CA2649755C - Method of inhibiting c-kit kinase - Google Patents
Method of inhibiting c-kit kinase Download PDFInfo
- Publication number
- CA2649755C CA2649755C CA2649755A CA2649755A CA2649755C CA 2649755 C CA2649755 C CA 2649755C CA 2649755 A CA2649755 A CA 2649755A CA 2649755 A CA2649755 A CA 2649755A CA 2649755 C CA2649755 C CA 2649755C
- Authority
- CA
- Canada
- Prior art keywords
- carboxylic acid
- cyano
- mmol
- imidazole
- cyclohex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title abstract description 86
- 230000002401 inhibitory effect Effects 0.000 title abstract description 8
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title description 14
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 331
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 230000008685 targeting Effects 0.000 claims description 18
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 15
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 12
- 208000008585 mastocytosis Diseases 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 229940127089 cytotoxic agent Drugs 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 9
- 238000001959 radiotherapy Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 51
- 206010028980 Neoplasm Diseases 0.000 abstract description 24
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 16
- 102000020233 phosphotransferase Human genes 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 14
- 230000002062 proliferating effect Effects 0.000 abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 289
- XTDRPNJABDWQFI-UHFFFAOYSA-N 5-cyano-1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC(C#N)=CN1 XTDRPNJABDWQFI-UHFFFAOYSA-N 0.000 description 161
- 239000000203 mixture Substances 0.000 description 143
- 239000000243 solution Substances 0.000 description 121
- -1 2,2,4-trimethylpentyl Chemical group 0.000 description 114
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- 238000001819 mass spectrum Methods 0.000 description 96
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 92
- 239000007787 solid Substances 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 76
- 238000005160 1H NMR spectroscopy Methods 0.000 description 74
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- 229910052739 hydrogen Inorganic materials 0.000 description 48
- 239000001257 hydrogen Substances 0.000 description 47
- 101150041968 CDC13 gene Proteins 0.000 description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 42
- 229910052938 sodium sulfate Inorganic materials 0.000 description 42
- 235000011152 sodium sulphate Nutrition 0.000 description 42
- 239000007832 Na2SO4 Substances 0.000 description 41
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 235000002639 sodium chloride Nutrition 0.000 description 27
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- 238000011282 treatment Methods 0.000 description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 24
- 125000000217 alkyl group Chemical group 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- 239000002253 acid Substances 0.000 description 20
- 125000003545 alkoxy group Chemical group 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 19
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 19
- 238000006467 substitution reaction Methods 0.000 description 19
- 239000000725 suspension Substances 0.000 description 18
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 150000002431 hydrogen Chemical class 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 16
- 238000004007 reversed phase HPLC Methods 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
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- 238000006069 Suzuki reaction reaction Methods 0.000 description 15
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- 125000004122 cyclic group Chemical group 0.000 description 15
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 125000002541 furyl group Chemical group 0.000 description 14
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 14
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- 230000015572 biosynthetic process Effects 0.000 description 13
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- 125000001309 chloro group Chemical group Cl* 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
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- SQMINWFWFXVWHK-UHFFFAOYSA-N 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid Chemical compound C[Si](C)(C)CCOCN1C=C(C#N)N=C1C(O)=O SQMINWFWFXVWHK-UHFFFAOYSA-N 0.000 description 11
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- 239000007858 starting material Substances 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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Landscapes
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- Plural Heterocyclic Compounds (AREA)
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| US60/793,471 | 2006-04-20 | ||
| PCT/US2007/066985 WO2007124369A2 (en) | 2006-04-20 | 2007-04-19 | Method of inhibiting c kit kinase |
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| CA2649755A1 CA2649755A1 (en) | 2007-11-01 |
| CA2649755C true CA2649755C (en) | 2014-12-02 |
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| CN104370880A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类蛋白酶抑制剂及其制备方法和用途 |
| US10259807B2 (en) | 2013-07-22 | 2019-04-16 | Idorsia Pharmaceuticals Ltd. | 1-(piperazin-1-yl)-2-([1,2,4]triazol-1-yl)-ethanone derivatives |
| CA2972952C (en) | 2015-01-15 | 2021-01-05 | Idorsia Pharmaceuticals Ltd | Hydroxyalkyl-piperazine derivatives as cxcr3 receptor modulators |
| AR103399A1 (es) | 2015-01-15 | 2017-05-10 | Actelion Pharmaceuticals Ltd | Derivados de (r)-2-metil-piperazina como moduladores del receptor cxcr3 |
| CN105753770A (zh) * | 2015-05-27 | 2016-07-13 | 上海佐林生物医药有限公司 | 蛋白激酶抑制剂制备方法、中间体、制备方法及应用 |
| CN114364798A (zh) | 2019-03-21 | 2022-04-15 | 欧恩科斯欧公司 | 用于治疗癌症的Dbait分子与激酶抑制剂的组合 |
| US20220401436A1 (en) | 2019-11-08 | 2022-12-22 | INSERM (Institute National de la Santé et de la Recherche Médicale) | Methods for the treatment of cancers that have acquired resistance to kinase inhibitors |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
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| DE69332948T2 (de) | 1992-03-05 | 2003-11-27 | Board Of Regents, The University Of Texas System | Verwendung von Immunokonjugate zur Diagnose und/oder Therapie der vaskularisierten Tumoren |
| WO2000064946A2 (en) | 1999-04-28 | 2000-11-02 | Board Of Regents, The University Of Texas System | Compositions and methods for cancer treatment by selectively inhibiting vegf |
| DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
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| ATE465731T1 (de) * | 2003-10-23 | 2010-05-15 | Ab Science | 2-aminoaryloxazol-verbindungen als tyrosinkinase- hemmer |
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