DK3009426T3 - 4-alkynyl-imidazol-derivat og lægemiddel omfattende samme som aktiv bestanddel - Google Patents
4-alkynyl-imidazol-derivat og lægemiddel omfattende samme som aktiv bestanddel Download PDFInfo
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- DK3009426T3 DK3009426T3 DK14811154.5T DK14811154T DK3009426T3 DK 3009426 T3 DK3009426 T3 DK 3009426T3 DK 14811154 T DK14811154 T DK 14811154T DK 3009426 T3 DK3009426 T3 DK 3009426T3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- ZIBCCORJSVRQFH-UHFFFAOYSA-N methyl 2-bromo-3-[2-(4-chlorophenoxy)ethyl]imidazole-4-carboxylate Chemical compound BrC=1N(C(=CN=1)C(=O)OC)CCOC1=CC=C(C=C1)Cl ZIBCCORJSVRQFH-UHFFFAOYSA-N 0.000 description 3
- ZZRYXPXGIUJMKV-UHFFFAOYSA-N methyl 2-bromo-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound BrC=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F ZZRYXPXGIUJMKV-UHFFFAOYSA-N 0.000 description 3
- OBPLYINRLSTJSD-UHFFFAOYSA-N methyl 2-chloro-3-[(4-fluorophenyl)methyl]-5-(3-hydroxy-3-methylbut-1-ynyl)imidazole-4-carboxylate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)OC)CC1=CC=C(C=C1)F OBPLYINRLSTJSD-UHFFFAOYSA-N 0.000 description 3
- NYPWIXLLQSIEGZ-UHFFFAOYSA-N methyl 2-chloro-3-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound ClC=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)F NYPWIXLLQSIEGZ-UHFFFAOYSA-N 0.000 description 3
- YAAGRDVGYYPUCK-UHFFFAOYSA-N methyl 2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F YAAGRDVGYYPUCK-UHFFFAOYSA-N 0.000 description 3
- QGAQMUGBLBOWFN-UHFFFAOYSA-N methyl 2-cyclopropyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound C1(CC1)C=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F QGAQMUGBLBOWFN-UHFFFAOYSA-N 0.000 description 3
- PGDHEGJZUJVLRZ-UHFFFAOYSA-N methyl 2-ethyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carboxylate Chemical compound C(C)C=1N(C(=CN=1)C(=O)OC)CC1=CC=C(C=C1)C(F)(F)F PGDHEGJZUJVLRZ-UHFFFAOYSA-N 0.000 description 3
- QURCROLANGZYQS-UHFFFAOYSA-N methyl 3-[(4-fluorophenyl)methyl]imidazole-4-carboxylate Chemical compound FC1=CC=C(CN2C=NC=C2C(=O)OC)C=C1 QURCROLANGZYQS-UHFFFAOYSA-N 0.000 description 3
- WZUKJRCWCOKJDE-UHFFFAOYSA-N methyl 3-[(4-methylphenyl)methyl]imidazole-4-carboxylate Chemical compound COC(=O)C1=CN=CN1CC1=CC=C(C)C=C1 WZUKJRCWCOKJDE-UHFFFAOYSA-N 0.000 description 3
- CTUNEFJJWFAGEP-UHFFFAOYSA-N methyl 4-(difluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C(F)F)C=C1 CTUNEFJJWFAGEP-UHFFFAOYSA-N 0.000 description 3
- KRRMKJHNLNKGME-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F KRRMKJHNLNKGME-UHFFFAOYSA-N 0.000 description 3
- DMKZRTFMGGQASS-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-methoxy-3-methylbut-1-ynyl)-3-[(4-methylphenyl)methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C DMKZRTFMGGQASS-UHFFFAOYSA-N 0.000 description 3
- LJAVAVQUNWCXNR-UHFFFAOYSA-N methyl 4-[1-[[2-chloro-5-(3-methoxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]cyclopropyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NC1(CC1)C1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F LJAVAVQUNWCXNR-UHFFFAOYSA-N 0.000 description 3
- RODIREPAJNQJFQ-UHFFFAOYSA-N methyl 4-[[[2-bromo-3-[2-(4-chlorophenoxy)ethyl]-5-(3-hydroxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CCOC1=CC=C(C=C1)Cl RODIREPAJNQJFQ-UHFFFAOYSA-N 0.000 description 3
- SIQXLICRVGRTCT-UHFFFAOYSA-N methyl 4-[[[2-bromo-3-[2-(4-chlorophenoxy)ethyl]-5-iodoimidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N(C(=C(N=1)I)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CCOC1=CC=C(C=C1)Cl SIQXLICRVGRTCT-UHFFFAOYSA-N 0.000 description 3
- DIPDFCPNNMRGSS-UHFFFAOYSA-N methyl 4-[[[2-chloro-3-[(4-fluorophenyl)methyl]-5-(3-methoxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)OC)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)F DIPDFCPNNMRGSS-UHFFFAOYSA-N 0.000 description 3
- PFCHONQRDONUMB-UHFFFAOYSA-N methyl 4-[[[2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=CN=1)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F PFCHONQRDONUMB-UHFFFAOYSA-N 0.000 description 3
- BZROHFHFYXUSCT-UHFFFAOYSA-N methyl 4-[[[2-chloro-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F BZROHFHFYXUSCT-UHFFFAOYSA-N 0.000 description 3
- CUMQUELVXPLZLO-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=CN=1)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F CUMQUELVXPLZLO-UHFFFAOYSA-N 0.000 description 3
- NFDSEZZAODNNHW-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-5-(3-hydroxy-3-methylbut-1-ynyl)-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=C(N=1)C#CC(C)(C)O)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F NFDSEZZAODNNHW-UHFFFAOYSA-N 0.000 description 3
- KTMVEQADPNRPSC-UHFFFAOYSA-N methyl 4-[[[2-cyclopropyl-5-iodo-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound C1(CC1)C=1N(C(=C(N=1)I)C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F KTMVEQADPNRPSC-UHFFFAOYSA-N 0.000 description 3
- YWNCLDGVONLMKQ-UHFFFAOYSA-N methyl 4-[[[3-[2-(4-chlorophenoxy)ethyl]-2-cyclopropyl-5-(3-methoxy-3-methylbut-1-ynyl)imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound ClC1=CC=C(OCCN2C(=NC(=C2C(=O)NCC2=CC=C(C(=O)OC)C=C2)C#CC(C)(C)OC)C2CC2)C=C1 YWNCLDGVONLMKQ-UHFFFAOYSA-N 0.000 description 3
- KTFJOWJYEBVKHN-UHFFFAOYSA-N methyl 4-[[[5-bromo-2-chloro-3-[[4-(trifluoromethyl)phenyl]methyl]imidazole-4-carbonyl]amino]methyl]benzoate Chemical compound BrC=1N=C(N(C=1C(=O)NCC1=CC=C(C(=O)OC)C=C1)CC1=CC=C(C=C1)C(F)(F)F)Cl KTFJOWJYEBVKHN-UHFFFAOYSA-N 0.000 description 3
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Claims (17)
1. 4-alkynylimidazolderivat med den generelle formel (I) eller et farmaceutisk acceptabelt salt deraf: [Formel 1]
[hvor ring A er en cyclohexyl substitueret med E i 4-stillingen eller en phenyl substitueret med E i 4-stillingen; ring B er cycloalkyl, aryl eller heteroaryl; m er et helt tal af en hvilken som helst af 0~2; n er et helt tal af en hvilken som helst af 1~3; R1 er et hydrogenatom, en Ci~C4-alkylgruppe, en Ci~C4-alkoxygruppe, et halogenatom eller en Ci~C4-halogenalkylgruppe; R2 og R3 er hver uafhængigt et hydrogenatom, et halogenatom eller en Ci~C4-alkylgruppe eller kan sammen med det carbonatom, hvortil R2 og R3 støder op til hinanden, danne en C3~C6-carbonring; R4 og R5 er hver uafhængigt et hydrogenatom eller en Ci~C4-alkylgruppe eller kan sammen med det carbonatom, hvortil R4 og R5 støder op til hinanden, danne en C3~C6-carbonring, og R5 og R7 hver uafhængigt er et hydrogenatom, en Ci~C4-alkylgruppe, en Ci~C4-alkoxygruppe, en Ci~C4-hydroxyalkylgruppe, en carboxylgruppe, en cyanogruppe, et halogenatom, en Ci~C4-halogenalkylgruppe, eller en Ci~C4-halogenalkoxygruppe; X er -OR8, -NR9R10 eller et halogenatom; R8 er et hydrogenatom, en Ci~C4-alkylgruppe eller en Ci~C4-halogenalkylgruppe; R9 og R10 er hver uafhængigt et hydrogenatom eller en Ci~C4-alkylgruppe eller kan, sammen med nitrogenatomet, hvortil R9 og R10 støder op til hinanden, danne en nitrogen-holdig heterocyklisk gruppe, Y er en enkeltbinding, et oxygenatom eller et svovlatom; og E er -CO2H, -CO2P, hvor P repræsenterer alkyl, proxetil eller medoxomil eller en bioi-soster af en carboxylgruppe repræsenteret ved hydroxamsyre (-CO-NH-OH), sulfonamid (-NH-S02-Ci~C6-alkyl), acylcyanamid (-CO-NH-CN), acylsulfonamid (-C0-NH-S02-Ci~C6-alkyl, -S02-NH-C0-Ci~C6-alkyl), tetrazolyl, oxadiazolonyl, oxadiazolthionyl, oxathiadi-azolyl, thiadiazolonyl, triazolthionyl og hydroxyisoxazolyl].
2. 4-alkynylimidazolderivat ifølge krav 1 eller et farmaceutisk acceptabelt salt deraf, hvor i den foregående generelle formel (I) X er -OR8 (R8 er som defineret i krav 1), og m er 0.
3.
4-alkynylimidazolderivat ifølge krav 1 eller 2 eller et farmaceutisk acceptabelt salt deraf, hvor R2 og R3 i den foregående generelle formel (I) begge er en methylgruppe. 4. 4-alkynylimidazolderivat ifølge et hvilket som helst af kravene 1 til 3 eller et farmaceutisk acceptabelt salt deraf, hvor R1 i den foregående generelle formel (I) er en methylgruppe, en ethylgruppe, en cyclopropylgruppe, et chloratom, en difluormethylgrup-pe eller en trifluormethylgruppe.
5. 4-alkynylimidazolderivat ifølge krav 4 eller et farmaceutisk acceptabelt salt deraf, hvor R1 i det foregående almene formel (I) er et chloratom.
6. 4-alkynylimidazolderivat ifølge et hvilket som helst af kravene 1 til 5 eller et farmaceutisk acceptabelt salt deraf, hvor E i den foregående formel (I) er -CO2H eller tetra-zolyl.
7. 4-alkynylimidazolderivat ifølge et hvilket som helst af kravene 1 til 6 eller et farmaceutisk acceptabelt salt deraf, hvor i den foregående formel (I) ring B er phenyl, n er 1, og Y er en enkeltbinding.
8. 4-alkynylimidazolderivat ifølge krav 7 eller et farmaceutisk acceptabelt salt deraf, hvor i den foregående formel (I) ring B er phenyl substitueret med R5 i 4-stillingen, R7 er et hydrogenatom, og R5 er enhver en af en Ci~C4-alkylgruppe, en Ci~C4-alkoxygruppe, en cyanogruppe, et halogenatom, en Ci~C4-halogenalkylgruppe og en Ci~C4-halogenalkoxygruppe.
9. 4-alkynylimidazolderivat ifølge krav 1 eller et farmaceutisk acceptabelt salt deraf, hvor forbindelsen repræsenteret ved den foregående formel (I) er en hvilken som helst af:
10. 4-alkynylimidazolderivat ifølge krav 9 eller et farmaceutisk acceptabelt salt deraf, hvor forbindelsen repræsenteret ved den foregående formel (I) er: [Formel 3]
11. Farmaceutisk middel omfattende 4-alkynylimidazolderivatet ifølge et hvilket som helst af kravene 1 til 10 eller et farmaceutisk acceptabelt salt deraf som en aktiv bestanddel.
12. EP4-receptorantagonist omfattende 4-alkynylimidazolderivatet ifølge et hvilket som helst af kravene 1 til 10 eller et farmaceutisk acceptabelt salt deraf.
13. Farmaceutisk middel som defineret i krav 11 til anvendelse til behandling af en inflammatorisk sygdom eller en inflammatorisk smerte.
14. Farmaceutisk middel til anvendelse ifølge krav 13, hvor den inflammatoriske sygdom eller inflammatoriske smerte er mindst én valgt fra gruppen bestående af arthri-tisk smerte, artikulær reumatisme, slidgigt, lumbago, scapulohumeral periarthritis, cervico-omo-brachial syndrom, tendonitis og thecitis.
15. Farmaceutisk middel til anvendelse ifølge krav 13 eller 14, hvor behandlingen er antiinflammation og/eller smertelindring.
16. Farmaceutisk middel som defineret i krav 11 til anvendelse ved behandlingen af mindst én sygdom valgt fra gruppen bestående af multipel sklerose, ulcerativ colitis, Crohns sygdom, atopisk dermatitis, psoriasis og kontaktdermatitis.
17. Farmaceutisk middel til anvendelse ifølge krav 16, hvor sygdommen er multipel sklerose.
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US9593081B2 (en) * | 2013-06-12 | 2017-03-14 | Kaken Pharmaceutical Co., Ltd. | 4-alkynyl imidazole derivative and medicine comprising same as active ingredient |
CR20180323A (es) | 2015-11-20 | 2018-08-06 | Idorsia Pharmaceuticals Ltd | Derivados de indol n-sustituídos como moduladores de los receptores de pge2 |
BR112019009801A2 (pt) * | 2016-11-18 | 2019-08-06 | Dow Agrosciences Llc | 4-((6-(2-(2,4-difluorofenil)-1,1-difluoro-2-hidróxi-3-(5-mercapto-1h-1,2,4-triazol-1-il)propil)piridin-3-il)óxi)benzonitrila e processos de preparação |
EP3625228B1 (en) | 2017-05-18 | 2021-07-07 | Idorsia Pharmaceuticals Ltd | Pyrimidine derivatives as pge2 receptor modulators |
CN110621671A (zh) | 2017-05-18 | 2019-12-27 | 爱杜西亚药品有限公司 | 作为pge2受体调节剂的苯并呋喃及苯并噻吩衍生物 |
CN110621667A (zh) | 2017-05-18 | 2019-12-27 | 爱杜西亚药品有限公司 | 嘧啶衍生物 |
WO2018210994A1 (en) | 2017-05-18 | 2018-11-22 | Idorsia Pharmaceuticals Ltd | Phenyl derivatives as pge2 receptor modulators |
RS62441B1 (sr) | 2017-05-18 | 2021-11-30 | Idorsia Pharmaceuticals Ltd | N-supstituisani derivati indola |
TW201900613A (zh) | 2017-05-22 | 2019-01-01 | 日商小野藥品工業股份有限公司 | Ep 拮抗劑 |
JP2020142989A (ja) * | 2017-06-21 | 2020-09-10 | Meiji Seikaファルマ株式会社 | イミダゾール誘導体及びそれを含有する医薬 |
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Publication number | Priority date | Publication date | Assignee | Title |
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RU2315746C2 (ru) * | 2001-08-09 | 2008-01-27 | Оно Фармасьютикал Ко., Лтд. | Производные карбоновых кислот и фармацевтическое средство, содержащее их в качестве активного ингредиента |
BR0311247A (pt) | 2002-05-23 | 2005-03-15 | Theratechnologies Inc | Peptìdeos antagonistas do receptor subtipo ep4 da prostaglandina e2 |
EP1663979B1 (en) | 2003-09-03 | 2013-10-09 | RaQualia Pharma Inc. | Phenyl or pyridyl amide compounds as prostaglandin e2 antagonists |
ES2327760T3 (es) | 2004-05-04 | 2009-11-03 | Raqualia Pharma Inc | Compuestos de aril-heteroaril-amida ortosustituidos. |
MXPA06011555A (es) | 2004-05-04 | 2006-12-15 | Pfizer | Compuestos de metil-aril o heteroaril-amida sustituida. |
WO2006087355A1 (en) * | 2005-02-16 | 2006-08-24 | Solvay Pharmaceuticals B.V. | 1h-imidiazole derivatives as cannabinoid cb2 receptor modulators |
ES2392192T3 (es) | 2006-04-24 | 2012-12-05 | Merck Canada Inc. | Derivados de indol amida como antagonistas del receptor EP4 |
WO2007143825A1 (en) | 2006-06-12 | 2007-12-21 | Merck Frosst Canada Ltd. | Indoline amide derivatives as ep4 receptor ligands |
CA2660133C (en) | 2006-08-11 | 2015-10-27 | Merck Frosst Canada Ltd. | Thiophenecarboxamide derivatives as ep4 receptor ligands |
US8158671B2 (en) * | 2007-02-26 | 2012-04-17 | Merck Canada Inc. | Indole and indoline cyclopropyl amide derivatives as EP4 receptor antagonists |
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WO2009005076A1 (ja) | 2007-07-03 | 2009-01-08 | Astellas Pharma Inc. | アミド化合物 |
PT2565191E (pt) | 2008-05-14 | 2014-12-04 | Astellas Pharma Inc | Derivados do ácido 4-(indol-7- ilcarbonilaminometil)ciclo-hexanocarboxílico como antagonistas de receptores ep4, úteis no tratamento de insuficiência renal crónica ou de nefropatia diabética |
US8404736B2 (en) | 2008-08-14 | 2013-03-26 | Beta Pharma Canada Inc. | Heterocyclic amide derivatives as EP4 receptor antagonists |
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US9593081B2 (en) * | 2013-06-12 | 2017-03-14 | Kaken Pharmaceutical Co., Ltd. | 4-alkynyl imidazole derivative and medicine comprising same as active ingredient |
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