Patent EA-002424-B1 (EA)
Title: Quaternary ammonium compounds as tachykinin antagonists
Inventor: MONAGHAN SANDRS MARINA
IPC: C07D453/02
Filed: 1998-06-05
Abstract: 1. A compound of the formula:   wherein R is phenyl, C3-C7 cycloalkyl or heteroaryl, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7cyctoalkyl-fused portion, by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4alkoxy, fluoro(C1-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, C1-C4 alkoxycarbonyl, C3-C7 cycloalkyl, -S(O)m(C1-C4 alkyl), cyano, -NR<2>R<3>, -S(O)mNR<2>R<3>, -NR<4>(C1-C4 alkanoyl) and -CONR<2>R<3>, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R<1> is H or C1-C6 alkyl; R<2> and R<3> are either each independently selected from H and C1-C6 alkyl, or when taken together, represent C4-C6 alkylene; R<4> is H or C1-C6 alkyl; W is a direct link, methylene or ethylene; X is unbranched C2-C4 alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, halo and cyano; Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; m is 0,1 or 2; Z<A> is a pharmaceutically acceptable anion; and "heteroaryl", used in the definition of R, means thienyl or a 5- or 6-membered ring heteroaryl group containing either from 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatom(s) and 1 oxygen or sulphur heteroatom. with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group. 2. A compound as claimed in Claim 1 wherein R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from C1-C4 alkyl, fluoro(C1-C4)alkyl, C1-C4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy and halo, or R is 2,3-dihydrobenzo[b]furanyl. 3. A compound as claimed in Claim 1 or 2, wherein R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl. 4. A compound as claimed in Claim 1, 2 or 3 wherein R is phenyl, naphthyl or tetrahydronaphthyl, each of which being optionally substituted by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl. 5. A compound as claimed in any one of Claims 1 to 4 wherein R is phenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo[b]furan-7-yl, naphth-2-yl, 4-fluoro-3-trifluoromethylphenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl, 2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis(trifluoromethyl)phenyl. 6. A compound as claimed in any one of Claims 1 to 5 wherein R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl. 7. A compound as claimed in any one of Claims 1 to 6 wherein R<1> is H. 8. A compound as claimed in any one of Claims 1 to 7 wherein W is a direct link or methylene. 9. A compound as claimed in any one of Claims 1 to 8 wherein W is a direct link. 10. A compound as claimed in any one of-Claims 1 to 9 wherein X is 1,2-ethylene. 11. A compound as claimed in any one of Claims 1 to 10 wherein Y is phenyl, naphthyl or cyclohexyl, each of which being optionally substituted by 1, 2 or 3 C1-C4 alkyl substituents. 12. A compound as claimed in any one of Claims 1 to 11 wherein Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphth-2-yl. 13. A compound as claimed in any one of Claims 1 to 12 wherein Y is phenyl. 14. A compound as claimed in any one of Claims 1 to 13 wherein Ar is phenyl optionally substituted by 1, 2 or 3 halo substituents. 15. A compound as claimed in any one of Claims 1 to 14 wherein Ar is phenyl substituted by 1 or 2 chloro substituents. 16. A compound as claimed in any one of Claims 1 to 15 wherein Ar is 3,4-dichlorophenyl. 17. A compound as claimed in any one of Claims 1 to 16 wherein Z<A> is chloride, bromide, nitrate, methanesulphonate, paratoluenesulphonate, benzenesulphonate, hydrogensulphate or sulphate. 18. A compound as claimed in any one of Claims 1 to 17 wherein Z<A> is chloride or methanesulphonate. 19. A compound as claimed in any one of Claims 1 to 18 wherein Z<A> is methanesulphonate. 20. A compound as claimed in Claim 1 wherein R<1> is H, X is -CH2CH2- and Ar is 3,4-dichlorophenyl, and wherein R-W- is 3,5-dimethylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2,3-dimethylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-trifluoromethoxyphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-methoxy-3-methylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2,3-dihydrobenzo[b]furan-7-yl, Y is phenyl.and Z<A> is CH3SO3<->; R-W- is naphth-2-yl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 1,2,3,4-tetrahydronaphth-6-yl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 5-chloro-2-methoxyphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-methoxyphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-trifluoromethylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W-is 2-isopropoxyphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-ethylphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 2-phenoxyphenyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is benzyl, Y is phenyl and Z<A> is CH3SO3<->; R-W- is 3,5-bis(trifluoromethyl)phenyl, Y is phenyl and Z<A> is Cl<->; R-W- is 2-methoxyphenyl, Y is cyclohexyl and Z<A> is CH3SO3<->; R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and Z<A> is CH3SO3<->; R-W- is 2-methoxyphenyl, Y is 3,5-dimethylphenyl and Z<A> is CH3SO3<->; or R-W- is 2-methoxyphenyl, Y is naphth-2-yl and Z<A> is CH3SO3<->; or wherein Z<A> is an alternative pharmaceutically acceptable anion in respect of any thereof. 21. A compound as claimed in Claim 1 which is 4-phenyl-1-(3(S)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate or 4-phenyl-1-(3(R)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate. 22. A process for the preparation of a compound of the formula (I) as claimed in Claim 1 wherein R, R<1>, W, X, Y, Ar and Z<A> are as defined in Claim 1 comprising reaction of a compound of the formula:   wherein R, R<1>, Ar, W and X are as previously defined for a compound of the formula (I), wherein Z is a leaving group capable of forming a pharmaceutically acceptable anion (Z<A>) and Z<1> is a leaving group, with a compound of the formula:   wherein Y is as previously defined for a compound of the formula (I), said process being followed by either (a), where Z<1> is a leaving group, exchange for a pharmaceutically acceptable anion (Z<A>), or (b), optionally, where Z<A> is a pharmaceutically acceptable anion, exchange for another pharmaceutically acceptable anion. 23. A process as claimed in Claim 22 wherein Z is C1-C4 alkanesulphonyloxy, benzenesulphonyloxy, para-toluenesulphonyloxy, chloro, bromo or iodo, and Z<1> is trifluoromethanesulphonyloxy. 24. A process as claimed in Claim 22 wherein Z is methanesulphonyloxy and Z<A> is methanesulphonate. 25. A pharmaceutical composition comprising the compound of formula (I) according to any of Claims 1-21 together with a pharmaceutically acceptable diluent or carrier. 26. The use of a compound of the formula (I) according to Claim 1, as an active agent for the treatment of diseases for which producing an antagonist effect on a tachykinin receptors is destined. 27. The use of a compound of the formula (I), as claimed in any one of Claims 1 to 21 for the manufacture of a medicament for the treatment of a disease by producing an antagonist effect on a tachykinin receptor or on a combination of tachykinin receptors. 28. Use as claimed in Claim 27 where the antagonist effect is on the human NK1 and NK2 tachykinin receptors. 29. Use as claimed in Claim 27 or 28 where the disease is an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (Gl) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn's disease, a disease caused by Helicobacter pylori or another urease-positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, emesis, cough, migraine or acute or chronic pain. 30. The method for the treatment of a human disease by producing an antagonist effect on a tachykinin receptor or on a combination of tachykinin receptors which comprises the treatment of a human with an effective amount of a compound of formula (I) or a pharmaceutically acceptable