JP4253188B2 - 血管新生制御剤としてのピリミジンアミン - Google Patents
血管新生制御剤としてのピリミジンアミン Download PDFInfo
- Publication number
- JP4253188B2 JP4253188B2 JP2002559412A JP2002559412A JP4253188B2 JP 4253188 B2 JP4253188 B2 JP 4253188B2 JP 2002559412 A JP2002559412 A JP 2002559412A JP 2002559412 A JP2002559412 A JP 2002559412A JP 4253188 B2 JP4253188 B2 JP 4253188B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- amino
- indazol
- pyrimidinyl
- phenyl
- 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.)
- Expired - Lifetime
Links
- 230000033115 angiogenesis Effects 0.000 title claims description 21
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 26
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 139
- 229910052739 hydrogen Inorganic materials 0.000 claims description 133
- 239000001257 hydrogen Substances 0.000 claims description 125
- -1 C (O) R 1 Chemical group 0.000 claims description 87
- 150000002431 hydrogen Chemical class 0.000 claims description 78
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 46
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 46
- 239000012453 solvate Substances 0.000 claims description 46
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 34
- 230000000694 effects Effects 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- ZXCBCUPACSFUHY-UHFFFAOYSA-N 4-methyl-4-N-(3-methyl-2H-indazol-6-yl)-2-N-[3-(methylsulfonylmethyl)phenyl]-1H-pyrimidine-2,4-diamine Chemical compound CC1(NC(=NC=C1)NC1=CC(=CC=C1)CS(=O)(=O)C)NC1=CC=C2C(=NNC2=C1)C ZXCBCUPACSFUHY-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- YTTBOOLPGZCTSF-UHFFFAOYSA-N 3-[[4-[[2-[(3-chlorophenyl)methyl]-3-methylindazol-6-yl]-methylamino]pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound C=1C=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=1N(C)C(=CC1=N2)C=CC1=C(C)N2CC1=CC=CC(Cl)=C1 YTTBOOLPGZCTSF-UHFFFAOYSA-N 0.000 claims description 4
- QDVXRMFTKAQZOJ-UHFFFAOYSA-N 4-n-(1,3-dimethylindazol-6-yl)-4-n-methyl-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NN(C)C2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 QDVXRMFTKAQZOJ-UHFFFAOYSA-N 0.000 claims description 4
- OKMPHEGFRRVGRS-UHFFFAOYSA-N 4-n-(2,3-dimethylindazol-6-yl)-4-n-methyl-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 OKMPHEGFRRVGRS-UHFFFAOYSA-N 0.000 claims description 4
- XJJKEJHOYVBADS-UHFFFAOYSA-N C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=C(C(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)F)N)OC Chemical compound C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=C(C(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)F)N)OC XJJKEJHOYVBADS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- ARZWRWBLDKOLFV-UHFFFAOYSA-N n-[5-[[5-fluoro-4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]-2-methylphenyl]methanesulfonamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(C(=CN=1)F)=NC=1NC1=CC=C(C)C(NS(C)(=O)=O)=C1 ARZWRWBLDKOLFV-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- OVTQMMYLOJBKOP-UHFFFAOYSA-N 1-[4-[[5-fluoro-4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]-n-methylmethanesulfonamide Chemical compound C1=CC(CS(=O)(=O)NC)=CC=C1NC1=NC=C(F)C(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 OVTQMMYLOJBKOP-UHFFFAOYSA-N 0.000 claims description 3
- BPGZHRULBGZUFP-UHFFFAOYSA-N 1-[4-methoxy-3-[[4-[(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]propan-1-one Chemical compound CCC(=O)C1=CC=C(OC)C(NC=2N=C(NC=3C=C4NN=C(C)C4=CC=3)C=CN=2)=C1 BPGZHRULBGZUFP-UHFFFAOYSA-N 0.000 claims description 3
- MGSXZPZPZIPVHO-UHFFFAOYSA-N 2-[(3-methyl-2h-indazol-6-yl)-[2-[3-(methylsulfonylmethyl)anilino]pyrimidin-4-yl]amino]acetonitrile Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC#N)C(N=1)=CC=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 MGSXZPZPZIPVHO-UHFFFAOYSA-N 0.000 claims description 3
- MQYXDHFLBFNMAM-UHFFFAOYSA-N 2-[(3-methyl-2h-indazol-6-yl)-[2-[4-(methylsulfonylmethyl)anilino]pyrimidin-4-yl]amino]acetonitrile Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC#N)C(N=1)=CC=NC=1NC1=CC=C(CS(C)(=O)=O)C=C1 MQYXDHFLBFNMAM-UHFFFAOYSA-N 0.000 claims description 3
- IBCFYVDVAYYIBT-UHFFFAOYSA-N 3-[[5-fluoro-4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]-4-methoxy-n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(OC)C(NC=2N=C(C(F)=CN=2)N(C)C=2C=C3NN=C(C)C3=CC=2)=C1 IBCFYVDVAYYIBT-UHFFFAOYSA-N 0.000 claims description 3
- CBNFOUWNKLWLNA-UHFFFAOYSA-N 3-[[5-fluoro-4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]-4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1NC1=NC=C(F)C(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 CBNFOUWNKLWLNA-UHFFFAOYSA-N 0.000 claims description 3
- RPRKQNOHZFUQTF-UHFFFAOYSA-N 4-(1H-indazol-6-yl)-4-N-methyl-2-N-[3-(methylsulfonylmethyl)phenyl]-1H-pyrimidine-2,4-diamine Chemical compound N1N=CC2=CC=C(C=C12)C1(NC(=NC=C1)NC1=CC(=CC=C1)CS(=O)(=O)C)NC RPRKQNOHZFUQTF-UHFFFAOYSA-N 0.000 claims description 3
- LITBTKAXHNNSMV-UHFFFAOYSA-N 4-(2,3-dimethylindazol-6-yl)-2-N-(5-ethylsulfonyl-2-methoxyphenyl)-4-N-methyl-1H-pyrimidine-2,4-diamine Chemical compound CN1N=C2C=C(C=CC2=C1C)C1(NC(=NC=C1)NC1=C(C=CC(=C1)S(=O)(=O)CC)OC)NC LITBTKAXHNNSMV-UHFFFAOYSA-N 0.000 claims description 3
- NRAGRPIQSKNAQS-UHFFFAOYSA-N 4-(2,3-dimethylindazol-6-yl)-4-N-methyl-2-N-[4-(methylsulfonylmethyl)phenyl]-1H-pyrimidine-2,4-diamine Chemical compound CN1N=C2C=C(C=CC2=C1C)C1(NC(=NC=C1)NC1=CC=C(C=C1)CS(=O)(=O)C)NC NRAGRPIQSKNAQS-UHFFFAOYSA-N 0.000 claims description 3
- MKQLDHOHEOAOHJ-UHFFFAOYSA-N 4-(3-ethyl-2H-indazol-6-yl)-5-fluoro-4-N-methyl-2-N-[3-(methylsulfonylmethyl)phenyl]-1H-pyrimidine-2,4-diamine Chemical compound C(C)C1=NNC2=CC(=CC=C12)C1(NC(=NC=C1F)NC1=CC(=CC=C1)CS(=O)(=O)C)NC MKQLDHOHEOAOHJ-UHFFFAOYSA-N 0.000 claims description 3
- ZUKWQTLSOWOKOR-UHFFFAOYSA-N 4-[[5-fluoro-4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]-3-methoxybenzenesulfonamide Chemical compound COC1=CC(S(N)(=O)=O)=CC=C1NC1=NC=C(F)C(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 ZUKWQTLSOWOKOR-UHFFFAOYSA-N 0.000 claims description 3
- HQPNYDGAKWXWJL-UHFFFAOYSA-N 4-ethyl-2-N-(5-ethylsulfonyl-2-methoxyphenyl)-4-N-(3-methyl-2H-indazol-6-yl)-1H-pyrimidine-2,4-diamine Chemical compound C(C)C1(NC(=NC=C1)NC1=C(C=CC(=C1)S(=O)(=O)CC)OC)NC1=CC=C2C(=NNC2=C1)C HQPNYDGAKWXWJL-UHFFFAOYSA-N 0.000 claims description 3
- WIQJFZRIFRHEAI-UHFFFAOYSA-N 4-ethyl-5-fluoro-2-N-(2-methoxy-5-methylsulfonylphenyl)-4-N-(3-methyl-2H-indazol-6-yl)-1H-pyrimidine-2,4-diamine Chemical compound C(C)C1(NC(=NC=C1F)NC1=C(C=CC(=C1)S(=O)(=O)C)OC)NC1=CC=C2C(=NNC2=C1)C WIQJFZRIFRHEAI-UHFFFAOYSA-N 0.000 claims description 3
- JRMPYMHBRVUPFL-UHFFFAOYSA-N 4-ethynyl-4-N-(3-methyl-2H-indazol-6-yl)-2-N-[3-(methylsulfonylmethyl)phenyl]-1H-pyrimidine-2,4-diamine Chemical compound C(#C)C1(NC(=NC=C1)NC1=CC(=CC=C1)CS(=O)(=O)C)NC1=CC=C2C(=NNC2=C1)C JRMPYMHBRVUPFL-UHFFFAOYSA-N 0.000 claims description 3
- IQNXIJSPNSRSLK-UHFFFAOYSA-N 4-methyl-4-N-(3-methyl-2H-indazol-6-yl)-2-N-(3-methylsulfinylphenyl)-1H-pyrimidine-2,4-diamine Chemical compound CC1(NC(=NC=C1)NC1=CC(=CC=C1)S(=O)C)NC1=CC=C2C(=NNC2=C1)C IQNXIJSPNSRSLK-UHFFFAOYSA-N 0.000 claims description 3
- GPVSHRYDJMVNJP-UHFFFAOYSA-N 4-methyl-4-N-(3-methyl-2H-indazol-6-yl)-2-N-(3-methylsulfonylphenyl)-1H-1,3,5-triazine-2,4-diamine Chemical compound CC1(NC=NC(=N1)NC1=CC(=CC=C1)S(=O)(=O)C)NC1=CC=C2C(=NNC2=C1)C GPVSHRYDJMVNJP-UHFFFAOYSA-N 0.000 claims description 3
- PNOUUBLTWLHHGL-UHFFFAOYSA-N 4-methyl-4-N-(3-methyl-2H-indazol-6-yl)-2-N-(3-methylsulfonylphenyl)-1H-pyrimidine-2,4-diamine Chemical compound CC1(NC(=NC=C1)NC1=CC(=CC=C1)S(=O)(=O)C)NC1=CC=C2C(=NNC2=C1)C PNOUUBLTWLHHGL-UHFFFAOYSA-N 0.000 claims description 3
- IDXNGTHGCYPLSM-UHFFFAOYSA-N 5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]-1,3,5-triazin-2-yl]amino]-2-methylbenzenesulfonamide Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=NC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 IDXNGTHGCYPLSM-UHFFFAOYSA-N 0.000 claims description 3
- CCAVHDVJKVYFCH-UHFFFAOYSA-N 5-fluoro-2-n-(2-methoxy-5-propan-2-ylsulfonylphenyl)-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)pyrimidine-2,4-diamine Chemical compound COC1=CC=C(S(=O)(=O)C(C)C)C=C1NC1=NC=C(F)C(N(C)C=2C=C3NN=C(C)C3=CC=2)=N1 CCAVHDVJKVYFCH-UHFFFAOYSA-N 0.000 claims description 3
- ANCNAKDZYQJJFB-UHFFFAOYSA-N 5-fluoro-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-(4-methylsulfonylphenyl)pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(C(=CN=1)F)=NC=1NC1=CC=C(S(C)(=O)=O)C=C1 ANCNAKDZYQJJFB-UHFFFAOYSA-N 0.000 claims description 3
- IJIKZGCUKZGSHO-UHFFFAOYSA-N 5-fluoro-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[3-(methylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(C(=CN=1)F)=NC=1NC1=CC=CC(CS(C)(=O)=O)=C1 IJIKZGCUKZGSHO-UHFFFAOYSA-N 0.000 claims description 3
- AQRABUUXKQANHS-UHFFFAOYSA-N 5-fluoro-4-n-methyl-4-n-(3-methyl-2h-indazol-6-yl)-2-n-[3-(propan-2-ylsulfonylmethyl)phenyl]pyrimidine-2,4-diamine Chemical compound CC(C)S(=O)(=O)CC1=CC=CC(NC=2N=C(C(F)=CN=2)N(C)C=2C=C3NN=C(C)C3=CC=2)=C1 AQRABUUXKQANHS-UHFFFAOYSA-N 0.000 claims description 3
- BRBLQOUCOAPWMS-UHFFFAOYSA-N C(C(C)C)C=1C=CC(=C(C1)C1(NC=CC(=N1)NC1=CC=C2C(=NNC2=C1)C)N)OC Chemical compound C(C(C)C)C=1C=CC(=C(C1)C1(NC=CC(=N1)NC1=CC=C2C(=NNC2=C1)C)N)OC BRBLQOUCOAPWMS-UHFFFAOYSA-N 0.000 claims description 3
- SYURXPQNHWWIQV-UHFFFAOYSA-N C(C)(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N)OC Chemical compound C(C)(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N)OC SYURXPQNHWWIQV-UHFFFAOYSA-N 0.000 claims description 3
- SOFVXWOEBIPQLP-UHFFFAOYSA-N C(C)(C)S(=O)(=O)CC=1C=C(C=CC=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N Chemical compound C(C)(C)S(=O)(=O)CC=1C=C(C=CC=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N SOFVXWOEBIPQLP-UHFFFAOYSA-N 0.000 claims description 3
- YCSRKCLLXHHELU-UHFFFAOYSA-N C(C)S(=O)(=O)C1=CC=C(C=C1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N Chemical compound C(C)S(=O)(=O)C1=CC=C(C=C1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N YCSRKCLLXHHELU-UHFFFAOYSA-N 0.000 claims description 3
- IDELGVLOWFHGCY-UHFFFAOYSA-N C(C)S(=O)(=O)C=1C=CC(=C(C1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N)OC Chemical compound C(C)S(=O)(=O)C=1C=CC(=C(C1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N)OC IDELGVLOWFHGCY-UHFFFAOYSA-N 0.000 claims description 3
- UQDHUOKPSGLKRS-UHFFFAOYSA-N C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C(C)C)N)OC Chemical compound C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C(C)C)N)OC UQDHUOKPSGLKRS-UHFFFAOYSA-N 0.000 claims description 3
- FAXGGDSKPYJFOH-UHFFFAOYSA-N C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)NC1=CC=C2C(=NNC2=C1)C)N)OC Chemical compound C(C)S(=O)(=O)C=1C=CC(=C(C=1)C1(NC=CC(=N1)NC1=CC=C2C(=NNC2=C1)C)N)OC FAXGGDSKPYJFOH-UHFFFAOYSA-N 0.000 claims description 3
- PRDBESRYYRCCHH-UHFFFAOYSA-N COC1=C(C=C(C=C1)S(=O)(=O)C)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N Chemical compound COC1=C(C=C(C=C1)S(=O)(=O)C)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N PRDBESRYYRCCHH-UHFFFAOYSA-N 0.000 claims description 3
- QEWLKWPRUPEKSW-UHFFFAOYSA-N FC(C(=O)O)(F)F.CC1=NNC2=CC(=CC=C12)C1(NC=NC(=N1)NC1=CC(=CC=C1)CS(=O)(=O)C)N Chemical compound FC(C(=O)O)(F)F.CC1=NNC2=CC(=CC=C12)C1(NC=NC(=N1)NC1=CC(=CC=C1)CS(=O)(=O)C)N QEWLKWPRUPEKSW-UHFFFAOYSA-N 0.000 claims description 3
- IWZSOGITOHUCSQ-UHFFFAOYSA-N FC1=C(C=C(C=C1)S(=O)(=O)C)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N Chemical compound FC1=C(C=C(C=C1)S(=O)(=O)C)C1(NC=CC(=N1)N(C1=CC=C2C(=NNC2=C1)C)C)N IWZSOGITOHUCSQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 3
- FHCXJZSNEBTJKE-UHFFFAOYSA-N n-[2-methyl-5-[[4-[methyl-(3-methyl-2h-indazol-6-yl)amino]-1,3,5-triazin-2-yl]amino]phenyl]methanesulfonamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=NC=NC=1NC1=CC=C(C)C(NS(C)(=O)=O)=C1 FHCXJZSNEBTJKE-UHFFFAOYSA-N 0.000 claims description 3
- YDHRSWAPJJCSGX-UHFFFAOYSA-N n-[3-[[4-[ethyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]acetamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(CC)C(N=1)=CC=NC=1NC1=CC=CC(NC(C)=O)=C1 YDHRSWAPJJCSGX-UHFFFAOYSA-N 0.000 claims description 3
- AXBKRLMNVZOBIH-UHFFFAOYSA-N n-[3-[[4-[methyl-(3-methyl-2h-indazol-6-yl)amino]pyrimidin-2-yl]amino]phenyl]acetamide Chemical compound C=1C=C2C(C)=NNC2=CC=1N(C)C(N=1)=CC=NC=1NC1=CC=CC(NC(C)=O)=C1 AXBKRLMNVZOBIH-UHFFFAOYSA-N 0.000 claims description 3
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- 229960001278 teniposide Drugs 0.000 description 1
- DHHKPEUQJIEKOA-UHFFFAOYSA-N tert-butyl 2-[6-(nitromethyl)-6-bicyclo[3.2.0]hept-3-enyl]acetate Chemical compound C1C=CC2C(CC(=O)OC(C)(C)C)(C[N+]([O-])=O)CC21 DHHKPEUQJIEKOA-UHFFFAOYSA-N 0.000 description 1
- HNKXDUWDVLHDOB-UHFFFAOYSA-N tert-butyl 6-[(2-chloro-5-fluoropyrimidin-4-yl)-methylamino]-3-methylindazole-1-carboxylate Chemical compound C=1C=C2C(C)=NN(C(=O)OC(C)(C)C)C2=CC=1N(C)C1=NC(Cl)=NC=C1F HNKXDUWDVLHDOB-UHFFFAOYSA-N 0.000 description 1
- ICQWBNUSYDNQEP-UHFFFAOYSA-N tert-butyl 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-3-methylindazole-1-carboxylate Chemical compound C=1C=C2C(C)=NN(C(=O)OC(C)(C)C)C2=CC=1NC1=NC(Cl)=NC=C1F ICQWBNUSYDNQEP-UHFFFAOYSA-N 0.000 description 1
- BQFWUQIBPHWZBA-UHFFFAOYSA-N tert-butyl 6-[(2-chloropyrimidin-4-yl)-methylamino]-3-methylindazole-1-carboxylate Chemical compound C=1C=C2C(C)=NN(C(=O)OC(C)(C)C)C2=CC=1N(C)C1=CC=NC(Cl)=N1 BQFWUQIBPHWZBA-UHFFFAOYSA-N 0.000 description 1
- XGTBHWCPIXKDGI-UHFFFAOYSA-N tert-butyl 6-[(2-chloropyrimidin-4-yl)amino]-3-methylindazole-1-carboxylate Chemical compound C=1C=C2C(C)=NN(C(=O)OC(C)(C)C)C2=CC=1NC1=CC=NC(Cl)=N1 XGTBHWCPIXKDGI-UHFFFAOYSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 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
- 229960003604 testosterone Drugs 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000008467 tissue growth Effects 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
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 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 description 1
- 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 1
- 229960004528 vincristine Drugs 0.000 description 1
- 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 1
- 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 description 1
- 229960004355 vindesine Drugs 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
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- C07D239/30—Halogen atoms or nitro radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Description
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2は水素、C1-C4アルキル、C1-C4ハロアルキル、C(O)R1、またはアラルキルである;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2であり、Dが:
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2は水素、C1-C4アルキル、C1-C4ハロアルキル、C(O)R1、またはアラルキルである;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2である]が提供される。
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2はC1-C4アルキル、C1-C4ハロアルキル、またはC(O)R1である;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2である]が提供される。
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2は水素、C1-C4アルキル、C1-C4ハロアルキル、C(O)R1、またはアラルキルである;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2である]が提供される。
本明細書で用いる場合、用語「有効な量」とは、例えば研究者あるいは臨床医により追求される、組織、系、動物またはヒトの生物学的あるいは医学的な応答を誘起する薬物または医薬の量を意味する。さらに、用語「治療的に有効な量」とは、そのような量を与えられていない対応の被験者に比較して、疾病、疾患、または副作用の改善された治療、治癒、予防、または回復、あるいは疾病または疾患の進行の度合いの低下、をもたらす量を意味する。この用語はまた通常の生理学的機能を高めるのに有効な量もその範囲内に含む。
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-4-メトキシ-N-メチルベンゼンスルホンアミド;
5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-N-イソプロピルベンゼンスルホンアミド;
5-フルオロ-N2-[5-(イソプロピルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[5-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-2-メチルフェニル]メタンスルホンアミド;
5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[4-(メチルスルホニル)フェニル]-2,4-ピリミジンジアミン;
N4-(3-エチル-1H-インダゾール-6-イル)-5-フルオロ-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチル-5-フルオロ-N2-[2-メトキシ-5-(メチルスルホニル)フェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
[4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]-N-メチルメタンスルホンアミド;
5-フルオロ-N2-{3-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-4-メトキシベンズアミド;
4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-3-メトキシベンゼンスルホンアミド;
N2-(3-メチル-1H-インダゾール-6-イル)-N4-{3-[(メチルスルホニル)メチル]フェニル}-1,3,5-トリアジン-2,4-ジアミントリフルオロ酢酸;
N2-メチル-N2-(3-メチル-1H-インダゾール-6-イル)-N4-{3-[(メチルスルホニル)メチル]フェニル}-1,3,5-トリアジン-2,4-ジアミン;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-1,3,5-トリアジン-2,4-ジアミン;
N-[2-メチル-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)フェニル]メタンスルホンアミド;
N2-メチル-N2-(3-メチル-1H-インダゾール-6-イル)-N4-[3-(メチルスルホニル)フェニル]-1,3,5-トリアジン-2,4-ジアミン;
N-[4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)フェニル]アセトアミド;
3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N-イソプロピル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N-シクロプロピル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチル-N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]メタンスルホンアミド;
N2-{3-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-{4-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[5-(イソブチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]アセトアミド;
N-[3-({4-[エチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]アセトアミド;
N2-(2-メトキシ-5-{[(5-メチル-3-イソオキサゾリル)メチル]スルホニル}フェニル)-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
4-メトキシ-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(イソプロピルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-イソプロピル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N4-(1H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(1,3-ジメチル-1H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-2,4-ピリミジンジアミン;
1-[4-メトキシ-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]-1-プロパノン;
4-メトキシ-N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]ベンゼンスルホンアミド;
4-メトキシ-N-メチル-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
[(3-メチル-1H-インダゾール-6-イル)(2-{4-[(メチルスルホニル)メチル]アニリノ}-4-ピリミジニル)アミノ]アセトニトリル;
[{2-[5-(エチルスルホニル)-2-メトキシアニリノ]-4-ピリミジニル}(3-メチル-1H-インダゾール-6-イル)アミノ]アセトニトリル;
[(3-メチル-1H-インダゾール-6-イル)(2-{3-[(メチルスルホニル)メチル]アニリノ}-4-ピリミジニル)アミノ]アセトニトリル;
4-メトキシ-N-メチル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンズアミド;
3-メトキシ-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチニル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
3-({4-[(3-メチル-1H-インダゾール-6-イル)(2-プロピニル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[3-(メチルスルホニル)フェニル]-2,4-ピリミジンジアミン;
4-メトキシ-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンズアミド;
N2-[4-(エチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンジル]エタンスルホンアミド;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンジル]メタンスルホンアミド;
2-クロロ-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
2-クロロ-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-クロロ-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
3-メチル-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
2-メチル-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-メチル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[3-(メチルスルフィニル)フェニル]-2,4-ピリミジンジアミン;
N2-[2-フルオロ-5-(メチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[2-メトキシ-5-(メチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
5-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)-2-メチルベンゼンスルホンアミド;
3-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
2-[4-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)フェニル]エタンスルホンアミド;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N4-メチル-N2-{4-[(メチルスルホニル)メチル]フェニル}ピリミジン-2,4-ジアミン;
3-({4-[[3-(ヒドロキシメチル)-2-メチル-2H-インダゾール-6-イル](メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(1,2-ジメチル-1H-ベンズイミダゾール-5-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2-ベンジル-1-メチル-1H-ベンズイミダゾール-5-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2-エチル-3-メチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[[2-(3-クロロベンジル)-3-メチル-2H-インダゾール-6-イル](メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)ベンゼンスルホンアミド;および
5-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)-2-メチルベンゼンスルホンアミド;
あるいはこれらの塩、溶媒和物、または生理学的に機能する誘導体。
(1) 細胞周期に特異的な抗癌薬としては、限定するものではないが、パクリタキセルとその類似体であるドセタキセルなどのジテルペノイド類;ビンブラスチン、ビンクリスチン、ビンデシン、およびビノレルビンなどのビンカアルカロイド類;エトポシドおよびテニポシドなどのエピポドフィルロトキシン類;5-フルオロウラシルおよびフルオロデオキシウリジンなどのフルオロピリミジン類;アロプリノール、フルデュラビン、メトトレキセート、クラドラビン、シタラビン、メルカプトプリンおよびチオグアニンなどの代謝拮抗物質;9-アミノカンプトテシン、イリノテカン、CPT-11および7-(4-メチルピペラジノ-メチレン)-10,11-エチレンジオキシ-20-カンプトテシンなどのカンプトテシン類;があり、
(2) 細胞障害性の化学療法薬としては、限定するものではないが、メルファラン、クロランブシル、シクロホスファミド、メクロレタミン、ヘキサメチルメラミン、ブスルファン、カルムスチン、ロムスチン、およびダカルバジンなどのアルキル化薬;ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、ミトマイシン-C、ダクチノマイシンおよびミトラマイシンなどの抗腫瘍抗生物質;シスプラチン、カルボプラチン、およびオキサリプラチンなどの白金配位錯体;があり、
(3) その他の化学療法剤としては、限定するものではないが、タモキシフェン、トレミフェン、ラロキシフェン、ドロロキシフェンおよびヨードキシフェンなどの抗エストロゲン剤;酢酸メゲストロールなどのプロゲストロゲン;アナストロゾール、レトラゾール、ボラゾール、およびエクセメスタンなどのアロマターゼ阻害剤;フルタミド、ニルタミド、ビカルタミド、および酢酸シプロテロンなどの抗男性ホルモン物質;酢酸ゴセレリンおよびルプロリドなどのLHRH作動薬および拮抗薬、フィナステリドなどのテストステロン5α-ジヒドロレダクターゼ阻害物質;マリマスタトなどのメタロプロテイナーゼ阻害剤;抗プロゲストゲン剤;ウロキナーゼプラスミノーゲンアクチベーターレセプター機能阻害剤;セレコキシブなどのシクロオキシゲナーゼタイプ2(COX-2)阻害剤;本明細書中で記載されたもの以外のVEGFR阻害物質、およびTIE-2阻害物質などのその他の血管新生阻害剤;肝細胞増殖因子機能阻害物質などの増殖因子機能阻害剤;アーブ(erb)-B2、アーブ-B4、上皮成長因子レセプター(EGFRr)、血小板由来増殖因子レセプター(PDGFr)、本発明で記述されたもの以外の血管内皮増殖因子レセプター(VEGFR)、およびTIE-2;ならびに、CDK2およびCDK4阻害物質のようなサイクリン依存阻害物質などのその他のチロシンキナーゼ阻害物質;がある。
g(グラム); mg(ミリグラム);
L(リットル); mL(ミリリットル);
μL(マイクロリットル); psi(ポンド/平方インチ);
M(モル濃度); mM(ミリモル濃度);
i. v.(静脈内); Hz(ヘルツ);
MHz(メガヘルツ); mol(モル);
mmol(ミリモル); RT(室温);
min(分); h(時間);
mp(融点); TLC(薄層クロマトグラフィ);
Tr(保持時間); RP(逆転相);
MeOH(メタノール); I-PrOH(イソプロパノール);
TEA(トリエチルアミン); TFA(トリフルオロ酢酸);
TFAA(トリフルオロ無水酢酸); THF(テトラヒドロフラン);
DMSO(ジメチルスルホキシド); EtOAc(酢酸エチル);
DME(1,2-ジメトキシエタン); DCM(ジクロロメタン);
DCE(ジクロロエタン); DMF(N,N-ジメチルホルムアミド);
DMPU(N,N’-ジメチルプロピレン尿素); CDI(1,1-カルボニルジイミダゾール);
IBCF(イソブチルクロロ蟻酸); HOAc(酢酸);
HOSu(N-ヒドロキシスクシンイミド); HOBT(1-ヒドロキシベンゾトリアゾール);
mCPBA(メタ-クロロペル安息香酸; EDC(塩酸エチルカルボジイミド);
BOC(tert-ブチルオキシカルボニル); FMOC(9-フルオレニルメトキシカルボニル);
DCC(ジシクロヘキシルカルボジイミド);CBZ(ベンジルオキシカルボニル);
Ac(アセチル); atm(気圧);
TMSE(2-(トリメチルシリル)エチル); TMS(トリメチルシリル);
TIPS(トリイソプロピルシリル); TBS(t-ブチルジメチルシリル);
DMAP(4-ジメチルアミノピリジン); Me(メチル);
OMe(メトキシ); Et(エチル);
HPLC(高圧液体クロマトグラフィ);
BOP(ビス(2-オキソ-3-オキサゾリジニル)塩化ホスフィン);
TBAF(テトラ-n-ブチルフッ化アンモニウム);
Et(エチル); tBu(tert-ブチル)。
3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド塩酸塩
本発明の化合物は、重要なまたはっきりと分かる薬理的な応答を誘発する。以下のVEGFR2 HTRFアッセイにより説明されるように、本実施例部分で説明された各化合物は高い親和性(IC50 < 1 μM)でもってVEGFR2レセプターのキナーゼドメインに結合する。VEGFR2のキナーゼドメインに結合することに加えて、本発明の上記の例示された化合物はまたはっきりとまた顕著に、VEGFによる活性化により増殖刺激される内皮細胞の増殖を阻害する。細胞増殖の阻害についてのデータを以下の表1に示す。
本アッセイは96-穴ブラックプレートで行った。10nM hVEGFR2を用いて、75μM ATP、5mM MgCl2、0.3mM DTT、0.1mg/mL BSA、および0.1M HEPES(pH 7.5)の存在下で0.36μMペプチド(Biotin-Ahx-EEEEYFELVAKKKK)をリン酸化した。負の対照として10μL 0.5M EDTAをこの反応物に加えた。5% DMSO中阻害剤有りまたは無しの50μLキナーゼ反応を室温で45分間行わせ、次に125mM EDTA 40μLにより停止させた。0.1mg/mL BSA、0.1M HEPES(pH7.5)の存在下、2.4μg/mL Streptavidin-APCおよび0.15μg/mL Eu-α-pYを加えて最終容量140μLとした。プレートを室温(22℃)で10分間インキュベートし、時間分解蛍光モードにしたVictorで340nmで励起してその発光を665nmで測定することにより読み取った。
ペプチドはSynpep(Dublin, CA)から
ATP、MgCl2、DTT、BSA、HEPES、EDTA、DMSOはSigmaから
Streptavidin-APCはMolecular Probes(Eugene, Oregon)から
Eu-α-pYはEG&G Wallac(Gaithersburg, MD)から。
ATP:アデノシン三リン酸
Streptavidin-APC:ストレプトアビジン、アロフィコシアニン架橋複合体
DMSO:ジメチルスルホキシド
DTT:ジチオトレイトール
BSA:ウシ血清アルブミン
HTRF:Homogenous Time Resolved Fluorescence[均一系時間分解蛍光発光]
EDTA:エチレンジニトリロテトラ酢酸
HEPES:N-2-ヒドロキシエチルピペラジンN-エタンスルホン酸
Eu-α-pY:ユーロピウム標識抗-ホスホチロシン抗体。
材料については以下のとおりである:
HUVEC細胞およびEGM-MV(Endothelial cell growth medium - microvascular[内皮細胞増殖培地-微小血管)はClonetics (San Diego, CA)から購入した。VEGFとbFGFはR&D Systems (Minneapolis, MN)から購入した。抗-BrdU抗体はChemicon International (Temecula, CA)から入手した。
HUVECをEGM-MV培地中に常に維持し、7継代[passage]以内に使用した。HUVECを、タイプIコラーゲンコートプレート(Becton Dickinson)に、5% FBS含有M199培地(Hyclone)中、密度2500細胞/穴でプレーティングした。このプレートを37℃で一晩インキュベートした。培地を吸引により除去し、試験化合物を無血清M199培地中容量0.1mL/穴で各穴に加えた。化合物の濃度は1.5nM〜30マイクロモルの範囲であった。このプレートを37℃で30分間インキュベートした。もう一つのBSAとVEGF(またはbFGF)含有無血清M199培地0.1mLを加えて最終濃度0.1% BSAおよび10ng/mL VEGF(0.3ng/mL bFGF)を得た。このプレートを37℃で72時間インキュベートした。最初の48時間後BrdUを各穴に加えて濃度10マイクロモルを得た。比色法ELISAアッセイをメーカー(Roche Molecular Sciences)の操作説明書に従い、検出を450nmにおける吸光度測定にして行った。結果を試験化合物の濃度vs.吸光度のプロットにして、BrdU取り込み阻害のIC50値を得た。
Claims (11)
- 下記式(I)の化合物またはその塩、もしくは溶媒和物:
Dは:
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2は水素、C1-C4アルキル、C1-C4ハロアルキル、C(O)R1、またはアラルキルである;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2であり、Dが:
- 下記式(III)の化合物またはその塩、もしくは溶媒和物:
X1は水素、C1-C4アルキル、C1-C4ハロアルキル、またはC1-C4ヒドロキシアルキルである;
X2はC1-C4アルキル、C1-C4ハロアルキル、またはC(O)R1である;
X3は水素またはハロゲンである;
X4は水素、C1-C4アルキル、C1-C4ハロアルキル、ヘテロアラルキル、シアノアルキル、-(CH2)pC=CH(CH2)tH、-(CH2)pC≡C(CH2)tH、またはC3-C7シクロアルキルである;
pは1、2、または3である;
tは0または1である;
WはNまたはC-R[式中Rは水素、ハロゲン、またはシアノである]である;
Q1は水素、ハロゲン、C1-C2ハロアルキル、C1-C2アルキル、C1-C2アルコキシ、またはC1-C2ハロアルコキシである;
Q2はA1またはA2である;
Q3はQ2がA2である場合はA1であり、Q2がA1である場合はA2である;
ここで、
A1は水素、ハロゲン、C1-C3アルキル、C1-C3ハロアルキル、-OR1である、
A2は-(Z)m-(Z1)-(Z2)で定義される基であり、この式中
ZはCH2であり、mは0、1、2、または3であるか、あるいは
ZはNR2であり、mは0または1であるか、あるいは
Zは酸素であり、mは0または1であるか、あるいは
ZはCH2NR2であり、mは0または1である;
Z1はS(O)2、S(O)、またはC(O)である;
Z2はC1-C4アルキル、NR3R4、アリール、アリールアミノ、アラルキル、アラルコキシ、またはヘテロアリールである、
R1はC1-C4アルキルである;
R2、R3、およびR4はそれぞれ独立に水素、C1-C4アルキル、C3-C7シクロアルキル、-S(O)2R5、および-C(O)R5から選択される;
R5はC1-C4アルキル、またはC3-C7シクロアルキルである;そして
Zが酸素である場合Z1はS(O)2である]。 - N2-[5-(エチルスルホニル)-2-メトキシフェニル]-5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-4-メトキシ-N-メチルベンゼンスルホンアミド;
5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-N-イソプロピルベンゼンスルホンアミド;
5-フルオロ-N2-[5-(イソプロピルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[5-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-2-メチルフェニル]メタンスルホンアミド;
5-フルオロ-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[4-(メチルスルホニル)フェニル]-2,4-ピリミジンジアミン;
N4-(3-エチル-1H-インダゾール-6-イル)-5-フルオロ-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチル-5-フルオロ-N2-[2-メトキシ-5-(メチルスルホニル)フェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
[4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]-N-メチルメタンスルホンアミド;
5-フルオロ-N2-{3-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-4-メトキシベンズアミド;
4-({5-フルオロ-4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)-3-メトキシベンゼンスルホンアミド;
N2-(3-メチル-1H-インダゾール-6-イル)-N4-{3-[(メチルスルホニル)メチル]フェニル}-1,3,5-トリアジン-2,4-ジアミントリフルオロ酢酸塩;
N2-メチル-N2-(3-メチル-1H-インダゾール-6-イル)-N4-{3-[(メチルスルホニル)メチル]フェニル}-1,3,5-トリアジン-2,4-ジアミン;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-1,3,5-トリアジン-2,4-ジアミン;
N-[2-メチル-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)フェニル]メタンスルホンアミド;
N2-メチル-N2-(3-メチル-1H-インダゾール-6-イル)-N4-[3-(メチルスルホニル)フェニル]-1,3,5-トリアジン-2,4-ジアミン;
N-[4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)フェニル]アセトアミド;
3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N-イソプロピル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N-シクロプロピル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチル-N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]メタンスルホンアミド;
N2-{3-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-{4-[(イソプロピルスルホニル)メチル]フェニル}-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[5-(イソブチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]アセトアミド;
N-[3-({4-[エチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]アセトアミド;
N2-(2-メトキシ-5-{[(5-メチル-3-イソオキサゾリル)メチル]スルホニル}フェニル)-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
4-メトキシ-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(イソプロピルスルホニル)-2-メトキシフェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-イソプロピル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N4-(1H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(1,3-ジメチル-1H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N4-メチル-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-メチル-2,4-ピリミジンジアミン;
1-[4-メトキシ-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]-1-プロパノン;
4-メトキシ-N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)フェニル]ベンゼンスルホンアミド;
4-メトキシ-N-メチル-3-({4-[(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
[(3-メチル-1H-インダゾール-6-イル)(2-{4-[(メチルスルホニル)メチル]アニリノ}-4-ピリミジニル)アミノ]アセトニトリル;
[{2-[5-(エチルスルホニル)-2-メトキシアニリノ]-4-ピリミジニル}(3-メチル-1H-インダゾール-6-イル)アミノ]アセトニトリル;
[(3-メチル-1H-インダゾール-6-イル)(2-{3-[(メチルスルホニル)メチル]アニリノ}-4-ピリミジニル)アミノ]アセトニトリル;
4-メトキシ-N-メチル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンズアミド;
3-メトキシ-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-エチニル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-{3-[(メチルスルホニル)メチル]フェニル}-2,4-ピリミジンジアミン;
3-({4-[(3-メチル-1H-インダゾール-6-イル)(2-プロピニル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[3-(メチルスルホニル)フェニル]-2,4-ピリミジンジアミン;
4-メトキシ-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N2-[5-(エチルスルホニル)-2-メトキシフェニル]-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンズアミド;
N2-[4-(エチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N-[4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンジル]エタンスルホンアミド;
N-[3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンジル]メタンスルホンアミド;
2-クロロ-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
2-クロロ-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-クロロ-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
3-メチル-4-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
2-メチル-5-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
4-メチル-3-({4-[メチル(3-メチル-1H-インダゾール-6-イル)アミノ]-2-ピリミジニル}アミノ)ベンゼンスルホンアミド;
N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-N2-[3-(メチルスルフィニル)フェニル]-2,4-ピリミジンジアミン;
N2-[2-フルオロ-5-(メチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
N2-[2-メトキシ-5-(メチルスルホニル)フェニル]-N4-メチル-N4-(3-メチル-1H-インダゾール-6-イル)-2,4-ピリミジンジアミン;
5-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)-2-メチルベンゼンスルホンアミド;
3-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
2-[4-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)フェニル]エタンスルホンアミド;
N4-(2,3-ジメチル-2H-インダゾール-6-イル)-N4-メチル-N2-{4-[(メチルスルホニル)メチル]フェニル}ピリミジン-2,4-ジアミン;
3-({4-[[3-(ヒドロキシメチル)-2-メチル-2H-インダゾール-6-イル](メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(1,2-ジメチル-1H-ベンズイミダゾール-5-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2-ベンジル-1-メチル-1H-ベンズイミダゾール-5-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2-エチル-3-メチル-2H-インダゾール-6-イル)(メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[[2-(3-クロロベンジル)-3-メチル-2H-インダゾール-6-イル](メチル)アミノ]ピリミジン-2-イル}アミノ)ベンゼンスルホンアミド;
3-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)ベンゼンスルホンアミド;および
5-({4-[(2,3-ジメチル-2H-インダゾール-6-イル)(メチル)アミノ]-1,3,5-トリアジン-2-イル}アミノ)-2-メチルベンゼンスルホンアミド;
からなる群から選択される、請求項1に記載の化合物またはその塩、もしくは溶媒和物。 - 請求項1〜3のいずれか1項に記載の化合物またはその塩、もしくは溶媒和物の治療的に有効な量、ならびに医薬的に許容される担体、希釈剤および賦形剤の1つ以上、を含む医薬組成物。
- 治療に使用される請求項1〜3のいずれか1項に記載の化合物またはその塩、もしくは溶媒和物。
- 不適切なVEGFR2活性が介在して起こる疾患の治療に使用される医薬の製造における、請求項1〜3のいずれか1項に記載の化合物またはその塩、もしくは溶媒和物の使用。
- 不適切な血管新生により特徴づけられる疾患の治療に使用される医薬の製造における、請求項1〜3のいずれか1項に記載の化合物またはその塩、もしくは溶媒和物の使用。
- WがC-Rであり、Rが水素である、請求項2に記載の化合物。
- 請求項9または10に記載の化合物を含む医薬組成物。
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PCT/US2001/049367 WO2002059110A1 (en) | 2000-12-21 | 2001-12-19 | Pyrimidineamines as angiogenesis modulators |
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