JP6691552B2 - ファルネソイドｘ受容体をモジュレートするのに有用である縮合三環式ピラゾール誘導体 - Google Patents
ファルネソイドｘ受容体をモジュレートするのに有用である縮合三環式ピラゾール誘導体 Download PDFInfo
- Publication number
- JP6691552B2 JP6691552B2 JP2017556538A JP2017556538A JP6691552B2 JP 6691552 B2 JP6691552 B2 JP 6691552B2 JP 2017556538 A JP2017556538 A JP 2017556538A JP 2017556538 A JP2017556538 A JP 2017556538A JP 6691552 B2 JP6691552 B2 JP 6691552B2
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- JP
- Japan
- Prior art keywords
- methyl
- chromeno
- pyrazol
- chloro
- formamide
- Prior art date
- 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.)
- Expired - Fee Related
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- 102100038495 Bile acid receptor Human genes 0.000 title claims description 82
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 title claims description 81
- 150000003217 pyrazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 214
- 150000003839 salts Chemical class 0.000 claims description 75
- 239000003814 drug Substances 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 64
- -1 tetrapyranyl Chemical group 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 230000001404 mediated effect Effects 0.000 claims description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 229940124597 therapeutic agent Drugs 0.000 claims description 37
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 36
- 206010008635 Cholestasis Diseases 0.000 claims description 31
- 230000007870 cholestasis Effects 0.000 claims description 27
- 231100000359 cholestasis Toxicity 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 239000003613 bile acid Substances 0.000 claims description 20
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 18
- 208000019423 liver disease Diseases 0.000 claims description 18
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 15
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
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- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 11
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 11
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
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- 206010012735 Diarrhoea Diseases 0.000 claims description 10
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 10
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
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- SYGSTRANUHFLOT-UHFFFAOYSA-N chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C1=CC=C2C3=NN=C(C(=O)N)C3=COC2=C1 SYGSTRANUHFLOT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- IAEQIQBKMOAWGP-UHFFFAOYSA-N 8-chloro-N-[2-(cyclopropylmethylcarbamoylamino)ethyl]-N-[(2-fluorophenyl)methyl]-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound ClC1=CC2=C(C=C1)OCC1=C2N(N=C1C(=O)N(CC1=C(C=CC=C1)F)CCNC(NCC1CC1)=O)C IAEQIQBKMOAWGP-UHFFFAOYSA-N 0.000 claims description 5
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- 201000003883 Cystic fibrosis Diseases 0.000 claims description 5
- RFSOIZWEFLJNBM-UHFFFAOYSA-N N-[(4-aminophenyl)methyl]-N-benzyl-8-chloro-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound NC1=CC=C(C=C1)CN(C(=O)C=1C2=C(N(N=1)C)C=1C=C(C=CC=1OC2)Cl)CC1=CC=CC=C1 RFSOIZWEFLJNBM-UHFFFAOYSA-N 0.000 claims description 5
- 206010057969 Reflux gastritis Diseases 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 229940011871 estrogen Drugs 0.000 claims description 5
- 239000000262 estrogen Substances 0.000 claims description 5
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 5
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
- 201000011374 Alagille syndrome Diseases 0.000 claims description 4
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 4
- 206010024715 Liver transplant rejection Diseases 0.000 claims description 4
- MACNYKLUIOMLPQ-UHFFFAOYSA-N N-(2-acetamidoethyl)-N-benzyl-8-bromo-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C(C1=CC=CC=C1)N(C(=O)C=1C2=C(N(N=1)C)C=1C=C(C=CC=1OC2)Br)CCNC(C)=O MACNYKLUIOMLPQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 208000001024 intrahepatic cholestasis Diseases 0.000 claims description 4
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- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 4
- 230000000750 progressive effect Effects 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
- AMXYZJHTNOIKFS-UHFFFAOYSA-N 8-bromo-N-[(3-fluorophenyl)methyl]-1-methyl-N-[2-(2-methylpropanoylamino)ethyl]-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound BrC1=CC2=C(C=C1)OCC1=C2N(N=C1C(=O)N(CC1=CC(=CC=C1)F)CCNC(C(C)C)=O)C AMXYZJHTNOIKFS-UHFFFAOYSA-N 0.000 claims description 3
- JAAGCQQDSFBJHC-UHFFFAOYSA-N 8-chloro-N-[(2-fluorophenyl)methyl]-1-methyl-N-[2-(2-methylpropanoylamino)ethyl]-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound ClC1=CC2=C(C=C1)OCC1=C2N(N=C1C(=O)N(CC1=C(C=CC=C1)F)CCNC(C(C)C)=O)C JAAGCQQDSFBJHC-UHFFFAOYSA-N 0.000 claims description 3
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- XEKGISSNNSOVTC-UHFFFAOYSA-N N-(2-acetamidoethyl)-8-bromo-N-[(3-fluorophenyl)methyl]-1-methyl-4H-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound BrC1=CC2=C(C=C1)OCC1=C2N(N=C1C(=O)N(CC1=CC(=CC=C1)F)CCNC(C)=O)C XEKGISSNNSOVTC-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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| US201562154862P | 2015-04-30 | 2015-04-30 | |
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| PCT/IB2016/052424 WO2016174616A1 (en) | 2015-04-30 | 2016-04-29 | Fused tricyclic pyrazole derivatives useful for modulating farnesoid x receptors |
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| JP2018519252A5 JP2018519252A5 (enExample) | 2019-05-09 |
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| SG11201603026PA (en) | 2013-11-05 | 2016-05-30 | Novartis Ag | Compositions and methods for modulating farnesoid x receptors |
| TW201808283A (zh) * | 2016-08-05 | 2018-03-16 | 廣東東陽光藥業有限公司 | 含氮三環化合物及其在藥物中的應用 |
| JP7599014B2 (ja) * | 2020-06-30 | 2024-12-12 | オクヴィルク，ゼレン | グアニル酸シクラーゼｃ（ｇｕｃｙ２ｃ）アゴニストおよび短鎖脂肪酸またはそのプロドラッグの組み合わせを含む医薬組成物 |
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| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| EP0463090A1 (en) * | 1989-03-09 | 1992-01-02 | E.I. Du Pont De Nemours And Company | Arthropodicidal tetrahydrobenzopyranopyrazoles |
| JP3006925B2 (ja) * | 1990-09-14 | 2000-02-07 | 協和醗酵工業株式会社 | ピラゾロキノリン誘導体 |
| WO2004078163A2 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| US20040259887A1 (en) * | 2003-06-18 | 2004-12-23 | Pfizer Inc | Cannabinoid receptor ligands and uses thereof |
| CA2586011C (en) * | 2004-07-12 | 2011-07-19 | Cadila Healthcare Limited | Tricyclic pyrazole derivatives as cannabinoid receptor modulators |
| CA2603254C (en) * | 2005-04-12 | 2013-10-29 | Vicore Pharma Ab | New bicyclic angiotensin ii agonists |
| DK2029547T3 (da) * | 2006-05-24 | 2010-07-26 | Lilly Co Eli | FXR-agonister |
| US20110263588A1 (en) | 2008-10-27 | 2011-10-27 | Glaxo Group Limited | Tricyclic compounds as glutamate receptor modulators |
| IT1394400B1 (it) * | 2009-02-25 | 2012-06-15 | Neuroscienze Pharmaness S C Ar L | Composizioni farmaceutiche |
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| IT1395724B1 (it) * | 2009-02-25 | 2012-10-19 | Neuroscienze Pharmaness S C A R L | Composti farmaceutici |
| US8071589B2 (en) * | 2009-07-31 | 2011-12-06 | N. V. Organon | Dihydrobenzoindazoles |
| TWI423980B (zh) * | 2009-09-28 | 2014-01-21 | Hoffmann La Roche | 苯并氧氮呯ｐｉ３ｋ抑制劑化合物及使用方法 |
| RU2663898C2 (ru) * | 2013-06-24 | 2018-08-13 | Мерк Патент Гмбх | Пиразольные соединения в качестве модуляторов fshr и их применение |
| SG11201603026PA (en) * | 2013-11-05 | 2016-05-30 | Novartis Ag | Compositions and methods for modulating farnesoid x receptors |
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| CN107531721A (zh) | 2018-01-02 |
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