TWI448286B - 新穎經取代的異喹啉及異喹啉酮衍生物 - Google Patents
新穎經取代的異喹啉及異喹啉酮衍生物 Download PDFInfo
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- TWI448286B TWI448286B TW096149802A TW96149802A TWI448286B TW I448286 B TWI448286 B TW I448286B TW 096149802 A TW096149802 A TW 096149802A TW 96149802 A TW96149802 A TW 96149802A TW I448286 B TWI448286 B TW I448286B
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- Prior art keywords
- alkyl
- aryl
- isoquinolin
- group
- compound according
- Prior art date
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- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 4
- 150000002537 isoquinolines Chemical class 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 324
- -1 cyclic amine Chemical class 0.000 claims description 160
- 150000001875 compounds Chemical class 0.000 claims description 136
- 125000000623 heterocyclic group Chemical group 0.000 claims description 104
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 67
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 36
- 125000002947 alkylene group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
- 206010020772 Hypertension Diseases 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 14
- 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims description 13
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 206010012601 diabetes mellitus Diseases 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 208000017169 kidney disease Diseases 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- 230000002093 peripheral effect Effects 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- BUHFDWONDZTSJT-ZIAGYGMSSA-N (2r,4r)-4-isoquinolin-6-yloxypiperidine-2-carboxylic acid Chemical compound C1CN[C@@H](C(=O)O)C[C@@H]1OC1=CC=C(C=NC=C2)C2=C1 BUHFDWONDZTSJT-ZIAGYGMSSA-N 0.000 claims description 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 4
- XYIUOCBWFKQPAV-UHFFFAOYSA-N 6-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C=2C1=CC(OC1CC3CCC(C1)N3C)=CC=2 XYIUOCBWFKQPAV-UHFFFAOYSA-N 0.000 claims description 4
- CTXLQMLJRIRHQY-UHFFFAOYSA-N 6-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]isoquinoline Chemical compound C1=NC=CC2=CC(OC3CC4CCC(C3)N4C)=CC=C21 CTXLQMLJRIRHQY-UHFFFAOYSA-N 0.000 claims description 4
- 208000030507 AIDS Diseases 0.000 claims description 4
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- 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 4
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- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 208000020431 spinal cord injury Diseases 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- WCSAMSWJHGFSQO-STQMWFEESA-N (2s,4s)-4-(isoquinolin-6-ylamino)pyrrolidine-2-carboxylic acid Chemical compound C1N[C@H](C(=O)O)C[C@@H]1NC1=CC=C(C=NC=C2)C2=C1 WCSAMSWJHGFSQO-STQMWFEESA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- ALNAIIYZPJKIJQ-UHFFFAOYSA-N 6-(1-benzyl-4-phenylpiperidin-4-yl)oxy-7-chloro-2h-isoquinolin-1-one Chemical compound ClC1=CC(C(NC=C2)=O)=C2C=C1OC(CC1)(C=2C=CC=CC=2)CCN1CC1=CC=CC=C1 ALNAIIYZPJKIJQ-UHFFFAOYSA-N 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
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- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010019663 Hepatic failure Diseases 0.000 claims description 3
- 206010020880 Hypertrophy Diseases 0.000 claims description 3
- GKBVXSRKTQNEPR-UHFFFAOYSA-N N-[(2-chlorophenyl)methyl]decan-1-amine Chemical compound CCCCCCCCCCNCC1=CC=CC=C1Cl GKBVXSRKTQNEPR-UHFFFAOYSA-N 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 208000027418 Wounds and injury Diseases 0.000 claims description 3
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
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- 208000028867 ischemia Diseases 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 208000007903 liver failure Diseases 0.000 claims description 3
- 231100000835 liver failure Toxicity 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 230000002269 spontaneous effect Effects 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- RBVAGQYJYWZJSR-ZIAGYGMSSA-N (2r,4r)-4-isoquinolin-6-yloxypiperidine-1,2-dicarboxylic acid Chemical compound C1CN(C(O)=O)[C@@H](C(=O)O)C[C@@H]1OC1=CC=C(C=NC=C2)C2=C1 RBVAGQYJYWZJSR-ZIAGYGMSSA-N 0.000 claims description 2
- REKLFQPYFQJVTN-STQMWFEESA-N (3s,4r)-4-(isoquinolin-6-ylamino)pyrrolidine-3-carboxylic acid Chemical compound OC(=O)[C@H]1CNC[C@@H]1NC1=CC=C(C=NC=C2)C2=C1 REKLFQPYFQJVTN-STQMWFEESA-N 0.000 claims description 2
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- DNPWKVSENNHELW-UHFFFAOYSA-N 6-(8-azabicyclo[3.2.1]octan-3-yloxy)-7-chloro-2h-isoquinolin-1-one Chemical compound C1C(N2)CCC2CC1OC1=CC(C=CNC2=O)=C2C=C1Cl DNPWKVSENNHELW-UHFFFAOYSA-N 0.000 claims description 2
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- KUFNJRMPMVBECI-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)decan-1-amine Chemical compound CCCCCCCCCCNCC1=CC=CC=N1 KUFNJRMPMVBECI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 33
- ITVWSBJAXNKGRU-OLZOCXBDSA-N (2s,4r)-4-isoquinolin-6-yloxypyrrolidine-2-carboxylic acid Chemical compound C1N[C@H](C(=O)O)C[C@H]1OC1=CC=C(C=NC=C2)C2=C1 ITVWSBJAXNKGRU-OLZOCXBDSA-N 0.000 claims 1
- KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-N 0.000 claims 1
- GIVZDHHJVIFNCR-UHFFFAOYSA-N 7-chloro-6-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2h-isoquinolin-1-one Chemical compound C1=CNC(=O)C(C=C2Cl)=C1C=C2OC(C1)CC2CCC1N2C GIVZDHHJVIFNCR-UHFFFAOYSA-N 0.000 claims 1
- UDJJFIWNQGRINB-UHFFFAOYSA-N CCCCCCCCCCNCCC1=CC=CC=C1 Chemical compound CCCCCCCCCCNCCC1=CC=CC=C1 UDJJFIWNQGRINB-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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| EP1899322B1 (en) | 2005-06-28 | 2009-09-02 | Sanofi-Aventis | Isoquinoline derivatives as inhibitors of rho-kinase |
| EP1910297B1 (en) | 2005-07-11 | 2016-05-25 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds |
| RU2440988C2 (ru) | 2005-07-26 | 2012-01-27 | Санофи-Авентис | ПРОИЗВОДНЫЕ ЦИКЛОГЕКСИЛАМИНИЗОХИНОЛОНА В КАЧЕСТВЕ ИНГИБИТОРОВ Rho-КИНАЗЫ |
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| WO2008036540A2 (en) | 2006-09-20 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
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| CN101616909B (zh) | 2006-12-27 | 2013-09-11 | 塞诺菲-安万特股份有限公司 | 作为Rho-激酶抑制剂的被取代的异喹啉和异喹啉酮衍生物 |
| JP5405315B2 (ja) | 2006-12-27 | 2014-02-05 | サノフイ | 置換イソキノリン及びイソキノリノン誘導体 |
| MX2009005862A (es) | 2006-12-27 | 2009-06-17 | Sanofi Aventis | Nuevos derivados de isoquinolina e isoquinolinona sustituidos. |
| RU2457203C2 (ru) | 2006-12-27 | 2012-07-27 | Санофи-Авентис | Замещенные циклоалкиламином производные изохинолона |
| KR20090092303A (ko) | 2006-12-27 | 2009-08-31 | 사노피-아벤티스 | 사이클로알킬아민 치환된 이소퀴놀린 유도체 |
| US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
| US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
| AU2009262509B2 (en) * | 2008-06-24 | 2014-01-30 | Sanofi | Bi-and polycyclic substituted isoquinoline and isoquinoline derivatives as Rho kinase inhibitors |
| BRPI0914696A2 (pt) | 2008-06-24 | 2016-10-18 | Sanofi Aventis | isoquinolinas e isoquinolinonas substituídas como inibidores da rho-quinase |
| KR101607090B1 (ko) | 2008-06-24 | 2016-03-29 | 사노피 | 6-치환된 이소퀴놀린 및 이소퀴놀리논 |
| US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
| CA2740783A1 (en) * | 2008-10-17 | 2010-04-22 | Exelixis, Inc. | Sphingosine-1-phosphate receptor antagonists |
| EP3053913B1 (en) | 2009-05-01 | 2018-03-07 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
| US8841289B2 (en) | 2009-10-13 | 2014-09-23 | Merck Sharp & Dohme B.V. | Heterocyclic derivatives |
| JP6357100B2 (ja) * | 2011-07-08 | 2018-07-11 | サノフイ | ６−（ピペリジン−４−イルオキシ）−２ｈ−イソキノリン−１−オン塩酸塩の結晶性溶媒和物 |
| CN102993178A (zh) * | 2012-12-04 | 2013-03-27 | 天津红日药业股份有限公司 | 具有Rho激酶抑制活性的异喹啉类化合物、制备方法及用途 |
| US9663524B2 (en) * | 2013-03-15 | 2017-05-30 | Celgene Car Llc | Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors |
| AR095464A1 (es) | 2013-03-15 | 2015-10-21 | Celgene Avilomics Res Inc | Compuestos de heteroarilo y usos de los mismos |
| CA2905089C (en) | 2013-03-15 | 2023-06-13 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds for the treatment of ocular diseases |
| EP3943087A1 (en) * | 2013-03-15 | 2022-01-26 | Celgene CAR LLC | Heteroaryl compounds and uses thereof |
| CN105940103B (zh) | 2014-01-31 | 2021-06-15 | 株式会社Api | 哌可酸4位羟化酶和利用该酶的4-羟基氨基酸的制造法 |
| FR3017868A1 (fr) | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CN116396991A (zh) | 2015-10-02 | 2023-07-07 | 株式会社Api | 羟基-l-哌可酸的制造方法 |
| WO2017086941A1 (en) | 2015-11-17 | 2017-05-26 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| KR102568079B1 (ko) | 2016-08-31 | 2023-08-17 | 에어리 파마슈티컬즈, 인코포레이티드 | 안과용 조성물 |
| AU2018243687C1 (en) | 2017-03-31 | 2020-12-24 | Alcon Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
| EP3849555A4 (en) | 2018-09-14 | 2022-05-04 | Aerie Pharmaceuticals, Inc. | Aryl cyclopropyl-amino-isoquinolinyl amide compounds |
| KR102889687B1 (ko) * | 2020-11-03 | 2025-11-21 | 주식회사 엘지화학 | 작물보호제용 신규 화합물 |
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| EP1550660A1 (en) * | 2002-09-12 | 2005-07-06 | Kirin Beer Kabushiki Kaisha | Isoquinoline derivatives having kinasae inhibitory activity and drugs containing the same |
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| RU2440988C2 (ru) | 2005-07-26 | 2012-01-27 | Санофи-Авентис | ПРОИЗВОДНЫЕ ЦИКЛОГЕКСИЛАМИНИЗОХИНОЛОНА В КАЧЕСТВЕ ИНГИБИТОРОВ Rho-КИНАЗЫ |
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| US7893088B2 (en) | 2006-08-18 | 2011-02-22 | N.V. Organon | 6-substituted isoquinoline derivatives |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1550660A1 (en) * | 2002-09-12 | 2005-07-06 | Kirin Beer Kabushiki Kaisha | Isoquinoline derivatives having kinasae inhibitory activity and drugs containing the same |
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