WO2002010146A1 - Carboxamide compounds and their use as antagonists of a human 11cby receptor - Google Patents

Carboxamide compounds and their use as antagonists of a human 11cby receptor Download PDF

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Publication number
WO2002010146A1
WO2002010146A1 PCT/EP2001/008637 EP0108637W WO0210146A1 WO 2002010146 A1 WO2002010146 A1 WO 2002010146A1 EP 0108637 W EP0108637 W EP 0108637W WO 0210146 A1 WO0210146 A1 WO 0210146A1
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WO
WIPO (PCT)
Prior art keywords
ethoxy
phenyl
benzamide
compound
formula
Prior art date
Application number
PCT/EP2001/008637
Other languages
French (fr)
Inventor
Christopher Norbert Johnson
Martin Jones
Catherine Anne O'toole
Geoffrey Stemp
Kevin Michael Thewlis
David Witty
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0018758.3A external-priority patent/GB0018758D0/en
Priority claimed from GB0112544A external-priority patent/GB0112544D0/en
Priority to JP2002515877A priority Critical patent/JP2004505070A/en
Priority to EA200300064A priority patent/EA200300064A1/en
Priority to CA002417638A priority patent/CA2417638A1/en
Priority to IL15364501A priority patent/IL153645A0/en
Priority to HU0302966A priority patent/HUP0302966A2/en
Priority to EP01956562A priority patent/EP1305304A1/en
Priority to US10/343,424 priority patent/US20040063686A1/en
Priority to APAP/P/2003/002720A priority patent/AP2003002720A0/en
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU2001278508A priority patent/AU2001278508A1/en
Priority to PL01365183A priority patent/PL365183A1/en
Priority to MXPA03000923A priority patent/MXPA03000923A/en
Priority to KR10-2003-7001409A priority patent/KR20030059084A/en
Priority to BR0112856-6A priority patent/BR0112856A/en
Priority to SK114-2003A priority patent/SK1142003A3/en
Publication of WO2002010146A1 publication Critical patent/WO2002010146A1/en
Priority to BG107510A priority patent/BG107510A/en
Priority to NO20030471A priority patent/NO20030471L/en

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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to a method of treatment using an antagonist of the human 1 ICBy receptor; a new therapeutic use of a class of carboxamide compounds which are antagonists to a human 1 ICBy receptor; also to novel compounds within that class, and to methods for making the compounds.
  • WO 98/00401 discloses benzamide derivatives as fibrinogen receptor antagonist prodrugs.
  • European Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bisaryl compounds as inhibitors of erythrocyte aggregation and useful in the treatment of cardiac and circulatory disease.
  • EP 0 968 999 discloses certain anilide derivatives useful in the treatment of arrhythmia.
  • WO 99/01127 discloses certain N- [(amino alkoxy)phenyl] benzamides that are active as CCR5 receptor ligands, including the compounds N- [4- [2- [bis ( 1 -methylethyl) amino] ethoxy] -2-fluorophenyl] -[1,1 -biphenyl] -4- carboxamide and N-[4-[2-[bis(l-methylethyl)amino]-ethoxy]-phenyl]-[l, -biphenyl]-4- carboxamide.
  • WO 99/06146 discloses certain substituted anilides that are antagonists of the CCR5 receptor, including the compounds: biphenyl-4-carboxylic acid [4-(2-dimethylamino-ethoxy)-phenyl]-amide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl] -amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N- [4-(2-diethylamino-ethoxy)- ⁇ henyI] -3 -phenoxy-benzamide, 4-cyclohexyl-N-[
  • the present invention is based on the finding that a class of carboxamides overlapping with the above-mentioned benzamides and anilides, are, surprisingly, antagonists of a human 1 ICBy receptor disclosed in Nature, 400, 261-265 (1999).
  • these compounds are believed to have a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HlN-2; pain; cancers; diabetes; obesity; feeding and drinking abnormalities, such as anorexia and bulimia; asthma; Parkinson's disease; both acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia or severe mental retardation; and dyskinesias, such as Huntingdon's disease or Gilles de la Tourette's syndrome, among others, hereinafter referred to as "the Disorders”.
  • infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HlN-2
  • pain cancers
  • diabetes obesity
  • a method of treating the Disorders which comprises administering to a mammal suffering from one or more of the Disorders an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:
  • each A is independently hydrogen, a C g alkyl optionally substituted by hydroxyl, C g alkoxy, C ⁇ 6 alkenyl or group or a halogen atom or hydroxyl, CN or CF3 group;
  • R3 is hydrogen, methyl or ethyl. Preferably R3 is methyl.
  • R4 is an optionally substituted aromatic carbocychc or heterocychc ring.
  • Z is an O or S atom, or an NH or CH 2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group.
  • Z is a bond.
  • Z is a bond at the 4-position of R4 relative to the carbonyl group.
  • R5 is an optionally substituted aromatic carbocychc or heterocychc ring, or an optionally substituted, saturated or unsaturated, carbocychc or heterocychc ring.
  • R5 is a phenyl ring.
  • R1 / and Q is -X-Y-N ⁇ R2 (a) where X is an O or S atom, preferably an O atom;
  • Y is a linear or branched C2.4 alkylene group, preferably a C3 alkylene group, optionally
  • Rl and R2 are independently a linear or branched C ⁇ . alkyl, preferably ethyl; phenyl C ⁇ .
  • Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group,
  • Rl and R2 are linked to form a 5, 6 or 7-membered ring, preferably a 5-membered ring, optionally containing one or more further heteroatoms selected from O, S or N, where N or C ring atoms are optionally substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, where Ra is a linear or branched C ⁇ . ⁇ alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fused to an optionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring is optionally linked by a single bond or methylene group to Y; or (c) where X is an O or S atom, Y is a C2-4 alkylene group, Rl is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or branched C ⁇ _6 alky
  • Y is a C2-4 alkylene group
  • Rl is a C2-4 alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched C ⁇ alkyl group.
  • Alkyl groups including alkyl groups that are part of alkoxy, acyl, etc groups, typically contain 1 to 6 carbon atoms, and may be linear or branched, such as methyl, ethyl, i- propyl and t-butyl, and optionally substituted by hydroxyl.
  • Aryl groups are typically phenyl, but may include bicyclic groups such as naphthyl. Cycloalkyl groups typically contain from 3 to 7 carbon atoms.
  • Heterocychc groups may be monocylic 5 to 7 membered rings containing up to three hetero atoms, such as pyridyl or imidazole, or bicyclic, especially heterocychc rings fused to benzene rings, such as benzoxazole or benzimidazole.
  • Aryl, cycloalkyl and heterocychc groups may be optionally subsituted by up to three substituents, which may suitably be selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or by linked substituents such as dioxymethylene.
  • Suitable aromatic rings for use as R4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl.
  • Suitable optional substituents for R4 include halogen, CF3, Cj_4 alkyl, C1.4 alkoxy.
  • R4 may have 2 or 3 substituents, but preferably has only 1 substituent in addition to Z, or more preferably is unsubstituted apart from Z.
  • Particularly suitable substituents for R4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.
  • R5 may be monocyclic, for example thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bicyclic ring system, for example naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl; or a bicyclic system in which a monocyclic ring has a cyclic substituent such as oxadiazolyl, benzyloxy.
  • Suitable optional substituents for R5 include halogen, CF3, CF3O, CHF2O,
  • R5 may have
  • substituents for R5 include chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.
  • all A substituents may be hydrogen, but it is advantageous that no more than 3 are hydrogen.
  • Suitable A substituents include halogen, C ⁇ _g alkyl optionally substituted with hydroxy, C ⁇ . alkoxy, acyl and alkenyl.
  • Particularly suitable A substituents include Cl-2alkoxy, Cl-2alkyl, Cl-2 acyl.
  • Preferable substituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferable substituents for A include methoxy.
  • the A substituent is adjacent to the group Q.
  • substituents for Rl and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl.
  • Y may especially be -(CH2)2- >
  • Y When Y is substituted by hydroxy, it may be for example -CH 2 -CH(OH)-CH 2 -.
  • the ring formed by linking Rl and R2 may be pyrrolidinyl, piperidinyl, azepanyl, or imidazolyl.
  • Fused rings include indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazepinyl.
  • suitable rings include thiazinyl, oxazinyl and piperazinyl.
  • a second N atom may be substituted, for example by phenyl, methyl, ethyl, isopwpyl or acetyl.
  • Y is typically -(CH2)2-- The ring may be linked back to Y to form a quinuclidinyl group.
  • the ring formed by linking Rl to Y may be a pyrrolidinyl or piperidinyl ring.
  • the linkage to Y may be such as to create a ring linked by a single bond from a ring carbon atom directly to X or via a methylene or ethylene linking group.
  • R2 is typically methyl so that the N atom of the ring is substituted by methyl.
  • the ring formed by linking Rl to N is suitably a 5 or 6- membered ring such as diazinyl or piperazinyl.
  • Y is typically -(CH2)2-- R2 is typically methyl so that the second N atom (other than X) of the ring is substituted by methyl.
  • R3 H
  • X O
  • Y CH 2 CH 2
  • Z a bond
  • R4 Ph
  • R5 is either meta or para substituted on R4
  • Rl, R2 and R5 are as defined for formula (I).
  • A H and OMe
  • R3 H
  • X N
  • R4 phenyl
  • Z a para substituted bond
  • R5 Ph or cyclohexyl (Cy)
  • Y and R2 form a piperazinyl ring between X and N
  • Rl is as defined in formula (I).
  • a preferred sub-class of compounds for use in the method of treatment of this invention are compounds of formula (I) in which R3 is methyl.
  • a particular group of novel compounds is a class of compounds of general formula (VI)
  • R5 is phenyl or cyclohexyl optionally substituted by halogen, haloalkyl, alkyl or alkoxy
  • Z is O, CH2 or a single bond
  • R8 and R9 are independently selected from hydrogen, halogen, alkyl and alkoxy
  • Rl and R2 are alkyl or linked together to form a ring
  • R3 is ethyl or methyl.
  • Another aspect of this invention is a class of novel compounds, or a salt or solvate thereof, which are the compounds of formula (I) excluding the compounds: N-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,l'-biphenyl]-4- carboxamide,
  • a further aspect of this invention is those compounds of the Examples herein which are novel.
  • the compounds of formulae (I) to (LX), or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Suitable salts and solvates include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
  • Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as Methylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkyla ines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, colhdine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium, sodium or potassium
  • Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
  • Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
  • Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, -keto glutarate and -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) to (IX) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) to (IX) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • the compounds of formula (I) to (LX) may exist in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
  • the compounds of formula (I) to (JX), or salts or solvates thereof may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivatisation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.
  • Compounds of formula (I) to (IX) may prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art.
  • suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I).
  • an activating reagent such as thionyl chloride
  • the compounds of formula (I) may be prepared by reacting a compound of formula (X)
  • groups convertible to Rl, R2, R3, R4 and R5 may be present during the coupling, and converted to Rl, R2, R3, R4 and R5 after coupling. Also it may be convenient to convert one Rl, R2, R3, R4 and R5 to another Rl, R2, R3, R4 and R5 group after coupling.
  • ring formation between the groups Rl, X,Y, R2 or the addition of suitable cyclic groups embodying Rl, X, Y, R2, may be performed after coupling.
  • the compounds of formula (XI) may be prepared in a number of ways, for example when X is O or S coupling an appropriately substituted nitrobenzene compound with a dialkyaminoalcohol or thiol, and converting the NO2 group to NH2 by hydrogenation in the presence of palladium catalyst (or with iron/ammonium chloride) before coupling with an acid chloride, for example as illustrated below:
  • Acid chlorides of formula (X) may be prepared from the corresponding acids which are commercially available or described in the literature or may be prepared by methods analogous to those of the literature.
  • the acids of fo ⁇ nula (X) may be prepared by combining moieties containing respectively R5 and R4 via Z.
  • This may also be achieved conveniently by first coupling a compound of R4-CO-L with the compound of formula (XI) followed by reaction with a compound R5-Z-L (or L-R4- CO-L with R5-Z).
  • a compound R5-Z-L or L-R4- CO-L with R5-Z.
  • an amine of formula (XI) may be reacted with an appropriately substituted bromobenzoyl chloride which may be then reacted with, for example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic amine, as in the following scheme:
  • Novel compounds of formula (I) where the amide nitrogen is alkylated (R3 is methyl or ethyl) may be prepared by alkylating an anilide of formula (XI) before coupling with an acid chloride of formula (X), for example, by utilising the following reductive animation procedure:
  • the compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula (I) may be formed by crystallization or recrystalhzation from the appropriate solvent.
  • hydrates may be formed by crystallization or recrystalhzation from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • the compounds of formula (I) are believed to have a role in preventing, ameliorating or correcting dysfunctions of diseases, including, but not limited to, "the Disorders" previously mentioned.
  • the invention also provides a method for the treatment of diabetes, major depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
  • the invention provides a method for the treatment of diabetes in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
  • the invention provides a method for the treatment of major depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human
  • the invention provides a method for the treatment of manic depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
  • the invention provides a method for the treatment of anxiety in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
  • the invention provides a method for the treatment of schizophrenia in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
  • the invention provides a method for the treatment of sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
  • administration of such compounds to a mammal may be by way of oral (including sub-lingual), parenteral, nasal, rectal or transdermal administration.
  • a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound.
  • Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
  • compounds of formula (I) are administered in the form of a unit-dose composition, such as a unit dose oral (including sub-lingual), nasal, rectal, topical or parenteral (especially intravenous) composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and is sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • Compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
  • the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of one or more of the Disorders which comprises a compound of this invention, or a pha ⁇ naceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides a method of treatment and/or prophylaxis of one or more of the Disorders comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of one or more of the Disorders.
  • the invention provides the use of a novel compound of this invention, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of one or more of the Disorders.
  • Example A5 Correspondingly Example A7 with 4-(2-pyridy ⁇ )-benzoic acid [J.Chem.Soc; 1940; 355, 356].
  • Example A6 Correspondingly Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid [Patent WO- 9743262].
  • Example A8 Utilizing the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], in place of (2'-methyl-biphenyl-4-carboxylic acid).
  • Example A9 Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J.Chem.Soc.Perkin Trans.1; 17; 1992; 2203].
  • Example A10 Correspondingly Example A7 with 4-( 1 -methyl- 1 H-pyrazol-4-yl)-benzoic acid [Paten WO-9906409].
  • Example A14 Correspondingly Example A7 with 3 -methanesulfonyl-biphenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1966; 62].
  • Example A7 with 4-acetyl-4-biphenylcarboxylic acid [Aldrich].
  • Example A18
  • Example A20 Correspondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J.Chem.Soc.B; 1970; 1595].
  • Example A93 Utilizing the procedures of Example A93 with 2-methoxyphenylboronic acid [Aldrich] in place of 4-methylphenylboronic acid, and Example A51 with 2-(diisopropylamino)- ethanol in place of l-(2-hydroxyethyl)-pyrrolidine .
  • Example A23 with 2-naphthylboronic acid [Lancaster].
  • Example A31 Co ⁇ espondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].
  • Example A37 Utilizing the procedure of Example A35 with 4-cyclohexylbenzoic acid [Aldrich]. in place of 4-biphenylcarboxylic acid.
  • Example A47 Correspondingly Example A51 with (S)-(-)-l-methyl-2-py ⁇ olidinemethanol [Aldrich].
  • Biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrroIidin-l-yl-ethoxy)-phenyI amide.
  • Example A54 Utilising the procedure of Example A51 with l-dimethylamino-2-propanol [Aldrich] in place of l-(2-hydroxyethyl)-pyrrolidine.
  • Example A56 Correspondingly Example A51 with l-(2-hydroxyethyl)-piperidine [Aldrich].
  • Example A70 Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].
  • Example A84 Utilizing the procedures of Example A93 with 4-methoxy-phenylboronic acid [Aldrich] in place of 2-methoxyphenylboronic acid and Example A51 with 2-diethylaminoethanol in place of l-(2-hydroxyethyl)pyrrolidine.
  • Example A88 Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [Patent WO-9924440] in place of 4-methoxy-phenylboronic acid.
  • the amide, 4-bromo-N-[3-methoxy-4(2-pyrrolidin-l-yl-ethoxy)-phenyl]-benzamide (O.lmM 42mg), and 4-methyl-benzene boronic acid [Aldrich] (O.lmM 14mg) were refluxed for 16 hours in a mixture of benzene (8ml), ethanol (2ml) and 2M aqueous sodium carbonate (2ml) in the presence of tetrakis-(triphenylphosphine)-palladium[0] (5mg) under an argon atmosphere.
  • Example A103 Utilizing the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.
  • Example A103 Utilizing the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.
  • Example C3 Co ⁇ espondingly Example Cl using 3-methylbiphenyl-4-carboxylic acid [Patent WO- 9534540].
  • Example Cl using 5-methyl-l-phenylpyrazole-4-carboxylic acid [Maybridge].
  • Example C7
  • Example C9 Correspondingly Example Cl using 5-(4-chlorophenyl)-2-trifluoromethyl-furan-3- carboxylic acid [Maybridge].
  • the reaction mixture was gently refluxed until t.l.c. analysis showed no starting material.
  • the mixture was filtered while hot and the inorganic residues washed with methanol.
  • the combined filtrates were partitioned between water (5ml) and ethyl acetate(3 x 10ml), the organic phase dried (MgSO4), filtered, and evaporated.
  • the aqueous phase was treated with satd. aq. sodium bicarbonate (lOml), extracted with ethyl acetate (3 x 10ml), dried (MgSO_ ⁇ ), and evaporated. Residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane - methanol - aq.
  • Example D20 Utilizing the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene
  • Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy- phenyl]-amide
  • Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-amide
  • Patent WO-9901127 (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate (lml), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture was sti ⁇ ed vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30ml) and extracted with dichloromethane (3 x 20ml). The combined organic phases were dried (MgSO4), filtered and evaporated, then subjected to flash chromatography on silica gel
  • Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-(l-hydroxy-ethyl)-phenyl]- a ide
  • To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (20mg, 0.05mmol) dissolved in a 1 :1 mixture of tetrahydrofuran / ethanol (3ml), was added sodium borohydride [Aldrich] (6mg, 0.15mmol). The reaction mixture was sti ⁇ ed at ambient temperature for 16 hours.
  • Example D28 [WO9901127] Utilizing the procedure of Example A51 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 2-diisopropylaminoethanol in place of l-(2- hydroxyethyl)-pyrrolidine
  • Example D30 [WO9901127] Utilizing the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol.
  • Example D38 [WO9901127] Utilizing the procedure of Example A22 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4- methoxyphenylboronic acid
  • Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl] - methyl-amide.
  • Example A7 To 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine (lmmol) [Example A7] were added triethylorthoformate (8ml) and trifluoroacetic acid (0.15ml). The resulting solution was heated to 90°C for 4hr. The solution was evaporated then redissolved in ethanol and cooled to approximately -10°C. Sodium borohydride (190mg, 5mmol) was introduced portionwise over 10 minutes then the mixture allowed to warm to room temperature. The solution was sti ⁇ ed at room temperature for 16h, then acidified to pH 1 with 2M hydrochloric acid.
  • Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl- amide [Example E9] (45mg, 0.1 mmol), was dissolved in chloroform (1ml) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.1 lmmol). The mixture was sti ⁇ ed at ambient temperature for 16 hours then evaporated and subjected to flash chromatography on silica gel (dichloromethane - methanol - aqueous ammonia) to afford the title compound as an oil.
  • Example E9 Utilizing the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3 -methoxy- phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy- phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4- methoxyphenylboronic acid and of Example 51 with (N-diethyl)ethanolamine in place of 1 -(2-hydroxyethyl)py ⁇ olidine.
  • Example E14 Utilizing the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3 -methoxy- phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy- phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4- methoxypheny
  • Example E22 Correspondingly Example E14 with 4-ethylphenylboronic acid [Aldrich] .
  • Example E25 Utihsing the procedure of Example El with 4-(2-diisopro ⁇ ylamino-ethoxy)-3-methyl- phenylamine [Example D20] in place of 4-(2-diisopropylamino-ethoxy)-3-methoxy- phenylamine and triethyl orthoacetate in place of triethyl orthoformate.
  • Example FI
  • Example A7 Utilizing the procedure of Example A7 with 6-phenyl-nicotinic acid (Patent WO- 0006085) in place of 2'-methyl-4-biphenylcarboxylic acid and N-dimethylethanolamine in place of 2-(diisopropylamino)ethanol.
  • Biphenyl-4-carboxylic acid [4-((R)-diethylamino-hydroxy-propoxy)-3-methoxy- phenyl]-amide 4- ⁇ itro-2-methoxyphenol [Aldrich] (845mg, 5mmol) was dissolved in DMF (25 ml) and treated with sodium hydride (60% oil dispersion, 200mg). When the effervescence ceased, the mixture was treated with (i?)-p-nitrophenylsulphonyl glycidol [Aldrich] and warmed to 50°C with sti ⁇ ing.
  • Example G5 Utilizing the procedure for the preparation of (/?)-diethylamino-(2-methoxy-4-nitro- phenoxy)-propan-2-ol [Example Gl] but replacing dichloromethane with 1,2- dichloroethane and diethylamine with diisopropylamine. In addition, the mixture of amine and epoxide was heated at 80°C for 12h rather than being kept at ambient temperature for 24 hours.
  • Example HI 4-Cyclohexyl-iV-[3-methoxy-4-(4-methyl-piperazin-l-yl)-phenyl]-benzamide
  • the activity of the compounds used in this invention may be assessed by competitive binding assays to 1 ICBy receptors, as follows:
  • Radioligand binding assays were carried out on well washed membranes from HEK293 cells stably expressing HCBy receptors. Membranes (5-15 mg protein) were incubated with [1251] -Melanin Concentrating Hormone (0.22 nM)(obtained from NEN) in the presence and absence of competing test compounds for 45 min at 37°C in a buffer (pH7.4), containing 50mM Tris and 0.2% BSA. Non-specific binding was defined using 0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compounds were added at concentrations between 10M and lOpM in 10 concentration steps.
  • Bound cpm in the presence of test compound was expressed as a fraction of the bound cpm in the absence of test compound and plotted against the concentration of compound. From this an IC50 was determined from which the pKi was calculated.
  • the most potent compounds of the present invention have pKi values in the range of 7.1 to 7.8 For example:

Abstract

Compounds of formula (I) in which: each A is independently hydrogen, C1-6alkyl optionally substituted by hydroxyl, C1-6alkoxy, C1-6alkenyl or C1-6acyl group or a halogen atom or hydroxyl, CN or CF3 group; R3 is hydrogen, methyl or ethyl; R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring; Z is an O or S atom, or an NH or CH2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group; R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring; and Q is (a) Where X, Y, R1 and R2 are as defined in claim 1; are antagonists of a human 11CBy receptor.

Description

CARBOXAMIDE COMPOUNDS AND THEIR USE AS ANTAGONISTS OF A HUMAN 11CBY RECEPTOR
This invention relates to a method of treatment using an antagonist of the human 1 ICBy receptor; a new therapeutic use of a class of carboxamide compounds which are antagonists to a human 1 ICBy receptor; also to novel compounds within that class, and to methods for making the compounds.
International Patent Application Publication Number WO 01/21577 (Takeda Chemical Industries Ltd.) discloses certain bisaryl compounds as melanin concentrating hormone antagonists.
WO 98/00401 (Merck & Co. Inc.) discloses benzamide derivatives as fibrinogen receptor antagonist prodrugs.
European Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bisaryl compounds as inhibitors of erythrocyte aggregation and useful in the treatment of cardiac and circulatory disease.
European Patent Application EP 0 968 999 (Mitsui Chemical Inc.) discloses certain anilide derivatives useful in the treatment of arrhythmia.
WO 99/01127 (SmithKline Beecham) discloses certain N- [(amino alkoxy)phenyl] benzamides that are active as CCR5 receptor ligands, including the compounds N- [4- [2- [bis ( 1 -methylethyl) amino] ethoxy] -2-fluorophenyl] -[1,1 -biphenyl] -4- carboxamide and N-[4-[2-[bis(l-methylethyl)amino]-ethoxy]-phenyl]-[l, -biphenyl]-4- carboxamide. Also WO 99/06146 (SmithKline Beecham) discloses certain substituted anilides that are antagonists of the CCR5 receptor, including the compounds: biphenyl-4-carboxylic acid [4-(2-dimethylamino-ethoxy)-phenyl]-amide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl] -amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N- [4-(2-diethylamino-ethoxy)-ρhenyI] -3 -phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-N - [4-(2-diethylamino-ethoxy)-phenyl] -benzamide, 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.
The present invention is based on the finding that a class of carboxamides overlapping with the above-mentioned benzamides and anilides, are, surprisingly, antagonists of a human 1 ICBy receptor disclosed in Nature, 400, 261-265 (1999).
Accordingly these compounds are believed to have a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HlN-2; pain; cancers; diabetes; obesity; feeding and drinking abnormalities, such as anorexia and bulimia; asthma; Parkinson's disease; both acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia or severe mental retardation; and dyskinesias, such as Huntingdon's disease or Gilles de la Tourette's syndrome, among others, hereinafter referred to as "the Disorders".
According to the present invention there is provided a method of treating the Disorders which comprises administering to a mammal suffering from one or more of the Disorders an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:
Figure imgf000004_0001
each A is independently hydrogen, a C g alkyl optionally substituted by hydroxyl, C g alkoxy, Cμ6 alkenyl or
Figure imgf000005_0001
group or a halogen atom or hydroxyl, CN or CF3 group;
R3 is hydrogen, methyl or ethyl. Preferably R3 is methyl. R4 is an optionally substituted aromatic carbocychc or heterocychc ring.
Z is an O or S atom, or an NH or CH2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group. Preferably, Z is a bond.
More preferably, Z is a bond at the 4-position of R4 relative to the carbonyl group. R5 is an optionally substituted aromatic carbocychc or heterocychc ring, or an optionally substituted, saturated or unsaturated, carbocychc or heterocychc ring. Preferably, R5 is a phenyl ring.
R1 / and Q is -X-Y-N \ R2 (a) where X is an O or S atom, preferably an O atom;
Y is a linear or branched C2.4 alkylene group, preferably a C3 alkylene group, optionally
substituted by a hydroxyl group, or is a C5.6 cycloalkylene group,
Rl and R2 are independently a linear or branched C\. alkyl, preferably ethyl; phenyl C\.
6 alkyl group; or (b) where X is an O or S atom;
Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group,
Rl and R2 are linked to form a 5, 6 or 7-membered ring, preferably a 5-membered ring, optionally containing one or more further heteroatoms selected from O, S or N, where N or C ring atoms are optionally substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, where Ra is a linear or branched C\.ζ alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fused to an optionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring is optionally linked by a single bond or methylene group to Y; or (c) where X is an O or S atom, Y is a C2-4 alkylene group, Rl is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or branched Cι_6 alkyl group; or (d) where X is a N atom,
Y is a C2-4 alkylene group, Rl is a C2-4 alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched Cμβ alkyl group.
Alkyl groups, including alkyl groups that are part of alkoxy, acyl, etc groups, typically contain 1 to 6 carbon atoms, and may be linear or branched, such as methyl, ethyl, i- propyl and t-butyl, and optionally substituted by hydroxyl. Aryl groups are typically phenyl, but may include bicyclic groups such as naphthyl. Cycloalkyl groups typically contain from 3 to 7 carbon atoms. Heterocychc groups may be monocylic 5 to 7 membered rings containing up to three hetero atoms, such as pyridyl or imidazole, or bicyclic, especially heterocychc rings fused to benzene rings, such as benzoxazole or benzimidazole. Aryl, cycloalkyl and heterocychc groups may be optionally subsituted by up to three substituents, which may suitably be selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or by linked substituents such as dioxymethylene.
Suitable aromatic rings for use as R4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl. Suitable optional substituents for R4 include halogen, CF3, Cj_4 alkyl, C1.4 alkoxy. R4 may have 2 or 3 substituents, but preferably has only 1 substituent in addition to Z, or more preferably is unsubstituted apart from Z. Particularly suitable substituents for R4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.
R5 may be monocyclic, for example thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bicyclic ring system, for example naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl; or a bicyclic system in which a monocyclic ring has a cyclic substituent such as oxadiazolyl, benzyloxy. Suitable optional substituents for R5 include halogen, CF3, CF3O, CHF2O,
CN, amino, mono- or di-Cι_6 alkylamino, C^g alkyl, C\. alkoxy, C .ζ acyl, Cμg alkyl- S-, Cι_6 alkyl-SO2~, C\.β alkenyl, phenyl-Cι.6 alkyl, phenyl-Cχ.6 alkoxy. R5 may have
2 or 3 substituents, but preferably has only 1 substituent, especially in the para position relative to Z. Particularly suitable substituents for R5 include chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.
As for the ring substituents A, all A substituents may be hydrogen, but it is advantageous that no more than 3 are hydrogen. Suitable A substituents include halogen, Cι_g alkyl optionally substituted with hydroxy, Cγ. alkoxy,
Figure imgf000007_0002
acyl and
Figure imgf000007_0001
alkenyl.
Particularly suitable A substituents include Cl-2alkoxy, Cl-2alkyl, Cl-2 acyl. Preferable substituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferable substituents for A include methoxy. Suitably, the A substituent is adjacent to the group Q.
In the system Q, in configuration (a) particularly suitable substituents for Rl and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl. Y may especially be -(CH2)2->
-(CH2)3-, -(CH2)4-, -CH2-CH(CH3)-CH2-. When Y is substituted by hydroxy, it may be for example -CH2-CH(OH)-CH2-.
In configuration (b) of system Q, the ring formed by linking Rl and R2 may be pyrrolidinyl, piperidinyl, azepanyl, or imidazolyl. Fused rings include indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazepinyl. When a second heteroatom is present, suitable rings include thiazinyl, oxazinyl and piperazinyl. A second N atom may be substituted, for example by phenyl, methyl, ethyl, isopwpyl or acetyl. Y is typically -(CH2)2-- The ring may be linked back to Y to form a quinuclidinyl group.
In configuration (c) of system Q, the ring formed by linking Rl to Y may be a pyrrolidinyl or piperidinyl ring. The linkage to Y may be such as to create a ring linked by a single bond from a ring carbon atom directly to X or via a methylene or ethylene linking group. R2 is typically methyl so that the N atom of the ring is substituted by methyl. In configuration (d) of system Q, the ring formed by linking Rl to N is suitably a 5 or 6- membered ring such as diazinyl or piperazinyl. Y is typically -(CH2)2-- R2 is typically methyl so that the second N atom (other than X) of the ring is substituted by methyl.
Within the scope of formula (I) is a class of compounds of general formula (II)
Figure imgf000008_0001
(II)
where A = H and OMe, R3 = H, X = O, Y = CH2CH2 , Z = a bond, R4 = Ph, R5 is either meta or para substituted on R4, and Rl, R2 and R5 are as defined for formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (III)
Figure imgf000008_0002
(HI) where A = H and OMe, R3 = H, X = O, Y = CH2-CH2 , Z = O, CH2 or NH and is either meta or para substituted on R4, R4 = Ph, R5 is Ph, and Rl and R2 are as defined for formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (IV)
Figure imgf000008_0003
(IV) where A = H and OMe, Rl = R2 = /Pr, R3 = H, X = O, Y = CH -CH , and R4 and R5 are substituted phenyl or heterocycles as defined for formula (I)
Also within the scope of formula (I) is a class of compounds of general formula (V)
Figure imgf000009_0001
R5^Z
(V) where R3 = H, X = O, Y = CH2-CH2, Z = O, CH2, NH or a bond, R4 = Ph, R5 is Ph or cyclohexyl (Cy), Z is either meta or para substituted on R4, and A (R6,R7) and R1,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VI)
Figure imgf000009_0002
(VI) where X = O, Y = CH2-CH2, R4 = phenyl, R5 = phenyl or cyclohexyl (Cy), Z = O, CH or a bond, and A (R8,R9), R3 and R1,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VII)
Figure imgf000010_0001
(VII) where A = H and OMe, X = O, R3 = H, R4 = 3 -pyridyl (with respect to the carbonyl group), R5 = phenyl, Z = a para bond , and R1,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (VIII)
Figure imgf000010_0002
(VIII) where A = H and OMe, R3 = H, X = O, R4 = phenyl, Z = O, CH or a bond, R5 = Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by an hydroxyl group, and R1,R2 are as defined in formula (I).
Also within the scope of formula (I) is a class of compounds of general formula (IX)
Figure imgf000010_0003
where A = H and OMe, R3 = H, X = N, R4 = phenyl, Z = a para substituted bond, R5 = Ph or cyclohexyl (Cy), Y and R2 form a piperazinyl ring between X and N, and Rl is as defined in formula (I). A preferred sub-class of compounds for use in the method of treatment of this invention are compounds of formula (I) in which R3 is methyl.
Within formula (I) is a novel group of compounds in which R3 is methyl or ethyl. The novel compounds, or a salt or solvate thereof, form a further aspect of this invention.
A particular group of novel compounds is a class of compounds of general formula (VI)
Figure imgf000011_0001
(VI) where R8 and R9 are as defined for A in formula (I), Rl, R2 and R5 are as defined in formula (I), and R3 is methyl or ethyl.
Suitably R5 is phenyl or cyclohexyl optionally substituted by halogen, haloalkyl, alkyl or alkoxy; Z is O, CH2 or a single bond; R8 and R9 are independently selected from hydrogen, halogen, alkyl and alkoxy; Rl and R2 are alkyl or linked together to form a ring; and R3 is ethyl or methyl.
Another aspect of this invention is a class of novel compounds, or a salt or solvate thereof, which are the compounds of formula (I) excluding the compounds: N-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,l'-biphenyl]-4- carboxamide,
N-[4-[2-[bis(l-methylemyl)aπύno]etJhoxy]phenyl]-[l, -biphenyl]-4-carboxarnide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,
N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-Ν - [4-(2-diethylamino-ethoxy)-phenyl] -benzamide, 4-benzyl-N- [4-(2-diisopropylamino-ethoxy)-phenyl] -benzamide, 4-benzyl-N -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl] -amide.
A further aspect of this invention is those compounds of the Examples herein which are novel.
The compounds of formulae (I) to (LX), or their salts or solvates, are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
Suitable salts and solvates include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as Methylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkyla ines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, colhdine, quinine or quinoline.
Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, -keto glutarate and -glycerophosphate.
Suitable pharmaceutically acceptable solvates include hydrates.
A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) to (IX) or its salt or solvate.
One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.
Examples of pharmaceutically acceptable salts of a compound of formula (I) to (IX) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
The compounds of formula (I) to (LX) may exist in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
The compounds of formula (I) to (JX), or salts or solvates thereof, may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivatisation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxy, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.
Compounds of formula (I) to (IX) may prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art. For example, suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I).
In particular, the preparation of certain carboxamides of formula (I) in which R3 is H is disclosed in WO 99/01127 and WO 99/06146 mentioned above, and analogous methods of preparation may be used in the present invention. Many additional methods for converting a carboxylic acid to an amide are known, and can be found in standard reference books such as "Compendium of Organic Synthetic Methods", Vol. I- VI
(published by Wiley-Interscience).
For example the compounds of formula (I) may be prepared by reacting a compound of formula (X)
R5-Z-R4-COL (X) where L is a leaving group such as halogen, especially chlorine or bromine with a compound of formula (XI)
Figure imgf000014_0001
where A, Z, R3, R4, R5 and Q are as defined for formula (I).
In this process, groups convertible to Rl, R2, R3, R4 and R5 may be present during the coupling, and converted to Rl, R2, R3, R4 and R5 after coupling. Also it may be convenient to convert one Rl, R2, R3, R4 and R5 to another Rl, R2, R3, R4 and R5 group after coupling. In particular, ring formation between the groups Rl, X,Y, R2 or the addition of suitable cyclic groups embodying Rl, X, Y, R2, may be performed after coupling.
Accordingly, there is provided a process for the preparation of a compound of formula (I), or a salt or solvate thereof, wherein R3 is methyl or ethyl which process comprises the reaction of a compound of formula (X) as hereinbefore defined with a compound of formula (XI) wherein A and Q are as hereinbefore defined and R3 is methyl or ethyl.
There therefore also provided a process for the preparation of a compound of formula (I), or a salt or solvate thereof, with the proviso that the following compounds are excluded;
N- [4- [2- [bis( 1 -methylethyl)amino] ethoxy] -2-fluorophenyl] -[1,1 '-biphenyl] -4- carboxamide,
N- [4- [2- [bis(l -methylethyl)amino]ethoxy]phenyl] -[1 , 1 -biphenyl] -4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,
N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,
N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,
N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,
4-cyclohexyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,
4-benzyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,
4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.
which process comprises the reaction of a compound of formula (X) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined.
The compounds of formula (XI) may be prepared in a number of ways, for example when X is O or S coupling an appropriately substituted nitrobenzene compound with a dialkyaminoalcohol or thiol, and converting the NO2 group to NH2 by hydrogenation in the presence of palladium catalyst (or with iron/ammonium chloride) before coupling with an acid chloride, for example as illustrated below:
Figure imgf000016_0001
Acid chlorides of formula (X) may be prepared from the corresponding acids which are commercially available or described in the literature or may be prepared by methods analogous to those of the literature.
Alternatively the acids of foπnula (X) may be prepared by combining moieties containing respectively R5 and R4 via Z.
This may also be achieved conveniently by first coupling a compound of R4-CO-L with the compound of formula (XI) followed by reaction with a compound R5-Z-L (or L-R4- CO-L with R5-Z). For example an amine of formula (XI) may be reacted with an appropriately substituted bromobenzoyl chloride which may be then reacted with, for example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic amine, as in the following scheme:
Figure imgf000017_0001
= (SJ-f+^^'-Bi phosphinoH.
Similar reactions building up the structure of formula (I) may be earned out starting with the compound of formula (X) and adding the equivalent of foπnula (XI) in sections, as in the scheme below where an N-protecting group on Q, here a piperazine ring, may be removed after coupling the components of formula (I) and replacement by a desired substituent:
Figure imgf000017_0002
Procedure H1
Figure imgf000017_0003
In an alternative strategy for building up the compounds of formula (XI) before coupling, so as to introduce a hydroxy group in Y, an appropriately substituted nitrophenol is linked to an epoxy compound wliich is then reacted with an amine forming a group Q which is - O-Y(OH)-NRlR2, before coupling with R5-Z-R4-CO-L, as illustrated by:
Figure imgf000018_0001
Nos = p-nitrobenzenesulp onyl
Novel compounds of formula (I) where the amide nitrogen is alkylated (R3 is methyl or ethyl) may be prepared by alkylating an anilide of formula (XI) before coupling with an acid chloride of formula (X), for example, by utilising the following reductive animation procedure:
Figure imgf000018_0002
The compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
Solvates of the compounds of formula (I) may be formed by crystallization or recrystalhzation from the appropriate solvent. For example, hydrates may be formed by crystallization or recrystalhzation from aqueous solutions, or solutions in organic solvents containing water. Also salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
The above-listed compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
By virtue of the activity of these compounds as antagonists of a human 11 CBy receptor, the compounds of formula (I) are believed to have a role in preventing, ameliorating or correcting dysfunctions of diseases, including, but not limited to, "the Disorders" previously mentioned.
It is also considered that the treatment of certain of the Disorders mentioned above by an antagonist to the human 1 ICBy receptor are novel. Accordingly, the invention also provides a method for the treatment of diabetes, major depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor. In particular the the invention provides a method for the treatment of diabetes in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor. In particular the invention provides a method for the treatment of major depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human
1 ICBy receptor. In particular the invention provides a method for the treatment of manic depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor. In particular the the invention provides a method for the treatment of anxiety in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor. In particular the the invention provides a method for the treatment of schizophrenia in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor. In particular the the invention provides a method for the treatment of sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
The administration of such compounds to a mammal may be by way of oral (including sub-lingual), parenteral, nasal, rectal or transdermal administration.
An amount effective to treat the Disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly prefeπed that compounds of formula (I) are administered in the form of a unit-dose composition, such as a unit dose oral (including sub-lingual), nasal, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and is sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
No adverse toxicological effects are expected for the compounds of the invention, when administered in accordance with the invention.
Accordingly, in a further aspect, the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of one or more of the Disorders which comprises a compound of this invention, or a phaπnaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prophylaxis of one or more of the Disorders comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of one or more of the Disorders. In a still further aspect the invention provides the use of a novel compound of this invention, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of one or more of the Disorders.
Compounds for use in this invention and their preparation are illustrated in the following Examples and Tables.
These Examples illustrate general procedures and sources of chemicals utilised to prepare compounds whose structures are shown in the Tables of data which follow the Examples. In the case of Examples prepared as members of a coupled array, the synthetic origin of all starting componants of the array are shown in the Examples. Rather than detailing the experimental procedure for each case, the method by which individual members of the array were prepared is indicated in a Table by reference to a related Example. Mass spectral characterisation of all Examples is provided in the tables of data. Additional characterisation is provided for selected representative Examples with full experimental procedures.
Example Al [WO-00/06146]
Utilising the procedure of Example A7 with 4-biphenylcarboxylic acid [Aldrich] in place of 2'-methyl-4-biphenylcarboxylic acid.
Example A2
Coπespondingly Example A7 with 4-(5-methyl-[l,2,4]oxadiazol-3-yl)-benzoic acid [J.Org.Chem. 50; 8; 1985; 1182].
Example A3
Correspondingly Example A7 with 4-pyrazol-l-yl-benzoic acid [Can.J.Chem.; 41; 1963;
1540].
Example A4
Correspondingly Example A7 with 3-biphenylcarboxylic [Med.Chem.Res.; 6; 2; 1996],
Example A5 Correspondingly Example A7 with 4-(2-pyridyι)-benzoic acid [J.Chem.Soc; 1940; 355, 356].
Example A6 Correspondingly Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid [Patent WO- 9743262].
Example A7
2-methylphenyl-4-phenylcarboxylic acid [3-methoxy-4-(2-bis-(2-methylethyl)amino)- ethoxy)-phenyl amide.
To a solution of the acid (2'-methyl-biphenyl-4-carboxylic acid) [Patent WO-9901127] (55mg, 0.26mmol) in dimethylformamide were added (l-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride [Aldrich] (50mg, 0.26mmol) and l-hydroxy-7- azabenzotriazole [Aldrich] (35mg, 0.26mmol) followed by diisopropylethylamine (0.04ml, 0.25mmol) and the aniline (4-(2-diisopropylamino-ethoxy)-3-methoxy- phenylamine) (69mg, 0.22mmol), [prepared using the method used to form 3-methoxy-4- (2-pyrrolidin-l-yl-ethoxy)-phenylamine in Example A51 but with 2-diisopropylamino- ethanol in place of l-(2-hydroxyethyl)-pyrrolidine]. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue re-dissolved in dichloromethane (10ml), filtered tlirough an SAX [Varian] column (2g), and the filtrate was then stirred with PS-isocyanate resin [Argonaut Technologies] (lOOmg, 0.38mmol) for 16 hours. The mixture was filtered, evaporated, and the residue purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluent, to afford the title compound as an oil. *H NMR (CDC13): δ 1.04 (12H, d), 2.28 (3H, s), 2.90 (2H, t), 3.05 (2H, m), 3.91 (3H, s), 3.95 (2H, t), 6.88 (IH, d), 7.03 (IH, dd), 7.27-7.32 (4H, m), 7.44, (2H, d), 7.53 (IH, d), 7.94 (2H, d) and 8.01 (IH, bs); MS (AP+ve): m/z 461 [M+H]+.
Example A8 Utilising the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], in place of (2'-methyl-biphenyl-4-carboxylic acid).
Example A9 Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J.Chem.Soc.Perkin Trans.1; 17; 1992; 2203].
Example A10 Correspondingly Example A7 with 4-( 1 -methyl- 1 H-pyrazol-4-yl)-benzoic acid [Paten WO-9906409].
Example All
Correspondingly Example A7 with 4'-(5-methyl-[l,2,4]oxadiazol-3-yl)-biphenyl-4- carboxylic acid [Patent: WO -9743262].
Example A12
Correspondingly Example A7 with 4-benzyl-carboxylic acid [Apin].
Example A13
Correspondingly Example A7 with 3 '-cyano-biphenyl-3 -carboxylic acid [J.Chem.Soc.Perkin Trans.2; 1; 1984; 35-38].
Example A14 Correspondingly Example A7 with 3 -methanesulfonyl-biphenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1966; 62].
Example A15
Correspondingly Example A7 with 3-thiophen-2-yl-benzoic acid [Tetrahedron Lett.; 39; 24; 1998; 4175].
Example A16
Correspondingly Example A7 with 3-thiophen-3-yl-benzoic acid [J.Chem.Soc.B; 1970; 1595].
Example A17
Correspondingly Example A7 with 4-acetyl-4-biphenylcarboxylic acid [Aldrich]. Example A18
Correspondingly Example A7 with 4'-cyano-3'-methylbiphenyl-4-carboxylic acid [WO- 9850358].
Example A19
Coπespondingly Example A7 with 4'-(5-methyl-[l,3,4]oxadiazol-2-yl)-biphenyl-4- carboxylic acid [Patent: WO-9743262].
Example A20 Correspondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J.Chem.Soc.B; 1970; 1595].
Example A21
Correspondingly Example A7 with 4-pyrazin-2-yl-benzoic acid [Patent WO-9854164].
Example A22
Utilising the procedures of Example A93 with 2-methoxyphenylboronic acid [Aldrich] in place of 4-methylphenylboronic acid, and Example A51 with 2-(diisopropylamino)- ethanol in place of l-(2-hydroxyethyl)-pyrrolidine .
Example A23
Utilising the procedure of Example A22 with 4-trifluoromethylphenylboronic acid
[Aldrich], in place of 2-methoxyphenylboronic acid [Aldrich]
Example A24
Correspondingly Example A23 with 3-aminophenylboronic acid [Aldrich].
Example A25
Correspondingly Example A23 with 4-benzyloxyphenylboronic acid [Lancaster].
Example A26
Correspondingly Example A23 with 2-naphthylboronic acid [Lancaster]. Example A27
Coπespondingly Example A23 with 3-naphthylboronic acid [Lancaster].
Example A28
Correspondingly Example A23 with 4-methylphenylboronic acid [Lancaster].
Example A29
Correspondingly Example A23 with 4-methylthiophenylboronic acid [Lancaster].
Example A30
Coπespondingly Example A23 with 3-trifluoromethylphenylboronic acid [Lancaster].
Example A31 Coπespondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].
Example A32
Coπespondingly Example A23 with 3,4-(methylenedioxy)phenylboronic acid [Aldrich].
Example A33
Correspondingly Example A23 with 4-vinylphenylboronic acid [Aldrich].
Example A34
Coπespondingly Example A23 with 3-methoxyphenylboronic acid [Lancaster].
Example A35
Utilising the procedure of Example A51 with l-(2-hydroxyethyl)morpholine [Aldrich] in place of l-(2-hydroxyethyl)pyπolidine.
Example A36
Utilising the procedure of Example A35 with 4-cyclohexylbenzoic acid [Aldrich]. in place of 4-biphenylcarboxylic acid. Example A37
Utilising the procedure of Example A51 with 2-dimethylaminoethanol [Aldrich], in place of l-(2-hydroxyethyl)pyrrolidine.
Example A39
Coπespondingly Example A51 with (R)-(+)-l-methyl-2-pyπolidinemethanol (Patent
WO-9932480).
Example A41
Correspondingly Example A51 with 3-hydroxy-l-methylpiperidine [Aldrich].
Example A43
Coπespondingly Example A51 with 2-dimethylamino-l-propanol [ICN-RF].
Example A45
Coπespondingly Example A51 with 2-(diethylamino)-ethanol [Aldrich].
Example A47 Correspondingly Example A51 with (S)-(-)-l-methyl-2-pyπolidinemethanol [Aldrich].
Example A49
Correspondingly Example A51 withN-benzyl-N-methylethanolamine [Aldrich].
Example A51
Biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrroIidin-l-yl-ethoxy)-phenyI amide.
To a solution of the hydroxy amine, (l-(2-hydroxyethyl)-pyπolidine) [Aldrich], (1.87ml, 16mmol) in dimethylfor amide was added portionwise sodium hydride [60% dispersion in oil, (544mg, 16mmol). After stiπing at room temperature for 10 minutes a solution of the halonitrobenzene, (l-chloro-2-methoxy-4-nitro-benzene) [Avocado] (3g, lβmmol) in dimethylformamide (10ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16hrs then concentrated. The residue was dissolved in ethyl acetate (200ml) and washed with water (3 x 50ml). The organic phase was dried with magnesium sulphate, evaporated and the residue purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluent to afford l-[2-(2-methoxy-4-nitro- phenoxy)-ethyl]-pyπolidine as a brown oil. lK NMR (CDC ): δl .82 (4H, m), 2.65 (4H, m), 3.01 (2H, t), 3.94 (3H, s), 4.24 (2H, t), 6.92 (IH, d), 7.74 (IH, d), and 7.89(1H, dd); MS (AP +ve): m/z 267 [M+H]+.
To a solution of the amine, l-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine (2.3g, 8.6mmol) in ethanol (100ml) was added 10% Pd/C (50mg). The mixture was stiπed at room temperature under an atmosphere of hydrogen at atmospheric pressure for 16h, then filtered through celite and the filtrate concentrated to give the corresponding aniline; 3- methoxy-4-(2-pyπolidin-l-yl-ethoxy)-phenylamine, as a brown solid. *HNMR (CDCI3): δ 1.80 (4H, m), 2.62 (4H, m), 2.89 (2H, t), 3.80 (3H, s), 4.06 (2h, t), 6.20 (IH, dd), 6.29 (IH, d) and 6.75 (IH, d); MS (AP +ve): m/z 237 [M+H]+.
To the carboxylic acid, (4-biphenyl carboxylic acid) [Aldrich] (47.5mg, 0.24mmol) suspended in dichloromethane (1ml) was added oxalyl chloride [Aldrich] (0.06ml, 0.72mmol) followed by one drop of dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour, concentrated, then co-evaporated three times with dichloromethane to give 4-phenylbenzoyl chloride. This was dissolved in dichloromethane (1ml) and added to a solution containing the amine, (3-methoxy-4-(2- pyreolidin-l-yl-ethoxy)-phenylamιne), (47 mg, 0.2mmol), triethylamine (0.14ml, lmmol) and dichloromethane (1ml). The reaction mixture was stiπed for 16 hours at room temperature, concentrated, re-dissolved in dichloromethane (10ml), filtered through an SAX column [Varian] (2g) and stiπed with PS-isocyanate resin [Argonaut Technologies] (lOOmg, 0.38mmol) for 16 hours. The mixture was filtered, evaporated then purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluent to afford the title compound as an oil. !H NMR (CDCI3): δ 1.88 (4H, m), 2.90 (4H, m), 3.08 (2H, t), 3.84 (3H, s), 4.21 (2H, t), 6.83 (IH, d), 7.03 (IH, dd), 7.27-7.70 (8H, m) and 8.01 (2H, d); MS (AP+ve): m/z All [M+H]+.
Example A54 Utilising the procedure of Example A51 with l-dimethylamino-2-propanol [Aldrich] in place of l-(2-hydroxyethyl)-pyrrolidine.
Example A56 Correspondingly Example A51 with l-(2-hydroxyethyl)-piperidine [Aldrich].
Example A58
Correspondingly Example A51 with 2-(hexamethyleneamino)-ethanol [Lancaster].
Example A60
Utilising the procedures of Example A93 with 3-aminophenylboronic acid in place of 2- methoxyphenylboronic acid and Example 51 with 2-dimethylaminoethanol in place of 1- (2-hydroxyethyl)pyrrolidine.
Example A63
Utilising the procedure of Example A60 with 4-carboxyphenylboronic acid [Aldrich] in place of 3-aminophenylboronic acid.
Example A70 Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].
Example A72
Utilising the procedure of Example 51 with N-(2-phenyl)-ethyl-N-methyl-ethanolamine [J. Org. Chem. 1985, 50(22), 4359] in place of l-(2-hydroxyethyl)-pyrrolidine.
Example A74
Correspondingly Example 51 with 2-dimethylaminocyclohexanol [J. Chem. Soc. C (1969), (2), 248-52].
Example A76
Correspondingly Example 51 with 2-(l,2,4,5-tetrahydro-benzo[cf]azepin-3-yl)-ethanol [Patent US-394682] Example A78
Correspondingly Example 51 with 2-(3,4-dihydro-lH-isoquinolin-2-yl)-ethanol [Patent WO-9719926].
Example A80
Coπespondingly Example 51 with 2-(4-phenyl-piperazin-l-yl)-ethanol
[J. Med. Chem. 1994, 37(13), 1964].
Example A82
Coπespondingly Example 51 with l-methyl-3-pyπolidinol [Aldrich].
Example A84 Utilising the procedures of Example A93 with 4-methoxy-phenylboronic acid [Aldrich] in place of 2-methoxyphenylboronic acid and Example A51 with 2-diethylaminoethanol in place of l-(2-hydroxyethyl)pyrrolidine.
Example A88 Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [Patent WO-9924440] in place of 4-methoxy-phenylboronic acid.
Example A89
Coπespondingly Example A88 with 2-methoxy-3-pyridylboronic acid [Patent WO- 9910331].
Example A90
Coπespondingly Example A88 with benzo-[&]-furan-2-boronic acid [Aldrich].
Example A91
Coπespondingly Example A88 with thiophene-3-boronic acid [Aldrich]. Example A92
Coπespondingly Example A88 with indole-5-boronic acid [Frontier].
Example A93 4'-Methyl-biphenyl~4-carboxylic acid [3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)- phenyl]-amide
A mixture of 3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine [Example A51] (4.7mM l.lg) and triethylamine (14mmol) was treated with 4-bromobenzoyl chloride [Aldrich] in dichloromethane (20ml) and kept at room temperature for 16 hours. The solvent was evaporated and the crude product purified by chromatography on silica gel using dichloromethane - methanol - aq. ammonia to afford 4-bromo -N-[3-methoxy-4(2-pyπolidin-l-yl-ethoxy)-phenyl]-benzamide as a white solid in 72% yield. JHΝMR (DMSO-d6): δ 7.91 (2H, dd), 7.73 (2H, dd), 7.50 (IH, d), 7.30 (IH, dd), 6.94 (IH, d), 4.02 (2H, t), 3.76 (3H, s), 2.77 (2H, t), 2.51 (4H, m under DMSO-d-5 signal) and 1.67 (4H, m); MS: (ES+ve) m/z 419, 421 [M+H]+
The amide, 4-bromo-N-[3-methoxy-4(2-pyrrolidin-l-yl-ethoxy)-phenyl]-benzamide (O.lmM 42mg), and 4-methyl-benzene boronic acid [Aldrich] (O.lmM 14mg) were refluxed for 16 hours in a mixture of benzene (8ml), ethanol (2ml) and 2M aqueous sodium carbonate (2ml) in the presence of tetrakis-(triphenylphosphine)-palladium[0] (5mg) under an argon atmosphere. The mixture was cooled, the upper layer decanted, and this solution purified by chromatography on silica gel using dichloromethane: methanol (10:1) followed by acetonitrile: satd. aqueous ammonia (25:1) to afford the title compound as a white solid.
*H NMR (CDC13): δ 7.92 (2H, dd), 7.68 (2H, dd), 7.50 (2H, dd), 7.26 (3H, dddd),
6.96 (IH, dd), 6.88 (IH, d), 4.13 (IH, t), 3.87 (3H, s), 2.92 (2H, t), 2.60 (4H, m),
2.41 (3H, s) and 1.80 (4H, m); MS: (AP-ve) m/z 429 [M-H]"; (AP+ve) m/z 431 [M+H]+
Example A100
Utilising the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid. Example A103
Coπespondingly Example A93 with furan-3 -boronic acid [Frontier].
Example A104
Coπespondingly Example A93 with mesityl-boronic acid [Frontier].
Example A105
Utilising the procedure of Example A51 except employing chloroform in place of dichloromethane as a solvent and eluent and utilising 3-quinuclidinol [Aldrich] in place of l-(2-hydroxyethylpyrrolidine)
Example A107
Utilising the procedure of Example B37 except using piperidine in place of aniline.
Example Bl
Utilising the procedure of Example A7 with 3-phenoxybenzoic acid [Aldrich] in place of
2'-methyl-biphenyl-4-carboxylic acid.
Example B2
Correspondingly Example Bl using 4-benzylbenzoic acid [Apin].
Example B34
Coπespondingly Example Bl using 3-benzylbenzoic acid [Patent WO-9828268].
Example B35
Coπespondingly Example Bl using 4-phenoxybenzoic acid [Aldrich].
Example B37 N-[-[3-Methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenyl] -4-phenylamino-benzamide
Dry cesium carbonate (0.15mM, 49mg), (S)-BINAP [Aldrich] (0.015 mM, 9mg) and palladium acetate (0.0075mM, 2mg) were sonicated in anhydrous ethyleneglycol dimethyl ether (15 ml) for 40 minutes under an argon atmosphere. This suspension was treated with 4-bromo-iV-[3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-benzamide [Example A93] (O.lmM, 42mg) and aniline (0.1 l M, lOmg) then refluxed for 40 hours. The suspension was filtered tlirough a hydrophobic membrane, concentrated, then purified on C 18 R.P. silica using acetonitrile: water to afford the title compound as a white solid. iHNMR (MeOH-d4): δ 7.96 (2H, dd) 7.92 (IH, d), 3.1 (2H, dd), 7.20 (IH, dd), 7.04
(IH, d), 4.28 (2H, t), 3.92 (3H, s), 3.78 (2H, m), 3.60 (2H, t), 3.58-3.13 (6H, m) and 2.26-
1.47 (10H, m); MS: (ES+ve) m/z 424 [M+H]+
Example Cl
Utilising the procedure of Example A7 with 2-methylbiphenyl-4-carboxylic acid [Patent
WO-9606079] in place of 2'-methyl-biphenyl-4-carboxylic acid.
Example C2
Correspondingly Example Cl using 3-methoxybiphenyl-4-carboxylic acid [Patent WO- 9534540].
Example C3 Coπespondingly Example Cl using 3-methylbiphenyl-4-carboxylic acid [Patent WO- 9534540].
Example C4
Coπespondingly Example Cl using 4-phenylthiophene-2-carboxylic acid [Specs].
Example C5
Correspondingly Example Cl using 4-(3,5-dichlorophenoxy)-furan-2-carboxylic acid
[Maybridge].
Example C6
Coπespondingly Example Cl using 5-methyl-l-phenylpyrazole-4-carboxylic acid [Maybridge]. Example C7
Correspondingly Example Cl using 6-phenyl-nicotinic acid [WO-0006085].
Example C8
Correspondingly Example Cl using 3-chloro-biphenyl-4-carboxylic acid [Patent JP- 09221476].
Example C9 Correspondingly Example Cl using 5-(4-chlorophenyl)-2-trifluoromethyl-furan-3- carboxylic acid [Maybridge].
Example CIO
Correspondingly Example Cl using 2-(4-chlorophenyl)-3-(trifluoromethyl)-pyrazole-4- carboxylic acid [Maybridge].
Example Cll
Correspondingly Example Cl using 5-(2-pyridyl)-thiophene-2-carboxylic acid [Maybridge].
Example C12
Correspondingly Example Cl using 5-(methyl-trifluoromethyl-2-H-pyrazol-3-yl)- thiophene-2-carboxylic acid [Maybridge].
Example DI
Utilising the procedure of Example D5 with 3,4-dichloronitrobenzene [Aldrich] in place of 2,4-dichloronitrobenzene.
Example D5 Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylamino-ethoxy)-phenyl]-amide.
To a three-neck flask (fitted with condenser, dropping funnel and thermometer) containing iron powder (938mg, 16.8mmol) mixed with a solution of ammonium chloride (28mmoι) in water (28ml), was added the amine [2-(3-chloro-4-nitro-phenoxy)-ethyl]- diisopropyl-amine [prepared by the method used to form l-[2-(2-methoxy-4-nitro- phenoxy)-ethyl]-pyrrolidine in Example A51 but with 2-4-dichloronitrobenzene [Aldrich] in place of 4-clιloro-3-methoxynitrobenzene and 2-diisopropylaminoethanol in place of l-(2-hydroxylethyl)-pyιτolidine], dropwise over 10 minutes. The reaction mixture was gently refluxed until t.l.c. analysis showed no starting material. The mixture was filtered while hot and the inorganic residues washed with methanol. The combined filtrates were partitioned between water (5ml) and ethyl acetate(3 x 10ml), the organic phase dried (MgSO4), filtered, and evaporated. The aqueous phase was treated with satd. aq. sodium bicarbonate (lOml), extracted with ethyl acetate (3 x 10ml), dried (MgSO_ι), and evaporated. Residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane - methanol - aq. ammonia as eluent to afford 2-chloro-4-(2-diisopropylamino-ethoxy)-phenylamine as a brown oil. *H NMR (CDC13): δ 1.02(12H, d), 2.77(2H, t), 3.03(2H, sept.), 3.72(2H, bs), 3.80(2H, t), 6.68(2H, m) and 6.85(1H, m); MS (AP+ve): m/z 271, 273 [M+H]+.
This material was used in place of 3-methoxy-4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine in the procedure of Example A51 to afford the title compound as clear oil. 1H NMR (CDCI3): δ 1.26 (12H, d), 3.07 (2H, m), 3.35 (2H, m), 4.22 (2H, m), 6.89 (IH, dd), 7.01 (IH, m), 7.44 (3H, q), 7.62 (2H, d), 7.71 (2H, d), 7.97 (2H, d) and 8.34 (IH, d); MS (AP+ve): m/z 452, 454 [M+H]+.
Example D9
Utilising the procedure of Example A51 with 2,4-difluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene.
Example D12 [WO-00/06146]
Utilising the procedure of Example A51 with 3,4-difluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene.
Example D16 Utilising the procedure of Example A51 with 2-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene
Example D20 Utilising the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene
Example D24
Utilising the procedure of Example A51 with 3-acetyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3 -methoxynitrobenzene
Example D25
Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy- phenyl]-amide Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-amide [Patent WO-9901127] (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate (lml), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture was stiπed vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30ml) and extracted with dichloromethane (3 x 20ml). The combined organic phases were dried (MgSO4), filtered and evaporated, then subjected to flash chromatography on silica gel
[chloroform - methanol - aqueous acetic acid] to obtain the title compound as the acetate salt, a white solid.
XH NMR (CDC13): δ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, hept.), 4.05 (3H, s), 4.10 (2H, t), 5.0 (IH, bs), 7.22 (IH, s), 7.40 (IH, t), 7.48 (2H, d), 7.65 (2H, d), 7.76 (2H, d), 8.14 (2H, d), 8.72 (IH, s) and 9.34 (IH, s); MS (AP+ve): m/z 475 [M+H+].
Example D26
Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-(l-hydroxy-ethyl)-phenyl]- a ide To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (20mg, 0.05mmol) dissolved in a 1 :1 mixture of tetrahydrofuran / ethanol (3ml), was added sodium borohydride [Aldrich] (6mg, 0.15mmol). The reaction mixture was stiπed at ambient temperature for 16 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluents, to afford the title compound as a white solid. *HNMR (CDCI3): δ 1.09 (6H, t), 1.49 (3H, d), 2.75 (4H, q), 2.95 (2H, t), 4.15(2H, t), 5.01 (IH, q), 6.84 (IH, d), 7.45-7.67 (9H, m) and 7.95 (2H, d) MS (AP+ve): m/z 433 [M+H+].
Example D27
Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-ethyl-phenyl]-amide
To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (25mg, 0.06mmol) dissolved in dichloromethane (1.5ml), was added triethylsilane (0.5ml) and trifluoroacetic acid (0.25ml). The resulting yellow solution was stiπed at room temperature for 120h. The solvents were evaporated and the residue purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluents to afford the title compound as white solid. 2H NMR (CDCI3): δ 1.17 (6H, m), 2.64 (2H, q), 2.8 (4H, q), 3.06 (2H, t), 4.15 (2H, t),
6.82 (IH, d), 7.35-7.71 (9H, m) and 7.96 (2H, d)
MS (AP+ve): m/z 417 [M+H]+
Example D28 [WO9901127] Utilising the procedure of Example A51 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 2-diisopropylaminoethanol in place of l-(2- hydroxyethyl)-pyrrolidine
Example D30 [WO9901127] Utilising the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol.
Example D32 [WO9901127]
Utilising the procedure of Example D28 with 2-diethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol
Example D38 [WO9901127] Utilising the procedure of Example A22 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4- methoxyphenylboronic acid
Example D39 [WO9901127]
Utilising the procedure of Example A84 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4- methoxyphenylboronic acid.
Example El
Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl] - methyl-amide.
To 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine (lmmol) [Example A7] were added triethylorthoformate (8ml) and trifluoroacetic acid (0.15ml). The resulting solution was heated to 90°C for 4hr. The solution was evaporated then redissolved in ethanol and cooled to approximately -10°C. Sodium borohydride (190mg, 5mmol) was introduced portionwise over 10 minutes then the mixture allowed to warm to room temperature. The solution was stiπed at room temperature for 16h, then acidified to pH 1 with 2M hydrochloric acid. The mixture was concentrated to approximately 10ml, then partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH 14 using 2M aq sodium hydroxide solution, and extracted with dichloromethane (x3), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluent to afford [4-(2- diisopropylamino-ethoxy)-3-methoxy-phenyl]-methyl-amine as an oil. *HNMR (CDC13): δ 1.03 (12H, d), 2.80 (3H, s), 2.85 (2H, t), 3.02 (2H, q), 3.80 (3H, s), 3.86 (2H5 1), 6.13 (IH, dd), 6.23 (IH, d) and 6.80 (IH, d); MS (AP+ve): m/z 281[M+H]+ .
To 4-phenylbenzoic acid (0.2mmol) suspended in dichloromethane was added oxalyl chloride (0.6mmol) followed by dimethylformamide (1 drop). The reaction mixture was stiπed for lh, evaporated, co-evaporated (x3) with dichloromethane then redissolved in dichloiOmethane(lml). A solution containing the amine [4-(2-diisopropylamino-ethoxy)- 3-methoxy-ρhenyl]-methyl-amine (0.2mmol) and triethylamine (140mg, lmmol) dissolved in dichloromethane (1ml) was added. This solution was stiπed at ambient temperature for 14 hours, evaporated, dissolved in dichloromethane (1ml) and treated with PS-isocyanate resin [Argonaut Technologies] (150mg). After a further 18h shaking at ambient temperature, the mixture was filtered, passed through an SAX column [Varian] (lg), evaporated, and the residue purified by chromatography on silica gel using dichloromethane - aq. ammonia - methanol as eluent to afford the title compound as an oil.
XHNMR (CDC13): δ 1.21 (12H, bd), 2.88-3.24 (4H, m), 3.32 (3H, s), 3.87 (3H, s), 4.11 (2H, m), 6.82-6.91 (3H, m) and 7.26-7.56 (9H, m); MS (AP+ve): m/z 416 [M+H]+.
Example E5
Utilising the procedure of Example El with triethyl orthoacetate [Aldrich] in place of triethyl orthoformate.
Example E12 Biphenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylamino-ethoxy)-5-methoxy- phenyl]-amide
Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl- amide [Example E9] (45mg, 0.1 mmol), was dissolved in chloroform (1ml) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.1 lmmol). The mixture was stiπed at ambient temperature for 16 hours then evaporated and subjected to flash chromatography on silica gel (dichloromethane - methanol - aqueous ammonia) to afford the title compound as an oil.
1HNMR (CDCI3): δ 1.06 (6H, t), 2.63 (4H, q), 2.90 (2H, t), 3.39 (3H, s), 3.67 (3H, s), 4.03 (2H, t), 6.57 (IH, s), 6.84 (IH, s) and 7.31-7.53 (9H, ); MS (AP+ve): m/z 467, 469 [M+H]+.
Example E13
Utilising the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3 -methoxy- phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy- phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4- methoxyphenylboronic acid and of Example 51 with (N-diethyl)ethanolamine in place of 1 -(2-hydroxyethyl)pyπolidine. Example E14
Utilising the procedure of Example E13 with 2-methylphenylboronic [Aldrich] in place of of 4-chlorophenylboronic acid.
Example E16
Correspondingly Example E14 with 2-chloromethylphenylboronic acid [Aldrich].
Example E17
Correspondingly Example E14 with 4-fluoromethylphenylboronic acid [Aldrich].
Example E21
Correspondingly Example E14 with 4-chloromethylphenylboronic acid [Aldrich].
Example E22 Correspondingly Example E14 with 4-ethylphenylboronic acid [Aldrich] .
Example E23
Correspondingly Example E14 with 4-tertbutylphenylboronic acid [Aldrich].
Example E24
4-Biphenylcarboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl-amide [Example E9] (45mg, 0. lmmol), was dissolved in acetonitrile (1ml) and treated with N- fluoro-N'-chloromethyl-triethylenediamine-bis(tetrafluoroborate) (43mg, 0.12mmol) and heated to 80°C for 6 hours. The solvent was evaporated and the residue subjected to flash chromatography on silica gel (dichloromethane - methanol - aqueous ammonia) to afford the title compound as an oil. MS (AP+ve): m/z 451 [M+H]+.
Example E25 Utihsing the procedure of Example El with 4-(2-diisoproρylamino-ethoxy)-3-methyl- phenylamine [Example D20] in place of 4-(2-diisopropylamino-ethoxy)-3-methoxy- phenylamine and triethyl orthoacetate in place of triethyl orthoformate. Example FI
Utilising the procedure of Example A7 with 6-phenyl-nicotinic acid (Patent WO- 0006085) in place of 2'-methyl-4-biphenylcarboxylic acid and N-dimethylethanolamine in place of 2-(diisopropylamino)ethanol.
Example Gl
Biphenyl-4-carboxylic acid [4-((R)-diethylamino-hydroxy-propoxy)-3-methoxy- phenyl]-amide 4-Νitro-2-methoxyphenol [Aldrich] (845mg, 5mmol) was dissolved in DMF (25 ml) and treated with sodium hydride (60% oil dispersion, 200mg). When the effervescence ceased, the mixture was treated with (i?)-p-nitrophenylsulphonyl glycidol [Aldrich] and warmed to 50°C with stiπing. After 16 hours, the mixture was cooled, evaporated, partitioned between water (20ml) and dichloromethane (3 x 25ml), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel (hexane - ether) to give (i?)-2-(2-methoxy-4-nifro-phenoxymethyl)-oxirane as a pale brown solid in 80% yield.
1HNMR (CDC13): δ 2.79 (IH, dd), 2.95 (IH, dd), 3.41 (IH, dddd), 3.96 (3H, s), 4.06 (IH, dd), 4.43 (IH, dd), 6.98 (IH, d), 7.75 (IH, d) and 7.87 (IH, dd).
(i?)-2~(2-Methoxy-4-nitro-phenoxymethyl)-oxirane (0.5rnmol, 113mg), in dichloromethane (3 ml) was treated with the amine (diethylamine) [Aldrich] (1.5 mmol, 110 mg) and titanium tetraisopropoxide [Aldrich] (50ul). The solution was stirred at ambient temperature for 24 h, treated with water (1ml) and shaken vigorously for 10 minutes. The resulting suspension was passed through a hydromatrix cartridge [Varian ChemElut] (5ml) eluting with dichloromethane (10ml) to give (i?)-diethylamino-(2- methoxy-4-nitro-phenoxy)-propan-2-ol as a yellow oil
1H NMR (CDC13): δ 1.07 (6H, t), 2.55-2.72 (7H, m), 3.94 (3H, s), 4.09-4.13 (3H, m), 6.97 (IH, d), 7.74 (IH, d) and 7.89 (IH, dd); MS (AP+ve): m/z 299 [M+H+].
This material was dissolved in ethanol (5ml) and treated with hydrogen chloride (2M in diethyl ether) 0.1 ml then 10% palladium on charcoal (20 mg) and hydrogenated at atmospheric pressure for 24 hours. The solution was purged with argon then filtered through celite and evaporated to give (JR)-(4-amino-2-methoxy-ρhenoxy)-diethylamino- propan-2-ol hydrochloride as a white crystalline solid.
1HNMR (CD3OD): δ 1.19 (6H, t), 3.36-3.45 (6H, m), 3.88 (s, 3H), 4.02-4.11 (2H, m),
4.03 (IH, m), 6.95-7.03 (2H, m) and 7.13 (IH, d).
A solution of this material in dichloromethane (2ml) was treated with Methylamine (2 mmol, 280ul) and triethylsilyl trifluoromethanesulphonate (lmmol, 264mg). After 30 minutes, 4-biphenylcarboxylic acid chloride [Example 1] (lmmol, 217mg) was introduced and the mixture stirred for 12 hours. The solvent was evaporated and the residue dissolved in methanol (100ml) and treated with potassium carbonate (2g). After stirring for six hours, the suspension was evaporated, formed into a sluπy with dichloromethane (20ml), filtered, the filtrate evaporated, and the residue purified by flash chromatography (dichloromethane - methanol - aq. ammonia) to give the title compound as a white solid. 1HNMR (CDC13): δ 1.11 (6H, t), 2.61-2.78 (6H, m,), 3.88 (3H, s), 3.5-4.5 (IH, vbs),
3.99-4.13 (3H, m), 6.92 (IH, d), 6.99 (IH, dd), 7.41-7.49 (3H, m), 7.56 (IH, d), 7.63 (2H, d), 7.69 (2H, d) and 7.97 (3H, d); MS (AP+ve): m/z 449 [M+H+].
Example G5 Utilising the procedure for the preparation of (/?)-diethylamino-(2-methoxy-4-nitro- phenoxy)-propan-2-ol [Example Gl] but replacing dichloromethane with 1,2- dichloroethane and diethylamine with diisopropylamine. In addition, the mixture of amine and epoxide was heated at 80°C for 12h rather than being kept at ambient temperature for 24 hours.
Example G8
Utihsing the procedure of Example Gl but using (^-p-nitrophenylsulphonyl-glycidol in place of (i?)-p-nitrophenylsulphonyl-glycidol, and pyπolidine in place of diethylamine.
Example G22
Utihsing the procedure of Example A51 but using 4-dimethylamino-l-butanol [ICN-RF] in place of l-(2-hydroxyethyl)-pyrrolidine. Example HI 4-Cyclohexyl-iV-[3-methoxy-4-(4-methyl-piperazin-l-yl)-phenyl]-benzamide
A solution of l-(2-methoxy-4-nitro-phenyl)-piperazine (Patent WO-9906382) (lOmmol, 2.37g) in dichloromethane (50ml) was treated with ditertbutyl dicarbonate (lOmmol, 2.18g) with stiπing. Vigorous evolution of gas occurred which ceased after 1 hour. The solution was then evaporated to a yellow solid 4-(2-methoxy-4-nitro-phenyl)-piperazine- 1 -carboxylic acid tertbutyl ester.
*HNMR (CDC13): δ 1.50 (9H, s), 3.16 (4H, t), 3.61 (4H, t), 3.96 (3H, s), 6.88 (IH, d), 7.72 (IH, d) and 7.86 (IH, dd).
This material was dissolved in ethanol (50ml) and treated with 10% Pd on carbon (lOOmg). The suspension was hydrogenated at 1 atmosphere for 2 hours, then filtered through celite and evaporated to give 4-(4-amino-2-methoxy-phenyl)-piperazine-l- carboxylic acid tertbutyl ester as a brown oil. LH NMR (CDCI3): δ 1.48 (9H, s), 2.86-2.91 (4H, t), 3.52-3.60 (4H, t), 3.81 (3H, s), 6.22- 6.27 (2H, m) and 6.73 (IH, d).
This aniline (0.2mmol, 61 mg) was dissolved in dichloromethane (1ml) and treated successively with DIE A resin [Argonaut Technologies] (0.5 g) and 4-cyclohexylbenzoyl chloride [Example A36]. The mixture was shaken gently for 12 hours then filtered, evaporated and the residue purified by flash chromatography on silica gel (dichloromethane - methanol - aq. ammonia) to afford 4-(4-{[l-(4-cyclohexyl-phenyl)- methanoyl] -amino }-2-methoxy-phenyl)-piperazine-l -carboxylic acid tertbutyl ester as a white crystalline solid NMR (CDCI3): δ 1.25-1.47 (5H, m), 1.54 (9H, s), 1.75-1.88 (5H, m), 2.56 (IH, m), 2.98 (4H, t), 3.61 (4H, t), 3.91 (3H, s), 6.87 (IH, d), 6.93 (IH, dd), 7.32 (2H, d), 7.54 (IH, s), 7.77, (IH, s) and 7.78 (2H, d); MS (AP+ve): /z 493 [M+H4].
This material was dissolved in dichloromethane (5ml) and treated with anisole (1ml) and trifluoroacetic acid (5ml). After 2 hours the solution was evaporated, then co-evaporated twice from toluene. The residue was dissolved in dichloromethane (10ml), washed with satd. sodium bicarbonate (2ml), the organic phase dried (MgSO4), filtered and evaporated to a brown oil, 4-cyclohexyl-N-(3-methoxy-4-piperazin-l-yl-phenyl)-benzamide. !H NMR (CDCI3): δ 1.22-1.87 (10, m), 2.57 (1, m), 3.04-3.12 (8H, m), 3.91 (3H, s), 6.95 (2H, bs), 7.32 (2H, d), 7.54 (IH, m), 7.77 (IH, s) and 7.78 (2H, d); MS (AP+ve): m/z 394 [M+H+].
This amine (0. lmmol, 39mg) was dissolved in ethanol (3ml) and treated with metafor aldehyde (1 OOmg), Amberlyst cyanoborohydride resin [Novabiochem] (lOOmg), and acetic acid (50ul). The mixture was stirred at ambient temperature for three hours then filtered, evaporated and the residue purified by flash chromatography on silica gel (dichloromethane - methanol - aq. ammonia) to afford the title compound as a pale brown oil. This was evaporated from dilute acetic acid to give the monoacetate salt hydrate.
*HNMR (CDCI3): δ 1.22-1.45 (5H, m), 1.76-1.87 (5H, m), 2.02 (6H, 2xs), 2.56 (IH, m), 3.22-3.23 (4H, t), 3.29-3.30 (4H, t), 3.88 (3H, s), 6.86 (IH, d), 6.94 (IH, dd), 7.30 (IH, d), 7.59 (IH, d), 7.79 (2H, d), 7.98 (IH, s) and 8.54 (4H, bs); MS (AP+ve): m/z 408 [M+H*] .
The following tables give Examples which illustrate but do not limit the invention in any way.
Table A
Encompassing compounds of general formula (II), a subset of formula (I) where A = H and OMe, R3 = H, X = O, Y = CH2CH2 , Z = a bond; R4 = Ph and R5 is either meta or para substituted on R4.
Figure imgf000046_0001
(II)
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Table B
Encompassing compounds of general formula (III), a subset of formula (1) where A = H and OMe, Rl = R2 = Me2, R3 = H, X = O, Y = CH2-CH2 , Z = O, CH2 or NH; R4 = Ph, R5 is Ph and Z is either meta or para substituted on R4.
Figure imgf000055_0001
(III)
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
Table C
Encompassing compounds of general formula (IV) a subset of formula (1) where A = H and OMe, Rl = R2 = Me2, R3 = H, X = O, Y = CH2-CH2 ; R4, R5 = substituted phenyl or heterocycle,
Figure imgf000058_0001
(IN)
Figure imgf000058_0002
Figure imgf000059_0001
Table D
Encompassing compounds of general formula (V) a subset of formula (I) where R3 = H, X = O, Y = CH2-CH2, Z = O, CH2, NH or a bond; R4 = Ph, R5 is Ph or cyclohexyl (Cy) and Z is either meta or para substituted on R4.
Figure imgf000060_0001
R5-
(V)
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Table E
Encompassing compounds of general formula (VI) a subset of formula (1) where A = H, Cl, F and OMe, X = O, Y = CH2-CH2 ; R4 = phenyl, R5 = phenyl or cyclohexyl (Cy), Z = = O, CH2 or a bond
Figure imgf000064_0001
(VI)
Figure imgf000064_0002
Figure imgf000065_0001
Table F
Encompassing compounds of general formula (VII) a subset of fomiula (1) where A = H and OMe, X =
Figure imgf000066_0001
(VII)
Figure imgf000066_0002
Table G
Encompassing compounds of general foπnula (VIII) a subset of foπnula (I) where A = H and OMe, R3 = H, X = O; R4 = phenyl, Z = O, CH2 or a bond and R5 = Ph or cyclohexyl (Cy), Y is a chain of 3 or 4 carbon atoms optionally substituted by an hydroxyl group.
Figure imgf000067_0001
(VIII)
Figure imgf000067_0002
Figure imgf000068_0001
Table H
Encompassing compounds of general formula (IX) a subset of formula (I) where A = H and OMe, R3 = H, X = N; R4 = phenyl, Z = a para substituted bond and R5 = Ph or cyclohexyl (Cy), Y and R2 form a piperazinyl ring between X and N.
Figure imgf000069_0001
(IX)
Figure imgf000069_0002
The activity of the compounds used in this invention may be assessed by competitive binding assays to 1 ICBy receptors, as follows:
Radioligand Binding Studies
Radioligand binding assays were carried out on well washed membranes from HEK293 cells stably expressing HCBy receptors. Membranes (5-15 mg protein) were incubated with [1251] -Melanin Concentrating Hormone (0.22 nM)(obtained from NEN) in the presence and absence of competing test compounds for 45 min at 37°C in a buffer (pH7.4), containing 50mM Tris and 0.2% BSA. Non-specific binding was defined using 0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compounds were added at concentrations between 10M and lOpM in 10 concentration steps. Following incubation, the reaction was stopped by filtration through GF/B filters and washed with 4 x 1ml of ice-cold 50mM Tris buffer. Microscint 20 (Packard) was added to the filters and the radioactivity measured using a Packard TopCount.
Bound cpm in the presence of test compound was expressed as a fraction of the bound cpm in the absence of test compound and plotted against the concentration of compound. From this an IC50 was determined from which the pKi was calculated.
The most potent compounds of the present invention have pKi values in the range of 7.1 to 7.8 For example:
Example pKi range
A48 7.5-7.8
B2 7.1-7.4
C8 7.1-7.4
D15 7.5-7.8
E9 7.5-7.8
F4 7.1-7.4
Gl 7.1-7.4
HI 7.1-7.4

Claims

1. A method of treating the Disorders which comprises administering to a mammal suffering from one or more of the Disorders an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:
Figure imgf000071_0001
each A is independently hydrogen, a C\. alkyl optionally substituted by hydroxyl, C\. alkoxy,
Figure imgf000071_0002
acyl group or a halogen atom or hydroxyl, CN or CF3 group;
R3 is hydrogen, methyl or ethyl; R4 is an optionally substituted aromatic carbocychc or heterocychc ring;
Z is an O or S atom, or an NH or CH2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group;
R5 is an optionally substituted aromatic carbocychc or heterocychc ring, or an optionally substituted, saturated or unsaturated, carbocychc or heterocychc ring;
R1
/ and Q is -X-Y-N
\ R2
(a) where X is an O or S atom;
Y is a linear or branched C2.4 alkylene group, optionally substituted by a hydroxyl group, or is a C5.6 cycloalkylene group, Rl and R2 are independently a linear or branched
Figure imgf000071_0003
alkyl group; or
(b) where X is an O or S atom;
Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group,
Rl and R2 are linked to form a 5, 6 or 7-membered ring optionally containing one or more further heteroatom selected from O, S or N, where N or C ring atoms are optionally substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, where Ra is a linear or branched
Cι_6 alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fused to an optionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring is optionally liked by a single bond or methylene group to Y; or (c) where X is an O or S atom,
Y is a C2-4 alkylene group, Rl is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or branched Cμg alkyl group; or (d) where X is a N atom,
Y is a C2.4 alkylene group, Rl is a C2.4 alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched
Figure imgf000072_0001
alkyl group.
2. A compound of formula (I) as defined in claim 1, or a salt or solvate thereof, in which R3 is methyl or ethyl.
3. A compound according to claim 2, which is any one of the compounds set out in Table E herein.
4. A compound of formula (I) as defined in claim 1 or a salt or solvate thereof, excluding the compounds: N-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,l'-biphenyl]-4- carboxamide,
N- [4- [2- [bis ( 1 -methylethyl)amino] ethoxy]phenyl] -[1,1 -biphenyl] -4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,
N-[4-(2-diisopiOpylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N- [4-(2-diethylamino-ethoxy)-phenyι] -4-phenoxy-benzamide,
N- [4-(2-diisopropylamino-ethoxy)-phenyl] -3 -phenoxy-benzamide
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide,
4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide,
4-cyclohexyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl] -benzamide, 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl] -benzamide,
4-benzyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide,
4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide.
5. A process for the preparation of a compound of fomiula (I), or a salt or solvate thereof, as defined in claim 2, which process comprises the reaction of a compound of foπnula (X)
R5-Z-R4-COL (X)
where R5, Z, and R4 are as defined for formula (I) in claim 1, and L is a leaving group with a compound of formula (XI)
Figure imgf000073_0001
wherein Q and A are as defined in formula (I) in claim 1 and R3 is methyl or ethyl.
6. A process for the preparation of a compound of formula (I), or a salt or solvate thereof, as defined in claim 1, which process comprises the reaction of a compound of formula (X) wherein R5, Z, and R4 are as defined for formula (I) in claim 1 with a compound of foπnula (XI) wherein Q, A, and R3 are as defined in claim 1, with the proviso that a process for the preparation of:
N-[4-[2-[bis(l-me ylethyl)arnino]ethoxy]-2-fluorophenyl]-[l, -biphenyl]-4- carboxamide,
N- [4- [2- [bis ( 1 -methylethyl) amino] ethoxy]phenyl] -[1,1 -biphenyl] -4-carboxamide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide,
N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide,
N- [4-(2-diethylamino-ethoxy)-phenyl] -4-phenoxy-benzamide,
N- [4-(2-diisopropylamino-ethoxy)-phenyl] -3 -phenoxy-benzamide,
N-[4-(2-diethylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, 4-cyclohexyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-cyclohexyl-N -[4-(2-diethylamino-ethoxy)-phenyl] -benzamide, 4-benzyl-N-[4-(2-diisopropylamino-ethoxy)-phenyl]-benzamide, 4-benzyl-Ν -[4-(2-diethylamino-ethoxy)-phenyl]-benzamide, 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl]-amide, and 4'-ethyl-biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-phenyl]-amide is excluded.
7. A pharmaceutical composition for use in the treatment and/or prophylaxis of one or more of the Disorders which comprises a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
8. A method of treatment and/or prophylaxis of one or more of the Disorders comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of this invention, or a phaπnaceutically acceptable salt or solvate thereof.
9. Use of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treahnent and/or prophylaxis of one or more of the Disorders .
10. Use of a novel compound of this invention, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of one or more of the Disorders.
11. A method for the treatment of diabetes, major depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
PCT/EP2001/008637 2000-07-31 2001-07-26 Carboxamide compounds and their use as antagonists of a human 11cby receptor WO2002010146A1 (en)

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CN1444573A (en) 2003-09-24
AU2001278508A1 (en) 2002-02-13
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EA200300064A1 (en) 2003-06-26
MXPA03000923A (en) 2003-06-09
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AP2003002720A0 (en) 2003-06-30
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