CN104098559A - Pim激酶抑制剂及其应用方法 - Google Patents

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Publication number

CN104098559A

CN104098559A CN201410286911.5A CN201410286911A CN104098559A CN 104098559 A CN104098559 A CN 104098559A CN 201410286911 A CN201410286911 A CN 201410286911A CN 104098559 A CN104098559 A CN 104098559A

Authority

CN

China

Prior art keywords

tert

solution

synthesis

added

butyl

Prior art date

2008-03-03

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 description 94
• 101000595531 Homo sapiens Serine/threonine-protein kinase pim-1 Proteins 0.000 title description 13
• 102100036077 Serine/threonine-protein kinase pim-1 Human genes 0.000 title description 13
• 229940043355 kinase inhibitor Drugs 0.000 title description 2
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 103
• 239000000203 mixture Substances 0.000 claims abstract description 76
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 33
• 201000011510 cancer Diseases 0.000 claims abstract description 28
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 239000003814 drug Substances 0.000 claims abstract description 19
• 238000011282 treatment Methods 0.000 claims abstract description 15
• 239000003937 drug carrier Substances 0.000 claims abstract description 8
• 229940124597 therapeutic agent Drugs 0.000 claims abstract description 7
• -1 amino, methyl Chemical group 0.000 claims description 190
• 229910052739 hydrogen Inorganic materials 0.000 claims description 35
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• 239000000126 substance Substances 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 206010060862 Prostate cancer Diseases 0.000 claims description 6
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
• 208000025113 myeloid leukemia Diseases 0.000 claims description 5
• 208000003200 Adenoma Diseases 0.000 claims description 3
• 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 claims description 3
• 208000036566 Erythroleukaemia Diseases 0.000 claims description 3
• 208000034578 Multiple myelomas Diseases 0.000 claims description 3
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
• 206010039491 Sarcoma Diseases 0.000 claims description 3
• 208000021841 acute erythroid leukemia Diseases 0.000 claims description 3
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 3
• NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 3
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
• 201000001441 melanoma Diseases 0.000 claims description 3
• 201000002528 pancreatic cancer Diseases 0.000 claims description 3
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
• 206010001233 Adenoma benign Diseases 0.000 claims 2
• 206010005003 Bladder cancer Diseases 0.000 claims 2
• 206010006187 Breast cancer Diseases 0.000 claims 2
• 208000026310 Breast neoplasm Diseases 0.000 claims 2
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• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
• 206010033128 Ovarian cancer Diseases 0.000 claims 2
• 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
• 208000024770 Thyroid neoplasm Diseases 0.000 claims 2
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 2
• 208000029742 colonic neoplasm Diseases 0.000 claims 2
• 201000005202 lung cancer Diseases 0.000 claims 2
• 208000020816 lung neoplasm Diseases 0.000 claims 2
• 201000002510 thyroid cancer Diseases 0.000 claims 2
• 201000005112 urinary bladder cancer Diseases 0.000 claims 2
• 230000000694 effects Effects 0.000 abstract description 17
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• 229940002612 prodrug Drugs 0.000 abstract description 14
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• 102000020233 phosphotransferase Human genes 0.000 abstract description 11
• 239000002207 metabolite Substances 0.000 abstract description 8
• 230000005764 inhibitory process Effects 0.000 abstract description 7
• 238000011321 prophylaxis Methods 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 419
• 239000000243 solution Substances 0.000 description 220
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 199
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 100
• 238000006243 chemical reaction Methods 0.000 description 97
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 65
• 229920006395 saturated elastomer Polymers 0.000 description 65
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 58
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• 239000012267 brine Substances 0.000 description 51
• 239000011541 reaction mixture Substances 0.000 description 51
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 48
• CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
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• 125000000217 alkyl group Chemical group 0.000 description 29
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 28
• JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 27
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
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• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 26
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
• 229910052938 sodium sulfate Inorganic materials 0.000 description 25
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 24
• 239000001257 hydrogen Substances 0.000 description 24
• 239000003921 oil Substances 0.000 description 24
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
• 238000005406 washing Methods 0.000 description 23
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 21
• 239000011780 sodium chloride Substances 0.000 description 21
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
• 125000003118 aryl group Chemical group 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 18
• 239000002904 solvent Substances 0.000 description 18
• 239000012043 crude product Substances 0.000 description 17
• 229910052736 halogen Inorganic materials 0.000 description 17
• 229910000029 sodium carbonate Inorganic materials 0.000 description 17
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
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• 239000007832 Na2SO4 Substances 0.000 description 15
• 239000013058 crude material Substances 0.000 description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
• 239000000725 suspension Substances 0.000 description 15
• 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 15
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
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• 230000014509 gene expression Effects 0.000 description 11
• YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 11
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
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