EP0994857A1 - (1h-imidazol-4-yl)piperidindeivate, ihre herstellung und ihre medizinische verwendung - Google Patents

(1h-imidazol-4-yl)piperidindeivate, ihre herstellung und ihre medizinische verwendung

Info

Publication number: EP0994857A1
Authority: EP; European Patent Office
Prior art keywords: group; compound; formula; alkyl group; phenyl
Prior art date: 1997-07-01
Legal status (The legal status 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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP98932236A

Other languages

English (en)

French (fr)

Inventor

Gérard Cremer

Christian Hoornaert

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Sanofi Aventis France

Original Assignee

Sanofi Synthelabo SA

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.)

1997-07-01

Filing date

1998-06-19

Publication date

2000-04-26

1998-06-19 Application filed by Sanofi Synthelabo SA filed Critical Sanofi Synthelabo SA

2000-04-26 Publication of EP0994857A1 publication Critical patent/EP0994857A1/de

Status Withdrawn legal-status Critical Current

Links

238000002360 preparation method Methods 0.000 title claims description 8
238000002560 therapeutic procedure Methods 0.000 title abstract 2
BSTAWYYHYJYBIZ-UHFFFAOYSA-N 1-(1h-imidazol-5-yl)piperidine Chemical class C1CCCCN1C1=CNC=N1 BSTAWYYHYJYBIZ-UHFFFAOYSA-N 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 86
125000000217 alkyl group Chemical group 0.000 claims abstract description 43
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 25
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
125000005843 halogen group Chemical group 0.000 claims abstract description 12
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 9
239000002253 acid Substances 0.000 claims abstract description 8
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 7
125000002252 acyl group Chemical group 0.000 claims abstract description 7
150000003839 salts Chemical class 0.000 claims abstract description 6
150000007513 acids Chemical class 0.000 claims abstract description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 5
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 4
125000001118 alkylidene group Chemical group 0.000 claims abstract description 4
238000000034 method Methods 0.000 claims description 19
230000008569 process Effects 0.000 claims description 9
-1 atom halogen Chemical class 0.000 claims description 6
150000002460 imidazoles Chemical class 0.000 claims description 6
238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
239000012312 sodium hydride Substances 0.000 claims description 4
229910000104 sodium hydride Inorganic materials 0.000 claims description 4
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 3
230000010933 acylation Effects 0.000 claims description 2
238000005917 acylation reaction Methods 0.000 claims description 2
239000000010 aprotic solvent Substances 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
230000009467 reduction Effects 0.000 claims description 2
238000006722 reduction reaction Methods 0.000 claims description 2
238000005932 reductive alkylation reaction Methods 0.000 claims description 2
230000006103 sulfonylation Effects 0.000 claims description 2
238000005694 sulfonylation reaction Methods 0.000 claims description 2
125000006531 (C2-C5) alkyl group Chemical group 0.000 claims 2
125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
239000003814 drug Substances 0.000 claims 1
229910052736 halogen Inorganic materials 0.000 claims 1
239000008194 pharmaceutical composition Substances 0.000 claims 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
229910052739 hydrogen Inorganic materials 0.000 abstract description 4
239000001257 hydrogen Substances 0.000 abstract description 4
125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
230000008018 melting Effects 0.000 description 23
238000002844 melting Methods 0.000 description 23
239000000203 mixture Substances 0.000 description 23
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
239000000047 product Substances 0.000 description 15
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
UWYKYRGAJYUFGM-UHFFFAOYSA-N 2-[4-(5-methyl-1-tritylimidazol-4-yl)piperidin-1-yl]aniline Chemical compound CC1=C(C2CCN(CC2)C=2C(=CC=CC=2)N)N=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UWYKYRGAJYUFGM-UHFFFAOYSA-N 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
239000002904 solvent Substances 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
210000001772 blood platelet Anatomy 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
239000000741 silica gel Substances 0.000 description 7
229910002027 silica gel Inorganic materials 0.000 description 7
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
239000012429 reaction media Substances 0.000 description 6
239000000243 solution Substances 0.000 description 6
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
230000008961 swelling Effects 0.000 description 5
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 4
210000004623 platelet-rich plasma Anatomy 0.000 description 4
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
HQLDVRDSCWCLKG-UHFFFAOYSA-N 4-(5-methyl-1h-imidazol-4-yl)-1-(2-nitrophenyl)piperidine Chemical compound N1C=NC(C2CCN(CC2)C=2C(=CC=CC=2)[N+]([O-])=O)=C1C HQLDVRDSCWCLKG-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
ZAYITQDIKSBHDD-UHFFFAOYSA-N benzene methane Chemical compound C.C1=CC=CC=C1.C1=CC=CC=C1 ZAYITQDIKSBHDD-UHFFFAOYSA-N 0.000 description 3
230000002401 inhibitory effect Effects 0.000 description 3
210000000056 organ Anatomy 0.000 description 3
235000019260 propionic acid Nutrition 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
239000000126 substance Substances 0.000 description 3
239000000725 suspension Substances 0.000 description 3
230000001225 therapeutic effect Effects 0.000 description 3
NGMGDJXNKOXZJR-UHFFFAOYSA-N 1-[2-[4-(5-methyl-1h-imidazol-4-yl)piperidin-1-yl]phenyl]pyrrolidin-2-one Chemical compound N1C=NC(C2CCN(CC2)C=2C(=CC=CC=2)N2C(CCC2)=O)=C1C NGMGDJXNKOXZJR-UHFFFAOYSA-N 0.000 description 2
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 2
HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
239000002775 capsule Substances 0.000 description 2
238000002845 discoloration Methods 0.000 description 2
238000011534 incubation Methods 0.000 description 2
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
OMGDJVPRMOLPOA-UHFFFAOYSA-N n-(methoxymethyl)-2-[4-(5-methyl-1h-imidazol-4-yl)piperidin-1-yl]aniline Chemical compound COCNC1=CC=CC=C1N1CCC(C2=C(NC=N2)C)CC1 OMGDJVPRMOLPOA-UHFFFAOYSA-N 0.000 description 2
ZVZJQMJGTJMZJW-UHFFFAOYSA-N n-[2-[4-(5-methyl-1-tritylimidazol-4-yl)piperidin-1-yl]phenyl]-3-phenylprop-2-enamide Chemical compound CC1=C(C2CCN(CC2)C=2C(=CC=CC=2)NC(=O)C=CC=2C=CC=CC=2)N=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 ZVZJQMJGTJMZJW-UHFFFAOYSA-N 0.000 description 2
BAYHIKXDTCGPJJ-UHFFFAOYSA-N n-[2-[4-(5-methyl-1-tritylimidazol-4-yl)piperidin-1-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC=C1N1CCC(C2=C(N(C=N2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C)CC1 BAYHIKXDTCGPJJ-UHFFFAOYSA-N 0.000 description 2
PLJZSVXHIMYOHM-UHFFFAOYSA-N n-[2-[4-(5-methyl-1-tritylimidazol-4-yl)piperidin-1-yl]phenyl]butanamide Chemical compound CCCC(=O)NC1=CC=CC=C1N1CCC(C2=C(N(C=N2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C)CC1 PLJZSVXHIMYOHM-UHFFFAOYSA-N 0.000 description 2
LHLOCKHNZFRAPA-UHFFFAOYSA-N n-[2-[4-(5-methyl-1h-imidazol-4-yl)piperidin-1-yl]phenyl]-3-phenylprop-2-enamide Chemical compound N1C=NC(C2CCN(CC2)C=2C(=CC=CC=2)NC(=O)C=CC=2C=CC=CC=2)=C1C LHLOCKHNZFRAPA-UHFFFAOYSA-N 0.000 description 2
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NQMSMAUQWRNJIB-UHFFFAOYSA-N n-[2-[4-(5-methyl-1h-imidazol-4-yl)piperidin-1-yl]phenyl]butanamide Chemical compound CCCC(=O)NC1=CC=CC=C1N1CCC(C2=C(NC=N2)C)CC1 NQMSMAUQWRNJIB-UHFFFAOYSA-N 0.000 description 2
VZXCCLYKLVDQNT-UHFFFAOYSA-N n-[2-[4-(5-methyl-1h-imidazol-4-yl)piperidin-1-yl]phenyl]methanesulfonamide Chemical compound N1C=NC(C2CCN(CC2)C=2C(=CC=CC=2)NS(C)(=O)=O)=C1C VZXCCLYKLVDQNT-UHFFFAOYSA-N 0.000 description 2
229910052759 nickel Inorganic materials 0.000 description 2
238000010992 reflux Methods 0.000 description 2
239000011734 sodium Substances 0.000 description 2
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235000017557 sodium bicarbonate Nutrition 0.000 description 2
229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
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HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
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WDAUAKBDZSYXEM-UHFFFAOYSA-N 1-(2-nitrophenyl)piperidine Chemical compound [O-][N+](=O)C1=CC=CC=C1N1CCCCC1 WDAUAKBDZSYXEM-UHFFFAOYSA-N 0.000 description 1
RSHKABUPZKEURK-UHFFFAOYSA-N 1-ethyl-3-[2-[4-(5-methyl-1H-imidazol-4-yl)piperidin-1-yl]phenyl]urea Chemical compound C(C)NC(=O)NC1=C(C=CC=C1)N1CCC(CC1)C=1N=CNC=1C RSHKABUPZKEURK-UHFFFAOYSA-N 0.000 description 1
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IJRKANNOPXMZSG-SSPAHAAFSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC(=O)CC(O)(C(O)=O)CC(O)=O IJRKANNOPXMZSG-SSPAHAAFSA-N 0.000 description 1
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DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
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FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
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125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
238000010586 diagram Methods 0.000 description 1
YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
108700003601 dimethylglycine Proteins 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
239000008298 dragée Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
230000004761 fibrosis Effects 0.000 description 1
239000001530 fumaric acid Substances 0.000 description 1
239000008103 glucose Substances 0.000 description 1
206010020718 hyperplasia Diseases 0.000 description 1
230000007574 infarction Effects 0.000 description 1
230000004941 influx Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
230000012105 intracellular pH reduction Effects 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
208000028867 ischemia Diseases 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
239000012948 isocyanate Substances 0.000 description 1
150000002513 isocyanates Chemical class 0.000 description 1
208000017169 kidney disease Diseases 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
229910001629 magnesium chloride Inorganic materials 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
208000031225 myocardial ischemia Diseases 0.000 description 1
AMAJLSJONIKVOI-UHFFFAOYSA-N n-[2-[4-(5-methyl-1-tritylimidazol-4-yl)piperidin-1-yl]phenyl]methanesulfonamide Chemical compound CC1=C(C2CCN(CC2)C=2C(=CC=CC=2)NS(C)(=O)=O)N=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 AMAJLSJONIKVOI-UHFFFAOYSA-N 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
235000011837 pasties Nutrition 0.000 description 1
230000007170 pathology Effects 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
150000003053 piperidines Chemical class 0.000 description 1
239000001103 potassium chloride Substances 0.000 description 1
235000011164 potassium chloride Nutrition 0.000 description 1
230000002265 prevention Effects 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
208000002815 pulmonary hypertension Diseases 0.000 description 1
150000003873 salicylate salts Chemical class 0.000 description 1
229910001415 sodium ion Inorganic materials 0.000 description 1
JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
239000004324 sodium propionate Substances 0.000 description 1
235000010334 sodium propionate Nutrition 0.000 description 1
229960003212 sodium propionate Drugs 0.000 description 1
239000007858 starting material Substances 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
239000010414 supernatant solution Substances 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
239000003826 tablet Substances 0.000 description 1
229960000103 thrombolytic agent Drugs 0.000 description 1
230000002537 thrombolytic effect Effects 0.000 description 1
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

the present invention relates to derivatives of (1H-imidazol -4 -yl) piperidine, their preparation and their therapeutic use.
the compounds of the invention correspond to formula (I)
R 1 and R 2 each independently of one another represent either a hydrogen atom or a (0 2 -0) straight or branched alkyl group
R 2 forms a cycle of type - (CH 2 ) n CO- where n can take a value between 2 and 6, in the form of free bases or of addition salts with pharmaceutically acceptable acids.
the preferred compounds are those for which R 2 represents a (C 2 -C 4 ) straight or branched alkyl group, R 2 represents either a hydrogen atom or a (C 2 -C 4 ) alkyl group straight or branched, R 3 represents either a hydrogen atom, a halogen atom, or a (C 1 -C) alkyl group, or a trifluoromethyl group, or a (C 2 -C 4 ) alkoxy group, R 4 represents either a hydrogen atom or a halogen atom, and A represents either a hydrogen atom, or a (C 1 -C 6 ) straight or branched alkyl group, or a phenyl (C 2 -C) group 4 ) alkyl, either a group -
R x , R 3 and R 4 being as defined above, A and R 2 form a cycle of type - (CH 2 ) n C0- where n can take a value between 2 and 6, in the state of free bases or addition salts with pharmaceutically acceptable acids.
the compounds of formula (I) can be prepared according to the process illustrated in scheme 1 in which the group -C (C 6 H 5 ) 3 represents a triphenylmethyl protective group (trityl group).
a compound of formula (II) in which Hal represents a halogen atom and R 3 and R 4 are as defined above is reacted with a compound of formula (III) in which R x is as defined above, in an aprotic solvent such as dimethylformamide in the presence Diagram 1
N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] -3-phenylprop-2-enamide This compound is obtained from N- [2- [ 4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] phenyl] - 3-phenylprop-2-enamide according to the method described in 1 example 1. 5.
N- 2 - [4- [5-methyl- (1-triphenylmethyl) - IH- imidazol -4- yl] piperidin- 1 -yl] phenyl] benzenemethane A 0.5 g (1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H- imidazol-4-yl] piperidin-1-yl] benzeneamine, in solution in 7 ml of toluene, 0.102 ml (1 mmol) of benzaldehyde and 0.05 g are added para-toluene sulfonic acid. The mixture is brought to reflux temperature, the solvent is evaporated and a gum is obtained.
N-2 - [4- (5-methyl-1H-imidazol-4 -yl) piperidin-1-yl] phenyl] benzenemethane This compound is obtained from N-2 - [4- [5-methyl- ( 1- triphenylmethyl) -IH- imidazol -4 -y1] piperidin-1-yl] phenyl] benzenemethanamine described in Example 1.5.
-cC 3 H 7 represents a cyclopropyl group, cCgl ⁇ a cyclohex group and -C 6 H 5 a phenyl group
(x: y) means x moles of acid for y moles of base, the absence of any mention means that the compound is in the basic state, fum. represents a fumarate, HC1 a hydrochloride
the compounds of the invention have been the subject of pharmacological studies which have demonstrated their inhibitory properties of the sodium / proton exchanger and their advantage as substances with therapeutic activity.
the compounds of the invention were subjected to a test for inhibiting the swelling of rabbit blood platelets in an acid medium according to the method of Grinstein et al. (In Methods in Enzymology, Fleisher S. And Flusher B., Vol 173, pp 777-790, Académie Press Inc., 1984).
Platelet-rich plasma is obtained by centrifugation at 1200 rpm for 20 minutes at room temperature. After measuring the initial average platelet volume, an aliquot of PRP is incubated for 20 minutes in a sodium propionate / propionic acid medium (140 mM) containing potassium chloride (1 mM), magnesium chloride (1 m), glucose (10 mM), all buffered with Hepes (20 mM) at pH 6.7 and the osmolarity of which is approximately 300 mosm / 1.
Propionic acid diffuses into the platelets where it dissociates, causing intra-cellular acidification and activation of the sodium / proton antiport.
the influx of sodium ions is accompanied by a capture of water which causes the swelling of the platelets.
the measurement of the mean platelet volume at the end of the incubation, minus the initial mean platelet volume, makes it possible to estimate the maximum swelling of the platelets.
the products to be tested are added to the propionic acid incubation medium at the desired concentrations, before the addition of PRP. The results are expressed as a percentage of inhibition of maximum swelling making it possible to calculate the IC 50 or concentration inhibiting by 50% the maximum swelling.
the IC 50 of the most interesting compounds of the invention are less than 10 ⁇ M.
the compounds of the invention can be used alone or in combination with other substances such as nitrates, calcium antagonists, beta-blockers, antithrombotics, thrombolytics, salicylates.

Landscapes

Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Cardiology (AREA)
Animal Behavior & Ethology (AREA)
Pharmacology & Pharmacy (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Heart & Thoracic Surgery (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Hospice & Palliative Care (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

EP98932236A 1997-07-01 1998-06-19 (1h-imidazol-4-yl)piperidindeivate, ihre herstellung und ihre medizinische verwendung Withdrawn EP0994857A1 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
FR9708256A FR2765580B1 (fr)	1997-07-01	1997-07-01	Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique
FR9708256		1997-07-01
PCT/FR1998/001287 WO1999001435A1 (fr)	1997-07-01	1998-06-19	Derives de (1h-imidazol-4-yl)piperidine, leur preparation et leur application en therapeutique

Publications (1)

Publication Number	Publication Date
EP0994857A1 true EP0994857A1 (de)	2000-04-26

Family

ID=9508676

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP98932236A Withdrawn EP0994857A1 (de)	1997-07-01	1998-06-19	(1h-imidazol-4-yl)piperidindeivate, ihre herstellung und ihre medizinische verwendung

Country Status (7)

Country	Link
EP (1)	EP0994857A1 (de)
JP (1)	JP2002507983A (de)
AR (1)	AR013149A1 (de)
AU (1)	AU8220598A (de)
FR (1)	FR2765580B1 (de)
WO (1)	WO1999001435A1 (de)
ZA (1)	ZA985727B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6887870B1 (en)	1999-10-12	2005-05-03	Bristol-Myers Squibb Company	Heterocyclic sodium/proton exchange inhibitors and method
GB0011089D0 (en)	2000-05-08	2000-06-28	Black James Foundation	Gastrin and cholecystokinin receptor ligands (11)
TW200614995A (en)	2004-11-10	2006-05-16	Nicholas Piramal India Ltd	Tricyclic guanidine derivatives as sodium-proton exchange inhibitors
WO2021127337A1 (en) *	2019-12-19	2021-06-24	Casma Therapeutics, Inc.	Trpml modulators

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4357341A (en) *	1981-05-22	1982-11-02	The United States Of America As Represented By The Department Of Health And Human Services	Specific irreversible antagonism of histamine receptors by photoaffinity actuated compounds
FR2674855B1 (fr) *	1991-04-03	1994-01-14	Synthelabo	Derives de piperidine, leur preparation et leur application en therapeutique.

1997
- 1997-07-01 FR FR9708256A patent/FR2765580B1/fr not_active Expired - Fee Related
1998
- 1998-06-19 JP JP50651199A patent/JP2002507983A/ja active Pending
- 1998-06-19 AU AU82205/98A patent/AU8220598A/en not_active Abandoned
- 1998-06-19 EP EP98932236A patent/EP0994857A1/de not_active Withdrawn
- 1998-06-19 WO PCT/FR1998/001287 patent/WO1999001435A1/fr not_active Application Discontinuation
- 1998-06-30 ZA ZA985727A patent/ZA985727B/xx unknown
- 1998-06-30 AR ARP980103161A patent/AR013149A1/es unknown

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9901435A1 *

Also Published As

Publication number	Publication date
JP2002507983A (ja)	2002-03-12
WO1999001435A1 (fr)	1999-01-14
ZA985727B (en)	1999-01-27
AU8220598A (en)	1999-01-25
AR013149A1 (es)	2000-12-13
FR2765580A1 (fr)	1999-01-08
FR2765580B1 (fr)	1999-08-06

Publication	Publication Date	Title
EP0302788B1 (de)	1992-02-05	2-[Methyl(4-piperidinyl)]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolderivate, ihre Herstellung und therapeutische Verwendung
EP0202164B1 (de)	1989-02-08	(Benzoyl-4-piperidino)-2-phenyl-1-alkanolderivate, ihre Herstellung und ihre Verwendung als Heilmittel
FR2676054A1 (fr)	1992-11-06	Nouveaux composes n-alkylenepiperidino et leurs enantiomeres, procede pour leur preparation et compositions pharmaceutiques les contenant.
EP0307303B1 (de)	1991-12-04	1-[(2-Pyrimidinyl)-aminoalkyl]-piperidine, deren Herstellung und Verwendung als Heilmittel
WO2004013100A2 (fr)	2004-02-12	Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
JP3739678B2 (ja)	2006-01-25	２−オキサゾリジノン誘導体のワンポット合成
EP0377528B1 (de)	1993-12-08	Piperidine, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel
EP0719775B1 (de)	2000-07-12	Substituierte 4-Phenyl-Thiazole Derivate, Verfahren zu deren Herstellung und pharmazeutische Zusammenstellungen die sie enthalten
EP0341231B1 (de)	1992-11-19	Substituierte 1-(1H-Imidazol-4-yl)alkyl-Benzamide
EP0306375A1 (de)	1989-03-08	2-[(4-Piperidinyl)methyl]-1,2,3,4-tetrahydrochinolin-Derivate, ihre Herstellung und ihre therapeutische Verwendung
EP0835254B1 (de)	1999-09-01	Oxazolidinone derivate, ihre herstellung und ihre therapeutische verwendung
EP0004494B1 (de)	1982-02-17	1,3-Dihydro-3-(1-(2-(2,3-dihydro-1,4-benzodioxin-2-yl)2-hydroxy-äthyl)piperidin-4-yl)2H-indol-2-on Derivate, Verfahren zu ihrer Herstellung, ihre Verwendung als Arzneimittel und diese enthaltende pharmazeutische Zubereitungen
EP0351255B1 (de)	1993-10-13	2-[(4-Piperidinyl)methyl]-1,2,3,4-tetrahydroisochinolin-Derivate, ihre Herstellung und ihre therapeutische Verwendung
CH617923A5 (de)	1980-06-30
EP1118610A1 (de)	2001-07-25	Benzolsulfonamidderivate und Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP0021924B1 (de)	1983-03-16	Indol-Derivate, Verfahren zu ihrer Herstellung, ihre Verwendung als Arzneimittel und sie enthaltende pharmazeutische Zusammensetzungen
EP0994857A1 (de)	2000-04-26	(1h-imidazol-4-yl)piperidindeivate, ihre herstellung und ihre medizinische verwendung
FR2758329A1 (fr)	1998-07-17	Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique
EP0998470B1 (de)	2003-05-07	Verfahren zur herstellung von alkoxyfuranon-amin-derivaten, durch dieses verfahren erhaltene verbindungen und verwendung dieser verbindungen
EP0301936A1 (de)	1989-02-01	Piperidin-Derivate, deren Herstellung und deren Verwendung als Heilmittel
EP0527079B1 (de)	1996-10-23	N-(Isochinolein-5-yl)-Sulfonyl Azazykloalkane, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammenstellungen
EP0718307A2 (de)	1996-06-26	1-Oxo-2-(phenylsulfonyl-amino)-pentylpiperidine Derivate, Verfahren zu ihrer Herstellung und ihre therapeutische Verwendung
WO1999000379A1 (fr)	1999-01-07	Derives de 4-[(1h-imidazol-4-yl)piperidin-1-yl]anilide, leur preparation et leur application en therapeutique
WO1999031097A1 (fr)	1999-06-24	Derives d'imidazole en tant qu'antagonistes des recepteurs muscariniques m3
CA2359103A1 (fr)	2000-07-27	1-(piperidin-4-yl)-3-(aryl)-isothiourees substituees, leur preparation et leur application en therapeutique

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