5.2 Hz, 1 H) .
HCl in ether (1 N, 5 mL) was added to the free base
(0.041 g, 0.073 mmol) in dichloromethane (4 mL) , and the solution was concentrated under reduced pressure. The product was recrystallized from ether, giving the hydrochloride salt as a pale yellow solid (42.0 mg, 96 %) ; mp 180-182 °C; Anal. Calcd. for C29H34N606C1 + 0.5 moles
H20: C, 57.47; H, 5.65; N, 13.87. Found: C, 57.42; H, 5.71; N, 13.70.
Example 19 2- (3, 4-DIFLUOROPHENYL) 4 , 5-DIHYDROIMIDAZOLE-l-CARBOXYLIC
ACID {3- [4-PHENYL-4- (4-BROMO-5-METHYLTHIOPNEN-2-YL) ] -PROPYL} -AMIDE: Anal. Calcd. for C30H30N4O5ClF3 + HCl + 1.5 H20: C, 55.26; H, 6.03; N, 8.59. Found: C, 55.29; H, 5.95; N, 8.39. Example 20
4- (3, 4-DIFLUORPHENYL) -6-METHYL-2-OXO-3- { [ 3- ( 4-SPIRO [ ISOBE NZO-FURAN-1 (3H) ,4 ' -PIPERIDINE] PROPYL} -1, 2 , 3, 4- TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER For the preparation of the ether piperidine precursor of the compound of Example 20, refer to W.E.Parham et al , J. Org. Chem . (1976) 41, 2268.
1-TERT-BUT0XYCARB0NYL-3- (4-SPIRO [ISOBENZOFURAN-1 (3H) , 4 ' - PIPERIDINE] ) PROPYLAMINE: N- ( tert-utoxycarbonyl) -3-bromopropylamine (0.772 g, 3.27 mmol) and potassium carbonate (0.904 g, 6.54 mmol) were added to a stirring solution of the amine (0.566 g, 3.27 mmol) in dioxane ( 20 mL) and the reaction mixture was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5), giving the desired product (0.856 g, 79 %) as a colorless oil; λR NMRδ 1.45 (s, 9 H) , 1.63-2.04 (m, 6 H) , 2.33-2.52 (m, 4 H) , 2.87 (d, J=11.0 Hz, 2 H) , 3.2 (br s, 2 H) , 5.07 (s, 2 H) , 5.6 (br s, 1 H) , 7.13-7.28 (m, 4 H) .
3- (4-SPIRO[ISOBENZO-FURAN-l (3H) , ' -PIPERIDINE] ) PROPYLAMINE: Trifluoroacetic acid (1 L) was added to 1-tert-butoxycarbonyl 3- (4-spiro [isobenzo-furan- 1 (3H) , 4 ' -piperidine] ) propylamine (0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, neutralized with 10 % KOH solution and extracted into dichloromethane (25 L) . The organic layer was dried over sodium sulfate, filtered and concentrated, giving the desired amine (0.340 g, 98%) which was used in the subsequent step without further purification.
4- (3, -DIFLUORPHENYL) -6-METHYL-2-OXO-3-{ [3- (4-SPIRO [ISOBE NZO-FURAN-1 (3H) , 4 ' -PIPERIDINE] PROPYL} -1, 2 , 3, 4- TETRAHYDROPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: 3- (4-spiro [isobenzo-furan-1 (3H) , 4 ' -piperidine] ) propylamine (0.0319 g, 0.123 mmol) was added to (+) -6- (3, 4-Difluorophenyl) -1, 6-dihydro- 2-methoxy-5- methoxycarbonyl-4-methyl-l- (4-nitrophenoxy) carbonylpyrimi dine (0.052 g, 0.112 mmol) in dry dichloromethane (10 mL) and the solution was stirred at room temperature for 24 h. Aqueous 6 N HCl (2 mL) was added and the reaction mixture was stirred for an' additional 1 h. After neutralization with 10% aqueous KOH solution, the reaction mixture was extracted with dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving the desired product (0.040 g, 64 %) as a syrup; lH-NMRδ 1.73-1.78 (m, 7 H) , 1.93-2.04 (m, 2 H) , 2.33-2.48 (m, , 6 H) , 2.83 (d, J=11.8 Hz, 2 H) , 3.35-3.41 (m, 2 H) , 3.71 (s, 3 H) , 5.06 (s, 2 H) , 6.75 (s, 1 H) , 7.04-7.26 (m, 7 H) , 8.82 (t, J=5.1 Hz, 1 H) .
A solution of 1 N HCl in ether (5 mL) was added to the free base (0.040 g, 0.072 mmol) in dichloromethane (4 L) and the solution was concentrated in vacuo . The product was recrystallized from ether, giving the dihydrochloride as a pale yellow solid (0.042 g, 99 %); mp 178-182 °C; Anal. Calcd. for C29H34F2N405C12 + 0.6 H20: C, 57.87; H, 5.73, N 9.31. Found: C, 58.11; H 5.90; N 8.95. Example 21
1,2,3, 6-TETRAHYDRO-l- {N- [ 4- ( DIHYDROINDENE) -1-YL } PROPYL } CA RBOXAMIDO-5-METHOXYCARBONYL- 2-0X0-6- (3, 4-BENZOFURAZAN) - 4-METHYLPYRIMID-INE
For the preparation of the indane piperidine precursor of the compound of Example 21, refer to M.S. Chambers J. Med. Chem . (1992) 35,2033.
N- (tert-butoxycarbonyl) 3- (4-spiro [isobenzo-furan-
1(3H),4'- piperidine] ) propylamine (1.10 g, 4.64 mmol) and potassium carbonate (1.17 g, 8.44 mmol) were added to a stirring solution of the amine (0.790 g, 4.22 mmol) in dioxane (20 ml) , and the resulting solution was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (40 mL) and water (5 L) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5), giving the desired product (0.886 g, 61 %) as a colorless oil; •LH NMRδ 1.46 (s, 9 H) , 1.55 (d, J = 11.3 Hz, 2 H) , 1.69 (t, J = 6.3 Hz, 2 H) , 1.88-2.47 (m, 6 H) , 2.47 (t, J = 6.3 Hz, 2 H) , 2.88 (t, J = 3.3 Hz, 4 H) , 3.23 (d, J = 5.6 Hz, 2 H) , 5.85 (br s, 1 H) , 7.18 (s, 4 H) .
Trifluoroacetic acid (1 ml) was added to 1-tert- butoxycarbonyl-3- (4-spiro [isobenzo-furan-1 (3H) , 4 ' - piperidine] ) propylamine ( 0.180 g, 0.52 mmol) in dichloromethane (5 ml) and the resulting solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into dichloromethane (25 ml) . The organic layer was dried over sodium sulfate, filtered and concentrated, giving propylamine (0.156 g, 100%) which was used in the subsequent step without further purification .
(±) -4- (3, 4-BENZOFURAZAN) -6-METHYL-2-OXO-3- { SPIRO [IH-INDAN E-l, 4 ' -PIPERIDINE] PROPYL} -1 , 2 , 3 , 4-TETRAHYDROPYRIMIDINE-5- CARBOXYLIC ACID METHYL ESTER HYDROCHLORIDE: To (+) -4- (3, 4-benzofurazan) -1, 6- dihydro-2-methoxy-5- methoxycarbonyl-4-methyl-l- (4-nitrophenoxy) - carbonylpyrimidine (0.059 g, 0.126 mmol) in dry dichloromethane (10 mL) , 1- (3-aminopropyl) spiro [lH-indane-1, 4 ' - piperidine] (0.062 g, 0.252 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted with dichloromethane (3 x 10 mL) . The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 0.070 g (100%) of the desired product as a syrup: XH NMRδ 1.51 (d, J=12.5 Hz, 2 H) , 1.76-2.08 (m, 4 H) , 2.12 (t, J=10.3 Hz, 2 H) , 2.45 (s, 5 H) , 2.86-2.91 (m, 4 H) , 3.30-3.45 (m, 2 H) , 3.75 (s, 3 H) , 6.83 (s, 1 H) , 7.02 (br s, 1 H) , 7.0 (m, 4 H) , 7.54 (d, J=9.6 Hz, 1 H) , 7.69 (s, 1 H) , 7.78 (d, J=9.2 Hz, 1 H) , 8.84, (t, J=5.2 Hz, 1 H) .
To the free base (0.070 g, 0.125 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution was concentrated under reduced pressure. Recrystallization from ether gave 0.088 g (100 %) of (+) -4- (3, 4-benzofurazan) -6-methyl-2-oxo-3- { spiro [lH-indan e- 1,4' -piperidine] propyl } -1, 2, 3, 4-tetrahydro- pyrimidine-5-carboxylic acid methyl ester hydrochloride as a white solid: m.p. 155-157 °C; Anal. Calcd. for C30H36N6O5Cl : C , 57 . 12 ; H , 5 . 76 ; N , 13 . 33 . Found : C , 57 . 40 ; H , 5 . 96 ; N , 13 . 02 .
Example 22 (+) -1,2, 3, 6-TETRAHYDRO-l- (N- [4- (BENZO-4' ,5' (H) FURAN) PIPER IDIN-1- YL] PROPYL } CARBOXAMIDO-4-ETHYL- 6- (3, 4- DIFLUOROPHENYL) -2-OXO- PYRIMIDINE-5-CARBOXAMIDE HYDROCHLORIDE: DMAP • ECD (0.250 mmol, 0.050 g) was added to a stirred mixture of (+) -1, 2, 3, 6-tetra-hydro-l- {N- [4- (benzo-4 ' , 5 ' (h) furan) piperidin-1-yl] propyl} carbox- amido-4-ethyl-6- (3, 4-difluorophenyl) -2-oxo-pyrimidine-5-c arboxyl-ic acid hydrochloride (0.100 mmol, 0.055 g) and N-methylmorpholine (0.330 mL) in dry dichloromethane (10 mL) . The resulting mixture was stirred at room temperature for 1 h and quenched with NH3. The reaction mixture was stirred at room temperature overnight, concentrated and chromatographed, giving the desired product. The HCl salt was prepared by the addition of HCl in ether to a solution of the product in dichloromethane, followed by evaporation of the solvents. Anal. Calc. For C29H33N504 F2 + HCl + 0.7 CHC13 : C, 52.96;. H, 5.29; N, 9.40. Found: C, 52.81; H, 5.69; N, 8.97.
Example 23 (1) -1,2,3, 6-TETRAHYDRO-l-{N-[4- ( 3 , 4-DIHYDRO-2-OXOSPIRO- NAPHTHALENE-1 (2H) ) -PIPERIDINE-1-YL] PROPYL} CARBOXAMIDO-5- METHOXYCARBONYL-2- 0X0-6- ( 3 , 4-BENZOFURAZAN) -4- METHYLPYRIMIDINE HYDROCHLORIDE
1- (3-TERT-BUTOXYCARBONYLAMINOPROPYL) SPIRO [ISOCHROMAN-3 , 4 ' PIPERIDIN] -1-ONE: To a stirred solution of spiro [piperidine- , 1 ' -tetralin] To a stirred solution of spiro [isochroman-3, 4 ' -piperidin] -1-one (K.Hashigaki et al . Chem . Pharm . Bull . (1984) 32, 3568.) (0.587 g, 2.58 mmol) in dioxane ( 20 mL) , N-(tert- butoxycarbonyl) - 3-bromopropylamine (0.615 g, 2.84 mmol) and potassium carbonate (0.714 g, 5.17 mmol) were added and the solution was refluxed for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5) to yield 0.465 g (47 %) of the desired product as a colorless oil; αH N Rδl.45 (s, 9 H) , 1.64-2.18 (m, 7 H) , 2.45-2.84 (m, 6 H) , 3.19-3.95 (m, 4 H) , 6.01 (br s, 1 H) , 7.13-7.26 ( , 3 H) , 7.42 (d, J=7.7 H) .
Step B. 1- (3-AMINOPROPYL) SPIRO [ISOCHROMAN-3 , 4 ' PIPERIDIN] -1-ONE : To 1- (3-tert-Butoxycarbonylaminopropyl) spiro [isochroman-3, 4 ' -piperidin] -1-one (0.144 g, 0.375 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid , was added and the solution stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.110 g (100%) of the product which was used as such for the subsequent step.
(+) -4- (3, 4-BENZOFURAZAN) -6-METHYL-2-OXO-3- { (SPIRO [ ISOCHRO MAN- 3,4' -PIPERIDIN] -1-ONE) PROPYL} -1, 2 , 3, 4- TETRAHYDROPYRIMIDINE-5- CARBOXYL-IC ACID METHYL ESTER: To (+) -4- (3, 4-Benzofurazan) -1, 6- dihydro-2-methoxy- 5-methoxycarbonyl-4-methyl-l- (4-nitrophenoxy) - carbonylpyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry dichloromethane, spiro [isochroman-3, 4 'piperidin] -1-one (44.0 mg, 0.173 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 50.0 mg (100%) of the desired product as a syrup: XR NMR δ 1.67-2.13 (m, 8 H) , 2.45 (m, 5 H) , 2.70 (t, J=7.4 Hz, 2 H) , 2.72-2.75 (m, 2 H) , 3.19 (t, J=7.4 Hz, 2 H) , 3.34-3.45 (m, 2 H) , 3.75 (s, 3 H) , 6.82 (s, 1 H) , 6.87 (s, 1 H) , 7.13-7.44 (m, 3 H) , 7.54 (d, J=9.6 Hz, 1 H) , 7.43 (d, J=7.4 Hz, 1 H) , 7.69 (s, 1 H) , 7.79 (d, J=9.6 Hz, 1 H) , 8.87 (t, J=5.2 Hz, 1 H) .
To the free base (50.0 mg, 0.084 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution concentrated under reduced pressure. Recrystallization from ether gave 30.0 mg (86 %) of the product as a white solid : m . p . 165-167 °C ; Anal . Calcd . for C31H36N606C1 + 1 . 5 H20 : C , 57 . 81 ; H , 5 . 95 . Found : C , 57 . 75 ; H , 5 . 91 .
Example 24
(1) -1,2,3, 6-TETRAHYDRO-l- {N- [4- (3, 4-DIHYDRO-2-OXOSPIRO- NAPHTHALENE-1 (2H) ) -PIPERIDINE-1-YL] PROPYL} CARBOXAMIDO-5-M ETHOXY-CARBONYL-2- OXO-6- (3, 4-DIFLUOROPHENYL) -4-METHYLPYRIMIDINE
(±)-4- (3, 4-DIFLUOROPHENYL) -6-METHYL-2-OXO-3- { (SPIRO [ISOCH ROMAN- 3,4' PIPERIDIN] -1-ONE) PROPYL } -1 , 2 , 3 , 4-TETRAHYDRO- PYRIMIDINE-5- CARBOXYLIC ACID METHYL ESTER: To
(±) - - (3, 4-Difluorophenyl) - 1, 6-dihydro-2-methoxy~5- methoxycarbonyl-4-methyl-l- (4-nitrophen-oxy) carbonyl- pyrimidine (40.0 mg, 0.0865 mmol) in 10 mL of dry dichloromethane, spiro [isochroman-3 , 4 ' piperidin] -1-one (44.0 mg, 0.173 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 45.0 mg (90%) of (+) -4- (3, 4-difluorophenyl) - 6-methyl-2-oxo-3- { (spiro- [ isochroman-3, 4 'piperidin] -1-one) propyl} -1,2,3, 4-tetrahyd ropyrimi-dine-5-carboxylic acid methyl ester as a syrup; XH NMRδ 1.75-1.94 (m, 9H) , 2.05-2.13 (m, 4 H) , 2.36-2.41 (m, 5 H) , 2.70 (t, J=7.35 Hz, 2 H) , 2.77 (m, 2 H) , 3.19 (t, J=7.4 Hz, 2 H) , 3.39-3.43 (m, 2 H) , 6.69 (s, 1 H) , 7.04-7.45 (m, 8 H) , 8.82 (t, J=5.2 Hz, 1 H) .
To the free base (45.0 g, 0.077 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution was concentrated in vacuo . Recrystallization from ether gave 0.050 g (100%) of (+) -4- (3, 4-difluorophenyl) -6-methyl-2-oxo-3- { (spiro- [isochroman-3, 4 'piperidin] - 1-one) propyl} -1, 2 , 3, 4- tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride as a white solid: m.p. 150-152 °C; Anal. Calcd. for C31H38F2N40C1 + 2 H,0: C, 56.49; H,5.96. Found: C, 56.40; H, 5.95.
Example 25
5- [ (Z) -1- (l-ETHYL-2, 2, -TRIMETHYL-l, 2-DIHYDRO-6-QUINOLINY L) -METHYLIDENE] -2-THIOXO-l, 3-THIAZOLAN-4-ONE Example 26
1-[BIS (4-FLUOROPHENYL) METHYL] -4- (3-PHENYL-2-PROPENYL) PIPE RAZINE
Example 27
4-[ (4-IMIDAZO[l,2-A]PYRIDIN-2-YLPHENYL)IMINO]METHYL-5-MET HYL-1, 3-BENZENEDIOL
Example 28 1- [3- (4-CHLOROBENZOYL) ] PROPYL-4-BENZAMIDOPIPERIDINE
Preparation of
1- [3- (4-chlorobenzoyl) propyl] -4-benzamidopiperidine
1- [3- (4-CHLOROBENZOYL) PROPYL] -4-BENZAMIDOPIPERIDINE: A mixture of 3- ( 4-chlorobenzol) propyl bromide (640 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2C03 (1.01 g, 7.34 mmol) in 50 ml of acetone was heated at reflux temperature for 48 h. The cooled reaction mixture was filtered to remove the solids, concentrated in vacuo, giving a yellow solid, which was purified by chromatography (MeOH/CHCl3, 5/95) . The product (320 mg , 33.9%) was isolated as a white powder: 1H NMR 51.46 (dq, Jl=1.0 Hz, J2=8.4 Hz, 2H) , 1.90-2.10 (m, 4H) , 2.16 (m, 2H) , 2.43 (t, J=6.9 Hz, 2H) , 2.80-2.90 ( , 2H) , 2.97 (t, J=6.9 Hz, 2H) , 3.97 (m, IH) , 5.92 (d, J=7.8 Hz, IH, N-H) , 7.40-8.00 (m, 9H) . The product was converted to the HCl salt and recrystallized from MeOH/Et20, m.p. 243-244 °C; Anal. Calcd for C22H25C1N,02 + HCl + H,0 : C, 60.15; H, 6.37; N, 6.37; Found: C, 60.18; H, 6.34; N, 6.29.
Example 29
4- [4- (4-CHLOROPHENYL) -4-HYDR0XY-1-PIPERIDINYL] -1- (4-CHLOR OPHEN-YL) -1-BUTANONE Example 30
N-METHYL- 8 - [ 4 - ( 4 - FLUOROPHENYL ) - 4 -OXOBUTYL ] - 1 - PHENYL- l , 3 , 8 -TRI -AZASPIRO- [ 4 . 5 ] DECAN- 4 -ONE
Example 31
1H-1,2,3-BENZ0TRIAZ0L-1-YL (2-NITROPHENYL) SULFONE
Example 32
( 1 ) -1 , 2 , 3 , 6-TETRAHYDRO-l- {N- [ 4- ( DIHYDROINDENE ) -1-YL } PROPY L}-
CARBOXAMIDO-5-METHOXYCARBONYL-2-OXO-6- ( 3 , 4-DIFLUORO) -4-ME THYL-PYRIMIDINE
1- (3-TERT-BUTOXYCARBONYLAMINOPROPYL) SPIRO [1H-INDANE-1 , 4 ' - PIPERIDINE] : To a stirred solution of spiro [lH-indane- 1, 4 ' -piperidine] (M. S . Chambers et al . J. Med. Chem . (1992) 35, 2033.) (0.790 g, 4.22 mmol) in dioxane (20 mL) , N- (tert-butoxy-carbonyl) -3-bromopropylamine (1.1 g, 4.64 mmol) and potassium carbonate (1.17 g, 8.44 mmol) were added and the resulting solution was heated at reflux temperature for 24 h. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL of chloroform and 5 mL of water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate/ methanol, 4.5/0.5) to yield 0.886 g (61 %) of the required product as a colorless oil: λR NMRδ 1.46 (s, 9 H) , 1.55 (d, J=11.3 Hz, 2 H) , 1.69 (t, J=6.3 Hz, 2 H) , 1.88-2.47 (m, 6 H) , 2.47 (t, J=6.3 Hz, 2 H) , 2.88 (t, J=3.3 Hz, 4 H) , 3.23 (d, J=5.6 Hz, 2 H) , 5.85 (br s, 1 H) , 7.18 (s, 4 H) .
1- (3-AMINOPROPYL) SPIRO [1H-INDANE-1, 4 '-PIPERIDINE] : To 1- (3-tert- Butoxycarbonylaminopropyl) spiro [lH-indane- 1, 4 ' -piperidine] (0.180 g, 0.52 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10 % KOH solution and extracted into 25 mL of dichloromethane.
The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.156 g (100%) of the product which was used as such for the subsequent step.
(+) -4- (3, 4-DIFLUORO) -6-METHYL-2-OXO-3- { SPIRO [ 1H-INDANE-1 , 4 '-PIPERIDINE] PROPYL} -1, 2 , 3 , 4-TETRAHYDROPYRIMIDINE-5-CARB OXYLIC ACID METHYL ESTER: To (+) -4- ( 3, 4-difluoro) 1 , 6- dihydro-2-methoxy- 5-methoxycarbonyl- 4-methyl-l- ( 4-nitrophenoxy) carbonylpyrimidine (50.0 g, 0.108 mmol) in 10 mL of dry dichloromethane, l-(3- aminopropyl) spiro [IH-indane-l, 4 ' -piperidine] (53.0 mg, 0.216 mmol) was added and the solution was stirred at room temperature for 24 h. The reaction mixture was stirred for another 1 h after addition of 2 mL of 6N HCl. The reaction mixture was basified with 10% aqueous KOH solution (pH = 9) and extracted into dichloromethane (3 x 10 mL) . The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (EtOAc/ MeOH, 4.5/0.5), giving 60.0 mg (100%) of the product as a syrup: 1H NMRδ 1.52 (d, J=13.2 Hz, 2 H) , 1.70-2.07 (m, 8 H) , 2.12 (t, J=10.3 Hz, 2 H) , 2.42 (s, 4 H) , 2.86-2.91 (m, 3 H) , 3.32-3.43 (m, 2 H) , 3.72 (s, 3 H) , 6.71 (s, 1 H) , 6.81 (br s, 1 H) , 7.04-7.19 (m, 7 H) , 8.82 (t, J=5.2 Hz, 1 H) .
To the free base (0.060 g, 0.108 mmol) in 4 mL of dichloromethane, 5 mL of 1 N HCl in ether was added, and the solution was concentrated under reduced pressure. Recrystallization from ether gave 0.070 g (100%) of the product as a white solid; rrt. p. 150-153 °C; Anal. Calcd. for C30H36F2N4O6Cl : C , 54 . 86 ; H, 5 . 53 ; N, 8 . 54 . Found : C , 54 . 96 ; H , 5 . 57 ; N , 8 . 27 .
Example 33
(+) -1, 2, 3, 6-TETRAHYDRO-l- {N- [4- (3 , 4 , 5-TRIFLUORO) -PHENYL-P IPER-IDIN-1-YL] PROPYL} CARBOXAMIDO-4- METHOXYMETHYL-6- (3,4- DIFLUOROPHENYL)-2-OXOPYRIMIDINE-5-CARBOXYLIC ACID METHYL ESTER: mp °C; [α]D = +123.0, (c = 0.15, MeOH); lR NMRδ 1.70-1.82 (m, 6H) , 1.97-2.08 (m, 2H) , 2.40 (t, J=6.9 Hz, 2H) , 2.74-2.87 (m, IH) , 3.01 (d, J=ll.l Hz, 2H) , 3.29-3.40 (m, 2H) , 3.49 (s, 3H) , 3.71 (s, 3H) , 4.69 (s, 2H) , 6.68 (s, IH) , 6.88-6.95 (m, 2H) , 7.05-7.11 ( , 2H) , 7.15-7.22 (m, IH) , 7.71 (s, IH) , 8.90 (t, J=5.4 Hz, IH) .
Example 34
(+)-l,2,3, 6-TETRAHYDRO-l- {N- [2- (S) -METHYL) -4- (2-NITROPHEN YL) -PIPERAZIN-1YL] PROPYL} -CARBOXAMIDO-4-METHYL-6- (3,4- DIFLUOROPHEN-YL) -2-OXO-PYRIMIDINE
(S)- (+)-3-METHYL-l-(2-NITROPHENYL) -PIPERAZINE: To a solution of 2-bromonitrobenzene (0.600 g, 3.00 mmol) in 1,4-dioxane (15 L) was added (S) - (+) -2-methylpiperazine (0.500 g, 0.500 mmol) and powdered K2C03 (15.0 mmol, 1.50 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was removed in vacuo . The resulting residue was purified by column chromatography (1/1 hexane/EtOAc followed by 4/1 EtOAc/MeOH) , giving
(S) -(+) -3-methyl-l- (2-nitrophenyl) -piperazine as an orange oil (0.53 g, 80%) .
(+)-l,2,3, 6-TETRAHYDRO-l- {N- [2- (S) -METHYL) -4- (2-NITROPHEN YL) PIPERAZIN-IYL] PROPYL} -CARBOXAMIDO-4-METHYL-6- (3, 4-DIFL UOROPHENYL) -2-OXO-PYRIMIDINE: To a solution of (+)-l-(3- bromo-propylcarbamoyl) - 6- (3, 4-difluorophenyl) -4-methyl- 2-oxo-l, 6-dihydro-pyrimidine-5- carboxylic acid methyl ester (0.200 g, 0.500 mmol) and (S) - (+) -3-methyl-l- (2- nitrophenyl) -piperazine (0.170 g, 0.750 mmol) in 20 mL of anhydrous acetone was added powdered K2C03 (0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated at reflux temperature for 10 h. TLC indicated a new spot for the product (Rf = 0.3, 3/0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography (EtOAc/MeOH, 5/1). (+)-l, 2,3,6- Tetrahydro-1- {N- [2- (S) -methyl) -4- (2-nitrophenyl) piperazin -1-yl] -propyl} -carboxamido-4-methyl-6- (3,4- difluorophenyl) -2-oxo-pyr-imidine was obtained as yellow oil (0.030 g, 10% yield) . The HCl salt was prepared by the addition of HCl in ether to a solution of the product in dichloromethane, followed by evaporation of the solvents; mp 150-153 °C; [α]D = 58.3 (c = 0.3, MeOH); XH NMR (CD3OD)d 1.04 (d, J=6.0 Hz, 3 H) , 1.71-1.78 (m, 2 H) , 2.33-2.49 (m, 3 H) , 2.42 (s, 3 H) , 2.55-2.92 (m, 5 H) , 3.00-3.10 (m, 3 H) , 3.34 -3.42 (m, 2 H) , 3.72 (s, 3 H) , 6.71 (s, 1 H) , 7.01-7.32 ( , 6 H) , 7.46 (dt, J=0.7 Hz, J=8.4 Hz, 1 H) , 7.74 (dd, J=1.5, 8.4 Hz, 1 H) , 8.82 (t, J=3.9 Hz, 1 H) . Anal calcd.. for C28H33N6F205 + 0.20 CH2C12 : C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H, 5.68; N, 12.94.
Example 35
1,2,3, 6-TETRAHYDRO-l {N- [4- (2 ' -METHYL-PHENYL) PIPERAZIN-1-Y
L] -PROPYD-CARBOXAMIDO-4-METHYL-6- (3, 4-
DIFLUOROPHENYL) -2-OXO- PYRIMIDINE: The amine used was 4- (2' -methyl-phenyl) piperazine. λR NMR 51.75-1.80 (m, 2 H) , 2.29 (s, 3 H) , 2.42 (s 3 H) , 2.41-2.48 ( , 2 H) , 2.58-2.62 (m, 4 H) , 2.91-2.97 (m, 4 H) , 3.35 -3.42 ( , 2 H), 3.72 (s, 3 H) , 6.71 (s, 1 H) , 6.97-7.26 (m, 8 H) , 8.81 (t, J=3.9 Hz, 1 H) . The product was dissolved in ether and 1 N HCl in ether was added. The ether was evaporated, giving the dihydrochloride salt; mp 66-71 °C . Anal calcd. for C28H35N5F204 Cl2 + 1.75 acetone: C, 55.73; H, 6.40; N, 9.78. Found: C, 56.16; H, 6.29; N, 10.06.
Example 36
(+) -1,2,3, 6-TETRAHYDRO-5-METHOXYCARBONYL-4-METHOXYMETHYL- 2-OXO-l-{N- [3- (4-METHYL-4-PHENYL PIPERIDINE-1-YL] PROPYL}- 6- (3, 4-DIFLUOROPHENYL) PYRIMIDINE: Hygroscopic; [α]D = + 82.1(c = 0.31, MeOH); λR NMR δl.14 (s, 3 H) , 1.61-1.72 (m, 4 H) , 2.03-2.08 (m, 2 H) , 2.25 (t, J=7.2 Hz, 2 H) , 2.30-2.42 (m, 4 H) , 3.19-3.31 (m, 2 H) , 3.40 (s, 3 H) , 3.63 (s, 3 H) , 4.60 (s, 2 H) , 6.60 (s, 1 H) , 6.97-7.29 (m, 8 H) , 7.63 (br s, 1 H) , 8.78 (t, J=5.7 Hz, 1 H) . Anal calcd. for C30H37N4O5F2Cl + CH,C12 : C, 53.80; H, 5.68;
N, 8.10. Found: C, 53.79; H, 6.03; N, 7.83.
EXAMPLE 37
5- (5-BUTYL-2-THIENYL) PYRIDO [2 , 3-d] PYRIMIDINE- 2,4,7 (IE, 3H,8H) -TRIONE
General Procedure for the reaction ,off pyrimidine-3- carboxylic acid-4-nitrophenyl esters with amines: A solution of substituted pyrimidine-3-carboxylic acid- 4-nitrophenyl ester ((0.29 mmol) and a substituted 4- phenyl-1- (3-propylaminopiperidine (0.30 mmol) in 10 mL of anhydrous THF was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography.
Example 38
METHYL (4S) -3-[ ( { 3- [ 4- (3-AMINOPHENYL) -1- PIPERIDINYL] PROPYL}AMINO) CARBONYL] -4- (3,4- DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-0X0-1, 2, 3, 4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 1H NMR (400 MHz, CDC13) δ 7.80 (s, IH) , 7.22-7.02 (m, 2H) , 6.95 (t, 2H,
J=8.7 Hz), 6.63-6.44 (m, 4H) , 4.56 (ABq, 2H) , 3.62 (s, 3H) , 3.33 (s, 3H) , 3.32 (m, 4H) , 2.96 (br s, 2H) , 2.34 (t, 2H, J=7.5 Hz), 2.11-1.94 (m, 3H) , 1.81-1.64 (m, 4H) ; ESMS m/e: 572.3 (M + H)+.
Example 39
The product was obtained according to the method described for Example 40.
METHYL ( 4S ) -4- (3 , 4-DIFLUOROPHENYL) -3- ({ [3- ( 4- { 3- [ (METHOXYACETYL) AMINO] PHENYL} -rl-
PIPERIDINYL) PROPYL] AMINO} CARBONYL) -6- (METHOXYMETHYL) -2- OXO-l,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 15.6 mg (69% yield); 1H NMR (400 MHz, CDC13) δ 9.01 (s, IH) , 8.25 (s, IH) , 7.60 (s, IH), 7.37 (d, IH, J=7.2 Hz), 7.30-7.05 (m, 5H) , 7.02 (d, IH, J=8.0 Hz), 6.71 (s, IH) , 4.70 (s, 2H) , 4.03 (s, 2H) , 3.73 (s, 3H) , 3.53 (s, 3H) , 3.47 (s, 3H) , 3.42-3.33 (m, 2H) , 3.08 (br s, 2H) , 2.49 (br s, 2H), 2.20 (s, 2H), 2.07 (br s, IH) , ,1.97-1.75 (m, 4H) ; ESMS m/e: 644.3 (M + H)+
Example 40 METHYL (4S) -4- (3, 4-DIFLUOROPHENYL) -3- ( { [3-(4-{3-[ (3,3- DIMETHYLBUTANOYL) AMINO] PHENYL } -1-
PIPERIDINYL) PROPYL] MINO} CARBONYL) -6- (METHOXYMETHYL) -2- OXO-l,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE
To the 20 ml vial was added methyl (4S) -3- [ ( {3- [4- (3- aminophenyl) -1-piperidiny1] propyl } amino) carbonyl] -4- ( 3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2,3,4- tetrahydro-5-pyrimidinecarboxylate (0.035 mmol), an acid chloride or sulfonyl chloride (1.5 eq) , N,N- diisopropylethylamine (5 eq) and dichloromethane (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 24 h, at which time the TLC analysis indicated the reaction was completed. The reaction mixture was concentrated to a small volume and purified by preparative TLC (silica, 2000 microns, 95:5 = dichloromethane : methanol with 1% of isopropylamine) to give 5.6 mg of methyl (4S) -4- (3, 4-difluorophenyl) -3- ({ [3-(4-{3-[(3, 3-dimethylbutanoyl) amino] phenyl } -1- piperidinyl) propyl] amino} carbonyl) -6- (methoxymethyl) -2- oxo-1, 2 , 3, 4-tetrahydro-5-pyrimidinecarboxylate : 24.6% yield; λR NMR (400 MHz, CDC1,) 5 7.50 (s, IH) , 7.26 (d, IH, J=8.3 Hz), 7.15-7.02 (m, 5H) , 6.88 (d, IH, J=8.3 Hz), 6.55 (s, IH) , 4.56 (ABq, 2H), 3.62 (s, 3H) , 3.32 (s, 3H) , 3.25 (t, 4H, J=9.0 Hz), 2.99 (d, 2H, J=10.8 Hz), 2.49-2.37 (m, 3H) , 2.08 (t, 2H, J=11.7 Hz), 1.78- 1.65 (m, 14H) ; ESMS m/e: 670.4 (M + H)+. Example 41
The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ({ [3- ( 4- { 3- [ (3, 3-dimethylbutanoyl) amino] phenyl } -1- piperidinyl) propyl] amino} carbonyl) -6- (methoxymethyl) -2- oxo-1 ,2,3, 4-tetrahydro-5-pyrimidinecarboxylate .
METHYL (4S) -4- ( 3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2- OXO-3-{ [ (3-{4- [3- (PROPIONYLAMINO) PHENYL] -1- PIPERIDINYL} PROPYL) AMINO] CARBONYL} -1 , 2 , 3 , 4-TETRAHYDRO-5- PYRIMIDINECARBOXYLATE: 9.9 mg (45% yield) δ 1H NMR (400 MHz, CDC13) δ7.36 (s, IH) , 7.28 (d, IH, J=8.0 Hz), 7.16- 7.02 (m, 5H), 6.86 (d, IH, J=7.6 Hz), 6.54 (s, IH) , 4.56 (ABq, 2H), 3.62 (s, 3H) , 3.32 (s, 3H), 3.27-3.19 ( , 4H) , 2.95 (d, 2H, J=10.3 Hz), 2.41 (m, IH) , 2.34 (t, 2H, J=7.7 Hz), 2.28 (q, 2H, J=7.6 Hz), 2.01 (t, 2H, J=ll.l Hz), 1.73-1.64 (m, 8H) ; ESMS m/e: 628.4 (M + H)+
Example 42 The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ({ [3- (4-{3- [ (3, 3-dimethylbutanoyl) amino] phenyl }-l- piperidinyl) propyl] mino} carbonyl) -6- (methoxymethyl ) -2- oxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylate .
METHYL (4S) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -3- ( { [3- (4-{3-[ ( 3-METHYLBUTANOYL) AMINO] PHENYL }-l- PIPERIDINYL) PROPYL] AMINO} CARBONYL) -2-0X0-1,2,3,4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 10.4 mg (45% yield) δ XH NMR (400 MHz, CDC13) δ 7.36 (s, IH) , 7.28 (d, IH, J=7.9 Hz), 7.16-7.03 (m, 5H) , 6.88 (d, IH, J=7.4 Hz), 6.56 (s, IH) , 4.56 (ABq, 2H) , 3.62 (s, 3H) , 3.32 (s, 3H) , 3.25 (t, 4H, J=6.7 Hz), 2.98 (d, 2H, J=ll.l Hz), 2.43 (m, IH) , 2.38 (t, 2H, J=7.5 Hz), 1.13 (d, 2H, J= .5 Hz), 2.10-2.01 (m, 2H) , 1.75-1.64 (m, 6H) , 0.91 (d, 6H, J=5.8 Hz); ESMS m/e: 656.4 (M + H)+
Example 43
The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ({ [3- (4-{3- [ (3, 3-dimethylbutanoyl) amino] phenyl} -1- piperidinyl) propyl] amino} carbonyl) -6- (methoxymethyl ) -2- oxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylate .
METHYL (4S) -4- (3, 4-DIFLUOROPHENYL) -3-{ [ (3-{4-[3-
(ISOBUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL} PROPYL) AMINO] CARBONYL} -6- (METHOXYMETHYL) -2- OXO-l,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 16.4 mg
(73% yield) δ λR NMR (400 MHz, CDC13) δ 7.37 (s, IH) , 7.28
(d, IH, J=7.3 Hz), 7.16-7.01 (m, 5H) , 6.88 (d, 2H, J=7.3 Hz), 6.54 (s, IH), 4.56 (ABq, 2H) , 3.62 (s, 3H) , 3.32
(s, 3H) , 3.25 (t, 2H, J=6÷8 Hz), 3.23-3.18 (m, 2H) , 3.03 (d, 2H, J=11.7 Hz), 2.57-2.48 (m, IH) , 2.43 (t, 2H, J=8.0 Hz), 2.14 (t, 2H, J=9.4 Hz), 1.8-1.65 (m, 5H) , 1.09 (d, 6H, J=6.3 Hz); ESMS m/e: 642.4 (M + H)+
Example 44 The product was obtained according to the method described for methyl (4S) -4- (3, 4-difluorophenyl) -3- ({ [3- (4-{3- [ (3, 3-dimethylbutanoyl) amino] phenyl }-l- piperidinyl) propyl] amino} carbonyl) -6- (methoxymethyl) -2- oxo-1, 2,3, 4-tetrahydro-5-pyrimidinecarboxylate .
METHYL (4S)-3-{ [ (3-{4-[3- (BUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL } PROPYL) AMINO] CARBONYL} -4- ( 3,4-
DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-OXO-l, 2 , 3, 4- TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: 14.7 mg (65.5% yield) δ 1H NMR (400 MHz-, CDCl3) δ 7.38 (s, IH) , 7.26 (s, IH), 7.17-6.99 (m, 5H) , 6.87 (s, IH) , 6.55 (s, IH) , 4.56 (ABq, 2H) , 3.63 (s, 3H) , 3.33 (s, 3H) , 3.28-3.17 (m, 6H), 3.0 (br s, 2H) , 2.51-2.36 (m, 3H) , 2.25 (t, 2H,
J=5.0 Hz), 2.10 (br s, 2H) , 1.8-1.56 (m, 6H) , 0.90 (t, 3H, J=5.0 Hz); ESMS m/e: 642.4 (M + H)+.
Example 45 (4R) -N-(3-{4-[3-(BUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL} PROPYL) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-OXO-l , 2,3, 4-TETRAHYDRO-5- PYRIMIDINECARBOXAMIDE
Method:
(4R) -4- (3 , -difluorophenyl) -6- (methoxymethyl) -2-oxo- 1 ,2 , 3,4-tetrahydro-5-pyrimidinecarboxylic acid: A stirred mixture of one mole equivalent of methyl (4i?)-4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2, 3, - tetrahydro-5-pyrimidinecarboxylate (10.0 g, 32.0 mmol) and lithium hydroxide (2 equivalents, 1.53 g, 64.0 mol) in H20-THF (2:1, 300 mL) was heated at reflux temperature for 1 h. The reaction mixture was concentrated, dissolved in water, washed with ethyl acetate and acidified (1 N HCl) to pH 3-4 • (pH paper). The precipitated product was collected, washed with water and dried under reduced pressure to give the desired product in 90% yield.
(41?) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -N-[3- (4- (3-NITROPHENYL) -3 , 6-DIHYDRO-l (2ff) -PYRIDINYL) ROPYL] -2- OXO-1 ,2,3, 4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE : A solution of (4.R) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2,3, 4-tetrahydro-5- pyrimidinecarboxylic acid (1.2 eq) , EDC (1.5 Eq.), N- methylmorpholine (2.0 Eq.) in dichloromethane was stirred at room temperature for 15 minutes, followed by addition of 3- (4- (3-nitrophenyl) -3, 6-dihydro-l (227) - pyridinyl) -1-propanamine (1.0 eq.) to the reaction mixture. The resulting solution was stirred for 18 hours, concentrated and chromatographed on silica to give [ 4R) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -N- [3- (4- (3-nitrophenyl) -3, 6-dihydro-l ( 2H) -pyridinyl) propyl] - 2-oxo-l, 2,3, -tetrahydro-5-pyrimidinecarboxamide .
(4R) -N-{3- [4- (3-AMINOPHENYL) -1-PIPERIDINYL] ROPYL} -4- (3 , 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-OXO-l ,2,3,4-
TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: A mixture of (4R)-4- (3, 4-difluorophenyl) -6- (methoxymethyl) -N- [3- (4- (3- nitrophenyl) -3, 6-dihydro-l (2if) -pyridinyl) propyl] -2-oxo- 1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxamide, 10% Pd/C in ethanol was hydrogenated (balloon method) for 2 days. The reaction mixture was filtered through Celite 545, washed with ethanol and concentrated to give the desired product.
(4R) -N- (3- {4- [3- (BUTYRYLAMINO) PHENYL] -1-
PIPERIDINYL}PROPYL) -4- (3 , -DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-OXO-l ,2,3, 4-TETRAHYDRO-5- PYRIMIDINECARBOXAMIDE : Into a 20 mL vial was added (4i?)- JV-{3- [4- (3-aminophenyl) -1-piperidinyl] propyl} -4- (3, 4- difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2,3,4- tetrahydro-5-pyrimidinecarboxamide (0.040 mmol), acid chloride (1.5 eq) and N, N-diisopropylethylamine (5.0 eq) in 2.0 mL of dichloromethane at room temperature. After 24 hrs, the reaction mixture was concentrated in vacuo and purified by preparative TLC (silica, 2000 microns, 95:5 = dichloromethane :. methanol with 1% of isopropylamine) to give 9.2 mg (45% yield) of the desired product: XH NMR (400 MHz, CD3OD) δ 7.49 (s, IH) , 7.25 (d, IH, J=7.6 Hz), 7.20-7.02 (m, 5H) , 6.91 (d, IH, "J=8 Hz), 5.29 (s, IH) , 4.24 (ABq, 2H) , 3.30 and 3.24 (two s, 3H) , 3.46-3.12 (m, partially hidden by three s, 4H) , 2.74 (br s, 4H) , 2.25 (t, 2H, J=8.2 Hz), 2.04-1.69 (m, 7H) , 1.63 (sextet, 2H, J=7.4 Hz), 0.91 (t, 3H, 7.4 Hz); ESMS m/e: 584.4 (M + H)+.
Example 46
The product was obtained according to the method described for (-4R) -N- (3-{4- [3- (butyrylamino) phenyl] -1- piperidinyl } propyl) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2, 3, 4-tetrahydro-5- pyrimidinecarboxamide .
(4R) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -2-OXO-N- (3- {4- [3- (PROPIONYLAMINO) PHENYL] -1-PIPERIDINYL} PROPYL) - l,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXAMIDE: 5.6 mg (24.6% yield); 1H NMR (400 MHz, CD3OD) δ 7.56 (s, IH) , 7.35 (d, IH, J=6.9 Hz), 7.3-7.03 ,(m, 4H) , 7.17 (br s, IH), 6.99 (d, IH, J=7.0 Hz), 5.45 (s, IH) , 4..33 (ABq,
2H) , 3.41 (s, 3H) , 3.37-3.23 (m, partially hidden, 4H) , 2.8 (br s, 4H) , 2.39 (d, 2H, J=9.3 Hz), 2.14-1.78 (m, 7H) , 1.21 (t, 3H, J=7.6 Hz); ESMS m/e: 570.4 (M + H)+.
Example 47
The product was obtained according to the method described for (4R) -N- (3-{4- [3- (butyrylamino) phenyl] -1- piperidinyl }propyl) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2, 3, 4-tetrahydro-5- pyrimidinecarboxamide .
(4R) -4- (3, 4-DIFLUOROPHENYL) -6- (METHOXYMETHYL) -N- [3- (4- { 3- [ (3-METHYLBUTANOYL AMINO] PHENYL}-l-
PIPERIDINYL) PROPYL] -2-OXO-l , 2,3, 4-TETRAHYDRO-5- , PYRIMIDINECARBOXAMIDE: 11.1 mg (46% yield); XH NMR (400 MHz, CD3OD) δ 7.81 (d, IH, J=8.5 Hz), 7.6 (s, IH) , 7.55 (s, IH) , 7.36 (br s, 1 H) , 7.31-7.17 (m, 3H) , 7.01 (t, IH, J=6.7 Hz) 6.64-6.61 (m, IH) , 5.45 (br s, IH) , 4.32 (ABq, 2H) , 3.94 and 3.87 (two s, 3H) , 3.42-3.12 (m, partially hidden, 2H) , 3.1 (br s, 2H) , 3.0 (t, 2H, J=ll.l Hz), 2.79-2.57 (m, 4H) , 2.27-1.73 (m, 8H) , 1.19 and 1.01 (two d, 6H, J=6.6 Hz); ESMS m/e: 598.4 (M + H)+.
Example 48
The product was obtained according to the method described for (4R) -N- (3- { 4- [3- (butyrylamino) phenyl] -1- piperidinyl }propyl) -4- (3, 4-difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2,3, 4-tetrahydro-5- pyrimidinecarboxamide .
(4R) -4- (3, -DIFLUOROPHENYL) -6- (METHOXYMETHYL) -N-[3- (4- {3-[ (2-METHYLBUTANOYL)AMINO] PHENYL} -1- PIPERIDINYL) PROPYL] -2-OXO-l, 2,3, 4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: 6.7 mg (28% yield); XH NMR (400 MHz, CD3OD) δ 7.59 (s, IH) , 7.35 (br s, IH) , 7.3-7.2 ( , 3H), 7.17 (br s, IH) , 7.01 (d, IH, J=6.8 Hz), 5.45 (s, IH) , 4.33 (ABq, 2H) , 3.39 (s, 3H) , 3.29 (m, 2H) , 2.84 (br s, 4H) , 2.42 (m, IH) , 2.14-1.78 ( , 9H) , 1.7 (m,
IH), 1.49 (m, IH) , 1.20 (d, 3H, J=6.7 Hz), 0.95 (t, 3H, J=6.6 Hz); ESMS m/e: 598.4 (M + H)+. Example 49
The product was obtained according to the method described for (4R) -N- (3-{4- [3- (butyrylamino)-phenyl] -1- piperidinyl }propyl) -4- (3, 4-difluorophenyl') -6- (methoxymethyl) -2-oxo-l, 2, 3, 4-tetrahydro-5- pyrimidinecarboxamide .
( 4R) -4- (3, 4-DIFLUOROPHENYL) -N-[ 3- ( 4- { 3- [ (3,3- DIMETHYLBUTANOYL) AMINO] PHENYL} -1-PIPERIDINYL) PROPYL] -6- (METHOXYMETHYL) -2-OXO-l, 2, 3, 4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: 1.1 mg (4.4% yield); XH NMR (400 MHz, CD3OD) δ 7.6-6.91 (m, 7H) , 5.43 (s, IH) , 4.31 (ABq, 2H) , 3.40 (s, 3H) , 3.27-1.26 (m, 17 H) , 1.09 (s, 9H) ; ESMS m/e: 612.4 (M + H)+.
Example 50
The product was obtained according to the method described for (4R) -N- (3- { 4- [3- (butyrylamino) phenyl] -1- piperidinyljpropyl) -4- (3, -difluorophenyl) -6- (methoxymethyl) -2-oxo-l, 2, 3, 4-tetrahydro-5- pyrimidinecarboxamide .
( 4R) -4- (3, 4-DIFLUOROPHENYL) -N- ( 3- { 4- [3- (ISOBUTYRYLAMINO) PHENYL] -1-PIPERIDINYL} PROPYL) -6- (METHOXYMETHYL) -2-OXO-l, 2,3, 4-TETRAHYDRO-5-
PYRIMIDINECARBOXAMIDE: 12.7 mg (54% yield); XH NMR (400 MHz, CD3OD) δ 7.59(s, 1H),.7.36 (d, IH, J=8.6 Hz), 7.31- 7.07 (m, 4H), 7.01 (d, IH, J=6.5 Hz), 5.39 (s, IH) , 4.34 (ABq, 2H) , 3.35 (s, 3H) , 3.33-3.19 (m, partially hidden, 2H) , 3.08-2.72 (m, 4H) , 2.63 (t, 2H, J=7.2 Hz), 2.14-
1.82 (m, 8H) , 1.19 (d, 6H, J=6.9 Hz); ESMS m/e: 584.4 (M + H) + . Example 51
The synthetic method is the same as described for the synthesis of (4S) -N- (3- { 4- [3- (acetylamino) phenyl] -1- piperidinyl}propyl) -4- (3, 5-dif luorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide.
5-ACETYL-N- (3- {4- [3- (ACETYLAMINO) PHENYL] -1- PIPERIDINYL} PROPYL) -4-METHYL-2-OXO-6- (3,4,5- TRI FLUOROPHENYL) -3, 6-DIHYDRO-l (2H) - PYRIMIDINECARBOXAMIDE: 14.5 mg (46% yield); XH NMR (400
MHz, CDC13) δ 9.56 (s, IH) , 9.20 (s, 1 H) , 8.21 (s, IH) , 7.52 (s, IH) , 7.18 (t, IH, J=7.8 Hz), 7.07-6.75 (m, 5H) , 3.59-3.37 (m, IH) , 3.48-3.38 ( , IH) , 3.08 (br s, 2H) , 2.57-2.39 (m, 5H) , 2.25 (s, 3H) , 2.21 (s, 3H) , 2.19-1.59 (m, 9H) ; ESMS m/e: 586.3 (M + H)+; Anal. Calc. for
C3oH34F3N5θ4+0.1CHCl3: C, 60.50; H, 5.75; N, 11.72. Found: C, 60.59; H, 5.40; N, 11.73.
Example 52 The synthetic method is the same as described for the synthesis of (4S) -N- (3-{4- [3- (acetylamino) phenyl] -1- piperidinyl}propyl) -4- (3, 5-difluorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide .
BENZYL 3-{ [ (3- { - [3- (ACETYLAMINO) PHENYL] -1- PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(2,4- ' DIFLUOROPHENYL)-6-ETHYL-2-OXO-l,2,3,4-TETRAHYDRO-5- PYRIMIDINECARBOXYLATE: 14.8 mg (41% yield); XH NMR (400 MHz, CDCI3) δ 9.05 (br s, IH) , 8.14 (s, IH) , 7.47 (s, IH) , 7.37-7.21 (m, 8H) , 7.18 (t, IH, J=7.7 Hz), 6.94 (d, IH, J=6.9 Hz), 6.87 (d, IH, J=7. Hz), 6.7-6.62 ( , 3H) , 5.09 (q, 2H, J=17.8 Hz), 3.48-3.24 (m, 2H) , 3.04 (ABq, 2H) , 2.88-2.71 (m, 2H) , 2.52-2.39 (m, 2H) , 2.19 (s, 3H) , 2.17-1.88 (m, 3H) , 1.77-1.58 (m, 3H) , 1.19 (t, 3H, J=7.5 Hz); ESMS m/e: 674.4 (M + H)+.
Example 53 The synthetic method is the same as described for the synthesis of (4S) -N- (3- { 4- [3- (acetylamino) phenyl] -1- piperidinyl}propyl) -4- (3, 5-difluorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide .
N- (3-{4- [3- (ACETYLAMINO) PHENYL] -1-PIPERIDINYL} PROPYL) -4- (1, 3-BENZODIOXOL-5-YL) -2 , 5-DIOXO-l, 2, 5, 7-
TETRAHYDROFURO[3, 4-D] PYRIMIDINE-3 (4H) -CARBOXAMIDE : 8.75 mg (28% yield); XH NMR (400 MHz, CDC13) δ 9.81 (s, IH) , 8.14 (s, IH) , 7.53 (s, IH) . 7.21 (t, IH, J-7.7 Hz), 6.99 (d, IH, J=7.7 Hz), 6.91-6.7 (m, 4H) , 6.42 (s, l'H) , 5.9 (s, 2H) , 4.75 (s, 2H) , 3.61-3.5 ( , IH) , 3.37-3.27 (m, IH) , 3.08 (br s, 2H) , 2.56-2.40 (m, 3H) , 2.18 (s, 3H) , 2.16-1.85 (m, 4H) , 1.78-1.6 (m, 5H) ; ESMS m/e : 576.3 (M + H)+.
Example 54
The synthetic method is the same as described for the synthesis of (4S) -N- (3- { 4- [3- (acetylamino) phenyl] -1- piperidinyl}propyl) -4- (3,5-difluorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide .
METHYL l-{ [ (3-{4- [3- (ACETYLAMINO) PHENYL] -1- PIPERIDINYL } PROPYL) AMINO] CARBONYL } -2- [ ( 4-
METHOXYBENZYL) SULFANYL] -4-METHYL-6- ( 4-NITROPHENYL) -1,6- DIHYDRO-5-PYRIMIDINECARBOXYLATE: 10.1 g (26% yield); XH NMR (400 MHz, CDC13) δ 8.02 (d, 2H, J=7.5 Hz), 7.53 (br s, IH), 7.44-7.27 (m, 6H) , 7.14 (d, 2H, J=8.5 Hz), 6.99 (d, IH, J=7.6 Hz), 6.75 (d, 2H, J=8.5 Hz), 6.2 (s, IH) , 4.23 (ABq, 2H) , 3.78 (s, 3H) , 3.7 (s, 3H) , 3.58-3.48 (m, IH) 3.37-3.26 (m, 2H) , 3.04 (m, 2H) , 2.61-2.43 (m, 3H) , 2.41 (s, 3H) , 2.16 (s, 3H) , 2.15-1.64 (m, 8H) ; ESMS m/e: 729.3 (M + H)+.
Example 55
The synthetic method is the same as described for the synthesis of (4S) -N- (3-{ 4- [3- (acetylamino) phenyl] -1- piperidinyl}propyl) -4- (3, 5-difluorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide.
N- (3-{4- [3- (ACETYLAMINO) PHENYL] -1-PIPERIDINYL} PROPYL) -4- (2, 1, 3-BENZOXADIAZOL-5-YL) -2 , 5-DIOXO-l, 2, 5, 7- TETRAHYDROFURO[3, 4-D] PYRIMIDINE-3 (4H) -CARBOXAMIDE : 7.7 mg (12% yield); λR NMR (400 MHz, CDC13) δ 7.97-6.83 (m, 7H) , 6.49 (s, IH) , 5.51(s, IH) , 3.43-2.02 ( , 17 H) , 1.82 (s, 3H) ; ESMS m/e: 574.3 (M + H)+.
Example 56 The synthetic method is the same as described for the synthesis of (4S) -N- (3— {4— [3- (acetylamino) phenyl] -1- piperidinyl }propyl) -4- (3, 5-difluorophenyl) -2-oxo-l, 3- oxazolidine-3-carboxamide .
METHYL (4S) -3-{ [ (3- { 4- [3- (ACETYLAMINO) PHENYL] -1- PIPERIDINYL} PROPYL) AMINO] CARBONYL} -4- (3, 4- DIFLUOROPHENYL)-6-METHYL-2-OXO-l,2,3,4-TETRAHYDRO-5- PYRIMIDINECARBOXYLATE : 16.6 mg (52% yield); XH NMR (400 MHz, CDC13) δ 9.55 ' (br s, IH) , 9.07 (s, IH) , 8.19 (s, IH), 7.54 (s, IH), 7.25-6.98 (m, 4H) , 6.95 (d, IH, J=8.0 Hz), 6.81 (d, IH, J=7.5 Hz), 6.69 (s, IH) , 3.70 (s, 3H) , 3.57-3.34 (m, 2H) , 3.06 (t, 2H, J=11.6 Hz), 2.47 (t, 2H, J=8.1 Hz), 2.42 (s, 3H) , 2.20 (s, 3H) , 2.18-1.61 (m, 9H) ; ESMS m/e: 584.3 (M + H)+; Anal. Calc. for C30H35F2N5O+O.25CHCI3: C, 59.23; H, 5.79; N, 11.42. Found: C, 59.61; H, 5.31; N, 11.48.
Peptide Synthesis :
Abbreviations: Fmoc: 9-Fluorenyloxycarbonyl-; Trityl : triphenylmethyl-; tBu- : tertiary butyl ester; OtBu- : tertiary butyl ether; Ng : N-guanidinyl; Nin : N-Indole; MBHA : methylbenzhydlamine; DMF: N,N-dimethylformamide; NMP: N-Methylpyrrolidinone; DIEA: diisopripylethyl amine; TFA: trifluoroacetic acid.
Small scale peptide syntheses were performed either manually, by using a sintered glass column with argon pressure to remove solvents and reagents, or by using an Advanced ChemTech 396-9000 automated peptide synthesizer (Advanced ChemTech, Louisville, KY) . Large scale peptide syntheses were performed on a CS Bio 536 (CS Bio Inc., San Carlos, CA) . Fmoc-Alanine-OH,
Fmoc-Cysteine (Trityl) -OH, Fmoc-Aspartic acid (tBu) -OH, Fmoc-Glutamic acid (tBu) -OH, Fmoc-Phenylalanine-OH, Fmoc-Glycine-OH, Fmoc-Histidine (Trityl) -OH,
F oc-Isoleucine-OH, Fmoc-Lysine (Boc) -OH, Fmoc-Leucine-OH, Fmoc-Methionine-OH, Fmoc-Asparagine (Trityl) -OH, Fmoc-Proline-OH, Fmoc-Glutamine (Trityl) -OH, Fmoc-Arginine (Ng-2, 2,4,6, 7-Pentamethyldihydrobenzofuran-5 -sulfonyl) -OH, Fmoc-Serine (OtBu-OH,
Fmoc-Threonine (OtBu) -OH, Fmoc-Valine-OH, Fmoc-Tryptophan (NinBoc) -OH, Fmoc-Tyrosine (OtBu) -OH, Fmoc-Cyclohexylalanine-OH, and Fmoc-Norleucine , Fmoc -O-benzyl-phosphotyrosine were used as protected amino acids. Any corresponding D-amino acids had the same side-chain protecting groups, with the exception of Fmoc-D-Arginine, which had a Ng-2, 2, 5, 7 , 8-pentamethyl- chroman-6-sulfonyl protecting group.
Peptides with C-terminal amides were synthesized on solid phase using Rink amide-MBHA resin. The Fmoc group of the Rink Amide MBHA resin was removed by treatment with 30% piperidine in DMF for 5 and 30 minutes respectively. After washing with DMF (3 times), methanol (2 times) and DMF/NMP (3 times), the appropriate Fmoc-protected amino acid (4 eq.) was coupled for 2 hours with HBTU or HATU (4eq.) as the activating agent and DIEA (8eq.) as the base. In manual syntheses, the ninhydrin test was used to test for complete coupling of the amino acids. The Fmoc groups were removed by treatment with 30% piperidine in DMF for 5 and 30 minutes respectively. After washing with DMF (3 times), methanol (2 times) and DMF/NMP (3 times), the next Fmoc-protected amino acid (4 eq.) was coupled for 2 hours with HBTU or HATU (4eq.) as the activating agent and DIEA (8eq.) as the base. This process of coupling and deprotection of the Fmoc group was continued until the desired peptide was assembled on the resin. The N-terminal Fmoc group was removed by treatment with 30% piperidine in DMF for 5 and 30 minutes respectively. After washing with DMF (3 times), methanol (2 times), the resin (s) was vacuum dried for 2 hours. Cleavage of the peptide-on-resin and removal of the side chain protecting groups was achieved by treating with TFA : ethanedithiol : thioanisole: m-cresol : water : triisopropyisiiane : phenol, 78/5/3/3/3/5/3 (5 mL per 100 mg resin) for 2.5-3 hours. The cleavage cocktail containing the peptide was filtered into a round bottom flask and the volatile liquids were removed by rotary evaporation at 30-40 °C . The peptides were precipitated with anhydrous ether, collected on a medium-pore sintered glass funnel by vacuum filtration, washed with ether and vacuum dried.
Peptides with C-terminal acids were synthesized using 2-chlorotrityl chloride resin. The first amino acid was attached to the resin by dissolving 0.6-1.2eq. of the appropriate Fmoc-protected amino acid described above in dichloromethane (a minimal amount of DMF was added to facilitate the dissolution, if necessary) . To this was added DIEA (4 eq. Relative to the Fmoc-amino acid) and the solution was added to the resin and shaken for 30-120 minutes. The solvents and the excess reagents were drained and the resin was washed with dichloromethane / methanol / DIEA (17/2/1) (3 times) , dichloromethane (3 times), DMF (2 times), dichloromethane (2 times), and vacuum dried. The process of deprotection of the Fmoc group and coupling the appropriate Fmoc-protected amino acid was continued as described above, until the desired, fully protected peptide was assembled on the resin. The process for removal of the final Fmoc group and the cleavage and deprotection of the peptides was the same as described above for the peptides with C-terminal amides .
Purification of the peptides was achieved by preparative high performance column chromatography (HPLC) , using a reverse-phase C-18 column (25 x 250mm) (Primesphere or Vydac) with a gradient of acetonitrile (0.1% TFA) in water (0.1% TFA) . The general gradient was from 10%-90% acetonitrile in water over 40 minutes. The fractions corresponding to each peak on the HPLC trace was collected, freeze dried and analyzed by electrospray mass spectrometery . The fraction having the correct mass spectral data corresponding to the desired peptide was then further analyzed by amino acid analysis, if necessary. All purified peptides were tested for homogeneity by analytical HPLC using conditions similar to that described above, but by using a 2.5x250 mm analytical column, and generally were found to have >95% purity. Ref erences :
See our published dihydropyrimidinone and oxazolidinone patents as references for the synthesis of the templates and the piperidines.
Also, for the synthesis of the aminopropyl piperidines and the templates, see:
Lagu, Bharat, et al . , Design and synthesis of novel αla adrenoceptor-selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chains. J. Med. Chem . (1999), 42(23), 4794-4803. CODEN: JMCMAR ISSN: 0022-2623. CAN 132:78527 AN 1999:680975 CAPLUS
Dhar, T. G. Murali, et al . , Design and Synthesis of
Novel la Adrenoceptor-Selective Antagonists. 2. Approaches To Eliminate Opioid Agonist Metabolites via Modification of Linker and 4-Methoxycarbonyl-4-phenyl piperidine Moiety. J". Med. Chem . (1999), 42(23),
4778-4793. CODEN: JMCMAR ISSN : 0022-2623. CAN 132:18483 AN 1999:680971 CAPLUS
Nagarathnam, Dhanapalan, et al., Design and Synthesis of Novel αla Adrenoceptor-Selective Antagonists. 1.
Structure-Activity Relationship in Dihydropyrimidinones .
J. Med. Chem . (1999), 42(23), 4764-4777. CODEN: JMCMAR ISSN:0022-2623. CAN 132:18482 AN 1999:680967 CAPLUS
Wong, Wai C, et al . , Design and Synthesis of Novel αla Adrenoceptor-Selective Antagonists. 4. Structure-Activity Relationship in the Dihydropyrimidine Series . J. Med. Chem . (1999), 42(23), 4804-4813. CODEN: JMCMAR ISSN:0022-2623. CAN 132:30317 AN 1999:680947 CAPLUS
Marzabadi, Mohammad R., et al . , Design and synthesis of novel dihydropyridine alpha-lA antagonists. Bioorg. Med. Chem . Lett . (1999), 9(19), 2843-2848. CODEN: BMCLE8 ISSN:0960-894X. CAN 132:44482 AN 1999:662323 CAPLUS
Wong, Wai C, et al . , Alpha-la adrenoceptor selective antagonists as novel agents for treating benign prostatic hyperplasia. Book of Abstracts, 217th ACS National Meeting, Anaheim, Calif., March 21-25 (1999), MEDI-156. CODEN: 67GHA6 AN 1999:92669 CAPLUS
Nagarathnam, D., et al . , Design, synthesis and evaluation of dihydropyrimidinones as alpha-la selective antagonists: 7. Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs. Book of Abstracts, 217th ACS National Meeting, Anaheim,
Calif., March 21-25 (1999), MEDI-110. CODEN: 67GHA6 AN 1999:92624 CAPLUS
Lagu, Bharat, et al . , Heterocyclic substituted oxazolidinones for use as selective antagonists for human a IA receptors. PCT Int. Appl. (1998), 258 pp. CODEN: PIXXD2 WO 9857940 Al 19981223 CAN 130:81508 AN 1999:9823 CAPLUS
Wong, Wai C, et al . , Preparation of piperidinylpropyl aminocarbonyldihydropyrimidones and related compounds as selective adrenergic a IA receptor antagonists. PCT Int. Appl. (1998), 314 pp. CODEN: PIXXD2 WO 9851311 A2 19981119 CAN 130:25077 AN 1998:764290 CAPLUS Nagarathnam, Dhanapalan, et al . , Design and synthesis of novel αla adrenoceptor-selective dihydropyridine antagonists for the treatment of benign prostatic hyperplasia. J. Med. Chem . (1998), 41(26), 5320-5333. CODEN: JMCMAR ISSN : 0022-2623. CAN 130:110137 AN 1998:742998 CAPLUS
For the general procedure for Pd coupling of vinyl triflate and bononic acids or tributyl tin reagents: See, Wuston, Wise Synthesis 1991, 993)
(For Typical References, See : Schroeter, G. Ber . (1909) 42, 3356; and Allen, C.F.H,; Bell, A. Org. Syn . Coll . Vol . 3, (1955) 846) .
For the preparation of the ether N- [4- (benzo-4 ' , 5 ' [H] - furanpiperidine refer to W.E.Parham et al , J. Org. Chem . (1976) 41, 2268.
For the preparation of the ether piperidine precursor of Example 20, refer to W.E.Parham et al , J. Org. Chem . (1976) 41, 2268.
For the preparation of the indane piperidine precursor of Example 21, refer to M.S. Chambers J. Med . Chem . (1992) 35, 2033.
For the preparation of the piperidine precursor of Example 23, (K.Hashigaki et al . Chem . Pharm . Bull . (1984) 32, 3568.)
For the preparation of the piperidine precursor of Example 32, spiro [lH-indane-1, 4 ' -piperidine] , refer to M.S. Chambers et al . J. Med . Chem . (1992) 35, 2033.) n o
Figure imgf000199_0001
ounds
CN, CHO, CONH2, CO2Et, Aryl, OCOMe
Figure imgf000200_0001
Figure imgf000200_0002
i) phthalimide-(CH2)nBr ii) hydrazine
Figure imgf000200_0003
so © o
Figure imgf000200_0004
90
o
H
^ Scheme 3. Synthesis of Precursor Compounds
Figure imgf000201_0001
Figure imgf000201_0002
so © o o
Figure imgf000202_0001
Scheme 5. Synthesis of Dihydropyrimidinones
Figure imgf000203_0001
i. O-Methylisourea, NaHC03, DMF ii. NaOAc/NaHC03, DMF iii. 4-Nitrophenyl chloroformate, DMAP, CH2C12 iv. Amine v. HCl/THF so © o o
Scheme 6. Resolution of dihydropyrimidinones,
Figure imgf000204_0001
i . S- (-) -α-Methylbenzylamine ii. Sepn. of diastereomers iii. DBU iv. p-nitrophenylchloroformate
C o o O
Figure imgf000205_0001
i)LAH LAH ii) BBr3
Figure imgf000205_0002
C o o O
Figure imgf000206_0001
Scheme 9. Synthesis of Example 12
Figure imgf000207_0001
i. Piperidine, Benzene
Figure imgf000207_0002
so © o
Scheme 10. Synthesis of Examples 4 and 22,
Figure imgf000208_0001
1. Piperidine, Benzene
Figure imgf000208_0002
ix H2, Pd-C, MeOH/water x. EDC, NMM, NH40H, CH2C12 so © o o
Scheme 11. Synthesis of Example 10 and its Tritiated Analog
Figure imgf000209_0001
Figure imgf000209_0002
o
Figure imgf000210_0001
a. p-methoxybenzyl chloride, THF, 0 to 65 °C; b. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate (prepared from p-nitrobenzaldehyde, methyl acetoacetate, piperidinium acetate in isopropanol), NaOAc, DMF, 65 °C;
© c. p-nitrophenyl chloroformate, NaHC03, dichloromethane o d. N-{3-[1 -(3-aminopropyl)-4-piperidinyl]phenyl}acetamide O
Figure imgf000211_0001
Figure imgf000211_0002
I o I (a) Br2, CHCI3 (b) Heat, 130 υC (c) RNH2, THF or CH2C12, 60-80% yield overall.
Figure imgf000211_0003
o o O
Figure imgf000212_0001
II . Synthetic Methods for General Structures
The examples described in Section I are merely illustrative of the methods used to synthesize MCHl antagonists. Further derivatives may be obtained utilizing generalized methods based on the synthetic methods used to synthesize the examples .
It may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid, and hydroxyl groups in the generalized synthetic methods to form further derivatives. Methods for protection and deprotection of such groups are well-known in the art, and may be found, for example in Green, T.W. and Wuts, P.G.M. (1991) Protection Groups in Organic Synthesis, 2nd Edition John Wiley & Sons, New York.
III . Oral Compositions
As a specific embodiment of an oral composition of a compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
IV. Pharmacological Evaluation of Compounds at Cloned MCHl r NPY. Galanin, and 5-HT2C Receptors
The pharmacological properties of the compounds of the present invention were evaluated at one or more of the cloned human MCHl, NPY1, NPY5, GALR1, GALR2, and GALR3 and rat 5-HT2C receptors using protocols described below.
Host cells
A broad variety of host cells can be used to study heterologously expressed proteins. These cells include but are not restricted to assorted mammalian lines such as; Cos-7, CHO, LM(tk-), HEK293, etc.; insect cell lines such as; Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and others.
COS-7 cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin) at 37°C, 5% C02. Stock plates of COS-7 cells are trypsinized and split 1:6 every 3-4 days.
Human embryonic kidney 293 cells are grown on 150 mm plates in DMEM with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin) at 37°C, 5% C02. Stock plates of 293 cells are trypsinized and split 1:6 every 3-4 days.
Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin) at 37°C, 5% C02. Stock plates of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days.
Chinese hamster ovary (CHO) cells were grown on 150 mm plates in HAM' s F-12 medium with supplements (10% bovine calf serum, 4 mM L-glutamine and 100 units/ml penicillin/ 100 μg/ml streptomycin) at 37°C, 5% C02. Stock plates of CHO cells are trypsinized and split 1:8 every 3-4 days.
Mouse embryonic fibroblast NIH-3T3 cells are grown on 150 mm plates in Dulbecco's Modified Eagle Medium (DMEM) with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 μg/ml streptomycin) at 37°C, 5% C02. Stock plates of NIH-3T3 cells are trypsinized and split 1:15 every 3-4 days.
Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culture dishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C, no C02. High Five insect cells are grown on 150 mm tissue culture dishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27 °C, no C02.
In some cases, cell lines that grow as adherent monolayers can be converted to suspension culture to increase cell yield and provide large batches of uniform assay material for routine receptor screening projects.
Transient expression
DNA encoding proteins to be studied can be transiently expressed in a variety of mammalian, insect, amphibian and other cell lines by several methods including but not restricted to; calcium phosphate-mediated, DEAE-dextran mediated, Liposomal-mediated, viral-mediated, electroporation-mediated and microin ection delivery. Each of these methods may require optimization of assorted experimental parameters depending on the DNA, cell line, and the type of assay to be subsequently employed.
A typical protocol for the calcium phosphate method as applied to LM(tk-) cells is described as follows; Adherent cells are harvested approximately twenty-four hours before transfection and replated at a density of 1-2 x 105 cells/cm2 in a 100 mm tissue culture dish and allowed to incubate over night at 37°C at 5% C02. 250 μl of a mixture of CaCl2 and DNA (20 μg DNA in 250 mM CaCl2) is added to a 5 ml plastic tube and 250 ul of 2X HBS (250 mM NaCl, 10 M KCl, 1.5 mM Na2HP04, 12 mM dextrose, 50 mM HEPES) is slowly added with gentle mixing. The mixture is allowed to incubate for 20 minutes at room temperature to allow a DNA precipitate to form. The cells are then washed with complete medium, 10 ml of culture medium is added to each plate, followed by addition of the DNA precipitate. The cells are then incubated for 24 to 48 hours at 37°C at 5% CO..
A typical protocol for the DEAE-dextran method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. Briefly, 8 μg of receptor DNA plus 8 μg of any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) are added to 9 ml of complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS) . Cos-7 cells plated into a T225 flask (sub-confluent) are washed once with PBS and the DNA mixture is added to each flask. The cells are allowed to incubate for 30 minutes at 37°C, 5% C02. Following the incubation, 36 ml of complete DMEM with 80 μM chloroquine is added to each flask and allowed to incubate an additional 3 hours. The medium is then aspirated and 24 ml of complete medium containing 10% DMSO for exactly 2 minutes and then aspirated. The cells are then washed 2 times with PBS and 30 ml of complete DMEM added to each flask. The cells are then allowed to incubate over night. The next day the cells are harvested by trypsinization and reseeded as needed depending upon the type of assay to be performed.
A typical protocol for liposomal-mediated transfection as applied to CHO cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. A total of lOμg of DNA which may include varying ratios of receptor DNA plus any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is used to fransfect each 75 cm2 flask of cells. Liposomal mediated transfection is carried out according to the manufacturer' s recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD) . Transfected cells are harvested 24 h post transfection and used or reseeded according the requirements of the assay to be employed.
A typical protocol for the electroporation method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are subconfluent at the time of transfection. The cells are harvested by trypsinization resuspended in their growth media and counted. 4 x 106 cells are suspended in 300 μl of DMEM and placed into an electroporation cuvette. 8 μg of receptor DNA plus 8 μg of any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is added to the cell suspension, the cuvette is placed into a BioRad Gene Pulser and subjected to an electrical pulse (Gene Pulser settings: 0.25 kV voltage, 950 μF capacitance) . Following the pulse, 800 μl of complete DMEM is added to each cuvette and the suspension transferred to a sterile tube. Complete medium is added to each tube to bring the final cell concentration to 1 x 105 cells/100 μl . The cells are then plated as needed depending upon the type of assay to be performed.
A typical protocol for viral mediated expression of heterologous proteins is described as follows for baculovirus infection of insect Sf9 cells. The coding region of DNA encoding the receptor disclosed herein may be subcloned into pBlueBacIII into existing restriction sites or sites engineered into sequences 5' and 3' to the coding region of the polypeptides. To generate baculovirus, 0.5 μg of viral DNA (BaculoGold) and 3 μg of DNA construct encoding a polypeptide may be co-transfected into 2 x 106 Spodoptera frugiperda insect Sf9 cells by the calcium phosphate co-precipitation method, as outlined in by Pharmingen (in "Baculovirus Expression Vector System: Procedures and Methods Manual") . The cells then are incubated for 5 days at 27 °C. The supernatant of the co- transfection plate may be collected by centrifugation and the recombinant virus plaque purified. The procedure to infect cells with virus, to prepare stocks of virus and to titer the virus stocks are as described in Pharmingen' s manual. Similar principals would in general apply to mammalian cell expression via retro-viruses, Simliki forest virus and double stranded DNA viruses such as adeno-, herpes-, and vacinia-viruses, and the like.
Stable expression Heterologous DNA can be stably incorporated into host cells, causing the cell to perpetually express a foreign protein. Methods for the delivery of the DNA into the cell are similar to those described above for transient expression but require the co-transfection of an ancillary gene to confer drug resistance on the targeted host cell. The ensuing drug resistance can be exploited to select and maintain cells that have taken up the heterologous DNA. An assortment of resistance genes are available including but not restricted to Neomycin, Kanamycin, and Hygromycin. For the purposes of receptor studies, stable expression of a heterologous receptor protein is carried out in, but not necessarily restricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc. Cell membrane preparation .
For binding assays, pellets of transfected cells are suspended in ice-cold buffer (20 mM Tris.HCl, 5 mM EDTA, pH 7.4) and homogenized by sonication for 7 sec. The cell lysates are centrifuged at 200 x g for 5 min at 4°C. The supernatants are then centrifuged at 40,000 x g for 20 min at 4°C. The resulting pellets are washed once in the homogenization buffer and suspended in binding buffer (see methods for radioligand binding) . Protein concentrations are determined by the method of Bradford (1976) using bovine serum albumin as the standard. Binding assays are usually performed immediately, however it is possible to prepare membranes in batch and store frozen in liquid nitrogen for future use.
Radioligand binding assays
Radioligand binding assays for the MCHl receptor were carried out using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197). Plasmid pEXJ.HR-TL231 comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to DNA encoding the human MCHl receptor so as to permit expression thereof. Plasmid pEXJ.HR-TL231 was deposited on September 17, 1998, with the American Type Culture Collection (ATCC) , 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and was accorded ATCC Accession No. 203197.
Human embryonic kidney 293 cells (A293 cells) were stably transfected with DNA encoding the MCHl receptor utilizing the calcium phosphate method and cell membranes were prepared as described above. Binding experiments with membranes from A293 cells transfected with the human MCHl receptor were performed with 0.08 nM [3H] Compound 10 (custom labeled by Amersham) using an incubation buffer consisting of 50 mM Tris pH 7.4 , 10 mM MgCl2, 0.16 mM PMSF, 1 mM 1,10 phenantroline and 0.2% BSA. Binding was performed at 25°C for 90 minutes. Incubations were terminated by rapid vacuum filtration over GF/C glass fiber filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding is defined using 10 μM. Compound 10.
The methods to obtain the cDNA of the human NPY1, NPY5, GALR1, GALR2, and GALR3 and rat 5-HT2C receptors, express said receptors in heterologous systems, and carry out assays to determine binding affinity are described in the following publications and above: human NPY1 (Larhammar et al., 1992), human NPY5 (U.S. Patent No. 5,602,024, the disclosure of which is hereby incorporated by reference in its entirety into this application) , human Gall (Habert- Ortoli et al . , 1994), human Gal2 (Smith et al . , 1997), human Gal3 (Smith et al . , 1998), and rat 5-HT2C (Julius et al., 1988) .
Functional assays
Cells may be screened for the presence of endogenous mammalian receptor using functional assays (described in detail below) . Cells with no or a low level of endogenous receptor present may be transfected with the exogenous receptor for use in the following functional assays.
A wide spectrum of assays can be employed to screen for receptor activation. These range from traditional measurements of phosphatidyl inositol, cAMP, Ca++, and K+, for example; to systems measuring these same second messengers but which have been modified or adapted to be higher throughput, more generic, and more sensitive; to cell based platforms reporting more general cellular events resulting from receptor activation such as metabolic changes, differentiation, and cell division/proliferation, for example; to high level organism assays which monitor complex physiological or behavioral changes thought to be involved with receptor activation including cardiovascular, analgesic, orexigenic, anxiolytic, and sedation effects, for example.
Functional assay:
Intracellular calcium mobilization assay
Intracellular calcium mobilization assays for the MCHl receptor were carried out using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197). COS-7 cells were transiently transfected with DNA encoding the MCHl receptor utilizing the DEAE-dextran method as described above. The intracellular free calcium concentration was measured by fluorescent imaging using the calcium sensitive fluorscent dye Fluo-3. COS-7 cells expressing the human MCHl receptor were seeded onto sterile 96 well plates, washed with Hank's balanced salt solution (HBSS) , containing 20 mM HEPES, 2.5 mM probenecid, and 0.1% BSA, and loaded with the same buffer containing 3.8 μM Fluo-3 for 1 hour at 37 °C . After washing with HBSS to remove the fluo-3 solution, cells were equilibrated for 10 minutes. Cells were then incubated with, or without MCH, and the fluorescence is measured using a Fluorescence Imaging Plate Reader (FLIPR, Molecular Devices) .
Materials
Cell culture media and supplements were from Specialty Media (Lavallette, NJ) . Cell culture plates (150 mm and 96-well microtiter) were from Corning (Corning, NY) . Sf9, Sf21, and High Five insect cells, as well as the baculovirus transfer plasmid, pBlueBacIII™, were purchased fro Invitrogen (San Diego, CA) . TMN-FH insect medium complemented with 10% fetal calf serum, and the baculovirus DNA, BaculoGold™, was obtained from Pharmingen (San Diego, CA.) . Ex-Cell 400™ medium with L-Glutamine was purchased from JRH Scientific. Polypropylene 96-well microtiter plates were from Co-star (Cambridge, MA) . Commercially available MCH and related peptide analogs were either from Bachem California (Torrance, CA) or Peninsula (Belmont, CA) . Bio-Rad Reagent was from Bio-Rad (Hercules, CA) . Bovine serum albumin (ultra-fat free, A-7511) was from Sigma (St. Louis. MO) . All other materials were reagent grade .
Functional Assay Results The compounds of Examples 1-37 were assayed using the cloned human MCHl receptor. The preferred compounds were found to be selective MCHl antagonists. The results are summarized in Table 1.
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Radioligand Binding Assay Results
The compounds of Examples 1 to 37 were assayed using cloned human MCHl, NPYl, NPY5, GALR1, GALR2, and GALR3 and rat 5- HT2C receptors. The binding affinities of several compounds are shown in Tables 2 and 3.
The compounds of Examples '38 to 56 were assayed using the cloned rat MCHl receptor. The binding affinities (Ki) of these compounds are shown in Table 4.
Table 2: Antagonist potency (Kb) at the human MCHl receptor, and binding affiity (Ki) NPY, galanin and 5HT2C receptors.
Figure imgf000231_0001
Table 3: Antagonist potency (Kb) at the human MCHl receptor, and binding affiity (Ki) at human MCHl, NPY1, NPY5, GALR1, GALR2 , GALR3, and rat 5HT2C receptors.
Figure imgf000232_0001
* Binding affinity (Ki) was determined in competition binding assays using membrane preparations of A293 cells expressing the human MCHl receptor and [3H] Compound 10 as the radioligand.
Table 4
Ki (nM)
EXAMPLE No. STRUCTURE
Figure imgf000233_0001
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000235_0001
REFERENCES
Auburger, G., et al . , (1992) Assignment of the second ( cuban) locus of autosomal dominant cerebellar ataxia to chromosome 12q23-24.1, between flanking markers D12S58 and PLA2. Cytogenet . Cell . Genet . 61:252-256.
Bahjaoui-Bouhaddi, M., et al . , (1994) Insulin treatment stimulates the rat melanin-concentrating hormone-producing neurons. Neuropeptides 2.4:251-258.
Baker, B.I. (1991) Melanin-concentrating hormone: a general vertebrate neuropeptide . Int. .Rev. Cytol . 126 : 1-47.
Baker, B.I. (1994) Melanin-concentrating hormone update: functional consideration. TEM 5.: 120-126.
Bassett, A.S., et al . , (1988) Partial trisomy chromosome 5 cosegregating with schizophrenia. Lancet 1:799-801.
Bittencourt, J.C., et al . , (1992) The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical characterization . J. Comp . Neurol . 319:218-245.
Burgaud, J.L., et al . , (1997) Melanin-concentrating hormone binding sites in human SVK14 keratinocytes. Biochem . Biophys . Res . Commun . 241 (3) : 622-629.
Craddock, N., et al . , (1993) The gene for Darier's disease maps to chromosome 12q23-q24.1. Hum . Mol . Genet . 2 : 1941- 1943.
Drozdz, R. and Eberle, A.N. (1995) Binding sites for melanin-concentrating hormone (MCH) in brain synaptosomes and membranes from peripheral tissues identified with highly tritiated MCH. J. Recept . Signal . Transduct . Res . 15 (1-4) .-487-502.
Drozdz, R., et al . , (1995) Melanin-concentrating hormone binding to mouse melanoma cells in vitro. FEBS 359 : 199-202.
Drozdz, R., et al . , (1998) Characterization of the receptor for melanin-concentrating hormone on melanoma cells by photocrosslinking. An . NY Acad. Sci . 839 (1) .-210-213.
Gilliam, T.C., et al . , (1989) Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia. Genomics 5.: 940-944.
Gonzalez, M.I., et al . , (1997) Stimulatory effect of melanin-concentrating hormone on luteinizing hormone release. Neuroendocrinology 6j5(4) :254-262.
Gonzalez, M.I., et al., .(1997) α-melanocyte-stimulating hormone (α-MSH) and melanin-concentrating hormone (MCH) modify monoaminergic levels in the preoptic area of the rat. Peptides 18:387-392.
Gonzalez, M.I., et al . , (1996) Behavioral effects of - melanocyte-stimulating hormone (α-MSH) and melanin- concentrating hormone (MCH) after central administration in female rats. Peptides 17 : 171-177.
Grillon, S., et al . , (1997) Exploring the expression of the melanin-concentrating hormone messenger RNA in the rat lateral hypothalamus after goldthioglucose injection. Neuropeptides 31(2) : 131-136. Habert-Ortoli, E., et al.,(1994) Molecular cloning of a functional human galanin receptor. Proc Na tl Acad Sci USA 91:9780-9783.
Herve, C. and Fellmann, D. (1997) Changes in rat melanin- concentrating hormone and dynorphin messenger ribonucleic acids induced by food deprivation. Neuropeptides 31.(3) :237- 242.
Hervieu, G., et al., (1996) Development and stage-dependent expression of melanin-concentrating hormone in mammalian germ cells. Biology of Reproduction 54 : 1161-1172.
Julius, D., et al . , (1988) Molecular characterization of a functional cDNA encoding the serotonin lc receptor. Science 241:558-564.
Kauwachi, H., et al . , (1983) Characterization of melanin- concentrating hormone in chum salmon pituitaries . Na ture 305:321-333.
Knigge, K.M., et al . , (1996) Melanotropic peptides in the mammalian brain: The melanin-concentrating hormone. Peptides 17.: 1063-1073.
Knigge, K.M. and Wagner, J.E. (1997) Melanin-concentrating hormone (MCH) involvement in pentylenetetrazole (PTZ)- induced seizure in rat and guinea pig. Peptides 1_8 (7) :1095- 1097.
Larhammar, D .' , et al . , (1992) Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Yl type. J Biol Chem . 267:10935-10938.
Ludwig, D.S., et al . , (1998) Melanin-concentrating hormone: a functional melanocortin -antagonist in the hypothalamus Am . J. Physiol . Endocrinol . Metab . 274.( ) :E627-E633.
MacKenzie, F.J., et al . , (1984) Evidence that the dopaminergic incerto-hypothalamic tract has a stimulatory effect on ovulation and gonadotropin release. Neuroendocrinology 39.: 289-295.
McBride, R.B., et al . , ■ (1994) The actions of melanin- concentrating hormone (MCH) on passive avoidance in rats: A preliminary study. Peptides 15 : 757-759.
Melki, J. , et al . , (1990) Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature (London) 344:767-768.
Miller, C.L., et al . , (1993) α-MSH and MCH are functional antagonists in a CNS auditory paradigm. Peptides 14 : 1-10.
Nahon, J.L., et al . , (1989) The rat melanin-concentrating hormone mRNA encodes multiple putative neuropeptides coexpressed in the dorsolateral hypothalamus. Endocrinology 125:2056-2065.
Nahon, J-L. (1994) The melanin-concentrating hormone: from the peptide to the gene. Critical Rev. in Neurobiol 221:221-262.
Parkes, D.G. (1996) Diuretic and natriuretic actions of melanin concentrating hormone in conscious sheep. J. Neuroendocrinol . £: 57-63.
Pedeutour, F., et al . , (1994) Assignment of the human pro- melanin-concentrating hormone gene (PMCH) to chromosome 12q23-24 and two variant genes (PMCHL1 and PMCHL2) to chromosome 5pl4 and 5ql2-ql3. Genomics 19 : 31-37.
Presse, F., et al . (1992) Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes during development and after stress and glucocorticoid stimuli. Endocrinology 131 : 1241-1250.
Qu, D., et al . (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380:243-247.
Rossi, M., et al . , (1997) Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 138 : 351-355.
Sahu, A. (1998) Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus . Endocrinology 13_9 (2) : 795-798.
Sakurai, T., et al . , (1998) Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein- coupled receptors that regulate feeding behavior. Cell 92:573-585.
Sanchez, M., et al . , (1997) Melanin-concentrating hormone (MCH) antagonizes the effects of α-MSH and neuropeptide E-I on grooming and locomotor activities in the rat. Peptides 18.:393-396.
Sherrington, R., et al . , (1988) Localization of a susceptibility locus for -schizophrenia on chromosome 5. Nature (London) 336:164-167. Smith. K.E., et al . , (1998) Cloned human and rat galanin GALR3 receptors . Pharmacology and activation of G-protein inwardly rectifying K+ channels. J Biol Chem 273:23321-23326.
Smith, K.E., et al . (1997) Expression cloning of a rat hypothalamic galanin receptor coupled to phosphoinositide turnover. J Biol Chem 272:24612-24616.
Twells, R., et al . , (1992) Chromosomal assignment of the locus causing olivo-ponto-cerebellar atrophy (SCA2) in a cuban founder population. Cytogent . Cell. Cenet . 61 : 262- 265.
Westbrook, C.A., et al . , (1992) Report of the second international workshop on human chromosome 5 mapping. Cytogenet. Cell. Genet. 61:225-231.

Claims

What is claimed is
1. A compound having the structure:
Figure imgf000242_0001
Figure imgf000242_0002
wherein A is
Figure imgf000243_0001
Figure imgf000243_0002
Figure imgf000243_0003
wherein each of Yx , Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; - OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3 ; or any two of Yx, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3;
wherein R is -H; -N02; -CN; straight chained or branched Cι~C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C 3~c 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2 or -C02(CH2)nV;
wherein R2 is -H; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C6-C7 al kenyl or alkynyl ; C,-C- cycloalkyl , monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-Cj^-Cig-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl- Ci-CiQ-polyfluoroalkyl; -CN; -CH2XR3, -CH2X(CH2)pNHR3, -(CH2)nNHR3, -CH2X (CH2) pN (R3) 2, -CH2X(CH2)pN3, or -CH2X (CH2) pNHCXR7 ; -OR3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is
Figure imgf000244_0001
Iii)
Figure imgf000245_0001
Figure imgf000245_0002
Figure imgf000245_0003
(v)
Figure imgf000245_0004
vi
Figure imgf000245_0005
Figure imgf000246_0001
Figure imgf000246_0002
,
Figure imgf000246_0003
wherein the dashed line represents a single bond or a double bond;
wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02 ; -CN; -C02R3; -OR3 ; or -CON(R3)2;
wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3 ; C02R3 ; -CON ( R3 ) 2 ; CN ; -N02 ; -N ( R3 ) 2 ; -OR3 ;
-SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched
Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; 03-07 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched Cx-Cη alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -C0N(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cx-Cη alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is -H; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; - C02R3; -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3 ; -C0N(R3)2; CN; -N02;
-N(R3)2; -OR3; -SR3; ' (CH2)qOR3; (CH2)qSR3; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R7 is H; F; Cl; Br; I; -N02; -N3; -CN; straight chained or branched C^C-y alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -C0R3; -C02R3; or -CON(R3)2;
wherein R8 is independently straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or -benzo [b] thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo [b] furanyl, or benzo [b] thiophenyl may be substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; - N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cj^-C- alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C alkenyl, C2-C7 alkynyl; C^-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof,
A (+) enantiomer of the compound of claim 1
A (-) enantiomer of the compound of claim 1
The compound of claim 1 having the structure:
Figure imgf000249_0001
Figure imgf000249_0002
The compound of claim 4 having the structure:
Figure imgf000250_0001
Figure imgf000250_0002
The compound of claim 5, having the structure
Figure imgf000250_0003
Figure imgf000250_0004
The compound of claim 6, wherein A is
Figure imgf000251_0001
The compound of claim 7, wherein the compound is
Figure imgf000251_0002
Figure imgf000251_0003
Figure imgf000251_0004
Figure imgf000252_0001
Figure imgf000252_0002
The compound of claim 1, wherein the compound has the structure :
Figure imgf000252_0003
10. The compound of claim 9, wherein the compound has the structure :
Figure imgf000252_0004
11. The compound of claim 10, wherein the compound has the structure :
Figure imgf000253_0001
12. The compound of claim 11, wherein A is
Figure imgf000253_0002
13. The compound of claim 12 having the structure
Figure imgf000253_0003
14. The compound of claim 1, having the structure
Figure imgf000254_0001
15. The compound of claim 14, having the structure:
Figure imgf000254_0002
16. The compound of claim 15 having the structure
Figure imgf000254_0003
17. The compound of claim 16 wherein A is
Figure imgf000255_0001
The compound of claim 17 having the structure:
Figure imgf000255_0002
19. The compound of claim 1 having the structure:
Figure imgf000255_0003
20. The compound of claim 19 having the structure
Figure imgf000256_0001
21. The compound of claim 20 having the structure
Figure imgf000256_0002
22. The compound of claim 21 wherein A is
Figure imgf000256_0003
23. The compound of claim 22 having the structure
Figure imgf000257_0001
24. The compound of claim 1 having the structure:
Figure imgf000257_0002
25. The compound of claim 24 having the structure
Figure imgf000257_0003
26. The compound of claim 25 having the structure:
Figure imgf000258_0001
27. The compound of claim 26 wherein A is
Figure imgf000258_0002
28. The compound of claim 27 having the structure
Figure imgf000258_0003
29. The compound of claim 1, wherein the compound is (+) -1,2,3, 6-tetrahydro-l- {n- [4- (3 , -acetamido) -phenyl -piperidin-1-yl] propyl }carboxamido-4 -methoxymethyl-
6- (3 , -difluoro-phenyl) -2-oxopyrimidine-5- carboxylic acid methyl ester.
30. The compound of claim 4 having the structure
Figure imgf000259_0001
31. The compound of claim 30 having the structure:
Figure imgf000259_0002
32. The compound of claim 31 having the structure:
Figure imgf000259_0003
33. A compound having the structure
Figure imgf000260_0001
34. A compound having the structure
Figure imgf000260_0002
wherein each R is independently -H; -F; straight chained or branched C]_-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~C7 alkenyl or alkynyl; -N(R3)2; -N02 ; -CN; -SR3 ; -C02R3 ; or
-OR 3'
wherein each Rx is independently -H; straight chained or branched C^-C-; alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 al kenyl or alkynyl ; cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -(CH2)pOR3; -C0R3; -C02R3; or -CON(R3)2;
wherein each R2 is -H; -N02; -N3; -CN; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; or aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3;
-CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3;
(CH2)qSR3; straight chained or branched
Cj^-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-Cy cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched C -C-/ . alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; straight chained or branched C -Cη alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; 03-07 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2)n, O, S or NR3;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; C02R3;
-C0N(R3)2; CN; -N02 ; -N(R3)2; -OR3; -SR3; (CH2)qOR3; -(CH2)qSR3; straight chained or branched Cχ-C-7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3;
-CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2) qOR3 ; (CH2 ) qSR3 ; straight chained or branched C1-C7 alkyl , monofluoroalkyl , po lyf luoroa lkyl , aminoa lkyl , or carboxamidoalkyl ; straight chained or branched C2-C7 alkenyl , C2 -C7 alkynyl ; C3-C7 cycloalkyl ; -
wherein m is an integer from 0 to 4 inclusive;
wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
35. A (+) enantiomer of the compound of claim 34.
36. A (-) enantiomer of the compound of claim 34.
37. The compound of claim 34 having the structure:
Figure imgf000263_0001
38. The compound of claim 37, wherein W is phenyl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; or (CH2)qSR3.
39. The compound of claim 38 having the structure
Figure imgf000263_0002
0. A compound having the structure
Figure imgf000264_0001
wherein each R is independently -H; -F; straight chained or branched C^C-/ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -C0N(R3)2;
wherein each Rx is independently -H; F; Cl; Br; I; -N02; -N3; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; ~OR3; -(CH2)pOR3; -COR3; -C02R3; -C0N(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cχ-C- alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently -H; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 is -H; -NO,; -N3; -CN; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -C0R3; -C02R3;
-CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl ; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cχ- C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; C02R3; -CON(R3)2; CN; -N02 ; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched ^ - Cη alkyl, monofluoroalkyl , polyfluoroalkyl , aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; C02R3;
-CON(R3)2; CN; -N02 ; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl ;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein n is an integer from 0 to 2 inclusive ,-
wherein p is an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
41. A (+) enantiomer of the compound of claim 40.
42. A (-) enantiomer of the compound of claim 40.
43. The compound of claim 40 having the structure:
Figure imgf000267_0001
44. The compound of claim 43 having the structure
Figure imgf000267_0002
45. A compound of claim 43 wherein W is phenyl optionally substituted with one or more F; Cl ; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)q0R3; (CH2)qSR3; or straight chained or branched C^C-y alkyl groups.
46. A compound of claim 45 having the structure
Figure imgf000268_0001
7. A method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure : having the structure:
Figure imgf000269_0001
Figure imgf000269_0002
wherein A is
Figure imgf000270_0001
Figure imgf000270_0002
Figure imgf000270_0003
wherein each of Yx, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yx , Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3; wherein R1 is -H; -N02; -CN; straight chained or branched Cχ-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; -CON(R3)2; or -C02 (CH2) nV;
wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-Ci-C^- monofluoroalkyl or C3-C10 cycloalkyl-C1-C10- polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3, or -CH2X(CH2)pNHCXR5 ; -OR3; or wherein Rx and.R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is
Figure imgf000271_0001
Figure imgf000272_0001
R7
Figure imgf000272_0002
Figure imgf000272_0003
Y,
Figure imgf000272_0004
Figure imgf000272_0005
[ ii)
Figure imgf000273_0001
Figure imgf000273_0002
R 7
:i )
Figure imgf000273_0003
Ix)
Figure imgf000273_0004
wherein each R is independently -H; -F; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS;
wherein each ϋ is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C-? alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR5;
wherein W is CR5; CR6 or N;
wherein Z is S; 0; C(R 3' 2' or NR 3'
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)p0R3; -C0R3; -C02R3; or -C0N(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C].-^ alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C1-C alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -0R3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2; •
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
48. The method of claim 47, wherein the compound has the structure
Figure imgf000276_0001
9. The method of claim 48, wherein the compound has the structure
Figure imgf000277_0001
Figure imgf000277_0002
50. The method of claim 49, wherein the compound has the structure
Figure imgf000278_0001
Figure imgf000278_0002
51. The method of claim 50, wherein at least one R5 group is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; -N02; -N(R3)2; -OR3; -XCOR8; or straight chained or branched C-L-C7 alkyl.
52 The method of claim 51, wherein A is:
Figure imgf000278_0003
3. The method of claim 52, wherein the compound is selected from the group consisting of:
(b)
Figure imgf000279_0001
;c)
Figure imgf000279_0002
Figure imgf000279_0003
(e)
Figure imgf000280_0001
Figure imgf000280_0002
54. The method of claim 47, wherein the compound has the structure
Figure imgf000280_0003
55. The method of claim 54, wherein the compound has the structure
Figure imgf000281_0001
56 The method of claim 55, wherein A is
and R7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XC0R8; or straight chained or branched Cχ-C7 alkyl.
57. The method of claim 56, wherein the compound has the structure
Figure imgf000281_0003
58. The method of claim 47, wherein the compound has the structure
Figure imgf000282_0001
59. The method of claim 58, wherein the compound has the structure
Figure imgf000282_0002
60 The method of claim 59, wherein A is
Figure imgf000282_0003
and Z is 0 or CH2 ,
1. The method of claim 60, wherein the compound is selected from the group consisting of
Figure imgf000283_0001
Figure imgf000283_0002
Figure imgf000283_0003
62. The method of claim 47, wherein the compound has the structure
Y,
Figure imgf000284_0001
63. The method of claim 62, wherein the compound has the structure
Y
Figure imgf000284_0002
64 The method of claim 63 , wherein A is
Figure imgf000284_0003
65. The method of claim 64, wherein the compound is
Figure imgf000285_0001
Figure imgf000285_0002
66. The method of claim 47, wherein the compound has the structure
Figure imgf000285_0003
67. The method of claim 66, wherein the compound has the structure
Figure imgf000285_0004
68. The method of claim 67, wherein the compound has the structure
Figure imgf000286_0001
69. The method of claim 47, wherein the compound has the structure
Figure imgf000286_0002
70 The method of claim 69, wherein the compound has the structure
Figure imgf000286_0003
71. The method of claim 70, wherein the compound has the structure
Figure imgf000287_0001
72. A method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure :
Figure imgf000287_0002
Figure imgf000287_0003
wherein A is
Figure imgf000288_0001
Figure imgf000288_0002
Figure imgf000288_0003
wherein each of Yx , Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -OR3, -0C0R3, -COR3, -CON(R3)2, or -C00R3; or any two of Yx, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; 0; or NR3; wherein R is -H; -N02; -CN; straight chained or branched Cx-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)p0R3; -C0R3; -C02R3; -CON(R3)2; or -C02(CH2)nV;
wherein R2 is -H; straight chained or branched C^^-C-7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-Cx-C10-alkyl, C3-C10 cycloalk l-Cx-CxQ- monofluoroalkyl or C3-C10 cycloalkyl-C1-C10- polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3, or -CH2X (CH2)pNHCXR5 ; -0R3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R is
Figure imgf000289_0001
R
Figure imgf000290_0001
Figure imgf000290_0002
Figure imgf000290_0003
Y5
Figure imgf000290_0004
Figure imgf000290_0005
(vii)
Figure imgf000291_0001
( viii)
Figure imgf000291_0002
R7
(ix)
Figure imgf000291_0003
(x)
Figure imgf000291_0004
wherein each R is independently -H; -F; straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -0R3; or -CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; ~SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched Cj^-C-y alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C^C-j alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; or -CON(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C;ι_-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched Cχ-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein R7 is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -CO,R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
A method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound effective to treat the subject's depression and/or anxiety wherein the compound has the structure:
Figure imgf000295_0001
wherein A is
Figure imgf000296_0001
Figure imgf000296_0002
Figure imgf000296_0003
wherein each of Y^ Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C^^ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -OR3, -OCOR3, -COR3, -CON(R3)2, or -COOR3; or any two of Yx , Y2, Y3, Y and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3; wherein Rx is -H; -N02; -CN; straight chained or branched Cx-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3i -CON(R3)2; or -C02(CH2)nV;
wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10
Figure imgf000297_0001
C3-C10 cycloalkyl-Cα-C10- monofluoroalkyl or C3-C10
Figure imgf000297_0002
polyfluoroalkyl; -CN; -CH2XR3, -CH2X (CH2) pNHR3, -(CH2)nNHR3, -CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3, or -CH2X(CH2)pNHCXR5 ; -OR3; or wherein Rx and R2 together form a lactone ring;
wherein each R3 is independently -H; straight chained or branched C^C-/ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl ;
wherein R4 is
Figure imgf000297_0003
R7
Figure imgf000298_0001
R^
Figure imgf000298_0002
Figure imgf000298_0003
Yc
Figure imgf000298_0004
Figure imgf000298_0005
(vii)
Figure imgf000299_0001
(viii;
Figure imgf000299_0002
R 7
(ix)
Figure imgf000299_0003
(x)
Figure imgf000299_0004
wherein each R is independently -H; -F; straight chained or branched Cj-C-? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -N02; -CN; -C02R3; -OR3; or -CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; 0; S; NR3; CO; or CS;
wherein each ϋ is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; ~SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C;ι.-C alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; 0; C(R3)2; or NR3;
wherein each R5 is -H; -N02; -N3; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -0R3; -(CH2)pOR3; -C0R3; -C02R3; or -CON(R3)2; -XC0R8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; C0R3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched Cx-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently -H; straight chained or branched Cx-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2;
wherein R is -H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; ~N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; -XCOR8; straight chained or branched C^C-y alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is -H; straight chained or branched C^^ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; -(CH2)pOR3; -COR3; -C02R3; or -CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; C02R3; -CON(R3)2; CN; -N02; -N(R3)2; -OR3; -SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C^C^ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
A method of modifying' feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of:
Figure imgf000303_0002
Figure imgf000304_0001
Figure imgf000304_0002
Figure imgf000304_0003
Figure imgf000304_0004
Figure imgf000305_0001
75. A method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of claim 34 or 38 effective to decrease the consumption of food by the subject.
76. A method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of claim 1, 34 or 38 effective to decrease the consumption of food by the subject.
77. The method of claim 76, wherein the feeding disorder is bulimia, obesity or bulimia nervosa.
78. A method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of claim 34 or 38 effective to reduce the body mass of the subject.
79. A method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of claim 34 or 38 effective to treat the subject's depression and/or anxiety.
80. The method of claim 47, 74, 75 or 76, wherein the subject is a vertebrate, a mammal, a human or a canine.
81. The method of claim 47, 74, 75 or 76, wherein the compound is administered in combination with food.
82. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, 34 or 38 and a pharmaceutically acceptable carrier .
83. The pharmaceutical composition of claim 82 wherein the amount of the compound is from about 0.01 mg to about 500 mg .
84. The pharmaceutical composition of claim 83 wherein the amount of the compound is from about 0.1 mg to about 60 mg.
85. The pharmaceutical composition of claim 84 wherein the amount of the compound is from about 1 mg to about 20 mg .
86. The pharmaceutical composition of claim 82, wherein the carrier is a liquid and the composition is a solution.
87. The pharmaceutical composition of claim 82, wherein the carrier is a solid and the composition is a tablet.
88. The pharmaceutical composition of claim 82, wherein the carrier is a gel and the composition is a suppository.
89. A pharmaceutical composition made by combining a therapeutically effective amount of the compound of claim 1, 34 or 38 and a pharmaceutically acceptable carrier. A process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of claim 1, 34 or 38 and a pharmaceutically acceptable carrier.
PCT/US2001/021286 2000-07-05 2001-07-05 Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof WO2002006245A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2002512149A JP2004504303A (en) 2000-07-05 2001-07-05 Selective melanin-concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
EP01952440A EP1299362A4 (en) 2000-07-05 2001-07-05 Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof
CA002384041A CA2384041A1 (en) 2000-07-05 2001-07-05 Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof
AU73192/01A AU783403B2 (en) 2000-07-05 2001-07-05 Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
AU2006200052A AU2006200052A1 (en) 2000-07-05 2006-01-06 Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US61021300A 2000-07-05 2000-07-05
US09/610,213 2000-07-05

Publications (1)

Publication Number Publication Date
WO2002006245A1 true WO2002006245A1 (en) 2002-01-24

Family

ID=24444133

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/021286 WO2002006245A1 (en) 2000-07-05 2001-07-05 Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof

Country Status (5)

Country Link
EP (1) EP1299362A4 (en)
JP (1) JP2004504303A (en)
AU (1) AU783403B2 (en)
CA (1) CA2384041A1 (en)
WO (1) WO2002006245A1 (en)

Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6569861B2 (en) 2000-07-06 2003-05-27 Neurogen Corporation Melanin concentrating hormone receptor ligands
WO2003070244A1 (en) * 2002-02-22 2003-08-28 Abbott Laboratories Antagonist of melanin concentrating hormone and their uses
WO2004002986A2 (en) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Novel benzimidazole derivatives
WO2004002987A1 (en) * 2002-06-27 2004-01-08 Schering Corporation Spirosubstituted piperidines as selective melanin concentrating hormone receptor antagonists for the treatment of obesity
WO2004024702A1 (en) * 2002-08-24 2004-03-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof
US6720324B2 (en) 2000-07-05 2004-04-13 Synaptic Pharmaceutical Corporation Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
WO2004039764A1 (en) * 2002-10-31 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel amide compounds with mch antagonistic effect and medicaments comprising said compounds
WO2004072018A1 (en) * 2003-02-12 2004-08-26 Takeda Pharmaceutical Company Limited Amine derivative
WO2004078745A1 (en) * 2003-02-28 2004-09-16 Schering Corporation Biaryltetrahydroisoquinoline piperidines as selective mch receptor antagonists for the treatment of obesity and related disorders
JP2004262931A (en) * 2003-02-12 2004-09-24 Takeda Chem Ind Ltd Amine derivative
US6809104B2 (en) 2001-05-04 2004-10-26 Tularik Inc. Fused heterocyclic compounds
US6818772B2 (en) 2002-02-22 2004-11-16 Abbott Laboratories Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
US6858619B2 (en) 2001-05-04 2005-02-22 Amgen Inc. Fused heterocyclic compounds
WO2005028438A1 (en) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
EP1531816A1 (en) * 2002-07-03 2005-05-25 H. Lundbeck A/S Spirocyclic piperidines as mch1 antagonists and uses thereof
WO2005047293A1 (en) * 2003-11-07 2005-05-26 Neurocrine Biosciences, Inc. Melanin-concentrating hormone receptor antagonists and compositions and methods related thereto
US6906075B2 (en) 2002-01-10 2005-06-14 Neurogen Corp. Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues
EP1556351A1 (en) * 2002-07-03 2005-07-27 H. Lundbeck A/S Secondary amino anilinic piperidines as mch1 antagonists and uses thereof
US6953801B2 (en) 2001-05-22 2005-10-11 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues
WO2006018280A2 (en) 2004-08-16 2006-02-23 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, method for the production thereof, and use thereof as a medicament
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
US7067509B2 (en) 2003-03-07 2006-06-27 Neurocrine Biosciences, Inc. Melanin-concentrating hormone receptor antagonists and compositions and methods related thereto
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
US7105544B2 (en) 2001-07-05 2006-09-12 Synaptic Pharmaceutical Corporation Substituted alkyl amido piperidines
JP2006522812A (en) * 2003-04-11 2006-10-05 スミスクライン ビーチャム コーポレーション Heterocyclic MCHR1 antagonist
WO2006129826A1 (en) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
US7157461B2 (en) 2003-07-23 2007-01-02 Bristol-Myers Squibb Co. Substituted dihydropyrimidine inhibitors of calcium channel function
US7160879B2 (en) 2002-01-10 2007-01-09 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 2-(4-benzyl-piperazin-1-ylmethyl)- and 2-(4-benzyl-diazepan-1-ylmethyl)-1H-benzoimidazole analogues
US7166603B2 (en) 2003-07-23 2007-01-23 Bristol-Myers Squibb Co. Dihydropyrimidone inhibitors of calcium channel function
WO2007018248A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
WO2007024004A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
WO2007029847A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
US7199135B2 (en) 2001-07-05 2007-04-03 H. Lundbeck A/S Substituted alkyl amido piperidines
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2007049798A1 (en) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Novel benzoxathiin derivative
WO2007055418A1 (en) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Aza-substituted spiro derivative
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
US7253179B2 (en) 2002-11-06 2007-08-07 Amgen Inc. Fused heterocyclic compounds
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
WO2008038692A1 (en) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
WO2008060476A2 (en) 2006-11-15 2008-05-22 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
WO2008120653A1 (en) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
US7524862B2 (en) 2004-04-14 2009-04-28 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
WO2009082346A1 (en) * 2007-12-21 2009-07-02 Astrazeneca Ab New acetyl coenzyme a carboxylase (acc) inhibitors and uses in treatments of obesity and diabetes mellitus - 087
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2009110510A1 (en) 2008-03-06 2009-09-11 萬有製薬株式会社 Alkylaminopyridine derivative
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US7592358B2 (en) 2004-04-14 2009-09-22 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
WO2009119726A1 (en) 2008-03-28 2009-10-01 萬有製薬株式会社 Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor
EP2127676A2 (en) 2004-11-01 2009-12-02 Amylin Pharmaceuticals, Inc. Treatment of obesity and related disorders
WO2009154132A1 (en) 2008-06-19 2009-12-23 萬有製薬株式会社 Spirodiamine-diarylketoxime derivative
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
WO2010013595A1 (en) 2008-07-30 2010-02-04 萬有製薬株式会社 (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
US7674792B2 (en) 2005-06-08 2010-03-09 Glaxosmithkline Llc 5(Z)-5-(6-quinoxalinylmethylidene)-2-[2,6-dichlorophenyl)amino]-1,3-thiazol-4(5H)-one
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051236A1 (en) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
US7727998B2 (en) 2003-02-10 2010-06-01 Banyu Pharmaceutical Co., Ltd. Melanin-concentrating hormone receptor antagonists containing piperidine derivatives as the active ingredient
US7732456B2 (en) 2004-03-05 2010-06-08 Banyu Pharmaceutical Co., Ltd. Pyridone derivative
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2010075069A1 (en) 2008-12-16 2010-07-01 Schering Corporation Bicyclic pyranone derivatives as nicotinic acid receptor agonists
WO2010075068A1 (en) 2008-12-16 2010-07-01 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
US7767701B2 (en) 2002-11-22 2010-08-03 Glaxosmithkline Llc Chemical compounds
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
EP2330124A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
EP2330125A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
EP2332526A2 (en) 2005-10-21 2011-06-15 Novartis AG Combination of a renin-inhibitor and an anti-dyslipidemic agent and/or an antiobesity agent
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2013059222A1 (en) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US8501771B2 (en) 2006-02-15 2013-08-06 Sanofi Aminoalcohol-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
US8552199B2 (en) 2009-02-13 2013-10-08 Sanofi Substituted indanes, method for the production thereof, and use thereof as drugs
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
EP2698157A1 (en) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
US8841290B2 (en) 2009-02-13 2014-09-23 Sanofi Substituted tetrahydronaphthalenes, method for the production thereof, and use thereof as drugs
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
CN104098562A (en) * 2013-04-12 2014-10-15 苏州科捷生物医药有限公司 Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2016030534A1 (en) 2014-08-29 2016-03-03 Tes Pharma S.R.L. INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2018069532A1 (en) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
WO2020104456A1 (en) 2018-11-20 2020-05-28 Tes Pharma S.R.L INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
WO2020167706A1 (en) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
WO2021026047A1 (en) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
WO2022040070A1 (en) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Bicycloheptane pyrrolidine orexin receptor agonists
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
EP4151210A3 (en) * 2020-01-10 2023-06-14 Harmony Biosciences, LLC Pyridine-carboline derivatives as mchr1 antagonists for use in therapy

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006247695B2 (en) * 2005-05-17 2012-08-09 Merck Sharp & Dohme Corp. Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6245773B1 (en) * 1996-05-16 2001-06-12 Synaptic Pharmaceutical Corporation 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2673381B2 (en) * 1990-02-23 1997-11-05 持田製薬 株式会社 Pre-diabetes treatment agent and / or lipid lowering agent
MX9703518A (en) * 1994-11-16 1997-08-30 Synaptic Pharma Corp Dihydropyrimidines and uses thereof.
EP1021185A4 (en) * 1996-05-16 2005-09-07 Synaptic Pharma Corp Didhydropyrimidines and uses thereof
CA2260983A1 (en) * 1996-07-23 1998-01-29 Charles A. Blum Certain amido- and amino-substituted benzylamine derivatives; a new class of neuropeptite y1 specific ligands
TW492957B (en) * 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
AU733883B2 (en) * 1997-02-04 2001-05-31 Bristol-Myers Squibb Company Dihydropyrimidone derivatives as NPY antagonists
SI0921125T1 (en) * 1997-12-05 2002-04-30 F. Hoffmann-La Roche Ag 1,3,8-Triazaspiro(4,5)decan-4-on derivatives
WO2000006565A1 (en) * 1998-07-30 2000-02-10 Merck & Co., Inc. ALPHA 1a ADRENERGIC RECEPTOR ANTAGONISTS
US6632836B1 (en) * 1998-10-30 2003-10-14 Merck & Co., Inc. Carbocyclic potassium channel inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245773B1 (en) * 1996-05-16 2001-06-12 Synaptic Pharmaceutical Corporation 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1299362A4 *

Cited By (149)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6720324B2 (en) 2000-07-05 2004-04-13 Synaptic Pharmaceutical Corporation Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
US6569861B2 (en) 2000-07-06 2003-05-27 Neurogen Corporation Melanin concentrating hormone receptor ligands
US6753336B2 (en) 2000-07-06 2004-06-22 Neurogen Corporation Melanin concentrating hormone receptor ligands
US7323478B2 (en) 2000-07-06 2008-01-29 Neurogen Corporation Melanin concentrating hormone receptor ligands
US6858619B2 (en) 2001-05-04 2005-02-22 Amgen Inc. Fused heterocyclic compounds
US7125885B2 (en) 2001-05-04 2006-10-24 Amgen Inc. Fused heterocyclic compounds
US6809104B2 (en) 2001-05-04 2004-10-26 Tularik Inc. Fused heterocyclic compounds
US6953801B2 (en) 2001-05-22 2005-10-11 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues
US7081458B2 (en) 2001-05-22 2006-07-25 Neurogen Corp. Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues
US7105544B2 (en) 2001-07-05 2006-09-12 Synaptic Pharmaceutical Corporation Substituted alkyl amido piperidines
US7199135B2 (en) 2001-07-05 2007-04-03 H. Lundbeck A/S Substituted alkyl amido piperidines
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
US7160879B2 (en) 2002-01-10 2007-01-09 Neurogen Corporation Melanin concentrating hormone receptor ligands: substituted 2-(4-benzyl-piperazin-1-ylmethyl)- and 2-(4-benzyl-diazepan-1-ylmethyl)-1H-benzoimidazole analogues
US6906075B2 (en) 2002-01-10 2005-06-14 Neurogen Corp. Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues
US6818772B2 (en) 2002-02-22 2004-11-16 Abbott Laboratories Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
WO2003070244A1 (en) * 2002-02-22 2003-08-28 Abbott Laboratories Antagonist of melanin concentrating hormone and their uses
CN100374440C (en) * 2002-06-27 2008-03-12 先灵公司 Spirosubstituted piperidines as selective melanin concentrating hormone receptor antagonists for the treatment of obesity
US7109207B2 (en) 2002-06-27 2006-09-19 Schering Corporation Spirosubstituted piperidines as selective melanin concentrating hormone receptor antagonists for the treatment of obesity
WO2004002987A1 (en) * 2002-06-27 2004-01-08 Schering Corporation Spirosubstituted piperidines as selective melanin concentrating hormone receptor antagonists for the treatment of obesity
WO2004002986A2 (en) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Novel benzimidazole derivatives
US7335665B2 (en) 2002-07-03 2008-02-26 H - Lundbeck A/S Spirocyclic piperidines as MCH1 antagonists and uses thereof
EP1531816A1 (en) * 2002-07-03 2005-05-25 H. Lundbeck A/S Spirocyclic piperidines as mch1 antagonists and uses thereof
EP1556351A4 (en) * 2002-07-03 2007-07-25 Lundbeck & Co As H Secondary amino anilinic piperidines as mch1 antagonists and uses thereof
EP1531816B1 (en) * 2002-07-03 2009-01-21 H. Lundbeck A/S Spirocyclic piperidines as mch1 antagonists and uses thereof
EP1531816A4 (en) * 2002-07-03 2005-12-28 Lundbeck & Co As H Spirocyclic piperidines as mch1 antagonists and uses thereof
EP1556351A1 (en) * 2002-07-03 2005-07-27 H. Lundbeck A/S Secondary amino anilinic piperidines as mch1 antagonists and uses thereof
US7473698B2 (en) 2002-07-03 2009-01-06 H. Lunbeck A/S Secondary amino anilinic piperidines as MCH1 antagonists and uses thereof
WO2004024702A1 (en) * 2002-08-24 2004-03-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof
EA012834B1 (en) * 2002-08-24 2009-12-30 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Novel carboxamide compounds having an mch-antagonistic effect, medicaments containing said compounds, and methods for the production thereof
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
WO2004039764A1 (en) * 2002-10-31 2004-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel amide compounds with mch antagonistic effect and medicaments comprising said compounds
EA009040B1 (en) * 2002-10-31 2007-10-26 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Novel amide compounds with mch antagonistic effect and medicaments comprising said compounds
US7253179B2 (en) 2002-11-06 2007-08-07 Amgen Inc. Fused heterocyclic compounds
US7767701B2 (en) 2002-11-22 2010-08-03 Glaxosmithkline Llc Chemical compounds
US7727998B2 (en) 2003-02-10 2010-06-01 Banyu Pharmaceutical Co., Ltd. Melanin-concentrating hormone receptor antagonists containing piperidine derivatives as the active ingredient
JP2004262931A (en) * 2003-02-12 2004-09-24 Takeda Chem Ind Ltd Amine derivative
US7601868B2 (en) 2003-02-12 2009-10-13 Takeda Pharmaceutical Company Limited Amine derivative
JP4630555B2 (en) * 2003-02-12 2011-02-09 武田薬品工業株式会社 Amine derivatives
WO2004072018A1 (en) * 2003-02-12 2004-08-26 Takeda Pharmaceutical Company Limited Amine derivative
WO2004078745A1 (en) * 2003-02-28 2004-09-16 Schering Corporation Biaryltetrahydroisoquinoline piperidines as selective mch receptor antagonists for the treatment of obesity and related disorders
US7498441B2 (en) 2003-02-28 2009-03-03 Schering Corporation Biaryltetrahydroisoquinoline piperidines as selective MCH receptor antagonists for the treatment of obesity and related disorders
US7067509B2 (en) 2003-03-07 2006-06-27 Neurocrine Biosciences, Inc. Melanin-concentrating hormone receptor antagonists and compositions and methods related thereto
JP2006522812A (en) * 2003-04-11 2006-10-05 スミスクライン ビーチャム コーポレーション Heterocyclic MCHR1 antagonist
US7157461B2 (en) 2003-07-23 2007-01-02 Bristol-Myers Squibb Co. Substituted dihydropyrimidine inhibitors of calcium channel function
US7166603B2 (en) 2003-07-23 2007-01-23 Bristol-Myers Squibb Co. Dihydropyrimidone inhibitors of calcium channel function
WO2005028438A1 (en) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
WO2005047293A1 (en) * 2003-11-07 2005-05-26 Neurocrine Biosciences, Inc. Melanin-concentrating hormone receptor antagonists and compositions and methods related thereto
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
US8299104B2 (en) 2004-01-25 2012-10-30 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
US7241787B2 (en) 2004-01-25 2007-07-10 Sanofi-Aventis Deutschland Gmbh Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments
US7732456B2 (en) 2004-03-05 2010-06-08 Banyu Pharmaceutical Co., Ltd. Pyridone derivative
EP2088154A1 (en) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
US7524862B2 (en) 2004-04-14 2009-04-28 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US7592358B2 (en) 2004-04-14 2009-09-22 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
US8357686B2 (en) 2004-08-16 2013-01-22 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, method for the production thereof, and use thereof as a medicament
WO2006018280A2 (en) 2004-08-16 2006-02-23 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, method for the production thereof, and use thereof as a medicament
US7838547B2 (en) 2004-08-16 2010-11-23 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, method for the production thereof, and use thereof as a medicament
EP2286840A2 (en) 2004-11-01 2011-02-23 Amylin Pharmaceuticals, Inc. Treatment of obesity and related diseases
EP2127676A2 (en) 2004-11-01 2009-12-02 Amylin Pharmaceuticals, Inc. Treatment of obesity and related disorders
EP2286838A2 (en) 2004-11-01 2011-02-23 Amylin Pharmaceuticals, Inc. Treatment of obesity and related disorders
EP2286839A2 (en) 2004-11-01 2011-02-23 Amylin Pharmaceuticals, Inc. Treatment of obesity and related diseases
EP2286837A2 (en) 2004-11-01 2011-02-23 Amylin Pharmaceuticals, Inc. Treatment of obesity and obesity related diseases
WO2006129826A1 (en) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Novel piperidine derivative
US7674792B2 (en) 2005-06-08 2010-03-09 Glaxosmithkline Llc 5(Z)-5-(6-quinoxalinylmethylidene)-2-[2,6-dichlorophenyl)amino]-1,3-thiazol-4(5H)-one
WO2007018248A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
EP2330124A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
EP2330125A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
US7875633B2 (en) 2005-08-24 2011-01-25 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
WO2007024004A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
WO2007029847A1 (en) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Bicyclic aromatic substituted pyridone derivative
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
EP2332526A2 (en) 2005-10-21 2011-06-15 Novartis AG Combination of a renin-inhibitor and an anti-dyslipidemic agent and/or an antiobesity agent
WO2007049798A1 (en) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Novel benzoxathiin derivative
WO2007055418A1 (en) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Aza-substituted spiro derivative
US8501771B2 (en) 2006-02-15 2013-08-06 Sanofi Aminoalcohol-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments
WO2008017381A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
EP2946778A1 (en) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
EP2698157A1 (en) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
WO2008038692A1 (en) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
WO2008060476A2 (en) 2006-11-15 2008-05-22 Schering Corporation Nitrogen-containing heterocyclic compounds and methods of use thereof
WO2008120653A1 (en) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
EP2998314A1 (en) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8609731B2 (en) 2007-08-15 2013-12-17 Sanofi Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2009082346A1 (en) * 2007-12-21 2009-07-02 Astrazeneca Ab New acetyl coenzyme a carboxylase (acc) inhibitors and uses in treatments of obesity and diabetes mellitus - 087
WO2009110510A1 (en) 2008-03-06 2009-09-11 萬有製薬株式会社 Alkylaminopyridine derivative
WO2009119726A1 (en) 2008-03-28 2009-10-01 萬有製薬株式会社 Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor
EP2810951A2 (en) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2009154132A1 (en) 2008-06-19 2009-12-23 萬有製薬株式会社 Spirodiamine-diarylketoxime derivative
WO2010003624A2 (en) 2008-07-09 2010-01-14 Sanofi-Aventis Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
EP3241839A1 (en) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders
WO2010013595A1 (en) 2008-07-30 2010-02-04 萬有製薬株式会社 (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010051236A1 (en) 2008-10-30 2010-05-06 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
WO2010051206A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
WO2010075069A1 (en) 2008-12-16 2010-07-01 Schering Corporation Bicyclic pyranone derivatives as nicotinic acid receptor agonists
WO2010075068A1 (en) 2008-12-16 2010-07-01 Schering Corporation Pyridopyrimidine derivatives and methods of use thereof
US8552199B2 (en) 2009-02-13 2013-10-08 Sanofi Substituted indanes, method for the production thereof, and use thereof as drugs
US8841290B2 (en) 2009-02-13 2014-09-23 Sanofi Substituted tetrahydronaphthalenes, method for the production thereof, and use thereof as drugs
WO2011023754A1 (en) 2009-08-26 2011-03-03 Sanofi-Aventis Novel crystalline heteroaromatic fluoroglycoside hydrates, pharmaceuticals comprising these compounds and their use
EP2923706A1 (en) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia
WO2011069038A2 (en) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
WO2011106273A1 (en) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP3243385A1 (en) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012116145A1 (en) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120050A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
WO2012120058A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120051A1 (en) 2011-03-08 2012-09-13 Sanofi Benzyl-oxathiazine derivates substituted with adamantane or noradamantane, medicaments containing said compounds and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2013059222A1 (en) 2011-10-19 2013-04-25 Merck Sharp & Dohme Corp. 2-pyridyloxy-4-nitrile orexin receptor antagonists
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
US9399626B2 (en) 2011-11-11 2016-07-26 Pfizer Inc. 2-thiopyrimidinones
US9873673B2 (en) 2011-11-11 2018-01-23 Pfizer Inc. 2-thiopyrimidinones
EP4309673A2 (en) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2013138352A1 (en) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations of guanylate cyclase c agonists and methods of use
EP3708179A1 (en) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations of guanylate cyclase c agonists and methods of use
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
WO2014151200A2 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014151206A1 (en) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
CN104098562A (en) * 2013-04-12 2014-10-15 苏州科捷生物医药有限公司 Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione
WO2014197720A2 (en) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Ultra-pure agonists of guanylate cyclase c, method of making and using same
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2016030534A1 (en) 2014-08-29 2016-03-03 Tes Pharma S.R.L. INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US10513499B2 (en) 2014-08-29 2019-12-24 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
WO2018069532A1 (en) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
WO2020104456A1 (en) 2018-11-20 2020-05-28 Tes Pharma S.R.L INHIBITORS OF α-AMINO-β-CARBOXYMUCONIC ACID SEMIALDEHYDE DECARBOXYLASE
WO2020167706A1 (en) 2019-02-13 2020-08-20 Merck Sharp & Dohme Corp. 5-alkyl pyrrolidine orexin receptor agonists
US11427540B2 (en) 2019-07-11 2022-08-30 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
US11649207B2 (en) 2019-07-11 2023-05-16 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
WO2021026047A1 (en) 2019-08-08 2021-02-11 Merck Sharp & Dohme Corp. Heteroaryl pyrrolidine and piperidine orexin receptor agonists
EP4151210A3 (en) * 2020-01-10 2023-06-14 Harmony Biosciences, LLC Pyridine-carboline derivatives as mchr1 antagonists for use in therapy
WO2022040070A1 (en) 2020-08-18 2022-02-24 Merck Sharp & Dohme Corp. Bicycloheptane pyrrolidine orexin receptor agonists

Also Published As

Publication number Publication date
JP2004504303A (en) 2004-02-12
AU7319201A (en) 2002-01-30
EP1299362A4 (en) 2004-11-03
CA2384041A1 (en) 2002-01-24
EP1299362A1 (en) 2003-04-09
AU783403B2 (en) 2005-10-20

Similar Documents

Publication Publication Date Title
AU783403B2 (en) Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
US6720324B2 (en) Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
AU727972B2 (en) Dihydropyrimidines and uses thereof
US6245773B1 (en) 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
US6248747B1 (en) 5-(heterocyclic alkyl)-6-aryl-dihydropyrimidines
EP1246847A2 (en) Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof
EP1318811B1 (en) Cyclopentyl modulators of chemokine receptor activity
EP1531816B1 (en) Spirocyclic piperidines as mch1 antagonists and uses thereof
JP4870163B2 (en) Indan derivatives as MCH receptor antagonists
JP2003525928A (en) Novel CCR5 modulators: benzimidazoles or benztriazoles
US7105544B2 (en) Substituted alkyl amido piperidines
WO2004064774A2 (en) Dna encoding a human melanin concentrating hormone receptor (mch1) and uses thereof
US7473698B2 (en) Secondary amino anilinic piperidines as MCH1 antagonists and uses thereof
AU2006200052A1 (en) Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof
EP1139972A1 (en) Dihydropyrimidines and uses thereof
JP2006525274A (en) Novel piperidine derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2002 512149

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 2384041

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 73192/01

Country of ref document: AU

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2001952440

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 2001952440

Country of ref document: EP

ENP Entry into the national phase

Country of ref document: RU

Kind code of ref document: A

Format of ref document f/p: F

WWG Wipo information: grant in national office

Ref document number: 73192/01

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 2001952440

Country of ref document: EP