CN107872977B - Irak4抑制剂与btk抑制剂的组合产品 - Google Patents
Irak4抑制剂与btk抑制剂的组合产品 Download PDFInfo
- Publication number
- CN107872977B CN107872977B CN201680038870.5A CN201680038870A CN107872977B CN 107872977 B CN107872977 B CN 107872977B CN 201680038870 A CN201680038870 A CN 201680038870A CN 107872977 B CN107872977 B CN 107872977B
- Authority
- CN
- China
- Prior art keywords
- carboxamide
- indazol
- pyridine
- hydroxypropan
- trifluoromethyl
- 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.)
- Active
Links
- 229940124291 BTK inhibitor Drugs 0.000 title description 17
- 229940127590 IRAK4 inhibitor Drugs 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 159
- 150000003839 salts Chemical class 0.000 claims abstract description 70
- 238000011282 treatment Methods 0.000 claims abstract description 47
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 14
- 230000002265 prevention Effects 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 10
- -1 2-hydroxypropan-2-yl Chemical group 0.000 claims description 217
- 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 claims description 71
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims description 68
- 229960001507 ibrutinib Drugs 0.000 claims description 68
- 210000004027 cell Anatomy 0.000 claims description 57
- 239000013066 combination product Substances 0.000 claims description 34
- 229940127555 combination product Drugs 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 34
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- KXBDTLQSDKGAEB-UHFFFAOYSA-N n-[3-[[5-fluoro-2-[4-(2-methoxyethoxy)anilino]pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound C1=CC(OCCOC)=CC=C1NC1=NC=C(F)C(NC=2C=C(NC(=O)C=C)C=CC=2)=N1 KXBDTLQSDKGAEB-UHFFFAOYSA-N 0.000 claims description 22
- ZTUJNJAKTLHBEX-UHFFFAOYSA-N 6-cyclopropyl-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=CC(C=2C(=C(C=CC=2)N2C(C3=C(F)C=C(C=C3C=C2)C2CC2)=O)CO)=CN(C)C1=O ZTUJNJAKTLHBEX-UHFFFAOYSA-N 0.000 claims description 20
- JIFCFQDXHMUPGP-UHFFFAOYSA-N 4-tert-butyl-n-[2-methyl-3-[4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxopyrazin-2-yl]phenyl]benzamide Chemical compound C1=CC=C(C=2N=C(NC=3C=CC(=CC=3)C(=O)N3CCOCC3)C(=O)N(C)C=2)C(C)=C1NC(=O)C1=CC=C(C(C)(C)C)C=C1 JIFCFQDXHMUPGP-UHFFFAOYSA-N 0.000 claims description 18
- 229960001756 oxaliplatin Drugs 0.000 claims description 16
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 16
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 11
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 10
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 10
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229960002197 temoporfin Drugs 0.000 claims description 10
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 8
- 229960001592 paclitaxel Drugs 0.000 claims description 8
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 claims description 8
- 229930012538 Paclitaxel Natural products 0.000 claims description 7
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 108010006654 Bleomycin Proteins 0.000 claims description 6
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 claims description 6
- 229960001561 bleomycin Drugs 0.000 claims description 6
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 6
- 229960003722 doxycycline Drugs 0.000 claims description 6
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims description 6
- 229940003234 medrox Drugs 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229940034208 thyroxine Drugs 0.000 claims description 6
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
- 229960005395 cetuximab Drugs 0.000 claims description 5
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 5
- 201000003444 follicular lymphoma Diseases 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 4
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 4
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 claims description 4
- WZNSJHMKGMYSPA-UHFFFAOYSA-N N-[2-(2-hydroxyethyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OCCN1N=C2C=C(C(=CC2=C1)NC(=O)C1=NC(=CC=C1)C(F)(F)F)C(C)(C)O WZNSJHMKGMYSPA-UHFFFAOYSA-N 0.000 claims description 4
- UDGUXBZYVQFQBZ-UHFFFAOYSA-N N-[2-(2-hydroxyethyl)-6-(hydroxymethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OCCN1N=C2C=C(C(=CC2=C1)NC(=O)C1=NC(=CC=C1)C(F)(F)F)CO UDGUXBZYVQFQBZ-UHFFFAOYSA-N 0.000 claims description 4
- GXOWUITWNVSHMM-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCCO)NC(=O)C1=NC(=CC=C1)C(F)(F)F GXOWUITWNVSHMM-UHFFFAOYSA-N 0.000 claims description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 4
- 229940011037 anethole Drugs 0.000 claims description 4
- 229960000397 bevacizumab Drugs 0.000 claims description 4
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 claims description 4
- 229960001573 cabazitaxel Drugs 0.000 claims description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 4
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 claims description 4
- 208000021937 marginal zone lymphoma Diseases 0.000 claims description 4
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 claims description 4
- IMSSROKUHAOUJS-MJCUULBUSA-N mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 claims description 4
- 229960001390 mestranol Drugs 0.000 claims description 4
- 229960003301 nivolumab Drugs 0.000 claims description 4
- RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 229960004641 rituximab Drugs 0.000 claims description 4
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 3
- LZENMJMJWQSSNJ-UHFFFAOYSA-N 3H-1,2-dithiole-3-thione Chemical compound S=C1C=CSS1 LZENMJMJWQSSNJ-UHFFFAOYSA-N 0.000 claims description 3
- ISYMNCGJTMTOLQ-UHFFFAOYSA-N 5-fluoro-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-methylpyridine-2-carboxamide Chemical compound FC=1C=CC(=NC=1C)C(=O)NC1=CC2=CN(N=C2C=C1C(C)(C)O)CCC(C)(C)O ISYMNCGJTMTOLQ-UHFFFAOYSA-N 0.000 claims description 3
- RYFZQBGEZMHRHH-UHFFFAOYSA-N 6-(2-hydroxypropan-2-yl)-N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)indazol-5-yl]pyridine-2-carboxamide Chemical compound OC(C)(C)C1=CC=CC(=N1)C(=O)NC1=CC2=CN(N=C2C=C1C(C)(C)O)CCCC(F)(F)F RYFZQBGEZMHRHH-UHFFFAOYSA-N 0.000 claims description 3
- KUVQZECJMMGNIY-UHFFFAOYSA-N 6-(difluoromethyl)-N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]pyridine-2-carboxamide Chemical compound FC(C1=CC=CC(=N1)C(=O)NC1=CC2=CN(N=C2C=C1C(C)(C)O)CCC(C)(C)O)F KUVQZECJMMGNIY-UHFFFAOYSA-N 0.000 claims description 3
- SAXMIUJPMUUWAN-UHFFFAOYSA-N 6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-2-(3-hydroxypropyl)indazol-5-yl]pyridine-2-carboxamide Chemical compound FC(C1=CC=CC(=N1)C(=O)NC1=CC2=CN(N=C2C=C1C(C)(C)O)CCCO)F SAXMIUJPMUUWAN-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- NWFPCWIBSBZRGV-UHFFFAOYSA-N N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(CCN1N=C2C=C(C(=CC2=C1)NC(=O)C1=NC(=CC=C1)C(F)(F)F)C(C)(C)O)(C)C NWFPCWIBSBZRGV-UHFFFAOYSA-N 0.000 claims description 3
- ZGLSMCVMIIQWMG-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-(2-methoxyethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F ZGLSMCVMIIQWMG-UHFFFAOYSA-N 0.000 claims description 3
- CDOUYADANCIGNZ-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-(3-methoxypropyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F CDOUYADANCIGNZ-UHFFFAOYSA-N 0.000 claims description 3
- PSPYNMNPWFRZGB-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-(4,4,4-trifluorobutyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCCC(F)(F)F)NC(=O)C1=NC(=CC=C1)C(F)(F)F PSPYNMNPWFRZGB-UHFFFAOYSA-N 0.000 claims description 3
- VFSGNUGYEMFXMN-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-(oxetan-3-ylmethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CC1COC1)NC(=O)C1=NC(=CC=C1)C(F)(F)F VFSGNUGYEMFXMN-UHFFFAOYSA-N 0.000 claims description 3
- ANRGZJLZBFJJTI-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-[3-(2,2,2-trifluoroethoxy)propyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCCOCC(F)(F)F)NC(=O)C1=NC(=CC=C1)C(F)(F)F ANRGZJLZBFJJTI-UHFFFAOYSA-N 0.000 claims description 3
- ZLISGGOEUZKZCL-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-2-[3-(trifluoromethoxy)propyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C=1C(=CC2=CN(N=C2C=1)CCCOC(F)(F)F)NC(=O)C1=NC(=CC=C1)C(F)(F)F ZLISGGOEUZKZCL-UHFFFAOYSA-N 0.000 claims description 3
- ZNGQNAHACQRGPL-UHFFFAOYSA-N N-[6-(hydroxymethyl)-2-(2-methoxyethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OCC=1C(=CC2=CN(N=C2C=1)CCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F ZNGQNAHACQRGPL-UHFFFAOYSA-N 0.000 claims description 3
- ORYDQYYBRXGJBR-UHFFFAOYSA-N N-[6-(hydroxymethyl)-2-(3-methoxypropyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OCC=1C(=CC2=CN(N=C2C=1)CCCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F ORYDQYYBRXGJBR-UHFFFAOYSA-N 0.000 claims description 3
- AUJQEAQOZZRWLQ-UHFFFAOYSA-N N-[6-(hydroxymethyl)-2-(oxetan-3-ylmethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OCC=1C(=CC2=CN(N=C2C=1)CC1COC1)NC(=O)C1=NC(=CC=C1)C(F)(F)F AUJQEAQOZZRWLQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960002833 aflibercept Drugs 0.000 claims description 3
- 108010081667 aflibercept Proteins 0.000 claims description 3
- 229960000548 alemtuzumab Drugs 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 229960005386 ipilimumab Drugs 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229960001972 panitumumab Drugs 0.000 claims description 3
- 229960002087 pertuzumab Drugs 0.000 claims description 3
- 229960004618 prednisone Drugs 0.000 claims description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229960003787 sorafenib Drugs 0.000 claims description 3
- 229960001796 sunitinib Drugs 0.000 claims description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 3
- 229960003433 thalidomide Drugs 0.000 claims description 3
- 229960000575 trastuzumab Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 claims description 2
- GDFGTRDCCWFXTG-SCTDSRPQSA-N (3r,4ar,10as)-3-(diethylsulfamoylamino)-6-hydroxy-1-propyl-3,4,4a,5,10,10a-hexahydro-2h-benzo[g]quinoline Chemical compound C1=CC=C2C[C@@H]3N(CCC)C[C@H](NS(=O)(=O)N(CC)CC)C[C@H]3CC2=C1O GDFGTRDCCWFXTG-SCTDSRPQSA-N 0.000 claims description 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims description 2
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 claims description 2
- SSNHGLKFJISNTR-DYSNNVSPSA-N (6ar,10ar)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1.C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 SSNHGLKFJISNTR-DYSNNVSPSA-N 0.000 claims description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 2
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 2
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 claims description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 2
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 claims description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 claims description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 claims description 2
- RYQOILLJDKPETL-UHFFFAOYSA-N 5-aminolevulinic acid hexyl ester Chemical compound CCCCCCOC(=O)CCC(=O)CN RYQOILLJDKPETL-UHFFFAOYSA-N 0.000 claims description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 2
- RYYCJUAHISIHTL-UHFFFAOYSA-N 5-azaorotic acid Chemical compound OC(=O)C1=NC(=O)NC(=O)N1 RYYCJUAHISIHTL-UHFFFAOYSA-N 0.000 claims description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 2
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 claims description 2
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 2
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 2
- 108090000935 Antithrombin III Proteins 0.000 claims description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 2
- 102000015790 Asparaginase Human genes 0.000 claims description 2
- 108010024976 Asparaginase Proteins 0.000 claims description 2
- VSEIDZLLWQQJGK-CHOZPQDDSA-N CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O Chemical compound CCC1=C(C)C2=N\C\1=C/C1=C(C)C(C(O)=O)=C(N1)\C(CC(=O)N[C@@H](CC(O)=O)C(O)=O)=C1/N=C(/C=C3\N/C(=C\2)C(C=C)=C3C)[C@@H](C)[C@@H]1CCC(O)=O VSEIDZLLWQQJGK-CHOZPQDDSA-N 0.000 claims description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 2
- 102000005367 Carboxypeptidases Human genes 0.000 claims description 2
- 108010006303 Carboxypeptidases Proteins 0.000 claims description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 claims description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 claims description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
- 108010092160 Dactinomycin Proteins 0.000 claims description 2
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 2
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 claims description 2
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 claims description 2
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 2
- 108010079505 Endostatins Proteins 0.000 claims description 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 2
- 208000009849 Female Genital Neoplasms Diseases 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 2
- ZPLQIPFOCGIIHV-UHFFFAOYSA-N Gimeracil Chemical compound OC1=CC(=O)C(Cl)=CN1 ZPLQIPFOCGIIHV-UHFFFAOYSA-N 0.000 claims description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 2
- VDJHFHXMUKFKET-UHFFFAOYSA-N Ingenol mebutate Natural products CC1CC2C(C)(C)C2C2C=C(CO)C(O)C3(O)C(OC(=O)C(C)=CC)C(C)=CC31C2=O VDJHFHXMUKFKET-UHFFFAOYSA-N 0.000 claims description 2
- 102000006992 Interferon-alpha Human genes 0.000 claims description 2
- 108010047761 Interferon-alpha Proteins 0.000 claims description 2
- 102000003996 Interferon-beta Human genes 0.000 claims description 2
- 108090000467 Interferon-beta Proteins 0.000 claims description 2
- 102000008070 Interferon-gamma Human genes 0.000 claims description 2
- 108010074328 Interferon-gamma Proteins 0.000 claims description 2
- NHTGHBARYWONDQ-JTQLQIEISA-N L-α-methyl-Tyrosine Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C=C1 NHTGHBARYWONDQ-JTQLQIEISA-N 0.000 claims description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims description 2
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 claims description 2
- 229920001491 Lentinan Polymers 0.000 claims description 2
- 108010000817 Leuprolide Proteins 0.000 claims description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N Methoxsalen Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 claims description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 claims description 2
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- AXDLCFOOGCNDST-UHFFFAOYSA-N N-methyl-DL-tyrosine Natural products CNC(C(O)=O)CC1=CC=C(O)C=C1 AXDLCFOOGCNDST-UHFFFAOYSA-N 0.000 claims description 2
- 108010021717 Nafarelin Proteins 0.000 claims description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 claims description 2
- 206010029098 Neoplasm skin Diseases 0.000 claims description 2
- 108010016076 Octreotide Proteins 0.000 claims description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 2
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 claims description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- 229920000388 Polyphosphate Polymers 0.000 claims description 2
- 239000005822 Propiconazole Substances 0.000 claims description 2
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 claims description 2
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 claims description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims description 2
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052772 Samarium Inorganic materials 0.000 claims description 2
- 108010086019 Secretin Proteins 0.000 claims description 2
- 102100037505 Secretin Human genes 0.000 claims description 2
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 2
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 2
- LKAJKIOFIWVMDJ-IYRCEVNGSA-N Stanazolol Chemical compound C([C@@H]1CC[C@H]2[C@@H]3CC[C@@]([C@]3(CC[C@@H]2[C@@]1(C)C1)C)(O)C)C2=C1C=NN2 LKAJKIOFIWVMDJ-IYRCEVNGSA-N 0.000 claims description 2
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 claims description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 claims description 2
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 claims description 2
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 2
- 102000036693 Thrombopoietin Human genes 0.000 claims description 2
- 108010041111 Thrombopoietin Proteins 0.000 claims description 2
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 claims description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 2
- PCWZKQSKUXXDDJ-UHFFFAOYSA-N Xanthotoxin Natural products COCc1c2OC(=O)C=Cc2cc3ccoc13 PCWZKQSKUXXDDJ-UHFFFAOYSA-N 0.000 claims description 2
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 claims description 2
- XJXKGUZINMNEDK-GPJOBVNKSA-L [(4r,5r)-5-(aminomethyl)-2-propan-2-yl-1,3-dioxolan-4-yl]methanamine;platinum(2+);propanedioate Chemical compound [Pt+2].[O-]C(=O)CC([O-])=O.CC(C)C1O[C@H](CN)[C@@H](CN)O1 XJXKGUZINMNEDK-GPJOBVNKSA-L 0.000 claims description 2
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 claims description 2
- LGXRRVXXRJRTHK-CWTMBVSESA-I [OH-].[Cl-].[99Tc+5].[O-]C(=O)CNCCNCC([O-])=O.C[C@@H](O)[C@@H](CO)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)c2ccc(NN)nc2)C(=O)N[C@@H](Cc2ccc([O-])cc2)C(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 Chemical compound [OH-].[Cl-].[99Tc+5].[O-]C(=O)CNCCNCC([O-])=O.C[C@@H](O)[C@@H](CO)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)c2ccc(NN)nc2)C(=O)N[C@@H](Cc2ccc([O-])cc2)C(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 LGXRRVXXRJRTHK-CWTMBVSESA-I 0.000 claims description 2
- 229960002184 abarelix Drugs 0.000 claims description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 claims description 2
- 108010023617 abarelix Proteins 0.000 claims description 2
- 229960000853 abiraterone Drugs 0.000 claims description 2
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 claims description 2
- 229960003526 acipimox Drugs 0.000 claims description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims description 2
- 229960004176 aclarubicin Drugs 0.000 claims description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 2
- 229960001686 afatinib Drugs 0.000 claims description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims description 2
- 108700025316 aldesleukin Proteins 0.000 claims description 2
- 229960005310 aldesleukin Drugs 0.000 claims description 2
- 229960004343 alendronic acid Drugs 0.000 claims description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- 229960000473 altretamine Drugs 0.000 claims description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims description 2
- 229960003437 aminoglutethimide Drugs 0.000 claims description 2
- 229960002550 amrubicin Drugs 0.000 claims description 2
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 claims description 2
- 229960001220 amsacrine Drugs 0.000 claims description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 2
- 229960002932 anastrozole Drugs 0.000 claims description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 2
- 229950006323 angiotensin ii Drugs 0.000 claims description 2
- 229960005348 antithrombin iii Drugs 0.000 claims description 2
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 claims description 2
- 229960001372 aprepitant Drugs 0.000 claims description 2
- UVJYAKBJSGRTHA-ZCRGAIPPSA-N arglabin Chemical compound C1C[C@H]2C(=C)C(=O)O[C@@H]2[C@@H]2C(C)=CC[C@]32O[C@]31C UVJYAKBJSGRTHA-ZCRGAIPPSA-N 0.000 claims description 2
- UVJYAKBJSGRTHA-UHFFFAOYSA-N arglabin Natural products C1CC2C(=C)C(=O)OC2C2C(C)=CCC32OC31C UVJYAKBJSGRTHA-UHFFFAOYSA-N 0.000 claims description 2
- 229960003272 asparaginase Drugs 0.000 claims description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- 239000011324 bead Substances 0.000 claims description 2
- 229960002707 bendamustine Drugs 0.000 claims description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 2
- 229960000997 bicalutamide Drugs 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 claims description 2
- 229960001292 cabozantinib Drugs 0.000 claims description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims description 2
- 239000011687 calcium folinate Substances 0.000 claims description 2
- 235000008207 calcium folinate Nutrition 0.000 claims description 2
- 229960001921 calcium levofolinate Drugs 0.000 claims description 2
- 229960004117 capecitabine Drugs 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 229960002438 carfilzomib Drugs 0.000 claims description 2
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 claims description 2
- 108010021331 carfilzomib Proteins 0.000 claims description 2
- 229960003261 carmofur Drugs 0.000 claims description 2
- 229960005243 carmustine Drugs 0.000 claims description 2
- 229960000590 celecoxib Drugs 0.000 claims description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 2
- 229960001602 ceritinib Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940045110 chitosan Drugs 0.000 claims description 2
- 229960004630 chlorambucil Drugs 0.000 claims description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 2
- 229960000724 cidofovir Drugs 0.000 claims description 2
- 229960003315 cinacalcet Drugs 0.000 claims description 2
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960002436 cladribine Drugs 0.000 claims description 2
- 229960002286 clodronic acid Drugs 0.000 claims description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 claims description 2
- 229960000928 clofarabine Drugs 0.000 claims description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 claims description 2
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 claims description 2
- 229950002550 copanlisib Drugs 0.000 claims description 2
- 229960005061 crizotinib Drugs 0.000 claims description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims description 2
- 229960003843 cyproterone Drugs 0.000 claims description 2
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- 229960003901 dacarbazine Drugs 0.000 claims description 2
- 229960000640 dactinomycin Drugs 0.000 claims description 2
- 229960002448 dasatinib Drugs 0.000 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 2
- 229960003603 decitabine Drugs 0.000 claims description 2
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 2
- 229960001271 desloratadine Drugs 0.000 claims description 2
- 108700025485 deslorelin Proteins 0.000 claims description 2
- 229960005408 deslorelin Drugs 0.000 claims description 2
- 229960000605 dexrazoxane Drugs 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- 229960004242 dronabinol Drugs 0.000 claims description 2
- 201000011523 endocrine gland cancer Diseases 0.000 claims description 2
- 229950011487 enocitabine Drugs 0.000 claims description 2
- 229960004671 enzalutamide Drugs 0.000 claims description 2
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 229950006835 eptaplatin Drugs 0.000 claims description 2
- 229960003649 eribulin Drugs 0.000 claims description 2
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 claims description 2
- 229960001433 erlotinib Drugs 0.000 claims description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004770 esomeprazole Drugs 0.000 claims description 2
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229960005309 estradiol Drugs 0.000 claims description 2
- 229930182833 estradiol Natural products 0.000 claims description 2
- 229960001842 estramustine Drugs 0.000 claims description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 2
- 229940009626 etidronate Drugs 0.000 claims description 2
- 229960005420 etoposide Drugs 0.000 claims description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 2
- 229960005167 everolimus Drugs 0.000 claims description 2
- 229960000255 exemestane Drugs 0.000 claims description 2
- 229950011548 fadrozole Drugs 0.000 claims description 2
- 229960002428 fentanyl Drugs 0.000 claims description 2
- 229960000961 floxuridine Drugs 0.000 claims description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960000390 fludarabine Drugs 0.000 claims description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
- 229960002949 fluorouracil Drugs 0.000 claims description 2
- 229960002074 flutamide Drugs 0.000 claims description 2
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000304 folic acid Drugs 0.000 claims description 2
- 235000019152 folic acid Nutrition 0.000 claims description 2
- 239000011724 folic acid Substances 0.000 claims description 2
- 229960004421 formestane Drugs 0.000 claims description 2
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 claims description 2
- 229960002891 fosaprepitant Drugs 0.000 claims description 2
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 claims description 2
- 229960002258 fulvestrant Drugs 0.000 claims description 2
- 229960003411 gadobutrol Drugs 0.000 claims description 2
- 229960005451 gadoteridol Drugs 0.000 claims description 2
- DPNNNPAKRZOSMO-UHFFFAOYSA-K gadoteridol Chemical compound [Gd+3].CC(O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 DPNNNPAKRZOSMO-UHFFFAOYSA-K 0.000 claims description 2
- 229940044658 gallium nitrate Drugs 0.000 claims description 2
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 claims description 2
- 229960003794 ganirelix Drugs 0.000 claims description 2
- 108700032141 ganirelix Proteins 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- 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 2
- 229960005277 gemcitabine Drugs 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 229950009822 gimeracil Drugs 0.000 claims description 2
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 claims description 2
- 229960003727 granisetron Drugs 0.000 claims description 2
- 210000003714 granulocyte Anatomy 0.000 claims description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940097293 hexyl 5-aminolevulinate Drugs 0.000 claims description 2
- 229960004931 histamine dihydrochloride Drugs 0.000 claims description 2
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 claims description 2
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 claims description 2
- 108700020746 histrelin Proteins 0.000 claims description 2
- 229960002193 histrelin Drugs 0.000 claims description 2
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 claims description 2
- 229960005236 ibandronic acid Drugs 0.000 claims description 2
- 229960000908 idarubicin Drugs 0.000 claims description 2
- 229960001101 ifosfamide Drugs 0.000 claims description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound 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 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002411 imatinib Drugs 0.000 claims description 2
- LWRDQHOZTAOILO-UHFFFAOYSA-N incadronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)NC1CCCCCC1 LWRDQHOZTAOILO-UHFFFAOYSA-N 0.000 claims description 2
- 229950006971 incadronic acid Drugs 0.000 claims description 2
- VDJHFHXMUKFKET-WDUFCVPESA-N ingenol mebutate Chemical compound C[C@@H]1C[C@H]2C(C)(C)[C@H]2[C@@H]2C=C(CO)[C@@H](O)[C@]3(O)[C@@H](OC(=O)C(\C)=C/C)C(C)=C[C@]31C2=O VDJHFHXMUKFKET-WDUFCVPESA-N 0.000 claims description 2
- 229960002993 ingenol mebutate Drugs 0.000 claims description 2
- 229960003130 interferon gamma Drugs 0.000 claims description 2
- 229960001388 interferon-beta Drugs 0.000 claims description 2
- NJKDOADNQSYQEV-UHFFFAOYSA-N iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 claims description 2
- 229960000780 iomeprol Drugs 0.000 claims description 2
- 229960004768 irinotecan Drugs 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 2
- 229960004130 itraconazole Drugs 0.000 claims description 2
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 claims description 2
- 229960002014 ixabepilone Drugs 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 229960002437 lanreotide Drugs 0.000 claims description 2
- 108010021336 lanreotide Proteins 0.000 claims description 2
- 229960003174 lansoprazole Drugs 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- 229960004942 lenalidomide Drugs 0.000 claims description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 2
- 229940115286 lentinan Drugs 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 2
- 229960004338 leuprorelin Drugs 0.000 claims description 2
- 229960001614 levamisole Drugs 0.000 claims description 2
- 229960004400 levonorgestrel Drugs 0.000 claims description 2
- 229960003918 levothyroxine sodium Drugs 0.000 claims description 2
- 229960003587 lisuride Drugs 0.000 claims description 2
- 229950008991 lobaplatin Drugs 0.000 claims description 2
- 229960002247 lomustine Drugs 0.000 claims description 2
- 229960003538 lonidamine Drugs 0.000 claims description 2
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 claims description 2
- 208000037841 lung tumor Diseases 0.000 claims description 2
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 claims description 2
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 2
- 229960004616 medroxyprogesterone Drugs 0.000 claims description 2
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 claims description 2
- 229960001786 megestrol Drugs 0.000 claims description 2
- 229960001924 melphalan Drugs 0.000 claims description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 2
- 229960001428 mercaptopurine Drugs 0.000 claims description 2
- 229960004469 methoxsalen Drugs 0.000 claims description 2
- YUUAYBAIHCDHHD-UHFFFAOYSA-N methyl 5-aminolevulinate Chemical compound COC(=O)CCC(=O)CN YUUAYBAIHCDHHD-UHFFFAOYSA-N 0.000 claims description 2
- 229960005033 methyl aminolevulinate Drugs 0.000 claims description 2
- 229960004584 methylprednisolone Drugs 0.000 claims description 2
- 229960001566 methyltestosterone Drugs 0.000 claims description 2
- 229960003775 miltefosine Drugs 0.000 claims description 2
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 claims description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 2
- 229960005485 mitobronitol Drugs 0.000 claims description 2
- 229960003539 mitoguazone Drugs 0.000 claims description 2
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 2
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 claims description 2
- 229950010913 mitolactol Drugs 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 229960000350 mitotane Drugs 0.000 claims description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001156 mitoxantrone Drugs 0.000 claims description 2
- 229950007699 mogamulizumab Drugs 0.000 claims description 2
- 229960005195 morphine hydrochloride Drugs 0.000 claims description 2
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 claims description 2
- 229960004715 morphine sulfate Drugs 0.000 claims description 2
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 claims description 2
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 claims description 2
- 229960002333 nafarelin Drugs 0.000 claims description 2
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims description 2
- 229960004127 naloxone Drugs 0.000 claims description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 2
- 229960003086 naltrexone Drugs 0.000 claims description 2
- 229950007221 nedaplatin Drugs 0.000 claims description 2
- 229960000801 nelarabine Drugs 0.000 claims description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 claims description 2
- 229950010733 neridronic acid Drugs 0.000 claims description 2
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 claims description 2
- 229960001346 nilotinib Drugs 0.000 claims description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 2
- 229960002653 nilutamide Drugs 0.000 claims description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 2
- 229960004918 nimorazole Drugs 0.000 claims description 2
- MDJFHRLTPRPZLY-UHFFFAOYSA-N nimorazole Chemical compound [O-][N+](=O)C1=CN=CN1CCN1CCOCC1 MDJFHRLTPRPZLY-UHFFFAOYSA-N 0.000 claims description 2
- 229950010203 nimotuzumab Drugs 0.000 claims description 2
- 229960001420 nimustine Drugs 0.000 claims description 2
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 claims description 2
- 229960002700 octreotide Drugs 0.000 claims description 2
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 claims description 2
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 claims description 2
- 229960000381 omeprazole Drugs 0.000 claims description 2
- 229950000193 oteracil Drugs 0.000 claims description 2
- 229960002131 palonosetron Drugs 0.000 claims description 2
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 claims description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003978 pamidronic acid Drugs 0.000 claims description 2
- 229960005019 pantoprazole Drugs 0.000 claims description 2
- 229960000639 pazopanib Drugs 0.000 claims description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 2
- 229960005079 pemetrexed Drugs 0.000 claims description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 2
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 claims description 2
- 229960005301 pentazocine Drugs 0.000 claims description 2
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 claims description 2
- 229950003332 perflubutane Drugs 0.000 claims description 2
- 229960001416 pilocarpine Drugs 0.000 claims description 2
- 229960001221 pirarubicin Drugs 0.000 claims description 2
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 claims description 2
- 229960004403 pixantrone Drugs 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229960003171 plicamycin Drugs 0.000 claims description 2
- 239000001205 polyphosphate Substances 0.000 claims description 2
- 235000011176 polyphosphates Nutrition 0.000 claims description 2
- 108010001062 polysaccharide-K Proteins 0.000 claims description 2
- 229940034049 polysaccharide-k Drugs 0.000 claims description 2
- 229960000688 pomalidomide Drugs 0.000 claims description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 2
- 229960004293 porfimer sodium Drugs 0.000 claims description 2
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 claims description 2
- 229960000214 pralatrexate Drugs 0.000 claims description 2
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 2
- 229960000624 procarbazine Drugs 0.000 claims description 2
- STJLVHWMYQXCPB-UHFFFAOYSA-N propiconazole Chemical compound O1C(CCC)COC1(C=1C(=CC(Cl)=CC=1)Cl)CN1N=CN=C1 STJLVHWMYQXCPB-UHFFFAOYSA-N 0.000 claims description 2
- 229960003712 propranolol Drugs 0.000 claims description 2
- 229960000924 quinagolide Drugs 0.000 claims description 2
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 2
- 229960004157 rabeprazole Drugs 0.000 claims description 2
- 229950011613 racotumomab Drugs 0.000 claims description 2
- 229960005562 radium-223 Drugs 0.000 claims description 2
- HCWPIIXVSYCSAN-OIOBTWANSA-N radium-223 Chemical compound [223Ra] HCWPIIXVSYCSAN-OIOBTWANSA-N 0.000 claims description 2
- 229960004622 raloxifene Drugs 0.000 claims description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 2
- 229960004432 raltitrexed Drugs 0.000 claims description 2
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 claims description 2
- 229950001588 ramosetron Drugs 0.000 claims description 2
- 229960002633 ramucirumab Drugs 0.000 claims description 2
- 229960003876 ranibizumab Drugs 0.000 claims description 2
- 229960002185 ranimustine Drugs 0.000 claims description 2
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims description 2
- 229960000620 ranitidine Drugs 0.000 claims description 2
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 claims description 2
- 229960000759 risedronic acid Drugs 0.000 claims description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 2
- 229960003452 romidepsin Drugs 0.000 claims description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 claims description 2
- 108010091666 romidepsin Proteins 0.000 claims description 2
- 229960002101 secretin Drugs 0.000 claims description 2
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 claims description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 claims description 2
- 229960002073 sertraline Drugs 0.000 claims description 2
- 201000004477 skin sarcoma Diseases 0.000 claims description 2
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 2
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 2
- FWYUJENICVGSJH-UHFFFAOYSA-M sodium;2-[bis[2-[2-(2-methyl-5-nitroimidazol-1-yl)ethoxy]-2-oxoethyl]amino]acetate Chemical compound [Na+].CC1=NC=C([N+]([O-])=O)N1CCOC(=O)CN(CC([O-])=O)CC(=O)OCCN1C([N+]([O-])=O)=CN=C1C FWYUJENICVGSJH-UHFFFAOYSA-M 0.000 claims description 2
- 229960000912 stanozolol Drugs 0.000 claims description 2
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 229960001052 streptozocin Drugs 0.000 claims description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 2
- 229950010924 talaporfin Drugs 0.000 claims description 2
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 claims description 2
- 229950010130 tamibarotene Drugs 0.000 claims description 2
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 229960002613 tamsulosin Drugs 0.000 claims description 2
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 claims description 2
- 229960005126 tapentadol Drugs 0.000 claims description 2
- 229950000864 technetium (99mtc) nofetumomab merpentan Drugs 0.000 claims description 2
- 229960001674 tegafur Drugs 0.000 claims description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 2
- 229960003188 temazepam Drugs 0.000 claims description 2
- 229960004964 temozolomide Drugs 0.000 claims description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 2
- 229960001278 teniposide Drugs 0.000 claims description 2
- 229960003604 testosterone Drugs 0.000 claims description 2
- 229960002952 tipiracil Drugs 0.000 claims description 2
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004066 trametinib Drugs 0.000 claims description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960001612 trastuzumab emtansine Drugs 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960003962 trifluridine Drugs 0.000 claims description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 claims description 2
- 229960004824 triptorelin Drugs 0.000 claims description 2
- 229960000875 trofosfamide Drugs 0.000 claims description 2
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 230000002485 urinary effect Effects 0.000 claims description 2
- 229960000653 valrubicin Drugs 0.000 claims description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 2
- 229960003048 vinblastine Drugs 0.000 claims description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims description 2
- 229960004355 vindesine Drugs 0.000 claims description 2
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 claims description 2
- 229960000922 vinflunine Drugs 0.000 claims description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 2
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- 229960004449 vismodegib Drugs 0.000 claims description 2
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 claims description 2
- 229960004276 zoledronic acid Drugs 0.000 claims description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000641 zorubicin Drugs 0.000 claims description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 claims description 2
- 208000002352 blister Diseases 0.000 claims 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 claims 2
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 claims 1
- 102000005862 Angiotensin II Human genes 0.000 claims 1
- 102000004411 Antithrombin III Human genes 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 102400001047 Endostatin Human genes 0.000 claims 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims 1
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 claims 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims 1
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims 1
- 241001061127 Thione Species 0.000 claims 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 claims 1
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 claims 1
- 108010036027 erythrogenin Proteins 0.000 claims 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 claims 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims 1
- 229960003180 glutathione Drugs 0.000 claims 1
- 235000003969 glutathione Nutrition 0.000 claims 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims 1
- 208000020816 lung neoplasm Diseases 0.000 claims 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 42
- 239000002207 metabolite Substances 0.000 abstract description 19
- 208000035475 disorder Diseases 0.000 abstract description 10
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 230000001613 neoplastic effect Effects 0.000 abstract description 5
- 229940127557 pharmaceutical product Drugs 0.000 abstract description 5
- 230000006806 disease prevention Effects 0.000 abstract description 3
- 201000009273 Endometriosis Diseases 0.000 abstract description 2
- 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 abstract description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract 1
- 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 abstract 1
- 201000004681 Psoriasis Diseases 0.000 abstract 1
- 208000002780 macular degeneration Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
- 239000000543 intermediate Substances 0.000 description 114
- 239000000203 mixture Substances 0.000 description 111
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 100
- 239000000243 solution Substances 0.000 description 89
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 74
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 71
- 238000000034 method Methods 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 47
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 239000000126 substance Substances 0.000 description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 32
- 230000000694 effects Effects 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 230000002209 hydrophobic effect Effects 0.000 description 27
- 230000019491 signal transduction Effects 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000003480 eluent Substances 0.000 description 24
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 23
- 108010072621 Interleukin-1 Receptor-Associated Kinases Proteins 0.000 description 23
- 102000006940 Interleukin-1 Receptor-Associated Kinases Human genes 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 208000028911 Temporomandibular Joint disease Diseases 0.000 description 21
- 208000008963 Transient myeloproliferative syndrome Diseases 0.000 description 21
- 238000002953 preparative HPLC Methods 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 20
- 239000001257 hydrogen Substances 0.000 description 20
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 20
- 239000011780 sodium chloride Substances 0.000 description 20
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 19
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 229910052731 fluorine Inorganic materials 0.000 description 17
- 239000011737 fluorine Substances 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000000470 constituent Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 14
- 102000003945 NF-kappa B Human genes 0.000 description 14
- 108010057466 NF-kappa B Proteins 0.000 description 14
- 238000003556 assay Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 101100016516 Caenorhabditis elegans hbl-1 gene Proteins 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 230000003833 cell viability Effects 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 11
- 150000002367 halogens Chemical class 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- 238000009097 single-agent therapy Methods 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 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 10
- 235000019270 ammonium chloride Nutrition 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 description 9
- YDRFNWNCCSQRKX-UHFFFAOYSA-N methyl 5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1H-indazole-6-carboxylate Chemical compound COC(=O)C1=C(C=C2C=NNC2=C1)NC(=O)C1=NC(=CC=C1)C(F)(F)F YDRFNWNCCSQRKX-UHFFFAOYSA-N 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 102000002689 Toll-like receptor Human genes 0.000 description 8
- 108020000411 Toll-like receptor Proteins 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 150000001350 alkyl halides Chemical class 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 239000002158 endotoxin Substances 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 229920006008 lipopolysaccharide Polymers 0.000 description 8
- IJMHHZDBRUGXNO-UHFFFAOYSA-N n-[3-(8-anilinoimidazo[1,2-a]pyrazin-6-yl)phenyl]-4-tert-butylbenzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)NC1=CC=CC(C=2N=C(NC=3C=CC=CC=3)C3=NC=CN3C=2)=C1 IJMHHZDBRUGXNO-UHFFFAOYSA-N 0.000 description 8
- 230000003647 oxidation Effects 0.000 description 8
- 238000007254 oxidation reaction Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 210000003719 b-lymphocyte Anatomy 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000000105 evaporative light scattering detection Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
- VVLHQJDAUIPZFH-UHFFFAOYSA-N 4-[4-[[5-fluoro-4-[3-(prop-2-enoylamino)anilino]pyrimidin-2-yl]amino]phenoxy]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC=3N=C(NC=4C=C(NC(=O)C=C)C=CC=4)C(F)=CN=3)=CC=2)=C1 VVLHQJDAUIPZFH-UHFFFAOYSA-N 0.000 description 6
- RBFVGQWGOARJRU-UHFFFAOYSA-N 4-bromo-2-methylbutan-2-ol Chemical compound CC(C)(O)CCBr RBFVGQWGOARJRU-UHFFFAOYSA-N 0.000 description 6
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- GXFDGYNWYIRHBC-UHFFFAOYSA-N N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide Chemical compound OC(C)(C)C1=C(C=C2C=NNC2=C1)NC(=O)C1=NC(=CC=C1)C(F)(F)F GXFDGYNWYIRHBC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000012894 fetal calf serum Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 5
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 5
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000012054 celltiter-glo Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 230000000155 isotopic effect Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- LMEIFDLPUOSPCQ-UHFFFAOYSA-N methyl 5-amino-1h-indazole-6-carboxylate Chemical compound C1=C(N)C(C(=O)OC)=CC2=C1C=NN2 LMEIFDLPUOSPCQ-UHFFFAOYSA-N 0.000 description 5
- CDOOFZZILLRUQH-GDLZYMKVSA-N n-[3-[6-[4-[(2r)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide Chemical compound CN1CCN(C)C(=O)[C@H]1C(C=C1)=CC=C1NC1=NC(C=2C(=C(NC(=O)C=3SC=4CCCCC=4C=3)C=CC=2)C)=CN(C)C1=O CDOOFZZILLRUQH-GDLZYMKVSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- ZCVXLQRFZNQFKB-UHFFFAOYSA-N 6-(difluoromethyl)-N-[6-(2-hydroxypropan-2-yl)-1H-indazol-5-yl]pyridine-2-carboxamide Chemical compound FC(C1=CC=CC(=N1)C(=O)NC=1C=C2C=NNC2=CC=1C(C)(C)O)F ZCVXLQRFZNQFKB-UHFFFAOYSA-N 0.000 description 4
- 108091008875 B cell receptors Proteins 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- TUSICEWIXLMXEY-UHFFFAOYSA-N methyl 1h-indazole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=NNC2=C1 TUSICEWIXLMXEY-UHFFFAOYSA-N 0.000 description 4
- XNOYFHQBTFZNGS-UHFFFAOYSA-N methyl 5-amino-2-(3-hydroxy-3-methylbutyl)indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCC(C)(C)O)N XNOYFHQBTFZNGS-UHFFFAOYSA-N 0.000 description 4
- 125000003566 oxetanyl group Chemical group 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- QGMROEZDWJTIDW-UHFFFAOYSA-N 3-bromopropoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCCBr QGMROEZDWJTIDW-UHFFFAOYSA-N 0.000 description 3
- SEJLPXCPMNSRAM-GOSISDBHSA-N 6-amino-9-[(3r)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one Chemical compound C1N(C(=O)C#CC)CC[C@H]1N1C(=O)N(C=2C=CC(OC=3C=CC=CC=3)=CC=2)C2=C(N)N=CN=C21 SEJLPXCPMNSRAM-GOSISDBHSA-N 0.000 description 3
- CEVAKNPHVXAOEC-UHFFFAOYSA-N COC(=O)C=1C(=CC2=CN(N=C2C=1)CCO[Si](C)(C)C(C)(C)C)NC(=O)C1=NC(=CC=C1)C(F)(F)F Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCO[Si](C)(C)C(C)(C)C)NC(=O)C1=NC(=CC=C1)C(F)(F)F CEVAKNPHVXAOEC-UHFFFAOYSA-N 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100024134 Myeloid differentiation primary response protein MyD88 Human genes 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000005239 aroylamino group Chemical group 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 230000016396 cytokine production Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 239000010408 film Substances 0.000 description 3
- 230000005802 health problem Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- MGZDURYJRFLGHT-UHFFFAOYSA-N methyl 2-(2-methoxyethyl)-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F MGZDURYJRFLGHT-UHFFFAOYSA-N 0.000 description 3
- LQJKRWNLZDWLSO-UHFFFAOYSA-N methyl 2-(3-methoxypropyl)-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCCOC)NC(=O)C1=NC(=CC=C1)C(F)(F)F LQJKRWNLZDWLSO-UHFFFAOYSA-N 0.000 description 3
- OXUCPZPEFFQIAK-UHFFFAOYSA-N methyl 2-(oxetan-3-ylmethyl)-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CC1COC1)NC(=O)C1=NC(=CC=C1)C(F)(F)F OXUCPZPEFFQIAK-UHFFFAOYSA-N 0.000 description 3
- DEZHKDZFGIGNPH-UHFFFAOYSA-N methyl 5-nitro-1h-indazole-6-carboxylate Chemical compound C1=C([N+]([O-])=O)C(C(=O)OC)=CC2=C1C=NN2 DEZHKDZFGIGNPH-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- CDOOFZZILLRUQH-LJAQVGFWSA-N n-[3-[6-[4-[(2s)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide Chemical compound CN1CCN(C)C(=O)[C@@H]1C(C=C1)=CC=C1NC1=NC(C=2C(=C(NC(=O)C=3SC=4CCCCC=4C=3)C=CC=2)C)=CN(C)C1=O CDOOFZZILLRUQH-LJAQVGFWSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000001603 reducing effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 2
- LNDGACQEAYKNOI-UHFFFAOYSA-N 1,1,1-trifluoro-4-iodobutane Chemical compound FC(F)(F)CCCI LNDGACQEAYKNOI-UHFFFAOYSA-N 0.000 description 2
- RHGHLOLDKNPYPK-UHFFFAOYSA-N 1-(2-methylsulfanylethyl)pyrazole Chemical class CSCCN1N=CC=C1 RHGHLOLDKNPYPK-UHFFFAOYSA-N 0.000 description 2
- NIEGKADUBXVLHF-UHFFFAOYSA-N 1-bromo-2-methylsulfonylethane Chemical compound CS(=O)(=O)CCBr NIEGKADUBXVLHF-UHFFFAOYSA-N 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- OXSDDDKLMCHNHF-UHFFFAOYSA-N 2-(6-bromopyridin-2-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=CC(Br)=N1 OXSDDDKLMCHNHF-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 2
- SQFDBQCBXUWICP-OAHLLOKOSA-N 5-amino-1-[(3r)-1-cyanopiperidin-3-yl]-3-[4-(2,4-difluorophenoxy)phenyl]pyrazole-4-carboxamide Chemical compound NC(=O)C1=C(N)N([C@H]2CN(CCC2)C#N)N=C1C(C=C1)=CC=C1OC1=CC=C(F)C=C1F SQFDBQCBXUWICP-OAHLLOKOSA-N 0.000 description 2
- OKBHXGBLXDNJJD-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=N1 OKBHXGBLXDNJJD-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 102100026008 Breakpoint cluster region protein Human genes 0.000 description 2
- OHNJNVRNRQGBLO-UHFFFAOYSA-N COC(=O)C=1C(=CC2=CN(N=C2C=1)CCCO[Si](C)(C)C(C)(C)C)NC(=O)C1=NC(=CC=C1)C(F)(F)F Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCCO[Si](C)(C)C(C)(C)C)NC(=O)C1=NC(=CC=C1)C(F)(F)F OHNJNVRNRQGBLO-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 101710082751 Carboxypeptidase S1 homolog A Proteins 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241001295925 Gegenes Species 0.000 description 2
- 102000005720 Glutathione transferase Human genes 0.000 description 2
- 108010070675 Glutathione transferase Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 101150053046 MYD88 gene Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- DUDSAXPWHNQELI-UHFFFAOYSA-N N-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)indazol-5-yl]-6-methylpyridine-2-carboxamide Chemical compound OC(CCN1N=C2C=C(C(=CC2=C1)NC(=O)C1=NC(=CC=C1)C)C(C)(C)O)(C)C DUDSAXPWHNQELI-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001347 alkyl bromides Chemical class 0.000 description 2
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 229960000578 gemtuzumab Drugs 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000000021 kinase assay Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- GKUSBDMGEDQNAA-UHFFFAOYSA-N methyl 2-(3-hydroxy-3-methylbutyl)-5-[(6-methylpyridine-2-carbonyl)amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCC(C)(C)O)NC(=O)C1=NC(=CC=C1)C GKUSBDMGEDQNAA-UHFFFAOYSA-N 0.000 description 2
- UDVPBZCQGNVPHN-UHFFFAOYSA-N methyl 2-(3-hydroxy-3-methylbutyl)-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCC(C)(C)O)NC(=O)C1=NC(=CC=C1)C(F)(F)F UDVPBZCQGNVPHN-UHFFFAOYSA-N 0.000 description 2
- OYPRUNJNKMFMEF-UHFFFAOYSA-N methyl 2-(3-hydroxy-3-methylbutyl)-5-nitroindazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCC(C)(C)O)[N+](=O)[O-] OYPRUNJNKMFMEF-UHFFFAOYSA-N 0.000 description 2
- DQPZWNAETKTYAP-UHFFFAOYSA-N methyl 2-[3-(2,2,2-trifluoroethoxy)propyl]-5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCCOCC(F)(F)F)NC(=O)C1=NC(=CC=C1)C(F)(F)F DQPZWNAETKTYAP-UHFFFAOYSA-N 0.000 description 2
- DLKASDPFKFPAOZ-UHFFFAOYSA-N methyl 5-[(5-fluoro-6-methylpyridine-2-carbonyl)amino]-2-(3-hydroxy-3-methylbutyl)indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCC(C)(C)O)NC(=O)C1=NC(=C(C=C1)F)C DLKASDPFKFPAOZ-UHFFFAOYSA-N 0.000 description 2
- DHTBHRZOZUJUJE-UHFFFAOYSA-N methyl 5-[[6-(2-hydroxypropan-2-yl)pyridine-2-carbonyl]amino]-1H-indazole-6-carboxylate Chemical compound COC(=O)C1=C(C=C2C=NNC2=C1)NC(=O)C1=NC(=CC=C1)C(C)(C)O DHTBHRZOZUJUJE-UHFFFAOYSA-N 0.000 description 2
- XEBWJOFHGVSOKL-UHFFFAOYSA-N methyl 5-[[6-(2-hydroxypropan-2-yl)pyridine-2-carbonyl]amino]-2-(4,4,4-trifluorobutyl)indazole-6-carboxylate Chemical compound COC(=O)C=1C(=CC2=CN(N=C2C=1)CCCC(F)(F)F)NC(=O)C1=NC(=CC=C1)C(C)(C)O XEBWJOFHGVSOKL-UHFFFAOYSA-N 0.000 description 2
- WOZIBMAGLNSOOJ-UHFFFAOYSA-N methyl 5-[[6-(difluoromethyl)pyridine-2-carbonyl]amino]-1H-indazole-6-carboxylate Chemical compound COC(=O)C1=C(C=C2C=NNC2=C1)NC(=O)C1=NC(=CC=C1)C(F)F WOZIBMAGLNSOOJ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000001174 sulfone group Chemical group 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- YMSXHRWUGLAAKL-JXMROGBWSA-N (e)-4-(dimethylamino)-n-[7-fluoro-4-(2-methylanilino)imidazo[1,5-a]quinoxalin-8-yl]-n-methylbut-2-enamide Chemical compound C1=C(F)C(N(C)C(=O)/C=C/CN(C)C)=CC(N2C=NC=C22)=C1N=C2NC1=CC=CC=C1C YMSXHRWUGLAAKL-JXMROGBWSA-N 0.000 description 1
- FDWLNTGRJRNWPF-UHFFFAOYSA-N 1-(2-methylsulfinylethyl)pyrazole Chemical class CS(=O)CCN1N=CC=C1 FDWLNTGRJRNWPF-UHFFFAOYSA-N 0.000 description 1
- HNRMFGWBEPNWNV-UHFFFAOYSA-N 1-(2-methylsulfonylethyl)pyrazole Chemical class CS(=O)(=O)CCN1C=CC=N1 HNRMFGWBEPNWNV-UHFFFAOYSA-N 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- SRAVJVCBIFCNAB-UHFFFAOYSA-N 1-bromo-3-(2,2,2-trifluoroethoxy)propane Chemical compound FC(F)(F)COCCCBr SRAVJVCBIFCNAB-UHFFFAOYSA-N 0.000 description 1
- CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 1
- BNECODFCHDCLDN-UHFFFAOYSA-N 1-bromo-3-methylsulfonylpropane Chemical compound CS(=O)(=O)CCCBr BNECODFCHDCLDN-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- BHNQPLPANNDEGL-UHFFFAOYSA-N 2-(4-octylphenoxy)ethanol Chemical compound CCCCCCCCC1=CC=C(OCCO)C=C1 BHNQPLPANNDEGL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- JBKINHFZTVLNEM-UHFFFAOYSA-N 2-bromoethoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OCCBr JBKINHFZTVLNEM-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- IEDRUQXJIWTVIL-UHFFFAOYSA-N 3-(bromomethyl)oxetane Chemical compound BrCC1COC1 IEDRUQXJIWTVIL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- DKJIZESVWJPTPV-UHFFFAOYSA-N 3-(trifluoromethoxy)propan-1-ol Chemical compound OCCCOC(F)(F)F DKJIZESVWJPTPV-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- ZJEGUWBJHQZLDE-UHFFFAOYSA-N 5-fluoro-6-methylpyridine-2-carboxylic acid Chemical compound CC1=NC(C(O)=O)=CC=C1F ZJEGUWBJHQZLDE-UHFFFAOYSA-N 0.000 description 1
- MDLTVYZCSSUQJR-UHFFFAOYSA-N 5-nitro-6-propan-2-yloxy-1h-indazole Chemical compound C1=C([N+]([O-])=O)C(OC(C)C)=CC2=C1C=NN2 MDLTVYZCSSUQJR-UHFFFAOYSA-N 0.000 description 1
- CQOXJYFTHXMTNS-UHFFFAOYSA-N 6-(difluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(C(F)F)=N1 CQOXJYFTHXMTNS-UHFFFAOYSA-N 0.000 description 1
- LTUUGSGSUZRPRV-UHFFFAOYSA-N 6-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CC(C(O)=O)=N1 LTUUGSGSUZRPRV-UHFFFAOYSA-N 0.000 description 1
- QWDTVYCVSZMQCD-UHFFFAOYSA-N 6-propan-2-yloxy-1h-indazol-5-amine Chemical compound C1=C(N)C(OC(C)C)=CC2=C1C=NN2 QWDTVYCVSZMQCD-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 102100022977 Antithrombin-III Human genes 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000037914 B-cell disorder Diseases 0.000 description 1
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 108091012583 BCL2 Proteins 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 108091071247 Beta family Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 1
- 238000001061 Dunnett's test Methods 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 1
- 101100058683 Homo sapiens BTK gene Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000852483 Homo sapiens Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 1
- 101000852255 Homo sapiens Interleukin-1 receptor-associated kinase-like 2 Proteins 0.000 description 1
- 101000852965 Homo sapiens Interleukin-1 receptor-like 2 Proteins 0.000 description 1
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 description 1
- 101000981728 Homo sapiens Myeloid differentiation primary response protein MyD88 Proteins 0.000 description 1
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 1
- 229940099539 IL-36 receptor antagonist Drugs 0.000 description 1
- 101710199015 Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 1
- 102100036433 Interleukin-1 receptor-associated kinase-like 2 Human genes 0.000 description 1
- 102100036697 Interleukin-1 receptor-like 2 Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 102000004890 Interleukin-8 Human genes 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- XFAZZQREFHAALG-UHFFFAOYSA-N N-{1-amino-6-[(5-nitro-2-furoyl)amino]-1-oxohexan-2-yl}-23-(indol-3-yl)-20-oxo-4,7,10,13,16-pentaoxa-19-azatricosan-1-amide Chemical compound C=1NC2=CC=CC=C2C=1CCCC(=O)NCCOCCOCCOCCOCCOCCC(=O)NC(C(=O)N)CCCCNC(=O)C1=CC=C([N+]([O-])=O)O1 XFAZZQREFHAALG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102100024894 PR domain zinc finger protein 1 Human genes 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010009975 Positive Regulatory Domain I-Binding Factor 1 Proteins 0.000 description 1
- 108010012271 Positive Transcriptional Elongation Factor B Proteins 0.000 description 1
- 102000019014 Positive Transcriptional Elongation Factor B Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 229910052771 Terbium Inorganic materials 0.000 description 1
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- JRIZSBGDMDSKRF-DEGSGYPDSA-N [(2s,3s,4s,5s)-5-(6-aminopurin-9-yl)-3,4-diphosphonooxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1O[C@@H](COP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H]1OP(O)(O)=O JRIZSBGDMDSKRF-DEGSGYPDSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- HOXZTTLLQYHOES-UHFFFAOYSA-N benzotriazol-1-yloxymethyl-(dimethylamino)-dimethylazanium Chemical compound CN(C)[N+](C)(C)CON1C2=CC=CC=C2N=N1 HOXZTTLLQYHOES-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000003857 carboxamides Chemical group 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- WRXDGGCKOUEOPW-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)NS(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 WRXDGGCKOUEOPW-UHFFFAOYSA-N 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 239000008120 corn starch Substances 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
- 239000006071 cream Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229950006137 dexfosfoserine Drugs 0.000 description 1
- FFCZHQLUEDCQKI-UHFFFAOYSA-N diarsenic Chemical compound [As]#[As] FFCZHQLUEDCQKI-UHFFFAOYSA-N 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical class N=N RAABOESOVLLHRU-UHFFFAOYSA-N 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
- 230000004069 differentiation Effects 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- SLYTULCOCGSBBJ-UHFFFAOYSA-I disodium;2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [Na+].[Na+].[Gd+3].CCOC1=CC=C(CC(CN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)N(CC([O-])=O)CC([O-])=O)C=C1 SLYTULCOCGSBBJ-UHFFFAOYSA-I 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- CDFOARSBQKJGNL-UHFFFAOYSA-N ethyl 6-(hydroxymethyl)pyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=CC(CO)=N1 CDFOARSBQKJGNL-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 239000012997 ficoll-paque Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 150000002238 fumaric acids Chemical class 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 1
- 102000046806 human IRAK4 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000001023 inorganic pigment Substances 0.000 description 1
- 108040006732 interleukin-1 receptor activity proteins Proteins 0.000 description 1
- 102000014909 interleukin-1 receptor activity proteins Human genes 0.000 description 1
- 229940076144 interleukin-10 Drugs 0.000 description 1
- 108040002014 interleukin-18 receptor activity proteins Proteins 0.000 description 1
- 102000008625 interleukin-18 receptor activity proteins Human genes 0.000 description 1
- 108040007659 interleukin-33 receptor activity proteins Proteins 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- SIXIIKVOZAGHPV-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=C[CH]C2=N1 SIXIIKVOZAGHPV-UHFFFAOYSA-N 0.000 description 1
- 201000003445 large cell neuroendocrine carcinoma Diseases 0.000 description 1
- ANMYAHDLKVNJJO-LTCKWSDVSA-M levothyroxine sodium hydrate Chemical compound O.[Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 ANMYAHDLKVNJJO-LTCKWSDVSA-M 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000007422 luminescence assay Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- BJTDTBKTCFOZHD-UHFFFAOYSA-N methyl 2-amino-7-chloro-3-methylbenzimidazole-4-carboxylate Chemical class NC1=NC2=C(N1C)C(=CC=C2Cl)C(=O)OC BJTDTBKTCFOZHD-UHFFFAOYSA-N 0.000 description 1
- NXVBFFWYAHXWKB-UHFFFAOYSA-N methyl 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate Chemical compound OC(C)(C)C1=CC=CC(=N1)C(=O)OC NXVBFFWYAHXWKB-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- VBXSERPGINMTDE-UHFFFAOYSA-N phenyl(2-phenylphosphanylethyl)phosphane Chemical compound C=1C=CC=CC=1PCCPC1=CC=CC=C1 VBXSERPGINMTDE-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- DAGKLTFLYAJPIL-UHFFFAOYSA-M potassium 6-(2-hydroxypropan-2-yl)pyridine-2-carboxylate Chemical compound OC(C)(C)C1=CC=CC(=N1)C(=O)[O-].[K+] DAGKLTFLYAJPIL-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000000101 thioether 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
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical class [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940095188 zydelig Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本申请涉及用于治疗和/或预防疾病的至少两种组分(组分A和组分B)的新颖组合产品:组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;组分B是BTK抑制性化合物,或其药学上可接受的盐;和,任选地一种或多种组分C,其为药品;其中上文所定义的化合物A和B中的一者或两者任选地存在于准备用于同时、分开或依次给药的药物制剂中,且涉及其用于生产用于治疗和/或预防疾病,尤其用于治疗和/或预防子宫内膜异位、淋巴瘤、黄斑变性、COPD、赘生性病症和牛皮癣的药剂的用途。
Description
技术领域
本发明涉及至少两种组分(组分A和组分B)的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;
●组分B是BTK抑制性化合物;
和,任选地,
●一种或多种组分C,其为药品;
其中上文所定义的化合物A和B中的一者或两者任选地存在于准备用于同时、分开或依次给药的药物制剂中。
本发明的另一个方面涉及至少两种组分(组分A和组分B)的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;
●组分B是选自以下目录的BTK抑制性化合物:
○依鲁替尼(ibrutinib),或其药学上可接受的盐;
○4-叔丁基-N-[2-甲基-3-(4-甲基-6-{[4-(吗啉-4-基羰基)苯基]氨基}-5-氧代-4,5-二氢吡嗪-2-基)苯基]苯甲酰胺(CGI-1746,CAS910232-84-7);
○N-{3-[(5-氟-2-{[4-(2-甲氧基乙氧基)苯基]氨基}嘧啶-4-基)氨基]苯基}丙烯酰胺(AVL-292,CAS1202757-89-8);
○6-环丙基-8-氟-2-[2-(羟基甲基)-3-(1-甲基-5-{[5-(4-甲基哌嗪-1-基)吡啶-2-基]氨基}-6-氧代-1,6-二氢吡啶-3-基)苯基]异喹啉-1(2H)-酮(RN486,CAS1242156-23-5);
○HM71224;
○N-{3-[6-({4-[(2R)-1,4-二甲基-3-氧代哌嗪-2-基]苯基}氨基)-4-甲基-5-氧代-4,5-二氢吡嗪-2-基]-2-甲基苯基}-4,5,6,7-四氢-1-苯并噻吩-2-甲酰胺(GDC-0834,CAS1133432-50-4);
○5-氨基-1-[(3R)-1-氰基哌啶-3-基]-3-[4-(2,4-二氟苯氧基)苯基]-1H-吡唑-4-甲酰胺(PF-06250112,J Immunol2013;191:4540-4550);
○(2E)-4-(二甲基氨基)-N-{7-氟-4-[(2-甲基苯基)氨基]咪唑并[1,5-a]喹喔啉-8-基}-N-甲基丁-2烯酰胺(CAS1345250-62-5,Bioorg.Med.Chem.Lett.21(2011)6258-6262);
○N-[3-(8-苯胺基咪唑并[1,2-a]吡嗪-6-基)苯基]-4-叔丁基苯甲酰胺(CGI-560,CAS845269-74-1);
○4-{4-[(4-{[3-(芳酰基氨基)苯基]氨基}-5-氟嘧啶-2-基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺(CNX-774,CAS1202759-32-7);
○ONO-4059(Arthritis and rheumatism2012,64Suppl10:1660)。
本发明的另一个方面涉及如本文中所描述的此类组合产品用于生产用于治疗或预防疾病,具体而言用于治疗赘生性病症的药剂的用途。
本发明的又另一个方面涉及用于治疗或预防赘生性病症的方法,其中给药治疗有效量的如本文所定义的组合产品。
本发明还涉及试剂盒,其包含以下物质的组合产品:
●一种或多种组分A,其由如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物组成;
●组分B,其为BTK抑制性化合物,或其药学上可接受的盐。
本发明的另一个方面涉及至少两种组分(组分A和组分B)的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;
●组分B是选自以下目录的BTK抑制性化合物:
■依鲁替尼,或其药学上可接受的盐;
■4-叔丁基-N-[2-甲基-3-(4-甲基-6-{[4-(吗啉-4-基羰基)苯基]氨基}-5-氧代-4,5-二氢吡嗪-2-基)苯基]苯甲酰胺(CGI-1746,CAS910232-84-7);
■N-{3-[(5-氟-2-{[4-(2-甲氧基乙氧基)苯基]氨基}嘧啶-4-基)氨基]苯基}丙烯酰胺(AVL-292,CAS1202757-89-8);
■6-环丙基-8-氟-2-[2-(羟基甲基)-3-(1-甲基-5-{[5-(4-甲基哌嗪-1-基)吡啶-2-基]氨基}-6-氧代-1,6-二氢吡啶-3-基)苯基]异喹啉-1(2H)-酮(RN486,CAS1242156-23-5);
■HM71224;
■N-{3-[6-({4-[(2R)-1,4-二甲基-3-氧代哌嗪-2-基]苯基}氨基)-4-甲基-5-氧代-4,5-二氢吡嗪-2-基]-2-甲基苯基}-4,5,6,7-四氢-1-苯并噻吩-2-甲酰胺(GDC-0834,CAS1133432-50-4);
■5-氨基-1-[(3R)-1-氰基哌啶-3-基]-3-[4-(2,4-二氟苯氧基)苯基]-1H-吡唑-4-甲酰胺(PF-06250112,J Immunol2013;191:4540-4550);
■(2E)-4-(二甲基氨基)-N-{7-氟-4-[(2-甲基苯基)氨基]咪唑并[1,5-a]喹喔啉-8-基}-N-甲基丁-2烯酰胺(CAS1345250-62-5,Bioorg.Med.Chem.Lett.21(2011)6258-6262);
■N-[3-(8-苯胺基咪唑并[1,2-a]吡嗪-6-基)苯基]-4-叔丁基苯甲酰胺(CGI-560,CAS 845269-74-1);
■4-{4-[(4-{[3-(芳酰基氨基)苯基]氨基}-5-氟嘧啶-2-基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺(CNX-774,CAS1202759-32-7);
■ONO-4059(Arthritis and rheumatism2012,64Suppl10:1660),
和任选地-
一种或多种药品;
其中上文所定义的化合物A和B中的一者或两者任选地存在于准备用于同时、分开或依次给药的药物制剂中。
组分A可通过经口、静脉内、局部、腹膜内、经鼻、肠胃外、经肺、舌下、经舌、经颊、经直肠、经真皮、经皮或结膜途径、经由耳或作为植入物或支架,或作为储库给药。
组分B可通过经口、静脉内、局部、腹膜内、经鼻、肠胃外、经肺、舌下、经舌、经颊、经直肠、经真皮、经皮或结膜途径、经由耳或作为植入物或支架,或作为储库给药。
背景技术
组分A:IRAK4抑制剂:
人类IRAK4(白介素-1受体相关激酶4)在免疫系统的活化中起关键作用。因此,该激酶是开发炎症抑制物质的重要靶分子。IRAK4由多种细胞表达且介导除TLR3以外的Toll样受体(TLR)和由IL-1R(受体)、IL-18R、IL-33R和IL-36R组成的白介素(IL)-1β家族的受体的信号转导(Janeway和Medzhitov,Annu.Rev.Immunol.,2002;Dinarello,Annu.Rev.Immunol.,2009;Flannery和Bowie,Biochemical Pharmacology,2010)。
IRAK4敲除小鼠和来自缺乏IRAK4的患者的人类细胞都不对TLR(除TLR3以外)和IL-1β家族的刺激反应(Suzuki,Suzuki,等人,Nature,2002;Davidson,Currie,等人,TheJournal ofImmunology,2006;Ku,von Bernuth,等人,JEM,2007;Kim,Staschke,等人,JEM,2007)。
TLR配体或IL-1β家族的配体与各自受体的结合导致MyD88[髓样分化初次应答基因(88)]对受体的募集和结合。作为结果,MyD88与IRAK4相互作用,导致形成活性复合物,其与激酶IRAK1或IRAK2相互作用且使其活化(Kollewe,Mackensen,等人,Journal ofBiological Chemistry,2004;Precious等人,J.Biol.Chem.,2009)。作为其结果,NF(核因子)-kB信号传导途径和MAPK(丝裂原活化蛋白激酶)信号传导途径被活化(Wang,Deng,等人,Nature,2001)。NF-kB信号传导途径和MAPK信号传导途径的活化导致与不同免疫过程相关的过程。例如,存在各种炎性信号分子和酶(诸如细胞因子、趋化因子和COX-2(环加氧酶-2))的表达增加,例如,以及炎症相关基因(例如COX-2、IL-6、IL-8)的mRNA稳定性增加(Holtmann,Enninga,等人,Journal of Biological Chemistry,2001;Datta,Novotny,等人,The Journal of Immunology,2004)。此外,这些过程可与特定细胞类型(例如单核细胞、巨噬细胞、树突状细胞、T细胞和B细胞)的增殖和分化相关(Wan,Chi,等人,NatImmunol,2006;McGettrick和J.O'Neill,British Journal of Haematology,2007)。
这也适用于一些肿瘤病症。特定淋巴瘤(例如ABC-DLBCL(活化的B细胞样弥漫性大细胞B细胞淋巴瘤)、套细胞淋巴瘤和瓦尔登斯特伦氏病(disease)以及慢性淋巴白血病、黑色素瘤和肝细胞癌由MyD88中的突变或MyD88活性的变化表征,其可由IRAK4抑制剂治疗(Ngo,Young,等人,Nature,2011;Puente,Pinyol,等人,Nature,2011;Srivastava,Geng,等人,Cancer Research,2012;Treon,Xu,等人,New England Journalof Medicine,2012;Choi,Kim,等人,Human Pathology,2013;Liang,Chen,等人,ClinicalCancer Research,2013)。此外,MyD88在ras依赖性肿瘤中起重要作用,且因此IRAK4抑制剂也适用于其治疗(Kfoury,A.,K.L.Corf,等人,Journal of the National CancerInstitute,2013)。
弥漫性大细胞B细胞淋巴瘤(DLBCL)是成年人中的B淋巴细胞的侵袭性肿瘤和最常见的非霍奇金氏淋巴瘤(MortonLM等人,Blood2006)。在形态方面,DLBCL细分为中心母细胞性、免疫母细胞性和间变性淋巴瘤,其基于基因表达分成在PRDM1突变和BCL2、BCL6、MYC易位之后活化的B细胞样淋巴瘤(ABC-DLBCL)或增殖中心B细胞样淋巴瘤(GCB-DLBCL)和遗传性淋巴瘤。DLBCL的标准治疗为R-CHOP,化学治疗药物环磷酰胺、多柔比星、长春新碱和强的松(CHOP)以及利妥昔单抗(一种嵌合单克隆CD20受体抗体)的组合产品(Roschewski M等人,Nature Reviews Clinical Oncology,2014)。约三分之一患者不对标准治疗起反应或经历复发,其使得明确需要开发新的治疗药物(Friedberg,J.W.HematologyAm.Soc.Hematol.Educ.Program 2011)。ABC-DLBCL亚型占所有DLBCL的约30%且意指患者的最差预后(Siegel,R.,等人,CACancerJ.Clin.2013)。已显示NF-κB信号传导途径(其对DLBCL细胞的存活是重要的)由B细胞受体(BCR)和Toll样受体(TLR)的活化调节(Rawlings,D.J.,等人Nat.Rev.Immunol.2012)。在ABC-DLBCL中,NF-κB信号传导途径通常由这两个信号传导途径中的突变组成型活化(Compagno,M.等人Nature 2009)。在几乎30%的所有ABC-DLBCL中发现MYD88(TLR信号传导途径的衔接子蛋白)中的活化突变。这些突变导致IRAK4的活化和随后NF-κB信号传导途径、白介素-6/白介素-10分泌的刺激以及JAK-STAT信号传导途径的活化。已显示IRAK4在细胞活力调节中的必要作用(Ngo,VN等人Nature,2011)。BCR和MYD88信号传导途径的异常活化表明两个信号传导途径的阻断可以是治疗上有效的。依鲁替尼(PCI-32765)是布鲁顿酪氨酸激酶(BTK)(BCR信号传导途径的一种组分)的不可逆抑制剂(Winer ES,等人,Expert Opin.Investig.Drugs,2012)。在复发性DLBCL患者中的依鲁替尼的2期研究中,40%患者对用依鲁替尼的治疗起反应,其表明其他信号传导途径在DLBCL中相关(Wilson WH等人ASH Annu Meet Abstr 2012,120(21):686.)。已显示依鲁替尼和PI3K信号传导途径的各种抑制剂的组合产品以及依鲁替尼和BCL-2家族的抑制剂的组合产品对ABC-DLBCL中的细胞活力具有加成或协同作用(Mathews Griner LA等人,ProcNatlAcadSciUSA.2014)。
现有技术公开了多种IRAK4抑制剂(参见例如Annual Reports in MedicinalChemistry (2014),49,117–133)。
US8293923和US20130274241公开了具有3-取代的吲唑结构的IRAK4抑制剂。不存在对2-取代的吲唑类化合物的说明。
WO2013106254和WO2011153588公开了2,3-二取代的吲唑衍生物。
WO2007091107描述2-取代的吲唑衍生物,其用于治疗杜氏肌肉不良。所公开的化合物不具有6-羟基烷基取代。
WO2015091426描述吲唑类化合物,诸如在位置2被甲酰胺侧链取代的实施例64。
WO2015104662描述具有以下通式的2-取代的吲唑类化合物:
其中R2为烷基-或环烷基。明确报导了在2-位具有甲基、2-甲氧基乙基和环戊基基团的2-取代的吲唑类化合物(实施例1、4和76)。此外,实施例117代表在1-位具有羟基乙基取代基的吲唑衍生物。然而,未描述在1-位或2-位展现3-羟基-3-甲基丁基-取代基的吲唑衍生物。
在2-位展现羟基-取代的烷基的吲唑类化合物通常由WO2015104662中的通式涵盖,但未例举。
在位置2展现烷基的吲唑类化合物(其在2-烷基基团处被甲基磺酰基基团取代)不由WO2015104662中取代基R2的通式和定义涵盖。
WO2015104662描述吲唑类化合物,其中在位置6,所描述的R1的取代基的实例为环丙基、环己基、氰基、3-氟苯基和饱和杂环取代基。WO2015104662中未明确描述在位置6具有羟基-取代的烷基基团的吲唑类化合物。
WO2015193846公开具有以下通式的2-取代的吲唑类化合物:
其中Z1和Z2都是任选地取代的环烷基-、芳基-或杂芳基基团。R2可具有氢、卤素、氨基、任选地取代的烷基-、环烷基-、芳基-、杂环基-、芳基烷基-或杂环烷基基团的含义。明确描述吲唑衍生物,其中R2意味着甲基且Z1和/或Z2意味着杂芳基基团;-NH(C=O)Z1-Z2-(R3)n取代基结合至吲唑骨架的6-位。未描述结合至5-位的展现-NH(C=O)Z1-Z2-(R3)n取代基的吲唑衍生物。
组分B:BTK抑制剂:
布鲁顿酪氨酸激酶(BTK)是哺乳动物中的酶,其催化特定蛋白的磷酸化。其为在B细胞中特定表达的Tec家族的酪氨酸激酶之一。BTK在细胞内的B细胞受体信号的介导中发挥重要功能。人类BTK基因中的突变是被称为布鲁顿氏综合征(XLA)的原因。
迄今为止,除通过同种异体干细胞移植以外,慢性淋巴白血病(CLL)是不可治愈的,且具有特定风险因子(具体地17p缺失)的患者几乎不受益于任一CD20抗体。现在已今详细研究B细胞淋巴瘤所必需的B细胞受体的信号传导途径且已导致新的治疗途径。布鲁顿氏酪氨酸激酶(BTK)是该信号传导途径中的重要组分,且在2014年10月对BTK抑制剂依鲁替尼的批准标志着对于具有CLL且类似地具有套细胞淋巴瘤的患者的规定的不同进展。
组分B是选自以下目录的BTK抑制剂:
■依鲁替尼,或其药学上可接受的盐;
■4-叔丁基-N-[2-甲基-3-(4-甲基-6-{[4-(吗啉-4-基羰基)苯基]氨基}-5-氧代-4,5-二氢吡嗪-2-基)苯基]苯甲酰胺(CGI-1746,CAS910232-84-7);
■N-{3-[(5-氟-2-{[4-(2-甲氧基乙氧基)苯基]氨基}嘧啶-4-基)氨基]苯基}丙烯酰胺(AVL-292,CAS1202757-89-8);
■6-环丙基-8-氟-2-[2-(羟基甲基)-3-(1-甲基-5-{[5-(4-甲基哌嗪-1-基)吡啶-2-基]氨基}-6-氧代-1,6-二氢吡啶-3-基)苯基]异喹啉-1(2H)-酮(RN486,CAS1242156-23-5);
■HM71224:
■N-{3-[6-({4-[(2R)-1,4-二甲基-3-氧代哌嗪-2-基]苯基}氨基)-4-甲基-5-氧代-4,5-二氢吡嗪-2-基]-2-甲基苯基}-4,5,6,7-四氢-1-苯并噻吩-2-甲酰胺(GDC-0834,CAS 1133432-50-4);
■5-氨基-1-[(3R)-1-氰基哌啶-3-基]-3-[4-(2,4-二氟苯氧基)苯基]-1H-吡唑-4-甲酰胺(PF-06250112,J Immunol 2013;191:4540-4550);
■(2E)-4-(二甲基氨基)-N-{7-氟-4-[(2-甲基苯基)氨基]咪唑并[1,5-a]喹喔啉-8-基}-N-甲基丁-2-烯酰胺(CAS 1345250-62-5,Bioorg.Med.Chem.Lett.21(2011)6258-6262);
■N-[3-(8-苯胺基咪唑并[1,2-a]吡嗪-6-基)苯基]-4-叔丁基苯甲酰胺(CGI-560,CAS 845269-74-1);
■4-{4-[(4-{[3-(芳酰基氨基)苯基]氨基}-5-氟嘧啶-2-基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺(CNX-774,CAS1202759-32-7);
■ONO-4059(Arthritis and rheumatism 2012,64Suppl 10:1660)。
依鲁替尼:
依鲁替尼(USAN(“美国采用名称”)),也称为PCI-32765,是式(II)的1-{(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基]哌啶-1-基}丙-2-烯-1-酮(CAS注册号936563-96-1):
(依鲁替尼,PCI-32765),
并在下文中称为“依鲁替尼”。
依鲁替尼(先前称为PCI-32765,来自Pharmacyclics and JanssenPharmaceutica)是来自酪氨酸激酶抑制剂的组的药剂,其以Imbruvica商品名用于治疗套细胞淋巴瘤。
依鲁替尼是经口服用的酪氨酸激酶抑制剂,其抑制布鲁顿酪氨酸激酶(BTK)。后者在B淋巴细胞中的细胞内信号传递中发挥中心作用。因此,设想的依鲁替尼的临床使用领域为恶性B-细胞病症、较狭义B-细胞非霍奇金氏淋巴瘤,但还有其中B细胞发挥作用的自身免疫病症,诸如类风湿性关节炎。
依鲁替尼在具有治疗抵抗性慢性淋巴白血病(CLL)或具有套细胞淋巴瘤的集中预先治疗的患者的情况下显示效力(Ibrutinib:Kinase-Inhibitor gegen B-Zell-Malignome aktiv.Deutsches2013年6月20日,2013年7月23日检索)。依鲁替尼于2013年11月13日由FDA批准用于治疗套细胞淋巴瘤。在美国的商品名为Imbruvica。依鲁替尼于2014年2月由FDA批准用于治疗CLL。
在2014年7月,欧洲药物管理局(European Medicines Agency;EMA)的用于人类使用的医学产品委员会(Committee for Medicinal Products for HumanUse)推荐批准依鲁替尼用于慢性淋巴白血病(CLL)的适应症。依鲁替尼额外接受批准用于套细胞淋巴瘤的适应症的建议,且Zydelig用于滤泡性淋巴瘤(FL)的适应症。
还参见以下关于依鲁替尼的参考文献:
Ibrutinib Receives Two Oncology Breakthrough Therapy Designationsfrom U.S.Food and Drug Administration.prnewswire.com,2013年2月12日,2013年7月29日检索(英文)。
依鲁替尼作为化合物本身在欧洲专利号EP2,201,840B1和美国专利号US7,514,444B2中被指定为化合物14。
然而,现有技术不含如本发明中所述的任何组合产品,所述组合产品含有如本文所定义的IRAK4抑制性式(I)化合物或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物,和依鲁替尼,或其药学上可接受的盐。
CGI-1746:
物质CGI-1746(CAS注册号910232-84-7)已于J.A.DiPaolo等人,Nature ChemicalBiology,2011,7,1,41–50,DOI:10.1038/nchembio.481中被描述为特异性BTK-抑制剂(对于制备,还参见补充信息)。
然而,现有技术不含本发明中所述的任何组合产品,所述组合产品含有如本文所定义的IRAK4抑制性式(I)化合物或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物,和CGI-1746,或其药学上可接受的盐。
AVL-292:
物质AVL-292(CAS注册号1202757-89-8)已于WO2009158571中被描述为BTK的抑制剂。此外,已描述AVL-292的制备。
然而,现有技术不含本发明中所述的任何组合产品,所述组合产品含有如本文所定义的IRAK4抑制性式(I)化合物或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物,和AVL-292,或其药学上可接受的盐。
RN486:
BTK-抑制剂RN486(CAS注册号1242156-23-6,在本文中还使用术语“RN-486”)已于L.Yan等人,J.Med.Chem.,2015,58,512-516中被描述为适用于治疗类风湿性关节炎。
然而,现有技术不含本发明中所述的任何组合产品,所述组合产品含有如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物,和RN486,或其药学上可接受的盐。
发明内容
已发现,令人惊讶地,当如本文所定义的式(I)的IRAK4抑制剂与BTK抑制剂依鲁替尼组合使用时,在肿瘤细胞系中产生协同抗增殖作用。
本发明的第一方面涉及至少两种组分(组分A和组分B)的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;
●组分B是BTK抑制性化合物,例如依鲁替尼,或其药学上可接受的盐。
本发明的第二方面涉及至少两种组分A和B的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物,或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物;
●组分B是BTK抑制性化合物,例如依鲁替尼。
本发明的第三方面涉及至少两种组分A和B的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物;
●组分B是BTK抑制性化合物,例如依鲁替尼,或其药学上可接受的盐。
本发明的第四方面涉及至少两种组分A和B的组合产品:
●组分A是如本文所定义的IRAK4抑制性式(I)化合物;
●组分B是依鲁替尼。
如本文中描述和定义的至少两种组分A和B的组合产品也被称为“本发明的组合产品”。
本发明进一步涉及试剂盒,其包含以下物质的组合产品:
●组分A,其由如本文所定义的IRAK4抑制性式(I)化合物或其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物组成;
●组分B,其为BTK抑制性化合物,例如依鲁替尼,或其药学上可接受的盐;
和任选地
-组分C,其由一种或多种药品组成;
其中上述组合产品中任一者中的上文所定义的化合物A和B中的一者或两者任选地存在于准备用于同时、分开或依次给药的药物制剂/组合物中。所述组分可各自独立地经由经口、静脉内、局部、腹膜内或经鼻途径或作为储库给药。
本发明的另一个方面涉及如本文所定义的组合产品,其用于治疗或预防疾病。
本发明的另一个方面涉及如本文所描述的此类组合产品用于生产用于治疗或预防疾病的药剂的用途。
所述组合产品意欲尤其适用于治疗和预防特征在于过度反应性免疫系统的增殖性和炎性病症。此处应特定提及炎性皮肤病症、心血管病症、肺病症、眼病症、自身免疫病症、妇科病症(尤其子宫内膜异位)和癌症。
所述组合产品意欲尤其适用于治疗癌症。
所述组合产品意欲非常尤其适用于治疗以下类型的癌症:非霍奇金氏淋巴瘤(缩写为“NHL”),尤其复发性或难治性、顽固性或侵袭性非霍奇金氏淋巴瘤(NHL),尤其滤泡性淋巴瘤(缩写为“FL”)、慢性淋巴白血病(缩写为“CLL”)、边缘区域淋巴瘤(缩写为“MZL”)、弥漫性大细胞B细胞淋巴瘤(缩写为“DLBCL”),尤其活化的B-细胞样弥漫性大细胞B-细胞淋巴瘤(缩写为“ABC-DLBCL”)、套细胞淋巴瘤(缩写为“MCL”)、转化的淋巴瘤(缩写为“TL”)、外周T-细胞淋巴瘤(缩写为“PTCL”)或淋巴浆细胞淋巴瘤(瓦尔登斯特伦氏巨球蛋白血症(缩写为“WM”))的主要疗法或次要疗法中。
组合产品中的组分A
组分A是通式(I)的化合物
其中:
R1是C1-C6-烷基,其中C1-C6-烷基基团未被取代或被以下基团相同或不同地单取代或多取代:
卤素、羟基、未被取代或被卤素单取代或多取代的C3-C6-环烷基或R6、R7SO2、R7SO或R8O基团,
或选自以下的基团:
其中*代表所述基团与分子的其余部分的键合位点;
R2和R3始终具有相同定义且均为氢或C1-C6-烷基;
R4是卤素、氰基、未被取代或单次或多次、相同或不同地取代的C1-C6-烷基、或未被取代或单次或多次、相同或不同地取代的C3-C6-环烷基,且所述取代基选自卤素和羟基;
R5是氢、卤素或未被取代或被卤素多取代的C1-C6-烷基;
R6是具有4至6个环原子的未被取代或被甲基单取代或二取代的单环饱和杂环,其含有选自O、S、SO和SO2的杂原子或杂基团;
R7是C1-C6-烷基,其中C1-C6-烷基基团未被取代或被以下基团相同或不同地单取代或多取代:卤素、羟基或C3-C6-环烷基;或R7是C3-C6-环烷基,
R8是C1-C6-烷基,其中C1-C6-烷基基团未被取代或被卤素相同或不同地单取代或多取代;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
在下文中所描述的本发明的合成中间体和操作实施例的情况下,以相应碱或酸的盐形式指定的任何化合物通常是精确化学计量组成未知的盐,如通过各自制备和/或纯化过程所获得的。除非更详细说明,否则在此类盐的情况下,对名称和结构式的添加,诸如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“xHCl”、“xCF3COOH”、“xNa+”不应以化学计量含义理解,但仅具有关于其中存在的成盐组分的描述性特征。
如果通过描述的制备和/或纯化过程以化学计量组成未知(如果其具有所定义的类型)的溶剂化物(例如水合物)形式获得合成中间体或操作实施例或其盐,这相应地适用。
如果由式(I)涵盖和下文所引用的化合物已不是盐、溶剂化物和盐的溶剂化物,则本发明的组合产品的成分是式(I)的化合物和其盐、溶剂化物和盐的溶剂化物、由式(I)涵盖和具有下文指定的各式的化合物及其盐、溶剂化物和盐的溶剂化物以及由式(I)涵盖和下文作为操作实施例引用化合物及其盐、溶剂化物和盐的溶剂化物。
在本发明的上下文中,优选的盐是化合物的生理学上可接受的盐。然而,还涵盖本身不适用于医学应用,但可用于例如分离或纯化化合物的盐。
化合物的生理学上可接受的盐包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
化合物的生理学上可接受的盐还包括常规碱的盐,通过实例的方式且优选碱金属盐(例如钠和钾盐)、碱土金属盐(例如钙和镁盐)以及衍生自氨或具有1至16个碳原子的有机胺的铵盐,所述有机胺通过实例的方式且优选乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、二甲基氨基乙醇、普鲁卡因(procaine)、二苄基胺、N-甲基吗啉、精氨酸、赖氨酸、乙二胺和N-甲基哌啶。
在本发明的上下文中,溶剂化物被描述为通过与溶剂分子配位而形成固态或液态的复合物的化合物的那些形式。水合物是与水配位的溶剂化物的特定形式。
作为本发明的组合产品的成分的式(I)的化合物根据其结构可以不同立体异构形式(即以构型异构体的形式或另外任选地作为构象异构体(对映异构体和/或非对映异构体,包括在阻转异构体的情况下的那些))存在。本发明因此涵盖对映异构体和非对映异构体和其各自的混合物。立体异构均质成分可以已知方式从对映异构体和/或非对映异构体的此类混合物分离;色谱方法优选用于该目的,尤其是非手性或手性相上的HPLC色谱。
如果作为本发明的组合产品的成分的式(I)的化合物可以互变异构形式存在,则本发明涵盖所有互变异构形式。
本发明还涵盖本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体在此处被理解为意指其中本发明化合物内的至少一个原子已由具有相同原子数、但具有与在自然界中通常或主要存在的原子质量不同的原子质量的另一个原子交换的化合物。可并入本发明化合物中的同位素的实例为氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,诸如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的特定同位素变体(诸如尤其其中已并入一种或多种放射性同位素的变体)对于例如作用机制或体内活性成分分布的检查可以是有利的;由于可制备性和可检测性的比较简易度,具体而言,用3H或14C同位素标记的化合物适用于该目的。此外,同位素(例如氘)的并入可由于化合物的较大代谢稳定性而导致特定治疗益处,例如体内半衰期的延长或所需活性剂量的降低;因此,化合物的此类修饰也可构成本发明的优选实施方案。化合物的同位素变体可通过本领域技术人员已知的方法,例如通过下文中进一步描述的方法和操作实施例中指定的程序、通过使用各自试剂和/或起始化合物的相应同位素修饰,来制备。
本发明进一步提供作为本发明的组合产品的成分的式(I)的化合物的所有可能的结晶和多晶型形式,其中多晶型物可以作为单一多晶型物或所有浓度范围内的多种多晶型物的混合物存在。
本发明还涵盖作为本发明组合产品的成分的式(I)的化合物的前药。在该上下文中,术语“前药”表示本身可以是生物活性或非活性、但在其体内保留时间期间转化(例如代谢或水解)成化合物的化合物。
除非另外规定,否则作为本发明的组合产品的成分的式(I)的化合物的取代基定义如下:
在本发明的上下文中,烷基是具有所指定的特定数目的碳原子的直链或支链烷基基团。实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、1-甲基丙基、2-甲基丙基、叔丁基、正戊基、1-乙基丙基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基和2-乙基丁基。优选甲基、乙基、正丙基、正丁基、2-甲基丁基、3-甲基丁基和2,2-二甲基丙基。
在本发明的上下文中,在每种情况下,环烷基是具有指定数目的碳原子的单环饱和烷基基团。优选实例包括环丙基、环丁基、环戊基、环己基和环庚基。
在本发明的上下文中,烷氧基是具有指定的特定数目的碳原子的直链或支链烷氧基基团。1至6个碳原子是优选的。实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、1-甲基丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、1-乙基丙氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基和正己氧基。特别优选具有1至4个碳原子的直链或支链烷氧基基团。可提及的优选实例为甲氧基、乙氧基、正丙氧基、1-甲基丙氧基、正丁氧基和异丁氧基。
在本发明的上下文中,卤素为氟、氯和溴。优选氟。
在本发明的上下文中,羟基为OH。
单环饱和杂环是具有4至6个环原子且含有选自O、S、SO和SO2的杂原子或杂基团的单环饱和杂环。具有选自O、SO和SO2的杂原子或杂基团的杂环是优选的。实例包括:氧杂环丁烷、四氢呋喃、四氢-2H-吡喃-4-基、1,1-二氧化四氢-2H-硫代吡喃-3-基、1,1-二氧化四氢-2H-硫代吡喃-2-基、1,1-二氧化四氢-2H-硫代吡喃-4-基、1,1-二氧化四氢噻吩-3-基、1,1-二氧化四氢噻吩-2-基、1,1-二氧化硫杂环丁-2-基或1,1-二氧化硫杂环丁烷-3-基。此处特别优选氧杂环丁烷和四氢呋喃。非常特别优选氧杂环丁烷-3-基。
键处的符号*表示分子中的键合位点。
当作为本发明的组合产品的成分的式(I)的化合物中的基团被取代时,除非另外规定,否则基团可被单取代或多取代。在本发明的上下文中,出现超过一次的所有基团彼此独立地定义。被一个、两个或三个相同或不同的取代基的取代是优选的。
R1的一个优选实施方案是被1、2或3个氟原子取代的C2-C6-烷基基团。特别优选2,2,2-三氟乙基、3,3,3-三氟丙基和4,4,4-三氟丁基。非常特别优选4,4,4-三氟丁基。
R1的另一个优选实施方案是被一个或两个羟基或一个C1-C3-烷氧基或三氟取代的C1-C3-烷氧基取代的C2-C6-烷基。特别优选被羟基或C1-C3-烷氧基或三氟甲氧基或2,2,2-三氟乙氧基或三氟甲基取代的C2-C5-烷基基团。非常特别优选3-羟基-3-甲基丁基、3-甲氧基丙基、3-羟基丙基、3-三氟甲氧基丙基、2-甲氧基乙基或2-羟基乙基。特别优选3-羟基-3-甲基丁基基团。
进一步优选地,R1是被C1-C6-烷基-SO2基团取代的C2-C6-烷基基团。甲基-SO2-取代的C2-C4-烷基是特别优选的。对于R1特别优选2-(甲基磺酰基)乙基或3-(甲基磺酰基)丙基。从后者基团,2-(甲基磺酰基)乙基是特别优选的。
额外优选地,R1是被以下取代的C1-C3-烷基基团:氧杂环丁烷基、四氢呋喃基、四氢-2H-吡喃-4-基、1,1-二氧化四氢-2H-硫代吡喃-3-基、1,1-二氧化四氢-2H-硫代吡喃-2-基、1,1-二氧化四氢-2H-硫代吡喃-4-基、1,1-二氧化四氢噻吩-3-基、1,1-二氧化四氢噻吩-2-基、1,1-二氧化硫杂环丁烷-2-基或1,1-二氧化硫杂环丁烷-3-基。特别优选被氧杂环丁烷基取代的C1-C3-烷基基团。对于R1特别优选氧杂环丁烷-3-基甲基基团。
对于始终具有相同定义的R2和R3,氢或甲基是优选的。甲基是特别优选的。
在R4的情况下,优选未被取代或被卤素单取代或多取代的C1-C3-烷基基团,或被一个羟基取代的C1-C3-烷基基团,或被一个羟基和三个氟原子取代的C1-C3-烷基基团。
对于R4,特别优选以下基团:甲基、乙基、三氟-C1-C3-烷基、二氟-C1-C3-烷基、羟基甲基、1-羟基乙基、2-羟基丙-2-基和2,2,2-三氟-1-羟基乙基。对于R4,特别优选甲基、三氟甲基和二氟甲基基团。此处特别优选三氟甲基基团。
R5的一个优选实施方案是氢、氟、氯或C1-C3-烷基。更优选地,R5为氢、氟或甲基。最优选地,R5为氢或氟。
还特别优选其中R4为甲基或三氟甲基且R5为氟的作为本发明组合产品的成分的式(I)的化合物。非常特别优选其中R4为甲基且R5为氟的化合物,其中R5在R4的邻位。
对于R6,优选实施方案包括氧杂环丁烷基、四氢呋喃基、四氢-2H-吡喃-4-基、1,1-二氧化四氢-2H-硫代吡喃-3-基、1,1-二氧化四氢-2H-硫代吡喃-2-基、1,1-二氧化四氢-2H-硫代吡喃-4-基、1,1-二氧化四氢噻吩-3-基、1,1-二氧化四氢噻吩-2-基、1,1-二氧化硫杂环丁-2-基或1,1-二氧化硫杂环丁烷-3-基。此处特别优选氧杂环丁烷基。非常特别优选氧杂环丁烷-3-基。
R7排他地连接至官能团–SO2-和-SO-,即为R7-取代的-SO2-或SO基团。在这方面,R7优选为C1-C4-烷基,其中C1-C4-烷基基团未被取代,或被羟基或被环丙基单取代,或被三个氟原子取代。此外,对于R7优选环丙基基团。对于R7特别优选甲基、乙基或羟基乙基。对于R7非常特别优选甲基。
这意味着在被R7SO2-或R7SO-取代的C1-C6-烷基的情况下,在R1的上下文中,优选为被C1-C6-烷基-SO2或C1-C6-烷基-SO取代的C1-C6-烷基。对于R1,此处特别优选甲基磺酰基乙基和甲基磺酰基丙基。此处非常特别优选甲基磺酰基乙基。
对于R8,优选未被取代的C1-C4-烷基或三氟取代的C1-C4-烷基基团。特别优选甲基、乙基、三氟甲基或2,2,2-三氟乙基。非常特别优选甲基、三氟甲基或2,2,2-三氟乙基。
优选作为本发明的组合产品的成分的式(I)的化合物,其中
R1是C1-C6-烷基,其中C1-C6-烷基基团未被取代或被以下基团相同或不同地单取代或多取代:氟、羟基或R6、R7SO2、R7SO或R8O基团;
R2和R3始终具有相同定义且均为氢或C1-C3-烷基;
R4是卤素、氰基或C1-C3-烷基,其中C1-C3-烷基基团未被取代或被以下基团相同或不同地单取代或多取代:卤素或羟基;
R5是氢、氟、氯或C1-C3-烷基;
R6是氧杂环丁烷基或四氢呋喃基;
R7是C1-C4-烷基,其中C1-C4-烷基未被取代或被羟基或环丙基单取代或被三个氟原子取代;
R8是未被取代的C1-C4-烷基或三氟取代的C1-C4-烷基;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
进一步优选作为本发明的组合产品的成分的式(I)的化合物,其中
R1是C2-C6-烷基,其中C2-C6-烷基未被取代,或
C2-C6-烷基被氟单取代、二取代或三取代,或
C2-C6-烷基被羟基、R6、R7SO2或R8O单取代,或其中R1是氧杂环丁烷基取代的C1-C3-烷基;
R2和R3始终具有相同定义且均为氢或甲基;
R4是未被取代或被卤素单取代或多取代的C1-C3-烷基基团,或被一个羟基基团取代的C1-C3-烷基基团,或被一个羟基基团和三个氟原子取代的C1-C3-烷基基团;
R5是氢、氟或C1-C3-烷基;
R7是C1-C3-烷基;
R8是C1-C4-烷基,其中C1-C4-烷基基团未被取代或被氟单取代、二取代或三取代;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
还特别优选作为本发明的组合产品的成分的通式(I)的化合物,其中
R1是被羟基或C1-C3-烷氧基或三氟甲氧基或2,2,2-三氟乙氧基或三氟甲基取代的C2-C5-烷基,或
是甲基-SO2-取代的C2-C4-烷基基团,或
是氧杂环丁烷-3-基取代的C1-C2-烷基基团;
R2和R3始终具有相同定义且均为氢或甲基;
R4是甲基、乙基、三氟-C1-C3-烷基、二氟-C1-C3-烷基、羟基甲基、1-羟基乙基、2-羟基丙-2-基和2,2,2-三氟-1-羟基乙基;
R5是氢、氟或甲基;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
非常特别优选作为本发明的组合产品的成分的式(I)的化合物,其中
R1是4,4,4-三氟丁基、3-羟基-3-甲基丁基、3-羟基丁基、3-甲氧基丙基、3-羟基丙基、3-羟基-2-甲基丙基、3-羟基-2,2-二甲基丙基、3-三氟甲氧基丙基、2-甲氧基乙基、2-羟基乙基、2-(甲基磺酰基)乙基或3-(甲基磺酰基)丙基;
R2和R3均为甲基或氢;且
R4是二氟甲基、三氟甲基或甲基;且
R5是氢或氟;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
还非常特别优选作为本发明的组合产品的成分的式(I)的化合物,其中
R1是3-羟基-3-甲基丁基、3-羟基丁基、3-羟基-2-甲基丙基、3-羟基-2,2-二甲基丙基、3-(甲基磺酰基)丙基或2-(甲基磺酰基)乙基;
R2和R3均为甲基;
R4是二氟甲基或三氟甲基;且
R5是氢;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
还进一步特别优选作为本发明的组合产品的成分的式(I)的化合物,其中
R1是3-羟基-3-甲基丁基、3-羟基丁基、3-羟基-2-甲基丙基、3-羟基-2,2-二甲基丙基、3-(甲基磺酰基)丙基或2-(甲基磺酰基)乙基;
R2和R3均为甲基;
R4是甲基,且
R5是氟,
其中R5在R4的邻位;
和其非对映异构体、对映异构体、代谢物、盐、溶剂化物或盐的溶剂化物。
本发明尤其提供作为本发明的组合产品的成分的以下式(I)的化合物:
1)N-[6-(2-羟基丙-2-基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
2)N-[6-(羟基甲基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
3)N-[6-(2-羟基丙-2-基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
4)N-[6-(羟基甲基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
5)N-[2-(2-羟基乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
6)N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
7)N-[2-(2-羟基乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
8)N-[6-(2-羟基丙-2-基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
9)N-[6-(羟基甲基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
10)N-{6-(2-羟基丙-2-基)-2-[3-(甲基磺酰基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
11)N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
12)N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
13)6-(二氟甲基)-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]吡啶-2-甲酰胺
14)6-(二氟甲基)-N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}吡啶-2-甲酰胺
15)6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]吡啶-2-甲酰胺
16)N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
17)N-{6-(2-羟基丙-2-基)-2-[3-(三氟甲氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
18)N-{6-(2-羟基丙-2-基)-2-[3-(2,2,2-三氟乙氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
19)5-氟-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺
20)N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺
21)6-(2-羟基丙-2-基)-N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]吡啶-2-甲酰胺。
式(I)的化合物充当IRAK4激酶的抑制剂且具有有价值范围的药理学活性。
因此,除上文提及的主题以外,本发明还提供本发明的组合产品用于治疗和/或预防人和动物中的疾病的用途。
非常特别优选治疗和/或预防由失控的细胞生长、细胞增殖和/或细胞存活、不成比例的细胞免疫反应或不成比例的细胞炎性反应引起的疾病,例如血液肿瘤、实体肿瘤和/或其转移(例如白血病和骨髓发育不良综合征)、恶性淋巴瘤、头颈部肿瘤(包括脑肿瘤和转移)、胸部肿瘤(包括非小细胞和小细胞肺肿瘤)、胃肠道肿瘤、内分泌肿瘤、乳房肿瘤和其他妇科肿瘤、泌尿肿瘤(包括肾脏、膀胱和前列腺肿瘤)、皮肤肿瘤和肉瘤和/或其转移。
此外,本发明还提供使用有效量的作为本发明的组合产品的成分的式(I)的化合物中的至少一种治疗和/或预防病症,尤其前述病症的方法。
在本发明的上下文中,术语“治疗(treatment)”或“治疗(treating)”包括抑制、延迟、检查、缓解、减弱、限制、减少、抑制、排斥或治愈疾病、病状、病症、损伤或健康问题,或此类病况和/或此类病况的症状的发展、病程或进程。术语“疗法”在此处理解为与术语“治疗”同义。
术语“预防(prevention)”、“防治(prophylaxis)”和“防止(preclusion)”在本发明的上下文中同义使用且是指避免或降低感染、经历、患有或具有疾病、病状、病症、损伤或健康问题或此类病况和/或此类病况的症状的发展或进展的风险。
疾病、病状、病症、损伤或健康问题的治疗或预防可以是部分或完全的。
本发明的组合产品可单独使用或(如果需要)与一种或多种其他药品(在本文中称为“组分C”)组合使用,条件是此组合产品不导致不期望和不可接受的副作用。因此,本发明还提供药剂,其包含本发明的组合产品和一种或多种其他活性成分,尤其用于上文提及的病症的预防和疗法。
例如,本发明的组合产品可与用于治疗癌症的已知抗过度增殖性、细胞抑制性、或细胞毒性物质组合。本发明的组合产品与通常用于癌症治疗的其他物质或另外与放射线疗法的组合是特别适当的。
合适的组分“C”的说明性但非详尽性目录包括以下药品:
131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、赤式-羟基壬基腺嘌呤(ado-trastuzumab emtansine)、阿法替尼、阿柏西普、阿地白介素、阿仑珠单抗、阿仑膦酸、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、己基-5-氨基乙酰丙酸酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴香脑二硫杂环戊二烯硫酮(anethole dithiolethione)、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、阿格拉宾、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、贝洛替康、苯达莫司汀、贝利司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来考昔、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、copanlisib、克立他酶(crisantaspase)、克里唑替尼、环磷酰胺、环丙特龙、阿糖胞苷、达卡巴嗪、放线菌素D、达拉菲尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素、地舒单抗、地普奥肽、地洛瑞林、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依屈洛单抗、依利醋铵、内皮他丁、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、促红素α、倍他铂、泽塔铂、依他铂、艾立布林、厄洛替尼、埃索美拉唑、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺盐、钆弗塞胺、钆塞酸二钠盐(gd-EOB-DTPA二钠盐)、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、羧肽酶、氧化型谷胱甘肽(glutoxim)、戈舍瑞林、格拉司琼、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、二盐酸组胺、组氨瑞林、羟基脲、I-125种子(I-125seeds)、伊班膦酸、替伊莫单抗、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、吡地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、兰瑞肽、兰索拉唑、拉帕替尼、lasocholine、来那度胺、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、lipegfilgrastim、利舒脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯嘌呤、美司钠、美沙酮、甲氨蝶呤、甲氧沙林、氨基酮戊酸甲酯、甲基泼尼松龙、甲睾酮、甲酪氨酸、米法莫肽、米替福新、米立铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫派达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮+喷他佐辛、纳曲酮、那托司亭、奈达铂、奈拉滨、奈立膦酸、nivolumab pentetreotide、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、尼曲吖啶、nivolumab、obinutuzumab、奥曲肽、奥法木单抗、高三尖杉酯碱(omacetaxin mepesuccinate)、奥美拉唑、昂丹司琼、奥古蛋白(orgotein)、orilotimod、奥沙利铂、羟考酮、羟甲烯龙、ozogamicin、p53基因疗法、紫杉醇、钯-103种子(palladium-103 seed)、帕洛诺司琼、帕米膦酸、帕尼单抗、泮托拉唑、帕唑帕尼、培门冬酶、派姆单抗、培干扰素α-2b、培美曲塞、喷司他丁、培洛霉素、全氟正丁烷、培磷酰胺、帕妥珠单抗、毕西巴尼、匹鲁卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、racotumomab、镭-223氯化物、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫芦单抗、雷莫司汀、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、依替膦酸铼-186、利妥昔单抗、罗米地新、罗莫肽、roniciclib、钐(153Sm)lexidronam、沙妥莫单抗、胰泌素、西普鲁塞-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼、司坦唑醇、链佐星、舒尼替尼、他拉泊芬、他米巴罗汀、他莫昔芬、他喷他多、他索纳明、替西白介素、锝(99mTc)nofetumomab merpentan、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、替曲膦、沙立度胺、塞替派、胸腺法新、促甲状腺素α、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲马多、曲妥珠单抗、曲奥舒凡、维甲酸、三氟尿苷+tipiracil、曲美替尼、曲洛司坦、曲普瑞林、曲磷胺、促血小板生成素、乌苯美司、戊柔比星、凡他尼布、伐普肽、瓦他拉尼、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉、伏林司他、钇-90玻璃微珠、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
特别合适的组分C是与P-TEFb或CDK9抑制剂的组合产品。
以有前景的方式,本发明的组合产品也可与生物制剂组合,所述生物制剂诸如抗体(例如阿柏西普、阿仑单抗、贝伐单抗、贝图西单抗(brentuximumab)、卡妥索单抗、西妥昔单抗、地舒单抗、依决洛单抗、吉妥珠单抗、替伊莫单抗、伊匹木单抗、奥法木单抗、帕尼单抗、帕妥珠单抗、利妥昔单抗、托斯图单抗(tositumumab)、曲妥珠单抗)和重组蛋白。
本发明的组合产品也可与针对血管生成的其他疗法组合实现积极作用,例如与贝伐单抗、阿西替尼、瑞戈非尼、西地尼布、索拉非尼、舒尼替尼或沙利度胺。与抗激素和甾族代谢酶抑制剂的组合产品由于其有利的副作用概况而特别合适。
通常,可用本发明的组合产品与其他细胞抑制或细胞毒性活性剂的组合实现以下目标:
●与用个别活性成分的治疗相比,在减缓肿瘤生长、降低其大小或甚至使其完全消除方面的改进的效力;
●与在单药疗法的情况下相比,以较低剂量使用的所用的化学治疗剂的可能性;
●与个别给药相比,具有较少副作用的更耐受的疗法的可能性;
●治疗更宽范围的赘生性病症的可能性;
●实现对疗法的较高反应率;
●与当今标准疗法相比,患者的存活时间更长。
此外,本发明的组合产品也可与放射疗法和/或手术介入结合使用。
本发明的组合产品可全身性和/或局部起作用。对于该目的,它们可以合适的方式给药,例如通过经口、肠胃外、经肺、经鼻、舌下、经舌、经颊、经直肠、经真皮、经皮或结膜途径、经耳或作为植入物或支架进行给药。
本发明的组合产品可以用于这些给药途径的合适的给药形式给药。
用于口服给药的合适的给药形式是根据现有技术起作用且快速和/或以修改的方式释放本发明的组合产品,且含有结晶和/或无定形和/或溶解形式的本发明的组合产品的给药形式,所述形式例如片剂(未包衣或包衣片剂,例如具有耐胃液性或迟延溶解或不可溶包衣,其控制本发明的组合产品的释放)、片剂或薄膜/扁剂(其在口腔中快速崩解)、薄膜/冻干物、胶囊(例如硬或软明胶胶囊)、糖包衣片剂、颗粒剂、小丸剂、散剂、乳剂、混悬剂、气雾剂或溶液剂。
可用绕过吸收步骤(例如静脉内、动脉内、心内、脊椎内或腰内)或包括吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)实现肠胃外给药。适用于肠胃外给药的给药形式包括呈溶液剂、混悬剂、乳剂、冻干物或无菌散剂的形式的用于注射和输注的制备物。
对于其他给药途径,合适的实例是可吸入药物形式(包括散剂吸入剂、雾化剂)、滴鼻剂、溶液剂或喷雾剂、片剂、薄膜/扁剂或胶囊剂(用于经舌、舌下或经颊给药)、栓剂、耳或眼制备物、阴道胶囊、水性悬浮液(洗剂、振荡混合物)、亲脂性混悬剂、软膏、乳膏、经皮治疗系统(例如贴片)、乳状物、糊剂、泡沫剂、喷洒散剂、植入物或支架。
优选经口或肠胃外给药,特别是经口给药。
本发明的组合产品可被转化成所提及的给药形式。这可以本身已知的方式通过与惰性、无毒性、药学上合适的赋形剂混合来实现。这些赋形剂包括载体(例如微晶纤维素、乳糖、甘露醇)、溶剂(例如液体聚乙二醇)、乳化剂和分散剂或湿润剂(例如十二烷基硫酸钠、聚氧脱水山梨糖醇油酸酯)、粘合剂(例如聚乙烯吡咯烷酮)、合成和天然聚合物(例如白蛋白)、稳定剂(例如抗氧化剂,例如抗坏血酸)、着色剂(例如无机色素,例如氧化铁)和风味和/或气味矫味剂。
本发明还提供药剂,其包含至少一种本发明的化合物,通常与一种或多种惰性、无毒性、药学上合适的赋形剂一起,和其用于前述目的的用途。
通常,已发现在肠胃外给药的情况下,可有利地给药约0.001至1mg/kg、优选约0.01至0.5mg/kg体重的量以实现有效结果。在经口给药的情况下,剂量为约0.01至100mg/kg,优选约0.01至20mg/kg且最优选0.1至10mg/kg体重。
然而,在一些情况下,有必要偏离所述量,尤其根据体重、给药途径、对活性成分的个别响应、制备物的性质和给药进行的时间或间隔时间而变化。因此,在一些情况下,小于上述最小量可以是足够的,而在其他情况下,必须超过所提及的上限。在较大量的给药的情况下,将其分成在一天中的几个个别剂量可以是可取的。
以下操作实施例说明本发明。本发明不限于实施例。
除非另外说明,否则在以下测试和实施例中,百分比为重量百分比;份为重量份。液体/液体溶液的溶剂比、稀释比和浓度数据在各情况下以体积计。
具体实施方式
作为本发明的组合产品的成分的式(I)的化合物的制备
通过以下合成方案说明作为本发明的组合产品的成分的式(I)的化合物的制备。
用于合成作为本发明的组合产品的成分的式(I)的化合物的起始物质为羧酸(中间体V3),其可商购或可通过从文献已知的途径或与从文献已知的途径类似地制备(参见例如European Journal of Organic Chemistry 2003,8,1559–1568,Chemical andPharmaceutical Bulletin,1990,38,9,2446–2458,Synthetic Communications 2012,42,658–666,Tetrahedron,2004,60,51,11869-11874)(参见例如,合成方案1)。可通过水解(参见例如6-(羟基甲基)吡啶-2-甲酸乙酯与氢氧化钠水溶液在甲醇中的反应,WO200411328)或–在叔丁酯的情况下–通过与酸(例如盐酸或三氟乙酸)反应(参见例如DaltonTransactions,2014,43,19,7176–7190),从羧酸酯(中间体V2)进行来制备一些羧酸V3。羧酸V3也可以其碱金属盐的形式使用。任选地也可从具有氯、溴或碘作为取代基X1的中间体V1,通过在一氧化碳气氛中,任选地在高压下,在膦配体(例如1,3-双(二苯基膦基)丙烷)、钯化合物(例如乙酸钯(II))和碱(例如三乙胺)存在的情况下,通过添加甲醇或溶剂(例如二甲亚砜)中的甲醇中的反应来制备中间体V2(对于制备方法,参见例如WO2012112743、WO2005082866、Chemical Communications(Cambridge,England),2003,15,1948–1949、WO200661715)。中间体V1可商购或可通过从文献已知的途径制备。说明性制备方法详述于WO2012061926、European Journal of Organic Chemistry,2002,2,327–330,Synthesis,2004,10,1619–1624、Journal of the American Chemical Society,2013,135,32,12122–12134、Bioorganic and Medicinal Chemistry Letters,2014,24,16,4039–4043、US2007185058、WO2009117421中。
合成方案1
X1为氯、溴或碘。
Rd为甲基、乙基、苄基或叔丁基。
R4、R5各自如通式(I)中所定义。
与Ohrai,Kazuhiko Chiba WO 2008/001883类似,可根据合成方案2,通过在钯/炭存在的情况下,用氢进行中间体1的硝基的硝化和还原,从1H-吲唑-6-甲酸甲酯(中间体0)进行来获得5-氨基-1H-吲唑-6-甲酸甲酯(中间体2)。对于从中间体2进行的中间体3的制备,可使用从文献(Amino Acids,Peptides and Proteins in Organic Chemistry,Vol.3–Building Blocks,Catalysis and Coupling Chemistry,Andrew B.Hughes,Wiley,Chapter 12-Peptide-Coupling Reagents,407-442;Chem.Soc.Rev.,2009,38,606)已知的多种偶联剂。例如,可使用1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐与作为偶联剂的1-羟基-1H-苯并三唑水合物(HOBt,WO2012107475;Bioorg.Med.Chem.Lett.,2008,18,2093)、四氟硼酸(1H-苯并三唑-1-基氧基)(二甲基氨基)-N,N-二甲基甲铵(TBTU,CAS125700-67-6)、六氟磷酸(二甲基氨基)-N,N-二甲基(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基氧基)甲铵(HATU,CAS148893-10-1)、丙烷膦酸酐(作为乙酸乙酯或DMF中的溶液,CAS68957-94-8)或二-1H-咪唑-1-基甲酮(CDI)的组合,同时在每种情况下向反应混合物中添加碱(诸如三乙胺或N-乙基-N-异丙基丙-2-胺)。优选使用TBTU和N-乙基-N-异丙基丙-2-胺/THF。
合成方案2
取代基R4、R5各自如通式(I)中所定义。
从中间体3进行,可制备2-取代的吲唑衍生物(中间体4)(参见合成方案3)。用于此目的的有用反应包括用任选地取代的烷基氯化物、烷基溴化物、烷基碘化物或4-甲基苯磺酸烷基酯的反应。所使用的烷基卤化物或4-甲基苯磺酸烷基酯可商购或可与从文献已知的途径类似地制备(对于4-甲基苯磺酸烷基酯的制备,一个实例是适合的醇与4-甲基苯磺酰氯在三乙胺或吡啶存在的情况下的反应;参见例如Bioorganic and MedicinalChemistry,2006,14,124277–4294)。任选地,在使用烷基氯化物或烷基溴化物的情况下,也可添加碱金属碘化物,诸如碘化钾或碘化钠。所使用的碱可以是例如碳酸钾、碳酸铯或氢化钠。在反应性烷基卤化物的情况下,在一些情况下也可使用N-环己基-N-甲基环己胺。有用的溶剂包括例如1-甲基吡咯烷-2-酮、DMF、DMSO或THF。任选地,所使用的烷基卤化物或4-甲基苯磺酸烷基酯可具有已任选地预先用保护基保护的官能团(还参见P.G.M.Wuts,T.W.Greene,Greene’sProtective Groups in Organic Synthesis,第四版,ISBN:9780471697541)。如果例如使用具有一个或多个羟基基团的烷基卤化物或4-甲基苯磺酸烷基酯,这些羟基基团可任选地由叔丁基(二甲基)甲硅烷基基团或本领域技术人员熟悉的类似含硅保护基保护。或者,羟基基团也可由四氢-2H-吡喃(THP)基团或由乙酰基或苯甲酰基基团保护。所使用的保护基然后可在中间体4的合成之后或另外在(I)的合成之后分离。如果例如使用叔丁基(二甲基甲硅烷基)基团作为保护基,则其可例如使用氟化四丁铵/溶剂(诸如THF)分离。THP保护基可例如使用4-甲基苯磺酸(任选地呈单水合物形式)分离。乙酰基基团或苯甲酰基基团可通过用氢氧化钠水溶液处理来分离。
任选地,所使用的烷基卤化物或4-甲基苯磺酸烷基酯可含有可通过本领域技术人员已知的氧化或还原反应来转化的官能团(参见例如Science of Synthesis,GeorgThieme Verlag)。例如,如果官能团是硫醚基,则这可通过文献中已知的方法氧化成亚砜或砜基团。在亚砜基团的情况下,这可类似地氧化成砜基团。对于这些氧化步骤,可使用例如3-氯过氧苯甲酸(CAS937-14-4)(在这方面,对于2-(甲基硫烷基)乙基-1H-吡唑衍生物氧化成2-(甲基亚磺酰基)乙基-1H-吡唑衍生物和另一种2-(甲基硫烷基)乙基-1H-吡唑衍生物氧化成2-(甲基磺酰基)乙基-1H-吡唑衍生物,还参见例如US201094000)。如果所使用的烷基卤化物或甲苯磺酸烷基酯含有酮基团,则这可通过本领域技术人员已知的还原方法还原成醇基团(对于硼氢化钠的用途,参见例如Chemische Berichte,1980,113,1907–1920)。可在中间体4的合成之后或另外在通式(I)的化合物的合成之后实现这些氧化或还原步骤。或者,可经由中间体3与任选地取代的烷基醇的Mitsunobu反应(参见例如K.C.K.Swamy等人Chem.Rev.2009,109,2551–2651)制备中间体4。可利用各种膦类化合物(诸如三苯基膦、三丁基膦或1,2-二苯基膦基乙烷)与偶氮二甲酸二异丙酯(CAS2446-83-5)或文献(K.C.K.Swamy等人Chem.Rev.2009,109,2551–2651)中提及的其他二氮烯衍生物的组合。优选使用三苯基膦和偶氮二甲酸二异丙酯。如果烷基醇具有官能团,则可使用已知保护基策略,如在上述与烷基卤化物的反应的情况下(其他指标可见于P.G.M.Wuts,T.W.Greene,Greene’sProtective Groups in Organic Synthesis,Fourth Edition,ISBN:9780471697541),和如在上述与烷基卤化物在反应的情况下,可在中间体4的合成之后或另外在通式(I)的化合物的合成之后进行氧化或还原步骤。从中间体4进行,可通过Grignard反应获得通式(I)的本发明化合物,其中R2和R3被定义为C1-C6-烷基(其中R2和R3具有相同定义)(参见例如EP2489663中1H-吲唑-6-甲酸甲酯衍生物与甲基溴化镁的反应)。对于Grignard反应,可使用烷基镁卤化物。特别优选THF或乙醚中的甲基氯化镁或甲基溴化镁,或另外THF和乙醚的混合物中的甲基氯化镁或甲基溴化镁。或者,从中间体4进行,可通过与烷基锂试剂的反应获得通式(I)的本发明化合物,其中R2和R3被定义为C1-C6-烷基(其中R2和R3具有相同定义)(参见例如WO2006116412中2-氨基-4-氯-1-甲基-1H-苯并咪唑-7-甲酸甲酯衍生物与异丙基锂或叔丁基锂的反应)。从中间体4进行,可通过任选地在添加甲醇的情况下用氢化锂铝/THF、硼氢化锂/THF或硼氢化钠/THF还原,或用硼氢化锂和硼氢化钠的混合物还原,来制备通式(I)的本发明化合物,其中R2和R3被定义为H。
合成方案3:
取代基R1、R2、R3、R4、R5各自如通式(I)中所定义。
从中间体3进行,可通过Grignard反应获得中间体5,其中R2和R3被定义为C1-C6-烷基(其中R2和R3具有相同定义)(参见例如,合成方案4)。对于该目的,可使用合适的烷基镁卤化物,例如THF或乙醚或另外THF和乙醚的混合物中的甲基氯化镁或甲基溴化镁。
从中间体5进行,然后可制备化合物(I)的部分(I-a),其中R2和R3被定义为C1-C6-烷基(其中R2和R3具有相同定义)。对于该目的,与合成方案3(中间体3的制备)类似,有用反应是中间体5与任选地取代的烷基氯化物、烷基溴化物、烷基碘化物或4-甲基苯磺酸烷基酯的反应。可使用与合成方案3中所述的策略类似的保护基策略。
或者,对于其中R2和R3被定义为C1-C6-烷基(其中R2和R3具有相同定义)的化合物(I)的部分(I-a)的制备,可使用中间体5与任选地取代的烷基醇的Mitsunobu反应(与合成方案3类似)。
如果式(I-a)的化合物中的R1包括合适的官能团,则与合成方案3类似,随后可任选地使用氧化或还原反应用于制备其他本发明化合物。
合成方案4
取代基R1、R4、R5各自如通式(I)中所定义。R2和R3始终具有相同定义且均为C1-C6-烷基。
从中间体1进行,可以替代方式制备中间体4(参见合成方案5)。首先,通过如合成方案3中的方法将中间体1转化成中间体6(从中间体3制备中间体4)。
然后,可通过硝基的还原将中间体6转化成中间体7。例如,可在氢气气氛下用钯/碳(对于6-异丙氧基-5-硝基-1H-吲唑还原成6-异丙氧基-1H-吲唑-5-胺,参见例如WO2013174744)或通过在水和乙醇中使用铁和氯化铵(还参见例如Journal of theChemical Society,1955,2412-2419)或使用氯化锡(II)(CAS7772-99-8)来还原硝基。使用水和乙醇中的铁和氯化铵是优选的。可与合成方案2类似地实现从中间体7制备中间体4(从中间体2制备中间体3)。
如对于合成方案3所述,同样在合成方案5的情况下可任选地使用保护基策略。任选地,可额外从中间体6开始,对于中间体7,如对于合成方案3所述,进行氧化,用于本领域技术人员已知的还原反应(参见例如Science of Synthesis,Georg Thieme Verlag)。
合成方案5
取代基R1、R4、R5各自如通式(I)中所定义。
作为本发明的组合产品的成分的式(I)的实施例化合物的合成
缩写和说明
DMF | N,N-二甲基甲酰胺 |
DMSO | 二甲亚砜 |
THF | 四氢呋喃 |
RT | 室温 |
HPLC | 高效液相色谱 |
H | 小时 |
min | 分钟 |
UPLC | 超高效液相色谱 |
DAD | 二极管阵列检测器 |
ELSD | 蒸发光散射检测器 |
ESI | 电喷雾电离 |
SQD | 单相四极柱检测器 |
CPG | 芯拉式精密玻璃 |
术语氯化钠溶液总是意味着饱和氯化钠水溶液。
中间体和实施例的化学名称使用ACD/LABS(批次版本12.01.)软件产生。
方法
在一些情况下,化合物和其前体和/或中间体通过LC-MS分析。
方法A1:UPLC(MeCN-HCOOH):
仪器:Waters Acquity UPLC-MS SQD 3001;柱:Acquity UPLC BEH C18 1.750x2.1mm;洗脱剂A:水+0.1体积%甲酸(99%),洗脱剂B:乙腈;梯度:0-1.6分钟1-99%B,1.6-2.0分钟,99%B;流动速率0.8ml/min;温度:60℃;注射:2μl;DAD扫描:210-400nm;MSESI+,ESI-,扫描范围160-1000m/z;ELSD。
方法A2:UPLC(MeCN-NH3):
仪器:Waters Acquity UPLC-MS SQD 3001;柱:Acquity UPLC BEH C18 1.750x2.1mm;洗脱剂A:水+0.2体积%氨(32%),洗脱剂B:乙腈;梯度:0-1.6分钟1-99%B,1.6-2.0分钟99%B;流动速率0.8ml/min;温度:60℃;注射:2μl;DAD扫描:210-400nm;MSESI+,ESI-,扫描范围160-1000m/z;ELSD。
方法A3:(LC-MS)
仪器:Agilent 1290 Infinity LC;柱:Acquity UPLC BEH C18 1.7 50x2.1mm;洗脱剂A:水+0.05体积%甲酸,洗脱剂B:乙腈+0.05体积%甲酸;梯度:0-1.7分钟2-90%B,1.7-2.0分钟90%B;流动速率1.2ml/min;温度:60℃;注射:2μl;DAD扫描:190-390nm;MS:AgilentTOF6230。
方法A4:(LC-MS)
仪器:Waters Acquity;柱:Kinetex(Phenomenex),50x2mm;洗脱剂A:水+0.05体积%甲酸,洗脱剂B:乙腈+0.05体积%甲酸;梯度:0-1.9分钟1-99%B,1.9-2.1分钟99%B;流动速率1.5ml/min;温度:60℃;注射:0.5μl;DAD扫描:200-400nm。
在一些情况下,作为本发明的组合产品的成分的式(I)的化合物和其前体和/或中间体通过以下制备型HPLC方法纯化:
方法P1:系统:Waters Autopurification系统:Pump 2545、Sample Manager2767、CFO、DAD 2996、ELSD 2424、SQD;柱:XBridge C18 5μm 100x30mm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈;梯度:0-8分钟10-100%B,8-10分钟100%B;流速:50ml/min;温度:室温;溶液:最大250mg/最大2.5ml DMSO或DMF;注射:1x2.5ml;检测:DAD扫描范围210-400nm;MSESI+,ESI-,扫描范围160-1000m/z。
方法P2:系统:Waters Autopurification系统:Pump 254、Sample Manager2767、CFO、DAD 2996、ELSD 2424、SQD 3100;柱:XBridge C18 5μm 10x30mm;洗脱剂A:水+0.2体积%氨(32%),洗脱剂B:甲醇;梯度:0-8分钟30-70%B;流速:50ml/min;温度:室温;检测:DAD扫描范围210-400nm;MSESI+,ESI-,扫描范围160-1000m/z;ELSD。
方法P3:系统:Labomatic,泵:HD-5000,级分收集器:LABOCOL Vario-4000,UV检测器:Knauer UVD 2.1S;柱:XBridge C18 5μm 100x30mm;洗脱剂A:水+0.2体积%氨(25%),洗脱剂B:乙腈;梯度:0-1分钟15%B,1-6.3分钟15-55%B,6.3-6.4分钟55-100%B,6.4-7.4分钟100%B;流速:60ml/min;温度:室温;溶液:最大250mg/2mlDMSO;注射:2x2ml;检测:UV218nm;软件:SCPA PrepCon5。
方法P4:系统:Labomatic,泵:HD-5000,级分收集器:LABOCOL Vario-4000,UV检测器:Knauer UVD 2.1S;柱:Chromatorex RP C18 10μm 125x30mm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈;梯度:0-15分钟65-100%B;流速:60ml/min;温度:室温;溶液:最大250mg/2mlDMSO;注射:2x2ml;检测:UV254nm;软件:SCPA PrepCon5。
方法P5:系统:Sepiatec:Prep SFC100,柱:Chiralpak IA 5μm 250x20mm;洗脱剂A:二氧化碳,洗脱剂B:乙醇;梯度:等度20%B;流速:80ml/min;温度:40℃;溶液:最大250mg/2ml DMSO;注射:5x0.4mL;检测:UV 254nm。
方法P6:系统:Agilent:Prep 1200、2x制备型泵、DLA、MWD、Gilson:LiquidHandler 215;柱:Chiralcel OJ-H 5μm 250x20mm;洗脱剂A:己烷,洗脱剂B:乙醇;梯度:等度30%B;流速:25ml/min;温度:25℃;溶液:187mg/8ml乙醇/甲醇;注射:8x1.0ml;检测:UV280nm。
方法P7:系统:Labomatic,泵:HD-5000,级分收集器:LABOCOL Vario-4000,UV检测器:Knauer UVD2.1S;柱:XBridge C18 5μm 100x30mm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈;梯度:0-3分钟:65%B等度,3-13分钟:65-100%B;流动速率:60ml/min;温度:室温;溶液:最大250mg/2ml DMSO;注射:2x2ml;检测:UV 254nm。
方法P8:系统:Agilent:Prep 1200、2x制备型泵、DLA、MWD、Gilson:LiquidHandler215;柱:Chiralpak IF 5μm 250x20mm;洗脱剂A:乙醇,洗脱剂B:甲醇;梯度:等度50%B;流速:25ml/min;温度:25℃;溶液:600mg/7mlN,N-二甲基甲酰胺;注射:10x0.7ml;检测:UV 254nm。
在一些情况下,物质混合物通过硅胶上的柱色谱纯化。
对于作为本发明的组合产品的成分的式(I)的化合物和其前体和/或中间体的制备,使用来自Biotage的装置在硅胶上进行柱色谱纯化(“快速色谱”)。这涉及使用来自Biotage的滤筒,例如不同大小的“SNAP Cartridge,KP_SIL”滤筒和不同大小的来自Interchim的“Interchim Puriflash Silica HP 15UM快速柱”滤筒。
起始物质
中间体V2-1
6-(2-羟基丙-2-基)吡啶-2-甲酸甲酯
将2.00g(9.26mmol)2-(6-溴吡啶-2-基)丙-2-醇(CAS 638218-78-7)溶解于20ml甲醇和20ml DMSO中。随后,添加250mg1,3-双(二苯基膦基)丙烷、130mg乙酸钯(II)和3ml三乙胺。反应混合物在室温下用一氧化碳吹扫三次并在13巴一氧化碳气氛下搅拌30分钟。通过施加真空来移除一氧化碳气氛并在100℃下,在14巴一氧化碳气氛下将混合物搅拌24小时。将高压釜减压,将水添加至反应混合物中,且反应混合物用乙酸乙酯萃取三次,用饱和碳酸氢钠水溶液和氯化钠氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。这得到1.60g粗产物。
UPLC-MS(方法A1):Rt=0.76min(UV检测器:TIC),实测的质量195.00。
中间体V3-1
6-(2-羟基丙-2-基)吡啶-2-甲酸钾
首先将1.60g中间体0-1的粗产物装入15ml甲醇中,添加0.74g氢氧化钾并将混合物在50℃下搅拌16.5小时。在浓缩之后,这得到2.1g固体,其未经进一步纯化即使用。
UPLC-MS(方法A1):Rt=0.47min(UV检测器:TIC),实测的质量181.00。
中间体1-1
5-硝基-1H-吲唑-6-甲酸甲酯
4.60g(26.1mmol)1H-吲唑-6-甲酸甲酯(CAS编号:170487-40-8)溶解于120ml硫酸(96%)中并在具有CPG搅拌器、滴液漏斗和内部温度计的三颈烧瓶中冷却至-15℃。在15分钟的周期内,将已预先制备和冷却的硝化酸(10ml96%硫酸/5ml65%硝酸)逐滴添加至该溶液中。在逐滴添加已完成之后,将混合物再搅拌1小时(内部温度为-13℃)。将反应混合物添加至冰中,并通过抽吸滤出形成的沉淀物,用水洗涤并在干燥箱中在50℃下在减压下干燥。获得5.49g标题化合物。
UPLC-MS(方法A2):Rt=0.75min
MS(ESIpos):m/z:222(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=3.87(s,3H),7.96(s,1H),8.44(s,1H),8.70(s,1H),13.98(br.s.,1H).
中间体2-1
5-氨基-1H-吲唑-6-甲酸甲酯
将4.40g(19.8mmol)5-硝基-1H-吲唑-6-甲酸甲酯(中间体1-1)溶解于236ml甲醇中并在标准氢压力下,在25℃下用1.06g(0.99mmol)钯/活性碳氢化3小时。将反应混合物过滤通过硅藻土,过滤器用甲醇洗涤并浓缩滤液。获得3.53g标题化合物。
1H NMR(300MHz,DMSO-d6):δ[ppm]=3.85(s,3H)6.01(s,2H)6.98(s,1H)7.79-7.91(m,1H)7.99(s,1H)12.84(br.s.,1H).
中间体:3-1
5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯
首先将4.95g(25.9mmol)6-(三氟甲基)吡啶-2-甲酸装入45ml THF中。添加9.07g(28.2mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓和4.92ml(28.2mmol)N-乙基-N-异丙基丙-2-胺并将混合物在25℃下搅拌30分钟。随后,添加4.50g(23.5mmol)5-氨基-1H-吲唑-6-甲酸甲酯(中间体2-1)并将混合物在25℃下搅拌24小时。将反应混合物用抽吸过滤通过膜过滤器并用THF和水洗涤,并在干燥箱中干燥过夜。获得7.60g标题化合物。
UPLC-MS(方法A2):Rt=1.16min
MS(ESIpos):m/z=365(M+H)+
1H NMR(400MHz,DMSO-d6):6[ppm]=3.97(s,3H),8.13-8.27(m,2H),8.30(s,1H),8.33-8.45(m,1H),8.45-8.51(m,1H),9.15(s,1H),12.57(s,1H),13.44(s,1H).
中间体3-2
5-({[6-(二氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯
首先将2.85g(23.5mmol)6-(二氟甲基)吡啶-2-甲酸装入30ml THF中。添加6.05g(18.8mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓和3.3ml N-乙基-N-异丙基丙-2-胺并将混合物在室温下搅拌10分钟。随后,添加3.00g(15.7mmol)5-氨基-1H-吲唑-6-甲酸甲酯并将混合物在室温下搅拌过夜。将反应混合物与水混合,并通过抽吸滤出沉淀物并用水和二氯甲烷重复洗涤。这得到1.53g(理论值的27%)标题化合物。分离滤液的各相,浓缩有机相,与少量二氯甲烷混合且悬浮于超声浴中,并通过抽吸滤出沉淀物。这得到另外的1.03g标题化合物。
1H-NMR(第一产物级分,300MHz,DMSO-d6):δ[ppm]=3.99(s,3H),7.09(t,1H),
8.00(d,1H),8.21-8.40(m,4H),9.14(s,1H),12.53(s,1H),13.44(s,1H).
中间体3-3
5-({[6-(2-羟基丙-2-基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯
首先将2.10g 6-(2-羟基丙-2-基)吡啶-2-甲酸钾(中间体V3-1)装入15ml THF中。添加3.69g(11.5mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓和2.00ml N-乙基-N-异丙基丙-2-胺并将混合物在室温下搅拌15分钟。随后,添加1.83g(9.58mmol)5-氨基-1H-吲唑-6-甲酸甲酯(中间体2-1)并将混合物在室温下搅拌19小时。将混合物与水和乙酸乙酯混合,滤出未溶解的固体,分离滤液的各相,且水相用乙酸乙酯萃取两次,用氯化钠溶液洗涤,过滤通过疏水性过滤器,浓缩并通过硅胶柱色谱(己烷/乙酸乙酯)纯化。在移除溶剂之后,获得1.56g作为黄色泡沫的标题化合物。
UPLC-MS(方法A1):Rt=1.00min(UV检测器:TIC Smooth),实测的质量354.00。
1H-NMR(500MHz,DMSO-d6):δ[ppm]=1.63(s,6H),3.97(s,3H),5.37(s,1H),7.90-7.95(m,1H),8.03-8.07(m,2H),8.23(s,1H),8.29(s,1H),9.19(s,1H),12.79(s,1H),13.41(br.s.,1H).
中间体4-1
2-(氧杂环丁烷-3-基甲基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
将1.00mg(2.66mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)溶解于10ml DMF中并在添加1.10mg(7.99mmol)碳酸钾和221mg(1.33mmol)碘化钾之后,将混合物在25℃下搅拌30分钟。添加603mg(3.99mmol)3-溴甲基氧杂环丁烷,并将混合物在25℃下搅拌24小时。将反应混合物分配于水和乙酸乙酯之间。混合物用乙酸乙酯萃取两次,并将合并的有机相过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。这得到260mg标题化合物。
UPLC-MS(方法A2):Rt=1.24min
MS(ESIpos):m/z=435(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=3.49-3.64(m,1H),3.95(s,3H),4.49(t,2H),4.68(dd,2H),4.81(d,2H),8.20(dd,1H),8.35-8.41(m,1H),8.43-8.49(m,2H),8.55-8.58(m,1H),9.06(s,1H),12.53(s,1H).
中间体4-2
2-(2-甲氧基乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
将1.00mg(2.75mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)溶解于5ml DMF中,并添加387μl(4.12mmol)2-溴乙基甲基醚、1.14g(8.23mmol)碳酸钾和228mg(1.37mmol)碘化钾,同时进行搅拌。将反应混合物在25℃下搅拌24小时,用水稀释并用乙酸乙酯萃取两次。将合并的有机相过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。这得到12mg标题化合物。
UPLC-MS(方法A1):Rt=1.24min
MS(FSIpos):m/z=423(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=3.24(s,3H),3.86(t,2H),3.96(s,3H),4.65(t,2H),8.21(dd,1H),8.35-8.42(m,1H),8.43-8.51(m,2H),8.52(d,1H),9.06(s,1H),12.53(s,1H).
中间体4-3
2-(3-甲氧基丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
将1.00mg(2.75mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)溶解于5ml DMF中,并添加460μl(4.12mmol)1-溴-3-甲氧基丙烷、1.14g(8.23mmol)碳酸钾和228mg(1.37mmol)碘化钾,同时进行搅拌。将反应混合物在25℃下搅拌72小时,用水稀释并用乙酸乙酯萃取两次。将合并的有机相过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。这得到28mg标题化合物。
UPLC-MS(方法A1):Rt=1.29min
MS(ESIpos):m/z=437(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=2.17(quin,2H),3.24(s,3H),3.33-3.36(m,2H),3.96(s,3H),4.53(t,2H),8.21(dd,1H),8.35-8.42(m,1H),8.45-8.49(m,2H),8.54(d,1H),9.06(s,1H),12.54(s,1H).
中间体4-4
2-(3-羟基-3-甲基丁基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
制备方法1
首先将930mg(2.55mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)、1.06g碳酸钾和212mg碘化钾装入9ml DMF中并将混合物搅拌15分钟。然后添加0.62ml 4-溴-2-甲基丁-2-醇并将混合物在60℃下搅拌过夜。将混合物与水混合并用乙酸乙酯萃取两次,且萃取物用饱和氯化钠溶液洗涤三次,过滤并浓缩。硅胶上的柱色谱纯化(己烷/乙酸乙酯)得到424g标题化合物。
UPLC-MS(方法A2):Rt=1.21min(UV检测器:TIC),实测的质量450.00。
1H-NMR(400MHz,DMSO-d6):6[ppm]=1.16(s,6H)2.02-2.11(m,2H)3.96(s,3H)4.51-4.60(m,3H)8.20(dd,J=7.83,1.01Hz,1H)8.39(s,1H)8.45(s,2H)8.55(d,J=0.76Hz,1H)9.05(s,1H)12.52(s,1H).
制备方法2
首先将1.95g(7.03mmol)5-氨基-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯(中间体7-1)装入30ml THF中。添加1.45g(7.73mmol)6-(三氟甲基)吡啶-2-甲酸、2.71g(8.44mmol)四氟硼酸O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓和1.47ml(8.44mmol)N-乙基-N-异丙基丙-2-胺并将混合物在25℃下搅拌20.5小时。添加水,混合物用乙酸乙酯萃取三次且萃取物用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)分离。这得到2.79g标题化合物。
UPLC-MS(方法A1):Rt=1.23min(UV检测器:TIC),实测的质量450.00。
中间体4-5
2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
首先将1.00g(2.66mmol,97%)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)装入50ml DMF中,添加1.10g(7.99mmol)碳酸钾和221mg(1.33mmol)碘化钾,同时进行搅拌,并将混合物在25℃下搅拌30分钟。随后,添加857μl(3.99mmol)(2-溴乙氧基)(叔丁基)二甲基甲硅烷并将混合物在25℃下搅拌24小时。反应混合物用水稀释并用乙酸乙酯萃取。将合并的有机相过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。这得到400mg标题化合物。
UPLC-MS(方法A1):Rt=1.58min
MS(ESIpos):m/z=523(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=-0.18--0.13(m,6H),0.74(s,9H),3.96(s,3H),4.08(t,2H),4.57(t,2H),8.15-8.25(m,1H),8.32-8.43(m,1H),8.43-8.52(m,3H),9.07(s,1H),12.53(s,1H).
中间体4-6
2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
与中间体4-5类似,将1.00g(2.75mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体7-1)溶解于10ml DMF中。添加1.14g(8.24mmol)碳酸钾和228mg(1.37mmol)碘化钾,同时进行搅拌,并将混合物在25℃下搅拌30分钟。随后,添加1.04g(4.12mmol)(3-溴丙氧基)(叔丁基)二甲基甲硅烷并将混合物在25℃下搅拌24小时。将反应混合物过滤且滤饼用乙酸乙酯洗涤。将反应混合物分配于水和乙酸乙酯之间,且水相用乙酸乙酯萃取两次。将合并的有机相过滤通过疏水性过滤器并浓缩。残余物通过制备型HPLC纯化,得到428mg标题化合物。
UPLC-MS(方法A1):Rt=1.63min
MS(ESIpos):m/z=537(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=-0.02-0.06(m,6H),0.87(s,9H),2.14(quin,2H),3.62(t,2H),3.96(s,3H),4.54(t,2H),8.20(d,1H),8.35-8.42(m,1H),8.43-8.48(m,2H),8.49-8.53(m,1H),9.06(s,1H).
中间体4-7
5-({[6-(2-羟基丙-2-基)吡啶-2-基]羰基}氨基)-2-(4,4,4-三氟丁基)-2H-吲唑-6-甲酸甲酯
首先将300mg 5-({[6-(2-羟基丙-2-基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-3)装入4.5ml DMF中。添加287mg 1,1,1-三氟-4-碘丁烷和333mg碳酸钾并将混合物在100℃下搅拌23小时。添加水,并将混合物用乙酸乙酯萃取三次。浓缩混合物并通过制备型HPLC纯化产物。这得到72mg标题化合物。
UPLC-MS(方法A1):Rt=1.26min(UV检测器:TIC),实测的质量464.17。
中间体4-8
5-{[(5-氟-6-甲基吡啶-2-基)羰基]氨基}-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯
与中间体4-4类似(制备方法2),在19.5小时内使195mg 5-氨基-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯(中间体7-1)与78mg 5-氟-6-甲基吡啶-2-甲酸反应。在类似水性处理之后获得228mg粗产物。
UPLC-MS(方法A1):Rt=1.20min(UV检测器:TIC),实测的质量414.00。
中间体4-9
2-(3-羟基-3-甲基丁基)-5-{[(6-甲基吡啶-2-基)羰基]氨基}-2H-吲唑-6-甲酸甲酯
与中间体4-4的制备(制备方法2)类似,在19.5小时内使195mg5-氨基-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯(中间体7-1)与70mg6-甲基吡啶-2-甲酸反应。在类似水性处理之后获得278mg作为粗产物的标题化合物。
UPLC-MS(方法A1):Rt=1.14min(UV检测器:TIC),实测的质量396.00。
中间体4-10
2-[3-(2,2,2-三氟乙氧基)丙基]-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯
将250mg5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体7-1)、193mg3-溴丙基2,2,2-三氟乙基醚、242mg碳酸钾和145mg碘化钾于3mlDMF中的混合物在100℃下搅拌20小时。添加水,混合物用乙酸乙酯萃取且萃取物用氯化钠溶液洗涤并浓缩。通过制备型HPLC纯化,得到52mg标题化合物。
UPLC-MS(方法A1):Rt=1.39min(UV检测器:TIC),实测的质量504.12。
中间体5-1
N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
向在冰-水冷却浴中冷却的1.50g(4.12mmol)5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-1)于20ml THF中的溶液中小心地添加6.9ml(5当量)3M甲基溴化镁于乙醚中的溶液。搅拌混合物,同时用冰浴冷却1小时,并在室温下持续19.5小时。添加另外2当量甲基溴化镁溶液并将混合物在室温下再搅拌24小时。添加饱和氯化铵水溶液并搅拌混合物并用乙酸乙酯萃取三次。合并的有机相用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。这得到763mg标题化合物。
1H-NMR(400MHz,DMSO-d6):6[ppm]=1.63(s,6H),5.99(s,1H),7.49(s,1H),8.06(s,1H),8.14-8.19(m,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.32(s,1H),12.97(s,1H).
中间体5-2
6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]吡啶-2-甲酰胺
与中间体5-1的制备类似,使2.40g(6.93mmol)5-({[6-(二氟甲基)吡啶-2-基]羰基}氨基)-1H-吲唑-6-甲酸甲酯(中间体3-2)/10ml THF与三份3M甲基溴化镁于乙醚中的溶液(6.9ml,然后在室温下搅拌45分钟;11.6ml,然后在室温下搅拌2小时;6.9ml,然后在室温下搅拌2小时)反应。正如对于中间体5-1的处理之后,获得2.39g粗产物,其未经进一步纯化即进一步使用。
中间体6-1
2-(3-羟基-3-甲基丁基)-5-硝基-2H-吲唑-6-甲酸甲酯
首先将5.00g(22.6mmol)5-硝基-1H-吲唑-6-甲酸甲酯(中间体1-1)装入40ml DMF中。添加5.65g(33.9mmol)4-溴-2-甲基丁-2-醇、9.37g(67.8mmol)碳酸钾和5.63g(33.9mmol)碘化钾并将混合物在100℃下搅拌20小时。添加水,混合物用乙酸乙酯萃取三次且萃取物用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化。获得的固体通过与乙醚一起搅拌来萃取,通过抽吸滤出,用乙醚洗涤并干燥。这得到2.49g标题化合物。
UPLC-MS(方法A1):Rt=0.93min(UV检测器:TIC),实测的质量307.00。
1H-NMR(400MHz,DMSO-d6):δ[PPm]=1.15(s,6H),2.02-2.11(m,2H),3.84(s,3H),4.54(s,1H),4.58-4.65(m,2H),8.05(s,1H),8.69(s,1H),8.86(s,1H).
中间体7-1
5-氨基-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯
将4.53g铁和217mg氯化铵添加至2.49g(8.10mmol)2-(3-羟基-3-甲基丁基)-5-硝基-2H-吲唑-6-甲酸甲酯(中间体6-1)于30ml乙醇和10ml水中,并将混合物在90℃下搅拌21.5小时。将混合物过滤通过硅藻土并用乙醇洗涤三次,并浓缩滤液且残余物与水混合。用乙酸乙酯实现萃取三次(以改善相分离,添加氯化钠溶液)。合并的有机相用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。这得到1.95g(理论值的85%)标题化合物。
UPLC-MS(方法A1):Rt=0.67min(UV检测器:TIC),实测的质量277.00。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.14(s,6H),1.96-2.08(m,2H),3.85(s,3H),4.39-4.51(m,3H),5.81(s,2H),6.80(s,1H),8.05(s,1H),8.18(s,1H).
操作实施例
实施例1
N-[6-(2-羟基丙-2-基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将75mg(0.18mmol)2-(2-甲氧基乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-2)溶解于500μl THF中且与887μl(0.89mmol)1M甲基溴化镁于THF中的溶液混合在一起。将反应混合物在25℃下搅拌60分钟。随后,小心地添加1ml饱和氯化铵水溶液且过滤混合物。水相用乙酸乙酯萃取两次,并将有机相合并,过滤通过疏水性过滤器并浓缩。将残余物溶解于3ml DMSO中并通过制备型HPLC纯化。将含有产物的级分冷冻干燥。这得到20mg标题化合物。
UPLC-MS(方法A1):Rt=1.08min
MS(ESIpos):m/z=423(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=1.62(s,6H),3.22(s,3H),3.82(t,J=5.2Hz,2H),4.55(t,J=5.2Hz,2H),5.96(s,1H),7.57(s,1H),8.16(d,J=7.2Hz,1H),8.29-8.42(m,2H),8.42-8.50(m,1H),8.71(s,1H),12.36(s,1H)
实施例2
N-[6-(羟基甲基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将13mg(0.36mmol)氢化锂铝悬浮于1ml THF中并将混合物冷却至0℃。逐滴添加溶解于500μl THF中的75mg(0.17mmol)2-(2-甲氧基乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-2)并将混合物在25℃下搅拌60分钟。混合物用水稀释并用乙酸乙酯萃取两次,且合并的有机相用氯化钠溶液洗涤,过滤通过疏水性过滤器,浓缩并在减压下干燥。这得到36mg标题化合物。
UPLC-MS(方法A2):Rt=0.97min
MS(ESIpos):m/z=409(M+H)+
1H NMR(400MHz,DMSO-d6):6[ppm]=1.62(s,6H),3.86(q,2H),4.43(t,2H),4.95(t,1H),5.94(s,1H),7.57(s,1H),8.16(dd,1H),8.30(s,1H),8.37(t,1H),8.45(d,1H),8.72(s,1H),12.36(s,1H).
实施例3
N-[6-(2-羟基丙-2-基}2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
使75mg(0.17mmol)2-(3-甲氧基丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-3)溶解于500μl THF中且与859μl(0.86mmol)iM甲基溴化镁于THF中的溶液混合。将反应混合物在25℃下搅拌60分钟。随后,小心地添加1ml饱和氯化铵溶液且过滤混合物。水相用乙酸乙酯萃取两次,并将有机相合并,过滤通过疏水性过滤器并浓缩。将残余物溶解于3ml DMSO中并通过制备型HPLC纯化。冷冻干燥含有产物的级分。这得到25mg标题化合物。
UPLC-MS(方法A1):Rt=1.13min
MS(ESIpos):m/z=437(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.62(s,6H),2.14(quin,2H),3.23(s,3H),3.26-3.32(m,2H),4.44(t,2H),5.95(s,1H),7.58(s,1H),8.16(d,1H),8.31-8.40(m,2H),8.43-8.48(m,1H),8.72(s,1H),12.36(s,1H).
实施例4
N-[6-(羟基甲基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将13mg氢化锂铝悬浮于THF中并将混合物冷却至0℃。逐滴添加75mg(0.17mmol)2-(3-甲氧基丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-3)/THF且使混合物在30分钟内达到室温。混合物用水稀释且过滤,用乙酸乙酯洗涤残余物并用乙酸乙酯萃取滤液。合并的乙酸乙酯相用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。通过制备型HPLC纯化残余物。
1H NMR(300MHz,DMSO-d6):δ[ppm]=2.14(quin,2H),3.23(s,3H),3.29(t,2H),4.45(t,J=7.0Hz,2H),4.68(d,2H),5.77(t,1H),7.58(s,1H),8.18(d,1H),8.32-8.48(m,3H),8.51(s,1H),11.21(s,1H).
实施例5
N-[2-(2-羟基乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
阶段A:
N-[2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺的制备
使100mg(0.19mmol)2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-5)溶解于1ml THF中并与669μl(0.67mmol)1M甲基溴化镁于THF中的溶液混合。将反应混合物在25℃下搅拌60分钟。添加另一287μl(0.29mmol)1M甲基溴化镁于THF中的溶液并将混合物在25℃下搅拌3小时。随后,小心地添加20ml饱和氯化铵溶液且过滤混合物。水相用乙酸乙酯萃取两次,且合并有机相,经硫酸镁干燥,过滤,浓缩并在减压下干燥。这得到50mg N-[2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺。
UPLC-MS(方法A2):Rt=1.51min
MS(ESIpos):m/z=523(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=-0.17--0.09(m,6H),0.78(s,9H),1.62(s,6H),4.04(t,2H),4.47(t,2H),5.98(s,1H),7.57(s,1H),8.16(d,1H),8.29(s,1H),8.37(t,1H),8.45(d,1H),8.73(s,1H),12.38(s,1H).
阶段B:
将50mg(96μ mol)N-[2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺溶解于1.0ml THF中并与144μl(0.14mmol)1M氟化四丁铵于THF中的溶液混合。将反应混合物在室温下搅拌1小时。将反应物用水稀释并用乙酸乙酯萃取两次,且合并的有机相用饱和氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。这得到36mg N-[2-(2-羟基乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(实施例5)。
1H-NMR(400MHz,DMSO-d6):d[ppm]=1.62(s,6H),3.86(q,2H),4.43(t,zH),4.95(t,1H),5.94(s,1H),7.57(s,1H),8.16(dd,1H),8.30(s,1H),8.37(t,1H),8.45(d,1H),8.72(s,1H),12.36(s,1H).
UPLC-MS(方法A2):Rt=0.97min(UV检测器:TIC),实测的质量408.00。
实施例6
N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
阶段A:
N-[2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺的制备
将50mg(0.09mmol)2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-6)溶解于500ml THF中并与326μl(0.33mmol)1M甲基溴化镁于THF中的溶液混合。将反应混合物在25℃下搅拌60分钟。随后,小心地添加20ml饱和氯化铵溶液且混合物用乙酸乙酯萃取两次。将合并的有机相过滤通过疏水性过滤器,浓缩并在减压下干燥。通过制备型HPLC纯化残余物。获得40mg N-[2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺。
UPLC-MS(方法A1):Rt=1.58min
MS(ESIpos):m/z=537(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=0.02-0.05(m,6H),0.84-0.91(m,9H),1.62(s,6H),2.02-2.18(m,2H),3.55-3.62(m,2H),4.45(t,2H),5.96(s,1H),7.57(s,1H),8.16(d,1H),8.31(s,1H),8,33-8.42(m,1H),8.45(d,1H),8.72(s,1H),12.37(s,1H).
阶段B:
将37mg(0.07mmol)N-[2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-6-(2-羟基丙-2-基)-2H-吲唑-5+基]-6-(三氟甲基)吡啶-2-甲酰胺溶解于500μl THF中且与207μl(0.21mmol)氟化四丁铵于THF中的1M溶液混合。将反应混合物在25℃下搅拌2h。混合物用水稀释并用乙酸乙酯萃取两次,且合并的有机相用饱和氯化钠溶液洗涤,过滤并浓缩。在通过制备型HPLC纯化之后,获得10mg N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(实施例6)。
UPLC-MS(方法A2):Rt=1.00min
MS(ESIpos):m/z=423(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.62(s,6H),2.00-2.07(m,2H),3.07-3.22(m,1H),3.39(t,2H),4.45(t,2H),4.63(br.s.,1H),5.94(br,s.,1H),7.56(s,1H),8,14(d,1H),8.28-8.39(m,2H),8.41-8.47(m,1H),8.72(s,1H),12.31(br.s.,1H).
实施例7
N-[2-(2-羟基乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
阶段A:
N-[2+(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将100mg(0.19mmol)2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-5)溶解于1ml THF中并与191μ1(0.38mmol)2M硼氢化锂溶液混合在一起。将混合物在25℃下搅拌24小时。添加14mg(0.38mmol)硼氢化钠和500μl甲醇,并将混合物在25℃下搅拌4小时。添加另一14mg(0.38mmol)硼氢化钠,并将混合物在25℃下搅拌24小时。小心地添加水并浓缩混合物。然后混合物用乙酸乙酯萃取两次,且合并的有机相用饱和氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。将残余物溶解于2ml DMSO中,并通过制备型HPLC纯化。这得到30mg N-[2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺。
UPLC-MS(方法A2):Rt=1.44min
MS(ESIpos):m/z=495(M+H)+
1H NMR(300MHz-DMSO-d6):δ[ppm]=-0.16--0.12(m,6H),0.75-0.79(m,9H),4.05(t,2H),4.48(t,2H),4.69(d,2H),5.75-5.77(m,1H),7.57(s,1H),8.18(dd,1H),8.30-8.33(m,1H),8.38(t,1H),8.45(d,1H),8.51(s,1H),11.20(s,1H).
阶段B:
将33mg(0.07mmol)N-[2-(2-{[叔丁基(二甲基)甲硅烷基]氧基}乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺溶解于1ml THF中并与100μl(0.10mmol)氟化四丁铵于THF中的1M溶液混合。将反应混合物在25℃下搅拌1小时。混合物用水稀释并用乙酸乙酯萃取两次,且合并的有机相用饱和氯化钠溶液洗涤,过滤通过疏水性过滤器,浓缩并在减压下干燥。获得25mg N-[2-(2-羟基乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(实施例7)。
UPLC-MS(方法A2):Rt=0.87min
MS(ESIpos):m/z=381(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=3.87(q,2H),4.44(t,2H),4.69(d,2H),4.98(t,1H),5.70-5.81(m,1H),7.57(s,1H),8.11-8.23(m,1H),8.31-8.42(m,2H),8.43-8.49(m,1H),8.51(s,1H),11.20(s,1H).
实施例8
N-[6-(2-羟基丙-2-基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将50mg(0.12mmol)2-(氧杂环丁烷-3-基甲基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-1)溶解于500μl THF中并与576μl(0.58mmol)甲基溴化镁于THF中的1M溶液混合。将反应混合物在25℃下搅拌60分钟。随后,小心地添加20ml饱和氯化铵水溶液并浓缩混合物。水相用乙酸乙酯萃取两次,且合并有机相,经硫酸镁干燥,过滤并浓缩。将残余物溶解于2.0ml DMSO中并通过制备型HPLC纯化。冷冻干燥含有产物的级分。这得到30mg标题化合物。
UPLC-MS(方法A2):Rt=1.03min
MS(ESIpos):m/z=435(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.62(s,6H),3.45-3.61(m,1H),4.48(t,2H),4.66(dd,2H),4.72(d,2H),5.94(s,1H),7.57(s,1H),8.16(d,1H),8.33-8.42(m,2H),8.42-8.47(m,1H),8.72(s,1H),12.36(s,1H).
实施例9
N-[6-(羟基甲基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将75mg(0.17mmol)2-(氧杂环丁烷-3-基甲基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-1)溶解于1ml THF/甲醇(1:1)的混合物中,并添加8mg(0.21mmol)硼氢化钠。将混合物在25℃下搅拌60分钟。将反应混合物浓缩,并将残余物与水混合。将悬浮液剧烈搅拌15分钟,并通过抽吸滤出固体,用水洗涤两次并用乙醚洗涤两次,并在减压下干燥。这得到48mg标题化合物。
UPLC-MS(方法A2):Rt=0.94min
MS(ESIpos):m/z=407(M+H)+
1H NMR(300MHz,DMSO-d6):δ[ppm]=3.55(s,1H),4.48(t,2H),4.61-4.77(m,6H),7.57(s,1H),8.18(dd,1H),8.33-8.49(m,3H),8.51(s,1H),11.21(s,1H).
实施例10
N-{6-(2-羟基丙-2-基)-2-[3-(甲基磺酰基)丙基]-2H-吲引唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
将500mg(1.32mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)、569mg碳酸钾和114mg碘化钾于5.0ml DMF中的混合物在室温下搅拌15分钟。添加414mg 1-溴-3-(甲基磺酰基)丙烷并将混合物在室温下搅拌过夜。添加水,混合物用乙酸乙酯萃取两次且萃取物用氯化钠溶液洗涤并浓缩。残余物通过柱色谱(二氯甲烷/甲醇梯度)纯化。通过与乙醚一起搅拌来萃取产物级分,得到59mg标题化合物。
UPLC-MS(方法A2):Rt=1.02min
MS(ESIpos):m/z=485(M+H)+
1H-NMR(300MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.26-2.42(m,2H),2.99(s,3H),3.06-3.16(m,2H),4.55(t,2H),5.96(s,1H),7.60(s,1H),8.16(d,1H),8.33-8.48(m,3H),8.73(s,1H),12.37(s,1H).
实施例11
N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
制备方法1
首先将705mg(1.57mmol)2-(3-羟基-3-甲基丁基)-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-4)装入10ml THF中并在冰-水冷却浴中冷却。添加2.6ml(5.0当量)3M甲基溴化镁溶液(于乙醚中)并保持搅拌混合物,同时用冰浴冷却1小时并在室温下持续4.5小时。添加另一1当量甲基溴化镁溶液并将混合物在室温下搅拌20.5小时。再次添加另一1当量甲基溴化镁溶液并将混合物在室温下搅拌22小时。将反应混合物与饱和氯化铵水溶液混合,搅拌并用乙酸乙酯萃取三次。合并的有机相用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。这得到790mg残余物,其借助制备型HPLC纯化。这得到234mg标题化合物和164mg产物级分,其通过与乙醚一起搅拌来萃取。在通过抽吸过滤、随后干燥之后,获得另外的146mg标题化合物。
UPLC-MS(方法A1):Rt=1.10min(UV检测器:TIC),实测的质量450.00。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.14(s,6H),1.61(s,6H),1.99-2.08(m,2H),4.42-4.55(m,3H),5.93(s,1H),7.56(s,1H),8.15(dd,1H),8.32-8.39(m,2H),8.41-8.47(m,1H),8.70(s,1H),12.34(s,1H).
制备方法2
将500mg(1.37mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)、569mg碳酸钾和114mg碘化钾于5ml DMF中的混合物在室温下搅拌15分钟。添加344mg(1.5当量)4-溴-2-甲基丁-2-醇并将混合物加热至100℃持续2小时。添加另一0.5当量4-溴-2-甲基丁-2-醇并将混合物在室温下搅拌过夜。将混合物与水混合并用乙酸乙酯萃取两次,且合并的有机相用饱和氯化钠溶液洗涤并过滤通过疏水性过滤器,并浓缩。残余物通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化来纯化。这得到100mg产物级分,其通过与乙醚一起搅拌来萃取。在干燥之后,获得60mg标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.14(s,6H),1.61(s,6H),1.99-2.07(m,2H),4.43-4.52(m,3H)5.94(s,1H)7.57(s,1H)8.15(dd,1H)8.33-8.40(m,2H),8.42-8.48(m,1H),8.71(s,1H),12.35(s,1H).
实施例12
N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
将160mg(0.44mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)与182mg碳酸钾和36mg碘化钾一起悬浮于1.0ml DMF中,并将混合物在室温下搅拌15分钟。然后,添加123mg 2-溴乙基甲基砜并将混合物在室温下搅拌过夜。添加水,混合物用乙酸乙酯萃取两次且萃取物用饱和氯化钠水溶液洗涤,过滤通过疏水性过滤器并浓缩。残余物通过制备型HPLC纯化,以得到20mg标题化合物。
UPLC(方法A2):Rt=1.01min;
MS(ESIpos):m/z=471(M+H)+
1H NMR(400MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.90(s,3H),3.85(t,2H),4.86(t,2H),5.97(s,1H),7.59(s,1H),8.13-8.19(m,1H),8.37(s,1H),8.41-8.48(m,2H),8.74(s,1H),12.37(s,1H).
实施例13
6-(二氟甲基)-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]吡啶-2-甲酰胺
将250mg 6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]吡啶-2-甲酰胺(中间体5-2的粗产物)、144mg碘化钾和239mg碳酸钾于2.5ml DMF中的混合物在室温下搅拌15分钟。添加145mg(0.87mmol)4-溴-2-甲基丁-2-醇,将混合物在110℃下搅拌3小时,添加另一96mg 4-溴-2-甲基丁-2-醇并将混合物在110℃下搅拌4小时。添加水,混合物用乙酸乙酯萃取两次且萃取物用饱和氯化钠水溶液洗涤,过滤通过疏水性过滤器并浓缩。通过硅胶上的柱色谱(己烷/乙酸乙酯)进行纯化。这得到61mg标题化合物。
UPLC-MS(方法A1):Rt=1.00min(UV检测器:TIC),实测的质量432.00。
1H-NMR(300MHz,DMSO-d6):δ[ppm]=1.14(s,6H),1.63(s,6H),1.97-2.08(m,2H),4.41-4.55(m,3H),5.99(s,1H),7.03(t,1H),7.56(s,1H),7.94-8.00(m,1H),8.24-8.38(m,3H),8.71(s,1H),12.49(s,1H),
实施例14
6-(二氟甲基)-N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}吡啶-2-甲酰胺
将250mg 6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]吡啶-2-甲酰胺(中间体5-2的粗产物)、144mg碘化钾和239mg碳酸钾于2.5ml DMF中的混合物在室温下搅拌15分钟。添加162mg 2-溴乙基甲基砜并将混合物在110℃下搅拌3小时。添加水,混合物用乙酸乙酯萃取两次且萃取物用饱和氯化钠水溶液洗涤,过滤通过疏水性过滤器并浓缩。残余物通过制备型HPLC纯化且产物级分额外地通过硅胶上的柱色谱(己烷/乙酸乙酯)纯化来纯化。这得到40mg标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.65(s,6H),2.90(s,3H),3.85(t,2H),4.85(t,2H),6.03(s,1H),7.04(t,1H),7.59(s,1H),7.98(d,1H),8.25-8.36(m,2H),8.43(s,1H),8.75(s,1H),12.52(s,1H).
实施例15
6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]吡啶-2-甲酰胺
阶段A:
N-[2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(二氟甲基)吡啶-2-甲酰胺的制备
将250mg 6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]吡啶-2-甲酰胺(中间体5-2)、48mg碘化钾和239mg碳酸钾于2.5ml DMF中的混合物在室温下搅拌15分钟。添加219mg(0.87mmol,1.5当量)(3-溴丙氧基)(叔丁基)二甲基甲硅烷并将混合物在110℃下搅拌3小时。添加1当量(3-溴丙氧基)(叔丁基)二甲基甲硅烷并将混合物在100℃下搅拌4小时。添加水,混合物用乙酸乙酯萃取且萃取物用氯化钠水溶液洗涤,过滤通过疏水性过滤器并浓缩。通过柱色谱(己烷/乙酸乙酯)纯化残余物。这得到92mg标题化合物。
阶段B:
与实施例6,阶段B的制备类似,使92mg N-[2-(3-{[叔丁基(二甲基)甲硅烷基]氧基}丙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(二氟甲基)吡啶-2-甲酰胺与0.53ml氟化四丁铵于THF中的1M溶液在1小时内反应。如实施例6中进行水性处理并通过制备型HPLC纯化,得到46mg标题化合物。UPLC-MS(方法A1):Rt=0.92min(UV检测器:TIC),实测的质量404.00。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.64(s,6H),2.05(quin,2H),3.35-3.46(m),4.45(t,2H),4.64(t,1H),5.99(s,1H),7.04(t,1H),7.57(s,1H),7.95-7.99(m,1H),8.25-8.36(m,3H),8.73(s,1H),12.50(s,1H).
实施例16
N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
将210mg(0.58mmol)N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)于3ml DMF中的混合物与0.11ml 1,1,1-三氟-4-碘丁烷和239mg碳酸钾混合,并将混合物在80℃下搅拌6小时。在添加水之后,混合物用乙酸乙酯萃取三次,且合并的有机相用饱和氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。通过制备型HPLC纯化粗产物。这得到19mg标题化合物。
UPLC-MS(方法A1):Rt=1.27min(UV检测器:TIC),实测的质量474.15。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.62(s,6H),2.10-2.33(m),4.49(t,2H),5.94(s,1H),7.59(s,1H),8.13-8.18(m,1H),8.32-8.41(m,2H),8.41-8.47(m,1H),8.72(s,1H),12.35(s,1H).
实施例17
N-{6-(2-羟基丙-2-基)-2-[3-(三氟甲氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
首先将150mg N-[6-(2-羟基丙-2-基)-1H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺(中间体5-1)装入2ml THF中。添加58mg 3-(三氟甲氧基)丙-1-醇、131mg三苯基膦和71μl偶氮二甲酸二异丙酯(DIAD,CAS 2446-83-5)并将混合物在室温下搅拌19小时。添加0.83ml氢氧化钠溶液(2M)并将混合物在40℃下搅拌5小时。混合物用水稀释并用乙酸乙酯萃取三次,并将合并的有机相浓缩并通过制备型HPLC纯化。获得16mg作为粗产物的标题化合物。
UPLC-MS(方法A2):Rt=1.26min(UV检测器:TIC),实测的质量490.14。
1H-NMR(400MHz,DMSO-d6,选择的信号):δ[ppm]=1.61(s,6H),1.84(d,1H),2.32(quint.,2H),4.08(t,2H),4.51(t,2H),7.58(s,1H),8.15(d,1H),8.31-8.39(m,2H),8.44(d,1H),8.72(s,1H),12.35(s,1H).
实施例18
N-{6-(2-羟基丙-2-基)-2-[3-(2,2,2-三氟乙氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
与实施例11的制备(制备方法1)类似,使52mg 2-[3-(2,2,2-三氟乙氧基)丙基]-5-({[6-(三氟甲基)吡啶-2-基]羰基}氨基)-2H-吲唑-6-甲酸甲酯(中间体4-10)/3ml THF与2x171微升3M溴化镁于乙醚中的溶液反应。通过制备型HPLC纯化,得到12mg标题化合物。
UPLC-MS(方法A1):Rt=1.25min(UV检测器:TIC),实测的质量504.16。
1H-NMR(500MHz,DMSO-d6):δ[ppm]=1.63(s,6H),2.20(quin,2H),3.58(t,2H),4.05(q,2H),4.47(t,2H),5.94(s,1H),7.58(s,1H),8.15(dd,1H),8.32(s,1H),8.36(t,1H),8.45(d,1H),8.73(s,1H),12.36(s,1H).
实施例19
5-氟-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺
首先将228mg 5-{[(5-氟-6-甲基吡啶-2-基)羰基]氨基}-2-(3-羟基-3-甲基丁基)-2H-吲唑-6-甲酸甲酯(中间体4-8)装入4.5ml THF中并用冰冷却浴冷却。添加0.63ml3M甲基溴化镁溶液(于乙醚中)并搅拌混合物,同时用冰浴冷却2小时,并在室温下持续21小时。将反应混合物与饱和氯化铵水溶液混合并用乙酸乙酯萃取三次。浓缩合并的有机相。通过制备型HPLC纯化残余物。这得到82mg标题化合物。
UPLC-MS(方法A2):Rt=1.03min(UV检测器:TIC),实测的质量414.21。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.13(s,6H),1.63(s,6H),1.99-2.05(m,2H),2.55-2.59(m,3H),4.42-4.50(m,3H),5.95(s,1H),7.54(s,1H),7.83(t,1H),8.05(dd,1H),8.31(s,1H),8.68(s,1H),12.33(s,1H).
实施例20
N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺
首先将278mg 2-(3-羟基-3-甲基丁基)-5-{[(6-甲基吡啶-2-基)羰基]氨基}-2H-吲唑-6-甲酸甲酯(中间体4-9)装入5.0ml THF中并用冰冷却浴冷却。添加0.97ml 3M甲基溴化镁溶液(于乙醚中)并搅拌混合物,同时用冰浴冷却2小时,并在室温下持续20.5小时。添加另一0.48ml 3M甲基溴化镁溶液并将混合物在室温下搅拌67小时。将混合物与饱和氯化铵水溶液混合并用乙酸乙酯萃取三次,且萃取物用氯化钠溶液洗涤,过滤通过疏水性过滤器并浓缩。通过制备型HPLC纯化残余物。这得到111mg标题化合物。
UPLC-MS(方法A2):Rt=0.97min(UV检测器:TIC),实测的质量396.22。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.15(s,6H),1.64(s,6H),2.00-2.08(m,2H),2.61(s,3H),4.41-4.59(m,3H),5.92(s,1H),7.50(dd,1H),7.56(s,1H),7.90-7.99(m,2H),8.33(s,1H),8.70(s,1H),12.39(s,1H).
实施例21
6-(2-羟基丙-2-基)-N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]吡啶-2-甲酰胺
将72mg(0.155mmol)5-({[6-(2-羟基丙-2-基)吡啶-2-基]羰基}氨基)-2-(4,4,4-三氟丁基)-2H-吲唑-6-甲酸甲酯(中间体4-7)于10ml THF中的溶液在冰/水冷却浴中冷却。添加0.26ml甲基溴化镁于乙醚中的3M溶液并将混合物搅拌2小时,且然后在室温下持续20小时。添加另一1当量3M甲基溴化镁溶液并将混合物在室温下搅拌24小时。添加饱和氯化铵水溶液,混合物用乙酸乙酯萃取三次且萃取物用氯化钠溶液洗涤并浓缩。制备型HPLC得到22mg(理论值的31%)标题化合物。
UPLC-MS(方法A2):Rt=1.15min(UV检测器:TIC),实测的质量464.20。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.56(s,6H),1.64(s,6H),2.07-2.34(m,4H),4.49(t,2H),5.32(s,1H),6.05(s,1H),7.60(s,1H),7.87(dd,1H),7.99-8.05(m,2H),8.35(s,1H),8.79(s,1H),12.45(s,1H).
生理学效力的评价
IRAK4激酶测定法
在下文描述的Irak4TR-FRET测定法(TR-FRET=时间分辨荧光共振能量转移)中测量作为本发明组合产品的成分的本发明的式(I)的物质的IRAK4抑制活性。
将表达于杆状病毒感染的昆虫细胞(Hi5,BTI-TN-5B1-4,购自Invitrogen的细胞系,目录号B855-02)中且经由亲和色谱法纯化的来自N-末端GST(谷胱甘肽S-转移酶)和人类Irak4的重组型融合蛋白用作酶。用于激酶反应的底物为生物素化的肽生物素-Ahx-KKARFSRFAGSSPSQASFAEPG(酰胺形式的C-末端),其可例如购自Biosyntan GmbH(Berlin-Buch)。
为了进行测定,从测试物质于DMSO中的2mM溶液制备在20μM至0.073nM范围内的11种不同浓度。将50nl各自溶液吸入黑色低体积384孔微量滴定板(Greiner Bio-One,Frickenhausen,Germany),添加2μl Irak4于测定缓冲液[50mM HEPES pH 7.5,5mMMgCl2,1.0mM二硫苏糖醇,30μM活化的原钒酸钠,0.1%(w/v)牛γ-球蛋白(BGG)0.04%(v/v)nonidet-P40(Sigma)]中的溶液且将混合物孵育15分钟以允许物质在激酶反应之前预结合至酶。然后通过添加3μl三磷酸腺苷(ATP,1.67mM=5μl测定体积中的最终浓度:1mM)和肽底物(0.83μM=5μl测定体积中的最终浓度:0.5μM)于测定缓冲液中的溶液来开始激酶反应,并将所得混合物在22℃下孵育45分钟的反应时间。将Irak4的浓度调节至酶的各自活性且设定,使得测定在线性范围内进行。典型浓度在约0.2nM的数量级内。通过添加5μlTR-FRET检测试剂[0.1μM链霉抗生物素蛋白-XL665(Cisbio Bioassays;France,目录号610SAXLG)]和1.5nM抗磷酸丝氨酸抗体[Merck Millipore,“STK抗体”,目录号35-002]和0.6nM LANCEEU-W1024标记的抗小鼠-IgG抗体(Perkin-Elmer,产品号AD0077,或者有可能使用来自Cisbio Bioassays的铽穴状化合物标记的抗小鼠-IgG抗体)于EDTA水溶液(100mM EDTA,0.4%[w/v]牛血清白蛋白[BSA],于25mM HEPES中,pH7.5)中的溶液来停止反应。
将所得混合物在22℃下孵育1小时以允许形成生物素化的磷酸化底物和检测试剂的复合物。然后通过测量从铕螯合剂标记的抗小鼠-IgG抗体至链霉抗生物素蛋白-XL665的共振能量转移来评估磷酸化底物的量。为此,在TR-FRET测量仪器,例如Rubystar(BMGLabtechnologies,Offenburg,Germany)或Viewlux(Perkin-Elmer)中在350nm下激发之后,测量在620nm和665nm下的荧光发射。将665nm和622nm下的发射比作为磷酸化底物的量的量度。将数据均一化(在无测试物质的情况下的酶反应=0%抑制;除酶以外的所有其他测定组分=100%抑制)。典型地,测试物质在相同微量滴定板上,以20μM至0.073nM的范围内的11种不同浓度(20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、11nM、3.1nM、0.89nM、0.25nM和0.073nM)下测试。在测定之前通过连续稀释制备稀释系列(2mM至7.3nM,于100%DMSO中)。使用4参数拟合计算IC50值。
表1:在IRAK4激酶测定中作为本发明组合产品的成分的式(I)的实施例化合物的IC50值
THP-1细胞中的TNF-α分泌
借助于该测试,有可能测试物质抑制THP-1细胞(人类单核细胞急性白血病细胞系)中的TNF-α(肿瘤坏死因子α)的分泌的能力。TNF-α是参与炎性过程的细胞因子。在该测试中,通过与细菌性脂多糖(LPS)一起孵育来触发TNF-α分泌。
将THP-1细胞保持于连续悬浮细胞培养物[具有L-Glutamax(Gibco,目录号61870-044)的RPMI 1460培养基,其补充有胎牛血清(FCS)10%(Invitrogen,目录号10082-147)、1%青霉素/链霉素(GibcoBRL,目录号15140-114)]中且不应超过1x106个细胞/ml的细胞浓度。在细胞培养基(具有L-Glutamax的RPMI 1460培养基,其补充有FCS10%)中进行测定。
在每种情况下,将每孔2-2.5μl的细胞悬浮液(对应于4000个细胞)分配至384孔测试板(Greiner,目录号784076)中,其中各自中,40-50nl物质已溶解于100%DMSO中。此处,在每种情况下,将在20μM至0.073nM范围内的10种不同浓度用于各物质。将细胞在室温下孵育15分钟。然后将2-2.5μl溶解于细胞培养基(最终浓度0.05μg/ml)中的0.1μg/mlLPS(Sigma,大肠杆菌055:B5,目录号L5418)分配至各孔中。作为中性对照,用0.05μg/mlLPS和1%DMSO处理细胞,且作为抑制剂对照,仅用1%DMSO处理一次。
将板以80g离心30秒并在37℃、5%CO2和95%大气湿度下孵育17小时。使用TNF-αHTRF检测试剂盒(Cisbio,目录号62TNFPEB/C)测定TNF-α的量。为此,在每种情况下,添加根据制造商说明溶解于重构缓冲液中的2μl由抗TNF-α-XL665缀合物和抗TNF-α-穴状化合物缀合物组成的检测溶液,用于HTRF(均质时间分辨荧光)测试。在添加之后,将混合物在室温下孵育3小时或在4℃下孵育过夜。然后使用HTRF启用的测量仪器(诸如BMGPheraStar)在620/665nm下读取信号。
物质的活性表示为中性和抑制剂对照之间的以百分比计的比率。使用4参数拟合计算IC50值。
表2:示例性化合物关于在THP-1细胞中的TNF-α的分泌的IC50值
人类PBMC(外周血液单核细胞)中体外LPS(脂多糖)诱导的细胞因子产生
检查作为本发明的组合产品的成分的通式(I)的化合物对人类PBMC中诱导的细胞因子产生的作用。此处,通过LPS(一种TLR4配体)诱导细胞因子产生,其引起IRAK4介导的信号传导途径的活化。
人类PBMC获自抗凝人类全血。为此,首先将15ml Ficoll-Paque(Biochrom,目录号L6115)装入Leucosep管中并添加20ml人类血液。在室温下以800g离心血液15分钟之后,移除包括血小板的血浆且丢弃。将PBMC转移至离心管中并用PBS(磷酸盐缓冲盐水)(Gibco,目录号14190)补足。在室温下在250g下离心细胞悬浮液10分钟且丢弃上清液。将PBMC再悬浮于完全培养基(RPMI 1640,无L-谷氨酰胺(PAA,目录号E15-039),10%FCS;50U/ml青霉素,50μg/ml链霉素(PAA,目录号P11-010)和1%L-谷氨酰胺(Sigma,目录号G7513))中。
还在完全培养基中进行测定。在96孔板中以2.5x105个细胞/孔的细胞密度接种PBMC。化合物在恒定体积的100%DMSO中经历连续稀释且以10μM至3nM范围中的8种不同浓度用于测定中,使得最终DMSO浓度为0.4%DMSO。在实际刺激之前,然后使其与细胞一起预孵育30分钟。为了诱导细胞因子分泌,用0.1μg/ml LPS(Sigma,大肠杆菌0128:B12,目录号L2887)刺激细胞24小时。使用CellTiter-Glo发光测定法(Promega,目录号G7571(G755/G756A))根据制造商说明测定细胞活力。使用人类促炎性9-Plex组织培养试剂盒(HumanProInflammatory 9-Plex Tissue Culture Kit)(MSD,目录号K15007B)根据制造商说明测定细胞培养上清液中的分泌的TNF-α的量。通过实例的方式提及活性≤1μM的实施例化合物11和实施例化合物12。
体内B细胞淋巴瘤相关的异种移植模型
在鼠异种移植模型中检查作为本发明的组合产品的成分的通式(I)的化合物的抗肿瘤活性。为此,将人类B细胞淋巴瘤的肿瘤细胞系(例如TMD-8)皮下植入雌性C.B-17SCID小鼠。在20-30mm2的平均肿瘤大小时,开始单药治疗或与标准依鲁替尼治疗组合的治疗,其中各自经口给药。在此之前进行动物的随机化。治疗在未处理的对照组一具有≤150mm2的肿瘤面积就结束。每周一次测定肿瘤大小和体重,进行三周。体重的变化是治疗相关的毒性的量度(>10%=重大,治疗停止直至恢复,>20%=毒性,终止)。借助于电子测径规检测肿瘤面积[长度(mm)x宽度(mm)]。抗肿瘤效力定义治疗vs.对照的肿瘤面积的比率[第X天的治疗组的肿瘤面积/第X天的对照组的肿瘤面积]。具有大于0.5的T/C的化合物被定义为活性的(有效)。使用单因子ANOVA进行统计分析且借助于逐对比较分析(Dunnett氏检验)来与对照组比较。
附图说明
图1显示呈单药疗法和与依鲁替尼的组合的实施例化合物11在治疗人类TMD-8ABC-DLBCL肿瘤中的效力。在第0天将TMD-8肿瘤细胞皮下植入雌性C.B-17SCID小鼠。在第15天,在约26mm2的肿瘤面积时开始治疗。以40mg/kg的日剂量经口给药实施例化合物11。类似地,以10mg/kg的日剂量经口给药依鲁替尼。通过测定肿瘤面积来评价肿瘤生长(参见图1,上部分A),并通过测定体重来评价动物的健康(参见图1,下部分B)。
实施例化合物11在其作为单药疗法给药时未显示对TMD-8的肿瘤生长的任何抑制性作用。单药疗法中的依鲁替尼显示对TMD-8的肿瘤生长的中度抑制性作用,其中T/C值为0.60,但与对照组相比是统计显著的。在包含实施例化合物11和依鲁替尼的组合治疗中,记录抗肿瘤作用的显著升高,其反映为0.09的T/C值且与对照和依鲁替尼相比,肿瘤面积的统计显著性降低。
治疗被非常良好地耐受;未记录重大体重减轻。
总之,该研究中显示实施例化合物11与BTK抑制剂依鲁替尼的组合产品在ABC-DLBCL的模型中可实现各自单药疗法的抗肿瘤作用的显著升高。
图1:
TMD-8 C.B-17 SCID小鼠中的单药疗法和与依鲁替尼的组合产品中的实施例化合物11的抗肿瘤活性
*P<0.05(与媒介物对照相比)
#P<0.05(与依鲁替尼单药疗法相比)
a)T/C=治疗vs对照的肿瘤面积的比率[第X天的治疗组的肿瘤面积/第X天的对照组的肿瘤面积]。
b)体重减轻:与治疗开始时的初始体重相比的体重变化(>10%=重大,停止治疗直至恢复,>20%=毒性,终止)。
图1显示TMD-8 C.B-17 SCID小鼠中的单药疗法和与依鲁替尼的组合产品中的实施例化合物11的抗肿瘤活性。图1的说明:缩写Ex意味着实施例,QD意味着每天一次且po意味着经口。
细胞增殖测量
在人类ABC-DLBCL细胞中在体外检查作为本发明的组合产品的成分的通式(I)的化合物的抗增殖活性。为此目的,将生长培养基(RPMI(Biochrom:FG1215),20%FCS(Biochrom:S0615))中30μl/孔的4000TMD-8或HBL-1细胞(均来自ATCC)或OCI-LY10转移至384孔板(Perkin Elmer,白色)中并在37℃下孵育过夜。在24小时之后,一个板(0小时板)上的细胞用30μl/孔的CTG溶液(Promega Cell Titer Glo(目录号G755B和G756B))处理并在室温下孵育10分钟,且借助于VICTOR V(Perkin Elmer)测量荧光,以测定处理开始时的细胞活力。测试板上的细胞用作为本发明的组合产品的成分的通式(I)的化合物处理并在37℃下孵育72小时。借助于HP D300数字分配器,以7-步的3-倍稀释系列向细胞中单独或作为不同浓度的两种化合物的组合(物质1(作为本发明的组合产品的成分的通式(I)的实施例化合物)和物质2(作为本发明的组合产品的成分的BTK抑制剂依鲁替尼或RN486或AVL-292或AVL-292)的比率:1:0;0.85:0.15;0.7:0.3;0.5:0.5;0.3:0.7;0.15:0.85;0:1)添加化合物。作为对照,用媒介物(DMSO)处理细胞。在72小时之后,细胞用30μl/孔的CTG溶液(Promega Cell Titer Glo(目录号G755B和G756B))处理并在室温下孵育10分钟,且借助于VICTOR V(Perkin Elmer)测量荧光,以测定在处理结束时的细胞活力。使用来自0小时板(=最大抑制)和DMSO对照(=最小抑制)的值测定各测试物质对细胞生长的作用百分比和由其获得的IC50。使用4参数拟合计算IC50值。基于上述IC50测定来测定测试物质的组合作用。基于Chou氏方程式计算组合指数(CI)(ChouTC等人,Pharmacological ReviewsSeptember 2006)。该指数允许物质相互作用的定量测定。CI<1、=1和>1分别描述协同、加合和拮抗作用。借助于等效线图实现可视化。
在用实施例化合物3或11或12或13或19和依鲁替尼或RN486或AVL-292或CGI-1746的组合治疗中,与单一治疗相比,几乎始终记录到抗肿瘤作用的显著升高。
图2a至2e和4a至c(Ex意味着实施例化合物)显示ABC-DLBCL细胞系TMD-8和HBL-1和OCI-LY10中对于BTK抑制剂依鲁替尼或RN486或AVL-292或CGI-1746与通式(I)的化合物的组合产品的组合性细胞增殖测量的结果(图2a:实施例03;图2b:实施例11;图2c:实施例12;图3d:实施例13,图2e:实施例19)。显示y轴上各自浓度的物质1(D1)(作为本发明的组合产品的成分的通式(I)的实施例化合物)和x轴上物质2(D2)(作为本发明的组合产品的成分的BTK抑制剂依鲁替尼或RN486或AVL-29或CGI-1746)的各种组合产品的IC50等效线图。低于、等于或高于斜边的数据点分别指示对细胞增殖的协同、加合和拮抗作用。
图2a的说明:依鲁替尼与实施例03的组合产品对TMD-8和HBL-1细胞的细胞活力的作用。
图2b的说明:依鲁替尼与实施例11的组合产品对TMD-8和HBL-1细胞的细胞活力的作用。
图2c的说明:依鲁替尼与实施例12的组合产品对TMD-8和HBL-1细胞的细胞活力的作用。
图2d的说明:依鲁替尼与实施例13的组合产品对TMD-8和HBL-1细胞的细胞活力的作用。
图2e的说明:依鲁替尼与实施例19的组合产品对TMD-8和HBL-1细胞的细胞活力的作用。
图4a的说明:BTK抑制剂RN468或AVL-292或CGI-1746与实施例11的组合产品对TMD-8细胞的细胞活力的作用。
图4b的说明:BTK抑制剂RN468或AVL-292或CGI-1746与实施例11的组合产品对HBL-1细胞的细胞活力的作用。
图4c的说明:BTK抑制剂RN468或AVL-292或CGI-1746与实施例11的组合产品对OCI-LY10细胞的细胞活力的作用。
NF-kB报导子测定法
在人类DLBCL细胞中在体外检查作为本发明的组合产品的成分的通式(I)的化合物对NF-kB信号传导途径的作用。将在生长培养基(RPMI(Biochrom:FG1215),20%FCS(Biochrom:S0615))中的在30μl/孔的10000个TMD-8-NF-kB-luc细胞或10000个HBL-1-NF-kB-luc报导子细胞转移至384孔板(Perkin Elmer,白色)中并在37℃下孵育过夜。在24小时之后,细胞用测试物质处理并在37℃下孵育6小时。借助于HPD300数字分配器以7-步3-倍稀释系列向细胞中添加化合物–单独或作为不同浓度的两种化合物的组合(物质1(作为本发明的组合产品的成分的通式(I)的实施例化合物)与物质2(作为本发明的组合产品的成分的BTK抑制剂依鲁替尼)的比率:1:0;0.85:0.15;0.7:0.3;0.5:0.5;0.3:0.7;0.15:0.85;0:1)。作为对照,用媒介物(DMSO)处理细胞。在6小时之后,用30μl/孔的One-Glo溶液(Promega,E6110)处理细胞并在室温下孵育10分钟,并使用VICTORV(Perkin Elmer)测量荧光以测定处理结束时的NF-kB报导子活性。使用对于已知NF-kB抑制剂(I-kappaB激酶抑制剂)(-)-7-[2-(环丙基甲氧基)-6-羟基苯基]-5-[(3S)-3-哌啶基]-1,4-二氢-2H-吡啶并[2,3-d][1,3]-噁嗪-2-酮(CAS编号600734-02-9,参见WO2003076447)(=最大抑制)和DMSO对照(=最小抑制)的值测定各测试物质对NF-kB报导子活性的作用百分比和由其获得的IC50。使用4参数拟合计算IC50值。基于上述IC50测定来测定测试物质的组合作用。基于Chou氏方程式计算组合指数(CI)(ChouTC等人,Pharmacological Reviews September 2006)。该指数允许物质相互作用的定量测定。CI<1、=1和>1分别描述协同、加合和拮抗作用。借助于等效线图实现可视化。
在用实施例化合物3或11或12或13或19和依鲁替尼的组合治疗中,与单一治疗相比,记录NF-kB信号传导途径抑制的显著升高。
图3a至3e(Ex意味着实施例化合物):依鲁替尼与通式(I)的化合物的组合产品在ABC-DLBCL细胞系TMD-8-NF-kB-luc和HBL-1-NF-kB-luc中的NF-kB报导子测定法的结果(图3a:实施例03;图3b:实施例11;图3c:实施例12;图3d:实施例13,图3e:实施例19)。显示y轴上具有各自浓度的物质1(D1)(作为本发明的组合产品的成分的通式(I)的实施例化合物)和x轴上物质2(D2)(作为本发明的组合产品的成分的BTK抑制剂依鲁替尼)的各种组合的IC50等效线图。低于、等于和高于斜边的数据点分别指示对NF-kB信号传导途径的协同、加合和拮抗作用。
图3a的说明:TMD-8和HBL-1细胞中依鲁替尼与实施例03的组合产品对NF-kB信号传导途径活性的作用。
图3b:TMD-8和HBL-1细胞中依鲁替尼与实施例11的组合产品对NF-kB信号传导途径活性的作用。
图3c:TMD-8和HBL-1细胞中依鲁替尼与实施例12的组合产品对NF-kB信号传导途径活性的作用。
图3d:TMD-8和HBL-1细胞中依鲁替尼与实施例13的组合产品对NF-kB信号传导途径活性的作用。
图3e:TMD-8和HBL-1细胞中依鲁替尼与实施例19的组合产品对NF-kB信号传导途径活性的作用。
药物组合物的操作实施例
作为本发明的组合产品的成分的式(I)的化合物可转化为如下药物制剂:
片剂:
组成:
100mg实施例11的化合物或实施例12的化合物、50mg乳糖(单水合物)、50mg玉米淀粉(天然)、10mg聚乙烯吡咯烷酮(PVP25)(来自BASF,Ludwigshafen,Germany)和2mg硬脂酸镁。
片剂重量212mg。直径8mm,曲率半径12mm。
生产:
作为本发明的组合产品的成分的式(I)的化合物、乳糖和淀粉的混合物用PVP于水中的5%溶液(m/m)制粒。干燥颗粒且然后与硬脂酸镁混合5分钟。在常规压片机中压缩该混合物(关于片剂的形式,参见上文)。用于压片的指导值为15kN的压力。
用于经口给药的悬浮液
组成:
10ml经口悬浮液对应于100mg化合物的单次剂量。
生产:
将Rhodigel悬浮于乙醇中;将化合物添加至悬浮液中。添加水,同时搅拌。将混合物搅拌约6小时,直至Rhodigel完成膨胀。
用于经口给药的溶液:
组成
500mg实施例11的化合物或实施例12的化合物、2.5g聚山梨醇酯和97g聚乙二醇400。20g经口溶液对应于100mg化合物的单次剂量。
生产
将化合物在搅拌下悬浮于聚乙二醇和聚山梨醇酯的混合物中。继续搅拌操作,直至化合物完全溶解。
Claims (14)
1.以下物质的药物组合产品:
·组分A,其为:
1)N-[6-(2-羟基丙-2-基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
2)N-[6-(羟基甲基)-2-(2-甲氧基乙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
3)N-[6-(2-羟基丙-2-基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
4)N-[6-(羟基甲基)-2-(3-甲氧基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
5)N-[2-(2-羟基乙基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
6)N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
7)N-[2-(2-羟基乙基)-6-(羟基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
8)N-[6-(2-羟基丙-2-基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
9)N-[6-(羟基甲基)-2-(氧杂环丁烷-3-基甲基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
10)N-{6-(2-羟基丙-2-基)-2-[3-(甲基磺酰基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
11)N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
12)N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
13)6-(二氟甲基)-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]吡啶-2-甲酰胺
14)6-(二氟甲基)-N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2H-吲唑-5-基}吡啶-2-甲酰胺
15)6-(二氟甲基)-N-[6-(2-羟基丙-2-基)-2-(3-羟基丙基)-2H-吲唑-5-基]吡啶-2-甲酰胺
16)N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]-6-(三氟甲基)吡啶-2-甲酰胺
17)N-{6-(2-羟基丙-2-基)-2-[3-(三氟甲氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
18)N-{6-(2-羟基丙-2-基)-2-[3-(2,2,2-三氟乙氧基)丙基]-2H-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺
19)5-氟-N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺
20)N-[2-(3-羟基-3-甲基丁基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基]-6-甲基吡啶-2-甲酰胺;或
21)6-(2-羟基丙-2-基)-N-[6-(2-羟基丙-2-基)-2-(4,4,4-三氟丁基)-2H-吲唑-5-基]吡啶-2-甲酰胺;或其非对映异构体、对映异构体、药学上可接受的盐;
·组分B,其为BTK抑制性化合物,其选自以下目录:
·依鲁替尼(ibrutinib);
·4-叔丁基-N-[2-甲基-3-(4-甲基-6-{[4-(吗啉-4-基羰基)苯基]氨基}-5-氧代-4,5-二氢吡嗪-2-基)苯基]苯甲酰胺(CGI-1746,CAS 910232-84-7);
·N-{3-[(5-氟-2-{[4-(2-甲氧基乙氧基)苯基]氨基}嘧啶-4-基)氨基]苯基}丙烯酰胺(AVL-292,CAS 1202757-89-8);
·6-环丙基-8-氟-2-[2-(羟基甲基)-3-(1-甲基-5-{[5-(4-甲基哌嗪-1-基)吡啶-2-基]氨基}-6-氧代-1,6-二氢吡啶-3-基)苯基]异喹啉-1(2H)-酮(RN486,CAS 1242156-23-5);
或其药学上可接受的盐。
2.根据权利要求1所述的组合产品,其进一步包括组分C,其中组分C为选自以下目录的药剂:
131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、赤式-羟基壬基腺嘌呤(ado-trastuzumabemtansine)、阿法替尼、阿柏西普、阿地白介素、阿仑珠单抗、阿仑膦酸、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、己基-5-氨基乙酰丙酸酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴香脑二硫杂环戊二烯硫酮(anetholedithiolethione)、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、阿格拉宾、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、贝洛替康、苯达莫司汀、贝利司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来考昔、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、copanlisib、克立他酶(crisantaspase)、克里唑替尼、环磷酰胺、环丙特龙、阿糖胞苷、达卡巴嗪、放线菌素D、达拉菲尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素、地舒单抗、地普奥肽、地洛瑞林、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依屈洛单抗、依利醋铵、内皮他丁、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、促红素α、倍他铂、泽塔铂、依他铂、艾立布林、厄洛替尼、埃索美拉唑、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺盐、钆弗塞胺、钆塞酸二钠盐(Gd-EOB-DTPA二钠盐)、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、羧肽酶、氧化型谷胱甘肽(glutoxim)、戈舍瑞林、格拉司琼、粒细胞集落刺激因子(G-CSF)、粒细胞巨噬细胞集落刺激因子(GM-CSF)、二盐酸组胺、组氨瑞林、羟基脲、I-125种子(I-125seeds)、伊班膦酸、替伊莫单抗、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、吡地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、兰瑞肽、兰索拉唑、拉帕替尼、lasocholine、来那度胺、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、lipegfilgrastim、利舒脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯嘌呤、美司钠、美沙酮、甲氨蝶呤、甲氧沙林、氨基酮戊酸甲酯、甲基泼尼松龙、甲睾酮、甲酪氨酸、米法莫肽、米替福新、米立铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫派达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮+喷他佐辛、纳曲酮、那托司亭、奈达铂、奈拉滨、奈立膦酸、nivolumab pentetreotide、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、尼曲吖啶、nivolumab、obinutuzumab、奥曲肽、奥法木单抗、高三尖杉酯碱(omacetaxine mepesuccinate)、奥美拉唑、昂丹司琼、奥古蛋白(orgotein)、orilotimod、奥沙利铂、羟考酮、羟甲烯龙、ozogamicin、p53基因疗法、紫杉醇、钯-103种子(palladium-103seed)、帕洛诺司琼、帕米膦酸、帕尼单抗、泮托拉唑、帕唑帕尼、培门冬酶、派姆单抗、培干扰素α-2b、培美曲塞、喷司他丁、培洛霉素、全氟正丁烷、培磷酰胺、帕妥珠单抗、毕西巴尼、匹鲁卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、racotumomab、镭-223氯化物、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫芦单抗、雷莫司汀、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、依替膦酸铼-186、利妥昔单抗、罗米地新、罗莫肽、roniciclib、钐(153Sm)lexidronam、沙妥莫单抗、胰泌素、西普鲁塞-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼、司坦唑醇、链佐星、舒尼替尼、他拉泊芬、他米巴罗汀、他莫昔芬、他喷他多、他索纳明、替西白介素、锝(99mTc)nofetumomab merpentan、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、替曲膦、沙立度胺、塞替派、胸腺法新、促甲状腺素α、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲马多、曲妥珠单抗、曲奥舒凡、维甲酸、三氟尿苷+tipiracil、曲美替尼、曲洛司坦、曲普瑞林、曲磷胺、促血小板生成素、乌苯美司、戊柔比星、凡他尼布、伐普肽、瓦他拉尼、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉、伏林司他、钇-90玻璃微珠、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
3.试剂盒,其包含根据权利要求1或2所述的组合产品。
4.药剂,其包含如权利要求1或2所述的组合产品与惰性、无毒性、药学上适合的赋形剂的组合。
5.如权利要求1或2所述的组合产品在制备用于治疗和/或预防疾病的药物中的用途,其中所述疾病为非霍奇金氏淋巴瘤(“NHL”)、慢性淋巴白血病(“CLL”)、边缘区域淋巴瘤(“MZL”)、弥漫性大细胞B-细胞淋巴瘤(“DLBCL”)、套细胞淋巴瘤(“MCL”)、转化型淋巴瘤(“TL”)、外周T细胞淋巴瘤( “PTCL”)或淋巴浆细胞淋巴瘤(瓦尔登斯特伦氏巨球蛋白血症(“WM”))。
6.如权利要求5所述的用途,其中所述非霍奇金氏淋巴瘤为复发性或难治性、顽固性或侵袭性非霍奇金氏淋巴瘤(NHL)。
7.如权利要求5所述的用途,其中所述非霍奇金氏淋巴瘤为滤泡性淋巴瘤(“FL”)。
8.如权利要求5所述的用途,其中所述弥漫性大细胞B-细胞淋巴瘤为活化的B-细胞样弥漫性大细胞B-细胞淋巴瘤( “ABC-DLBCL”)。
9.如权利要求1或2所述的组合产品在制备用于治疗和/或预防疾病的药物中的用途,其中所述疾病为血液肿瘤;实体肿瘤和/或其转移。
10.如权利要求9所述的用途,其中所述血液肿瘤为白血病或骨髓发育不良综合征。
11.如权利要求9所述的用途,其中所述实体肿瘤为恶性淋巴瘤;头颈部肿瘤;胸部肿瘤;胃肠道肿瘤;内分泌肿瘤;乳房肿瘤和其他妇科肿瘤;泌尿肿瘤;皮肤肿瘤和肉瘤。
12.如权利要求11所述的用途,其中所述头颈部肿瘤为脑肿瘤。
13.如权利要求11所述的用途,其中所述胸部肿瘤为非小细胞或小细胞肺肿瘤。
14.如权利要求11所述的用途,其中所述泌尿肿瘤为肾脏、膀胱或前列腺肿瘤。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15166016.4 | 2015-04-30 | ||
EP15166016 | 2015-04-30 | ||
EP16152499.6 | 2016-01-25 | ||
EP16152499.6A EP3195865A1 (de) | 2016-01-25 | 2016-01-25 | Kombinationen von irak4 inhibitoren und btk inhibitoren |
PCT/EP2016/059576 WO2016174183A1 (en) | 2015-04-30 | 2016-04-29 | Combinations of inhibitors of irak4 with inhibitors of btk |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107872977A CN107872977A (zh) | 2018-04-03 |
CN107872977B true CN107872977B (zh) | 2021-07-09 |
Family
ID=56014963
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680038870.5A Active CN107872977B (zh) | 2015-04-30 | 2016-04-29 | Irak4抑制剂与btk抑制剂的组合产品 |
Country Status (8)
Country | Link |
---|---|
US (3) | US20180289685A1 (zh) |
EP (1) | EP3288558B1 (zh) |
JP (1) | JP6847855B2 (zh) |
CN (1) | CN107872977B (zh) |
CA (1) | CA2984259C (zh) |
TW (1) | TW201701879A (zh) |
UY (1) | UY36660A (zh) |
WO (1) | WO2016174183A1 (zh) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TR201815683T4 (tr) | 2014-01-13 | 2018-11-21 | Aurigene Discovery Tech Ltd | Irak4 inhibitörleri olarak bisiklik heterosiklil türevleri. |
JO3705B1 (ar) | 2014-11-26 | 2021-01-31 | Bayer Pharma AG | إندازولات مستبدلة جديدة، عمليات لتحضيرها، مستحضرات دوائية تحتوي عليها واستخدامها في إنتاج أدوية |
CN109153665B (zh) | 2016-03-03 | 2021-10-15 | 拜耳医药股份有限公司 | 新的2-取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途 |
EP3219329A1 (en) * | 2016-03-17 | 2017-09-20 | Bayer Pharma Aktiengesellschaft | Combinations of copanlisib |
EP3448847A1 (en) | 2016-04-29 | 2019-03-06 | Bayer Pharma Aktiengesellschaft | Crystalline forms of n-[2-(3-hydroxy-3-methylbutyl)-6-(2-hydroxypropan-2-yl)-2h-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide |
CN109415340B (zh) | 2016-04-29 | 2021-10-12 | 拜耳医药股份有限公司 | N-{6-(2-羟基丙-2-基)-2-[2-(甲基磺酰基)乙基]-2h-吲唑-5-基}-6-(三氟甲基)吡啶-2-甲酰胺的多晶型物 |
TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
WO2017207481A1 (en) * | 2016-06-01 | 2017-12-07 | Bayer Animal Health Gmbh | Substituted indazoles ueful for treatment and prevention of allergic and/or inflammatory diseases in animals |
CA3025826A1 (en) | 2016-06-01 | 2017-12-07 | Bayer Pharma Aktiengesellschaft | Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases |
US20180072718A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
BR112019004586A2 (pt) | 2016-09-09 | 2019-06-11 | Incyte Corp | derivados de pirazolopiridina como moduladores de hpk1 e usos dos mesmos para o tratamento de câncer |
WO2018049191A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyridone derivatives as hpk1 modulators and uses thereof for the treatment of cancer |
TW201811799A (zh) | 2016-09-09 | 2018-04-01 | 美商英塞特公司 | 吡唑并嘧啶化合物及其用途 |
US10925967B2 (en) | 2016-11-22 | 2021-02-23 | Dana-Farber Cancer Institute, Inc. | Degradation of Bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with E3 ligase ligand and methods of use |
WO2018134254A1 (en) | 2017-01-17 | 2018-07-26 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
WO2018152220A1 (en) | 2017-02-15 | 2018-08-23 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
JOP20180011A1 (ar) | 2017-02-16 | 2019-01-30 | Gilead Sciences Inc | مشتقات بيرولو [1، 2-b]بيريدازين |
AU2018314234A1 (en) * | 2017-08-11 | 2020-02-13 | Board Of Regents, The University Of Texas System | Targeting kinases for the treatment of cancer metastasis |
US10722495B2 (en) | 2017-09-08 | 2020-07-28 | Incyte Corporation | Cyanoindazole compounds and uses thereof |
US11358948B2 (en) | 2017-09-22 | 2022-06-14 | Kymera Therapeutics, Inc. | CRBN ligands and uses thereof |
AU2018338314A1 (en) | 2017-09-22 | 2020-04-09 | Kymera Therapeutics, Inc | Protein degraders and uses thereof |
WO2019111218A1 (en) | 2017-12-08 | 2019-06-13 | Cadila Healthcare Limited | Novel heterocyclic compounds as irak4 inhibitors |
JP2021508703A (ja) | 2017-12-26 | 2021-03-11 | カイメラ セラピューティクス, インコーポレイテッド | Irak分解剤およびそれらの使用 |
WO2019127008A1 (zh) * | 2017-12-26 | 2019-07-04 | 清华大学 | 一种靶向降解btk的化合物及其应用 |
EP3737666A4 (en) | 2018-01-12 | 2022-01-05 | Kymera Therapeutics, Inc. | PROTEIN DEGRADANTS AND USES THEREOF |
EP3737675A4 (en) | 2018-01-12 | 2022-01-05 | Kymera Therapeutics, Inc. | CRBN LIGANDS AND THEIR USES |
EP3746426A4 (en) * | 2018-01-29 | 2021-12-29 | Dana Farber Cancer Institute, Inc. | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use |
US10800761B2 (en) | 2018-02-20 | 2020-10-13 | Incyte Corporation | Carboxamide compounds and uses thereof |
US10745388B2 (en) | 2018-02-20 | 2020-08-18 | Incyte Corporation | Indazole compounds and uses thereof |
US10752635B2 (en) | 2018-02-20 | 2020-08-25 | Incyte Corporation | Indazole compounds and uses thereof |
US11299473B2 (en) | 2018-04-13 | 2022-04-12 | Incyte Corporation | Benzimidazole and indole compounds and uses thereof |
US11292792B2 (en) | 2018-07-06 | 2022-04-05 | Kymera Therapeutics, Inc. | Tricyclic CRBN ligands and uses thereof |
TWI721483B (zh) | 2018-07-13 | 2021-03-11 | 美商基利科學股份有限公司 | 吡咯并[1,2-b]嗒𠯤衍生物 |
CA3108065A1 (en) | 2018-07-31 | 2020-02-06 | Loxo Oncology, Inc. | Spray-dried dispersions, formulations, and polymorphs of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide |
US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
WO2020048471A1 (zh) * | 2018-09-06 | 2020-03-12 | 浙江海正药业股份有限公司 | 7-取代吲唑类衍生物及其制备方法和其在医药上的用途 |
US11111247B2 (en) | 2018-09-25 | 2021-09-07 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
AU2019389174A1 (en) | 2018-11-30 | 2021-07-01 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
CN111362920B (zh) * | 2018-12-25 | 2024-06-07 | 上海美悦生物科技发展有限公司 | 一种作为irak抑制剂的化合物 |
EP3889150A4 (en) * | 2018-12-25 | 2022-02-23 | Shanghai Meiyue Biotech Development Co., Ltd. | IRAQ INHIBITOR COMPOUND |
CN111499612B (zh) * | 2019-01-30 | 2022-12-30 | 上海美悦生物科技发展有限公司 | 一种作为irak抑制剂的化合物及其制备方法和用途 |
KR20200114776A (ko) * | 2019-03-29 | 2020-10-07 | 한미약품 주식회사 | 퓨로피리미딘 화합물의 산 부가염의 결정형 |
AU2020326703A1 (en) | 2019-08-06 | 2022-02-17 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
BR112022001568A2 (pt) * | 2019-09-24 | 2022-03-22 | Shanghai Meiyue Biotech Dev Co Ltd | Composto, método para preparação do composto, composição farmacêutica, e, uso do composto |
EP3800188A1 (en) | 2019-10-02 | 2021-04-07 | Bayer AG | Substituted pyrazolopyrimidines as irak4 inhibitors |
CN112812109B (zh) * | 2019-11-18 | 2022-06-21 | 中国科学院微生物研究所 | 化合物DaP-01及其制备方法和应用 |
WO2021127190A1 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
CN113521079A (zh) * | 2020-04-20 | 2021-10-22 | 上海领泰生物医药科技有限公司 | Irak4抑制剂在治疗ali/ards中的应用 |
TW202210483A (zh) | 2020-06-03 | 2022-03-16 | 美商凱麥拉醫療公司 | Irak降解劑之結晶型 |
CN111728960B (zh) * | 2020-07-03 | 2022-11-25 | 郝延璋 | 富马酸比索洛尔联合多西他赛在制备抗肿瘤药物中的应用 |
US11866405B2 (en) | 2020-12-10 | 2024-01-09 | Astrazeneca Ab | Substituted indazoles as IRAK4 inhibitors |
MX2023011790A (es) * | 2021-04-08 | 2023-10-11 | Curis Inc | Terapias combinadas para tratar el cancer. |
CN113402499B (zh) | 2021-06-21 | 2022-05-13 | 上海勋和医药科技有限公司 | 一种亚磺酰亚胺取代的吲唑类irak4激酶抑制剂、制备方法及用途 |
KR102348901B1 (ko) * | 2021-08-26 | 2022-01-07 | 충북대학교 산학협력단 | 레고라페닙을 유효성분으로 포함하는 만성폐쇄성 폐질환의 예방 또는 치료용 조성물 |
KR20240051921A (ko) | 2022-02-14 | 2024-04-22 | 아스트라제네카 아베 | Irak4 억제제 |
WO2023227703A1 (en) | 2022-05-26 | 2023-11-30 | Astrazeneca Ab | Solid forms of heterocyclylamides as irak4 inhibitors |
WO2024108010A1 (en) * | 2022-11-17 | 2024-05-23 | Bayer Animal Health Gmbh | Methods and compositions for control of pain and inflammation |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107406416A (zh) * | 2014-11-26 | 2017-11-28 | 拜耳医药股份有限公司 | 新型取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途 |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003277383A (ja) | 2002-03-14 | 2003-10-02 | Bayer Ag | 光学活性ピリジン誘導体およびそれを含む医薬 |
ES2246606B1 (es) | 2002-07-23 | 2007-06-01 | Izar Construcciones Navales S.A. | Unidad semi-sumergible auto-propulsada para transporte y engorde de peces vivos. |
WO2005082866A2 (en) | 2004-02-20 | 2005-09-09 | Pfizer Limited | Substituted 1, 2, 4- triazole derivatives as oxytocin antagonists |
CA2591332A1 (en) | 2004-12-08 | 2006-06-15 | Warner-Lambert Company Llc | Methylene inhibitors of matrix metalloproteinase |
TWI370820B (en) | 2005-04-27 | 2012-08-21 | Takeda Pharmaceutical | Fused heterocyclic compounds |
US7745477B2 (en) | 2006-02-07 | 2010-06-29 | Hoffman-La Roche Inc. | Heteroaryl and benzyl amide compounds |
EP1986643A1 (en) | 2006-02-10 | 2008-11-05 | Summit Corporation Plc | Treatment of duchenne muscular dystrophy |
JP5258563B2 (ja) | 2006-06-29 | 2013-08-07 | 日産化学工業株式会社 | αアミノ酸誘導体及びそれを有効成分として含む医薬 |
JP2010502717A (ja) | 2006-09-07 | 2010-01-28 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | インターロイキン1受容体関連キナーゼの調節物質 |
CN102887900B (zh) | 2006-09-22 | 2015-04-29 | 药品循环公司 | 布鲁顿酪氨酸激酶的抑制剂 |
WO2009117421A2 (en) | 2008-03-17 | 2009-09-24 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
WO2009158571A1 (en) | 2008-06-27 | 2009-12-30 | Avila Therapeutics And Uses Thereof | Heteroaryl compounds and uses thereof |
US20100094000A1 (en) | 2008-09-03 | 2010-04-15 | Takeda Pharmaceutical Company Limited | Pyrazole compounds |
WO2011153588A1 (en) | 2010-06-10 | 2011-12-15 | Biota Scientific Management Pty Ltd | Viral polymerase inhibitors |
WO2012061926A1 (en) | 2010-11-08 | 2012-05-18 | Zalicus Pharmaceuticals Ltd. | Bisarylsulfone and dialkylarylsulfone compounds as calcium channel blockers |
PT2655357T (pt) | 2010-12-20 | 2016-09-28 | Merck Serono Sa | Derivados indazolil-triazol como inibidores de irak |
EP2673264A1 (en) | 2011-02-10 | 2013-12-18 | Syngenta Participations AG | Microbiocidal pyrazole derivatives |
EP2489663A1 (en) | 2011-02-16 | 2012-08-22 | Almirall, S.A. | Compounds as syk kinase inhibitors |
AU2012217616B2 (en) | 2011-02-18 | 2017-03-02 | Vertex Pharmaceuticals Incorporated | Chroman - spirocyclic piperidine amides as modulators of ion channels |
ES2624981T3 (es) * | 2011-07-01 | 2017-07-18 | Dana-Farber Cancer Institute, Inc. | Descubrimiento de una mutación somática en el gen MYD88 en linfoma linfoplasmocitario |
WO2013106254A1 (en) | 2012-01-11 | 2013-07-18 | Dow Agrosciences Llc | Pesticidal compositions and processes related thereto |
CA2873975A1 (en) | 2012-05-21 | 2013-11-28 | Bayer Pharma Aktiengesellschaft | Thienopyrimidines |
TWI667233B (zh) | 2013-12-19 | 2019-08-01 | 德商拜耳製藥公司 | 新穎吲唑羧醯胺,其製備方法、含彼等之醫藥製劑及其製造醫藥之用途 |
SG11201605408RA (en) | 2014-01-10 | 2016-07-28 | Aurigene Discovery Tech Ltd | Indazole compounds as irak4 inhibitors |
EA201692418A1 (ru) | 2014-06-20 | 2017-04-28 | Ауриджен Дискавери Текнолоджиз Лимитед | Замещенные индазольные соединения в качестве irak4 ингибиторов |
-
2016
- 2016-04-29 UY UY0001036660A patent/UY36660A/es not_active Application Discontinuation
- 2016-04-29 JP JP2017556169A patent/JP6847855B2/ja active Active
- 2016-04-29 TW TW105113633A patent/TW201701879A/zh unknown
- 2016-04-29 CA CA2984259A patent/CA2984259C/en active Active
- 2016-04-29 US US15/570,212 patent/US20180289685A1/en not_active Abandoned
- 2016-04-29 WO PCT/EP2016/059576 patent/WO2016174183A1/en active Application Filing
- 2016-04-29 EP EP16723280.0A patent/EP3288558B1/en active Active
- 2016-04-29 CN CN201680038870.5A patent/CN107872977B/zh active Active
-
2019
- 2019-05-31 US US16/428,669 patent/US20190388410A1/en not_active Abandoned
-
2021
- 2021-12-07 US US17/544,641 patent/US20220241261A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107406416A (zh) * | 2014-11-26 | 2017-11-28 | 拜耳医药股份有限公司 | 新型取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途 |
Non-Patent Citations (2)
Title |
---|
A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstr¨om macroglobulinemia;Guang Yang et al.;《BLOOD》;20130815;第122卷(第7期);1222-1232 * |
IRAK4 inhibitors display synergistic activity when combined with BTK or PI3K inhibitors in B-cell lymphomas;Eric G. Vajda et al.;《The American Association for Cancer Research (AACR) Annual Meeting》;20150422;785 * |
Also Published As
Publication number | Publication date |
---|---|
EP3288558B1 (en) | 2022-05-11 |
CA2984259C (en) | 2024-02-13 |
TW201701879A (zh) | 2017-01-16 |
WO2016174183A1 (en) | 2016-11-03 |
US20220241261A1 (en) | 2022-08-04 |
JP6847855B2 (ja) | 2021-03-24 |
EP3288558A1 (en) | 2018-03-07 |
UY36660A (es) | 2016-11-30 |
CN107872977A (zh) | 2018-04-03 |
US20180289685A1 (en) | 2018-10-11 |
JP2018514539A (ja) | 2018-06-07 |
CA2984259A1 (en) | 2016-11-03 |
US20190388410A1 (en) | 2019-12-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107872977B (zh) | Irak4抑制剂与btk抑制剂的组合产品 | |
US20210069188A1 (en) | Pyrazolo[3,4-b]pyrazine shp2 phosphatase inhibitors and methods of use thereof | |
CN110305109B (zh) | 新型取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途 | |
CN108699057B (zh) | 5-取代的2-(吗啉-4-基)-1,7-萘啶 | |
US20230104574A1 (en) | Fgfr inhibitors and methods of use thereof | |
US10786492B2 (en) | Formylated N-heterocyclic derivatives as FGFR4 inhibitors | |
EP3219329A1 (en) | Combinations of copanlisib | |
US11964953B2 (en) | Substituted aminothiazoles as DGKzeta inhibitors for immune activation | |
TW202108572A (zh) | Cdk抑制劑 | |
US20220363696A1 (en) | Amino-substituted heterocycles for treating cancers with egfr mutations | |
CN114901277A (zh) | 用于egfr降解的异吲哚啉酮和吲唑化合物 | |
US11529350B2 (en) | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof | |
CA3115068A1 (en) | Method for preparing and delivering bisantrene formulations | |
WO2018178679A1 (en) | Combination of isoindolinone derivatives with sgi-110 | |
EP3195865A1 (de) | Kombinationen von irak4 inhibitoren und btk inhibitoren | |
US20200114001A1 (en) | Combinations of copanlisib with anti-pd-1 antibody | |
WO2020164997A1 (en) | Combination of pi3k-inhibitors | |
CN117500803A (zh) | 用于治疗具egfr突变的癌症的氨基取代杂环 | |
WO2023147015A1 (en) | Substituted heterocyclic csnk1 inhibitors | |
WO2021260443A1 (en) | Combinations of 2,3-dihydroimidazo[1,2-c]quinazolines | |
WO2023183652A1 (en) | Dual cxcr4-btk inhibitors | |
CN117440813A (zh) | 治疗脑或cns的癌转移的egfr降解剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |