Patent EA-002773-B1 (EA)
Title: Azetidinylpropylpiperidine derivatives, intermediates and use as tachykinin antagonists
Inventor: ALKER DAVID
IPC: A61K31/551
Filed: 1998-07-01
Abstract: 1. A compound of the formula (I):   and pharmaceutically-acceptable salts thereof, wherein A is CO, SO2 or CH2; AR<1> is phenyl optionally substituted by substituted by one or more halogen; X1 is phenyl optionally substituted by halogen; X is a direct link or NR<1>; R is SO2phenyl, SO2(C1-6 alkyl optionally substituted by one or more halogen),  or   R<1> is H, C1-6 alkyl or phenyl; Y is O, NCO(C1-6), NCO2(C1-6), NSO2(C1-6 alkyl optionally substituted by one or more halogen), NCOphenyl, NCO2phenyl, NSO2phenyl, NH, NCH2phenyl, NCH2CH2Ph; with the proviso that X is not NR<1> when R is   or   2. A compound or salt according to Claim 1 wherein A is CO or SO2 wherein wherein X1 is aryl or C1-6 alkyl, said C1-6 alkyl being optionally substituted by C3-7 cycloalkyl. 3. A compound or salt according to any preceding Claim wherein X is a direct link or NR<1> or R<1> is C1-6 alkyl or phenyl 4. A compound or salt according to any preceding Claim wherein R is SO2phenyl, SO2(NSO2(C1-6 alkyl optionally substituted by one or more halogen),  or   wherein  Y is O, NCO(C1-6), NCO2(C1-6), NSO2(C1-6 alkyl optionally substituted by one or more halogen), NCOphenyl, NH, NCH2phenyl. 5. A compound or salt according to any preceding Claim wherein A is CO. 6. A compound or salt according to any preceding Claim wherein AR<1> is phenyl optionally substituted by up to two halogen atoms. 7. A compound or salt according to any preceding Claim wherein X<1> is C1-6, alkyl substituted by C3-7 cycloalkyl, or phenyl optionally substitited by halogen. 8. A compound or salt according to any preceding Claim wherein X is a direct link, N-methyl or N-phenyl. 9. A compound or salt according to any preceding Claim wherein R is SO2phenyl, SO2(C1-6 alkyl optionally substituted by one or more halogen),   or   10. A compound or salt according to any preceding Claim wherein AR<1> is phenyl optionally substituted by one or two chlorine atoms. 11. A compound or salt according to any preceding Claim wherein X<1> is C1-6 alkyl substituted by C3-7 cycloalkyl, or is phenyl optionally substituted by one or more halogen. 12. A compound or salt according to any preceding Claim wherein R is SO2Ph, SO2CH3,  or   where Y is O, NCOCH3, NCO2C(CH3)3, NSO2CH3, NSO2C2H5, NSO2Ph, NSO2CH2Ph, NSO2CH(CH3)2, NSO2CH2CF3 NCOPh, CHF, NH, NCH2Ph. 13. A compound or salt according to any preceding Claim wherein AR<1> is phenyl, 4-chlorophenyl or 3,4-dichlorophenyl. 14. A compound or salt according to any preceding Claim wherein X<1> is (C3-7 cycloalkyl)methyl or phenyl optionally substituted by one or more halogen. 15. A compound or salt according to any preceding Claim wherein R is SO2Ph, SO2CH3,  or   where Y is O, NCOCH3, NCO2C(CH3)3, NSO2CH3, NSO2C2H5, NSO2Ph, NSO2CH2Ph,b NSO2CH(CH3)2, NSO2CH2CF3, NCOPh 16. A compound or salt according to any preceding Claim wherein X<1> is phenyl, 3-chlorophenyl or 3,4-difluorophenyl. 17. A compound or salt according to Claim 1 which is selected from: (+)-3(R)-1-benzoyl-3-(3-[3-(4-tert-butoxycarbonylpiperazin-1-yl)azetidin-1-yl]propyl)-3-(3,4-dichlorophenyl)piperidine; 3(R)-1-benzoyl 3-(3-[3-(4-tent-butoxycarbonylhomopiperazin-1-yl)azetidin-1-yl)propyl)-3-(3,4-dichlorophenyl)piperidine; (+)-3 (R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-(4-methanesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-3-(3-[3-(4-acetylpiperazin-1-yl)azetidin-1-yl]propyl)-1-benzoyl-3- (3,4-dichlorophenyl)piperidine; (+)-3(R)-1-benzoyl-3-(3-[3-(4-benzoylpiperazin-1-yl)azetidin-1-yl]propyl)-3- (3,4-dichlorophenyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-(4-methanesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-3-(3-[3-(4-benzenesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)-1-benzoyl-3-(3,4-dichlorophenyl)piperidine; (+)-3(R)-1-benzoyl-3-(3-[3-(4-benzylsulphonylpiperazin-1-yl)azetidin-1-yl]propyl)-3-(3,4-dichlorophenyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-(4-iso-propylsulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-(3-(4-(2,2,2-trifluoroethane)sulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-morpholinoazetidin-1-yl]propyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)3-(3-[3-(N-methyl benzenesulphonamido)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-(N-phenyl methanesulphonamido)azetidin-1-yl]propyl)piperidine; 3(R)-1-benzoyl-3-(3,4-dichlorophenyl)3-{3-[3-(4-methanesulphonylhomopiperazin-1-yl)azetidin-1-yl]propyl)piperidine; 3(R)-1-benzenesulphonyl-3-(3,4-dichlorophenyl)3-{3-[3-(4-methanesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-(cyclopropylacetyl)-3-(3,4-dichlorophenyl)3-(3-[3-(4-methanesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-3-(3,4-dichlorophenyl)-1-(3,4-difluorobenzoyl)-3-(3-[3-(4-methanesulphonyl-piperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-(3-chlorobenzoyl)-3-(3,4-dichlorophenyl)3-(3-[3-(4-methanesulphonylpiperazin-1-yl)azetidin-1-yl]propyl)piperidine; (+)-3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-(3-[3-piperazinoazetidin-1-yl]propyl)piperidine; and 3(R)-1-benzoyl-3-(3,4-dichlorophenyl)-3-{3-[3-(homopiperazin-1-yl)azetidin-1-yl]propyl)piperidine; and the pharmaceutically-acceptable salts thereof. 19. A pharmaceutical composition comprising a compound or salt according to any preceding Claim together with pharmaceutically acceptable diluent, adjuvant or carrier. 20. A compound or salt according to any one of Claims 1 to 18 for use as a medicament. 21. A compound or salt according to of Claim 19 for use as a medicament. 22. The use of a compound or salt according to any one of Claims 1 to 18 for the manufacture of a medicament for the treatment of a disease by producing an antagonist effect on a tachykinin acting at the human NK1, NK2- or NK3- receptor, or a combination of two or more thereof. 23. The use of a compound or salt according to any one of Claims 1 to 18 for the manufacture of a medicament for the treatment of 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 (GI) disorder such as functional bowel disease, dyspepsia, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis, ulcerative colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia, impotence or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a vasospastic disease such as angina or Reynaud's disease, a proliferative disorder such as cancer or a disorder involving fibroblast proliferation, a fibrosing or collagen disease such as scleroderma or eosinophillic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stress-related somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Parkinson's disease, Alzheimer's disease or multiple sclerosis, a disorder related to immune enhancement or suppression such as systemic lupus erythematosis, a rheumatic disease such as fibrositis, emesis, cough, acute or chronic pain, migraine, an opthalmic disease such as proliferative retinopathy, occular inflammation, conjunctivitis, a bladder disorder, or a viral disease such as influenza or a cold. 24. A method of treatment of a human or non-human animal which comprises producing an antagonist effect on a tachykinin acting at the human NK1, NK2- or NK3- receptor, or a combination of two or more thereof, which comprises treating said human with an effective amount of a compound or salt according to any one of Claims 1 to 18 or a composition aaccording to Claim 19. 25. A method of treatment of a human or non-human animal which comprises producing an antagonist effect on a tachykinin acting at the human NK1, NK2- or NK3- receptor, or a combination of two or more thereof, which comprises treating said human with an effective amount of a compound or salt according to any one of Claims 1 to 18 or a composition aaccording to Claim 19, 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 (GI) disorder such as functional bowel disease, dyspepsia, irritable bowel syndrome, gastrooesophageal reflux, faecal incontinence, colitis, ulcerative colitis or Crohn's disease, a disease caused by Helicobacter pylori or other urease positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia, impotence or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a vasospastic disease such as angina or Reynaud's disease, a proliferative disorder such as cancer or a disorder involving fibroblast proliferation, a fibrosing or collagen disease such as scleroderma or eosinophillic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stressrelated somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Parkinson's disease, Alzheimer's disease or multiple sclerosis,