ES2572908T3 - Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIa - Google Patents
Compuestos de tetrahidroisoquinolina sustituidos como inhibidores del factor XIa Download PDFInfo
- Publication number
- ES2572908T3 ES2572908T3 ES12778912.1T ES12778912T ES2572908T3 ES 2572908 T3 ES2572908 T3 ES 2572908T3 ES 12778912 T ES12778912 T ES 12778912T ES 2572908 T3 ES2572908 T3 ES 2572908T3
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- Prior art keywords
- alkyl
- group
- alkylene
- substituted
- phenyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 55
- 108010080805 Factor XIa Proteins 0.000 title description 36
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 title description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 322
- -1 -OH Chemical group 0.000 claims abstract description 177
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 70
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 63
- 125000005843 halogen group Chemical group 0.000 claims abstract description 61
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 51
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 50
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 48
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 42
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 13
- 229910003813 NRa Inorganic materials 0.000 claims abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 57
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- 238000000034 method Methods 0.000 claims description 49
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
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- 239000008280 blood Substances 0.000 claims description 17
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 15
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
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- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
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- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
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- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 6
- 206010014513 Embolism arterial Diseases 0.000 claims description 6
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical group C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 claims description 6
- 206010063544 Renal embolism Diseases 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 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 6
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- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 2
- 101100439662 Arabidopsis thaliana CHR5 gene Proteins 0.000 claims description 2
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- 150000002473 indoazoles Chemical group 0.000 claims description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N tetrahydroquinoline Natural products C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 45
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- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 187
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 76
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- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
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- 239000012267 brine Substances 0.000 description 47
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 36
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Classifications
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- 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
- C07D401/10—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 linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
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- 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
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- 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
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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| PCT/US2012/059859 WO2013055984A1 (en) | 2011-10-14 | 2012-10-12 | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
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| IN (1) | IN2014CN02806A (en, 2012) |
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| EA023649B1 (ru) | 2011-10-14 | 2016-06-30 | Бристол-Майерс Сквибб Кампани | ЗАМЕЩЕННЫЕ СОЕДИНЕНИЯ ТЕТРАГИДРОИЗОХИНОЛИНА В КАЧЕСТВЕ ИНГИБИТОРОВ ФАКТОРА XIa |
| CN103987697B (zh) | 2011-10-14 | 2017-04-26 | 百时美施贵宝公司 | 作为因子xia抑制剂的取代的四氢异喹啉化合物 |
| CN103987696B (zh) | 2011-10-14 | 2016-12-21 | 百时美施贵宝公司 | 作为因子xia抑制剂的取代的四氢异喹啉化合物 |
| JP6137193B2 (ja) | 2011-12-21 | 2017-05-31 | 小野薬品工業株式会社 | 第ＸＩａ因子阻害剤としての新規ピリジノンおよびピリミジノン誘導体 |
| US20140378474A1 (en) | 2012-01-27 | 2014-12-25 | Novartis Ag | 5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
| WO2013111107A1 (en) | 2012-01-27 | 2013-08-01 | Novartis Ag | Aminopyridine derivatives as plasma kallikrein inhibitors |
| JP2015083542A (ja) | 2012-02-08 | 2015-04-30 | 大日本住友製薬株式会社 | ３位置換プロリン誘導体 |
| CN104684932B (zh) | 2012-05-10 | 2019-03-12 | 拜耳药业股份公司 | 能够结合凝血因子XI和/或其活化形式因子XIa的抗体及其用途 |
| WO2014014050A1 (ja) | 2012-07-19 | 2014-01-23 | 大日本住友製薬株式会社 | １－（シクロアルキルカルボニル）プロリン誘導体 |
| DK2880026T3 (en) | 2012-08-03 | 2017-06-06 | Bristol Myers Squibb Co | DIHYDROPYRIDON-P1 AS A FACTOR XIA INHIBITORS |
| UY34959A (es) | 2012-08-03 | 2014-01-31 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Dihidropiridona p1 como inhibidores del factor xia |
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2012
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- 2012-10-12 IN IN2806CHN2014 patent/IN2014CN02806A/en unknown
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- 2012-10-12 EP EP14195397.6A patent/EP2899183B1/en active Active
- 2012-10-12 EP EP12778912.1A patent/EP2766345B1/en active Active
- 2012-10-12 US US14/350,417 patent/US9108951B2/en active Active
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- 2012-10-12 JP JP2014535894A patent/JP6033317B2/ja not_active Expired - Fee Related
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| US9725435B2 (en) | 2017-08-08 |
| US20180265494A1 (en) | 2018-09-20 |
| ES2699226T3 (es) | 2019-02-08 |
| CN103987697B (zh) | 2017-04-26 |
| JP6033317B2 (ja) | 2016-11-30 |
| US20140275061A1 (en) | 2014-09-18 |
| EP2899183A1 (en) | 2015-07-29 |
| EP2899183B1 (en) | 2018-09-19 |
| US20150315200A1 (en) | 2015-11-05 |
| WO2013055984A1 (en) | 2013-04-18 |
| US9394276B2 (en) | 2016-07-19 |
| US10000466B2 (en) | 2018-06-19 |
| US9108951B2 (en) | 2015-08-18 |
| EP2766345B1 (en) | 2016-03-16 |
| IN2014CN02806A (en, 2012) | 2015-07-03 |
| US20170305880A1 (en) | 2017-10-26 |
| CN103987697A (zh) | 2014-08-13 |
| EP2766345A1 (en) | 2014-08-20 |
| US10906886B2 (en) | 2021-02-02 |
| JP2014528479A (ja) | 2014-10-27 |
| US20160289209A1 (en) | 2016-10-06 |
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