JP6385352B2 - 治療化合物および組成物 - Google Patents
治療化合物および組成物 Download PDFInfo
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- JP6385352B2 JP6385352B2 JP2015536951A JP2015536951A JP6385352B2 JP 6385352 B2 JP6385352 B2 JP 6385352B2 JP 2015536951 A JP2015536951 A JP 2015536951A JP 2015536951 A JP2015536951 A JP 2015536951A JP 6385352 B2 JP6385352 B2 JP 6385352B2
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- Prior art keywords
- alkyl
- phenyl
- aryl
- nmr
- mhz
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- 150000001875 compounds Chemical class 0.000 title claims description 221
- 239000000203 mixture Substances 0.000 title claims description 56
- 230000001225 therapeutic effect Effects 0.000 title description 3
- -1 C 1-6 alkyl-OH Chemical group 0.000 claims description 261
- 125000000217 alkyl group Chemical group 0.000 claims description 167
- 230000035772 mutation Effects 0.000 claims description 78
- 125000003118 aryl group Chemical group 0.000 claims description 74
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 74
- 206010028980 Neoplasm Diseases 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 63
- 201000011510 cancer Diseases 0.000 claims description 55
- 125000001072 heteroaryl group Chemical group 0.000 claims description 48
- 238000011282 treatment Methods 0.000 claims description 41
- 102100037845 Isocitrate dehydrogenase [NADP], mitochondrial Human genes 0.000 claims description 37
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 101000599886 Homo sapiens Isocitrate dehydrogenase [NADP], mitochondrial Proteins 0.000 claims description 35
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 33
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 claims description 32
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 claims description 32
- 229940124597 therapeutic agent Drugs 0.000 claims description 26
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 25
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 23
- 102000004190 Enzymes Human genes 0.000 claims description 23
- 108090000790 Enzymes Proteins 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 claims description 19
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
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- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims description 16
- 230000001419 dependent effect Effects 0.000 claims description 16
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical compound OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 claims description 14
- 230000009467 reduction Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
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- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
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- 125000004104 aryloxy group Chemical group 0.000 claims description 6
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
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- 125000001475 halogen functional group Chemical group 0.000 claims 6
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 282
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 221
- 238000000034 method Methods 0.000 description 149
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
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- 239000011734 sodium Substances 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 39
- 125000005843 halogen group Chemical group 0.000 description 36
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- 239000000243 solution Substances 0.000 description 34
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- 229940088598 enzyme Drugs 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 101100441092 Danio rerio crlf3 gene Proteins 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 15
- 125000001309 chloro group Chemical group Cl* 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 14
- 125000001153 fluoro group Chemical group F* 0.000 description 14
- 229940124530 sulfonamide Drugs 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
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- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 9
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- 125000002619 bicyclic group Chemical group 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
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- CYCFHZPFMAXQRB-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[5-morpholin-4-ylsulfonyl-2-(2-oxopyrrolidin-1-yl)phenyl]urea Chemical compound C1=CC(Cl)=CC=C1NC(=O)NC1=CC(S(=O)(=O)N2CCOCC2)=CC=C1N1C(=O)CCC1 CYCFHZPFMAXQRB-UHFFFAOYSA-N 0.000 description 7
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- RSIFRBLCVZDPFI-UHFFFAOYSA-N 1-[3-(azepan-1-ylsulfonyl)-4-methylphenyl]-3-[2-(3-prop-1-en-2-ylphenyl)propan-2-yl]urea Chemical compound CC(=C)C1=CC=CC(C(C)(C)NC(=O)NC=2C=C(C(C)=CC=2)S(=O)(=O)N2CCCCCC2)=C1 RSIFRBLCVZDPFI-UHFFFAOYSA-N 0.000 description 7
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Classifications
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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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
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| US9579324B2 (en) | 2013-07-11 | 2017-02-28 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
| US20150031627A1 (en) | 2013-07-25 | 2015-01-29 | Agios Pharmaceuticals, Inc | Therapeutically active compounds and their methods of use |
| KR20220070066A (ko) | 2014-03-14 | 2022-05-27 | 아지오스 파마슈티컬스 아이엔씨. | 치료적으로 활성인 화합물의 약제학적 조성물 |
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| US10202339B2 (en) | 2019-02-12 |
| CA2888360A1 (en) | 2014-04-24 |
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| CN104822373B (zh) | 2018-08-28 |
| JP2015536306A (ja) | 2015-12-21 |
| CN104822373A (zh) | 2015-08-05 |
| US20150299115A1 (en) | 2015-10-22 |
| JP2018199677A (ja) | 2018-12-20 |
| HK1213798A1 (zh) | 2016-07-15 |
| AU2013331626B2 (en) | 2018-08-02 |
| EP2906212A1 (en) | 2015-08-19 |
| MX2015004762A (es) | 2016-05-24 |
| EP2906212A4 (en) | 2016-06-08 |
| MX365747B (es) | 2019-06-12 |
| NZ706999A (en) | 2018-12-21 |
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