CA2539235A1 - 5-arylpyrimidines as anticancer agents - Google Patents
5-arylpyrimidines as anticancer agents Download PDFInfo
- Publication number
- CA2539235A1 CA2539235A1 CA002539235A CA2539235A CA2539235A1 CA 2539235 A1 CA2539235 A1 CA 2539235A1 CA 002539235 A CA002539235 A CA 002539235A CA 2539235 A CA2539235 A CA 2539235A CA 2539235 A1 CA2539235 A1 CA 2539235A1
- Authority
- CA
- Canada
- Prior art keywords
- chloro
- pyrimidin
- amine
- pharmaceutically acceptable
- trifluoroethyl
- 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.)
- Abandoned
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 319
- 150000003839 salts Chemical class 0.000 claims abstract description 159
- 238000000034 method Methods 0.000 claims abstract description 119
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 76
- 241000124008 Mammalia Species 0.000 claims abstract description 64
- 206010048723 Multiple-drug resistance Diseases 0.000 claims abstract description 58
- 230000012010 growth Effects 0.000 claims abstract description 36
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 230000002265 prevention Effects 0.000 claims abstract description 20
- 230000029115 microtubule polymerization Effects 0.000 claims abstract description 14
- -1 cyano, hydroxy Chemical group 0.000 claims description 93
- 102000004243 Tubulin Human genes 0.000 claims description 90
- 108090000704 Tubulin Proteins 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 61
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 53
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 102000029749 Microtubule Human genes 0.000 claims description 45
- 108091022875 Microtubule Proteins 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 44
- 210000004688 microtubule Anatomy 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 39
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 125000006413 ring segment Chemical group 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 21
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 230000001737 promoting effect Effects 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 125000001589 carboacyl group Chemical group 0.000 claims description 18
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 18
- 230000000087 stabilizing effect Effects 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- VKAOCYPNKOPRSE-UHFFFAOYSA-N 3-[4-(4-chloro-6-cycloheptyl-2-pyrazin-2-ylpyrimidin-5-yl)-3,5-difluorophenoxy]-n-methylpropan-1-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1C1CCCCCC1 VKAOCYPNKOPRSE-UHFFFAOYSA-N 0.000 claims description 10
- ZXUDPCQCQFLPJR-UHFFFAOYSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-(2,2,2-trifluoroethylamino)pyrimidin-2-yl]-methylcyanamide Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(N(C)C#N)N=C1NCC(F)(F)F ZXUDPCQCQFLPJR-UHFFFAOYSA-N 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 9
- USZDFOPAUAEWBC-ZETCQYMHSA-N 6-chloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC(F)(F)[C@H](C)NC1=NC(C=2N=CC=NC=2)=NC(Cl)=C1C1=C(F)C=C(F)C=C1F USZDFOPAUAEWBC-ZETCQYMHSA-N 0.000 claims description 9
- CBWLEMXYPINBTA-NSHDSACASA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyrazin-2-yl-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1N[C@@H](C)C(F)(F)F CBWLEMXYPINBTA-NSHDSACASA-N 0.000 claims description 9
- ODURFEQFDLNVNA-UHFFFAOYSA-N [4-chloro-6-(2,2,2-trifluoroethylamino)-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl]-methylcyanamide Chemical compound FC(F)(F)CNC1=NC(N(C#N)C)=NC(Cl)=C1C1=C(F)C=C(F)C=C1F ODURFEQFDLNVNA-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- LDESLYKWJNFLSX-UHFFFAOYSA-N 6-chloro-5-[4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl]-2-pyrazin-2-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1NCC(F)(F)F LDESLYKWJNFLSX-UHFFFAOYSA-N 0.000 claims description 8
- QIHITHOIUNZULD-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-imidazol-1-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(N2C=NC=C2)N=C1NCC(F)(F)F QIHITHOIUNZULD-UHFFFAOYSA-N 0.000 claims description 8
- HXJHMTCVYUBCGI-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-pyrazin-2-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1NCC(F)(F)F HXJHMTCVYUBCGI-UHFFFAOYSA-N 0.000 claims description 8
- ZIHOWUDDUIKPMZ-UHFFFAOYSA-N 6-chloro-5-[4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl]-2-pyrazin-2-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1NCC(F)(F)F ZIHOWUDDUIKPMZ-UHFFFAOYSA-N 0.000 claims description 8
- UGCOTKFGCFLGSC-UHFFFAOYSA-N [4-chloro-5-[4-[2-(dimethylamino)ethoxy]-2,6-difluorophenyl]-6-(2,2,2-trifluoroethylamino)pyrimidin-2-yl]-methylcyanamide Chemical compound FC1=CC(OCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(N(C)C#N)N=C1NCC(F)(F)F UGCOTKFGCFLGSC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 7
- LNCPZOZLBVKFPW-UHFFFAOYSA-N 6-chloro-2-(5-nitropyridin-2-yl)-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound N1=CC([N+](=O)[O-])=CC=C1C1=NC(Cl)=C(C=2C(=CC(F)=CC=2F)F)C(NCC(F)(F)F)=N1 LNCPZOZLBVKFPW-UHFFFAOYSA-N 0.000 claims description 7
- LILWNAIAPCBLHU-UHFFFAOYSA-N 6-chloro-2-imidazol-1-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(N2C=NC=C2)N=C1NCC(F)(F)F LILWNAIAPCBLHU-UHFFFAOYSA-N 0.000 claims description 7
- SXRPINFLPQMOJG-LBPRGKRZSA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyridin-2-yl-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CC=2)N=C1N[C@@H](C)C(F)(F)F SXRPINFLPQMOJG-LBPRGKRZSA-N 0.000 claims description 7
- GBKOAMQVMBTXRG-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-n-methyl-4-n-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine Chemical compound FC(F)(F)CNC1=NC(NC)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F GBKOAMQVMBTXRG-UHFFFAOYSA-N 0.000 claims description 7
- CMRXBBZWPSTMEC-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-pyrimidin-2-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CN=2)N=C1NCC(F)(F)F CMRXBBZWPSTMEC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- USCQBKSUWCKHKG-UHFFFAOYSA-N 2-(5-azidopyridin-2-yl)-6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC(=CC=2)N=[N+]=[N-])N=C1NCC(F)(F)F USCQBKSUWCKHKG-UHFFFAOYSA-N 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- FGDWZLMPZYDLKE-UHFFFAOYSA-N 6-chloro-2-(1-methylimidazol-2-yl)-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound CN1C=CN=C1C1=NC(Cl)=C(C=2C(=CC(F)=CC=2F)F)C(NCC(F)(F)F)=N1 FGDWZLMPZYDLKE-UHFFFAOYSA-N 0.000 claims description 6
- AAVPJMAUGKOJNP-UHFFFAOYSA-N 6-chloro-2-(1h-pyrrol-2-yl)-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2NC=CC=2)N=C1NCC(F)(F)F AAVPJMAUGKOJNP-UHFFFAOYSA-N 0.000 claims description 6
- ADGOHMZGCSFAOQ-UHFFFAOYSA-N 6-chloro-2-(4-methylpyridin-2-yl)-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound CC1=CC=NC(C=2N=C(NCC(F)(F)F)C(=C(Cl)N=2)C=2C(=CC(F)=CC=2F)F)=C1 ADGOHMZGCSFAOQ-UHFFFAOYSA-N 0.000 claims description 6
- RFSSBTBRSZAIBG-UHFFFAOYSA-N 6-chloro-2-pyrazin-2-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1NCC(F)(F)F RFSSBTBRSZAIBG-UHFFFAOYSA-N 0.000 claims description 6
- IOOKTIUCSYUVRN-UHFFFAOYSA-N 6-chloro-2-pyridin-4-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2C=CN=CC=2)N=C1NCC(F)(F)F IOOKTIUCSYUVRN-UHFFFAOYSA-N 0.000 claims description 6
- YDUXGZDCHMEEGU-UHFFFAOYSA-N 6-chloro-2-pyrrol-1-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(N2C=CC=C2)N=C1NCC(F)(F)F YDUXGZDCHMEEGU-UHFFFAOYSA-N 0.000 claims description 6
- ZDOGRDYQRDOYPT-UHFFFAOYSA-N 6-chloro-2-quinolin-2-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=C3C=CC=CC3=CC=2)N=C1NCC(F)(F)F ZDOGRDYQRDOYPT-UHFFFAOYSA-N 0.000 claims description 6
- CBWLEMXYPINBTA-UHFFFAOYSA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyrazin-2-yl-n-(1,1,1-trifluoropropan-2-yl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1NC(C)C(F)(F)F CBWLEMXYPINBTA-UHFFFAOYSA-N 0.000 claims description 6
- XCWLPLOUCMTHFI-NSHDSACASA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-[[(2s)-1,1,1-trifluoropropan-2-yl]amino]pyrimidin-2-yl]methylcyanamide Chemical compound FC(F)(F)[C@H](C)NC1=NC(CNC#N)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F XCWLPLOUCMTHFI-NSHDSACASA-N 0.000 claims description 6
- IVTAIPZURLELLV-UHFFFAOYSA-N [4-chloro-5-[4-[4-(dimethylamino)butoxy]-2,6-difluorophenyl]-6-(2,2,2-trifluoroethylamino)pyrimidin-2-yl]methylcyanamide Chemical compound FC1=CC(OCCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(CNC#N)N=C1NCC(F)(F)F IVTAIPZURLELLV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- JOGZZTFIGKYTSV-UHFFFAOYSA-N ethylcyanamide Chemical compound CCNC#N JOGZZTFIGKYTSV-UHFFFAOYSA-N 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 6
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 6
- QBYHZMDVKBPHAA-UHFFFAOYSA-N 6-chloro-2-isoquinolin-1-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2C3=CC=CC=C3C=CN=2)N=C1NCC(F)(F)F QBYHZMDVKBPHAA-UHFFFAOYSA-N 0.000 claims description 5
- GNJIOXWXWUUCQZ-UHFFFAOYSA-N 6-chloro-2-isoquinolin-3-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC3=CC=CC=C3C=2)N=C1NCC(F)(F)F GNJIOXWXWUUCQZ-UHFFFAOYSA-N 0.000 claims description 5
- PYOACZADEZQCJS-UHFFFAOYSA-N 6-chloro-2-pyridin-2-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CC=2)N=C1NCC(F)(F)F PYOACZADEZQCJS-UHFFFAOYSA-N 0.000 claims description 5
- ODKBOKAYDWNIFV-UHFFFAOYSA-N 6-chloro-2-pyridin-3-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2C=NC=CC=2)N=C1NCC(F)(F)F ODKBOKAYDWNIFV-UHFFFAOYSA-N 0.000 claims description 5
- SXRPINFLPQMOJG-UHFFFAOYSA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyridin-2-yl-n-(1,1,1-trifluoropropan-2-yl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CC=2)N=C1NC(C)C(F)(F)F SXRPINFLPQMOJG-UHFFFAOYSA-N 0.000 claims description 5
- DDOWVXUYVOTAEQ-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-quinolin-2-yl-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=C3C=CC=CC3=CC=2)N=C1NCC(F)(F)F DDOWVXUYVOTAEQ-UHFFFAOYSA-N 0.000 claims description 5
- XCWLPLOUCMTHFI-UHFFFAOYSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-(1,1,1-trifluoropropan-2-ylamino)pyrimidin-2-yl]methylcyanamide Chemical compound FC(F)(F)C(C)NC1=NC(CNC#N)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F XCWLPLOUCMTHFI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims 13
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims 6
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 6
- CBWLEMXYPINBTA-LLVKDONJSA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyrazin-2-yl-n-[(2r)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1N[C@H](C)C(F)(F)F CBWLEMXYPINBTA-LLVKDONJSA-N 0.000 claims 2
- SXRPINFLPQMOJG-GFCCVEGCSA-N 6-chloro-5-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-2-pyridin-2-yl-n-[(2r)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC1=CC(OCCCNC)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CC=2)N=C1N[C@H](C)C(F)(F)F SXRPINFLPQMOJG-GFCCVEGCSA-N 0.000 claims 2
- XCWLPLOUCMTHFI-LLVKDONJSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-[[(2r)-1,1,1-trifluoropropan-2-yl]amino]pyrimidin-2-yl]methylcyanamide Chemical compound FC(F)(F)[C@@H](C)NC1=NC(CNC#N)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F XCWLPLOUCMTHFI-LLVKDONJSA-N 0.000 claims 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 67
- 201000011510 cancer Diseases 0.000 abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- 229930012538 Paclitaxel Natural products 0.000 description 52
- 229960001592 paclitaxel Drugs 0.000 description 52
- 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 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Natural products C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 44
- 210000004027 cell Anatomy 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 28
- 229910052799 carbon Inorganic materials 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
- 238000010998 test method Methods 0.000 description 23
- 230000000144 pharmacologic effect Effects 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 229960001338 colchicine Drugs 0.000 description 19
- 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 18
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 18
- 239000003814 drug Substances 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 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 description 18
- 229960004528 vincristine Drugs 0.000 description 18
- 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 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 229910000104 sodium hydride Inorganic materials 0.000 description 17
- 230000027455 binding Effects 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 239000012312 sodium hydride Substances 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 125000003282 alkyl amino group Chemical group 0.000 description 13
- 125000004663 dialkyl amino group Chemical group 0.000 description 13
- 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 description 12
- 125000004414 alkyl thio group Chemical group 0.000 description 12
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine 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-CFWMRBGOSA-N 0.000 description 12
- 102000009664 Microtubule-Associated Proteins Human genes 0.000 description 11
- 229910052740 iodine Inorganic materials 0.000 description 11
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 108010078791 Carrier Proteins Proteins 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 108010020004 Microtubule-Associated Proteins Proteins 0.000 description 10
- 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 description 10
- 229940123237 Taxane Drugs 0.000 description 10
- 238000006116 polymerization reaction Methods 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000002835 absorbance Methods 0.000 description 9
- 229960003668 docetaxel Drugs 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- MCLITRXWHZUNCQ-UHFFFAOYSA-N methylcyanamide Chemical compound CNC#N MCLITRXWHZUNCQ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 206010009944 Colon cancer Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 101100313649 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) POT1 gene Proteins 0.000 description 8
- 101100161758 Yarrowia lipolytica (strain CLIB 122 / E 150) POX3 gene Proteins 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000002480 mineral oil Substances 0.000 description 8
- 235000010446 mineral oil Nutrition 0.000 description 8
- 229960004679 doxorubicin Drugs 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 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 6
- 201000009030 Carcinoma Diseases 0.000 description 6
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 241000863480 Vinca Species 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- FCVKLVNLBIBCCU-UHFFFAOYSA-N hydron;pyrazine-2-carboximidamide;chloride Chemical compound Cl.NC(=N)C1=CN=CC=N1 FCVKLVNLBIBCCU-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- XKMLYUALXHKNFT-UHFFFAOYSA-N rGTP Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O XKMLYUALXHKNFT-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 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 description 5
- 229960001156 mitoxantrone Drugs 0.000 description 5
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 229960003048 vinblastine Drugs 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- VCCISIBKCNTCLR-UHFFFAOYSA-N diethyl 2-(2,4,6-trifluorophenyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C1=C(F)C=C(F)C=C1F VCCISIBKCNTCLR-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000000833 heterodimer Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- YFNHCZXWVMBHAC-UHFFFAOYSA-N 2-(5-aminopyridin-2-yl)-6-chloro-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound N1=CC(N)=CC=C1C1=NC(Cl)=C(C=2C(=CC(F)=CC=2F)F)C(NCC(F)(F)F)=N1 YFNHCZXWVMBHAC-UHFFFAOYSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 3
- XJULAXDLPMEOEL-UHFFFAOYSA-N 4,6-dichloro-2-imidazol-1-yl-5-(2,4,6-trifluorophenyl)pyrimidine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(N2C=NC=C2)N=C1Cl XJULAXDLPMEOEL-UHFFFAOYSA-N 0.000 description 3
- SAWHIQMQGZZGTO-UHFFFAOYSA-N 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1Cl SAWHIQMQGZZGTO-UHFFFAOYSA-N 0.000 description 3
- FRUHHVIOSKAPJF-UHFFFAOYSA-N 5,7-dichloro-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N2N=CN=C2N=C1Cl FRUHHVIOSKAPJF-UHFFFAOYSA-N 0.000 description 3
- BBRKHARXDYTRSK-UHFFFAOYSA-N 5-chloro-3-methyl-n-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-imine Chemical compound CN1C=NN(C2=NCC(F)(F)F)C1=NC(Cl)=C2C1=C(F)C=C(F)C=C1F BBRKHARXDYTRSK-UHFFFAOYSA-N 0.000 description 3
- FEOXAMHBHGUNHP-UHFFFAOYSA-N 5-chloro-n-(2,2,2-trifluoroethyl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(NCC(F)(F)F)N2N=CN=C2N=C1Cl FEOXAMHBHGUNHP-UHFFFAOYSA-N 0.000 description 3
- GFZIFIOUTHTQDI-UHFFFAOYSA-N 6-hydroxy-5-(2,4,6-trifluorophenyl)-1h-pyrimidine-2,4-dione Chemical compound OC1=NC(O)=NC(O)=C1C1=C(F)C=C(F)C=C1F GFZIFIOUTHTQDI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 102100021339 Multidrug resistance-associated protein 1 Human genes 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241001116500 Taxus Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001946 anti-microtubular Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000002254 cytotoxic agent Substances 0.000 description 3
- 231100000599 cytotoxic agent Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- SZWVYJLZOMWPLJ-UHFFFAOYSA-N ethyl 3-cycloheptyl-3-oxo-2-(2,4,6-trifluorophenyl)propanoate Chemical compound FC=1C=C(F)C=C(F)C=1C(C(=O)OCC)C(=O)C1CCCCCC1 SZWVYJLZOMWPLJ-UHFFFAOYSA-N 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 3
- 239000000391 magnesium silicate Substances 0.000 description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 description 3
- 235000019792 magnesium silicate Nutrition 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 108010066052 multidrug resistance-associated protein 1 Proteins 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 3
- DVOBHVDPGRBJCG-UHFFFAOYSA-N tert-butyl n-[3-[4-(6-cycloheptyl-4-oxo-2-pyrazin-2-yl-1h-pyrimidin-5-yl)-3,5-difluorophenoxy]propyl]-n-methylcarbamate Chemical compound FC1=CC(OCCCN(C)C(=O)OC(C)(C)C)=CC(F)=C1C1=C(O)N=C(C=2N=CC=NC=2)N=C1C1CCCCCC1 DVOBHVDPGRBJCG-UHFFFAOYSA-N 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- WJQAKFRHCZWOKB-UHFFFAOYSA-N 1-methylimidazole-2-carboximidamide;hydrochloride Chemical compound Cl.CN1C=CN=C1C(N)=N WJQAKFRHCZWOKB-UHFFFAOYSA-N 0.000 description 2
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 2
- ZLCUYPLENIBECZ-UHFFFAOYSA-N 2,4,6-trichloro-5-(2,4,6-trifluorophenyl)pyrimidine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(Cl)N=C1Cl ZLCUYPLENIBECZ-UHFFFAOYSA-N 0.000 description 2
- GDINSHAUACPWMU-UHFFFAOYSA-N 2-(5-aminopyridin-2-yl)-6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-n-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC(N)=CC=2)N=C1NCC(F)(F)F GDINSHAUACPWMU-UHFFFAOYSA-N 0.000 description 2
- RAZDJZZSHLZQFL-UHFFFAOYSA-N 4-hydroxy-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-1h-pyrimidin-6-one Chemical compound OC1=NC(C=2N=CC=NC=2)=NC(O)=C1C1=C(F)C=C(F)C=C1F RAZDJZZSHLZQFL-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- YZDHDHMJKCKESU-UHFFFAOYSA-N 5-nitropyridine-2-carbonitrile Chemical compound [O-][N+](=O)C1=CC=C(C#N)N=C1 YZDHDHMJKCKESU-UHFFFAOYSA-N 0.000 description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)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 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 2
- OLXAKYXIDWGSGT-UHFFFAOYSA-N 6-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-2-n-methyl-4-n-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.FC(F)(F)CNC1=NC(NC)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F OLXAKYXIDWGSGT-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
- 241000894006 Bacteria Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- VZFUCHSFHOYXIS-UHFFFAOYSA-N Cycloheptanecarboxylic acid Chemical compound OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 238000000719 MTS assay Methods 0.000 description 2
- 231100000070 MTS assay Toxicity 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- LMLINTMWNXXATR-UHFFFAOYSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-(2,2,2-trifluoroethylamino)pyrimidin-2-yl]-methylcyanamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(N(C)C#N)N=C1NCC(F)(F)F LMLINTMWNXXATR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940044684 anti-microtubule agent Drugs 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000009137 competitive binding Effects 0.000 description 2
- 230000006957 competitive inhibition Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 description 2
- CIYPNZYEUZQIHN-UHFFFAOYSA-N cycloheptanecarbonyl chloride Chemical compound ClC(=O)C1CCCCCC1 CIYPNZYEUZQIHN-UHFFFAOYSA-N 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001419 dependent effect Effects 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
- 239000002612 dispersion medium Substances 0.000 description 2
- 101150042537 dld1 gene Proteins 0.000 description 2
- YNRBMAMRMQJKBW-UHFFFAOYSA-N ethyl 2-(2,4,6-trifluorophenyl)acetate Chemical compound CCOC(=O)CC1=C(F)C=C(F)C=C1F YNRBMAMRMQJKBW-UHFFFAOYSA-N 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 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 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000002424 x-ray crystallography Methods 0.000 description 2
- KQODQNJLJQHFQV-UHFFFAOYSA-N (-)-hemiasterlin Natural products C1=CC=C2C(C(C)(C)C(C(=O)NC(C(=O)N(C)C(C=C(C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-UHFFFAOYSA-N 0.000 description 1
- KQODQNJLJQHFQV-MKWZWQCGSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-(1-methylindol-3-yl)butanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound C1=CC=C2C(C(C)(C)[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](\C=C(/C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-MKWZWQCGSA-N 0.000 description 1
- CNTMOLDWXSVYKD-PSRNMDMQSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-phenylbutanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound OC(=O)C(/C)=C/[C@H](C(C)C)N(C)C(=O)[C@H](C(C)(C)C)NC(=O)[C@@H](NC)C(C)(C)C1=CC=CC=C1 CNTMOLDWXSVYKD-PSRNMDMQSA-N 0.000 description 1
- YDZONKXUTROEFD-UHFFFAOYSA-N 1-methylimidazole-2-carbaldehyde;1-methylimidazole-2-carbonitrile Chemical compound CN1C=CN=C1C=O.CN1C=CN=C1C#N YDZONKXUTROEFD-UHFFFAOYSA-N 0.000 description 1
- VUHMRVLSRIYKKU-UHFFFAOYSA-N 1-methylimidazole-2-carbonitrile Chemical compound CN1C=CN=C1C#N VUHMRVLSRIYKKU-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- DBEYVIGIPJSTOR-UHFFFAOYSA-N 12alpha-fumitremorgin C Natural products O=C1C2CCCN2C(=O)C2CC(C3=CC=C(C=C3N3)OC)=C3C(C=C(C)C)N21 DBEYVIGIPJSTOR-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- RKLWTEBQQMTGBF-UHFFFAOYSA-N 2-(2,2,2-trifluoroethyl)pyrimidin-4-amine Chemical compound NC1=CC=NC(CC(F)(F)F)=N1 RKLWTEBQQMTGBF-UHFFFAOYSA-N 0.000 description 1
- NGEKZFHYZPHNKQ-UHFFFAOYSA-N 2-(2,4,6-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=C(F)C=C(F)C=C1F NGEKZFHYZPHNKQ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- YWARNRIBWGHMIS-UHFFFAOYSA-N 2-[3-[2-(4,5-dimethyl-1,3-thiazol-2-yl)-3-(4-sulfophenyl)-1h-tetrazol-5-yl]phenoxy]acetic acid Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC(=CC=2)S(O)(=O)=O)N=C(C=2C=C(OCC(O)=O)C=CC=2)N1 YWARNRIBWGHMIS-UHFFFAOYSA-N 0.000 description 1
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical class C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- SMSBRGXJBHXFMW-UHFFFAOYSA-N 5-methyl-1h-imidazole-2-carbonitrile Chemical compound CC1=CN=C(C#N)N1 SMSBRGXJBHXFMW-UHFFFAOYSA-N 0.000 description 1
- LVXOXXGCJHYEOS-UHFFFAOYSA-N 5-phenylpyrimidine Chemical class C1=CC=CC=C1C1=CN=CN=C1 LVXOXXGCJHYEOS-UHFFFAOYSA-N 0.000 description 1
- ILYCKCZXFXHRMJ-UHFFFAOYSA-N 6-chloro-2-(furan-2-yl)-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2OC=CC=2)N=C1NCC(F)(F)F ILYCKCZXFXHRMJ-UHFFFAOYSA-N 0.000 description 1
- CBESMOQBSQZIGA-UHFFFAOYSA-N 6-chloro-2-pyrazol-1-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(N2N=CC=C2)N=C1NCC(F)(F)F CBESMOQBSQZIGA-UHFFFAOYSA-N 0.000 description 1
- KNFWEQCTFQIEMA-QMMMGPOBSA-N 6-chloro-2-pyridin-2-yl-5-(2,4,6-trifluorophenyl)-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC(F)(F)[C@H](C)NC1=NC(C=2N=CC=CC=2)=NC(Cl)=C1C1=C(F)C=C(F)C=C1F KNFWEQCTFQIEMA-QMMMGPOBSA-N 0.000 description 1
- BIKBKLCRFOIENH-UHFFFAOYSA-N 6-chloro-2-pyrimidin-2-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=CN=2)N=C1NCC(F)(F)F BIKBKLCRFOIENH-UHFFFAOYSA-N 0.000 description 1
- JPNHKLURIKULOR-UHFFFAOYSA-N 6-chloro-2-thiophen-2-yl-n-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2SC=CC=2)N=C1NCC(F)(F)F JPNHKLURIKULOR-UHFFFAOYSA-N 0.000 description 1
- AVMZTTMEKCSZEV-UHFFFAOYSA-N 6-cycloheptyl-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-1h-pyrimidin-4-one Chemical compound FC=1C=C(F)C=C(F)C=1C=1C(O)=NC(C=2N=CC=NC=2)=NC=1C1CCCCCC1 AVMZTTMEKCSZEV-UHFFFAOYSA-N 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010072471 HTI-286 Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 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 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108091077621 MAPRE family Proteins 0.000 description 1
- 108700041567 MDR Genes Proteins 0.000 description 1
- 108090000301 Membrane transport proteins Proteins 0.000 description 1
- 102000003939 Membrane transport proteins Human genes 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 102000014842 Multidrug resistance proteins Human genes 0.000 description 1
- 108050005144 Multidrug resistance proteins Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 241000202349 Taxus brevifolia Species 0.000 description 1
- 241000015728 Taxus canadensis Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- NQFPWIWTMFBTTI-UHFFFAOYSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-(2,2,2-trifluoroethylamino)pyrimidin-2-yl]-methylcyanamide;hydron;chloride Chemical compound Cl.FC1=CC(OCCCN(C)C)=CC(F)=C1C1=C(Cl)N=C(N(C)C#N)N=C1NCC(F)(F)F NQFPWIWTMFBTTI-UHFFFAOYSA-N 0.000 description 1
- JHCLBLFHSPBZQU-MERQFXBCSA-N [4-chloro-5-[4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl]-6-[[(2s)-1,1,1-trifluoropropan-2-yl]amino]pyrimidin-2-yl]methylcyanamide;hydrochloride Chemical compound Cl.FC(F)(F)[C@H](C)NC1=NC(CNC#N)=NC(Cl)=C1C1=C(F)C=C(OCCCN(C)C)C=C1F JHCLBLFHSPBZQU-MERQFXBCSA-N 0.000 description 1
- HDRRAMINWIWTNU-PRJDIBJQSA-N [[(5r)-5-(2-amino-6-oxo-3h-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CCC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HDRRAMINWIWTNU-PRJDIBJQSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 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
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000012999 benign epithelial neoplasm Diseases 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000012578 cell culture reagent Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000007958 cherry flavor Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 108010011222 cyclo(Arg-Pro) Proteins 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- DBEYVIGIPJSTOR-FHWLQOOXSA-N fumitremorgin C Chemical compound O=C1[C@@H]2CCCN2C(=O)[C@@H]2CC(C3=CC=C(C=C3N3)OC)=C3[C@H](C=C(C)C)N21 DBEYVIGIPJSTOR-FHWLQOOXSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 108010057806 hemiasterlin Proteins 0.000 description 1
- 229930187626 hemiasterlin Natural products 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 102000054896 human PML Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- FODOUIXGKGNSMR-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O FODOUIXGKGNSMR-UHFFFAOYSA-L 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 230000003641 microbiacidal effect Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000009448 modified atmosphere packaging Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- DRYYOLGDWVJUCL-UHFFFAOYSA-N pyrimidin-2-ylcyanamide Chemical class N#CNC1=NC=CC=N1 DRYYOLGDWVJUCL-UHFFFAOYSA-N 0.000 description 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 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 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50548703P | 2003-09-24 | 2003-09-24 | |
| US60/505,487 | 2003-09-24 | ||
| PCT/US2004/030682 WO2005030216A1 (en) | 2003-09-24 | 2004-09-17 | 5-arylpyrimidines as anticancer agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2539235A1 true CA2539235A1 (en) | 2005-04-07 |
Family
ID=34393022
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002539235A Abandoned CA2539235A1 (en) | 2003-09-24 | 2004-09-17 | 5-arylpyrimidines as anticancer agents |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US7524849B2 (enExample) |
| EP (1) | EP1663241B1 (enExample) |
| JP (1) | JP2007506746A (enExample) |
| KR (1) | KR20060089215A (enExample) |
| CN (1) | CN1871009A (enExample) |
| AR (1) | AR045811A1 (enExample) |
| AT (1) | ATE432077T1 (enExample) |
| AU (1) | AU2004275733A1 (enExample) |
| BR (1) | BRPI0414736A (enExample) |
| CA (1) | CA2539235A1 (enExample) |
| CO (1) | CO5690592A2 (enExample) |
| DE (1) | DE602004021269D1 (enExample) |
| EC (1) | ECSP066457A (enExample) |
| GT (1) | GT200400188A (enExample) |
| IL (1) | IL174305A0 (enExample) |
| MX (1) | MXPA06003207A (enExample) |
| NO (1) | NO20061319L (enExample) |
| PA (1) | PA8613201A1 (enExample) |
| PE (1) | PE20050470A1 (enExample) |
| RU (1) | RU2006107578A (enExample) |
| SA (1) | SA04250303A (enExample) |
| TW (1) | TW200512198A (enExample) |
| WO (1) | WO2005030216A1 (enExample) |
| ZA (1) | ZA200602386B (enExample) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200637556A (en) * | 2005-01-31 | 2006-11-01 | Basf Ag | Substituted 5-phenyl pyrimidines I in therapy |
| EP1891052A1 (en) * | 2005-06-13 | 2008-02-27 | Wyeth | Tubulin inhibitor and process for its preparation |
| CN101193884A (zh) | 2005-06-13 | 2008-06-04 | 惠氏公司 | 微管蛋白抑制剂和其制备方法 |
| US20110201496A1 (en) * | 2006-03-27 | 2011-08-18 | Joachim Rheinheimer | Substituted 5-Hetaryl-4-Aminopyrimidines |
| CL2007002231A1 (es) * | 2006-08-02 | 2008-04-11 | Basf Ag | Uso de compuestos derivados de 5-(het) arilpirimidina para combatir hongos daninos; compuestos derivados de 5-(het) arilpirimidina; agente fungicida; y agente farmaceutico. |
| AR064852A1 (es) * | 2007-01-11 | 2009-04-29 | Basf Ag | Pirimidinas sustituidas en posicion 2 |
| WO2009007187A1 (de) * | 2007-07-09 | 2009-01-15 | Basf Se | Substituierte 5-hetarylpyrimidine |
| PE20140502A1 (es) | 2011-04-22 | 2014-05-02 | Signal Pharm Llc | Pirimidinas sustituidas de diaminocarboxamida y diaminocarbonitrilo, composiciones de las mismas y metodos de tratamiento con las mismas |
| WO2014047257A2 (en) | 2012-09-19 | 2014-03-27 | The Trustees Of The University Of Pennsylvania | Heterocyclic compounds and their use for the treatment of neurodegenerative tauopathies |
| NZ715903A (en) | 2014-01-30 | 2017-06-30 | Signal Pharm Llc | Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use |
| BR112017012795A2 (pt) | 2014-12-16 | 2018-01-02 | Signal Pharmaceuticals, Llc | Formulações de 2-(terc-butilamino)-4-((1r,3r,4r)-3- hidroxi-4-metilciclo-hexilamino)-pirimidina-5- carboxamida |
| JP6903577B2 (ja) | 2014-12-16 | 2021-07-14 | シグナル ファーマシューティカルズ，エルエルシー | 皮膚におけるｃ−Ｊｕｎ Ｎ末端キナーゼの阻害の測定方法 |
| CA2975260C (en) | 2015-01-29 | 2024-05-21 | Signal Pharmaceuticals Llc | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
| MX2018001004A (es) | 2015-07-24 | 2018-06-07 | Celgene Corp | Metodos de sintesis de clorhidrato de (1r,2r,5r)-5-amino-2-metilci clohexanol e intermedios utiles en este. |
| WO2019169111A1 (en) | 2018-03-02 | 2019-09-06 | The Trustees Of The University Of Pennsylvania | [1,2,4]triazolo[1,5-a]pyrimidine compounds and use in stabilizing microtubules |
| EP4052759A4 (en) * | 2019-11-01 | 2023-12-20 | Unimatec Co., Ltd. | FLUORINE-CONTAINING PYRIMIDINE COMPOUND AND METHOD FOR THE PRODUCTION THEREOF |
| TW202132285A (zh) * | 2019-11-13 | 2021-09-01 | 美商愛彼特生物製藥股份有限公司 | 經取代異吲哚啉基2,2’-聯嘧啶基化合物、其類似物及使用其之方法 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US88096A (en) * | 1869-03-23 | t h a y e r | ||
| US116429A (en) * | 1871-06-27 | Improvement in dial-telegraph apparatus | ||
| US61889A (en) * | 1867-02-05 | Improvement in animal teaps | ||
| US69242A (en) * | 1867-09-24 | Calvin pepper | ||
| US147744A (en) * | 1874-02-24 | Improvement in locomotive-furnaces | ||
| GB9700664D0 (en) | 1997-01-14 | 1997-03-05 | British Tech Group | Anti-cancer agents |
| US6117876A (en) | 1997-04-14 | 2000-09-12 | American Cyanamid Company | Fungicidal trifluorophenyl-triazolopyrimidines |
| AU3536699A (en) | 1998-04-27 | 1999-11-16 | Ihara Chemical Industry Co. Ltd. | 3-arylphenyl sulfide derivatives and insecticides and miticides |
| US5986135A (en) | 1998-09-25 | 1999-11-16 | American Cyanamid Company | Fungicidal trifluoromethylalkylamino-triazolopyrimidines |
| US6156925A (en) | 1998-09-25 | 2000-12-05 | American Cyanamid Company | Process for the preparation of halogenated phenylmaloates |
| AU778913B2 (en) * | 2000-06-13 | 2004-12-23 | Basf Aktiengesellschaft | Fungicidal 5-phenyl substituted 2-(cyanoamino) pyrimidines |
| US6670362B2 (en) | 2000-09-20 | 2003-12-30 | Pfizer Inc. | Pyridazine endothelin antagonists |
| WO2002074753A2 (de) | 2001-03-15 | 2002-09-26 | Basf Aktiengesellschaft | 5-phenylpyrimidine, verfahren und zwischenprodukte zu ihrer herstellung und ihre verwendung zur bekaempfung von schadpilzen |
| DE60204509T2 (de) | 2001-04-20 | 2006-03-16 | Ciba Speciality Chemicals Holding Inc. | 4-Amino-2-(2-pyridinyl)pyrimidine als mikrobizide Wirksubstanzen |
| CN1312134C (zh) | 2001-11-19 | 2007-04-25 | 巴斯福股份公司 | 5－苯基嘧啶化合物、包含它们的组合物、其制备方法及其用途 |
| ATE428705T1 (de) | 2002-02-21 | 2009-05-15 | Basf Se | 2-(2-pyridyl)-5-phenyl-6-aminopyrimidine, verfahren und zwischenprodukte zu ihrer herstellung und ihre verwendung zur bekämpfung von schadpilzen |
| CN1642422A (zh) | 2002-03-15 | 2005-07-20 | 西巴特殊化学品控股有限公司 | 4－氨基嘧啶及其在表面抗菌处理中的应用 |
| PT2316831E (pt) | 2002-11-21 | 2013-06-06 | Novartis Ag | 2-(morfolin-4-il)pirimidinas como inibidores da fosfatidilinositol (pi) quinase e a sua utilização no tratamento do cancro |
-
2004
- 2004-09-17 MX MXPA06003207A patent/MXPA06003207A/es unknown
- 2004-09-17 CA CA002539235A patent/CA2539235A1/en not_active Abandoned
- 2004-09-17 CN CNA200480031581XA patent/CN1871009A/zh active Pending
- 2004-09-17 KR KR1020067005903A patent/KR20060089215A/ko not_active Withdrawn
- 2004-09-17 RU RU2006107578/04A patent/RU2006107578A/ru not_active Application Discontinuation
- 2004-09-17 WO PCT/US2004/030682 patent/WO2005030216A1/en not_active Ceased
- 2004-09-17 EP EP04784529A patent/EP1663241B1/en not_active Expired - Lifetime
- 2004-09-17 BR BRPI0414736-7A patent/BRPI0414736A/pt not_active IP Right Cessation
- 2004-09-17 JP JP2006528086A patent/JP2007506746A/ja not_active Withdrawn
- 2004-09-17 AT AT04784529T patent/ATE432077T1/de not_active IP Right Cessation
- 2004-09-17 AU AU2004275733A patent/AU2004275733A1/en not_active Withdrawn
- 2004-09-17 DE DE602004021269T patent/DE602004021269D1/de not_active Expired - Fee Related
- 2004-09-21 TW TW093128501A patent/TW200512198A/zh unknown
- 2004-09-22 SA SA04250303A patent/SA04250303A/ar unknown
- 2004-09-22 PE PE2004000922A patent/PE20050470A1/es not_active Application Discontinuation
- 2004-09-23 GT GT200400188A patent/GT200400188A/es unknown
- 2004-09-23 AR ARP040103441A patent/AR045811A1/es not_active Application Discontinuation
- 2004-09-24 PA PA20048613201A patent/PA8613201A1/es unknown
- 2004-09-24 US US10/950,375 patent/US7524849B2/en not_active Expired - Fee Related
-
2006
- 2006-03-13 IL IL174305A patent/IL174305A0/en unknown
- 2006-03-23 NO NO20061319A patent/NO20061319L/no not_active Application Discontinuation
- 2006-03-23 ZA ZA200602386A patent/ZA200602386B/xx unknown
- 2006-03-24 EC EC2006006457A patent/ECSP066457A/es unknown
- 2006-04-21 CO CO06038135A patent/CO5690592A2/es not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1663241B1 (en) | 2009-05-27 |
| AR045811A1 (es) | 2005-11-16 |
| US20050075357A1 (en) | 2005-04-07 |
| PA8613201A1 (es) | 2005-11-25 |
| BRPI0414736A (pt) | 2006-11-21 |
| TW200512198A (en) | 2005-04-01 |
| ECSP066457A (es) | 2006-09-18 |
| RU2006107578A (ru) | 2007-10-27 |
| CN1871009A (zh) | 2006-11-29 |
| EP1663241A1 (en) | 2006-06-07 |
| SA04250303A (ar) | 2005-12-03 |
| JP2007506746A (ja) | 2007-03-22 |
| WO2005030216A1 (en) | 2005-04-07 |
| GT200400188A (es) | 2005-05-02 |
| PE20050470A1 (es) | 2005-10-03 |
| KR20060089215A (ko) | 2006-08-08 |
| ZA200602386B (en) | 2009-03-25 |
| CO5690592A2 (es) | 2006-10-31 |
| DE602004021269D1 (de) | 2009-07-09 |
| MXPA06003207A (es) | 2006-06-23 |
| US7524849B2 (en) | 2009-04-28 |
| NO20061319L (no) | 2006-04-20 |
| IL174305A0 (en) | 2008-02-09 |
| AU2004275733A1 (en) | 2005-04-07 |
| ATE432077T1 (de) | 2009-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1663241B1 (en) | 5-arylpyrimidines as anticancer agents | |
| EA016301B1 (ru) | Пирролопиримидины и их применение | |
| KR20150129010A (ko) | Ido 억제제 | |
| JP2009502801A (ja) | Ａｕｒｏｒａキナーゼインヒビターとして有用なピラゾロピリミジン | |
| US7507739B2 (en) | 6-[(substituted)phenyl]triazolopyrimidines as anticancer agents | |
| CN1809570B (zh) | [1,2,4]三唑并[1,5-a]嘧啶-2-基脲衍生物及其用途 | |
| JP2008534609A (ja) | Ｈｓｐ９０阻害剤としてのアルキニルピロロピリミジンおよび関連類似体 | |
| AU2018337138B2 (en) | 2-substituted pyrazole amino-4-substituted amino-5-pyrimidine formamide compound, composition, and application thereof | |
| US20230137932A1 (en) | Cyano-pyrimidine inhibitors of egfr/her2 | |
| KR20220123446A (ko) | Btk 억제제 | |
| KR20130118731A (ko) | 항증식성 질환 치료에 사용하기 위한 ｐｉ3ｋ 억제제로서 피페라지노트리아진 | |
| US7915266B2 (en) | 6-aryl-7-halo-imidazo[1,2-a]pyrimidines as anticancer agents | |
| KR20160089378A (ko) | 단백질 키나제 저해제 | |
| US20240132492A1 (en) | Pyridopyrimidine-based compound and application thereof | |
| HK1090374B (en) | 6- [(substituted)phenyl] triazolopyrimidines as anticancer agents | |
| AU2006329862A1 (en) | Dimers and adducts of 6-[(substituted) phenyl] triazolopyrimidines useful as anticancer agents | |
| HK40033932B (en) | 2-substituted pyrazole amino-4-substituted amino-5-pyrimidine formamide compound, composition, and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |