KR102644889B1 - Rock 억제제로서의 스피로헵타닐 히단토인 - Google Patents
Rock 억제제로서의 스피로헵타닐 히단토인 Download PDFInfo
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- KR102644889B1 KR102644889B1 KR1020207003731A KR20207003731A KR102644889B1 KR 102644889 B1 KR102644889 B1 KR 102644889B1 KR 1020207003731 A KR1020207003731 A KR 1020207003731A KR 20207003731 A KR20207003731 A KR 20207003731A KR 102644889 B1 KR102644889 B1 KR 102644889B1
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- KR
- South Korea
- Prior art keywords
- alkyl
- oxy
- spiro
- heptan
- heterocycle
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- 239000011435 rock Substances 0.000 title abstract description 44
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- 229940091173 hydantoin Drugs 0.000 title description 12
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 453
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 126
- 125000000623 heterocyclic group Chemical group 0.000 claims description 117
- -1 carbocycle Chemical group 0.000 claims description 110
- 125000003545 alkoxy group Chemical group 0.000 claims description 103
- 125000003003 spiro group Chemical group 0.000 claims description 93
- 229910052799 carbon Inorganic materials 0.000 claims description 85
- 235000005152 nicotinamide Nutrition 0.000 claims description 72
- 239000011570 nicotinamide Substances 0.000 claims description 72
- 125000003342 alkenyl group Chemical group 0.000 claims description 65
- 229910052736 halogen Inorganic materials 0.000 claims description 62
- 150000002367 halogens Chemical class 0.000 claims description 62
- 229910052760 oxygen Inorganic materials 0.000 claims description 57
- 125000000304 alkynyl group Chemical group 0.000 claims description 54
- 229960003966 nicotinamide Drugs 0.000 claims description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 150000001721 carbon Chemical group 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 27
- 229910004013 NO 2 Inorganic materials 0.000 claims description 20
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 8
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 2
- YCQSLEISUONEGC-UHFFFAOYSA-N C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCC(F)(F)F Chemical compound C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCC(F)(F)F YCQSLEISUONEGC-UHFFFAOYSA-N 0.000 claims 2
- YNLHATFZTJHOOW-UHFFFAOYSA-N C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCCC(F)(F)F Chemical compound C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCCC(F)(F)F YNLHATFZTJHOOW-UHFFFAOYSA-N 0.000 claims 2
- UBYOZYKBKOAYNT-UHFFFAOYSA-N C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCOC(F)(F)F Chemical compound C1C(CC12CC(C2)OC3=C(C=CC=N3)C(=O)N)N4C(=O)C(NC4=O)CCOC(F)(F)F UBYOZYKBKOAYNT-UHFFFAOYSA-N 0.000 claims 2
- FKKWJFLPINUYLI-UHFFFAOYSA-N C1CCCC(CC1)CCC2C(=O)N(C(=O)N2)C3CC4(C3)CC(C4)OC5=C(C=CC=N5)C(=O)N Chemical compound C1CCCC(CC1)CCC2C(=O)N(C(=O)N2)C3CC4(C3)CC(C4)OC5=C(C=CC=N5)C(=O)N FKKWJFLPINUYLI-UHFFFAOYSA-N 0.000 claims 2
- 125000004282 imidazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])N([H])C1([H])* 0.000 claims 2
- KNLPVTUQSKJODM-UHFFFAOYSA-N C#CCC1C(=O)N(C(=O)N1)C2CC3(C2)CC(C3)OC4=C(C=CC=N4)C(=O)N Chemical compound C#CCC1C(=O)N(C(=O)N1)C2CC3(C2)CC(C3)OC4=C(C=CC=N4)C(=O)N KNLPVTUQSKJODM-UHFFFAOYSA-N 0.000 claims 1
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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
- C07D401/12—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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
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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
-
- 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
- C07D401/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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
- C07D487/04—Ortho-condensed systems
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201762531604P | 2017-07-12 | 2017-07-12 | |
| US62/531,604 | 2017-07-12 | ||
| PCT/US2018/041563 WO2019014304A1 (en) | 2017-07-12 | 2018-07-11 | SPIROHEPTANYL HYDANTOIDS AS ROCK INHIBITORS |
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| KR20200027990A KR20200027990A (ko) | 2020-03-13 |
| KR102644889B1 true KR102644889B1 (ko) | 2024-03-06 |
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| ES2821877T3 (es) | 2016-07-07 | 2021-04-28 | Bristol Myers Squibb Co | Espirolactamas como inhibidores de ROCK |
| KR102511441B1 (ko) | 2016-11-30 | 2023-03-16 | 브리스톨-마이어스 스큅 컴퍼니 | 트리시클릭 Rho 키나제 억제제 |
| TW201908293A (zh) | 2017-07-12 | 2019-03-01 | 美商必治妥美雅史谷比公司 | 作為rock抑制劑之5員及雙環雜環醯胺 |
| JP7206253B2 (ja) | 2017-07-12 | 2023-01-17 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｏｃｋ阻害剤としてのフェニルアセトアミド |
| US12060341B2 (en) * | 2017-07-12 | 2024-08-13 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as ROCK inhibitors |
| KR102680160B1 (ko) | 2017-07-12 | 2024-06-28 | 브리스톨-마이어스 스큅 컴퍼니 | 심부전의 치료를 위한 rock의 5원-아미노헤테로사이클 및 5,6- 또는 6,6-원 비시클릭 아미노헤테로시클릭 억제제 |
| WO2019089868A1 (en) | 2017-11-03 | 2019-05-09 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
| AU2019377087B2 (en) | 2018-11-06 | 2025-03-06 | Cervello Therapeutics, Llc | Rock kinase inhibitors |
| US11248004B2 (en) | 2018-11-06 | 2022-02-15 | Cervello Therapeutics, Llc. | Substituted isoquinolines as rock kinase inhibitors |
| TW202122382A (zh) * | 2019-09-06 | 2021-06-16 | 日商小野藥品工業股份有限公司 | 乙內醯脲衍生物 |
| WO2023085369A1 (ja) | 2021-11-11 | 2023-05-19 | 学校法人同志社 | 角膜内皮細胞の凍結保存製剤およびその製造法 |
| TW202508595A (zh) | 2023-05-04 | 2025-03-01 | 美商銳新醫藥公司 | 用於ｒａｓ相關疾病或病症之組合療法 |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025150038A1 (en) * | 2024-01-09 | 2025-07-17 | Adama Makhteshim Ltd. | A method for separation of cis and trans isomers of hydantoin-containing spiro-compound from an isomeric mixture |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025240847A1 (en) | 2024-05-17 | 2025-11-20 | Revolution Medicines, Inc. | Ras inhibitors |
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| WO2017123860A1 (en) | 2016-01-13 | 2017-07-20 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
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| CA2653424A1 (en) | 2006-06-08 | 2007-12-13 | Ube Industries, Ltd. | Novel indazole derivative having spiro ring structure in side chain |
| CA2664335C (en) | 2006-09-20 | 2014-12-02 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
| RU2457203C2 (ru) * | 2006-12-27 | 2012-07-27 | Санофи-Авентис | Замещенные циклоалкиламином производные изохинолона |
| CL2007003874A1 (es) | 2007-01-03 | 2008-05-16 | Boehringer Ingelheim Int | Compuestos derivados de benzamida; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar enfermedades cardiovasculares, hipertension, aterosclerosis, reestenosis, ictus, insuficiencia cardiaca, lesion isquemica, hipertensio |
| UY33726A (es) | 2010-11-15 | 2012-06-29 | Abbott Lab | Inhibidores de nampt y rock |
| CA2898440A1 (en) | 2013-01-18 | 2014-07-24 | Bristol-Myers Squibb Company | Phthalazinones and isoquinolinones as rock inhibitors |
| AR094929A1 (es) | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2 |
| JP6423372B2 (ja) | 2013-02-28 | 2018-11-14 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 強力なｒｏｃｋ１およびｒｏｃｋ２阻害剤としてのフェニルピラゾール誘導体 |
| EP3016950B1 (en) | 2013-07-02 | 2017-06-07 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
| CN105492444B (zh) | 2013-07-02 | 2018-09-07 | 百时美施贵宝公司 | 作为rock抑制剂的三环吡啶-甲酰胺衍生物 |
| US9902702B2 (en) * | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
| JP6633618B2 (ja) | 2014-08-21 | 2020-01-22 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 強力なｒｏｃｋ阻害剤としてのタイドバックのベンズアミド誘導体 |
| WO2016112236A1 (en) | 2015-01-09 | 2016-07-14 | Bristol-Myers Squibb Company | Cyclic ureas as inhibitors of rock |
| WO2016144936A1 (en) | 2015-03-09 | 2016-09-15 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
| JP6987792B2 (ja) | 2016-05-27 | 2022-01-05 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Ｒｏｃｋ阻害剤としてのトリアゾロンおよびテトラゾロン |
| ES2821877T3 (es) | 2016-07-07 | 2021-04-28 | Bristol Myers Squibb Co | Espirolactamas como inhibidores de ROCK |
| ES2829550T3 (es) | 2016-07-07 | 2021-06-01 | Bristol Myers Squibb Co | Ureas cíclicas espiro-condensadas como inhibidores de ROCK |
| CN110049977B (zh) | 2016-07-07 | 2022-01-18 | 百时美施贵宝公司 | 作为强效和选择性rock抑制剂的内酰胺、环状脲和氨基甲酸酯及三唑酮衍生物 |
| KR102511441B1 (ko) | 2016-11-30 | 2023-03-16 | 브리스톨-마이어스 스큅 컴퍼니 | 트리시클릭 Rho 키나제 억제제 |
| TW201908293A (zh) | 2017-07-12 | 2019-03-01 | 美商必治妥美雅史谷比公司 | 作為rock抑制劑之5員及雙環雜環醯胺 |
| JP7206253B2 (ja) | 2017-07-12 | 2023-01-17 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｏｃｋ阻害剤としてのフェニルアセトアミド |
| KR102680160B1 (ko) | 2017-07-12 | 2024-06-28 | 브리스톨-마이어스 스큅 컴퍼니 | 심부전의 치료를 위한 rock의 5원-아미노헤테로사이클 및 5,6- 또는 6,6-원 비시클릭 아미노헤테로시클릭 억제제 |
| WO2019089868A1 (en) | 2017-11-03 | 2019-05-09 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
-
2018
- 2018-07-11 JP JP2020501515A patent/JP7313331B2/ja active Active
- 2018-07-11 CN CN201880046379.6A patent/CN110914257B/zh active Active
- 2018-07-11 KR KR1020207003731A patent/KR102644889B1/ko active Active
- 2018-07-11 US US16/629,784 patent/US11447487B2/en active Active
- 2018-07-11 EP EP18752653.8A patent/EP3652167B1/en active Active
- 2018-07-11 WO PCT/US2018/041563 patent/WO2019014304A1/en not_active Ceased
- 2018-07-11 ES ES18752653T patent/ES2878054T3/es active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017123860A1 (en) | 2016-01-13 | 2017-07-20 | Bristol-Myers Squibb Company | Spiroheptane salicylamides and related compounds as inhibitors of rock |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20200027990A (ko) | 2020-03-13 |
| US11447487B2 (en) | 2022-09-20 |
| EP3652167B1 (en) | 2021-06-02 |
| ES2878054T3 (es) | 2021-11-18 |
| JP7313331B2 (ja) | 2023-07-24 |
| CN110914257B (zh) | 2023-05-26 |
| US20210155618A1 (en) | 2021-05-27 |
| JP2020526565A (ja) | 2020-08-31 |
| EP3652167A1 (en) | 2020-05-20 |
| WO2019014304A1 (en) | 2019-01-17 |
| CN110914257A (zh) | 2020-03-24 |
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