EA030481B1 - Ингибиторы аргининметилтрансферазы и их применения - Google Patents
Ингибиторы аргининметилтрансферазы и их применения Download PDFInfo
- Publication number
- EA030481B1 EA030481B1 EA201591531A EA201591531A EA030481B1 EA 030481 B1 EA030481 B1 EA 030481B1 EA 201591531 A EA201591531 A EA 201591531A EA 201591531 A EA201591531 A EA 201591531A EA 030481 B1 EA030481 B1 EA 030481B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- methyl
- mmol
- compound according
- ethyl
- compound
- Prior art date
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- 101000757232 Homo sapiens Protein arginine N-methyltransferase 2 Proteins 0.000 title claims abstract 9
- 102000046485 human PRMT2 Human genes 0.000 title claims abstract 9
- 239000003697 methyltransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 238000000034 method Methods 0.000 claims abstract description 93
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 230000001404 mediated effect Effects 0.000 claims abstract 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract 2
- -1 alkenyl alkynyl Chemical group 0.000 claims description 295
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 254
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 88
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 70
- 229910052757 nitrogen Inorganic materials 0.000 claims description 47
- 101000796142 Homo sapiens Protein arginine N-methyltransferase 8 Proteins 0.000 claims description 36
- 101000924541 Homo sapiens Protein arginine N-methyltransferase 3 Proteins 0.000 claims description 35
- 102100031365 Protein arginine N-methyltransferase 8 Human genes 0.000 claims description 35
- 102100034603 Protein arginine N-methyltransferase 3 Human genes 0.000 claims description 34
- 101000757216 Homo sapiens Protein arginine N-methyltransferase 1 Proteins 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 102100022985 Protein arginine N-methyltransferase 1 Human genes 0.000 claims description 30
- 101000775582 Homo sapiens Protein arginine N-methyltransferase 6 Proteins 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 102100032140 Protein arginine N-methyltransferase 6 Human genes 0.000 claims description 28
- 102100025210 Histone-arginine methyltransferase CARM1 Human genes 0.000 claims description 27
- 108010030886 coactivator-associated arginine methyltransferase 1 Proteins 0.000 claims description 27
- 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 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 230000014509 gene expression Effects 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims 26
- 125000000623 heterocyclic group Chemical group 0.000 claims 21
- 125000001072 heteroaryl group Chemical group 0.000 claims 16
- 125000003342 alkenyl group Chemical group 0.000 claims 14
- 125000003118 aryl group Chemical group 0.000 claims 12
- 125000004452 carbocyclyl group Chemical group 0.000 claims 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 10
- 208000035475 disorder Diseases 0.000 claims 10
- 125000000304 alkynyl group Chemical group 0.000 claims 8
- 239000002671 adjuvant Substances 0.000 claims 7
- 230000001028 anti-proliverative effect Effects 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 6
- 125000005842 heteroatom Chemical group 0.000 claims 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 206010028980 Neoplasm Diseases 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 208000032839 leukemia Diseases 0.000 claims 2
- 125000002950 monocyclic group Chemical group 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Chemical group 0.000 claims 2
- IBBLRJGOOANPTQ-JKVLGAQCSA-N quinapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 IBBLRJGOOANPTQ-JKVLGAQCSA-N 0.000 claims 2
- 125000003107 substituted aryl group Chemical group 0.000 claims 2
- 229910052717 sulfur Chemical group 0.000 claims 2
- 239000011593 sulfur Chemical group 0.000 claims 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 1
- 206010059245 Angiopathy Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 125000006193 alkinyl group Chemical group 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 125000002619 bicyclic group Chemical group 0.000 claims 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 208000030159 metabolic disease Diseases 0.000 claims 1
- 201000006938 muscular dystrophy Diseases 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 150000003053 piperidines Chemical class 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 7
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- 235000019439 ethyl acetate Nutrition 0.000 description 130
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 130
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 125
- 239000000203 mixture Substances 0.000 description 120
- 238000005481 NMR spectroscopy Methods 0.000 description 115
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 86
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 85
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 77
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 63
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 61
- 239000012044 organic layer Substances 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 58
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
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- 238000006243 chemical reaction Methods 0.000 description 36
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Classifications
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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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- 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
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- 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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- C07D405/02—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 two hetero rings
- C07D405/08—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 two hetero rings linked by a carbon chain containing alicyclic rings
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
Landscapes
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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| CA2894157A1 (en) | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| WO2014100716A1 (en) | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| JP2016505000A (ja) | 2012-12-21 | 2016-02-18 | エピザイム,インコーポレイティド | Prmt5阻害剤およびその使用 |
| JP2016505002A (ja) | 2012-12-21 | 2016-02-18 | エピザイム,インコーポレイティド | ジヒドロイソキノリンまたはテトラヒドロイソキノリンを含有するprmt5阻害剤およびその使用 |
| US9120757B2 (en) | 2013-03-14 | 2015-09-01 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| EP2970134B1 (en) | 2013-03-14 | 2018-02-28 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| SG11201506972PA (en) * | 2013-03-14 | 2015-10-29 | Epizyme Inc | Arginine methyltransferase inhibitors and uses thereof |
| WO2014153208A1 (en) | 2013-03-14 | 2014-09-25 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| EP2970136A1 (en) | 2013-03-14 | 2016-01-20 | Epizyme, Inc. | Arginine methyl transferase inhibtors and uses thereof |
| US9394258B2 (en) | 2013-03-14 | 2016-07-19 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| EP2970133B1 (en) | 2013-03-14 | 2018-10-24 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| AU2014260433A1 (en) | 2013-03-14 | 2015-09-10 | Epizyme, Inc. | Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof |
| WO2014144659A1 (en) | 2013-03-14 | 2014-09-18 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
| US20160031839A1 (en) | 2013-03-14 | 2016-02-04 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
| EP2970266B1 (en) | 2013-03-15 | 2018-01-31 | Epizyme, Inc. | 1-phenoxy-3-(alkylamino)-propan-2-ol derivatives as carm1 inhibitors and uses thereof |
| KR20160003647A (ko) | 2013-03-15 | 2016-01-11 | 에피자임, 인코포레이티드 | Carm1 억제제 및 이의 용도 |
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| CA2953572A1 (en) | 2014-08-04 | 2016-02-11 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| WO2016044576A1 (en) * | 2014-09-17 | 2016-03-24 | Epizyme, Inc. | Salts, co-crystals, amorphous forms, and crystalline forms of an arginine methyltransferase inhibitor |
| AU2017367300A1 (en) | 2016-12-01 | 2019-06-13 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
| CN110225983A (zh) * | 2016-12-01 | 2019-09-10 | 葛兰素史密斯克莱知识产权发展有限公司 | 治疗癌症的方法 |
| US20190343803A1 (en) * | 2016-12-01 | 2019-11-14 | Glaxosmithkline Intellectual Property Development Limited | Combination therapy |
| CA3092579A1 (en) | 2018-03-01 | 2019-09-06 | Board Of Regents, The University Of Texas System | Ethanediamine-heterocycle derivatives as inhibitors of protein arginine methyltransferases |
| BR112020023459A2 (pt) * | 2018-05-31 | 2021-02-23 | Glaxosmithkline Intellectual Property Development Limited | terapia combinada com proteínas de ligação a icos e inibidores de arginina metiltransferase |
| WO2020182018A1 (zh) * | 2019-03-12 | 2020-09-17 | 四川科伦博泰生物医药股份有限公司 | 氮杂环化合物、其制备方法及用途 |
| IL318073A (en) * | 2019-03-25 | 2025-02-01 | California Inst Of Techn | PRMT5 inhibitors and their uses |
| WO2021023609A1 (en) * | 2019-08-02 | 2021-02-11 | Glaxosmithkline Intellectual Property Development Limited | Combination of a type i protein arginine methyltransferase (type i prmt) inhibitor and a methionine adenosyltransferase ii alpha (mat2a) inhibitor |
| CN110950841A (zh) * | 2019-11-22 | 2020-04-03 | 济南大学 | 一类新型三唑类化合物的合成及应用 |
| KR102219251B1 (ko) | 2020-03-03 | 2021-02-22 | 김명수 | 전문가 추천 플랫폼을 제공하는 서버 및 그 운용방법 |
| CN111481532B (zh) * | 2020-06-28 | 2020-09-22 | 南京中澳转化医学研究院有限公司 | 化合物28d在制备提高γ-珠蛋白表达量的药物中的应用 |
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| WO2008008286A2 (en) * | 2006-07-12 | 2008-01-17 | Merck & Co., Inc. | Substituted pyrazoles as ghrelin receptor antagonists |
| WO2008104077A1 (en) * | 2007-02-28 | 2008-09-04 | Methylgene Inc. | Small molecule inhibitors of protein arginine methyltransferases (prmts) |
| WO2010094609A1 (de) * | 2009-02-20 | 2010-08-26 | Albert-Ludwigs-Universität Freiburg | Pharmazeutische zusammensetzung enthaltend hemmstoffe der proteinmethyltransferase i und deren verwendung zur behandlung von tumorerkrankungen |
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| JPH085859B2 (ja) | 1986-07-01 | 1996-01-24 | 日本バイエルアグロケム株式会社 | 新規アルキレンジアミン類 |
| US5204482A (en) | 1988-07-28 | 1993-04-20 | Hoffman-Laroche Inc. | Compounds for treating and preventing cognitive diseases and depression and methods of making same |
| EP0352581A3 (de) | 1988-07-28 | 1990-07-04 | F. Hoffmann-La Roche Ag | Aethylendiaminmonoamid-Derivate |
| JPH11501289A (ja) | 1994-12-02 | 1999-02-02 | 藤沢薬品工業株式会社 | No介在疾患の予防および/または治療のためのペプチド化合物 |
| SE9902765D0 (sv) | 1999-07-21 | 1999-07-21 | Astra Pharma Prod | Novel compounds |
| CN1331326A (zh) * | 2000-06-30 | 2002-01-16 | 上海博德基因开发有限公司 | 一种新的多肽——人精氨酸甲基转移酶(hrmt)32.12和编码这种多肽的多核苷酸 |
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