RU2760359C2 - Соединения и способы для ингибирования JAK - Google Patents
Соединения и способы для ингибирования JAK Download PDFInfo
- Publication number
- RU2760359C2 RU2760359C2 RU2018112993A RU2018112993A RU2760359C2 RU 2760359 C2 RU2760359 C2 RU 2760359C2 RU 2018112993 A RU2018112993 A RU 2018112993A RU 2018112993 A RU2018112993 A RU 2018112993A RU 2760359 C2 RU2760359 C2 RU 2760359C2
- Authority
- RU
- Russia
- Prior art keywords
- methyl
- amino
- pyrazol
- methoxy
- indol
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 339
- 238000000034 method Methods 0.000 title claims description 60
- 230000002401 inhibitory effect Effects 0.000 title description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 607
- 239000001257 hydrogen Substances 0.000 claims abstract description 324
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 324
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 290
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 146
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 143
- 150000003839 salts Chemical class 0.000 claims abstract description 109
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 105
- 238000011282 treatment Methods 0.000 claims abstract description 101
- 239000011737 fluorine Chemical group 0.000 claims abstract description 76
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 76
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 75
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 65
- 201000011510 cancer Diseases 0.000 claims abstract description 46
- 239000000460 chlorine Chemical group 0.000 claims abstract description 34
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 33
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 29
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 28
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 239000012453 solvate Substances 0.000 claims abstract description 11
- -1 4-ethylpiperazin-1-yl Chemical group 0.000 claims description 155
- 229960003278 osimertinib Drugs 0.000 claims description 145
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical group COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 claims description 144
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 118
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 113
- CVCVOSPZEVINRM-MRXNPFEDSA-N COC1=NN(C=C1NC1=NC=CC(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](C)N1CCN(CC1)C)=O)C Chemical compound COC1=NN(C=C1NC1=NC=CC(=N1)C1=CNC2=C(C=CC=C12)NC([C@@H](C)N1CCN(CC1)C)=O)C CVCVOSPZEVINRM-MRXNPFEDSA-N 0.000 claims description 101
- 229940125216 golidocitinib Drugs 0.000 claims description 101
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 85
- 229960002584 gefitinib Drugs 0.000 claims description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 70
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical class C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 51
- 235000019439 ethyl acetate Nutrition 0.000 claims description 25
- 229940121647 egfr inhibitor Drugs 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 13
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 11
- 108010024121 Janus Kinases Proteins 0.000 claims description 10
- 102000015617 Janus Kinases Human genes 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
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- 239000003085 diluting agent Substances 0.000 claims description 6
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- PCJQEPKPLJLWMX-OAHLLOKOSA-N BrC=1C(=NC(=NC=1)NC=1C(=NN(C=1)C)OC)C1=CNC2=C(C=CC=C12)NC([C@@H](C)N1CCN(CC1)C)=O Chemical compound BrC=1C(=NC(=NC=1)NC=1C(=NN(C=1)C)OC)C1=CNC2=C(C=CC=C12)NC([C@@H](C)N1CCN(CC1)C)=O PCJQEPKPLJLWMX-OAHLLOKOSA-N 0.000 claims description 2
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| WO2012116247A1 (en) * | 2011-02-25 | 2012-08-30 | Synta Pharmaceuticals Corp. | Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers |
| EA017405B9 (ru) * | 2006-12-08 | 2014-05-30 | АйАрЭм ЭлЭлСи | Соединения и композиции в качестве ингибиторов протеинкиназы |
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| US9908884B2 (en) * | 2009-05-05 | 2018-03-06 | Dana-Farber Cancer Institute, Inc. | EGFR inhibitors and methods of treating disorders |
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| TWI466885B (zh) * | 2009-07-31 | 2015-01-01 | Japan Tobacco Inc | 含氮螺環化合物及其醫藥用途 |
| US9198911B2 (en) | 2010-11-02 | 2015-12-01 | The Trustees Of Columbia University In The City Of New York | Methods for treating hair loss disorders |
| JP2014500254A (ja) * | 2010-11-09 | 2014-01-09 | セルゾーム リミティッド | Ｔｙｋ２阻害剤としてのピリジン化合物およびそのアザ類似体 |
| PE20140146A1 (es) * | 2010-11-19 | 2014-02-06 | Incyte Corp | Derivados de pirrolopiridina y pirrolopirimidina sustituidos con ciclobutilo como inhibidores de jak |
| CN103797010B (zh) * | 2011-06-20 | 2016-02-24 | 因塞特控股公司 | 作为jak抑制剂的氮杂环丁烷基苯基、吡啶基或吡嗪基甲酰胺衍生物 |
| DK2830662T3 (da) | 2012-03-29 | 2019-01-02 | Univ Columbia | Fremgangsmåder til behandlng af hårtabsforstyrrelser |
| JP6767491B2 (ja) * | 2015-09-25 | 2020-10-14 | ディザル（ジァンスー）ファーマシューティカル・カンパニー・リミテッド | Ｊａｋを阻害するための化合物及び方法 |
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| EA017405B9 (ru) * | 2006-12-08 | 2014-05-30 | АйАрЭм ЭлЭлСи | Соединения и композиции в качестве ингибиторов протеинкиназы |
| WO2012030910A1 (en) * | 2010-09-01 | 2012-03-08 | Ambit Biosciences Corporation | 2-cycloquinazoline derivatives and methods of use thereof |
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