EA027147B1 - Ингибиторы c-концевого домена hsp90 - Google Patents
Ингибиторы c-концевого домена hsp90 Download PDFInfo
- Publication number
- EA027147B1 EA027147B1 EA201491496A EA201491496A EA027147B1 EA 027147 B1 EA027147 B1 EA 027147B1 EA 201491496 A EA201491496 A EA 201491496A EA 201491496 A EA201491496 A EA 201491496A EA 027147 B1 EA027147 B1 EA 027147B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- acetamide
- biphenyl
- oxy
- methoxy
- ethyl
- Prior art date
Links
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 23
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 305
- 229910052739 hydrogen Inorganic materials 0.000 claims description 114
- 239000001257 hydrogen Substances 0.000 claims description 106
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 86
- 150000002431 hydrogen Chemical class 0.000 claims description 80
- -1 C 1 -C 6 atoms Chemical compound 0.000 claims description 79
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 57
- 125000002837 carbocyclic group Chemical group 0.000 claims description 56
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 43
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- 239000008103 glucose Substances 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
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- 125000004429 atom Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 230000000324 neuroprotective effect Effects 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
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- 231100000419 toxicity Toxicity 0.000 claims description 18
- 230000001988 toxicity Effects 0.000 claims description 18
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 17
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- 125000005842 heteroatom Chemical group 0.000 claims description 15
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- 208000024891 symptom Diseases 0.000 claims description 10
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- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- VBMJHAAMTRDGAN-UHFFFAOYSA-N n-[2-[2-(3-fluorophenyl)-4-(4-phenylmethoxycyclohexyl)oxyphenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC(CC1)CCC1OCC1=CC=CC=C1 VBMJHAAMTRDGAN-UHFFFAOYSA-N 0.000 claims description 4
- LOGWBHYAVRGPRK-UHFFFAOYSA-N n-[2-[4-(4-tert-butylcyclohexyl)oxy-2-(3-fluorophenyl)phenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC1CCC(C(C)(C)C)CC1 LOGWBHYAVRGPRK-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- XAWGNQVOGSWZJO-UHFFFAOYSA-N n-[2-[2-(3-fluorophenyl)-4-(4-piperidin-4-ylcyclohexyl)oxyphenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC(CC1)CCC1C1CCNCC1 XAWGNQVOGSWZJO-UHFFFAOYSA-N 0.000 claims 2
- JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 claims 1
- 150000002829 nitrogen Chemical class 0.000 claims 1
- 210000004899 c-terminal region Anatomy 0.000 abstract description 9
- 239000003112 inhibitor Substances 0.000 abstract description 9
- 230000002265 prevention Effects 0.000 abstract description 6
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- 125000003710 aryl alkyl group Chemical group 0.000 description 22
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- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
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- 229920006395 saturated elastomer Polymers 0.000 description 19
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- 239000011734 sodium Chemical class 0.000 description 14
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Classifications
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
- C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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- C07C2601/00—Systems containing only non-condensed rings
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- C07C2601/14—The ring being saturated
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| RS59719B1 (sr) | 2012-02-09 | 2020-01-31 | Univ Kansas | C-terminalni inhibitori hsp90 |
| US9994556B2 (en) | 2014-06-13 | 2018-06-12 | University Of Kansas | Triazole modified coumarin and biphenyl amide-based HSP90 inhibitors |
| EA201790070A1 (ru) * | 2014-06-24 | 2017-10-31 | Дзе Юниверсити оф Канзас | Бифениламиды, содержащие модифицированные простые эфирные группы, в качестве ингибиторов hsp90 и стимуляторов hsp70 |
| WO2016145219A1 (en) * | 2015-03-10 | 2016-09-15 | University Of Florida Research Foundation, Inc. | Treatment of peripheral neuropathies |
| US20210036245A1 (en) * | 2017-12-20 | 2021-02-04 | Merck Patent Gmbh | Heteroaromatic compounds |
| EP3749675B1 (en) * | 2018-02-07 | 2025-12-31 | Reata Pharmaceuticals, Inc. | CO-CRISTALLIN FORMS OF A NOVOBIOCIN AND PROLINE ANALOGUE |
| EA202092727A1 (ru) * | 2018-05-14 | 2021-04-20 | Рита Фармасьютикалз, Инк. | Биариламиды с модифицированными сахарными группами для лечения заболеваний, связанных с путем белка теплового шока |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US20250049810A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| TW202530228A (zh) | 2023-10-12 | 2025-08-01 | 美商銳新醫藥公司 | Ｒａｓ抑制劑 |
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| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
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| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
Citations (1)
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| US20100105630A1 (en) * | 2007-05-10 | 2010-04-29 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
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| US8212011B2 (en) | 2004-11-03 | 2012-07-03 | University Of Kansas | Novobiocin analogues |
| US8212012B2 (en) | 2004-11-03 | 2012-07-03 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
| US7622451B2 (en) | 2004-11-03 | 2009-11-24 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
| US9120774B2 (en) | 2004-11-03 | 2015-09-01 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
| CA2585091C (en) | 2004-11-03 | 2016-07-19 | University Of Kansas | Novobiocin analogues as anticancer agents |
| WO2007095586A2 (en) * | 2006-02-14 | 2007-08-23 | The Trustees Of Columbia University In The City Of New York | Neuronal pain pathway modulators |
| GB0620259D0 (en) * | 2006-10-12 | 2006-11-22 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| EP2131656A4 (en) | 2006-11-15 | 2011-12-07 | Forest Lab Holdings Ltd | phthalazine |
| NZ579635A (en) | 2007-03-20 | 2011-07-29 | Curis Inc | Fused amino pyridine as hsp90 inhibitors |
| JP5766617B2 (ja) * | 2009-02-20 | 2015-08-19 | ユニバーシティ・オブ・カンザス | 修飾された糖部分を有するノボビオシン類似体 |
| WO2011041593A1 (en) | 2009-09-30 | 2011-04-07 | University Of Kansas | Novobiocin analogues and treatment of polycystic kidney disease |
| US20130116227A1 (en) | 2010-07-13 | 2013-05-09 | Dainippon Sumitomo Pharma Co., Ltd. | Biaryl amide derivative or pharmaceutically acceptable salt thereof |
| CN101967125B (zh) * | 2010-10-08 | 2012-07-04 | 广州暨南生物医药研究开发基地有限公司 | 一种Hsp90抑制剂Xbj-B16-1及其制备方法与应用 |
| EA024647B1 (ru) | 2011-04-05 | 2016-10-31 | Слоун-Кеттеринг Инститьют Фо Кэнсэ Рисерч | ИНГИБИТОРЫ Hsp90 |
| US9056104B2 (en) | 2011-05-20 | 2015-06-16 | The University Of Kansas | Dynamic inhibitors of heat shock protein 90 |
| RS59719B1 (sr) | 2012-02-09 | 2020-01-31 | Univ Kansas | C-terminalni inhibitori hsp90 |
| EP3066072B1 (en) | 2013-11-07 | 2021-11-03 | The University of Kansas | Biphenylamide derivative hsp90 inhibitors |
| EP4585267A3 (en) | 2013-11-11 | 2025-10-22 | The University of Kansas | Coumarin based hsp90 inhibitors with urea and ether substituents |
| US9994556B2 (en) | 2014-06-13 | 2018-06-12 | University Of Kansas | Triazole modified coumarin and biphenyl amide-based HSP90 inhibitors |
| EA201790070A1 (ru) | 2014-06-24 | 2017-10-31 | Дзе Юниверсити оф Канзас | Бифениламиды, содержащие модифицированные простые эфирные группы, в качестве ингибиторов hsp90 и стимуляторов hsp70 |
| EA202092727A1 (ru) | 2018-05-14 | 2021-04-20 | Рита Фармасьютикалз, Инк. | Биариламиды с модифицированными сахарными группами для лечения заболеваний, связанных с путем белка теплового шока |
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Patent Citations (1)
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| US20100105630A1 (en) * | 2007-05-10 | 2010-04-29 | University Of Kansas | Novobiocin analogues as neuroprotective agents and in the treatment of autoimmune disorders |
Non-Patent Citations (1)
| Title |
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| JOSEPH A. BURLISON, LEN NECKERS, ANDREW B. SMITH, ANTHONY MAXWELL, BRIAN S. J. BLAGG: "Novobiocin: Redesigning a DNA Gyrase Inhibitor for Selective Inhibition of Hsp90", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ¬AMERICAN CHEMICAL SOCIETY|, vol. 128, no. 48, 1 December 2006 (2006-12-01), pages 15529 - 15536, XP055057623, ISSN: 00027863, DOI: 10.1021/ja065793p * |
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