BR112016009630B1 - receptores de farnesoide x, seus usos, combinação e composição farmacêutica - Google Patents

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Publication number

BR112016009630B1

BR112016009630B1 BR112016009630-4A BR112016009630A BR112016009630B1 BR 112016009630 B1 BR112016009630 B1 BR 112016009630B1 BR 112016009630 A BR112016009630 A BR 112016009630A BR 112016009630 B1 BR112016009630 B1 BR 112016009630B1

Authority

BR

Brazil

Prior art keywords

methyl

carboxamido

dihydrochromene

pyrazol

acid

Prior art date

2013-11-05

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
• 102100038495 Bile acid receptor Human genes 0.000 title claims description 73
• 101150027485 NR1H4 gene Proteins 0.000 title description 7
• 150000001875 compounds Chemical class 0.000 claims abstract description 224
• 150000003839 salts Chemical class 0.000 claims abstract description 90
• 150000001413 amino acids Chemical class 0.000 claims abstract description 15
• 102000005962 receptors Human genes 0.000 claims abstract description 5
• 108020003175 receptors Proteins 0.000 claims abstract description 5
• -1 pyrazol-3-carboxamido Chemical group 0.000 claims description 423
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 260
• 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 148
• 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 134
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 128
• 239000002253 acid Substances 0.000 claims description 113
• 239000005711 Benzoic acid Substances 0.000 claims description 95
• 235000010233 benzoic acid Nutrition 0.000 claims description 95
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 69
• 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 claims description 66
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 61
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 55
• 239000003814 drug Substances 0.000 claims description 54
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 52
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
• 125000005843 halogen group Chemical group 0.000 claims description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 36
• 230000001404 mediated effect Effects 0.000 claims description 34
• 125000001424 substituent group Chemical group 0.000 claims description 34
• 201000010099 disease Diseases 0.000 claims description 32
• 206010008635 Cholestasis Diseases 0.000 claims description 31
• 230000007870 cholestasis Effects 0.000 claims description 28
• 231100000359 cholestasis Toxicity 0.000 claims description 28
• 229940124597 therapeutic agent Drugs 0.000 claims description 26
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 25
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
• 239000000460 chlorine Substances 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 23
• 125000006519 CCH3 Chemical group 0.000 claims description 21
• 229910052731 fluorine Inorganic materials 0.000 claims description 20
• 239000011737 fluorine Substances 0.000 claims description 19
• 150000002431 hydrogen Chemical group 0.000 claims description 19
• 229940079593 drug Drugs 0.000 claims description 18
• 125000004076 pyridyl group Chemical group 0.000 claims description 18
• 125000006413 ring segment Chemical group 0.000 claims description 18
• 229910052760 oxygen Inorganic materials 0.000 claims description 17
• 229910052717 sulfur Inorganic materials 0.000 claims description 17
• 125000005842 heteroatom Chemical group 0.000 claims description 16
• 208000019423 liver disease Diseases 0.000 claims description 16
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 16
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 15
• 230000001476 alcoholic effect Effects 0.000 claims description 15
• 210000004185 liver Anatomy 0.000 claims description 12
• 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 11
• 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 11
• 239000007983 Tris buffer Substances 0.000 claims description 11
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 11
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 10
• 125000001153 fluoro group Chemical group F* 0.000 claims description 10
• 238000004519 manufacturing process Methods 0.000 claims description 10
• BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 8
• 125000001041 indolyl group Chemical group 0.000 claims description 8
• 229960003194 meglumine Drugs 0.000 claims description 7
• 235000016236 parenteral nutrition Nutrition 0.000 claims description 7
• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 6
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
• MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 208000010643 digestive system disease Diseases 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000018685 gastrointestinal system disease Diseases 0.000 claims description 6
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 5
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 5
• 229940011871 estrogen Drugs 0.000 claims description 5
• 239000000262 estrogen Substances 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 claims description 5
• 230000000750 progressive effect Effects 0.000 claims description 5
• 208000010157 sclerosing cholangitis Diseases 0.000 claims description 5
• 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 4
• 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 4
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
• 206010057969 Reflux gastritis Diseases 0.000 claims description 4
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 208000017169 kidney disease Diseases 0.000 claims description 4
• SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 4
• KJTRXVXWSSPHRV-UHFFFAOYSA-N 4-benzoyl-5-methyl-2-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(C(=O)C=2C=CC=CC=2)=C(C)NN1C1=CC=CC=C1 KJTRXVXWSSPHRV-UHFFFAOYSA-N 0.000 claims description 3
• 201000011374 Alagille syndrome Diseases 0.000 claims description 3
• 206010069703 Bile acid malabsorption Diseases 0.000 claims description 3
• 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 3
• 206010024715 Liver transplant rejection Diseases 0.000 claims description 3
• 208000001024 intrahepatic cholestasis Diseases 0.000 claims description 3
• 230000007872 intrahepatic cholestasis Effects 0.000 claims description 3
• 230000035935 pregnancy Effects 0.000 claims description 3
• 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 3
• 238000002054 transplantation Methods 0.000 claims description 3
• GGZMIQOZEZVMFU-UHFFFAOYSA-N 3-[[2-[(8-chloro-1-methyl-4,5-dihydrobenzo[g]indazole-3-carbonyl)-[(2-fluorophenyl)methyl]amino]acetyl]amino]benzoic acid Chemical compound Cn1nc(C(=O)N(CC(=O)Nc2cccc(c2)C(O)=O)Cc2ccccc2F)c2CCc3ccc(Cl)cc3-c12 GGZMIQOZEZVMFU-UHFFFAOYSA-N 0.000 claims description 2
• KJMXTDPPYTXLEQ-UHFFFAOYSA-N 4-fluoro-3-[[2-[(2-fluorophenyl)methyl-(1-methyl-4,5-dihydropyrazolo[4,3-h]quinoline-3-carbonyl)amino]acetyl]amino]benzoic acid Chemical compound Cn1nc(C(=O)N(CC(=O)Nc2cc(ccc2F)C(O)=O)Cc2ccccc2F)c2CCc3cccnc3-c12 KJMXTDPPYTXLEQ-UHFFFAOYSA-N 0.000 claims description 2
• OHKQMEARTYNBDN-UHFFFAOYSA-N 4-fluoro-3-[[2-[(3-fluorophenyl)methyl-(1,5,5-trimethyl-4H-benzo[g]indazole-3-carbonyl)amino]acetyl]amino]benzoic acid Chemical compound Cn1nc(C(=O)N(CC(=O)Nc2cc(ccc2F)C(O)=O)Cc2cccc(F)c2)c2CC(C)(C)c3ccccc3-c12 OHKQMEARTYNBDN-UHFFFAOYSA-N 0.000 claims description 2
• 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
• 208000024908 graft versus host disease Diseases 0.000 claims description 2
• 229960003512 nicotinic acid Drugs 0.000 claims description 2
• 235000001968 nicotinic acid Nutrition 0.000 claims description 2
• 239000011664 nicotinic acid Substances 0.000 claims description 2
• 229940081066 picolinic acid Drugs 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
• LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims 1
• 230000000694 effects Effects 0.000 abstract description 11
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 220
• 239000000203 mixture Substances 0.000 description 126
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 114
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 113
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• 238000000034 method Methods 0.000 description 81
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 61
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
• 235000019439 ethyl acetate Nutrition 0.000 description 48
• KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 43
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• 239000000543 intermediate Substances 0.000 description 33
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• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
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• 239000003153 chemical reaction reagent Substances 0.000 description 27
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• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 24
• 239000002244 precipitate Substances 0.000 description 23
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• 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 description 13
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• IRWPYRJIIWYISR-UHFFFAOYSA-N methyl 3-[(2-aminoacetyl)amino]-4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C(NC(=O)CN)=C1 IRWPYRJIIWYISR-UHFFFAOYSA-N 0.000 description 6
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