CA3030377C - Nitrogen-containing tricyclic compounds and uses thereof in medicine - Google Patents
Nitrogen-containing tricyclic compounds and uses thereof in medicine Download PDFInfo
- Publication number
- CA3030377C CA3030377C CA3030377A CA3030377A CA3030377C CA 3030377 C CA3030377 C CA 3030377C CA 3030377 A CA3030377 A CA 3030377A CA 3030377 A CA3030377 A CA 3030377A CA 3030377 C CA3030377 C CA 3030377C
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- Prior art keywords
- alkyl
- methyl
- independently
- hydroxy
- deuterium
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 298
- 239000003814 drug Substances 0.000 title claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 83
- 201000010099 disease Diseases 0.000 claims abstract description 75
- 230000001404 mediated effect Effects 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 14
- 239000012453 solvate Substances 0.000 claims abstract description 10
- -1 hydroxy, amino Chemical group 0.000 claims description 249
- 125000000217 alkyl group Chemical group 0.000 claims description 127
- 125000000623 heterocyclic group Chemical group 0.000 claims description 115
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 107
- 229910052739 hydrogen Inorganic materials 0.000 claims description 101
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 100
- 239000001257 hydrogen Substances 0.000 claims description 99
- 150000002431 hydrogen Chemical class 0.000 claims description 97
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 95
- 229910052805 deuterium Inorganic materials 0.000 claims description 95
- 229910052794 bromium Inorganic materials 0.000 claims description 82
- 229910052740 iodine Inorganic materials 0.000 claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
- 229910052801 chlorine Inorganic materials 0.000 claims description 70
- 229910052731 fluorine Inorganic materials 0.000 claims description 69
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 60
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 56
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 53
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- 125000001424 substituent group Chemical group 0.000 claims description 49
- 125000004432 carbon atom Chemical group C* 0.000 claims description 47
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 125000001188 haloalkyl group Chemical group 0.000 claims description 45
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- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 38
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- 125000003342 alkenyl group Chemical group 0.000 claims description 26
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- 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 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000001797 benzyl group Chemical class [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
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- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 125000003386 piperidinyl group Chemical group 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 17
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- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 13
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 13
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 12
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 12
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 12
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 12
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 12
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 12
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 11
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- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 11
- 201000002150 Progressive familial intrahepatic cholestasis Diseases 0.000 claims description 11
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- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
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- 230000003463 hyperproliferative effect Effects 0.000 claims description 11
- 208000027866 inflammatory disease Diseases 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000006413 ring segment Chemical group 0.000 claims description 11
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 230000004761 fibrosis Effects 0.000 claims description 10
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
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- 210000000232 gallbladder Anatomy 0.000 claims description 9
- 235000020824 obesity Nutrition 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
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- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 230000007882 cirrhosis Effects 0.000 claims description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
- 208000002672 hepatitis B Diseases 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 7
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 7
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 7
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- 208000007536 Thrombosis Diseases 0.000 claims description 7
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 7
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- 231100000359 cholestasis Toxicity 0.000 claims description 7
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- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
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- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 6
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 6
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- AIYJYRUYFLYREU-UHFFFAOYSA-N tert-butyl-[2-(diethoxyphosphorylmethyl)-6-methoxypyridin-3-yl]oxy-diphenylsilane Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OC=1C(=NC(=CC=1)OC)CP(OCC)(OCC)=O AIYJYRUYFLYREU-UHFFFAOYSA-N 0.000 description 1
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- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
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| CN107973790A (zh) | 2016-10-22 | 2018-05-01 | 合帕吉恩治疗公司 | 杂环fxr调节剂 |
| US10597391B2 (en) | 2016-10-26 | 2020-03-24 | Enanta Pharmaceuticals, Inc. | Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof |
| CN108017636A (zh) | 2016-11-04 | 2018-05-11 | 合帕吉恩治疗公司 | 作为fxr调节剂的含氮杂环化合物 |
| CN108218852A (zh) | 2016-12-15 | 2018-06-29 | 宁波百纳西药业有限公司 | 一种螺环化合物、其制备方法、组合物及用途 |
| CN106632294A (zh) | 2016-12-15 | 2017-05-10 | 宁波百纳西药业有限公司 | 一种螺环化合物及其药物用途 |
| WO2018133730A1 (zh) | 2017-01-20 | 2018-07-26 | 四川科伦博泰生物医药股份有限公司 | 一种杂环化合物及其制备方法和用途 |
| CN108341822B (zh) | 2017-01-23 | 2021-04-16 | 广州市恒诺康医药科技有限公司 | Fxr受体调节剂及其制备方法和应用 |
| CN108264506B (zh) | 2018-01-17 | 2021-01-26 | 中国药科大学 | 异黄酮衍生物、其制备方法和医药用途 |
| CN110128432B (zh) * | 2018-02-02 | 2021-03-02 | 广东东阳光药业有限公司 | 含氮三环化合物及其在药物中的应用 |
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2017
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- 2017-08-02 EP EP17836406.3A patent/EP3494118B1/en active Active
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| JP6983225B2 (ja) | 2021-12-17 |
| ES2950412T3 (es) | 2023-10-09 |
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| US20190169203A1 (en) | 2019-06-06 |
| WO2018024224A1 (en) | 2018-02-08 |
| US10562910B2 (en) | 2020-02-18 |
| JP2019524784A (ja) | 2019-09-05 |
| EP3494118B1 (en) | 2023-06-21 |
| TW201808283A (zh) | 2018-03-16 |
| CN107686486B (zh) | 2020-12-22 |
| EP3494118A4 (en) | 2020-02-26 |
| CA3030377A1 (en) | 2018-02-08 |
| EP3494118A1 (en) | 2019-06-12 |
| AR109295A1 (es) | 2018-11-14 |
| AU2017306605B2 (en) | 2021-08-05 |
| AU2017306605A1 (en) | 2019-02-14 |
| CN107686486A (zh) | 2018-02-13 |
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