JP2009298775A - 置換オキシ基を有する2,2,4−トリメチル−6−フェニル−1,2−ジヒドロキノリン誘導体からなるグルココルチコイド受容体アゴニスト - Google Patents
置換オキシ基を有する2,2,4−トリメチル−6−フェニル−1,2−ジヒドロキノリン誘導体からなるグルココルチコイド受容体アゴニスト Download PDFInfo
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- JP2009298775A JP2009298775A JP2009115070A JP2009115070A JP2009298775A JP 2009298775 A JP2009298775 A JP 2009298775A JP 2009115070 A JP2009115070 A JP 2009115070A JP 2009115070 A JP2009115070 A JP 2009115070A JP 2009298775 A JP2009298775 A JP 2009298775A
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- trimethyl
- dihydroquinoline
- methoxy
- compound
- phenyl
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- 229940124750 glucocorticoid receptor agonist Drugs 0.000 title claims abstract description 38
- JFUAWXPBHXKZGA-IBGZPJMESA-N 4-fluoro-2-[(4r)-5,5,5-trifluoro-4-hydroxy-2-methyl-4-(1h-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-yl]phenol Chemical compound C([C@@](O)(CC=1NC2=CN=CC=C2C=1)C(F)(F)F)C(C)(C)C1=CC(F)=CC=C1O JFUAWXPBHXKZGA-IBGZPJMESA-N 0.000 title claims abstract description 32
- XKBGEVHKVFIMLY-UHFFFAOYSA-N 2,2,4-trimethyl-6-phenyl-1h-quinoline Chemical class C1=C2C(C)=CC(C)(C)NC2=CC=C1C1=CC=CC=C1 XKBGEVHKVFIMLY-UHFFFAOYSA-N 0.000 title abstract description 9
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 467
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 40
- 201000004624 Dermatitis Diseases 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- -1 5-Fluoro-2-methylphenoxymethyl Chemical group 0.000 claims description 47
- 239000003814 drug Substances 0.000 claims description 45
- 229940124597 therapeutic agent Drugs 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 230000000069 prophylactic effect Effects 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 230000003449 preventive effect Effects 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 14
- 206010013774 Dry eye Diseases 0.000 claims description 14
- 208000002780 macular degeneration Diseases 0.000 claims description 14
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 13
- 201000008937 atopic dermatitis Diseases 0.000 claims description 13
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 12
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 12
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 6
- 201000011190 diabetic macular edema Diseases 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- GQMFIXUQVVWKGE-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] n,n-dimethylcarbamate Chemical compound COC1=CC(OC(=O)N(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C GQMFIXUQVVWKGE-UHFFFAOYSA-N 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- APVJMXTVEFHGKX-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] furan-2-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3OC=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 APVJMXTVEFHGKX-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- CYPFPZWYOVSNND-UHFFFAOYSA-N 3-o-[3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 1-o-methyl benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=CC(C(=O)OC=2C=C(OC)C(=CC=2)C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=CC=2)OC)=C1 CYPFPZWYOVSNND-UHFFFAOYSA-N 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- PPAPLJSJXHNDML-UHFFFAOYSA-N [3-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-4-methoxyphenyl] furan-2-carboxylate Chemical compound C1=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=C1OC(=O)C1=CC=CO1 PPAPLJSJXHNDML-UHFFFAOYSA-N 0.000 claims description 2
- PJYUDGDSEBLAIU-UHFFFAOYSA-N [3-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-4-methoxyphenyl] pyridine-3-carboxylate Chemical compound C1=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=C1OC(=O)C1=CC=CN=C1 PJYUDGDSEBLAIU-UHFFFAOYSA-N 0.000 claims description 2
- WXHDURQQYXSQJK-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(2-methyl-5-nitrophenoxy)methyl]-1h-quinolin-6-yl]phenyl] n,n-dimethylcarbamate Chemical compound COC1=CC(OC(=O)N(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC([N+]([O-])=O)=CC=C1C WXHDURQQYXSQJK-UHFFFAOYSA-N 0.000 claims description 2
- UUFUPWQZPLPDMK-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(2-methyl-5-nitrophenoxy)methyl]-1h-quinolin-6-yl]phenyl] propane-1-sulfonate Chemical compound COC1=CC(OS(=O)(=O)CCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC([N+]([O-])=O)=CC=C1C UUFUPWQZPLPDMK-UHFFFAOYSA-N 0.000 claims description 2
- MSKLIAMYHIJSHE-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(2-methyl-5-nitrophenoxy)methyl]-1h-quinolin-6-yl]phenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(C=2)[N+]([O-])=O)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1 MSKLIAMYHIJSHE-UHFFFAOYSA-N 0.000 claims description 2
- NARMUGMVXIUQMJ-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] 1,3-thiazole-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CSC=N1 NARMUGMVXIUQMJ-UHFFFAOYSA-N 0.000 claims description 2
- LQXSLCUCYKJTDQ-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] 2-methoxypyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CN=C1OC LQXSLCUCYKJTDQ-UHFFFAOYSA-N 0.000 claims description 2
- JZMLROKBPNGWMT-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] 2-methylpyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CN=C1C JZMLROKBPNGWMT-UHFFFAOYSA-N 0.000 claims description 2
- DHDNRMSJHVAIMR-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] 3-methylfuran-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C=1OC=CC=1C DHDNRMSJHVAIMR-UHFFFAOYSA-N 0.000 claims description 2
- IHTYHBYTSDBHNM-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] 6-methylpyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=C(C)N=C1 IHTYHBYTSDBHNM-UHFFFAOYSA-N 0.000 claims description 2
- NMGGVEIYVVDIHL-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] furan-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C=1C=COC=1 NMGGVEIYVVDIHL-UHFFFAOYSA-N 0.000 claims description 2
- GIZUWOWXEQAHTG-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] morpholine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)N1CCOCC1 GIZUWOWXEQAHTG-UHFFFAOYSA-N 0.000 claims description 2
- ZCZVUUGAANFGKX-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CN=C1 ZCZVUUGAANFGKX-UHFFFAOYSA-N 0.000 claims description 2
- NLSFZQSFBMZTPN-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] pyridine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=NC=C1 NLSFZQSFBMZTPN-UHFFFAOYSA-N 0.000 claims description 2
- XGGSAIQPWMLKDL-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxy-5-nitrophenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] cyclopropanesulfonate Chemical compound COC1=CC=C([N+]([O-])=O)C=C1OCC1=C(C=2C(=CC(OS(=O)(=O)C3CC3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 XGGSAIQPWMLKDL-UHFFFAOYSA-N 0.000 claims description 2
- POERGSQZEMSOJN-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxy-5-nitrophenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] thiophene-3-carboxylate Chemical compound COC1=CC=C([N+]([O-])=O)C=C1OCC1=C(C=2C(=CC(OC(=O)C3=CSC=C3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 POERGSQZEMSOJN-UHFFFAOYSA-N 0.000 claims description 2
- VKICKJDHBUZHOA-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 2-chlorobenzoate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C(=CC=CC=3)Cl)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 VKICKJDHBUZHOA-UHFFFAOYSA-N 0.000 claims description 2
- SWSGZJOLYPMITI-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 2-fluorobenzoate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C(=CC=CC=3)F)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 SWSGZJOLYPMITI-UHFFFAOYSA-N 0.000 claims description 2
- FDLDWJJDQMLCML-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 2-methoxypyridine-3-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C(=NC=CC=3)OC)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 FDLDWJJDQMLCML-UHFFFAOYSA-N 0.000 claims description 2
- FZLVALQWUJPDKI-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 2-methylpyridine-3-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C(=NC=CC=3)C)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 FZLVALQWUJPDKI-UHFFFAOYSA-N 0.000 claims description 2
- QCDCEKIZUNBXHK-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 3-methylfuran-2-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C3=C(C=CO3)C)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 QCDCEKIZUNBXHK-UHFFFAOYSA-N 0.000 claims description 2
- WZTMYQCFENJEBZ-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 4-fluorobenzoate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C=CC(F)=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 WZTMYQCFENJEBZ-UHFFFAOYSA-N 0.000 claims description 2
- KBYUELDOSLOVBH-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] benzoate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C=CC=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 KBYUELDOSLOVBH-UHFFFAOYSA-N 0.000 claims description 2
- SOSBJDLVERJQCQ-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] furan-3-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C3=COC=C3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 SOSBJDLVERJQCQ-UHFFFAOYSA-N 0.000 claims description 2
- FVHCWWUOQIGTJE-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] methanesulfonate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OS(C)(=O)=O)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 FVHCWWUOQIGTJE-UHFFFAOYSA-N 0.000 claims description 2
- ZQWMUCLWNLKPBT-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] morpholine-4-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)N3CCOCC3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 ZQWMUCLWNLKPBT-UHFFFAOYSA-N 0.000 claims description 2
- MNCIKIARUFHKGN-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] pyridine-3-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C=NC=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 MNCIKIARUFHKGN-UHFFFAOYSA-N 0.000 claims description 2
- SHWGFMPNJCLOJQ-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] pyridine-4-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3C=CN=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 SHWGFMPNJCLOJQ-UHFFFAOYSA-N 0.000 claims description 2
- OPYMCPHOVNKJJK-UHFFFAOYSA-N [4-[5-[(5-bromothiophene-2-carbonyl)oxymethyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] furan-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(Br)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CO1 OPYMCPHOVNKJJK-UHFFFAOYSA-N 0.000 claims description 2
- KIRUMWWSSPEAEQ-UHFFFAOYSA-N [4-[5-[(5-bromothiophene-2-carbonyl)oxymethyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(Br)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CN=C1 KIRUMWWSSPEAEQ-UHFFFAOYSA-N 0.000 claims description 2
- JHVNWKGDRLRANQ-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-chlorobenzoate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CC=C1Cl JHVNWKGDRLRANQ-UHFFFAOYSA-N 0.000 claims description 2
- SIUHZCNHXMSKFP-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-methoxypyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1OC SIUHZCNHXMSKFP-UHFFFAOYSA-N 0.000 claims description 2
- XBGFEIRYBTYBER-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-methylpyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1C XBGFEIRYBTYBER-UHFFFAOYSA-N 0.000 claims description 2
- PTCAQLSKMAJKHR-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 3-methylfuran-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C=1OC=CC=1C PTCAQLSKMAJKHR-UHFFFAOYSA-N 0.000 claims description 2
- XPHLYBMZLDVDNY-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] furan-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CO1 XPHLYBMZLDVDNY-UHFFFAOYSA-N 0.000 claims description 2
- RMEIFGARBIWQSK-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1 RMEIFGARBIWQSK-UHFFFAOYSA-N 0.000 claims description 2
- BQCNGDSUKMITQP-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] pyridine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)CNC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=NC=C1 BQCNGDSUKMITQP-UHFFFAOYSA-N 0.000 claims description 2
- CAPDCIWMXQZDJC-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 1,3-thiazole-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CSC=N1 CAPDCIWMXQZDJC-UHFFFAOYSA-N 0.000 claims description 2
- UCDWKEWGRJHSHN-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2,2-dimethylpropanoate Chemical compound COC1=CC(OC(=O)C(C)(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C UCDWKEWGRJHSHN-UHFFFAOYSA-N 0.000 claims description 2
- PDPHMPNWNMKUNX-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-acetyloxybenzoate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CC=C1OC(C)=O PDPHMPNWNMKUNX-UHFFFAOYSA-N 0.000 claims description 2
- BNWWSYHPBMQDAH-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-chlorobenzoate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CC=C1Cl BNWWSYHPBMQDAH-UHFFFAOYSA-N 0.000 claims description 2
- QBTBKGGCWLNNTM-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-chloropyridine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=NC(Cl)=C1 QBTBKGGCWLNNTM-UHFFFAOYSA-N 0.000 claims description 2
- AXZXHTOMPSJADL-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-fluorobenzoate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CC=C1F AXZXHTOMPSJADL-UHFFFAOYSA-N 0.000 claims description 2
- LKRRTDIHHZDPRH-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 2-methylpyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1C LKRRTDIHHZDPRH-UHFFFAOYSA-N 0.000 claims description 2
- BTAPJNXIVWYZMY-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 3-methylfuran-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C=1OC=CC=1C BTAPJNXIVWYZMY-UHFFFAOYSA-N 0.000 claims description 2
- YBIGGGDFXNMGJZ-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 5-methylfuran-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=C(C)O1 YBIGGGDFXNMGJZ-UHFFFAOYSA-N 0.000 claims description 2
- BCGQEKMQONEUJQ-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 6-methylpyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=C(C)N=C1 BCGQEKMQONEUJQ-UHFFFAOYSA-N 0.000 claims description 2
- FLVLHPZPJWWWSS-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] butane-1-sulfonate Chemical compound COC1=CC(OS(=O)(=O)CCCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C FLVLHPZPJWWWSS-UHFFFAOYSA-N 0.000 claims description 2
- JTSBVCRAZWJVKL-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] butanoate Chemical compound COC1=CC(OC(=O)CCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C JTSBVCRAZWJVKL-UHFFFAOYSA-N 0.000 claims description 2
- OPUNVORGNKXRCX-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] cyclopropanesulfonate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OS(=O)(=O)C1CC1 OPUNVORGNKXRCX-UHFFFAOYSA-N 0.000 claims description 2
- XHRRPOWOIJQQBU-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] ethanesulfonate Chemical compound COC1=CC(OS(=O)(=O)CC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C XHRRPOWOIJQQBU-UHFFFAOYSA-N 0.000 claims description 2
- MQHGWZXZNWRXRE-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] furan-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CO1 MQHGWZXZNWRXRE-UHFFFAOYSA-N 0.000 claims description 2
- PYWYJOHCULWIEG-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] furan-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C=1C=COC=1 PYWYJOHCULWIEG-UHFFFAOYSA-N 0.000 claims description 2
- COVBQWCPJSZFHY-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] morpholine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)N1CCOCC1 COVBQWCPJSZFHY-UHFFFAOYSA-N 0.000 claims description 2
- DTRXUPOYAPPEFM-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] n-[2-(dimethylamino)ethyl]-n-ethylcarbamate Chemical compound COC1=CC(OC(=O)N(CCN(C)C)CC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C DTRXUPOYAPPEFM-UHFFFAOYSA-N 0.000 claims description 2
- UPJVLHVFNRZGNR-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=CN=C1 UPJVLHVFNRZGNR-UHFFFAOYSA-N 0.000 claims description 2
- QTYOCUDKASYSHN-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] pyridine-4-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C1=CC=NC=C1 QTYOCUDKASYSHN-UHFFFAOYSA-N 0.000 claims description 2
- ADQWTIGVVAOBMO-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] thiophene-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)C(OC)=CC=1OC(=O)C=1C=CSC=1 ADQWTIGVVAOBMO-UHFFFAOYSA-N 0.000 claims description 2
- OYSSSSZZOBPPND-UHFFFAOYSA-N [6-(2-methoxy-4-propan-2-ylsulfonyloxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC(OS(=O)(=O)C(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC(=O)C1=CC=C(C)S1 OYSSSSZZOBPPND-UHFFFAOYSA-N 0.000 claims description 2
- VYQLOCIJGGTOBS-UHFFFAOYSA-N [6-(2-methoxy-4-propylsulfonyloxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC(OS(=O)(=O)CCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC(=O)C1=CC=C(C)S1 VYQLOCIJGGTOBS-UHFFFAOYSA-N 0.000 claims description 2
- ACYOMMYDCFDNRU-UHFFFAOYSA-N [6-(4-benzoyloxy-2-methoxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1 ACYOMMYDCFDNRU-UHFFFAOYSA-N 0.000 claims description 2
- WVSNRFDBAMOMRY-UHFFFAOYSA-N [6-(4-cyclopentylsulfonyloxy-2-methoxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OS(=O)(=O)C1CCCC1 WVSNRFDBAMOMRY-UHFFFAOYSA-N 0.000 claims description 2
- JDDCGXKXDKXZQS-UHFFFAOYSA-N [6-(4-cyclopropylsulfonyloxy-2-methoxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OS(=O)(=O)C1CC1 JDDCGXKXDKXZQS-UHFFFAOYSA-N 0.000 claims description 2
- NXMKIPVEUBFWCU-UHFFFAOYSA-N [6-(4-ethylsulfonyloxy-2-methoxyphenyl)-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC(OS(=O)(=O)CC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC(=O)C1=CC=C(C)S1 NXMKIPVEUBFWCU-UHFFFAOYSA-N 0.000 claims description 2
- VRXOYIJPPPTYID-UHFFFAOYSA-N [6-[2-methoxy-4-(2-methoxybenzoyl)oxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC=CC=C1C(=O)OC1=CC=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=C1 VRXOYIJPPPTYID-UHFFFAOYSA-N 0.000 claims description 2
- GXQZBDPJBRYSQH-UHFFFAOYSA-N [6-[2-methoxy-4-(2-methylbenzenecarbothioyl)oxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=S)C1=CC=CC=C1C GXQZBDPJBRYSQH-UHFFFAOYSA-N 0.000 claims description 2
- AZEUKYBBBCQBKN-UHFFFAOYSA-N [6-[2-methoxy-4-(2-methylbenzoyl)oxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1C AZEUKYBBBCQBKN-UHFFFAOYSA-N 0.000 claims description 2
- OAHKGRWBQALFHZ-UHFFFAOYSA-N [6-[2-methoxy-4-(2-methylpropanoyloxy)phenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC(OC(=O)C(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC(=O)C1=CC=C(C)S1 OAHKGRWBQALFHZ-UHFFFAOYSA-N 0.000 claims description 2
- VPHMEHSQAWJYSE-UHFFFAOYSA-N [6-[2-methoxy-4-(2-nitrobenzoyl)oxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1[N+]([O-])=O VPHMEHSQAWJYSE-UHFFFAOYSA-N 0.000 claims description 2
- XHCHARRVIFDJQM-UHFFFAOYSA-N [6-[2-methoxy-4-(3,3,3-trifluoropropylsulfonyloxy)phenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound COC1=CC(OS(=O)(=O)CCC(F)(F)F)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC(=O)C1=CC=C(C)S1 XHCHARRVIFDJQM-UHFFFAOYSA-N 0.000 claims description 2
- ATMAOWUYFDZWJY-UHFFFAOYSA-N [6-[2-methoxy-4-(thiophene-3-carbonyloxy)phenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C=1C=CSC=1 ATMAOWUYFDZWJY-UHFFFAOYSA-N 0.000 claims description 2
- XRCCMBHHKLLVKN-UHFFFAOYSA-N [6-[4-(2-acetyloxybenzoyl)oxy-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1OC(C)=O XRCCMBHHKLLVKN-UHFFFAOYSA-N 0.000 claims description 2
- MVRMNJHWHRKCJW-UHFFFAOYSA-N [6-[4-(2-chlorobenzoyl)oxy-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1Cl MVRMNJHWHRKCJW-UHFFFAOYSA-N 0.000 claims description 2
- RLNTWLMTKQPNSA-UHFFFAOYSA-N [6-[4-(2-fluorobenzoyl)oxy-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CC=C1F RLNTWLMTKQPNSA-UHFFFAOYSA-N 0.000 claims description 2
- VGAUKLPKTADDBY-UHFFFAOYSA-N [6-[4-(4-chlorobenzoyl)oxy-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=C(Cl)C=C1 VGAUKLPKTADDBY-UHFFFAOYSA-N 0.000 claims description 2
- BSBNNJHDSWXFHP-UHFFFAOYSA-N [6-[4-(4-fluorobenzoyl)oxy-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=C(F)C=C1 BSBNNJHDSWXFHP-UHFFFAOYSA-N 0.000 claims description 2
- CYAZSZCOXLUDNV-UHFFFAOYSA-N [6-[4-[(4-chlorophenyl)carbamoyloxy]-2-methoxyphenyl]-2,2,4-trimethyl-1h-quinolin-5-yl]methyl 5-methylthiophene-2-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2SC(C)=CC=2)C(OC)=CC=1OC(=O)NC1=CC=C(Cl)C=C1 CYAZSZCOXLUDNV-UHFFFAOYSA-N 0.000 claims description 2
- IUNIOJJIYLIUGC-UHFFFAOYSA-N o-[3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] 2-methylbenzenecarbothioate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=S)C=3C(=CC=CC=3)C)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 IUNIOJJIYLIUGC-UHFFFAOYSA-N 0.000 claims description 2
- DBUNUYNOLHVAEL-UHFFFAOYSA-N 3-o-[4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 1-o-methyl benzene-1,3-dicarboxylate Chemical compound COC(=O)C1=CC=CC(C(=O)OC=2C=C(OC)C(=CC=2)C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)=C1 DBUNUYNOLHVAEL-UHFFFAOYSA-N 0.000 claims 1
- NKCGNPTXGXUNGK-UHFFFAOYSA-N [3-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-4-methoxyphenyl] propanoate Chemical compound CCC(=O)OC1=CC=C(OC)C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC=2C(=CC=C(F)C=2)C)=C1 NKCGNPTXGXUNGK-UHFFFAOYSA-N 0.000 claims 1
- NXANKGXYYYNWFM-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(4-methylbenzoyl)oxymethyl]-1h-quinolin-6-yl]phenyl] pyridine-3-carboxylate Chemical compound C=1C=C(C=2C(=C3C(C)=CC(C)(C)NC3=CC=2)COC(=O)C=2C=CC(C)=CC=2)C(OC)=CC=1OC(=O)C1=CC=CN=C1 NXANKGXYYYNWFM-UHFFFAOYSA-N 0.000 claims 1
- MIYGXFIBFAABCB-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] propane-1-sulfonate Chemical compound COC1=CC(OS(=O)(=O)CCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1CNC1=CC=CC=C1OC MIYGXFIBFAABCB-UHFFFAOYSA-N 0.000 claims 1
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Abstract
Description
R2−O−は、ベンゼン環Aの4又は5位に置換し;
R3は低級アルキル基を示し;
R4、R5、R6又はR7は、ハロゲン原子、置換基を有してもよい低級アルキル基、低級アルケニル基、低級アルキニル基、低級アルコキシ基、ニトロ基又はホルミル基を示し;
m、n、p又はqは、0、1又は2を示し;
m、n、p又はqが2を示す場合、各R4、R5、R6又はR7は同一又は異なっていてもよく;
R8、R9、R10又はR11は、置換基を有してもよい低級アルキル基、低級アルケニル基、低級シクロアルキル基、置換基を有してもよいアリール基又は置換基を有してもよい複素環基を示し;
R12及びR13は同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又は複素環基を示す。以下、同じ。]
本明細書中で使用される文言(原子、基等)の定義について以下に詳しく説明する。また、以下の文言の定義が別の文言の定義に準用される場合、各定義の好ましい範囲及び特に好ましい範囲も準用する。
ハロゲン原子、低級シクロアルキル基、アリール基、複素環基、低級アルコキシ基及び-NRaRb。
ハロゲン原子、アリール基、複素環基、低級アルコキシ基及び-NRaRb。
ハロゲン原子、低級アルキル基、ヒドロキシ基、低級アルコキシ基、メルカプト基、低級アルキルチオ基、ホルミル基、低級アルキルカルボニル基、カルボキシ基、低級アルコキシカルボニル基、低級アルキルカルボニルオキシ基、ニトロ基及びシアノ基。
ハロゲン原子、低級アルキル基、低級アルコキシ基、低級アルキルチオ基、低級アルキルカルボニル基、低級アルコキシカルボニル基、低級アルキルカルボニルオキシ基、ニトロ基及びシアノ基。
水素原子、低級アルキル基及び低級アルコキシカルボニル基。
水素原子及び低級アルキル基。
(A3)R2−O−は、ベンゼン環Aの4又は5位に置換し;及び/又は
(A4)R3は低級アルキル基を示し;及び/又は
(A5)R4、R5、R6又はR7は、ハロゲン原子、置換基を有してもよい低級アルキル基、低級アルケニル基、低級アルキニル基、低級アルコキシ基、ニトロ基又はホルミル基を示し;及び/又は
(A6)m、n、p又はqは、0、1又は2を示し;及び/又は
(A7)m、n、p又はqが2を示す場合、各R4、R5、R6又はR7は同一又は異なっていてもよく;及び/又は
(A8)R8、R9、R10又はR11は、置換基を有してもよい低級アルキル基、低級アルケニル基、低級シクロアルキル基、置換基を有してもよいアリール基又は置換基を有してもよい複素環基を示し;及び/又は
(A9)R12及びR13は同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又は複素環基を示す。
(B3)R2−O−がベンゼン環Aの4又は5位に置換し;及び/又は
(B4)R3が低級アルキル基を示し;及び/又は
(B5)R4がハロゲン原子、低級アルキル基、低級アルコキシ基又はニトロ基を示し;及び/又は
(B6)R5がハロゲン原子、低級アルキル基又は低級アルコキシ基を示し;及び/又は
(B7)R6がハロゲン原子、低級アルキル基又は低級アルコキシ基を示し;及び/又は
(B8)R7がハロゲン原子又は低級アルキル基を示し;及び/又は
(B9)m、n又はpが1又は2を示し;及び/又は
(B10)m、n又はpが2を示す場合、各R4、R5又はR6は同一又は異なっていてもよく;及び/又は
(B11)qが1を示し;及び/又は
(B12)R8が置換基を有してもよい低級アルキル基、低級アルケニル基、低級シクロアルキル基、置換基を有してもよいアリール基又は置換基を有してもよい複素環基を示し;及び/又は
(B13)R9が置換基を有してもよい低級アルキル基又は置換基を有してもよいアリール基を示し;及び/又は
(B14)R10又はR11が、置換基を有してもよい低級アルキル基又は低級シクロアルキル基を示し;及び/又は
(B15)R12及びR13が同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又は複素環基を示す。
参考例1
5−ヒドロキシメチル−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物1−1)
2−(2,4−ジメトキシフェニル)−5−ニトロ安息香酸メチル(参考化合物1−1−(1))
2,4−ジメトキシフェニルボロン酸(25.0g、137mmol)、2−ブロモ−5−ニトロ安息香酸メチル(35.7g、137mmol)、炭酸セシウム(89.4g、274mmol)及び二塩化ビス(トリフェニルホスフィン)パラジウム(II)(4.81g、6.85mmol)の混合物をN,N−ジメチルホルムアミド(450mL)に懸濁し、アルゴン窒素雰囲気下、80℃で一晩攪拌した。放冷後、酢酸エチル(200mL)、ジエチルエーテル(400mL)及び水(1000mL)を加えて分配した。水層を酢酸エチル(150mL)−ジエチルエーテル(150mL)の混合溶媒で抽出(2回)した。有機層を合わせて、水(500mL、3回)及び飽和食塩水(500mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより標記参考化合物を褐色油状物として得た。(定量的)
2−(2,4−ジメトキシフェニル)−5−ニトロ安息香酸メチル(参考化合物1−1−(1)、43.5g、137mmol)の無水塩化メチレン(250mL)溶液を−78℃に冷却し、三臭化ホウ素(96.2g、384mmol)を滴下後、室温で1時間攪拌した。−50℃に冷却し、メタノール(300mL)を加えた。析出物をメタノールでろ取することにより標記参考化合物(18.0g)を黄色固体として得た。(収率51%)
3−ヒドロキシ−8−ニトロベンゾ[c]クロメン−6−オン(参考化合物1−1−(2)、52.01g、202mmol)をメタノール(150mL)−N,N−ジメチルホルムアミド(600mL)に溶解し、10%パラジウム−炭素(5.00g)を加え、加圧(3kgf/cm2)水素雰囲気下、室温で一晩攪拌した。不溶物を濾去した後、減圧下メタノールを留去した。残留物に水(2L)を加えた。析出した固体を濾取し、減圧下90℃で乾燥することにより標記参考化合物(44.02g)を淡黄色固体として得た。(収率96%)
耐圧管中で、8−アミノ−3−ヒドロキシベンゾ[c]クロメン−6−オン(参考化合物1−1−(3)、40.0g、176mmol)をアセトン(440mL)−N−メチルピロリドン(240mL)に溶解し、よう素(17.9g、70.5mmol)を加え密封した後、110℃で3日間攪拌した。放冷後、減圧下アセトンを留去した。得られた残留物に酢酸エチル(700mL)、ヘキサン(150mL)及び1%チオ硫酸ナトリウム水溶液(700mL)を加えて分配した。水層を酢酸エチル(250mL)−ヘキサン(50mL)の混合溶媒で抽出(3回)した。有機層を合わせて、水(500mL、3回)及び飽和食塩水(500mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物にクロロホルム(150mL)を加え不溶物を濾去した。濾液を濃縮した後、シリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(26.0g)を黄色固体として得た。(収率48%)
8−ヒドロキシ−2,2,4−トリメチル−1,2−ジヒドロ−6−オキサ−1−アザクリセン−5−オン(参考化合物1−1−(4)、1.00g、3.25mmol)、クロロジメチルエーテル(420μl、5.53mmol)及び炭酸カリウム(1.35g、9.77mmol)の混合物を無水N,N−ジメチルホルムアミド(15mL)に懸濁し、50℃で一晩攪拌した。放冷後、酢酸エチル(100mL)及びジエチルエーテル(100mL)を加えた。水(150mL、100mL)及び飽和食塩水(100mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(747mg)を黄色固体として得た。(収率66%)
水素化リチウムアルミニウム(167mg、4.40mmol)を無水テトラヒドロフラン(3mL)に懸濁した。0℃で8−メトキシメトキシ−2,2,4−トリメチル−1,2−ジヒドロ−6−オキサ−1−アザクリセン−5−オン(参考化合物1−1−(5)、744.1mg、2.12mmol)の無水テトラヒドロフラン(10mL)溶液を滴下し、同温で30分間攪拌した。反応液に酢酸エチル(2mL)及び水(1mL)を順次滴下した後、酢酸エチル(150mL)を加えた。1規定塩酸(6mL)を加えた後、水(100mL、2回)及び飽和食塩水(50mL)で順次洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去することにより標記参考化合物(750.6mg)を淡黄色アモルファスとして得た。(定量的)
6−(2−ヒドロキシ−4−メトキシメトキシフェニル)−5−ヒドロキシメチル−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物1−1−(6)、746.1mg、2.10mmol)、よう化メチル(131μl、2.10mmol)及び炭酸カリウム(582mg、4.21mmol)の混合物を無水N,N−ジメチルホルムアミド(10mL)に懸濁し、50℃で1時間攪拌した。放冷後、酢酸エチル(50mL)及びジエチルエーテル(50mL)を加え希釈した。水(100mL、2回)及び飽和食塩水(50mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(513.2mg)を無色固体として得た。(収率66%)
5−クロロメチル−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物2)
5−ヒドロキシメチル−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物1−1、1.02g、2.76mmol)を無水ジクロロメタン(10mL)に溶解し、トリエチルアミン(0.490mL、3.52mmol)及び塩化メタンスルホニル(231μL、2.98mmol)を順次加えた。反応液を室温で5時間攪拌した。反応液にクロロホルム(50mL)及び水(50mL)を加えて分配した。有機層を飽和食塩水(50mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(515mg)を橙色アモルファスとして得た。(収率49%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物3−1)
5−ヒドロキシメチル−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物1−1、511.7mg、1.39mmol)、5−フルオロ−2−メチルフェノール(182μL、1.67mmol)、トリ−n−ブチルホスフィン(521μL、2.09mmol)、1,1’−(アゾジカルボニル)ジピペリジン(526mg、2.08mmol)を無水ベンゼン(8mL)に溶解し、アルゴン雰囲気下、室温で1時間攪拌した。反応液にヘキサン(15mL)を加えて、不溶物をろ去した。ろ液を減圧下濃縮し、残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(411.4mg)を無色アモルファスとして得た。(収率62%)
6−(2−メトキシ−4−メトキシメトキシフェニル)−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物4−1)
5−クロロメチル−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物2、262mg、0.675mmol)、2−メトキシアニリン(84μL、0.74mmol)及び炭酸カリウム(151mg、1.09mmol)の混合物を無水N,N−ジメチルホルムアミド(4mL)に懸濁し、80℃で一晩攪拌した。放冷後、酢酸エチル(20mL)及び水(20mL)を加えて分配した。有機層を飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(196mg)を黄色アモルファスとして得た。(収率61%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−メトキシメトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物3−1、424mg、0.888mmol)を1,4−ジオキサン(5mL)に溶解し、4規定塩化水素/1,4−ジオキサン(666μL)を加え、室温で一晩攪拌した。酢酸エチル(150mL)を加え希釈した。水(100mL、2回)及び飽和食塩水(50mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(241.7mg)を無色固体として得た。(収率63%)
6−(4−ヒドロキシ−2−メトキシフェニル)−5−[N−(2−メトキシフェニル)−N−(9−フルオレニルメトキシカルボニル)アミノメチル]−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物6)
6−(4−ヒドロキシ−2−メトキシフェニル)−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−10、37.7mg、0.0876mmol)及び炭酸水素ナトリウム(9.5mg、0.113mmol)を1,4−ジオキサン(0.5mL)−水(0.5mL)に溶解し、氷冷下、塩化9−フルオレニルメトキシカルボニル(25.6mg、0.0990mmol)を加えた。反応液を室温で3時間攪拌した後、酢酸エチル(10mL)を加え希釈した。1規定塩酸(10mL)、水(10mL)及び飽和食塩水(10mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記参考化合物(19.7mg)を無色アモルファスとして得た。(収率34%)
6−(4−ベンゾイルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物1−1)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、25.5mg、0.588mmol)を無水テトラヒドロフラン(0.5mL)に溶解し、トリエチルアミン(19.7μl、0.141mmol)及び塩化ベンゾイル(8.2μl、0.071mmol)を加えた。反応液を室温で30分間攪拌した。反応液に酢酸エチル(100mL)を加え希釈した。水(100mL)、飽和食塩水(50mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(26.7mg)を無色固体として得た。(収率63%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、30.2mg、0.070mmol)、Boc−グリシン(15.1mg、0.086mmol)をN,N−ジメチルホルムアミド(1ml)に溶解し、N,N−ジイソプロピルエチルアミン(31.4μl、0.18mmol)とO−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェート(35.4mg、0.093mmol)を加え、室温で一晩攪拌した。反応液に酢酸エチル(10ml)を加え、水(10ml)、飽和食塩水(10ml)で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(35.3mg)を無色アモルファスとして得た。(収率86%)
6−(4−ヒドロキシ−2−メトキシフェニル)−5−[N−(2−メトキシフェニル)−N−(9−フルオレニルメトキシカルボニル)アミノメチル]−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物6、17.4mg、0.0267mmol)をジクロロメタン(0.5mL)に溶解し、トリエチルアミン(10μL、0.072mmol)及び塩化2−フロイル(3.6μL、0.036mmol)を順次加えた。反応液を室温で3時間攪拌した後、シリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製し無色アモルファス(15.6mg)を得た。得られた無色アモルファス(11.8mg)をN,N−ジメチルホルムアミド(0.3mL)に溶解し、ピペリジン(15.6μL、0.158mmol)を加えた。反応液を室温で1分間攪拌した後、酢酸エチル(10mL)で希釈した。水(10mL)及び飽和食塩水(10mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(6.0mg)を無色固体として得た。(収率76%)
6−(5−アセトキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物2)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(5−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−2、62.5mg、0.14mmol)、トリエチルアミン(154μL、1.11mmol)を無水ジクロロメタン(1mL)に溶解し、無水酢酸(52μL、0.55mmol)を加え、室温で1.5時間攪拌した。反応液にクロロホルム(10mL)を加え、水(10mL)及び飽和食塩水(300mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(56.6mg)を無色アモルファスとして得た。(収率83%)
6−(4−アミノアセトキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン・1塩酸塩(化合物3−1)
6−(4−t−ブトキシカルボニルアミノアセトキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物1−2、20.1mg、0.034mmol)を1,4−ジオキサン(0.5mL)に溶解し、4規定塩化水素/1,4−ジオキサン溶液(34μL)を加え、室温で一晩攪拌した。反応液を減圧下濃縮することにより標記化合物(17.5mg)を無色固体として得た。(収率98%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−メチルスルホニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物4−1)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、61.0mg、0.141mmol)を塩化メチレン(2mL)に溶解し、塩化メタンスルホニル(26μL、0.34mmol)、トリエチルアミン(92μL、0.66mmol)を加え、室温で一晩撹拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(58.0mg)を淡桃色固体として得た。(収率82%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−メトキシカルボニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物5−1)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、25.0mg、0.058mmol)をテトラヒドロフラン(0.5mL)に溶解し、トリエチルアミン(23μL、0.17mmol)、クロロ炭酸メチル(6.8μL、0.088mmol)を加え、室温で20分間撹拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(28.0mg)を無色アモルファスとして得た。(収率99%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−フェニルアミノカルボニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(化合物6−1)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、25.0mg、0.058mmol)をテトラヒドロフラン(0.5mL)に溶解し、トリエチルアミン(19.3μL、0.138mmol)、イソシアン酸フェニル(9.5μL、0.087mmol)を加え、室温で2時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(27.3mg)を無色アモルファスとして得た。(収率86%)
6−(4−ヒドロキシ−2−メトキシフェニル)−5−[N−(2−メトキシフェニル)−N−(9−フルオレニルメトキシカルボニル)アミノメチル]−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物6、25.0mg、0.0383mmol)、1,1’−カルボニルジイミダゾール(62.0mg、0.382mmol)及び4−ジメチルアミノピリジン(0.5mg、0.004mmol)の混合物を無水テトラヒドロフラン(1mL)に溶解し、室温で4.5時間攪拌した。N,N,N’−トリメチルエチレンジアミン(39.2mg、0.383mmol)を加え、60℃で2時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製した。得られた無色アモルファスをN,N−ジメチルホルムアミド(1mL)に溶解し、ピペリジン(50μL)を加えた。反応液を室温で15分間攪拌した後、酢酸エチル(20mL)で希釈した。水(15mL)及び飽和食塩水(15mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(ヘキサン−酢酸エチル)で精製することにより標記化合物(9.9mg)を無色アモルファスとして得た。(収率47%)
5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−ヒドロキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン(参考化合物5−1、25mg、0.058mmol)をピリジン(1mL)に溶解し、塩化N,Nージメチルカルバモイル(6.9μL、0.075mmol)を加え、100℃で3時間撹拌した。反応液に塩化N,Nージメチルカルバモイル(3.0μL、0.033mmol)を加え、100℃にて1時間攪拌した。反応液を酢酸エチル(20mL)で希釈した。0.2規定塩酸(75mL)、水(50mL)及び飽和食塩水(50mL)で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー(1回目:ヘキサン−酢酸エチル、2回目:トルエンー酢酸エチル)で精製することにより標記化合物(8.5mg)を無色アモルファスとして得た。(収率29%)
以下に本化合物を含む一般的な製剤例を示す。
1)錠剤(150mg中)
本化合物 1mg
乳糖 100mg
トウモロコシデンプン 40mg
カルボキシメチルセルロースカルシウム 4.5mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 0.5mg
上記処方の錠剤にコーティング剤(例えば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等の通常のコーティング剤)3mgを用いてコーティングを施し、目的とする錠剤を得ることができる。また、本化合物並びに添加物の種類及び/又は量を適宜変更することで、所望の錠剤を得ることもできる。
2)カプセル剤(150mg中)
本化合物 5mg
乳糖 135mg
カルボキシメチルセルロースカルシウム 4.5mg
ヒドロキシプロピルセルロース 4mg
ステアリン酸マグネシウム 1.5mg
本化合物並びに添加剤の種類及び又は量を適宜変更することで、所望のカプセル剤を得ることができる。
3)点眼剤(100ml中)
本化合物 100mg
塩化ナトリウム 900mg
ポリソルベート80 500mg
水酸化ナトリウム 適量
塩酸 適量
滅菌精製水 適量
本化合物及び添加物の種類及び/又は量を適宜変更することで、所望の点眼剤を得ることができる。
1.GR結合活性評価試験
本化合物のGRに対する結合活性を評価するために、偏光蛍光法によるGR受容体競合アッセイを実施した。アッセイにはGR競合アッセイキット(Invitrogen社製、Cat No.P2816)を使用して、本キットに添付のプロットコールに準じて行った。以下にその具体的な方法を記載する。
GRスクリーニング緩衝液:10mM リン酸カリウム(pH 7.4)、20mM モリブデン酸ナトリウム(Na2MoO4)、0.1mM エチレンジアミン四酢酸(以下、「EDTA」とする)、5mM ジチオスレイトール(DTT)、0.1mM 安定化ペプチド及び2% ジメチルスルホキシドの緩衝液となるよう調製した。
被験化合物をジメチルスルホキシドに溶解後、GRスクリーニング緩衝液で希釈し、20μMの被験化合物溶液を調製した。
1) 384穴プレートに被験化合物溶液を1ウェルあたり10μLずつ注入し、次いで、4×GS1溶液及び4×GR溶液を1ウェルあたり各々5μLずつ添加した。
GR結合率(%)は以下の式により算出した。
(試験結果及び考察)
試験結果の一例として、化合物1−3、化合物1−6、化合物1−7、化合物1−8、化合物1−9、化合物1−12、化合物1−13、化合物1−14、化合物1−15、化合物1−17、化合物1−18、化合物1−19、化合物1−25、化合物1−33、化合物1−36、化合物1−38、化合物1−40、化合物1−45、化合物1−48、化合物1−49、化合物1−54、化合物1−55、化合物1−57、化合物1−58、化合物1−68、化合物1−69、化合物1−72、化合物1−81、化合物1−91、化合物1−92、化合物1−95、化合物1−97、化合物1−98、化合物1−99、化合物1−101、化合物1−102、化合物1−104、化合物1−105、化合物1−106、化合物1−107、化合物1−110、化合物1−111、化合物1−114、化合物1−117、化合物1−119、化合物1−122、化合物1−125、化合物1−126、化合物1−128、化合物1−133、化合物1−136、化合物1−137、化合物1−138、化合物1−139、化合物1−141、化合物1−142、化合物1−143、化合物1−144、化合物1−147、化合物1−148、化合物1−151、化合物1−153、化合物1−155、化合物1−156、化合物1−157、化合物1−160、化合物1−162、化合物1−164、化合物1−165、化合物1−166、化合物1−169、化合物1−170、化合物1−171、化合物4−3、化合物4−4、化合物4−5、化合物4−6、化合物4−8、化合物4−11、化合物4−12、化合物4−14、化合物4−18、化合物4−20、化合物4−21、化合物4−26、化合物4−27、化合物4−29、化合物4−30、化合物4−32、化合物4−34、化合物6−3、化合物6−20、化合物6−26、化合物6−27、化合物6−31、化合物6−33、化合物6−35又は化合物6−37を被験化合物として使用した場合の試験結果を以下に示す。
本化合物のGRアゴニストとしての作用を評価するために、LPS刺激後のヒト角膜上皮細胞株におけるIL-6産生抑制作用を検討した。サンプル中のIL-6産生量の測定にはHTRF法(Boehringer-Ingelheim社製、Cat No.62IL6PEB)を使用し、添付のプロトコールに準じて行った。以下にその具体的な方法を記載する。
LPS調製液:LPSをリン酸緩衝生理食塩液(以下、「PBS(-)」とする)に溶解後、培養液で希釈して1 μg/mL LPS溶液を調製した。
被験化合物をジメチルスルホキシド(以下、「DMSO」とする)に溶解後、培養液で希釈して100μMの被験化合物溶液を調製した。また、DEXを同様に溶解して100μM DEX溶液を調製し、DEXのIL-6産生抑制率を測定し、Efficacy(%DEX)の算出に用いた。
使用細胞:ヒト角膜上皮細胞株(HCE-T)(理化学研究所)
培養方法:
1) サブコンフルエントな状態まで増殖したHCE-TをPBS(-)で洗浄、trypsin-EDTA処理により細胞を剥離した。
1) 継代培養したHCE-Tを回収し、96穴平底培養プレートに細胞を2.0×104cells/0.1mL/wellずつ播種した。
IL-6産生抑制率(%)は以下の式により算出した。
さらに、DEX処置群を100としたときのIL-6産生抑制率(Efficacy(%DEX))を算出した。
(試験結果及び考察)
試験結果の一例として、化合物1−3、化合物1−6、化合物1−7、化合物1−8、化合物1−9、化合物1−12、化合物1−13、化合物1−14、化合物1−15、化合物1−17、化合物1−18、化合物1−19、化合物1−25、化合物1−33、化合物1−36、化合物1−38、化合物1−40、化合物1−45、化合物1−48、化合物1−49、化合物1−54、化合物1−55、化合物1−57、化合物1−58、化合物1−68、化合物1−69、化合物1−72、化合物1−81、化合物1−91、化合物1−92、化合物1−95、化合物1−97、化合物1−98、化合物1−99、化合物1−101、化合物1−102、化合物1−104、化合物1−105、化合物1−106、化合物1−107、化合物1−110、化合物1−111、化合物1−114、化合物1−117、化合物1−119、化合物1−122、化合物1−125、化合物1−126、化合物1−128、化合物1−133、化合物1−136、化合物1−137、化合物1−138、化合物1−139、化合物1−141、化合物1−142、化合物1−143、化合物1−144、化合物1−147、化合物1−148、化合物1−151、化合物1−153、化合物1−155、化合物1−156、化合物1−157、化合物1−160、化合物1−162、化合物1−164、化合物1−165、化合物1−166、化合物1−169、化合物1−170、化合物1−171、化合物4−3、化合物4−4、化合物4−5、化合物4−6、化合物4−8、化合物4−11、化合物4−12、化合物4−14、化合物4−18、化合物4−20、化合物4−21、化合物4−26、化合物4−27、化合物4−29、化合物4−30、化合物4−32、化合物4−34、化合物6−3、化合物6−20、化合物6−26、化合物6−27、化合物6−31、化合物6−33、化合物6−35又は化合物6−37を被験化合物として使用した場合のIL-6産生抑制作用(%DEX)を表I−1、表I−2に示す。
表I−1、表I−2に示したとおり本化合物は優れたIL-6産生抑制作用を示した。よって、本化合物はGRアゴニストとして使用でき、炎症性疾患、特に前眼部若しくは後眼部炎症性疾患並びに炎症性の骨・関節疾患の予防又は治療剤として有用である。
本化合物の抗アレルギー作用を評価するため、マウスのアレルギー性結膜炎モデルに対する本化合物の血管透過性亢進抑制効果を検討した。尚、本効果は基剤投与群(コントロール群)の色素漏出量と被験化合物投与群の色素漏出量とから算出した。
被験化合物に0.5%ポリソルベート80/生理食塩液を加えて、1%(W/V)の被験化合物懸濁液を調製した。
(アレルギー性結膜炎モデルの作製及び評価方法)
1) 水酸化アルミニウムゲル吸着オブアルブミン(20μg/mL)を生理食塩液に溶解し、6週齢の雄性BALB/c系マウスの腹腔内に500μLずつ注射し、能動感作を行った。
被験化合物投与群の血管透過性亢進抑制率(%) = (1-Ax/Ao)×100
Ao: 基剤投与群(コントロール群)の色素漏出量
Ax: 被験化合物投与群の色素漏出量
(試験結果及び考察)
試験結果の一例として、化合物1−7、化合物1−12、化合物1−13、化合物1−18、化合物1−72、化合物1−97、化合物1−102、化合物1−105、化合物1−136、化合物1−137、化合物1−138、化合物1−139又は化合物4−18を被験化合物として使用した場合の血管透過性亢進抑制率(%)を表IIに示す。
薬物の脈絡膜血管新生阻害効果を評価する一般的な方法の一つとして、ラット脈絡膜血管新生モデルを用いた新生血管発現試験が知られており、その試験方法がGraefe’s Arch. Cli. Exp. Ophthalmol., 235,313-319(1997)に報告されている。そこで、前記文献記載の方法に準じて、本化合物の新生血管発現試験を行い、基剤投与群(コントロール群)の新生血管発現率に対する本化合物投与群の新生血管発現率の割合を算出して、それを指標に本化合物の脈絡膜血管新生阻害効果を評価した。
点眼投与の場合は、被験化合物に0.5%ポリソルベート80/生理食塩液を加えて懸濁し、1%(W/V)の被験化合物懸濁液を調製した。結膜下投与の場合は、被験化合物に0.5%硬化ヒマシ油/生理食塩液を加えて懸濁し、20mg/mLの被験化合物懸濁液を調製した。
1) ラット(Brown Norway雄性ラット、7-8週齢、体重140-240g)に5%塩酸ケタミン注射液と2%塩酸キシラジン注射液の7 : 1混合液(1mL/kg)を筋肉内投与し、全身麻酔した。
1) 点眼投与の場合は、レーザー照射日(1日目)から8日目まで、被験化合物懸濁溶液を1日4回、連日点眼投与した。結膜下投与の場合は、レーザー照射直後に1回50μLを注射した。
1) 光凝固7日目に10%フルオロセイン水溶液0.1mLをラットの尾静脈から注入して、蛍光眼底造影を実施した。
新生血管発現率(%) = (陽性光凝固部位数/全光凝固部位数)×100
(計算式2)
被験化合物投与群の新生血管抑制率(%) = (1-Ax/Ao)×100
Ao: 基剤投与群(コントロール群)の新生血管発現率
Ax: 被験化合物投与群の新生血管発現率
(試験結果及び考察)
試験結果の一例として、化合物1−9、化合物1−12、化合物1―13、化合物1−14、化合物1−17、化合物1−19、化合物1−25、化合物1−33、化合物1―49、化合物1−72、化合物4−5、化合物4−8、化合物4−18、化合物6−3、化合物6―31又は化合物6−35を被験化合物として使用した場合の新生血管抑制率(%)を表IIIに示す。
薬物のドライアイに伴う角膜障害の改善効果を検討するため、雄性SDラットを用い、Fujiharaらの方法(Invest. Ophthalmol. Vis. Sci 42(1):96−100 (2001))に準じ、角膜障害モデルを作製した。角膜障害モデル作成後、村上らの方法(あたらしい眼科 21(1):87-90(2004))に準じて、角膜障害の改善率を判定した。
被験化合物にポリソルベート80や一般的な添加剤を含む基剤を加えて、0.03%(W/V)の被験化合物懸濁液を調製した。
1) 雄性SDラットを用い、ソムノペンチルを投与して全身麻酔を施した後、眼窩外涙腺を摘出し、2ヶ月かけて角膜障害を誘発させた。
0:染色されていない
1:染色が疎であり、各点状の染色部分は離れている
2:染色が中程度であり、点状の染色部分の一部が隣接している
3:染色が密であり、各点状の染色部分は隣接している
(計算式)
被験化合物投与群の改善率(%) = (Ao-Ax)/(Ao-An)×100
Ao: 基剤投与群(コントロール群)の角膜障害スコア平均値
Ax: 被験化合物投与群の角膜障害スコア平均値
An: 正常ラットの角膜障害スコア平均値
(試験結果及び考察)
試験結果の一例として、化合物1−12、化合物1―13、化合物1−72又は化合物4−18を被験化合物として使用した場合の角膜障害改善率(%)を表IVに示す。
本化合物のアトピー性皮膚炎に対する作用を評価するため、マウスのアトピー性皮膚炎モデルとして報告されているNagaiらの手法(J. Pharmacol. Exp. Ther., 283: 321-327 (1997))に修正を加えた方法で血管透過性亢進抑制効果を検討した。尚、本効果は基剤投与群(コントロール群)の色素漏出量と被験化合物投与群の色素漏出量とから算出した。
被験化合物に白色ワセリンを加えて、1%(W/W)の被験化合物軟膏を調製した。
1) 週に1回、4週間にかけて5回、マウスの両耳介の両面に0.15%DNFB溶液25μLを塗布して皮膚炎を惹起した。
被験化合物投与群の血管透過性亢進抑制率(%) = (1-Ax/Ao)×100
Ao: 基剤投与群(コントロール群)の色素漏出量
Ax: 被験化合物投与群の色素漏出量
(試験結果及び考察)
試験結果の一例として、化合物1−12、化合物1―13、化合物1−72又は化合物4−18を被験化合物として使用した場合の血管透過性亢進抑制率(%)を表Vに示す。
Claims (19)
- 下記一般式(1)で表される化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
[R1は下記一般式(2a)、(3a)、(4a)又は(5a)を示し;
R2は−(CO)−R8、−(CO)O−R9、−(SO)−R10、−(SO2)−R11又は−(CO)NR12R13を示し;
R2−O−は、ベンゼン環Aの4又は5位に置換し;
R3は低級アルキル基を示し;
R4、R5、R6又はR7は、ハロゲン原子、置換基を有してもよい低級アルキル基、低級アルケニル基、低級アルキニル基、低級アルコキシ基、ニトロ基又はホルミル基を示し;
m、n、p又はqは、0、1又は2を示し;
m、n、p又はqが2を示す場合、各R4、R5、R6又はR7は同一又は異なっていてもよく;
R8、R9、R10又はR11は、置換基を有してもよい低級アルキル基、低級アルケニル基、低級シクロアルキル基、置換基を有してもよいアリール基又は置換基を有してもよい複素環基を示し;
R12及びR13は同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又は複素環基を示す。]
- 一般式(1)において、
R1が下記一般式(2a)、(3a)、(4a)又は(5a)を示し;
R2が−(CO)−R8、−(CO)O−R9、−(SO)−R10、−(SO2)−R11又は−(CO)NR12R13を示し;
R2−O−がベンゼン環Aの4又は5位に置換し;
R3が低級アルキル基を示し;
R4がハロゲン原子、低級アルキル基、低級アルコキシ基又はニトロ基を示し;
R5がハロゲン原子、低級アルキル基又は低級アルコキシ基を示し;
R6がハロゲン原子、低級アルキル基又は低級アルコキシ基を示し;
R7がハロゲン原子又は低級アルキル基を示し;
m、n又はpが1又は2を示し、
m、n又はpが2を示す場合、各R4、R5又はR6は同一又は異なっていてもよく;
qが1を示し;
R8が置換基を有してもよい低級アルキル基、低級アルケニル基、低級シクロアルキル基、置換基を有してもよいアリール基又は置換基を有してもよい複素環基を示し;
R9が置換基を有してもよい低級アルキル基又は置換基を有してもよいアリール基を示し;
R10又はR11が、置換基を有してもよい低級アルキル基又は低級シクロアルキル基を示し;
R12及びR13が同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいアリール基又は複素環基を示す請求項1記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 一般式(1)において、
R2が−(CO)−R8、−(CO)O−R9、−(SO2)−R11又は−(CO)NR12R13を示す請求項1又は2記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 一般式(1)において、
R2が−(CO)−R8又は−(SO2)−R11を示す請求項5記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 一般式(1)において、
R2が−(CO)−R8を示す請求項6記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 一般式(1)において、
R3がメチル基を示す請求項1又は2記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 一般式(1)において、
R2−O−がベンゼン環Aの4位に置換している請求項1又は2記載の化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- ・6−[4−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(2−メトキシベンゾイルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−クロロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ブチリルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(チオフェン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[4−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−イソブチリルオキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−フェニルアセトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[5−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−5−プロピオニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−5−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[4−(フラン−3−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(ピリジン−4−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−アセトキシベンゾイルオキシ)−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(2−メチルチオベンゾイルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(チアゾール−4−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−フルオロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(5−メチルフラン−2−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(2−メチルピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(3−メトキシカルボニルベンゾイルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(6−メチルピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(3−メチルフラン−2−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−t−ブチルカルボニルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−クロロピリジン−4−イルカルボニルオキシ)−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[4−(3−フルオロピリジン−4−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−5−(2−メチル−5−ニトロフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(2−メトキシ−5−ニトロフェノキシメチル)−6−[2−メトキシ−4−(チオフェン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メチルピリジン−3−イルカルボニルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ベンゾイルオキシ−2−メトキシフェニル)−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(フラン−3−イルカルボニルオキシ)−2−メトキシフェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(2−メトキシフェニルアミノメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−クロロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−クロロベンゾイルオキシ)−2−メトキシフェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−フルオロベンゾイルオキシ)−2−メトキシフェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(2−メトキシフェニルアミノメチル)−6−[2−メトキシ−4−(ピリジン−4−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(2−メトキシフェニルアミノメチル)−6−[2−メトキシ−4−(チオフェン−2−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[4−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(3−メトキシカルボニルベンゾイルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(4−フルオロベンゾイルオキシ)−2−メトキシフェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メチルチオベンゾイルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(3−メチルフラン−2−イルカルボニルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メトキシピリジン−3−イルカルボニルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[2−メトキシ−4−(ピリジン−4−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[2−メトキシ−4−(2−メチルピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[2−メトキシ−4−(2−メトキシピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−[2−メトキシ−4−(3−メチルフラン−2−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(6−メチルピリジン−3−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(4−メチルベンゾイルオキシメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メトキシベンゾイルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−クロロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(4−クロロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ベンゾイルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メチルベンゾイルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−フルオロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(チオフェン−3−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(フラン−3−イルカルボニルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メチルチオベンゾイルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メチルピリジン−3−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(チアゾール−4−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(ピリジン−4−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(4−メトキシベンゾイルオキシメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−ブロモチオフェン−2−イルカルボニルオキシメチル)−6−[2−メトキシ−4−(ピリジン−3−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−ブロモチオフェン−2−イルカルボニルオキシメチル)−6−[4−(フラン−2−イルカルボニルオキシ)−2−メトキシフェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−イソプロピルカルボニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(2−アセトキシベンゾイルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−メトキシピリジン−3−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(4−フルオロベンゾイルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(2−ニトロベンゾイルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(3−メチルフラン−2−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−(2−メトキシ−4−プロピルスルホニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−エチルスルホニルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−(4−イソプロピルスルホニルオキシ−2−メトキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ブチルスルホニルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−シクロプロピルスルホニルオキシ−2−メトキシフェニル)−5−(2−メトキシ−5−ニトロフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−エチルスルホニルオキシ−2−メトキシフェニル)−5−(2−メチル−5−ニトロフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(2−メトキシ−4−プロピルスルホニルオキシフェニル)−5−(2−メチル−5−ニトロフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−シクロプロピルスルホニルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(2−メトキシフェニルアミノメチル)−6−(2−メトキシ−4−プロピルスルホニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(2−メトキシ−4−メチルスルホニルオキシフェニル)−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェニルアミノメチル)−6−(2−メトキシ−4−プロピルスルホニルオキシフェニル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(3,3,3−トリフルオロプロピルスルホニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(2−メトキシ−4−プロピルスルホニルオキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−イソプロピルスルホニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−シクロペンチルスルホニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−エチルスルホニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−シクロプロピルスルホニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ジメチルアミノカルボニルオキシ−2−メトキシフェニル)−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−[N−(2−ジメチルアミノエチル)−N−エチルアミノカルボニルオキシ]−2−メトキシフェニル]−5−(5−フルオロ−2−メチルフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(モルホリン−4−イルカルボニルオキシ)フェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[4−(4−クロロフェニルアミノカルボニルオキシ)−2−メトキシフェニル]−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・5−(5−フルオロ−2−メチルフェノキシメチル)−6−[2−メトキシ−4−(モルホリン−4−イルカルボニルオキシ)フェニル]−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−(4−ジメチルアミノカルボニルオキシ−2−メトキシフェニル)−5−(2−メチル−5−ニトロフェノキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、
・6−[2−メトキシ−4−(モリホリン−4−イルカルボニルオキシ)フェニル]−5−(2−メトキシフェニルアミノメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリン、及び
6−(4−ジメチルアミノカルボニルオキシ−2−メトキシフェニル)−5−(5−メチルチオフェン−2−イルカルボニルオキシメチル)−2,2,4−トリメチル−1,2−ジヒドロキノリンからなる群より選択される化合物又はその塩からなるグルココルチコイド受容体アゴニスト。
- 請求項1〜10記載のグルココルチコイド受容体アゴニストの少なくとも1つを有効成分として含有する医薬組成物。
- 請求項1〜10記載のグルココルチコイド受容体アゴニストの少なくとも1つを有効成分として含有する炎症性疾患又は免疫疾患の予防又は治療剤。
- 請求項1〜10記載のグルココルチコイド受容体アゴニストの少なくとも1つを有効成分として含有する眼炎症性疾患又は皮膚炎の予防又は治療剤。
- 眼炎症性疾患が前眼部炎症性疾患である請求項13記載の予防又は治療剤。
- 前眼部炎症性疾患が、眼球乾燥症候群又はアレルギー性結膜炎である請求項14記載の予防又は治療剤。
- 眼炎症性疾患が後眼部炎症性疾患である請求項13記載の予防又は治療剤。
- 後眼部炎症性疾患が、加齢黄斑変性、糖尿病網膜症又は糖尿病黄斑浮腫である請求項16記載の予防又は治療剤。
- 皮膚炎がアトピー性皮膚炎である請求項13記載の予防又は治療剤。
- 請求項1〜10記載のグルココルチコイド受容体アゴニストの少なくとも1つを有効成分として含有する自己免疫疾患の予防又は治療剤。
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WO2017034006A1 (ja) * | 2015-08-25 | 2017-03-02 | 参天製薬株式会社 | [4-(1,3,3-トリメチル-2-オキソ-3,4-ジヒドロ-1h-キノキサリン-7-イル)フェノキシ]エチルオキシ化合物またはその塩 |
WO2018230713A1 (ja) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | カスパーゼ阻害活性を有する化合物、これらの化合物を含む、角膜内皮の症状、障害または疾患を治療または予防するための医薬およびその応用 |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
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KR101933217B1 (ko) * | 2017-12-28 | 2018-12-27 | (주) 에빅스젠 | 피부 염증 억제용 펩티드 및 이를 포함하는 피부 염증 예방 또는 치료용 조성물 |
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JP2012180345A (ja) * | 2011-02-09 | 2012-09-20 | Santen Pharmaceut Co Ltd | 3−ヒドロキシ−6H−ベンゾ[c]クロメン−6−オン誘導体およびその製造方法 |
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JP7037687B2 (ja) | 2015-08-25 | 2022-03-16 | 参天製薬株式会社 | [4-(1,3,3-トリメチル-2-オキソ-3,4-ジヒドロ-1h-キノキサリン-7-イル)フェノキシ]エチルオキシ化合物またはその塩 |
WO2018230713A1 (ja) | 2017-06-16 | 2018-12-20 | 学校法人同志社 | カスパーゼ阻害活性を有する化合物、これらの化合物を含む、角膜内皮の症状、障害または疾患を治療または予防するための医薬およびその応用 |
US11433090B2 (en) | 2017-06-16 | 2022-09-06 | The Doshisha | mTOR-inhibitor-containing medicine for treating or preventing ophthalmic symptoms, disorders, or diseases, and application thereof |
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CA2724055C (en) | 2016-08-02 |
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