WO2004098602A1 - Melanocortin receptor-specific compounds - Google Patents
Melanocortin receptor-specific compounds Download PDFInfo
- Publication number
- WO2004098602A1 WO2004098602A1 PCT/US2004/013803 US2004013803W WO2004098602A1 WO 2004098602 A1 WO2004098602 A1 WO 2004098602A1 US 2004013803 W US2004013803 W US 2004013803W WO 2004098602 A1 WO2004098602 A1 WO 2004098602A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- propyl
- piperazin
- naphthalen
- phenyl
- Prior art date
Links
- 0 CCC(*)(CC*C)N1CC*CC1 Chemical compound CCC(*)(CC*C)N1CC*CC1 0.000 description 10
- FXKUKPDMOLUQLE-UHFFFAOYSA-N C=Cc(ccc(N)c1)c1N Chemical compound C=Cc(ccc(N)c1)c1N FXKUKPDMOLUQLE-UHFFFAOYSA-N 0.000 description 1
- HFHJEKPCGRUUKC-KBKXWFDOSA-N C[C@H](C1)N(CCc2c[nH]c3ccccc23)C[C@H](CCCNC(N)=N)N1C([C@@H](Cc1ccc(cccc2)c2c1)N)=O Chemical compound C[C@H](C1)N(CCc2c[nH]c3ccccc23)C[C@H](CCCNC(N)=N)N1C([C@@H](Cc1ccc(cccc2)c2c1)N)=O HFHJEKPCGRUUKC-KBKXWFDOSA-N 0.000 description 1
- KSLBZUIMVNLVLV-PUZWTLIVSA-N C[C@H](C1)N(Cc2cnc[nH]2)C[C@H](CCCNC(N)=N)N1C([C@@H](Cc1ccc(cccc2)c2c1)N)=O Chemical compound C[C@H](C1)N(Cc2cnc[nH]2)C[C@H](CCCNC(N)=N)N1C([C@@H](Cc1ccc(cccc2)c2c1)N)=O KSLBZUIMVNLVLV-PUZWTLIVSA-N 0.000 description 1
- KADDFHJZQINRAC-GRRRMQDASA-N C[C@H](CN([C@H]1CCCNC(N)=N)C([C@@H](Cc2cc(cccc3)c3cc2)N)=O)N(CCc2cc3ccccc3cc2)C1=O Chemical compound C[C@H](CN([C@H]1CCCNC(N)=N)C([C@@H](Cc2cc(cccc3)c3cc2)N)=O)N(CCc2cc3ccccc3cc2)C1=O KADDFHJZQINRAC-GRRRMQDASA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic 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
-
- 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
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P35/00—Antineoplastic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- Piperazines are an important class of molecular templates that have been employed in the development of several drugs. However, in the prior art generally only mono- or di-substituted piperazine templates have been employed.
- a tri-substituted piperazine such as Indinavir (Merck), an HIV protease inhibitor drug that incorporates a trisubstituted piperazine.
- Indinavir Merk
- an HIV protease inhibitor drug that incorporates a trisubstituted piperazine.
- melanocortin 1 receptors MC1-R
- melanocortin 2 receptors M2-R
- ACTH adrenocorticotropin
- MC3- R and MC4-R melanocortin 4 receptors
- MC5-R melanocortin 5 receptors
- compounds specific for MC1 -R are believed to be useful for treatment of melanoma.
- Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia and cachexia, for treatment of obesity, and treatment of other food intake and metabolism-related indications.
- Compounds specific for MC3-R and MC4-R, among other melanocortin receptors can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction.
- Other clinical uses are being explored, such as use of MC4-R antagonists as anxiolytic or antidepressant drugs.
- melanocortin receptor-specific compounds such as MCR-1 agonists
- MCR-1 and MCR-3 may further be useful in regulation of inflammatory processes.
- Compounds specific for MCR-5 may be used for treatment of acne and related skin disorders due to over stimulation of sebaceous gland.
- Compounds specific for MCR-4 and MCR-5 may be used for treatment of depression.
- Compounds specific for MCR-3 may find use as a therapeutic for treating salt-induced hypertension.
- the melanocortin system is involved in diverse physiological functions, including energy balance, pigmentation, sexual function and inflammation.
- melanocortin receptors There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as for compounds that are agonists, inverse agonists, antagonists, or otherwise bind to specific melanocortin receptors.
- High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with melanocortin receptors, as agonists, antagonists, inverse agonists or otherwise.
- melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
- Piperazine Compounds There are piperazine and piperidine compounds known, such as those disclosed in WO 03/009850 (Amgen), WO 03/009847 (Amgen), WO 03/094918 (Neurocrine Biosciences), WO 03/1093234 (Procter & Gamble), WO 03/092690 (Procter & Gamble), WO 03/061660 (Eli Lilly and Company), WO 03/053927 (Taisho Pharm.), WO 03/031410 (Neurocrine Biosciences), WO 03/007949 (Merck & Co.), WO 02/092566 (Taisho Pharm.), WO 02/079146
- WO 02/085925 "Melanocortin Receptor Ligands", to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, piperazine structures with four substituted groups, methods to synthesize piperazine structures, methods to synthesize piperazine or ketopiperazine structures with four substituted groups, or methods to synthesize optically pure structures, and further does not disclose structures with a single substituent group that is a single D-Phe residue, or a derivative or homolog thereof, optionally with an amine capping group.
- the invention provides a compound having the formula of structure I:
- R 2a and R 2b are -L 2 -W and the remaining of R 2 and R 2b is hydrogen;
- R 3 is -U-Q; is a bond or a linker unit comprising from one to eight backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
- J is a ring structure selected from the group consisting of substituted or unsubstituted aromatic carbocyclic rings, substituted or unsubstituted non-aromatic carbocyclic rings, substituted or unsubstituted aromatic fused carbobicyclic ring groups, two substituted or unsubstituted aromatic carbocyclic rings wherein the rings are joined by a bond or -0-, and substituted or unsubstituted aromatic fused heterobicyclic ring groups; wherein in each instance the rings include 5 or 6 ring atoms;
- L 2 is a bond or -(CH 2 ) y -;
- W is a heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor wherein at least one heteroatom is nitrogen or oxygen;
- L 3 is a bond or a linker unit comprising from one to nine backbone atoms selected from the group consisting of carbon, sulfur, oxygen or nitrogen;
- Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
- R 4a , R 4b , ⁇ a , and R 5 are independently -L 2 -W or a Ci to C 6 aliphatic linear or branched chain and the remaining of R 4a , R 4b , R 5a , and R s are hydrogen, provided that at least one of R 4a and R 4b and at least one of R 5a and R 5b are hydrogen; and y is at each occurrence independently from 1 to 6.
- X is CH 2 in the compound of structure I.
- J is a substituted or unsubstituted ring structure selected from the group consisting of
- J is substituted with one or more ring substituents independently selected from the group consisting of hydroxyl, halogen, sulfonamide, alkyl or aryl groups attached directly or through an ether linkage in the compound of structure I.
- L 2 is (CH 2 ) y wherein y is between 1 and 4.
- L 3 may be a linker unit selected from the group consisting of:
- R 6a and R 6b are each independently selected from the group consisting of hydrogen, R 7 and R 7 -R 8 ;
- R 7 is an amino acid residue or an amine capping group, provided that if R 8 is present, R 7 is an amino acid residue; R 8 is H or an amine capping group; and y is from 1 to 6, provided that where any linker unit includes two y index values, the total of such y index values is from 2 to 6.
- the amino acid residue at R 7 may be an L-amino acid selected from the group consisting of Abu, 2-Abz, 3-Abz, 4-Abz, Ache, Acpc, Aib, Amb,
- the amine capping group may be selected from the group consisting of methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7'-amino heptanoyl, 6-Ahx, Amc and 8-Aoc.
- the amine capping group is polyethylene glycol with a formula molecular weight of between 100 and 10,000.
- R 9a and R gb are optional ring substituents, and when one or both are present, are the same or different and independently hydroxyl, halogen, alkyl, or aryl groups attached directly or through an ether linkage.
- at least one of R 9a or R g is an alkyl selected from the group consisting of -CH 3 and -OCH 3 .
- at least one of R 9a or R 9b is a halogen selected from the group consisting of -Cl and -CF 3 .
- one of R a , R 4b , Rs a , and R 5 is a Ci to C 6 aliphatic linear or branched chain.
- one of R a or R 4b and one of R 5a and R 5b is a C-, to C 6 aliphatic linear or branched chain.
- the Ci to C 6 aliphatic linear or branched chain can be selected from the group consisting of methyl and isobutyl.
- X is CH 2 ;
- J a ring structure selected from the group consisting of naphthyl, phenyl, substituted phenyl, indole and substituted indole;
- L 2 is (CH 2 ) 3 ;
- Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl and naphthyl;
- R a , R 4b , R 5a , and R 5b is methyl or isobutyl, and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen;
- R 6a and R 6b are each independently selected from the group consisting of hydrogen and R 7 ;
- R 7 is selected from the group consisting of acetyl, methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, benzoyl, hexanoyl, and polyethylene glycol.
- the invention includes the following compounds and pharmaceutically acceptable salts thereof: N- ⁇ 3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-6(R)-methyl-4-(2-naphthalen-
- the invention can be characterized as a compound of the formula of structure II:
- Z is N, NH, CH, CH 2 or N-CH 3 ;
- Rn. i 2> R 13 and R are independently hydrogen or a C-i to C 6 linear or branched chain on the proviso that either Rn and R-
- R- I5 , Ri 6 . and R ⁇ 9 are independently hydrogen or a hydroxyl, halogen, alkyl or aryl groups attached directly or through an ether linkage;
- R 7 and R 18 are independently hydrogen, a hydroxyl, halogen, alkyl or aryl groups attached directly or through an ether linkage, or together constitute a fused aromatic ring;
- R 20 is hydrogen or a Ci to C 6 aliphatic linear or branched chain, optionally containing at least one N;
- R 21 is optionally not present, or if present is a C-i to C 6 aliphatic linear or branched chain;
- R 22a and R 22b are independently hydrogen or a ⁇ to C 6 linear or branched chain on the proviso that R 20 and one of R 22a and R 22b can form a nonaromatic heterocyclic ring; m is from 0 to 6; n is 0 or 1 ; and the dashed lines are an optional double bond.
- Compounds of the invention thus include compounds wherein one of R Sa and R 5b is an (R)- configuration Ci to C 6 aliphatic linear or branched chain, preferably (R)-methyl or (R)-isobutyl, and the remaining of R 4a , R 4b , R 5a , and R 5b are hydrogen, and optionally further wherein L
- such compounds can be characterized in that they bind to the melanocortin 4 receptor with high affinity and exhibit no intrinsic activity at the melanocortin 4 receptor.
- the invention further includes a pharmaceutical composition including such compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- the invention still further includes a method of treating obesity or feeding-related disorders, comprising administration of a therapeutically effective amount of such a pharmaceutical composition.
- such compounds can be characterized in that they are an agonist or partial agonist at the melanocortin 4 receptor.
- a method of treating obesity or feeding- related disorders including administration of a therapeutically effective amount of a compound of the invention wherein the compound binds to the melanocortin 4 receptor with high affinity and exhibits no intrinsic activity at the melanocortin 4 receptor.
- the present invention provides a compound that is an agonist of a melanocortin receptor, including MC1-R, MC3-R, MC4-R, or MC5-R. In another embodiment, the present invention provides a compound that is an antagonist of a melanocortin receptor, including MC1-R, MC3-R, MC4-R, or MC5-R.
- the present invention provides a compound that is an inverse agonist of a melanocortin receptor, including MCl-R, MC3-R, MC4-R, or MC5-R.
- the present invention provides a compound that is an antagonist of an inverse agonist, such as agouti-related protein (AgRP), of a melanocortin receptor, including MC4-R.
- AgRP agouti-related protein
- the present invention provides a compound that binds with high affinity to a melanocortin receptor, including MCI-R, MC3-R, MC4-R, or MC5-R, but which is functionally inactive at physiologically relevant concentrations, is a weak agonist or antagonist (EC 50 of 100 nM or higher), is an inverse agonist or is an antagonist of an inverse agonist.
- a melanocortin receptor including MCI-R, MC3-R, MC4-R, or MC5-R, but which is functionally inactive at physiologically relevant concentrations, is a weak agonist or antagonist (EC 50 of 100 nM or higher), is an inverse agonist or is an antagonist of an inverse agonist.
- the present invention provides a compound that binds with high affinity and specificity to MC4-R but which has no intrinsic activity at MC4-R, and which may be employed for attenuating food intake and body weight gain, including but not limited to treatment of a disorder or condition such as obesity and associated impairment of energy homeostasis.
- the invention further includes a method for altering a disorder or condition associated with the activity of a melanocortin receptor, comprising administering to a patient a therapeutically effective amount a compound of this invention.
- the disorder or condition is an eating disorder such as cachexia.
- the disorder or condition is obesity and associated impairment of energy homeostasis.
- a primary object of the present invention is to provide conformationally constrained isomers of tetra- or penta-substituted piperazines or derivatives thereof, wherein the pendant group substituents are amino acid moieties, amino acid side chain moieties or derivatives thereof, such that the resulting ring compound biologically mimics a relevant reverse turn peptide structure that is characteristic of melanocortin peptides.
- Another object of the present invention is to provide tetra- or penta-substituted piperazine compounds and derivatives thereof.
- Another object of the present invention is to provide piperazine compounds and derivatives of piperazine compounds with at least four pendant groups, such pendant groups consisting of any moiety other than H, O, S, or a halogen.
- Another object of the present invention is to provide a method for synthesis of tetra- substituted piperazine compounds.
- Figs. 1 A and 1 B illustrate steric interaction by placement of the R 5 group in an (S)- or (R)- configuration, respectively;
- Fig. 2 is a chart showing behavior in an animal model following administration of the compound of Example 10 or a control;
- Fig. 3 is a chart of one hour food intake in an animal model following administration of the compound of Example 10 or a control
- Fig. 4 is a chart showing behavior in an animal model following administration of the compound of Example 6 or a control
- Fig. 5 is a chart of one hour food intake in an animal model following administration of the compound of Example 6 or a control
- Fig. 6 is a chart of saccharin intake in a conditioned taste aversion response test of the compound of Example 10 compared to positive and negative controls;
- Fig. 7 is a chart of saccharin intake in a conditioned taste aversion response test of the compound of Example 6 compared to positive and negative controls; and Fig. 8 is a graph of percent change in body weight in an animal model of animals in growth phase for a 21 day period where negative control and the compounds of Examples 6 and 10 were administered for 7 days.
- piperazine rings including piperazine ring derivatives
- each descriptor is a separate pendant group unique to a given ring atom.
- the inventors have further found that the chirality of the ring, and stereo structure generally, is fixed in a desired structure, thereby more closely mimicking the desired pharmacophores, and with the descriptors positioned in the most relevant chemical space.
- This invention thus discloses the use of tetra- or penta-substituted piperazine and related derivative templates for drug design.
- the invention further also relates to enantiomerically pure tetra-substituted piperazines, preferably made by the synthetic schemes disclosed herein or variants thereof.
- a classic piperazine ring is a conformationally dynamic six-membered ring structure. It can exist in a variety of conformational states, commonly referred to as chair, boat, twisted chair or twisted boat conformations.
- the location of descriptors on the ring plays an important role in stabilizing the ring in a single conformational state; if the appropriate conformational state is selected, this is conducive to making a molecule more selective for its receptor in terms of binding affinity and intrinsic functional activity.
- a 1 ,3 axial placement of two bulky descriptors generally causes unfavorable steric interactions between these two groups, and thus make a chair conformation energetically less stable. Consequently, the chair conformation is less preferred, resulting in a twisted chair or boat conformation.
- the twisted chair or boat conformation results in a specific stereochemical alignment of the descriptors, which is specifically relevant to interaction with the desired receptor.
- a conformation resulting from 1 ,3 axial placement of two descriptors may result in a structure more selective for a given receptor sub-type.
- the invention describes and discloses the use of tetra- or penta- substituted piperazine and related piperazine-derivative ring compounds as biologically active agents.
- the invention describes and discloses the use of tetra- or penta- substituted piperazine and related piperazine-derivative ring compounds as mimetics of desired pharmacophores, including but not limited to pharmacophores derived from biologically active metallopeptides, which biologically active metallopeptides may in turn be derived from biologically active peptides, polypeptides or proteins.
- the invention describes tetra- or penta-substituted piperazine and related piperazine-derivative ring compounds specific for G-protein coupled receptor systems, such systems including, but not limited to, melanotropin or melanocortin receptors (MC1 -R, MC3-R, MC4- R and MC5-R).
- the invention provides novel schemes and methods of synthesis of tetra-substituted piperazine and related piperazine-derivative ring compounds.
- amino acid and amino acids used in this invention, and the terms as used in the specification and claims, include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User's Guide, GA Grant, editor, W.H. Freeman & Co., New York, 1992, the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24.
- amino acid also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User's Guide, cited above; Hruby VJ, Al-obeidi F and Kazmierski W: Biochem J 268:249-262, 1990; and Toniolo C: IntJ Peptide Protein Res 35:287-300, 1990; the teachings of all of which are incorporated herein by reference.
- amino acid side cha tiin moiety used in this invention includes any side chain of any amino acid, as the term “amino ac :iid” is defined herein, including any derivative of an amino acid side chain moiety, as the term “derivat Liive” is defined herein. Therefore, this includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid disclosed herein is included within the definition of an amino acid side chain moiety.
- derivatives of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties.
- derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, and saturated or unsaturated alkyl, aryl or aralkyl moieties.
- amino acids amino acids, amino acid side chain moieties and derivatives and constituents thereof have the meanings giving, it being understood that any amino acid may be in either the L- or D-configuration:
- Tyr(2,6-DiCI-Bzl) 0-(2,6 dichloro)benzyl-tyrosine Conventional amino acid residues have their conventional meaning as given in Chapter 2400 of the Manual of Patent Examining Procedure, 7 th Ed.
- “Nle” is norieucine
- "Asp” is aspartic acid
- "His” is histidine
- "D-Phe” is D-phenylalanine
- "Arg” is arginine
- 'Trp” is tryptophan
- “Lys” is lysine
- Gly is glycine
- Pro is praline
- 'Tyr is tyrosine
- Ser is serine and so on.
- the following amino acids, or side chains thereof may be employed, in either the L- or D- configuration as appropriate, in certain embodiments of this invention:
- homolog includes, without limitation, (a) a D-amino acid residue or side chain substituted for an L-amino acid residue side chain, (b) a post-translationally modified residue or side chain substituted for the residue or side chain, (c) a non-protein or other modified amino acid residue or side chain based on another such residue or side chain, such as phenylglycine, homophenylalanine, ring-substituted halogenated, and alkylated or arylated phenylalanines for a phenylalanine residue, diamino proionic acid, diamino butyric acid, ornithine, lysine and homoarginine for an arginine residue, and the like, and (d) any amino acid residue or side chain, coded or otherwise, or a construct or structure that mimics an amino acid residue or side chain, and which has at least a similarly charged side chain (neutral, positive or negative), preferably a similar hydro
- alkene includes unsaturated hydrocarbons that contain one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.
- alkenyl includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond; examples thereof include ethenyl, 2-propenyl, and the like.
- alkyl groups specified herein include those alkyl radicals of the designated length in either a straight or branched configuration.
- alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
- alkynal includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond; examples thereof include ethynyl, propynal, butynyl, and the like.
- aryl includes a monovalent or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, or alkoxy-carbonyl.
- substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, or alkoxy-carbonyl.
- Examples of an aryl group include phenyl, biphenyl, naphthyl, 1 -naphthyl, and 2-naphthyl, derivatives thereof, and the like.
- aralkyl includes a radical - R a R b where R a is an alkylene (a bivalent alkyl) group and R b is an aryl group as defined above.
- R a is an alkylene (a bivalent alkyl) group
- R b is an aryl group as defined above.
- aralkyl groups include benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
- aliphatic includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.
- acyl includes a group RCO-, where R is an organic group.
- R is an organic group.
- An example is the acetyl group CH 3 CO-.
- An “omega amino derivative” includes an aliphatic moiety with a terminal amino group.
- omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.
- heteroaryl includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
- 5- or 6-membered heteroaryl are monocyclic heteroaromatic rings; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like.
- Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.
- amide includes compounds that have a trivalent nitrogen attached to a carbonyl group (-CO.NH 2 ), such as methylamide, ethylamide, propylamide, and the like.
- An “imide” includes compounds containing an imido group (-CO.NH.CO-).
- An “amine” includes compounds that contain an amino group (-NH 2 ).
- a “nitrile” includes compounds that are carboxylic acid derivatives and contain a (-CN) group bound to an organic group. '
- An amino acid side chain moiety is "hydrogen bonding" when the side chain includes hydrogen donors or alternatively hydrogen acceptors.
- An “amine capping group” includes any terminal group attached through a terminal amine, including but not limited to any omega amino derivative, acyl group or terminal aryl or aralkyl including groups such as methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7'-amino heptanoyl, 6-Ahx, Amc or 8-Aoc, as
- composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
- pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and one or more pharmaceutically acceptable carriers, and optionally one or more pharmaceutically active ingredients and agents.
- a variety of chemicals and compounds are employed in this invention, and the following abbreviations have the meanings given: AcOH acetic acid Boc tertiary butyloxycarbonyl
- NMP 1-methyl-2-pyrrolidinone Prt A protecting group such as Boc, Cbz or Fmoc
- a "tetra-substituted piperazine” or "penta-substituted piperazine”, as used herein, is a piperazine compound or derivative thereof wherein a group other than solely H, and preferably including an amino acid residue or an amino acid side chain moiety, is attached to each ring N member, and further wherein a group other than solely H, O, S or a halogen, preferably including an amino acid side chain moiety, is attached to two ring C members for a tetra-substituted piperazine and to three ring C members for a penta-substituted piperazine.
- “Sexual dysfunction” means any condition that inhibits or impairs normal sexual function, including coitus. The term is not limited to physiological conditions, and includes psychogenic conditions or perceived impairment without a formal diagnosis of pathology or disorder. Sexual dysfunction includes erectile dysfunction in a male mammal and female sexual dysfunction in a female mammal.
- Erectile dysfunction is a disorder involving the failure of a male mammal to achieve functional erection, ejaculation, or both. Erectile dysfunction is accordingly synonymous with impotence, and includes the inability to attain or sustain an erection of sufficient rigidity for coitus. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction is often associated with age or may be caused by a physical disease or as a side-effect of drug treatment.
- Female sexual dysfunction is a disorder including sexual arousal disorder.
- the term "sexual arousal disorder” includes a persistent or recurrent failure to attain or maintain the lubrication-swelling response of sexual excitement until completion of sexual activity.
- Sexual dysfunction in females can also include inhibited orgasm and dyspareunia, which is painful or difficult coitus.
- Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including hypoactive sexual desire disorder, sexual anhedonia, sexual arousal disorder, dyspareunia and vaginismus.
- Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties.
- Hypoactive sexual desire disorder can be related to boredom or unhappiness in a long-standing relationship, depression, dependence on alcohol or psychoactive drugs, side effects from prescription drugs, or hormonal deficiencies.
- Sexual anhedonia includes decreased or absent pleasure in sexual activity.
- sexual anhedonia can be caused by depression, drugs, or interpersonal factors.
- Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants, or antihypertensive agents.
- Dyspareunia and vaginismus are sexual pain disorders characterized by pain resulting from penetration and may be caused, for example, by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
- a melanocortin receptor "agonist” is meant an endogenous or drug substance or compound, including a compound of this invention that can interact with a melanocortin receptor and initiate a pharmacological response, including but not limited to adenyl cyclase expression, characteristic of the melanocortin receptor.
- a melanocortin receptor "antagonist” is meant a drug or a compound, including a compound of this invention, that opposes the melanocortin receptor- associated responses normally induced by a melanocortin receptor agonist agent, but without itself initiating a pharmacological response characteristic of the melanocortin receptor, such as increasing or decreasing adenyl cyclase expression.
- a melanocortin receptor inverse agonist
- a drug or a compound, including a compound of this invention that is an antagonist with respect to an agonist, and which by itself induces or initiates a pharmacological response characteristic of the melanocortin receptor, such as reducing basal or constitutive adenyl cyclase expression.
- binding affinity is meant the ability of a compound or drug to bind to its biological target.
- intrinsic activity is meant the maximal stimulation of adenyl cyclase achievable by a compound in a melanocortin receptor cell system.
- the maximal stimulation achieved by ⁇ -MSH or NDP- ⁇ -MSH is designated as an intrinsic activity of 1.0 (or 100%) and a compound capable of stimulating half the maximal activity that of ⁇ -MSH or NDP- ⁇ -MSH is designated as having an intrinsic activity of 0.5 (or 50%).
- a compound of this invention that under assay conditions described herein has an intrinsic activity of 0.7 (70%) or higher is classified as an agonist, a compound with intrinsic activity between 0.1 (10%) and 0.7 (70%) is classified as a partial agonist, and a compound with intrinsic activity below 0.1 (10%) is classified as inactive or having no intrinsic activity.
- the compounds disclosed herein can be used for both medical applications and animal husbandry or veterinary applications. Typically, the product is used in humans, but may also be used in other mammals.
- the term "patient” is intended to denote a mammalian individual, and is so used throughout the specification and in the claims. The primary applications of this invention involve human patients, but this invention may be applied to laboratory, farm, zoo, wildlife, pet, sport or other animals.
- Melanocortin receptor-specific compounds of this invention that are MC1-R specific can be used as chemoprevention agents against sun-induced, such as by UV radiation, neoplastic activity in human skin.
- MC1-R agonist compounds of this invention may be employed to stimulate epidermal melanocytes to produce melanin as well as to convert pheomelanin to eumelanin.
- Eumelanin which is dark brown or black pigmentation, is considered more photo-protective than pheomelanin, which is yellow or red pigmentation.
- the process of melanogenesis is believed to involve stimulation of MC1-R in epidermal melanocytes, thereby mediating the stimulation of tyrosinase enzymes within these pigment cells, inducing the conversion of tyrosine to dopa and then through dopaquinone to eumelanin.
- Sun tanning due to direct sun exposure is proposed to result from the same pathway by local production of melanotropic peptide from a POMC gene in the epidermis.
- stimulation of eumelanin production and conversion of pheomelanin to eumelanin may be a desirable chemoprevention modality in blocking sun- or UV-induced neoplastic activity in skin.
- a potent, high-affinity and highly selective MC1-R agonist peptidomimetic compound of this invention can accordingly be used as a therapeutic chemoprevention agent for combating harmful sun or UV exposure that induces neoplastic activity in skin melanocytes.
- compounds of this invention that are MC4-R agonists can be used as a therapeutic agent to modify energy metabolism and feeding behavior, including treatment of pathologic obesity and related conditions.
- Compounds of this invention that are MC4-R antagonists can be used as a therapeutic agent in eating disorders, such as treatment of anorexia and cachexia, which is malnutrition and wasting due to illness. Control centers for eating and satiety reside in the hypothalamus. These responses are determined by diverse hormones and soluble factors that signal through specific receptors in the hypothalamus.
- MC4-R is known to be expressed in the brain, and inactivation of this receptor by gene targeting has resulted in mice with a maturity-onset obesity syndrome associated with hyperphagia, hyperinsulinemia and hyperglycemia.
- This invention include compounds that are MC4-R agonists or partial agonists with demonstrated efficacy, in animal models, in modifying energy metabolism and feeding behavior, and further includes compounds that are inactive or have no intrinsic activity with respect to MC4-R, but bind MC4-R with high affinity and, in some instances, selectivity, and further have demonstrated efficacy, in animal models, in modifying energy metabolism and feeding behavior.
- At least some compounds of this invention that bind MC4-R with high affinity are neutral antagonists of the inverse agonist AgRP, but independently are inactive or have no intrinsic activity with respect to MC4-R, and that such compounds may be used as a therapeutic agent to modify energy metabolism and feeding behavior, including treatment of pathologic obesity and related conditions.
- compounds of this invention can be used as therapeutic agents for treatment of sexual dysfunction, including treatment of both male erectile dysfunction and female sexual dysfunction.
- compounds of this invention may be used as therapeutic agents for treatment of inflammation, including specifically MC1-R, MC3-R and MC5-R agonists.
- compounds of this invention that are MC5-R specific can be used as agents to decrease sebum production, and thus may be efficacious in the treatment of acne and related diseases.
- the compounds for this application may be conveniently formulated for local administration, as through a gel, lotion, cream or other topical formulation.
- the compounds may be formulated by any means known in the art, including but not limited to tablets, capsules, caplets, suspensions, powders, lyophilized forms and aerosols and may be mixed and formulated with buffers, binders, stabilizers, anti-oxidants and other agents known in the art.
- the compounds may be administered by any systemic or partially systemic means known in the art, including but not limited to intravenous injection, subcutaneous injection, administration through mucous membranes, oral administration, dermal administration, skin patches, aerosols and the like.
- the invention further provides a pharmaceutical composition that includes a compound of this invention and a pharmaceutically acceptable carrier.
- the compound of this invention may thus be formulated or compounded into pharmaceutical compositions that include at least one compound of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
- pharmaceutically acceptable carriers including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
- Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- water containing at least one or more buffering constituents is suitable, and stabilizing agents, preservatives and solubilizing agents may also be employed.
- stabilizing agents, preservatives and solubilizing agents may also be employed.
- solid administration formulations any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, fatty acids and the like.
- topical administration formulations any of a variety of creams, ointments, gels, lotions and the like may be employed.
- non-active ingredients will constitute the greater part, by weight or volume, of the preparation.
- any of a variety of measured-release, slow-release or time-release formulations and additives may be employed, such that the dosage may be formulated so as to effect delivery of a compound of this invention over a period of time.
- the compounds of this invention may be in the form of any pharmaceutically acceptable salt.
- Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic acids.
- the acetate salt form is especially useful.
- suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
- the compounds and pharmaceutical compositions of this invention may be administered by injection, which injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art.
- injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art.
- Administration means may include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration and the like.
- the dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect.
- Therapeutically Effective Amount In general, the actual quantity of compound of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired. This may readily be determined by one of ordinary skill in the art through means such as pharmacokinetic studies, plasma half-life studies, dose escalation studies, and the like.
- the dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect.
- a therapeutically effective amount includes an amount of a compound or pharmaceutical composition of this invention that is sufficient to induce the desired therapeutic effect.
- the compounds of this invention are highly active.
- the compound can be administered at 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, or 500 ⁇ g/kg body weight, depending on specific compound selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.
- Conventional dose response studies and other pharmacological means may be employed to determine the optimal dose for a desired effect with a given compound, given formulation and given route of administration.
- Combination Therapy and sexual Dysfunction It is also possible and contemplated to use the compounds of this invention in combination with other drugs or agents for treatment of sexual dysfunction.
- drugs and agents may include melanocortin receptor-specific agents that induce erectile activity, including specifically MC3-R and MC4-R agonists, phosphodiesterase-5 inhibitors, testosterone, prostaglandin and the like.
- compounds of the invention are used in combination with a therapeutically effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist.
- the compounds of this invention may be used in combination with any known mechanical aids or devices.
- the present invention thus provides methods of treating sexual dysfunction, the methods comprising the step of administering to the patient having or at risk of having sexual dysfunction a therapeutically effective amount of a compound of this invention in combination with a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
- the compound of this invention may be administered simultaneously with, prior to or subsequent to administration with a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
- the compound of this invention is administered within one hour, preferably within less than one-half hour, of administration of a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
- the hormone or hormone-related sexual dysfunction pharmaceutical agent may be administered on an independent schedule, such that there is no set or specific temporal relationship between administration of the compound of this invention and the hormone or hormone-related sexual dysfunction pharmaceutical agent.
- the hormone or hormone-related sexual dysfunction pharmaceutical agent may be administered on a daily or other dose, or by means of patches or other continuous administration schedules, with administration of the compound of this invention when desired or needed by the patient.
- the present invention thus provides methods of treating sexual dysfunction, the methods comprising the step of administering to a patient having or at risk of having sexual dysfunction a therapeutically effective amount of a compound of this invention in combination with a compound that is a melanocortin receptor agonist.
- the present invention further also provides methods of treating sexual dysfunction, the methods comprising the step of administering to a patient having or at risk of having sexual dysfunction a therapeutically effective amount of a compound of this invention in combination with a compound that is a melanocortin receptor agonist and in combination with another compound that is useful in the treatment of sexual dysfunction.
- the sexual dysfunction is female sexual dysfunction.
- the sexual dysfunction is erectile dysfunction.
- the melanocortin receptor agonist is an agonist of MC3-R or MC4-R, and preferably MC4-R.
- the agonist may be a non-selective MC3-R and MC4-R agonist.
- the present invention also provides pharmaceutical compositions that comprise 1) a compound of this invention and 2) a compound that is a melanocortin receptor agonist.
- the present invention further provides pharmaceutical compositions that comprise 1) a compound of this invention; 2) a compound that is a melanocortin receptor agonist; and 3) a third compound useful for the treatment of sexual dysfunction.
- the present invention further provides pharmaceutical compositions that comprise 1) a compound of this invention and 2) a second compound useful for the treatment of sexual dysfunction.
- the agonists are MSH including ⁇ -, ⁇ -, and y- MSH and/or ACTH.
- the melanocortin receptor agonist is Melanotan-ll (MT-ll).
- a preferred melanocortin receptor agonist includes any linear or cyclic melanocortin receptor-specific agonist peptide disclosed in International Application WO 03/006620 or a metallopeptide disclosed in International Application WO 02/064091.
- a particularly preferred melanocortin receptor agonist is Ac-Nle-cyc/o(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, as disclosed in U.S. Patent No. 6,579,968.
- the agonist may be any agonist disclosed in any of the following patents or patent applications: U.S. Patent Nos.
- the agonist of the melanocortin receptor may preferably be selective for MC4-R.
- the additional compounds useful for the treatment of sexual dysfunction are preferably selected from but not limited to the group consisting of a phosphodiesterase inhibitor; a cyclic-GMP-specific phosphodiesterase inhibitor; prostaglandins; apomorphin; oxytocin modulators; ⁇ -adrenergic antagonists; dopanergic ligands; androgens; selective androgen receptor modulators (SARMs); buproprion; vasoactive intestinal peptide (VIP); neutral endopeptidase inhibitors (NEP); neuropeptide Y receptor antagonists (NPY); and bombesin receptor-3 antagonists.
- VIP vasoactive intestinal peptide
- NEP neutral endopeptidase inhibitors
- NPY neuropeptide Y receptor antagonists
- the second sexual dysfunction pharmaceutical agent is testosterone.
- the second sexual dysfunction pharmaceutical agent is a type V phosphodiesterase inhibitor (PDE-5).
- PDE-5 inhibitor may be Viagra®, a brand of sildenafil, Levitra®, Cialis®, or may be 1-[[3-(6,7-dihydro-1- methyl-7-oxo-3-propyl-1-H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-ethoxy-phenyl]sufonyl)-4- methylpiperazine citrate salt, as disclosed in U.S. Published Application No. 2003/0083228.
- the compound useful for the treatment of sexual dysfunction is an estrogen agonist/antagonist.
- the estrogen agonist/antagonist is (-)-cis-6-phenyl-5-[-4-(2-pyrrolidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro- napth-thalene-2-ol (also known as lasofoxifene) or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt; or a prodrug thereof.
- the estrogen agonist/antagonist is in the form of a D-tartrate salt.
- the estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidine-1 -yl-ethoxy)-benzyl]- napthalen-2-ol, ⁇ 4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ -[6-hydroxy-2-(4-hydroxy- phenyl)-benzo[b]thiopehn-3-yl]-methanone, EM-652, EM-800, GW 5368, GW 7604, TSE-424 and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
- a compound of this invention may be used in combination with any known mechanical aids or devices.
- the present invention also provides kits for the treatment of sexual dysfunction (including erectile dysfunction), the kits comprising: a first pharmaceutical composition including a compound of this invention; a second pharmaceutical composition comprising a second compound useful for the treatment of sexual dysfunction; and, a container for the first and second compositions.
- Female sexual Dysfunction The compounds of this invention may be used to treat female sexual dysfunction as well as male sexual dysfunction. In general, the dosing schedules and doses for females are comparable to those for males.
- Combination Therapy and Weight Regulation It is also possible and contemplated to use compounds of this invention in combination with other drugs or agents for treatment of various weight and feeding-related disorders.
- the compound is an agonist or partial agonist
- the compound may be employed for decreasing food intake and/or body weight in combination with any other agent or drug heretofore employed as a diet aid, or for decreasing food intake and/or body weight.
- the compound binds with high affinity and specificity to MC4-R but has no intrinsic activity at MC4-R, the compound may be employed for decreasing food intake and/or body weight in combination with any other agent or drug heretofore employed as a diet aid, or for decreasing food intake and/or body weight.
- the compound may be employed for increasing food intake and/or body weight in combination with any other agent or drug heretofore employed for increasing food intake and/or body weight.
- Drugs that reduce energy intake include, in part, various pharmacological agents, referred to as anorectic drugs, which are used as adjuncts to behavioral therapy in weight reduction programs.
- Classes of anorectic drugs include, but are not limited to, noradrenergic and serotonergic agents.
- Noradrenergic medications may be described as those medications generally preserving the anorectic effects of amphetamines but with weaker stimulant activity.
- the noradrenergic drugs, except phenylpropanolamine generally act through a centrally mediated pathway in the hypothalamus that causes anorexia. Phenylpropanolamine, a racemic mixture of norephedrine esters, causes a release of norepinephrine throughout the body and stimulates hypothalamic adrenoreceptors to reduce appetite.
- Suitable noradrenergic agents include, but are not limited to, diethylpropion such as TENUATETM (1-propanone, 2-(diethylamino)-1 -phenyl-, hydrochloride) commercially available from Merrell; mazindol (or 5-(p-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-oI) such as SANOREXTM commercially available from Novartis or MAZANORTM commercially available from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol, alpha-(l-aminoethyl)-, hydrochloride); phentermine (or Phenol, 3-[[4,5-duhydro-1H-imidazol-2-yl)ethyl](4-methylphenyl)amino], monohydrochloride) such as ADIPEX-PTM commercially available from Lemmon, F
- Suitable non-limiting serotonergic agents include sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1-(4-chlorophenyl)- N,N-dimethyl-(alpha)-(2-methylpropyl)-, hydrochloride, monohydrate) commercially available from Knoll, fenfluramine such as PondiminTM (Benzeneethanamine, N-ethyl-alpha-methyl-3- (trifluorom ethyl)-, hydrochloride) commercially available from Robbins; dexfenfluramine such as ReduxTM (Benzeneethanamine, N-ethyl-alpha-methyl-3-(trifluoromethyl)-, hydrochloride) commercially available from Interneuron.
- sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers of cyclo
- Fenfluramine and dexfenfluramine stimulate release of serotonin and inhibit its reuptake.
- Sibutramine inhibits the reuptake of serotonin, norepinephrine and dopamine, but does not stimulate secretion of serotonin.
- serotonergic agents useful with the practice of the present invention include, but are not limited to, certain auoretic gene 5HT1 a inhibitors (brain, serotonin) such as carbidopa and benserazide as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; and certain neurokinin 1 receptor antagonists and selective serotonin reuptake inhibitors including fluoxetine, fluvoxamine, paroxtine, sertraline and other useful compounds as disclosed by U.S. Pat. No. 6,162,805 which is incorporated herein by reference.
- Other potential inhibitors that may be employed include 5HT2c inhibitors.
- Other useful compounds for reducing energy intake include, but are not limited to, certain aryl-substituted cyclobutylalkylamines as disclosed by U.S. Pat. No. 6,127,424 which is incorporated herein by reference; certain trifluoromethylthiophenylethylamine derivatives as disclosed by U.S. Pat. No. 4,148,923 which is incorporated herein by reference; certain compounds as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; certain kainite or AMPA receptor antagonists as disclosed by U.S. Pat. No. 6,191 ,117 which is incorporated herein by reference; certain neuropeptide receptor subtype 5 as disclosed by U.S. Pat. No.
- Non-limiting examples of useful compounds affecting feeding behavior include certain leptin-lipolysis stimulated receptors as disclosed by WO 01/21647 which is incorporated herein by reference; certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970 which is incorporated herein by reference; certain compounds having nucleotide sequences of the mahogany gene as disclosed by WO 00/05373 which is incorporated herein by reference; and certain sapogenin compounds as disclosed by U.S. Pat. No. 4,680,289 which is incorporated herein by reference.
- PPAR peroxisome proliferator activated receptor
- monoamine oxidase inhibitors that decrease energy intake or increase energy expenditure are useful with the practice of the present invention.
- Suitable, but non-limiting examples of monoamine oxidase inhibitors include befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, avalycation, azabemide, milacemide, caroxazone and other certain compounds as disclosed by WO 01/12176 which is incorporated herein by reference.
- Certain compounds that increase lipid metabolism are also useful with the practice of the present invention. Such compounds include, but are not limited to, useful evodiamine compounds as disclosed by U.S. Pat. No. 6,214,831 which is incorporated herein by reference.
- Nutrient partitioning agents and digestive inhibitors are another strategy in the treatment of obesity by interfering with the breakdown, digestion or absorption of dietary fat in the gastrointestinal tract.
- Gastric and pancreatic lipases aid in the digestion of dietary triglycerides by forming them into free fatty acids that are then absorbed in the small intestine. Inhibition of these enzymes leads to inhibition of the digestion of dietary triglycerides.
- Non-limiting examples include a lipase inhibitor, orlistat, such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)- 3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247 which is incorporated herein by reference.
- orlistat such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)- 3-hexyl-4-oxo-2-oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247 which is incorporated herein by reference.
- thermogenic medications Agents that increase energy expenditure are also referred to as thermogenic medications.
- suitable thermogenic medications include xanthines, such as caffeine and theophylline, selective ⁇ -3-adrenergic agonists for example certain compounds in U.S. Pat. No. 4,626,549 which is incorporated by reference herein, and ⁇ -2-adrenergic and growth hormones compounds as described in U.S. Pat. Nos. 4,937,267 and 5,120,713 which are incorporated by reference herein.
- a total dosage of the above-described obesity control agents or medications, when used in combination with a compound of this invention can range from 0.1 to 3,000 mg/day, preferably from about 1 to 1 ,000 mg/day and more preferably from about 1 to 200 mg/day in single or 2-4 divided doses.
- the exact dose is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.
- Agents or drugs employed for increasing food intake and/or body weight include appetite stimulants such as megastrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheplidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoterone.
- appetite stimulants such as megastrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheplidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as flutamide, nilutamide, and zanoterone.
- one preferred method of making the compounds of the invention includes synthesis of a linear intermediate composed of chiral building blocks such as amino acid residues or derivatives, which intermediate includes the R 1 group and an R 2 group, and one of or, if provided, both an R 4 and R 5 group, as shown below.
- the linear intermediate is then cyclicized, and other groups, such as R 3 , are then added.
- RT and R 4 can be considered to be amino acid side chain moieties, as defined above.
- the linear intermediate includes the R 2 group, and one of R 4 or R 5 , with the Ri group synthetically added post-cyclization.
- R 3 group is an amino acid residue or derivative, optionally with an amine capping group, second amino acid residue or derivative, or second amino acid residue or derivative and amine capping group. It may thus be seen that the compounds of the invention may be considered as a 6-membered ring compound of the formula:
- R-i is an amino acid side chain moiety including at least one carbocyclic aromatic or non-aromatic ring or heterocyclic aromatic ring, and in a preferred embodiment includes a substituted or unsubstituted phenyl, naphthyl or indole group;
- R 2 is an amino acid side chain moiety with at least one heteroatom cationic center, hydrogen bond donor or hydrogen bond acceptor, wherein the least one heteroatom is nitrogen or oxygen;
- R 3 includes at least one amino acid residue with at least one carbocyclic aromatic ring and in a preferred embodiment, includes a substituted or unsubstituted phenyl or naphthyl group;
- At least one of R and R 5 is R 2 or a C-i to C 6 aliphatic linear or branched chain. It may readily be seen that the foregoing description is simplified, in that at each of R 2 , R 4 and R 5 there is assumed to further be a hydrogen atom bound to the respective ring carbon.
- Ri can be an amino acid side chain moiety, including but not limited to one of the following:
- any ring may be substituted with one or more ring substitutents, such as hydroxyl, halogen, sulfonamide, alkyl or aryl groups attached directly or through an ether linkage.
- R 2 may be an amino acid side chain moiety, including but not limited to one of the following:
- R 3 which includes least one amino acid residue with at least one carbocyclic aromatic ring, may be of any of the formulas -AL -A cGp, -A A 2 or- A A 2 -cGp, where A 1 is an amino acid with an aromatic carbocyclic ring, A 2 is an L-amino acid, and cGp is an amine capping group.
- a 1 is an amino acid with an aromatic carbocyclic ring
- a 2 is an L-amino acid
- cGp is an amine capping group.
- A-i is a D-amino acid with an aromatic carbocyclic ring.
- A-i may be a D-isomer of Phe, Phe(2-CI), Phe(4-Cl), Phe(2,4-diCI), Phe(2,4-diF), Phe(3,4-diCI), Phe(4-N0 2 ), Phe(4-Me), Phe(4-Phenyl), HPhe, Phe(4-F), Phe(4-Br), Phe(4-CF 3 ), Phe(3,4-diF), Phe(4-I), Phe(2- Cl, 4-Me), Phe(2-Me, 4-CI), Phe(2-F, 4-CI), Phe(2,4-diMe), Phe(2-CI, 4-CF 3 ), or Phe(3,4-di-OMe).
- AT may be a D-isomer of Pgl, Trp, Nal 1 , Nal 2, Bi
- a 2 can be an L-isomer of Abu, 2- Abz, 3-Abz, 4-Abz, Ache, Acpc, Aib, Amb, Arg(Tos), Asp(anilino), Asp(3-CI-anilino), Asp(3,5-diCI- anilino), 11-Aun, AVA, Beta-hHyp(Bzl), Cha, Chg, Cmpi, Disc, Dpr(beta-Ala), GAA, GBzA, B-Gpa, GVA(CI), His, hSer, Ser(Bzl), Tic, hHyp, Hyp(Bzl), Inp, 2-Naphthylacetyl, (Nlys)Gly, OcHx, Pip,
- the amine capping group cGp can be methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7'-amino heptanoyl, 6-Ahx, Amc, 8-Aoc or polyethylene glycol.
- the efficacy and functional activity of compounds of this invention can be modulated by selection of the linker units and other substituents, such as R 4 and/or R 5 groups, which influence the conformational biasness of R ⁇ and R 3 groups.
- Efficacy and functional activity may be determined by any number of means, such as assaying the stimulation of adenyl cyclase in a cAMP assay as hereafter described.
- the chemical nature of either or both the Li or L 3 linker units, and the incorporation of a substituent at one or more specific R 4a , R 4b , R 5a or R 5b positions can change otherwise identical compounds from a partial agonist to a full agonist as determined by adenyl cyclase assays in an hMCR-4 transfected HEK cell system.
- a commercially available computer based molecular modeling software system such as Alchemy (Tripos), can be used to study the conformational dynamics within the compounds of this invention.
- a piperazine ring can exhibit conformational dynamics between chair and boat conformations, with twisted chair and twisted boat conformations being special cases.
- chair and boat conformations are used for purposes of illustration. Assume a piperazine, where X is CH 2 , and a conventional ring atom numbering system as follows:
- both the 1 and 4 position nitrogens are substituted with an R group.
- the conformation of the ring is biased toward a chair conformation, because this conformation offers a very low likelihood of steric interactions involving aromatic RT and R 3 groups.
- This may be seen in the following illustration, wherein the equatorial placement of R ⁇ and R 3 in the Chair Form results in a conformationally preferred structure, while the close proximity of the ring nitrogens with R-i and R 3 groups in the Boat Form (indicated by the double arrow) make the Boat Form conformationally disfavored.
- both nitrogens are in the sp 3 configuration if U and L 3 are of the (CH 2 ) y type.
- the R ⁇ and R 3 groups orient as equatorial groups on the chair configuration and have a high degree of conformational freedom in space due to rotational freedom of C-C single bonds in these groups as shown:
- both nitrogens exist in the sp 2 configuration if L
- and have, for example, an initial carbonyl group, such as a linker unit of the -C( 0)-(CH 2 ) y - type.
- the carbonyl groups of the ring nitrogen amide functions necessarily exist in one of two rigid forms, similar to cis or trans amide forms. This specific orientation of the carbonyl groups in turn restricts the orientation of the J and Q groups. Therefore, where U and L 3 include an initial carbonyl group, the R- and R 3 groups have conformational orientations that are different from those in compounds without ring nitrogen amide functions, as shown below:
- is attached through an ethylene group are antagonists or partial agonists with significantly lower intrinsic activity, or have no intrinsic activity, either with or without loss of affinity for MC4-R (see the compounds of Examples 1 , 2, 3, 4, 7 and 8).
- the substituents at position 5 and 6 of the piperazine ring also have a significant influence on the orientation of the R-i and R 3 groups.
- an R 4 group in the general structure of this invention influences the spatial preference of the R 3 group
- an R 5 group influences the spatial preference of the Ri group.
- the major influence of these groups on biological activity is seen in a stereo-specific manner.
- an R 5 substituent such as methyl or isobutyl
- an (S)-configuration cause severe steric constraint on the J group in compounds where is a -(CH 2 ) y - linker unit.
- both J as well as the (S)-configuration of the R 5 group are positioned in a close chemical space.
- Steric hindrance between these two groups causes perturbations in the overall orientation of the R-i group, resulting in a structure that is less conducive to receptor affinity and functional efficacy of the compounds.
- a 5-15 fold loss of MC4-R affinity has been observed.
- (R)-configuration positions the R 5 group away from the R-i group. Since there is no perturbation in the positioning of R ⁇ group, this causes no change in MC4-R receptor affinity and selectivity.
- R 4 group in its equatorial (S)-configuration form causes severe steric interaction with the carbonyl of the L 3 linker, as well as the Q group when L 3 is a linker unit such as -(CH 2 ) y -. Therefore, incorporation of an R 4 group in either sterochemical orientation leads to compounds that have somewhat weaker receptor affinity (typically a 5-7 fold decrease has been observed). These three situations can be shown as:
- Example 129 in PCT/US02/25574, entitled Peptidomimetics of Biologically Active Molecules, filed on August 12, 2002, and incorporated herein by reference.
- intrinsic efficacy or activity less than about 10% is not distinguishable from no intrinsic activity.
- the compound of Example 8 binds with high affinity (4 nM) at MC4-R, but has no intrinsic activity.
- the compound of Example 8 is accordingly inactive as to MC4-R in terms of agonist/antagonist status with respect to NDP- ⁇ -MSH.
- Synthetic Schemes Distinct and separate methods for synthesis of piperazines and ketopiperazines are required.
- piperazine molecules as described herein cannot be obtained from ketopiperazine molecules or synthetic schemes as described herein.
- One obvious limitation to employing ketopiperazine synthetic schemes to synthesize piperazine molecules is that the presence of other reactive groups, such as amide, halogen and aromatic functional groups, can interfere with the process of reducing a ketopiperazine to a piperazine.
- One general strategy for either class of compounds includes developing a linear intermediate using chiral building blocks such as amino acid derivatives.
- the linear intermediate can be cyclized using a Mitsunobo reaction strategy (Mitsunobo, O.
- Scheme 4 presented hereafter is an example of a Mitsunobo reaction mediated cyclization. This methodology incorporates conditions that do not involve inversion or racemization of chiral centers, other than inversion of the chiral center on the carbon to which an -OH group is attached.
- the piperazine compounds of the invention have three stereocenters, such that at each of three distinct carbon atoms the molecule can assume any permissible sterochemical configuration, such that eight distinct stereo configurations (2 n where n is 3) are both possible and contemplated in this invention.
- R 2 may be in either the R 2a or R 2b position, with the remaining position being hydrogen.
- Dipeptide (1-2) The dipeptide (1-2) synthesized in Scheme 1 employs an amino alcohol derivative of a suitable omega-protected alpha omega amino acid. This omega protecting group is orthogonal to the N-Prt group, such that one protecting group can be removed in the presence of the other. 7.8 mL (56 mmol, 1.35 equiv) of TEA was added to a solution of 40 mmol of protected amino acid (1.1) in 200 mL dry THF, kept at -20° C under N 2 , followed by the slow addition of 7.2 mL (55 mmol, 1.35 equiv) of IBCF. The reaction mixture was stirred for 5 minutes.
- the dipeptide can also be prepared by any common peptide synthesis protocol, such as for example using HBTU as the coupling reagent.
- HBTU dry dimethylformamide
- DIEA diisopropylethyl amine
- ketopiperazine (1-3) To a solution of 5.75 mmol of dipeptide (1-2) in 40 mL of dry DCM, kept at -20° C under N 2 , was added 1.0 mL (7.5 mmol, 1.3 equiv) of TEA, followed by the slow addition of 530 ⁇ L (6.9 mmol, 1.2 equiv) of methanesulfonyl chloride, keeping the temperature below -10° C. The mixture was stirred at -10° C for 15 minutes, and then allowed to warm to room temperature. It was stirred at room temperature until HPLC showed the reaction was completed. The reaction mixture was then concentrated and partitioned between 25 mL of ether and 25 mL of water.
- reaction mixture was cooled to room temperature, and then quenched by the slow addition of 1 N hydrochloric acid.
- the reaction mixture was diluted with 25 mL of EtOAc and 15 mL of water. The layers were separated, and the organic layer was dried over magnesium sulfate.
- the product (1-4) was purified by silica gel chromatography as necessary.
- Alkylation can be accomplished by a reductive amination reaction with an aldehyde (for example, formaldehyde) under the conditions described in synthesis of 3-4, using alkyl bromide (for example, CH 3 -Br), or acylation using a carboxylic acid (CH 3 -COOH), with guanidation using triphenylphorphine, DIAD, and 1,3-Bis(tert-butoxycarbonyl)guanidine as reagents followed by removal of Boc groups as described in Scheme 5.
- aldehyde for example, formaldehyde
- alkyl bromide for example, CH 3 -Br
- acylation using a carboxylic acid CH 3 -COOH
- a guanidation reaction can also be performed using 1 ,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.1 equiv) and silver nitrate (1.1 equiv) and NMM (2.2 equiv) as reagents in acetonitrile as discussed in Scheme 4.
- Scheme 2 Synthesis Of Tetra- And Penta-Substituted Ketopiperazines
- ketopiperazines (2-2 and 2-3) The NH-Prt' group in ketopiperazine (1-3) is removed and the resulting amine is processed further to introduce an R 3 group as generally described for the synthesis of substituted piperazine (1-6) in Scheme 1.
- the amine function of 2-2 can be introduced to produce compound 2-3 using a similar approach as described for the conversion of 1-7 to 1-8 in Scheme 1.
- Reagents (a) i) HOAt, EDC, DMF; ii) NaBH 4 , HOAc, Dioxane, reflux; (b) i) NHMeOMe, HCl, TBTU, NMM; ii) LAH, THF; (c) 4A molecular sieves, Compound 3-1, NaBCNH 3 , HOAc/THF; (d) i) 20% Et 2 NH/EtOAc; ii) Ph 3 P, DIAD, THF; (e) i) Q-COOH, HOAt, DIG, DMF; ii) TFA/DCM.
- reaction mixture was poured into water and extracted by EtOAc twice.
- organic layer was washed by 1 N hydrochloric acid twice, 1 N sodium hydroxide twice, brine and dried over sodium sulfate. After evaporation, the product was purified on silica gel column with 10% methanol in methylene chloride.
- the crude product (4-1) was dissolved in 5 mL of THF and to the solution was added NMM (1 equiv). The solution was cooled to -15° C with a salt-ice bath, and IBCF (1 equiv) added. After 10 minutes, the reaction mixture was filtered to remove formed solid salt. The solid was washed twice with adequate amounts of THF. The filtrate was cooled to -10° C and to it was added NaBH 4 (1.5 equiv) in water. The reaction mixture was stirred for another 15 minutes, and then concentrated in vacuo.
- the compounds with Boc groups were subjected to treatment with TFA/DCM (50/50) for one hour. After evaporation of solvent the final compound 6-5 was purified on HPLC.
- Compound 7-1 is synthesized by the methods described for compound 5-3.
- the starting material is an (R)- or (S)-isomer of Fmoc-alaninol.
- the aldehyde thus obtained is subsequently reacted with Orn(Boc)-OMe under reductive amination conditions, and with cyclization gives compound 7-1 after removal of the Fmoc group.
- compound 7-2 is synthesized by a method similar to that described for compound 6-1
- compound 7-3 is synthesized by a method similar to that described for compound 6-2
- compound 7-4 is synthesized by a method similar to that described for compound 6-5
- compound 7-5 is synthesized by a method similar to that described for compound 4-10.
- Compound 7-5 is treated with hydrogen in the presence of catalytic amounts of palladium on carbon in a suitable solvent at room temperature for 16 hours. After filtration the solvent is evaporated and the resulting compound is processed to give compound 7-6 in a manner similar to that described for synthesis of compound 5-8.
- the resulting compound 7-6 iillustrates an alternative route for making an enantomeric form of the compounds. However, depending on selection of the chiral starting materials, similar results and other stereoisomers can be obtained by any of the synthetic schemes disclosed.
- compound 8-1 is synthesized by a method similar to that described for compound 6-2; compound 8-3 is synthesized by a method similar to that described for compound 6-1; compound 8-4 is synthesized by a method similar to that described for compound 4-10; and compound 8-5 is synthesized by a method similar to that described for compound 7-6.
- 8-3 can be processed directly to 8-6 as shown to get compounds that have amino groups instead of guanidines.
- Compound 8-5 and 8-6 thus has two identical R ⁇ groups, or alternatively has two identical R 3 groups, and further has two identical R 2 groups.
- Compounds of Scheme 8 are thus special cases of the general formula, in which the group corresponding to R 5 is identical to the group corresponding to R 2 .
- Compound 9-3 is synthesized by a method similar to that described for compound 6-2.
- Compound 9-4 is synthesized by a method similar to that described for compound 6-4.
- Compound 9-5 is synthesized by a method similar to that described for compound 7-6.
- 9-3 can be processed in a manner similar to synthesis of compound 9-5 from 9-4 to give 9-6.
- Compounds 9-5 and 9-6 thus has two identical R-, groups, or alternatively has two identical R 3 groups, at the R-i and R 3 positions, and further has two identical R 2 groups, at the R 2 and R 5 positions.
- Compounds of Scheme 9 are thus special cases of the general formula, in which the group corresponding to R 5 is identical to the group corresponding to R 2 .
- the protecting group Prt (Fmoc or Cbz) is removed by either 20% diethyl amine in EtOAc or by hydrogen catalyzed with 10% palladium on carbon.
- the resulting compound is dissolved in dry THF with triphenylphosphine (3 equiv). To this solution is added DEAD ( 3 equiv) in THF slowly. The reaction is stirred for an additional 12 hours. After the solvent is evaporated the product (10-4) is purified on silica gel column.
- Compound 10-4 is coupled with desired amino acids (2 equiv) by use of HOAt (2 equiv) and DIC (2 equiv) in N, N-dimethylformamide solution overnight at room temperature. Flash chromatograph gives the product with protecting groups. The Fmoc group is removed by treatment with 20% diethyl amine in EtOAc and the Boc group is removed by treatment with 30% TFA in methylene chloride for 1 hour, as applicable to the compounds. The final pure compound (10-5) is obtained by purification on HPLC.
- a competitive inhibition binding assay was conducted using membranes prepared from hMC3-R, hMC4-R, hMC5-R, and B-16 mouse melanoma cells
- the assay tube also contained a chosen concentration of the test compound of this invention, typically a 1 ⁇ M concentration, for determining its efficacy in inhibiting the binding of 125 l-NDP- ⁇ -MSH to its receptor. Non-specific binding was measured by complete inhibition of binding of 2s l-NDP- ⁇ -MSH in the assay with the presence of 1 ⁇ M ⁇ -MSH.
- EC 50 determination in functional activity assay The Ki (nM) of certain compounds of the invention were determined. Functional evaluation of compounds at melanocortin receptors was performed by measuring the accumulation of intracellular cAMP in HEK-293 cells expressing MC3- R, MC4-R or MC5-R, and in B-16 mouse melanoma cells (containing MC1-R).
- MC1-4, MC4-R, and MC5- R Functional status.
- Antagonistic activity was determined by measuring the inhibition of ⁇ -MSH-induced or NDP- ⁇ -MSH-induced cAMP levels following exposure to the compounds as in the preceding descriptions.
- Penile erection induction The ability of compounds to induce penile erection (PE) in male rats were evaluated with selected compounds.
- IV intravenous
- ICV intracerebroventricular
- rats were placed into individual polystyrene cages (27 cm long, 16 cm wide, and 25 cm high) for behavioral observation. Rats were observed for 30 minutes IV or 90 minutes ICV, and the number of yawns, grooming bouts and PEs were recorded in 10-minute bins.
- ICV food intake and body weight change Change in food intake and body weight was evaluated for selected compounds. Rats with indwelling intracerebroventricular cannulas (ICV rats) were obtained from Hilltop Lab Animals, Inc. (Scottdale, PA). Animals were individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/12 hour off light cycle. Water and powdered (LabDiet, 5P00 Prolab RMH 3000) or pelleted (Harlan Teklad 2018 18% Protein Rodent Diet) food was provided ad libitum. For 1 week before treatment, 24-hour food intake and body weight change was recorded to assess a baseline for the group during vehicle treatment. The rats were dosed ICV with vehicle or selected compounds (1 - 3 nmol).
- the changes in body weight and food intake for the 24 hour period after dosing were determined.
- the changes in body weight and food intake for the 48 hour period, and in same cases for 72 hours as well, after dosing were also measured to determined reversal of changes in body weight and food intake effect back to baseline.
- the changes in body weight and food intake for the 24 hour period after dosing were determined.
- the changes in body weight and food intake for the 48 hour period, and in same cases for 72 hours as well, after dosing were also measured to determined reversal of changes in body weight and food intake effect back to baseline.
- Behavioral Satiety Sequence Male Sprague-Dawley rats were maintained on a restricted 20 g powdered food/day schedule. Food was presented at the same time during the lights on period dosed with either saline or the test compound 2 hours before presentation of food and the start of observation. Pre-weighed bowls (containing 20g of food) were presented and the behavior of the rats was observed for 1 hour. Behavioral observations were divided into 3 categories: Feeding, Active (includes grooming, drinking and sniffing/exploration), and Resting (decreased activity and sleep). The amount of time spent in each behavior was recorded. The amount of food intake was determined after the observation period.
- Mass and nuclear magnetic resonance analysis were determined using a Waters MicroMass ZQ device utilizing a positive mode. Mass determinations were compared with calculated values and expressed in the form of mass weight plus one (M+1 or M+H).
- Example 4 In a cAMP assay using MC1 -R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 4 exhibited no intrinsic activity at MC1 -R and MC5-R, and was a partial agonist at MC4-R.
- conditioned taste avoidance studies rats were conditioned to associate a 0.1% saccharin solution with a dose of either lithium chloride or the compound of Example 6. Two days later, a 0.1% saccharin solution was presented again. A decrease in fluid intake suggests development of a conditioned taste aversion. As shown in Fig. 7, there was no conditioned taste avoidance associated with the compound of Example 6.
- the compound of Example 6 was diluted in sterile saline, 0.6 mg/mL and dosed IP at 5 ml_/kg at 11 :00 am.
- mice were administered at 11 :00 am and 4:30 pm. Mice were dosed with the compound of Example 6 (3 mg/kg) twice a day for the first 3 days and once per day for the next 4 days. As shown in Fig. 8, which also includes data on the compound of Example 10, mice in growth phase administered the compound of Example 6 initiated net wet gain after cessation of treatment (after day 7), but consistently maintained average weights less than control animals receiving saline.
- Example 8 N- ⁇ 3-[1-[2(R)-Amino-3-(2,4-dichloro-phenyl)-propionyl]-5(R)-isobutyl-4-(2- naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- Example 9 N- ⁇ 3-[1-[2(R)-Amino-3-(4-chloro-2-fluoro-phenyl)-propionyl]-5(R)-methyl-4-(2- naphthalen-2-yl-ethyl)-pipera ⁇ in-2(S)-yl]-propyl ⁇ -guanidine
- Example 9 In a cAMP assay using MC1-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 9 was a partial agonist at MC1-R and MC4-R and an agonist at MC5-R.
- Example 6 In behavioral satiety studies as in Example 6, the compound of Example 10 administered IV 2 hours prior to food presentation caused a decrease in food intake and feeding behavior and an earlier onset in resting behavior consistent with a satiety effect, as shown Fig. 2, showing behavior compared to saline, and Fig. 3, showing total one-hour food intake in grams. No abnormal behavior was seen.
- conditioned taste avoidance studies rats or were conditioned to associate a 0.1% saccharin solution with a dose of either lithium chloride or the compound of Example 10. Two days later, a 0.1 % saccharin solution was presented again. A decrease in fluid intake suggests development of a conditioned taste aversion. As shown in Fig. 6, there was no conditioned taste avoidance associated with the compound of Example 10.
- Example 6 was diluted in sterile saline, 0.6 mg/mL and dosed IP at 5 mL/kg at 11 :00 am. Mice were dosed with the compound of Example 10 (3 mg/kg) once per day for 7 days. As shown in Fig. 8, which also includes data on the compound of Example 6, mice in growth phase administered the compound of Example 10 had a significant decrease in body weight during the initial 7 days, with a gradual increase in body weight, but consistently below control animals, for the two week period following cessation of administration of the compound of Example 10.
- Example 12 N- ⁇ 3-[1-[2(R)-Amino-3-(4-chloro-phenyl)-propionyl]-5(R)-methyl-4-(2- naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- Example 14 N- ⁇ 3-[1-[2(R)-Amino-3-(2,4-dimethyI-phenyi)-propionyl]-5(R)-methyl-4-(2- naphthalen-2-yl-methyl)-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- Example 16 In a cAMP assay using MC1-R, MC3-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 16 exhibited no intrinsic activity at MC3-R, and was a partial agonist at MC1-R, MC4-R and MC5-R.
- Example 19 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 19 exhibited no intrinsic activity at MC3-R, and was a partial agonist at MC1- R, MC4-R and MC5-R.
- Example 20 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 20 exhibited no intrinsic activity at MC1-R and MC3-R, and was a partial agonist at MC4-R and MC5-R.
- Example 23 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 23 exhibited no intrinsic activity at MC1-R, MC3-R and MC5-R, and was a partial agonist at MC4-R.
- Example 25 N-(3- ⁇ 1 -(2(R)-Amino-3-naphthalen-2-yl-propionyl)-5(R)-methyl-4-[2-(1 -methyl- 1H-indol-3-yl)-ethyl]-piperazin-2(S)-yl ⁇ -propyl)-guanidine
- the following compound was synthesized by the method of Scheme 6 using 1-methyl- indole-3-acetaldehyde as J-aldehyde, D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3 , and Boc-D- 2-Nal-OH as Q-COOH. It was tested as described above with the results shown. The mass was analyzed as 554.7 (M+H).
- Example 26 In a cAMP assay using MC1 -R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 26 exhibited no intrinsic activity at MC3-R, was a partial agonist at MC1-R and MC5-R, and an agonist at MC4-R.
- Example 27 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 27 exhibited no intrinsic activity at MC1-R and MC3-R, and was a partial agonist at MC4-R and MC5-R.
- Example 29 N- ⁇ 3-[1-[2(R)-Amino-3-(4-methyl-phenyl)-propionyl]-5(R)-methyI-4-(2- naphthalen-2-yl-ethyl)-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- 2- naphthylacetic acid as J-COOH
- D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3
- Boc-D-4- methyl-Phe-OH Q-COOH
- Example 35 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 35 exhibited no intrinsic activity at MC1-R, MC3-R and MC4-R, and was a partial agonist at MC5-R.
- Example 36 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 36 exhibited no intrinsic activity at MC1-R, MC3-R and MC4-R, and was a partial agonist at MC5-R.
- a cAMP assay for determination of agonist/antagonist status it was determined that the compound was a partial agonist as to MC3-R, and an agonist as to MC1-R, MC4-R and MC5-R.
- rat model IV penile erection induction experiments at doses ranging from 0.3 to 30 ⁇ g/Kg, no penile erection response was observed.
- Example 39 N- ⁇ 3-[1-(2(R)-Amino-3-naphthalen-2-yl-propionyl)-4-(3H-imidazol-4-ylmethyl)- 5(R)-methyl-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- the following compound was synthesized by the method of Scheme 6 using 4(5)-imidazole carboxyaldehyde as J-aldehyde, D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3 , and Boc-D-2-Nal- OH as Q-COOH. It was tested as described above with the results shown. The mass was analyzed as 477.2 (M+H).
- the following compound was synthesized by the method of Scheme 6.
- the compound of Example 38 was treated by the method of Example 36 to introduce an acetyl group at the amino group of the D-2-Nal residue. It was tested as described above with the results shown. The mass was analyzed as 607.7 (M+H).
- the J-COOH moiety was further modified by removal of the Fmoc group and reacting with methanesulfonyl chloride to form a sulfonamide moiety. It was tested as described above with the results shown. The mass was analyzed as 672.4 (M+H).
- Example 42 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 42 exhibited no intrinsic activity at MC3-R, was a partial agonist at MC1-R, and an agonist at MC4-R and MC5-R.
- Example 43 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 43 exhibited no intrinsic activity at MC3-R, was a partial agonist at MC1-R and was an agonist at MC4-R and MC5-R.
- Example 45 N- ⁇ 3-[1-[2(R)-Amino-3-(4-chloro-2-dimethyl-phenyl)-propionyl]-5(R)-methyl-4- (2-naphthalen-2-yl-acetyl)-piperazin-2(S)-yl]-propyl ⁇ -guanidine
- 2-naphthyl acetic acid as J-COOH
- L-Orn(Boc) methyl ester as NH 2 -CH(R 2 )-COOCH 3
- Boc-D-4-chloro-2- methyl-Phe-OH as Q-COOH. It was tested as described above with the results shown. The mass was analyzed as 543.4 (M+H).
- a cAMP assay for determination of agonist/antagonist status it was determined that the compound was a partial agonist as to MC1-R and MC3-R, and an agonist as to MC4-R and MC5-R.
- rat model IV penile erection induction experiments at doses ranging from 0.3 to 30 ⁇ g/Kg, 0.5 to 0.7 mean penile erections per rat were observed.
- Example 46 In a cAMP assay using MC1-R, MC3-R, MC4-R and MC5-R, at 1 ⁇ M concentrations the compound of Example 46 exhibited no intrinsic activity at MC1-R, MC3-R and MC5-R, and was a partial agonist at MC4-R.
- Example 48 - ⁇ 3-[1-[2(R)-Amino-3-(2,4-dimethyl-phenyl)-propionyl]-6(R)-methyl-4-(2- naphthalen-2-yl-acetyl)-piperazin-3(S)-yl]-propyl ⁇ -guanidine
- the compound is synthesized by the method of Scheme 10 using 2-naphthyl acetic acid as J-COOH that is reacted with an aminopropanol derivative to obtain 10-1.
- D-4-CI-Phe is employed as Q-COOH.
- Example 54 2(S)-Amino-N- ⁇ 1(R)-(4-chloro-benzyl)-2-[2(S)-(3-guanidino-propyl)-5(R)-methyl- 4-(2-naphthalen-2-yl-ethyl)-3-oxo-piperazin-1-yl]-2-oxo-ethyl ⁇ -3-(1H-imidazol-4- yl)-propionamide
- the following compound is synthesized by the method of Example 48 where after introduction of D-4-CI-Phe to the compound, a His derivative is attached at the N-terminus by methods similar to those described for the conversion of 10-4 to 10-5.
- the following compound is synthesized by the method of example 48 where after introduction of D-4-chloro-Phe to the compound, a polyethylene glycol (FW 100-10000) carboxylic acid derivative is attached at the N-terminus by methods similar to those described for the conversion of 10-4 to 10-5.
- the following compound is synthesized by the method of Scheme 6 using Fmoc-D- Trp(Boc)-OH as J-COOH, D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3 , and Boc-D-2,4- dimethyl-Phe-OH as Q-COOH.
- the J-COOH moiety is further modified by removal of the Fmoc group and reacting with acetic anhydride to form an acetamide moiety.
- the following compound is synthesized by the method of Scheme 6 using Fmoc-D-Phe-OH as J-COOH, D-alanine methyl ester as NH 2 -CH(R 5 )-COOCH 3 , and 3-(2,4-dichlorophenyl)-propionic acid as Q-COOH.
- the J-COOH moiety is further modified by removal of the Fmoc group and reacting with acetic anhydride to form anacetamide moiety.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004235792A AU2004235792A1 (en) | 2003-05-01 | 2004-05-03 | Melanocortin receptor-specific compounds |
EA200501724A EA012502B1 (en) | 2003-05-01 | 2004-05-03 | Melanocortin receptor-specific compounds |
MXPA05011729A MXPA05011729A (en) | 2003-05-01 | 2004-05-03 | Melanocortin receptor-specific compounds. |
BRPI0410694-6A BRPI0410694A (en) | 2003-05-01 | 2004-05-03 | tetra and penta-substituted piperazine compounds and piperazine-derived ring |
JP2006514263A JP2006525369A (en) | 2003-05-01 | 2004-05-03 | Specific compounds for melanocortin receptor |
EP04751262A EP1622618A4 (en) | 2003-05-01 | 2004-05-03 | Melanocortin receptor-specific compounds |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US46744203P | 2003-05-01 | 2003-05-01 | |
US60/467,442 | 2003-05-01 | ||
US54639304P | 2004-02-19 | 2004-02-19 | |
US60/546,393 | 2004-02-19 | ||
US10/837,519 | 2004-04-30 | ||
US10/837,519 US7456184B2 (en) | 2003-05-01 | 2004-04-30 | Melanocortin receptor-specific compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004098602A1 true WO2004098602A1 (en) | 2004-11-18 |
Family
ID=33425190
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/013803 WO2004098602A1 (en) | 2003-05-01 | 2004-05-03 | Melanocortin receptor-specific compounds |
Country Status (10)
Country | Link |
---|---|
US (2) | US7456184B2 (en) |
EP (1) | EP1622618A4 (en) |
JP (1) | JP2006525369A (en) |
KR (1) | KR20060009285A (en) |
AU (1) | AU2004235792A1 (en) |
BR (1) | BRPI0410694A (en) |
CO (1) | CO5700752A2 (en) |
EA (1) | EA012502B1 (en) |
MX (1) | MXPA05011729A (en) |
WO (1) | WO2004098602A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009504672A (en) * | 2005-08-11 | 2009-02-05 | パラティン テクノロジーズ, インコーポレイテッド | Melanocortin receptor specific piperazine and keto-piperazine compounds |
WO2009144432A1 (en) * | 2008-05-30 | 2009-12-03 | Palatin Technologies, Inc. | Mc4-r agonists for the treatment of obesity |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7517884B2 (en) * | 1998-03-30 | 2009-04-14 | Kalypsys Inc. | Sulfonyl-substituted bicyclic compounds as modulators of PPAR |
US7494999B2 (en) | 2004-10-29 | 2009-02-24 | Kalypsys, Inc | Sulfonyl-substituted bicyclic compounds as modulators of PPAR |
US7732451B2 (en) | 2001-08-10 | 2010-06-08 | Palatin Technologies, Inc. | Naphthalene-containing melanocortin receptor-specific small molecule |
US7655658B2 (en) | 2001-08-10 | 2010-02-02 | Palatin Technologies, Inc. | Thieno [2,3-D]pyrimidine-2,4-dione melanocortin-specific compounds |
US7718802B2 (en) | 2001-08-10 | 2010-05-18 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific piperazine compounds |
US7456184B2 (en) | 2003-05-01 | 2008-11-25 | Palatin Technologies Inc. | Melanocortin receptor-specific compounds |
CA2462200A1 (en) | 2001-08-10 | 2003-02-20 | Palatin Technologies, Inc. | Peptidomimetics of biologically active metallopeptides |
US7727991B2 (en) | 2003-05-01 | 2010-06-01 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific single acyl piperazine compounds |
US7968548B2 (en) | 2003-05-01 | 2011-06-28 | Palatin Technologies, Inc. | Melanocortin receptor-specific piperazine compounds with diamine groups |
US7727990B2 (en) | 2003-05-01 | 2010-06-01 | Palatin Technologies, Inc. | Melanocortin receptor-specific piperazine and keto-piperazine compounds |
US7709484B1 (en) | 2004-04-19 | 2010-05-04 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific piperazine compounds |
US20070190079A1 (en) * | 2004-10-29 | 2007-08-16 | Kalypsys, Inc. | Methods for the selective modulation of ppar |
CA2624030A1 (en) | 2005-09-29 | 2007-04-12 | Tianying Jian | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
WO2007051095A1 (en) * | 2005-10-25 | 2007-05-03 | Kalypsys, Inc. | Salts of modulators of ppar and methods of treating metabolic disorders |
EA200802060A1 (en) | 2006-03-30 | 2009-10-30 | Палатин Текнолоджиз, Инк. | AMINO ACID SURROGATES FOR PEPTIDE STRUCTURES |
US7964181B2 (en) * | 2006-03-30 | 2011-06-21 | Palatin Technologies, Inc. | Amino acid surrogates for peptidic constructs |
US20070249519A1 (en) * | 2006-04-20 | 2007-10-25 | Kalypsys, Inc. | Methods for the upregulation of glut4 via modulation of ppar delta in adipose tissue and for the treatment of disease |
AR060937A1 (en) * | 2006-05-16 | 2008-07-23 | Kalypsys Inc | SUBSTITUTED BICYCLIC COMPOUNDS WITH SULFONYL AS PPAR MODULATORS |
WO2008017852A1 (en) * | 2006-08-11 | 2008-02-14 | Palatin Technologies, Inc. | Diamine-containing, tetra- substituted piperazine compounds as melanocortin receptor modulators |
US7834017B2 (en) | 2006-08-11 | 2010-11-16 | Palatin Technologies, Inc. | Diamine-containing, tetra-substituted piperazine compounds having identical 1- and 4-substituents |
WO2008039418A2 (en) * | 2006-09-27 | 2008-04-03 | Merck & Co., Inc. | Acylated piperidine derivatives as melanocortin-4 receptor modulators |
WO2008091863A1 (en) | 2007-01-23 | 2008-07-31 | Kalypsys, Inc. | Sulfonyl-substituted bicyclic compounds as ppar modulators for the treatment of non-alcoholic steatohepatitis |
WO2008090357A2 (en) * | 2007-01-24 | 2008-07-31 | Palatin Technologies, Inc. | N, n; -substituted piperazines binding to melanocortin receptor |
US20090081197A1 (en) * | 2007-06-01 | 2009-03-26 | Palatin Technologies, Inc. | Methods for Selection of Melanocortin Receptor-Specific Agents for Treatment of Obesity |
US20090076029A1 (en) * | 2007-06-01 | 2009-03-19 | Palatin Technologies, Inc. | Compounds and Methods for Treating Obesity |
WO2010065801A1 (en) * | 2008-12-04 | 2010-06-10 | Palatin Technologies, Inc. | Amine substituted piperazine melanocortin receptor-specific compounds |
UY32690A (en) * | 2009-06-08 | 2011-01-31 | Astrazeneca Ab | SPECIFIC PEPTIDES FOR MELANOCORTIN RECEPTORS |
WO2013067309A1 (en) | 2011-11-04 | 2013-05-10 | Xion Pharmaceutical Corporation | Methods and compositions for oral administration of melanocortin receptor agonist compounds |
WO2016168388A2 (en) | 2015-04-14 | 2016-10-20 | Palatin Technologies, Inc. | Therapies for obesity, diabetes and related indications |
EP3333165B1 (en) * | 2015-08-04 | 2019-09-18 | Astellas Pharma Inc. | Piperazine derivative |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207665B1 (en) * | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
WO2003013571A1 (en) * | 2001-08-10 | 2003-02-20 | Palatin Technologies, Inc. | Peptidomimetics of biologically active metallopeptides |
Family Cites Families (146)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4148923A (en) * | 1972-05-31 | 1979-04-10 | Synthelabo | 1-(3'-Trifluoromethylthiophenyl)-2-ethylaminopropane pharmaceutical composition and method for treating obesity |
US4626549A (en) * | 1974-01-10 | 1986-12-02 | Eli Lilly And Company | Treatment of obesity with aryloxyphenylpropylamines |
IT1157365B (en) * | 1977-10-24 | 1987-02-11 | Sandoz Ag | MEDICATIONS TO TREAT OBESITY OR REDUCE BODY WEIGHT |
US4711957A (en) * | 1979-07-13 | 1987-12-08 | The B. F. Goodrich Company | Synthesis of 2-keto-1,4-diazacycloalkanes |
US4766125A (en) * | 1981-06-23 | 1988-08-23 | Janssen Pharmaceutica N.V. | N-aryl-piperazinealkanamides useful for protecting hearts from myocardial injury caused by ischaemia, anoxia or hypoxia |
US4680289A (en) * | 1985-06-05 | 1987-07-14 | Progenics, Inc. | Treatment of obesity and diabetes using sapogenins |
GB8607312D0 (en) * | 1986-03-25 | 1986-04-30 | Ici Plc | Therapeutic agents |
US4968684A (en) * | 1987-04-01 | 1990-11-06 | Janssen Pharmaceutica N.V. | Method of improving sleep |
DK247789A (en) * | 1988-05-23 | 1989-11-24 | Glaxo Group Ltd | piperazine |
US4938763B1 (en) * | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US4997836A (en) * | 1988-11-11 | 1991-03-05 | Takeda Chemical Industries, Ltd. | Trisubstituted piperazine compounds, their production and use |
US5120713A (en) * | 1990-09-10 | 1992-06-09 | Applied Research Systems Ars Holding N.V. | Treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide |
US5331573A (en) * | 1990-12-14 | 1994-07-19 | Balaji Vitukudi N | Method of design of compounds that mimic conformational features of selected peptides |
US5292726A (en) * | 1991-05-22 | 1994-03-08 | Merck & Co., Inc. | N,N-diacylpiperazines |
US5334830A (en) * | 1991-05-29 | 1994-08-02 | Olympus Optical Co., Ltd. | Scanning optical microscope having a compact confocal optical system for adjusting position of aperture |
SE9202266D0 (en) * | 1992-07-31 | 1992-07-31 | Kabi Pharmacia Ab | NOVEL PIPERAZINE CARBOXAMIDES |
US5344830A (en) * | 1992-12-10 | 1994-09-06 | Merck & Co., Inc. | N,N-diacylpiperazine tachykinin antagonists |
EP0690843B1 (en) * | 1993-03-25 | 2000-08-30 | PHARMACIA & UPJOHN COMPANY | Formyl- or cyano- substituted indole derivatives having dopaminergic activity |
HUT70045A (en) * | 1993-06-17 | 1995-09-28 | Takeda Chemical Industries Ltd | 2-piperazinone derivatives parmaceutical compositions containing them and process for producing them |
JPH09500109A (en) * | 1993-06-18 | 1997-01-07 | メルク エンド カンパニー インコーポレーテッド | Inhibitors of farnesyl protein transferase |
US5348955A (en) * | 1993-06-22 | 1994-09-20 | Merck & Co., Inc. | N,N-diacylpiperazines |
US5494919A (en) * | 1993-11-09 | 1996-02-27 | Merck & Co., Inc. | 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5721251A (en) * | 1993-12-10 | 1998-02-24 | Merck & Co., Inc. | Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone |
US5721250A (en) | 1993-12-23 | 1998-02-24 | Merck & Co. Inc. | Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5464788A (en) * | 1994-03-24 | 1995-11-07 | Merck & Co., Inc. | Tocolytic oxytocin receptor antagonists |
US5753445A (en) * | 1994-04-26 | 1998-05-19 | The Mount Sinai Medical Center Of The City University Of New York | Test for the detection of anti-heparin antibodies |
US5599809A (en) * | 1994-09-29 | 1997-02-04 | Merck & Co., Inc. | Method for improving reproductive efficiency in farm animals |
US6245764B1 (en) * | 1995-03-24 | 2001-06-12 | Molecumetics Ltd. | β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins |
US5856326A (en) * | 1995-03-29 | 1999-01-05 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
ATE277021T1 (en) * | 1995-04-13 | 2004-10-15 | Aventis Pharma Inc | NEW SUBSTITUTED PIPERAZINE DERIVATIVES WITH TACHYKINE RECEPTOR ANTAGONISTIC EFFECT |
WO1996033982A1 (en) * | 1995-04-26 | 1996-10-31 | Takeda Chemical Industries, Ltd. | Piperazinones useful as inhibitors of platelet aggregation |
US5719156A (en) * | 1995-05-02 | 1998-02-17 | Schering Corporation | Piperazino derivatives as neurokinin antagonists |
ES2235171T3 (en) * | 1995-05-29 | 2005-07-01 | Pfizer Inc. | DIPEPTIDES THAT PROMOTE THE RELEASE OF THE GROWTH HORMONE. |
DE19518988A1 (en) * | 1995-05-29 | 1996-12-05 | Basf Ag | Use of aryl substituted cyclobutylalkylamines to treat obesity |
US6027711A (en) * | 1995-06-07 | 2000-02-22 | Rhomed Incorporated | Structurally determined metallo-constructs and applications |
US5891418A (en) * | 1995-06-07 | 1999-04-06 | Rhomed Incorporated | Peptide-metal ion pharmaceutical constructs and applications |
US6184223B1 (en) * | 1995-10-27 | 2001-02-06 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
US5753653A (en) * | 1995-12-08 | 1998-05-19 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
AU714931B2 (en) * | 1995-12-18 | 2000-01-13 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives as tachykinin antagonists |
US6303611B1 (en) | 1996-03-08 | 2001-10-16 | Adolor Corporation | Kappa agonist compounds and pharmaceutical formulations thereof |
US6239154B1 (en) * | 1996-03-08 | 2001-05-29 | Adolor Corporation | Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith |
US5763445A (en) * | 1996-03-08 | 1998-06-09 | Adolor Corporation | Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith |
GB9612276D0 (en) * | 1996-06-12 | 1996-08-14 | Merck & Co Inc | 4-Spiroindoline piperidines promote release of growth hormone |
US5804578A (en) * | 1996-04-03 | 1998-09-08 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5880128A (en) * | 1996-05-08 | 1999-03-09 | Schering Corporation | Carbonyl piperazinyl and piperidinyl compounds |
US6331285B1 (en) | 1996-06-05 | 2001-12-18 | Palatin Technologies, Inc. | Structurally determined cyclic metallo-constructs and applications |
US5998421A (en) * | 1996-06-12 | 1999-12-07 | Kyowa Hakko Kogyo Co., Ltd. | Lipid metabolism ameliorants |
AU4342097A (en) | 1996-09-13 | 1998-04-02 | Merck & Co., Inc. | Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone |
US5877182A (en) * | 1996-09-13 | 1999-03-02 | Merck & Co., Inc. | Piperidines promote release of growth hormone |
US5734054A (en) * | 1996-11-05 | 1998-03-31 | Pharmacopeia, Inc. | Hydroxy-amino acid amides |
US5965565A (en) | 1996-12-12 | 1999-10-12 | Merck & Co., Inc. | Piperidines promote release of growth hormone |
KR20000057595A (en) * | 1996-12-17 | 2000-09-25 | 후지야마 아키라 | Piperazine compounds as inhibitors of mmp or tnf |
DE69705746T2 (en) * | 1996-12-20 | 2001-10-31 | Alza Corp | INJECTABLE DEPOT GEL PREPARATION AND PRODUCTION METHOD |
US6162805A (en) * | 1997-04-24 | 2000-12-19 | Merck Sharp & Dohme Limited | Use of an NK-1 receptor antagonist and an SSRI for treating obesity |
KR100467058B1 (en) | 1997-05-27 | 2005-01-24 | 디렉트-할러 아/에스 | Inhaler for powdered medicaments |
US5968938A (en) * | 1997-06-18 | 1999-10-19 | Merck & Co., Inc. | Piperazine oxytocin receptor antagonists |
US6287587B2 (en) * | 1997-07-15 | 2001-09-11 | Takeda Chemical Industries, Ltd. | Process for producing sustained-release preparation by in-water drying |
US6211626B1 (en) * | 1997-08-26 | 2001-04-03 | Color Kinetics, Incorporated | Illumination components |
US6193991B1 (en) | 1997-10-29 | 2001-02-27 | Atul J. Shukla | Biodegradable delivery systems of biologically active substances |
US5892038A (en) * | 1997-12-08 | 1999-04-06 | Pharmacopeia, Inc. | Hydroxy-amino acid amides |
US6084098A (en) * | 1999-02-26 | 2000-07-04 | Neurogen Corporation | Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands |
US6284735B1 (en) | 1998-04-28 | 2001-09-04 | Lion Bioscience Ag | HP-3228 and related peptides to treat sexual dysfunction |
US6127381A (en) | 1998-04-28 | 2000-10-03 | Basu; Amaresh | Isoquinoline compound melanocortin receptor ligands and methods of using same |
US6534503B1 (en) * | 1998-04-28 | 2003-03-18 | Lion Bioscience Ag | Melanocortin receptor-3 ligands to treat sexual dysfunction |
US6140354A (en) * | 1998-04-29 | 2000-10-31 | Ortho-Mcneil Pharmaceutical, Inc. | N-substituted aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders |
US6294534B1 (en) * | 1998-06-11 | 2001-09-25 | Merck & Co., Inc. | Spiropiperidine derivatives as melanocortin receptor agonists |
FR2780649B1 (en) * | 1998-07-06 | 2001-03-09 | Univ Paris Vii Denis Diderot | PIPERAZINE DERIVATIVES FOR THE INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION |
EP1098977A2 (en) | 1998-07-21 | 2001-05-16 | Millennium Pharmaceuticals, Inc. | Methods and compositions for the diagnosis and treatment of body weight disorders, including obesity |
US6169006B1 (en) * | 1998-07-29 | 2001-01-02 | Advanced Micro Devices, Inc. | Semiconductor device having grown oxide spacers and method of manufacture thereof |
ATE297908T1 (en) * | 1998-08-12 | 2005-07-15 | Pfizer Prod Inc | TACE INHIBITORS |
US6800636B2 (en) * | 1998-12-18 | 2004-10-05 | Schering Corporation | Farnesyl protein transferase inhibitors |
US6372747B1 (en) * | 1998-12-18 | 2002-04-16 | Schering Corporation | Farnesyl protein transferase inhibitors |
US6432959B1 (en) * | 1998-12-23 | 2002-08-13 | Schering Corporation | Inhibitors of farnesyl-protein transferase |
US6294539B1 (en) * | 1999-01-19 | 2001-09-25 | Advanced Syntech, Llc | Heterocyclic hydroxamic acid derivatives as MMP inhibitors |
AR022303A1 (en) * | 1999-01-22 | 2002-09-04 | Lundbeck & Co As H | DERIVATIVES OF PIPERIDINE, TETRAHYDROPIRIDINE AND PIPERAZINE, ITS PREPARATION AND USE |
WO2000051672A1 (en) * | 1999-03-03 | 2000-09-08 | Optinose As | Nasal delivery device |
US6033656A (en) * | 1999-05-04 | 2000-03-07 | Sumitomo Chemical Company, Limited | Method of preventing or alleviating mammalian obesity |
US6420369B1 (en) * | 1999-05-24 | 2002-07-16 | Ortho-Mcneil Pharmaceutical, Inc. | Anticonvulsant derivatives useful in treating dementia |
AU766191B2 (en) * | 1999-06-04 | 2003-10-09 | Merck & Co., Inc. | Substituted piperidines as melanocortin-4 receptor agonists |
US6469006B1 (en) * | 1999-06-15 | 2002-10-22 | Bristol-Myers Squibb Company | Antiviral indoleoxoacetyl piperazine derivatives |
US6207699B1 (en) * | 1999-06-18 | 2001-03-27 | Richard Brian Rothman | Pharmaceutical combinations for treating obesity and food craving |
US6579968B1 (en) * | 1999-06-29 | 2003-06-17 | Palatin Technologies, Inc. | Compositions and methods for treatment of sexual dysfunction |
US6699873B1 (en) * | 1999-08-04 | 2004-03-02 | Millennium Pharmaceuticals, Inc. | Melanocortin-4 receptor binding compounds and methods of use thereof |
US6774138B2 (en) * | 1999-08-31 | 2004-08-10 | Merck & Co., Inc. | Thiazolyl(pyridyl)ethyne compounds |
US6294525B1 (en) * | 1999-09-01 | 2001-09-25 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
CA2388417A1 (en) | 1999-09-22 | 2001-03-29 | Genset | Methods of screening for compounds that modulate the lsr-leptin interaction and their use in the prevention and treatment of obesity-related diseases |
US6515122B1 (en) * | 1999-09-24 | 2003-02-04 | Lion Bioscience Ag | Tetracyclic benzimidazole derivatives and combinatorial libraries thereof |
US6458789B1 (en) | 1999-09-29 | 2002-10-01 | Lion Bioscience Ag | 2-aminopyridine derivatives and combinatorial libraries thereof |
US20030064921A1 (en) * | 1999-10-27 | 2003-04-03 | The Regents Of The University Of California | Methods and compounds for modulating melanocortin receptor ligand binding and activity |
SE9904738D0 (en) * | 1999-12-22 | 1999-12-22 | Astra Pharma Prod | Novel compounds |
DE19963234A1 (en) * | 1999-12-27 | 2002-01-24 | Boehringer Ingelheim Pharma | New N,N-disubstituted piperazine and diazacycloheptane derivatives useful in treatment of hyperlipidemia, atherosclerosis, diabetes mellitus, adiposity and pancreatitis |
US6462046B2 (en) * | 2000-01-06 | 2002-10-08 | Advanced Syntech, Llc | Heterocycle derivatives as PPAR-gamma agonists |
EP1125579A3 (en) * | 2000-01-18 | 2003-01-02 | Pfizer Products Inc. | Uses of agrp-melanocortin receptor binding modulating compounds |
US20030195212A1 (en) * | 2000-01-28 | 2003-10-16 | Torbjorn Lundstedt | Novel melanocortin receptor agonists and antagonists |
US6451798B2 (en) * | 2000-02-22 | 2002-09-17 | Cv Therapeutics, Inc. | Substituted alkyl piperazine derivatives |
WO2001070347A1 (en) | 2000-03-17 | 2001-09-27 | Fit Express, Inc. | Golf swing conditioner |
EP1136071A3 (en) * | 2000-03-22 | 2003-03-26 | Pfizer Products Inc. | Use of glycogen phosphorylase inhibitors |
WO2001070337A1 (en) * | 2000-03-23 | 2001-09-27 | Merck & Co., Inc. | Spiropiperidine derivatives as melanocortin receptor agonists |
US6458790B2 (en) * | 2000-03-23 | 2002-10-01 | Merck & Co., Inc. | Substituted piperidines as melanocortin receptor agonists |
EE200200567A (en) * | 2000-03-31 | 2004-06-15 | Pfizer Products Inc. | New piperazine derivatives |
AU6497701A (en) * | 2000-05-30 | 2001-12-11 | Merck & Co Inc | Melanocortin receptor agonists |
WO2002000259A1 (en) | 2000-06-27 | 2002-01-03 | Taisho Pharmaceutical Co., Ltd. | Remedial agent for anxiety neurosis or depression and piperazine derivative |
BR0111567A (en) * | 2000-06-28 | 2003-05-06 | Pfizer Prod Inc | Melanocortin Receptor Ligands |
JP2004516239A (en) * | 2000-07-06 | 2004-06-03 | ニューロジェン コーポレイション | Melanin-concentrating hormone receptor ligand |
US20020032238A1 (en) * | 2000-07-08 | 2002-03-14 | Henning Priepke | Biphenylcarboxylic acid amides, the preparation thereof and the use thereof as medicaments |
US6191117B1 (en) * | 2000-07-10 | 2001-02-20 | Walter E. Kozachuk | Methods of producing weight loss and treatment of obesity |
JP2002056510A (en) * | 2000-08-07 | 2002-02-22 | Matsushita Electric Ind Co Ltd | Shielding type magnetic head and magnetic reproducing device |
KR100483300B1 (en) * | 2000-08-30 | 2005-04-15 | 에프. 호프만-라 로슈 아게 | Selective cyclic peptides |
US20020183316A1 (en) * | 2000-10-27 | 2002-12-05 | Kevin Pan | Amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders |
KR100394083B1 (en) * | 2000-12-04 | 2003-08-06 | 학교법인 성신학원 | Novel 4,5-dihydroisoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D3 and D4 receptors, and preparation thereof |
US6612805B2 (en) | 2000-12-05 | 2003-09-02 | Emu Unterwasserpumpen Gmbh | Hydrodynamic machine |
EP1236723A1 (en) | 2001-03-01 | 2002-09-04 | Pfizer Products Inc. | Sulfamide derivatives useful as beta3 agonists and pharmaceutical uses thereof |
HUP0303484A2 (en) * | 2001-03-02 | 2004-01-28 | Bristol-Myers Squibb Company | Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same |
JP2005506286A (en) * | 2001-03-02 | 2005-03-03 | ブリストル−マイヤーズ スクイブ カンパニー | Combined administration of melanocortin receptor agonist and phosphodiesterase inhibitor for the treatment of cyclic-AMP related diseases |
US7456183B2 (en) * | 2001-04-09 | 2008-11-25 | Novartis Vaccines And Diagnostics, Inc. | Guanidino compounds |
US6911447B2 (en) * | 2001-04-25 | 2005-06-28 | The Procter & Gamble Company | Melanocortin receptor ligands |
EP1406884A1 (en) * | 2001-05-11 | 2004-04-14 | Biovitrum Ab | Arylsusfonamide compounds for the treatment of obesity, type ii diabetes and cns-disorders |
JP4010951B2 (en) * | 2001-05-15 | 2007-11-21 | 大正製薬株式会社 | Arginine derivatives |
RU2278859C2 (en) * | 2001-05-15 | 2006-06-27 | Ф.Хоффманн-Ля Рош Аг | Oxazole derivatives substituted with carboxylic acids as ppar-alpha and ppar-gamma activators in diabetes treatment |
US6593362B2 (en) * | 2001-05-21 | 2003-07-15 | Guilford Pharmaceuticals Inc. | Non-peptidic cyclophilin binding compounds and their use |
CZ20033455A3 (en) * | 2001-06-20 | 2004-06-16 | Pfizer Products Inc. | Novel sulfonic acid derivatives |
US6825198B2 (en) * | 2001-06-21 | 2004-11-30 | Pfizer Inc | 5-HT receptor ligands and uses thereof |
US6977264B2 (en) * | 2001-07-25 | 2005-12-20 | Amgen Inc. | Substituted piperidines and methods of use |
GB0118479D0 (en) | 2001-07-28 | 2001-09-19 | Astrazeneca Ab | Novel compounds |
US7655658B2 (en) * | 2001-08-10 | 2010-02-02 | Palatin Technologies, Inc. | Thieno [2,3-D]pyrimidine-2,4-dione melanocortin-specific compounds |
US7732451B2 (en) * | 2001-08-10 | 2010-06-08 | Palatin Technologies, Inc. | Naphthalene-containing melanocortin receptor-specific small molecule |
US7354923B2 (en) * | 2001-08-10 | 2008-04-08 | Palatin Technologies, Inc. | Piperazine melanocortin-specific compounds |
US7456184B2 (en) | 2003-05-01 | 2008-11-25 | Palatin Technologies Inc. | Melanocortin receptor-specific compounds |
US7718802B2 (en) | 2001-08-10 | 2010-05-18 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific piperazine compounds |
HUP0202719A3 (en) * | 2001-08-21 | 2006-01-30 | Pfizer Prod Inc | Pharmaceutical compositions for the treatment of female sexual dysfunctions |
AU2002326948A1 (en) * | 2001-09-18 | 2003-04-01 | Bristol-Myers Squibb Company | Piperizinones as modulators of chemokine receptor activity |
US20030158209A1 (en) * | 2001-10-09 | 2003-08-21 | Neurocrine Biosciences Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
BR0213452A (en) * | 2001-10-22 | 2004-11-09 | Pfizer Prod Inc | Piperazine derivatives with ccr1 receptor antagonist activity |
US7319107B2 (en) | 2001-11-08 | 2008-01-15 | Johnson & Johnson Consumer Companies, Inc. | 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators |
WO2003040117A1 (en) | 2001-11-08 | 2003-05-15 | Ortho-Mcneil Pharmaceutical Corporation | Novel 1,2,4-thiadiazole derivatives as melanocortin receptor modulators |
US20060084657A1 (en) * | 2001-12-21 | 2006-04-20 | Atsuro Nakazato | Piperazine derivative |
AU2003230367A1 (en) * | 2002-05-10 | 2003-11-11 | Neurocrine Biosciences, Inc. | Substituted piperazine as melanocortin receptors ligands |
GB0224917D0 (en) * | 2002-10-25 | 2002-12-04 | Novartis Ag | Organic compounds |
US7160886B2 (en) | 2003-03-03 | 2007-01-09 | Merck & Co., Inc. | Acylated piperazine derivatives as melanocortin-4 receptor agonists |
US7968548B2 (en) | 2003-05-01 | 2011-06-28 | Palatin Technologies, Inc. | Melanocortin receptor-specific piperazine compounds with diamine groups |
US7727990B2 (en) | 2003-05-01 | 2010-06-01 | Palatin Technologies, Inc. | Melanocortin receptor-specific piperazine and keto-piperazine compounds |
US7727991B2 (en) | 2003-05-01 | 2010-06-01 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific single acyl piperazine compounds |
US7709484B1 (en) * | 2004-04-19 | 2010-05-04 | Palatin Technologies, Inc. | Substituted melanocortin receptor-specific piperazine compounds |
TW200609219A (en) * | 2004-06-17 | 2006-03-16 | Neurogen Corp | Aryl-substituted piperazine derivatives |
US7834017B2 (en) * | 2006-08-11 | 2010-11-16 | Palatin Technologies, Inc. | Diamine-containing, tetra-substituted piperazine compounds having identical 1- and 4-substituents |
US20090076029A1 (en) * | 2007-06-01 | 2009-03-19 | Palatin Technologies, Inc. | Compounds and Methods for Treating Obesity |
-
2004
- 2004-04-30 US US10/837,519 patent/US7456184B2/en not_active Expired - Fee Related
- 2004-05-03 KR KR1020057020785A patent/KR20060009285A/en not_active Application Discontinuation
- 2004-05-03 MX MXPA05011729A patent/MXPA05011729A/en unknown
- 2004-05-03 WO PCT/US2004/013803 patent/WO2004098602A1/en active Application Filing
- 2004-05-03 EA EA200501724A patent/EA012502B1/en not_active IP Right Cessation
- 2004-05-03 AU AU2004235792A patent/AU2004235792A1/en not_active Abandoned
- 2004-05-03 BR BRPI0410694-6A patent/BRPI0410694A/en not_active IP Right Cessation
- 2004-05-03 EP EP04751262A patent/EP1622618A4/en not_active Withdrawn
- 2004-05-03 JP JP2006514263A patent/JP2006525369A/en not_active Withdrawn
-
2005
- 2005-12-01 CO CO05122256A patent/CO5700752A2/en not_active Application Discontinuation
-
2008
- 2008-06-02 US US12/131,822 patent/US7964601B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6207665B1 (en) * | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
WO2003013571A1 (en) * | 2001-08-10 | 2003-02-20 | Palatin Technologies, Inc. | Peptidomimetics of biologically active metallopeptides |
Non-Patent Citations (1)
Title |
---|
See also references of EP1622618A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009504672A (en) * | 2005-08-11 | 2009-02-05 | パラティン テクノロジーズ, インコーポレイテッド | Melanocortin receptor specific piperazine and keto-piperazine compounds |
JP2009504671A (en) * | 2005-08-11 | 2009-02-05 | パラティン テクノロジーズ, インコーポレイテッド | Melanocortin receptor-specific piperazine compounds with diamine groups |
WO2009144432A1 (en) * | 2008-05-30 | 2009-12-03 | Palatin Technologies, Inc. | Mc4-r agonists for the treatment of obesity |
Also Published As
Publication number | Publication date |
---|---|
EA200501724A1 (en) | 2006-06-30 |
MXPA05011729A (en) | 2006-02-13 |
EP1622618A4 (en) | 2008-08-27 |
CO5700752A2 (en) | 2006-11-30 |
US7456184B2 (en) | 2008-11-25 |
AU2004235792A2 (en) | 2008-06-26 |
BRPI0410694A (en) | 2006-06-20 |
US20080234289A1 (en) | 2008-09-25 |
US20040224957A1 (en) | 2004-11-11 |
US7964601B2 (en) | 2011-06-21 |
KR20060009285A (en) | 2006-01-31 |
JP2006525369A (en) | 2006-11-09 |
EA012502B1 (en) | 2009-10-30 |
EP1622618A1 (en) | 2006-02-08 |
AU2004235792A1 (en) | 2004-11-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7964601B2 (en) | Melanocortin receptor-specific compounds | |
US7718802B2 (en) | Substituted melanocortin receptor-specific piperazine compounds | |
US7326707B2 (en) | Bicyclic melanocortin-specific compounds | |
US7732451B2 (en) | Naphthalene-containing melanocortin receptor-specific small molecule | |
US7968548B2 (en) | Melanocortin receptor-specific piperazine compounds with diamine groups | |
US7354923B2 (en) | Piperazine melanocortin-specific compounds | |
US7727991B2 (en) | Substituted melanocortin receptor-specific single acyl piperazine compounds | |
US7655658B2 (en) | Thieno [2,3-D]pyrimidine-2,4-dione melanocortin-specific compounds | |
US7727990B2 (en) | Melanocortin receptor-specific piperazine and keto-piperazine compounds | |
US7834017B2 (en) | Diamine-containing, tetra-substituted piperazine compounds having identical 1- and 4-substituents | |
US20090076029A1 (en) | Compounds and Methods for Treating Obesity | |
WO2008017852A1 (en) | Diamine-containing, tetra- substituted piperazine compounds as melanocortin receptor modulators | |
WO2005079574A1 (en) | Bicyclic melanocorin-specific compounds | |
WO2007021990A2 (en) | Melanocortin receptor-specific piperazine compounds with diamine groups | |
US7709484B1 (en) | Substituted melanocortin receptor-specific piperazine compounds | |
WO2005102340A1 (en) | Piperazine melanocortin-specific compounds | |
ZA200509683B (en) | Melanocortin receptor-specific compounds | |
US7550602B1 (en) | Small molecule compositions for sexual dysfunction | |
WO2009144432A1 (en) | Mc4-r agonists for the treatment of obesity |
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 BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG 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 NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
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: 2006514263 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2005/011729 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020057020785 Country of ref document: KR Ref document number: 171720 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004235792 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004751262 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005/09683 Country of ref document: ZA Ref document number: 200509683 Country of ref document: ZA Ref document number: 12005502139 Country of ref document: PH Ref document number: 200501724 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 05122256 Country of ref document: CO Ref document number: 5588/DELNP/2005 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 2004235792 Country of ref document: AU Date of ref document: 20040503 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004235792 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 20048189075 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 1020057020785 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2004751262 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0410694 Country of ref document: BR |