CN103113375A - 一类吡唑并[3,4-d]嘧啶类化合物及其制备方法 - Google Patents
一类吡唑并[3,4-d]嘧啶类化合物及其制备方法 Download PDFInfo
- Publication number
- CN103113375A CN103113375A CN2013100554258A CN201310055425A CN103113375A CN 103113375 A CN103113375 A CN 103113375A CN 2013100554258 A CN2013100554258 A CN 2013100554258A CN 201310055425 A CN201310055425 A CN 201310055425A CN 103113375 A CN103113375 A CN 103113375A
- Authority
- CN
- China
- Prior art keywords
- palladium
- reaction
- compound
- preparation
- alkali
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 23
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052763 palladium Inorganic materials 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 10
- -1 acrylamido Chemical group 0.000 claims description 9
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 235000015320 potassium carbonate Nutrition 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 125000006267 biphenyl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 150000003230 pyrimidines Chemical class 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 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 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 3
- POUXCZFBIBTXOL-UHFFFAOYSA-N C=CC(=O)C(=O)C(=O)C=C Chemical compound C=CC(=O)C(=O)C(=O)C=C POUXCZFBIBTXOL-UHFFFAOYSA-N 0.000 claims description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 206010025135 lupus erythematosus Diseases 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 2
- WYKCIIKELYKXIY-UHFFFAOYSA-N C(C)(C)OC1=C(C(=CC=C1)OC(C)C)C1=CC=CC=C1.P Chemical group C(C)(C)OC1=C(C(=CC=C1)OC(C)C)C1=CC=CC=C1.P WYKCIIKELYKXIY-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 2
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 claims description 2
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000005905 mesyloxy group Chemical group 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229940093916 potassium phosphate Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 6
- 206010020718 hyperplasia Diseases 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 235000002639 sodium chloride Nutrition 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229960001507 ibrutinib Drugs 0.000 description 4
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 0 *[N+]c1ncnc(N)c1C=N Chemical compound *[N+]c1ncnc(N)c1C=N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102100021752 Corticoliberin Human genes 0.000 description 3
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 102000015617 Janus Kinases Human genes 0.000 description 2
- 108010024121 Janus Kinases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 150000004982 aromatic amines Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical group [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- GWYPDXLJACEENP-UHFFFAOYSA-N 1,3-cycloheptadiene Chemical compound C1CC=CC=CC1 GWYPDXLJACEENP-UHFFFAOYSA-N 0.000 description 1
- GQJMSJGOEZDGBP-UHFFFAOYSA-N 1-(oxolan-2-yl)pyrrolidine Chemical compound C1CCCN1C1OCCC1 GQJMSJGOEZDGBP-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 1
- YMXQUFUYCADCFL-UHFFFAOYSA-N 4-chloro-1h-pyrazolo[3,4-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=NN2 YMXQUFUYCADCFL-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 229940124291 BTK inhibitor Drugs 0.000 description 1
- YWZLLOVWTKTYQM-OAHLLOKOSA-N CC(C)(C)OC(N(CCC1)C[C@@H]1[n]1ncc2c1ncnc2Nc(cc1)ccc1O)=O Chemical compound CC(C)(C)OC(N(CCC1)C[C@@H]1[n]1ncc2c1ncnc2Nc(cc1)ccc1O)=O YWZLLOVWTKTYQM-OAHLLOKOSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N CC(C)(C)OC(N1CCCCC1)=O Chemical compound CC(C)(C)OC(N1CCCCC1)=O RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- LMCUHQCRDUSFID-LJQANCHMSA-N CCC(N(CCC1)C[C@@H]1[n]1ncc2c1ncnc2Nc(cc1)ccc1Oc1ccccc1)=O Chemical compound CCC(N(CCC1)C[C@@H]1[n]1ncc2c1ncnc2Nc(cc1)ccc1Oc1ccccc1)=O LMCUHQCRDUSFID-LJQANCHMSA-N 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 102000007528 DNA Polymerase III Human genes 0.000 description 1
- 108010071146 DNA Polymerase III Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 102100033839 Glucose-dependent insulinotropic receptor Human genes 0.000 description 1
- 101000996752 Homo sapiens Glucose-dependent insulinotropic receptor Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- XBWOFSRPXCEEFB-UHFFFAOYSA-O Nc1c(C=N)c([NH3+])ncn1 Chemical compound Nc1c(C=N)c([NH3+])ncn1 XBWOFSRPXCEEFB-UHFFFAOYSA-O 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical group CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Abstract
本发明涉及一类吡唑并[3,4-d]嘧啶类化合物（如式I所示）及其合成方法。该路线原料易得，步骤简单，反应产率较高。本发明还涉及此类化合物在治疗细胞增生类疾病和自身免疫疾病中的应用。
Description
技术领域
本发明涉及一类吡唑并[3,4-d]嘧啶类化合物或其可药用盐，和其制备方法以及该类化合物单独或和其他药物联合使用在治疗细胞增生类疾病和自身免疫疾病中的应用。
背景技术
随着分子生物学的发展，人们对肿瘤的认识逐渐从细胞水平上升到亚细胞水平和分子水平，一些与肿瘤发生密切相关的生物过程越来越清晰。基于致癌基因的高端生物技术不断的被医学临床应用，分子靶向治疗逐渐兴起。格列卫、拉帕替尼、索拉菲尼和舒尼替尼等多个酪氨酸激酶抑制剂的成功上市和优异的临床表现，吸引了科学界和工业界对以酪氨酸为靶点的抗肿瘤药物的研发兴趣。
抗肿瘤化疗药物容易产生耐药性，毒副作用也急需提高，因此基于完全不同作用靶点的安全有效的新药，将会受到市场的青眯。2012年8月，美国强生制药公司向Pharmacyclics制药公司支付高达五千万美元费用，用于淋巴瘤新药Bruton酪氨酸激酶（BTK）抑制剂ibrutinib的后续研发项目，目前处于Ⅲ期临床试验阶段。2013年初，美国食品药品管理局（FDA）已授予Ibrutinib“突破性疗法”用于治疗两种B-细胞恶性肿瘤：复发或难治性套细胞淋巴瘤及Waldenstrom巨球蛋白血症(WM)。汤森路透预测，该药如果获得批准，到2017年将达到“重磅炸弹”级销量。因此BTK抑制剂具有十分广阔的前景。
吡唑并嘧啶衍生物因其结构与嘌呤的结构非常相似，而具有广泛的生物活性，在抗肿瘤、抗菌、消炎、治疗失眠症和心血管疾病、治疗消沉焦虑等精神紊乱的疾病等方面的研究颇受关注。生物学上，吡唑并嘧啶类衍生物可以抑制DNA聚合酶Ⅲ、Bruton酪氨酸激酶(BTK)、细胞周期蛋白CyclinB1及细胞周期蛋白依赖性激酶CDK1(CDK-1/cyclin B)、促肾上腺皮质激素释放因子(CRF)和两面神激酶(JAK)等，因此上述靶点诱发或促进的疾病领域，均有所应用。
吡唑并[3,4-d]嘧啶母核在酪氨酸激酶抑制剂的研究方面尤其得到重视。US20090286812、US20110160222报道了几类1-哌啶基-4-芳胺基-吡唑并[3,4-d]嘧啶和1-哌啶基-4-芳氧基-吡唑并[3,4-d]嘧啶衍生物，作为GPR119受体激动剂，用于治疗糖尿病和代谢紊乱。Sim和Gray研究组报道了一类4-三氟甲氧基苯胺基-吡唑并[3,4-d]嘧啶衍生物，在抑制野生型和突变型的Bcr-Abl活性上，比未稠环的嘧啶母核的相应化合物具有5-10倍的改善[J.Med.Chem.2010,53,6934]。
合成方面，US20090286812、US20110160222采用4-氯-吡唑并[3,4-d]嘧啶为起始原料，与芳香胺在碱性条件下反应而得目标物。Sim和Gray研究组将芳香胺片段接入嘧啶环后，与肼碱性关环而成。
发明内容
本发明的目的在于提供一类吡唑并[3,4-d]嘧啶类化合物或其可药用盐；本发明的另一目的在于提供一种简捷高效的制备吡唑并[3,4-d]嘧啶类化合物的方法；本发明的又一目的在于提供该类吡唑并[3,4-d]嘧啶类化合物或其可药用盐或和其他药物联用在治疗细胞增生类疾病（如淋巴瘤）和自身免疫疾病（如类风湿关节炎）中的应用。
本发明报道了一类吡唑并[3,4-d]嘧啶类化合物或其药学上可接受的盐，其结构如通式如I所示：
其特征在于
R1选自C3-C8环烷基、C3-C6杂环烷基、C3-C8环烷基C1-C2亚烷基、C3-C6杂环烷基C1-C2亚烷基，所述C3-C8环烷基可进一步被丙烯酰胺基、2-丁烯酰胺基取代；C3-C6杂环烷基可进一步地被丙烯酮、2-丁烯酮、4-二甲氨基取代的2-丁烯酮取代；
R2选自苯基、C5-C6杂芳基或苯氧苯基。
更具体的，本发明所述的化合物中的R1优选于：
波浪线表示与吡唑并[3,4-d]嘧啶1-位氮的连接点。
当本发明化合物含有一个或多个手性中心时，当然包括这些化合物的对映异构体、外消旋体和各个非对映异构体。更优选的，式I化合物包括但不限于：
发明详述
术语“C3-C8环烷基”是指具有总共3至8个碳原子的单环或稠合的环（稠合环意味着系统中的每个环与系统中的其他环共享毗邻的一对碳原子）基团，其中一个或多个环不具有完全连接的π电子系统。此类基团的实例包括但不限于环丙烷基、环丁烷基、环戊烷基、环戊烯基、环己烷基、金刚烷基、环己烯基、环己二烯基、环庚烷基、环辛烷基、环庚二烯基和环庚三烯基等；所述C3-C8环烷基可进一步被丙烯酰胺基、2-丁烯酰胺基、2-戊烯酰胺基等基团取代。
术语“C3-C6杂环烷基”表示在环中具有3到6个环原子，其中一个、两个或三个环原子合理存在地选自N、O或S(O)m的杂原子，m是0至2的整数，其余环原子是C，这些环可以具有零条、一条或多条双键，但这些环不具有完全共轭的π电子系统，C3-C6杂环基的实例包括但不限于哌嗪子基指基团
吗啉代基
哌啶子基
吡咯烷基四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基；
所述C3-C6杂环烷基可进一步地被丙烯酮、2-丁烯酮、4-二甲氨基取代的2-丁烯酮取代；
术语“C1-C2亚烷基”的实例包括但不限于-CH2-、-CH2CH2-。
术语“C5-C6杂芳基”是指在其环中含有5至6个碳原子并含有1至3个各自独立地选自O、S和N的杂原子的芳族杂环基团。条件是所述基团的环上不含两个相邻的O原子或两个相邻的S原子。C5-C6杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯基。所述C5-C6杂芳基在可能的情况下可以为C-连接的或N连接的。
术语“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
（1）与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、亚硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、丙酸、丙烯酸、草酸、（D）或（L）苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
（2）存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、三乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺、氨丁三醇、N-甲基葡糖胺等。
本发明还涉及式I化合物的制备方法，其特征在于：
式A2的吡唑并嘧啶-4-胺与卤代芳香烃在非质子溶剂中，在惰性气体氛围、钯-配体催化和碱作用下，通过常规加热或微波加热发生Buchwald-Hartwig胺化反应，生成化合物1-取代-吡唑并嘧啶-4-芳胺（I），其中，R1与R2如上所定义，X为Cl、Br或I；反应温度为80℃至180℃，优选100℃至150℃，进一步优选100℃至140℃；反应时间为10分钟至24小时，选用微波加热时，反应时间优选20分钟至1小时，选用常温加热时，反应时间优选6至12小时，进一步优选8至10小时；非质子溶剂选自：N,N-二甲基甲酰胺、甲苯、1,4-二氧六环、四氢呋喃或乙二醇二甲醚，优选自N,N-二甲基甲酰胺或1,4-二氧六环；金属催化剂选自：钯（Pd）、醋酸钯[Pd(OAc)2]、三(二亚苄基丙酮)二钯（Pd2dba3）或四(三苯基膦)钯[Pd(PPh3)4]，优选醋酸钯[Pd(OAc)2]、三(二亚苄基丙酮)二钯（Pd2dba3）或四(三苯基膦)钯[Pd(PPh3)4]，进一步优选醋酸钯[Pd(OAc)2]；配体L选自：2,2'-双二苯膦基-1,1'-联萘（BINAP）、2-（二叔丁基磷）-1,1'-联萘（JohnPhos）、1,1'-双(二苯基膦)二茂铁（DPPF）、4,5-双二苯基膦-9,9-二甲基氧杂蒽（XantPhos）或2-双环己基膦-2',6'-二异丙氧基联苯（RuPhos），优选2,2'-双二苯膦基-1,1'-联萘（BINAP）或4,5-双二苯基膦-9,9-二甲基氧杂蒽（XantPhos）；碱选自：叔丁醇钠、碳酸铯、碳酸钾或磷酸钾，优选叔丁醇钠、叔丁醇钾、碳酸铯或碳酸钾，进一步优选叔丁醇钠或碳酸铯。
本发明同时报道了式A2化合物的制备方法，其特征在于：
在非质子极性溶剂中，在碱作用下，式A1的吡唑并嘧啶-4-胺与R1-LG发生SN2反应，生成A2，其中，R1如上所定义，LG为离去基团如Cl、Br、I、OMs甲磺酰氧基）或OTs（对甲苯磺酰氧基）等。反应温度为40℃至130℃，优选100℃至120℃；反应时间为4至20小时，优选12至16小时，非质子极性溶剂选自：丙酮、乙酸乙酯、DMF(N/，N-二甲基甲酰胺)、N,N-二甲基乙酰胺、DMSO(二甲亚砜基)、NMP(N-甲基吡咯烷酮)、四氢呋喃、二氧六环、甲苯、乙腈中的一种或多种，优选N,N-二甲基甲酰胺；碱选自：氢氧化钠、氢氧化钾、氢氧化锂、乙醇钠、叔丁醇钾、氢化钠、碳酸钠、碳酸钾或碳酸铯中的一种或多种，优选碳酸铯或碳酸钾。当R1中与吡唑并嘧啶-1-氮原子相连的碳原子有手性中心时，该步反应后，手性中心的构型得到翻转。式A1化合物很容易得到，或通过常规合成方法制备。
本发明的技术方案，原料易得，操作步骤简捷可行，为制备吡唑并[3,4-d]嘧啶类化合物提供了一条产率高，副反应少的合成路线。
本发明的另一方面在于提供本发明所定义的通式化合物（I）在制备酪氨酸激酶抑制剂中的应用，特别是治疗细胞增生类疾病和自身免疫疾病中的应用。所述细胞增生类疾病包括B-细胞淋巴瘤、急性淋巴细胞性白血病、乳腺瘤、慢性粒细胞性白血病。所述自身免疫疾病包括类风湿性关节炎、系统性红斑狼疮、多发性硬化症、过敏性鼻炎。
典型地，本发明所定义的通式化合物（I）在制备药物中的用途，该药物用于预防和/或治疗因BTK（Bruton酪氨酸激酶）活性抑制而改善的疾病。该疾病选自恶性肿瘤和自身免疫疾病，如B-细胞淋巴瘤、急性淋巴细胞性白血病、乳腺瘤、类风湿性关节炎、系统性红斑狼疮等。
具体实施方式
为了更详细说明本发明，给出下述制备实例，但并不因此将本发明限制在所述的实施例范围之中。
实施例1：化合物II的制备
将A10.54g(4mmol)、A31.67g(6mmol,1.5eq.)和碳酸钾1.1g(8mmol,2eq.)加到10mLDMF溶液中，100℃反应过夜，浓缩后乙酸乙酯萃取，干燥，Biotage硅胶柱层析（二氯甲烷/甲醇=1%），得浅黄固体A40.92g，产率72%。
将A40.18g(0.58mmol)、溴苯0.14g(0.87mmol,1.5eq.)、醋酸钯0.013g(0.06mmol,0.1eq.)、XantPhos0.035g(0.06mmol,0.1eq.)、叔丁醇钠0.14g(1.45mmol,2.5eq.)的1,4-二氧六环(15mL)溶液氩气鼓泡5分钟，放入CEM微波反应器，140℃反应20分钟后，加饱和食盐水，二氯甲烷萃取干燥，Biotage硅胶柱层析（石油醚/乙酸乙酯=15%，添加二氯甲烷8%），得浅黄固体A50.15g，产率67%。LCMS(ESI)m/z[M+H]+=359.2.
将A50.08g(0.2mmol)溶于二氯甲烷(5mL)，滴加三氟乙酸(1mL)，1小时后加入碳酸氢钠饱和溶液，分液后有机相干燥。浓缩溶剂后得到的粗品溶于二氯甲烷(5mL)，加入三乙胺(58uL,2.0eq.)，冷却至-10℃后，缓慢滴加丙烯酰氯(16uL，1.0eq.)的二氯甲烷溶液。1小时后加水淬灭，二氯甲烷萃取干燥，Biotage硅胶柱层析（二氯甲烷/甲醇=1~2%），得浅黄固体0.052g，为化合物II，两步产率76%，HPLC纯度99.8%。LCMS(ESI)m/z[M+H]+=349.2.HNMR(400MHz,DMSO-d6)δ9.32(s,1H),8.11(s,1H),8.02(s,1H),7.76(d,J=8.0Hz,2H),7.23(t,J=7.2Hz,2H),6.90(t,J=7.2Hz,1H),6.60(dd,J=16.4,9.6Hz,1H),6.31(dd,J=16.4,9.6Hz,1H),5.66(dd,J=16.4,9.6Hz,1H),5.68-5.53(m,1H),4.90-4.82(m,1.5H),4.61-4.52(m,0.5H),4.24-4.11(m,0.5H),4.09-3.97(m,0.5H),3.85-3.77(m,0.5H),3.41-3.32(m,0.5H),3.23-3.15(m,0.5H),2.96-2.84(m,0.5H),2.41-2.19(m,1H),2.05-1.94(m,1H),1.76-1.64(m,1H).
实施例2：化合物Ⅲ的制备
(S)-A4的制备：根据实施例1的方法，将(R)-A3置换消旋体A3，即可制得。产率83%。
将(S)-A40.2g(0.64mmol)、4-苯氧基溴苯0.24g(0.96mmol,1.5eq.)、醋酸钯0.013g(0.06mmol,0.1eq.)、BINAP0.037g(0.06mmol,0.1eq.)、碳酸铯0.52g(1.6mmol,2.5eq.)抽换氩气后，加入DMF(4mL)，100℃反应8小时，浓缩后加饱和食盐水，二氯甲烷萃取干燥，Biotage硅胶柱层析（石油醚/乙酸乙酯=28%），得浅黄固体A70.27g，产率87%。
化合物Ⅲ的制备：根据实施例1的方法，将A7置换消旋体A5，即可制得。产率91%。HPLC纯度98.2%。LCMS(ESI)m/z[M+H]+=441.2.HNMR(400MHz,DMSO-d6)δ9.28(s,1H),8.09(s,1H),8.03(s,1H),7.65(d,J=8.4Hz,2H),7.39(t,J=7.6Hz,2H),7.24-7.18(m,3H),7.17-7.14(m,2H),6.62(dd,J=16.4,9.6Hz,1H),6.35(dd,J=16.4,9.6Hz,1H),5.72(dd,J=16.4,9.6Hz,1H),5.43(s,1H),5.22(s,1H),5.02(d,J=12.4Hz,1H),4.81(d,J=12.4Hz,1H),4.27(d,J=12.9Hz,1H),4.12(d,J=13.2Hz,0.5H),3.18-3.09(m,1H),2.97-2.86(m,1H),2.29-2.18(m,1H),1.99-1.87(m,1H),1.78-1.65(m,1H).
实施例3：化合物Ⅳ的制备
将A10.7g(5.2mmol)、溴代环戊烷1.55g(10.4mmol,2eq.)和碳酸铯3.39g(10.4mmol,2eq.)，在12mL DMF溶液中，110℃反应过夜，浓缩后乙酸乙酯萃取，干燥，Biotage硅胶柱层析（二氯甲烷/甲醇=1%），得浅黄固体A90.84g，产率80%。
将A90.1g(0.5mmol)、3-溴吡唑0.11g(0.75mmol,1.5eq.)、醋酸钯0.011g(0.05mmol,0.1eq.)、XantPhos0.029g(0.05mmol,0.1eq.)、叔丁醇钠0.12g(1.25mmol,2.5eq.)的1,4-二氧六环(15mL)溶液氩气鼓泡5分钟，放入CEM微波反应器，130℃反应60分钟后，加饱和食盐水，二氯甲烷萃取干燥，Biotage硅胶柱层析（石油醚/乙酸乙酯=15%，添加二氯甲烷5%），得浅黄固体0.083g，为产品Ⅳ，产率62%。HPLC纯度98.5%。LCMS(ESI)m/z[M+H]+=270.1.HNMR(400MHz,DMSO-d6)δ12.33(brs,1H),11.03(brs,1H),8.09(s,1H),8.03(s,1H),7.69-7.58(m,1H),7.39-7.28(m,1H),5.40-5.25(m,1H),2.22-2.14(m,4H),2.08-1.95(m,2H),1.79-1.67(m,2H).
实施例4：所得化合物体外生化酶水平的BTK抑制活性测试
酶活测定：
1.星孢菌素、PCI-32765和待测化合物溶解在100%的DMSO中，起始稀释浓度分别为2uM0.1uM and10uM,然后在96孔板中用20%DMSO10个浓度点、三倍梯度稀释。
2.转移4ul稀释好的化合物到384孔板中。
3.准备底物和酶的缓冲液。
4.使用微孔板加样器分别加8ul底物和酶到384孔板内。
5.轻轻震荡384孔板，1000g室温短时间离心，室温孵育30分钟。
6.准备终止液，用微孔板加样器分别加入SA-XL665和TK抗体各10ul，震荡1分钟，然后离心，室温孵育60分钟。
7.PHERAstar多功能读板器读数。
8.GraphPad prism分析软件分析数据。
列公式求得抑制率：
所述化合物BTK抑制活性:
| 化合物编号 | BTK1000nM抑制率 | JAK31000nM抑制率 |
| Ⅱ | +++ | + |
| III | +++ | + |
| IV | ++ | + |
| PCI-32765 | +++ | +++ |
+++表示抑制率>80%；++表示抑制率为50~80%；+表示抑制率<50%.
结论：从上表可以看出，所合成的化合物体外均具有较好的BTK抑制活性。
Claims (10)
1.一类吡唑并[3,4-d]嘧啶类化合物或其药学上可接受的盐，其特征在于结构如通式I所示：
其中，
R1选自C3-C8环烷基、C3-C6杂环烷基、C3-C8环烷基C1-C2亚烷基、C3-C6杂环烷基C1-C2亚烷基，所述C3-C8环烷基可进一步被丙烯酰胺基、2-丁烯酰胺基取代；C3-C6杂环烷基可进一步地被丙烯酮、2-丁烯酮、4-二甲氨基取代的2-丁烯酮取代；
R2选自苯基、C5-C6杂芳基或苯氧苯基。
2.根据权利要求1所述的化合物，其中R1选自：
3.化合物或其药学上可接受的盐，所述化合物选自：
4.一种式I化合物的制备方法，其特征在于：
在非质子溶剂中，在惰性气体氛围、钯-配体催化和碱作用下，式A2的吡唑并嘧啶-4-胺与卤代芳香烃通过常规加热或微波加热反应发生Buchwald-Hartwig胺化反应，生成化合物1-取代-吡唑并嘧啶-4-芳胺（I），其中，R1与R2如权利要求1中所定义，X为Cl、Br或I；反应温度为80℃至180℃，反应时间为10分钟至16小时，非质子溶剂选自：N,N-二甲基甲酰胺、甲苯、1,4-二氧六环、四氢呋喃或乙二醇二甲醚，金属催化剂选自：钯（Pd）、醋酸钯[Pd(OAc)2]、三(二亚苄基丙酮)二钯（Pd2dba3）或四(三苯基膦)钯[Pd(PPh3)4]，配体L选自：2,2'-双二苯膦基-1,1'-联萘（BINAP）、2-（二叔丁基磷）-1,1'-联萘（JohnPhos）、1,1'-双(二苯基膦)二茂铁（DPPF）、4,5-双二苯基膦-9,9-二甲基氧杂蒽（XantPhos）或2-双环己基膦-2',6'-二异丙氧基联苯（RuPhos），碱选自：叔丁醇钠、叔丁醇钾、碳酸铯、碳酸钾或磷酸钾。
5.权利要求4中所述的制备方法，其特征在于反应温度为100℃至150℃，反应时间为微波加热20分钟至1小时或常温加热6至12小时，非质子溶剂选自：N,N-二甲基甲酰胺或1,4-二氧六环，金属催化剂选自：醋酸钯[Pd(OAc)2]、三(二亚苄基丙酮)二钯（Pd2dba3）或四(三苯基膦)钯[Pd(PPh3)4]，配体L选自：2,2'-双二苯膦基-1,1′-联萘（BINAP）或4,5-双二苯基膦-9,9-二甲基氧杂蒽（XantPhos），碱选自：叔丁醇钠、叔丁醇钾、碳酸铯或碳酸钾。
6.权利要求4中所述的制备方法，其特征在于反应温度为100℃至140℃，反应时间为微波加热20分钟至1小时或常温加热8至10小时，非质子溶剂选自：N,N-二甲基甲酰胺或1,4-二氧六环，金属催化剂选自：醋酸钯[Pd(OAc)2]，配体L选自：2,2'-双二苯膦基-1,1'-联萘（BINAP）或4,5-双二苯基膦-9,9-二甲基氧杂蒽（XantPhos），碱选自：叔丁醇钠或碳酸铯。
7.一种式A2化合物的制备方法，其特征在于：
在非质子极性溶剂中，在碱作用下，式A1的吡唑并嘧啶-4-胺与R1-LG发生SN2反应，生成A2，其中，R1如权利要求1中所定义，LG为离去基团如Cl、Br、I、OMs（甲磺酰氧基）或OTs（对甲苯磺酰氧基）；反应温度为40℃至130℃，反应时间为4至20小时，非质子极性溶剂选自：丙酮、乙酸乙酯、DMF(N，N-二甲基甲酰胺)、DMA(N，N-二甲基乙酰胺)、DMSO(二甲亚砜基)、NMP(N-甲基吡咯烷酮)、四氢呋喃、二氧六环、甲苯、乙腈中的一种或多种，碱选自：氢氧化钠、氢氧化钾、氢氧化锂、乙醇钠、叔丁醇钾、氢化钠、碳酸钠、碳酸钾或碳酸铯中的一种或多种。
8.权利要求7中所述的制备方法，其特征在于：反应温度为100℃至120℃，反应时间为12至16小时，非质子极性溶剂选自：N,N-甲基甲酰胺，碱选自：碳酸铯或碳酸钾。
9.权利要求1-3中任意一项所述的化合物或其药学上可接受的盐在制备药物中的用途，所述药物用于预防和/或治疗因BTK（Bruton酪氨酸激酶）活性抑制而改善的疾病。
10.根据权利要求9中的用途，其中所述因BTK活性抑制而改善的疾病选自B-细胞淋巴瘤、急性淋巴细胞性白血病、乳腺瘤、类风湿性关节炎、系统性红斑狼疮。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310055425.8A CN103113375B (zh) | 2013-02-21 | 2013-02-21 | 一类吡唑并[3,4‑d]嘧啶类化合物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310055425.8A CN103113375B (zh) | 2013-02-21 | 2013-02-21 | 一类吡唑并[3,4‑d]嘧啶类化合物及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103113375A true CN103113375A (zh) | 2013-05-22 |
| CN103113375B CN103113375B (zh) | 2017-09-15 |
Family
ID=48411795
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310055425.8A Active CN103113375B (zh) | 2013-02-21 | 2013-02-21 | 一类吡唑并[3,4‑d]嘧啶类化合物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103113375B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650092A (zh) * | 2013-11-16 | 2015-05-27 | 广东东阳光药业有限公司 | 取代的杂芳基化合物及其组合物和用途 |
| CN106674228A (zh) * | 2016-12-09 | 2017-05-17 | 河南农业大学 | 多元杂环化合物及其制备方法和用途 |
| WO2017128917A1 (zh) | 2016-01-29 | 2017-08-03 | 北京诺诚健华医药科技有限公司 | 吡唑稠环类衍生物、其制备方法及其在治疗癌症，炎症和免疫性疾病上的应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102036991A (zh) * | 2008-05-19 | 2011-04-27 | 霍夫曼-拉罗奇有限公司 | Gpr119受体激动剂 |
| US20110160222A1 (en) * | 2008-11-26 | 2011-06-30 | Metabolex, Inc. | Modulators of glucose homeostasis for the treatment of diabetes and metabolic disorders |
| CN102659764A (zh) * | 2012-04-16 | 2012-09-12 | 中国科学院广州生物医药与健康研究院 | 酪氨酸激酶不可逆抑制剂及其制备方法和用途 |
-
2013
- 2013-02-21 CN CN201310055425.8A patent/CN103113375B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102036991A (zh) * | 2008-05-19 | 2011-04-27 | 霍夫曼-拉罗奇有限公司 | Gpr119受体激动剂 |
| US20110160222A1 (en) * | 2008-11-26 | 2011-06-30 | Metabolex, Inc. | Modulators of glucose homeostasis for the treatment of diabetes and metabolic disorders |
| CN102659764A (zh) * | 2012-04-16 | 2012-09-12 | 中国科学院广州生物医药与健康研究院 | 酪氨酸激酶不可逆抑制剂及其制备方法和用途 |
Non-Patent Citations (1)
| Title |
|---|
| XIANMING DENG ET AL.: "Expanding the Diversity of Allosteric Bcr-Abl Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650092A (zh) * | 2013-11-16 | 2015-05-27 | 广东东阳光药业有限公司 | 取代的杂芳基化合物及其组合物和用途 |
| WO2017128917A1 (zh) | 2016-01-29 | 2017-08-03 | 北京诺诚健华医药科技有限公司 | 吡唑稠环类衍生物、其制备方法及其在治疗癌症，炎症和免疫性疾病上的应用 |
| CN106674228A (zh) * | 2016-12-09 | 2017-05-17 | 河南农业大学 | 多元杂环化合物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103113375B (zh) | 2017-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Desplat et al. | Synthesis and evaluation of the antiproliferative activity of novel pyrrolo [1, 2-a] quinoxaline derivatives, potential inhibitors of Akt kinase. Part II | |
| KR101104666B1 (ko) | 단백질 키나제 억제제로서의 헤테로아릴 유도체 | |
| CN106660996B (zh) | 作为pde4抑制剂的2,5-取代的嘧啶类 | |
| WO2005085252A1 (en) | Imidazo ‘1,2-a’ pyrazine compounds which interact with protein kinases | |
| KR20080066069A (ko) | 키나제 억제제로서 유용한 아미노피리미딘 | |
| US11161846B2 (en) | Substituted pyrazolo[4,3-b]pyridines and their use as GluN2B receptor modulators | |
| CN103965120A (zh) | 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用 | |
| CN101857588B (zh) | 4-芳香胺基喹唑啉类衍生物及其用途 | |
| EP3523292B1 (en) | Heteroaryl compounds and their use as mer inhibitors | |
| EP3658552B1 (en) | Process for preparing n-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1h-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide by reacting the corresponding amine with a 3-halo-propionyl chloride | |
| EP3954689B1 (en) | Pyrazolopyrazine derived compounds, pharmaceutical composition and use thereof | |
| CN104844566A (zh) | 一种新型结构的激酶抑制剂 | |
| Hocek et al. | Synthesis of carba-analogues of myoseverin by regioselective cross-coupling reactions of 2, 6-dichloro-9-isopropylpurine | |
| Zhao et al. | Discovery of thieno [3, 2-c] pyridin-4-amines as novel Bruton’s tyrosine kinase (BTK) inhibitors | |
| WO2021062327A1 (en) | Fused pyrimidine compounds, compositions and medicinal applications thereof | |
| CN103113375A (zh) | 一类吡唑并[3,4-d]嘧啶类化合物及其制备方法 | |
| CN103333119A (zh) | 1,2-二氢-6-甲基-4-取代氨基-5-嘧啶羧酸类化合物及其制备方法和用途 | |
| Xu et al. | Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the ‘reversed’amide scaffold | |
| JP2022517723A (ja) | Ｃｄｋ阻害剤としての大環状化合物、その製造方法及びその医薬品における応用 | |
| Wang et al. | Identification of 4-(2-furanyl) pyrimidin-2-amines as Janus kinase 2 inhibitors | |
| TW201925202A (zh) | 新穎哌啶基衍生物、其製備方法及含其之醫藥組合物 | |
| Kato et al. | Synthesis of poly-substituted pyrazolo [1, 5-a] quinolines through one-pot two component cascade reaction | |
| EP4140997A1 (en) | Pyridine acetamide derivative serving as cdk inhibitor, and preparation method therefor and use thereof | |
| CN113105434B (zh) | 新型cdk4/6抑制剂及其制备方法和应用 | |
| EP3915990A1 (en) | 4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1-(2h)-carboxamide derivatives as limk and/or rock kinases inhibitors for use in the treatment of cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| ASS | Succession or assignment of patent right |
Owner name: NANJING MTC BIOPHARMA TECHNOLOGY CO., LTD. Free format text: FORMER OWNER: JIANGSU SIMCERE PHARMACEUTICAL RESEARCH COMPANY LIMITED Effective date: 20150126 Free format text: FORMER OWNER: JIANGSU SIMCERE PHARMACEUTICAL CO., LTD. Effective date: 20150126 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20150126 Address after: 210042, Xuanwu Avenue, Xuanwu District, Nanjing, Jiangsu, Nanjing 699-18 Applicant after: NANJING BIOSCIKIN LTD. Address before: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Applicant before: Jiangsu Simcere Pharmaceutical Research Company Limited Applicant before: Jiangsu Simcere Pharmaceutical Co., Ltd. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190626 Address after: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Patentee after: Jiangsu Simcere Pharmaceutical Co., Ltd. Address before: 210042 Xuanwu Avenue 699-18, Xuanwu District, Nanjing City, Jiangsu Province Patentee before: NANJING BIOSCIKIN LTD. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20201224 Address after: 570311 No. 2 Yaogu No. 3 Road, Xiuying District, Haikou City, Hainan Province Patentee after: Hainan Simcere Pharmaceutical Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |