TWI510240B - 由具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物組成之糖皮質激素受體激動劑 - Google Patents
由具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物組成之糖皮質激素受體激動劑 Download PDFInfo
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- TWI510240B TWI510240B TW098115620A TW98115620A TWI510240B TW I510240 B TWI510240 B TW I510240B TW 098115620 A TW098115620 A TW 098115620A TW 98115620 A TW98115620 A TW 98115620A TW I510240 B TWI510240 B TW I510240B
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- Prior art keywords
- dihydroquinoline
- trimethyl
- methoxy
- compound
- phenyl
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- 229940124750 glucocorticoid receptor agonist Drugs 0.000 title claims description 51
- 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 description 48
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 title description 8
- 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 description 7
- 150000001875 compounds Chemical class 0.000 claims description 443
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 79
- 208000027866 inflammatory disease Diseases 0.000 claims description 57
- -1 6-(4-Tertiary butyloxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl- 1,2-dihydroquinoline Chemical compound 0.000 claims description 56
- 239000003814 drug Substances 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 44
- 201000004624 Dermatitis Diseases 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 229940124597 therapeutic agent Drugs 0.000 claims description 40
- 230000000069 prophylactic effect Effects 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 206010061218 Inflammation Diseases 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 230000004054 inflammatory process Effects 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 21
- 208000002780 macular degeneration Diseases 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000004480 active ingredient Substances 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 201000008937 atopic dermatitis Diseases 0.000 claims description 15
- 206010013774 Dry eye Diseases 0.000 claims description 14
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 13
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 13
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 13
- 208000010668 atopic eczema 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 9
- 238000011282 treatment Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 201000011190 diabetic macular edema Diseases 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 208000026278 immune system disease Diseases 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 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
- 230000000172 allergic effect Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- QVNLGKBDHOGKNX-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(2-methyl-5-nitrophenoxy)methyl]-1h-quinolin-6-yl]phenyl] ethanesulfonate Chemical compound COC1=CC(OS(=O)(=O)CC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC([N+]([O-])=O)=CC=C1C QVNLGKBDHOGKNX-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- CCJLNHNATHYQDP-UHFFFAOYSA-N [3-methoxy-4-[2,2,4-trimethyl-5-[(5-methylthiophene-2-carbonyl)oxymethyl]-1h-quinolin-6-yl]phenyl] furan-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=CO1 CCJLNHNATHYQDP-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- UVDDSAGDMJRQKM-UHFFFAOYSA-N [3-methoxy-4-[5-[(2-methoxyanilino)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]phenyl] thiophene-2-carboxylate Chemical compound COC1=CC=CC=C1NCC1=C(C=2C(=CC(OC(=O)C=3SC=CC=3)=CC=2)OC)C=CC2=C1C(C)=CC(C)(C)N2 UVDDSAGDMJRQKM-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- VAQRFDXAUANJJX-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] 3-fluoropyridine-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=C1F VAQRFDXAUANJJX-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- ATXVIBPIRXFZGE-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] propane-1-sulfonate Chemical compound COC1=CC(OS(=O)(=O)CCC)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C ATXVIBPIRXFZGE-UHFFFAOYSA-N 0.000 claims 1
- XBFZPNSSZKFTKC-UHFFFAOYSA-N [4-[5-[(5-fluoro-2-methylphenoxy)methyl]-2,2,4-trimethyl-1h-quinolin-6-yl]-3-methoxyphenyl] propane-2-sulfonate Chemical compound COC1=CC(OS(=O)(=O)C(C)C)=CC=C1C1=CC=C(NC(C)(C)C=C2C)C2=C1COC1=CC(F)=CC=C1C XBFZPNSSZKFTKC-UHFFFAOYSA-N 0.000 claims 1
- 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 1
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Description
本發明是關於可用於作為醫藥之由具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物組成之糖皮質激素受體激動劑(glucocorticoid receptor agonist)。本發明之糖皮質激素受體激動劑可用於作為發炎性疾病或免疫疾病之預防或治療劑,特別是眼發炎性疾病或皮膚炎之預防或治療劑。
糖皮質激素受體是屬於核內受體超級家族(nuclear receptor superfamily)、94kDa之配體-活化細胞內轉錄調節因子。已知該受體經由其轉錄調節作用,對碳水化合物‧蛋白質‧脂肪等的代謝調節、免疫‧發炎症反應的抑制、中樞神經系統的活性化、心血管系統機能的調節、基礎‧壓力有關之恆定性等具有影響。(非專利文獻1、專利文獻1)。
結合該糖皮質激素受體之藥物,具有糖皮質激素受體激動劑作用或糖皮質激素受體拮抗劑作用。但這些作用是完全不同的事,經由藥物的微細化學構造不同而決定顯示哪種作用。
作為代表的糖皮質激素受體激動劑,已知在生物體內作為糖皮質激素受體激動劑之皮質醇(cortisol)、皮質酮(corticosterone)等,以及地塞米松(dexamethasone)、潑尼松(prednisone)、潑尼松龍(prednisolone)等之合成糖皮質激素受體激動劑(專利文獻1)。這些糖皮質激素受體激動劑是具有類固醇構造的總稱,稱為類固醇類,可應用於各種疾病的治療。
但這些類固醇類經使用發現有類固醇消化性潰瘍、類固醇紫斑、類固醇胰臟炎、類固醇糖尿病、類固醇白內障、類固醇青光眼等副作用的情形。(非專利文獻2)。因此為回避這些副作用,寄望創造沒有類固醇構造的藥劑。
另一方面,作為類固醇受體調節子(modulator)之具有1,2-二氫喹啉構造的化合物,已揭示於專利文獻2、專利文獻3、專利文獻4等。已揭示於專利文獻2、專利文獻3及專利文獻4之化合物非常地廣泛,且具有各種化學構造,其中之一為1,2-二氫喹啉構造之化合物。但這些之中,哪種化學構造的化合物具有糖皮質激素受體激動劑作用,亦即關於具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物是否具有糖皮質激素受體激動劑作用,完全沒有具體的揭示。
[專利文獻1]特開2002-193955號公報
[專利文獻2]國際公開第04/018429號小冊
[專利文獻3]特表平10-0510840號公報
[專利文獻4]國際公開第06/019716號小冊
[非專利文獻1]綜合臨床,54(7),1951-2076(2005)
[非專利文獻2]南山堂醫學大辭典第17版,1038-1040頁
發現具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物的新藥理作用,是令人非常感興趣的課題。
因此,本發明者們為發現具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物的新藥理作用,銳意研究的結果發現具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物對糖皮質激素受體具有優異的激動劑活性,可用於作為發炎性疾病的預防或治療劑。
又點眼投與具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物於眼發炎性疾病模式(小鼠過敏性結膜炎模式、大鼠脈絡膜血管新生模式或大鼠角膜病症模式)時,對這些疾病模式確認有優異的抑制效果(各種血管通透性亢進阻害效果、脈絡膜血管新生阻害效果、角膜病症改善效果)。
再者確認該衍生物也在小鼠異位性皮膚炎(atopic dermatitis)模式中有優異的血管通透性亢進阻害效果,發現該衍生物特別可用於作為眼發炎性疾病或皮膚炎的預防或治療劑而完成本發明。
本發明中具有取代氧基之2,2,4-三甲基-6-苯基-1,2-二氫喹啉衍生物,意指下述一般式(1)所示之化合物或其鹽(以下稱為「本化合物」),本發明是本化合物構成之糖皮質激素受體激動劑以及含有至少一該糖皮質激素受體激動劑為有效成分之醫藥組成物,本發明較佳為含有至少一該糖皮質激素受體激動劑為有效成分之發炎性疾病的預防或治療劑,更佳為含有至少一該糖皮質激素受體激動劑為有效成分之眼發炎性疾病或皮膚炎的預防或治療劑。
[R1
為下述一般式(2a)、(3a)、(4a)或(5a)所示:
R2
表示-(CO)-R8
、-(CO)O-R9
、-(SO)-R10
、-(SO2
)-R11
或-(CO)NR12
R13
;R2
-O-為取代於苯環A的4或5位置;R3
表示低級烷基;R4
、R5
、R6
或R7
表示鹵素原子、可有取代基之低級烷基、低級烯基、低級炔基、低級烷氧基、硝基或甲醯基;m、n、p或q表示0、1或2;當m、n、p或q為2時,各R4
、R5
、R6
或R7
可相同或不同;R8
、R9
、R10
或R11
表示可有取代基之低級烷基、低級烯基、低級環烷基、可有取代基之芳基或可有取代基之雜環基;R12
及R13
表示相同或不同之氫原子、可有取代基之低級烷基、可有取代基之芳基或雜環基。以下同]。
以下詳細說明本說明書中使用之用語(原子、基等)的定義。又以下用語的定義適用於別的用語之定義時,各定義之較佳及特佳範圍也適用。
「鹵素原子」是表示氟、氯、溴或碘原子。
「低級烷基」是表示碳原子數1~8個、較佳1~6個的直鏈或分枝的烷基。作為具體例可舉出甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基、正辛基、異丙基、異丁基、第二丁基、第三丁基、異戊基等。
「低級烯基」是表示碳原子數2~8個、較佳2~6個的直鏈或分枝的烯基。作為具體例可舉出乙烯基、丙烯基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、異丙烯基、2-甲基-1-丙烯基、2-甲基-2-丁烯基等。
「低級炔基」是表示碳原子數2~8個、較佳2~6個的直鏈或分枝的炔基。作為具體例可舉出乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、異丁炔基、異戊炔基等。
「低級環烷基」是表示碳原子數3~10個、較佳3~8個的環烷基。作為具體例可舉出環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基或環癸基。
「芳基」是表示從碳原子數6~14個的單環芳香族烴基或2環或3環之稠合多環芳香族烴除去1氫原子之殘基。作為具體例可舉出苯基、萘基、蒽基、菲基等,特佳為苯基。
「雜環」是表示環內具有1或複數個選自氮原子、氧原子及硫原子之雜原子的飽和或不飽和單環式雜環(較佳為環內具有1或2個雜原子、碳原子數3~5個之飽和或不飽和單環式雜五或六員環)或2環或3環之稠合多環式雜環(較佳為環內具有1或2個雜原子、碳原子數7~13個之2環或3環稠合多環式雜環)。
作為「飽和單環式雜環」的具體例,可舉出環內具有氮原子之吡咯啶、吡唑啶、咪唑啶、三唑啶、哌啶、六氫嗒、六氫嘧啶、哌、高哌啶、高哌環等,環內具有氧原子之四氫呋喃、四氫哌喃環等,環內具有硫原子之四氫噻吩、四氫噻哌喃環等,環內具有氮原子及氧原子之唑啶、異唑啶、嗎福啉環等,環內具有氮原子及硫原子之噻唑啶、異噻唑啶、噻嗎福啉環等。
此外,這些飽和單環式雜環與苯環等稠合可形成二氫吲、二氫吲唑、二氫苯并咪唑、四氫喹啉、四氫異喹啉、四氫喏啉、四氫呔、四氫喹唑啉、四氫喹喏啉、二氫苯并呋喃、二氫異苯并呋喃、色滿(chroman)、異色滿、二氫苯并噻吩、二氫異苯并噻吩、硫色滿(thiochroman)、異硫色滿、二氫苯并唑、二氫苯并異唑、二氫苯并、二氫苯并噻唑、二氫苯并異噻唑、二氫苯并噻、、4a-咔唑、啶環等之2環或3環稠合多環式雜環。
作為「不飽和單環式雜環」之具體例,可舉出環內具有氮原子之二氫吡咯、吡咯、二氫吡唑、吡唑、二氫咪唑、咪唑、二氫三唑、三唑、四氫吡啶、二氫吡啶、吡啶、四氫嗒、二氫嗒、嗒、四氫嘧啶、二氫嘧啶、嘧啶、四氫吡、二氫吡、吡環等,環內具有氧原子之二氫呋喃、呋喃、二氫哌喃、哌喃環等,環內具有硫原子之二氫噻吩、噻吩、二氫噻哌喃、噻哌喃環等,環內具有氮原子及氧原子之二氫唑、唑、二氫異唑、異唑、二氫、環等,環內具有氮原子及硫原子之二氫噻唑、噻唑、二氫異噻唑、異噻唑、二氫噻、噻環等。
此外,這些不飽和單環式雜環與苯環等稠合可形成吲、二氫吲唑、苯并咪唑、苯并三唑、二氫喹啉、喹啉、二氫異喹啉、異喹啉、啡啶、二氫喏啉、喏啉、二氫呔、呔、二氫喹唑啉、喹唑啉、二氫喹喏啉、喹喏啉、苯并呋喃、異苯并呋喃、烯(chromene)、異烯、苯并噻吩、異苯并噻吩、噻烯、異噻烯、苯并唑、苯并異唑、苯并、苯并噻唑、苯并異噻唑、苯并噻、啡(phenoxanthin)、咔唑、β-咔啉(β-carbolin)、啡啶、吖啶(acridine)、啡啉、啡、啡噻、啡環等之2環或3環稠合多環式雜環。
又前述之「雜環」中較佳為哌啶、嗎福啉、咪唑、吡啶、嘧啶、呋喃、噻吩、唑或噻唑環。
「雜環基」是表示從前述雜環除去1氫原子之殘基。
「低級烷氧基」是表示羥基的氫原子經低級烷基取代之基。作為具體例可舉出甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正己氧基、正庚氧基、正辛氧基、異丙氧基、異丁氧基、第二丁氧基、第三丁氧基、異戊氧基等。
「低級烷硫基」是表示巰基的氫原子經低級烷基取代之基。作為具體例可舉出甲硫基、乙硫基、正丙硫基、正丁硫基、正戊硫基、正己硫基、正庚硫基、正辛硫基、異丙硫基、異丁硫基、第二丁硫基、第三丁硫基、異戊硫基等。
「低級烷羰基」是表示甲醯基的氫原子經低級烷基取代之基。作為具體例可舉出甲羰基、乙羰基、正丙羰基、正丁羰基、正戊羰基、正己羰基、正庚羰基、正辛羰基、異丙羰基、異丁羰基、第二丁羰基、第三丁羰基、異戊羰基等。
「低級烷氧羰基」是表示甲醯基的氫原子經低級烷氧基取代之基。作為具體例可舉出甲氧羰基、乙氧羰基、正丙氧羰基、正丁氧羰基、正戊氧羰基、正己氧羰基、正庚氧羰基、正辛氧羰基、異丙氧羰基、異丁氧羰基、第二丁氧羰基、第三丁氧羰基、異戊氧羰基等。
「低級烷羰氧基」是表示羥基的氫原子經低級烷羰基取代之基。作為具體例可舉出甲羰氧基、乙羰氧基、正丙羰氧基、正丁羰氧基、正戊羰氧基、正己羰氧基、正庚羰氧基、正辛羰氧基、異丙羰氧基、異丁羰氧基、第二丁羰氧基、第三丁羰氧基、異戊羰氧基等。
「可有取代基之低級烷基」是表示可有選自下述α1
群之1或複數個取代基、較佳為可有選自α2
群之1或複數個取代基之「低級烷基」。
鹵素原子、低級環烷基、芳基、雜環基、低級烷氧基及-NRa
Rb
。
鹵素原子、芳基、雜環基、低級烷氧基及-NRa
Rb
。
「可有取代基之芳基」及/或「可有取代基之雜環基」是表示可有選自下述β1
群之1或複數個取代基、較佳為可有選自β2
群之1或複數個取代基之「芳基」及/或「雜環基」。
鹵素原子、低級烷基、羥基、低級烷氧基、巰基、低級烷硫基、甲醯基、低級烷羰基、羧基、低級烷氧羰基、低級烷羰氧基、硝基及氰基。
鹵素原子、低級烷基、低級烷氧基、低級烷硫基、低級烷羰基、低級烷氧羰基、低級烷羰氧基、硝基及氰基。
又前述「-NRa
Rb
」之Ra
及Rb
是表示相同或不同之選自下述γ1
群之取代基、較佳為選自γ2
群之取代基。
氫原子、低級烷基及低級烷氧羰基。
氫原子及低級烷基。
本發明中所謂「複數個基」是表示每一基可相同或不同、取代部位中2個以上、可取代數以下之數目的基,該之數目為2或3個時較佳,2個時特佳。
此外,在本發明中氫原子及鹵素原子也包括「基」的概念。
本發明中所謂「糖皮質激素受體激動劑」是指經由與糖皮質激素受體結合,表現完全激動劑作用或部分激動劑作用者。
本發明中所謂「預防或治療劑」意指以疾病的預防及/或治療為目的之藥劑。
此外,本發明之作為「糖皮質激素受體激動劑」之醫藥用途,若為糖皮質激素受體激動劑可預防或治療之疾病,則無特別限制,通常可適用於以糖質類固醇類可治療之所有疾病。
舉例而言,可舉出慢性腎上腺皮質機能不全(原發性、續發性、下垂體性、醫源性)、急性腎上腺皮質機能不全(腎上腺亢進)、腎上腺性生殖腺症候群、亞急性甲狀腺炎、甲狀腺中毒症[甲狀腺(中毒性)亢進]、甲狀腺疾病伴隨之惡性眼球突出症、ACTH單獨缺損症、特發性低血糖症等之內分泌疾病;全身性紅斑性狼瘡(全身性及慢性圓板狀)、全身性血管炎(包括大動脈炎症候群、結節性動脈周圍炎、多發性動脈炎、韋格納肉芽腫症(Wegener's granulomatosis)、多發性肌炎(皮肌炎)、硬皮症(scleroderma)等膠原病;腎病、腎病症候群等腎疾病;充血性心衰竭等心臟疾病;支氣管氣喘、氣喘性支氣管炎(包括幼兒氣喘性支氣管炎)、經由藥劑之其他化學物質的過敏、中毒(包括藥疹、中毒疹)、血清病等過敏性疾病;紫斑病(血小板減少性及血小板非減少性)、再生不良性貧血、白血病(包括急性白血病、慢性骨髄性白血病之急性轉化、慢性淋巴性白血病、皮膚白血病)、溶血性貧血、顆粒球減少症等血液疾病;潰瘍性大腸炎、限局性腸炎、重症消耗性疾病之全身狀態的改善(包括癌末期、腹瀉)等之消化器疾病;猛暴性肝炎、膽汁滯留型急性肝炎、慢性肝炎、肝硬化等肝疾病;類肉瘤病(sarcoidosis)、彌漫性間質性肺炎(包括肺纖維化、放射線肺臟炎)等肺疾病;重症感染症;肺結核、結核性腦膜炎、結核性胸膜炎、結核性腹膜炎、結核性心膜炎等結核性疾病;腦脊髄炎(包括腦炎、脊髄炎)、末梢神經炎(包括基林芭瑞症候群(Guillain-Barre syndrome))、肌強直(myotonia),重症肌無力、多發性硬化症(包括視神經脊髄炎)、小舞蹈症、顏面神經麻痺、脊髄蜘蛛網膜炎等神經疾病;惡性淋巴腫(淋巴肉瘤症、網狀細胞肉瘤、何杰金氏病(Hodgkin's disease)、網狀皮膚症、菌狀息肉症)及類似疾病(有關疾病)、好酸性肉芽腫、乳癌之復發轉移等惡性腫瘤;投與抗惡性腫瘤劑(西斯鉑(cisplatin)等)伴隨之消化器症狀(噁心、嘔吐);對腎上腺摘除、腎上腺皮質機能不全患者之外科的侵襲、侵襲後肺水腫、臟器‧組織移植、蛇毒‧昆蟲毒(包括嚴重的蟲咬)、原因不明的發熱等外科疾病;輸卵管整形術後的黏合防止等之婦產科疾病;前列腺癌、陰莖硬結症等之泌尿器科疾病;急性、慢性中耳炎、滲出性中耳炎‧耳管狹窄美尼爾氏症(Meniere's Disease)症及美尼爾氏症候群、急性感音性聽力損失、血管運動(神經)性鼻炎、過敏性鼻炎、花粉症(枯草熱)、進行性壞疽性鼻炎、喉頭炎‧喉頭浮腫、耳鼻咽喉科領域之手術後的後療法、嗅覺障礙、急性‧慢性(反複性)唾液腺炎等耳鼻咽喉科疾病;難治性口內炎及舌炎等口腔外科疾病;風濕熱(包括風濕性心臟炎)、風濕性多發肌痛、強直性脊椎炎(風濕性脊椎炎)等風濕性疾病、下述發炎性疾病等。
本發明中所謂「發炎性疾病」若為伴隨炎症之疾病,則無特別限制。
舉例而言,可舉出發炎性的骨、關節疾病、眼發炎性疾病、氣喘、支氣管炎、鼻炎、皮膚炎、炎症性腸疾病等,較佳可舉出發炎性的骨、關節疾病、眼發炎性疾病、皮膚炎。
於此所謂「發炎性的骨、關節疾病」若為在關節部伴隨炎症之疾病,則無特別限制。舉例而言,可舉出關節風濕、幼年型關節風濕(包括史迪爾氏病(Still’s Disease))變形性關節症、骨質疏鬆症、脊椎關節炎等,較佳為關節風濕或變形性關節症。
又所謂「眼發炎性疾病」若為在眼部伴隨炎症之疾病,則無特別限制。舉例而言,若為前眼部發炎性疾病,可舉出角膜炎、角結膜炎、結膜炎、眼瞼炎、眼球乾燥症候群(亦可稱為「乾眼症」)、過敏性結膜炎、前部葡萄膜炎、前眼部的手術後炎症、因眼組織移植排斥反應之炎症等,較佳為眼球乾燥症候群(亦可稱為「乾眼症」)或過敏性結膜炎。此外,若為後眼部發炎性疾病,可舉出老年黃斑病變(初期老年黃斑病變、萎縮型老年黃斑病變及/或滲出型老年黃斑病變)、糖尿病視網膜症、糖尿病黄斑浮腫、血管新生黄斑症、突發性黄斑上膜、增殖性玻璃體視網膜症、視網膜色素變性症、視網膜中心靜脈閉塞症、視網膜中心動脈閉塞症、視網膜靜脈分枝閉塞症、視網膜動脈分枝閉塞症、視網膜剝離或外傷造成之炎症或變性、後眼部的手術後炎症、視網膜炎、葡萄膜炎、鞏膜炎、視神經炎等,較佳為老年黃斑病變(初期老年黃斑病變、萎縮型老年黃斑病變及/或滲出型老年黃斑病變)、糖尿病視網膜症、糖尿病黄斑浮腫、血管新生黄斑症、突發性黄斑上膜、增殖性玻璃體視網膜症、視網膜色素變性症、視網膜中心靜脈閉塞症、視網膜中心動脈閉塞症、視網膜靜脈分枝閉塞症、視網膜動脈分枝閉塞症、視網膜剝離或外傷造成之炎症或變性、視網膜炎等視網膜疾病,特佳為老年黃斑病變、糖尿病視網膜症或糖尿病黄斑浮腫。
再者所謂「皮膚炎」若為在皮膚伴隨炎症之疾病,則無特別限制。舉例而言,可舉出濕疹‧皮膚炎類(急性濕疹、亞急性濕疹、慢性濕疹、接觸性皮膚炎、貨幣狀濕疹、自身敏感性皮膚炎(autOsensitizatiOn dermatitis)、乳‧幼‧小兒濕疹、慢性單純性苔癬、其他神經皮膚炎、脂漏性皮膚炎、進行性指掌角皮症、其他的手指皮膚炎、陰部或肛門濕疹、耳殼及外耳道的濕疹‧皮膚炎、鼻前庭及鼻翼周邊的濕疹‧皮膚炎等)、癢疹類(包括嬰兒丘疹性麻疹(strophulus)、蕁麻疹樣苔癬、固定蕁麻疹)、蕁麻疹、乾癬及同類病症(尋常性乾癬(重症例)、關節症性乾癬、乾癬性紅皮症、膿疱性乾癬、連續性肢端皮膚炎(acrodermatitis continua)、疱疹狀膿痂疹、雷德氏症候群(Reiter's syndrome))、掌蹠膿疱症(Pustulosis Palmoplantaris)、扁平苔癬、成年性浮腫性硬化症、紅斑症(多形滲出性紅斑、結節性紅斑)、類過敏性紫斑(單純型、Schoenlein型、Henoch型)、韋伯-克里斯欣氏病(Weber-Christian disease)、粘膜皮膚眼症候群(開口部糜爛性外皮症、Stevens-Johnson病、皮膚口內炎、Fuchs氏症候群、貝西氏病(Behcet's Disease)、Lipschuetz式急性外陰潰瘍)、RAY-noz病、圓形脫毛症、天疱瘡類(尋常性天疱瘡、葉狀天疱瘡、Senear-Usher症候群、增殖性天疱瘡)、Duhring疱疹狀皮膚炎(包括類天疱瘡、妊娠性疱疹)、先天性表皮水疱症、帶狀疱疹、紅皮症(包括海普拉氏紅糠疹(Hebra Pityriasis Rubra))、顏面播種狀粟粒性狼瘡、過敏性血管炎及其同類病症(包括急性痘瘡樣苔癬狀糠疹)、潰瘍性慢性膿皮症、新生兒皮膚病等之皮膚科疾病,較佳為濕疹‧皮膚炎類、癢疹類、蕁麻疹、乾癬及同類病症或異位性皮膚炎,特佳為異位性皮膚炎。
本發明中所謂「免疫疾病」若為與免疫有關之疾病,則無特別限制,特別可舉出「自體免疫疾病」。
本化合物中之「鹽」,若是作為醫藥之可接受鹽,則無特別限制,可舉出鹽酸、氫溴酸、氫碘酸、硝酸、硫酸、磷酸等之無機酸的鹽,乙酸、反丁烯二酸、順丁烯二酸、琥珀酸、檸檬酸、酒石酸、己二酸、葡萄糖酸、葡萄糖庚酸(glucoheptic acid)、葡萄糖醛酸、對苯二甲酸、甲磺酸、乳酸、馬尿酸(Hippuric acid)、1,2-乙二磺酸、羥乙磺酸(isethionate)、乳糖醛酸、油酸、帕莫酸(pamoate)、聚半乳糖醛酸、硬脂酸、單寧酸、三氟甲磺酸、苯磺酸、對甲苯磺酸、硫酸十二基酯、硫酸甲酯、萘磺酸、磺基水楊酸等之有機酸的鹽,溴化甲烷、碘化甲烷等之四級銨鹽,溴離子、氯離子、碘離子等之鹵素離子的鹽,鋰、鈉、鉀等之鹼金屬的鹽,鈣、鎂等之鹼土金屬的鹽,鐵、鋅等之金屬鹽,氨之鹽,三伸乙二胺、2-胺基乙醇、2,2-亞胺基二(乙醇)、1-去氧基-1-(甲胺基)-2-D-山梨醇、2-胺基-2-(羥甲基)-1,3-丙二醇、普羅卡因(procaine)、N,N-二(苯基甲基)-1,2-乙二胺等之有機胺的鹽等。
本化合物存在幾何異構物或光學異構物時,這些異構物也包含於本發明之範圍內。此外,本化合物可為水合物或溶劑合物之形態。
本化合物存在質子互變異構性(proton tautomerism)時,這些互變異構物也包含於本發明內。
本化合物存在結晶多形及結晶多形群(結晶多形系統)時,這些結晶多形體及結晶多形群(結晶多形系統)也包含於本發明內。於此之結晶多形群(結晶多形系統)意指經由這些結晶之製造、結晶、保存等條件及狀態(又本狀態也包括製劑化之狀態),結晶形變化時之各階段中各個結晶形及其過程全體。
(A)作為本化合物之例,可舉出一般式(1)所示之化合物或其鹽中各基為以下所示之基之化合物或其鹽。
(A1)R1
表示下述一般式(2a)、(3a)、(4a)或(5a);及/或
(A2)R2
表示-(CO)-R8
、-(CO)O-R9
、-(SO)-R10
、-(SO2
)-R11
或-(CO)NR12
R13
;及/或
(A3)R2
-O-為取代於苯環A的4或5位置;及/或
(A4)R3
表示低級烷基;及/或
(A5)R4
、R5
、R6
或R7
表示鹵素原子、可有取代基之低級烷基、低級烯基、低級炔基、低級烷氧基、硝基或甲醯基;及/或
(A6)m、n、p或q表示0、1或2;及/或
(A7)m、n、p或q表示2時,各R4
、R5
、R6
或R7
可相同或不同;及/或
(A8)R8
、R9
、R10
或R11
表示可有取代基之低級烷基、低級烯基、低級環烷基、可有取代基之芳基或可有取代基之雜環基;及/或
(A9)R12
及R13
表示相同或不同、氫原子、可有取代基之低級烷基、可有取代基之芳基或雜環基。
換言之,一般式(1)所示化合物或其鹽,是選自上述(A1)、(A2)、(A3)、(A4)、(A5)、(A6)、(A7)、(A8)及(A9)之1或2以上之各組合而成之化合物或其鹽。
(B)作為本化合物之較佳例,可舉出一般式(1)所示之化合物或其鹽中各基為以下所示之基之化合物或其鹽。
(B1)R1
表示下述一般式(2a)、(3a)、(4a)或(5a);及/或
(B2)R2
表示-(CO)-R8
、-(CO)O-R9
、-(SO)-R10
、-(SO2
)-R11
或-(CO)NR12
R13
;及/或
(B3)R2
-O-為取代於苯環A的4或5位置;及/或
(B4)R3
表示低級烷基;及/或
(B5)R4
表示鹵素原子、低級烷基、低級烷氧基或硝基;及/或
(B6)R5
表示鹵素原子、低級烷基或低級烷氧基;及/或
(B7)R6
表示鹵素原子、低級烷基或低級烷氧基;及/或
(B8)R7
表示鹵素原子或低級烷基;及/或
(B9)m、n或p表示1或2;及/或
(B10)m、n或p表示2時,各R4
、R5
或R6
可相同或不同;及/或
(B11)q表示1;及/或
(B12)R8
表示可有取代基之低級烷基、低級烯基、低級環烷基、可有取代基之芳基或可有取代基之雜環基;及/或
(B13)R9
表示可有取代基之低級烷基或可有取代基之芳基;及/或
(B14)R10
或R11
表示可有取代基之低級烷基或低級環烷基;及/或
(B15)R12
及R13
表示相同或不同之氫原子、可有取代基之低級烷基、可有取代基之芳基或雜環基。
換言之,一般式(1)所示之化合物或其鹽為選自上述(B1)、(B2)、(B3)、(B4)、(B5)、(B6)、(B7)、(B8)、(B9)、(B10)、(B11)、(B12)、(B13)、(B14)及(B15)之1或2以上各組合而成之化合物或其鹽。
(C)作為本化合物中R1
的較佳例,可舉出一般式(1)中R1
表示下述一般式(2a-1)、(2a-2)、(2a-3)、(3a-1)、(3a-2)、(4a-1)、(4a-2)、(4a-3)、(5a-1)或(5a-2)之例,
更佳為可舉出R1
表示下述一般式(2a-1)、(2a-2)、(2a-3)、(3a-1)、(3a-2)、(4a-2)或(5a-1)之例。
又滿足該條件(C)與前述(A)及/或(B)之條件的化合物或其鹽特佳。
(D)作為本化合物中R2
的較佳例,可舉出一般式(1)中R2
表示-(CO)-R8
、-(SO2
)-R11
或-(CO)NR12
R13
之例,更佳為R2
表示-(CO)-R8
或-(SO2
)-R11
之例,又更佳為R2
表示-(CO)-R8
之例。
又滿足該條件(D)與前述(A)及/或(B)之條件的化合物或其鹽特佳。
(E)作為本化合物中R3
的較佳例,可舉出一般式(1)中R3
表示甲基之例。
又滿足該條件(E)與前述(A)及/或(B)之條件的化合物或其鹽特佳。
(F)作為本化合物中R2
-O-之較佳取代位置,可舉出一般式(1)中R2
-O-為取代於苯環A的4或5位置之例。
又滿足該條件(F)與前述(A)及/或(B)之條件的化合物或其鹽特佳。
(G)作為本化合物之較佳具體例,可舉出以下之化合物或其鹽。
‧6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲氧基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-丁醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-(4-異丁醯氧基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-苯基乙醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[5-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-5-丙醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-5-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-乙醯氧基苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(噻唑-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(5-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(3-甲氧羰基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(6-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-第三丁基羰氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氯吡啶-4-基羰氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[4-(3-氟吡啶-4-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(2-甲氧基-5-硝基苯氧基甲基)-6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-苯甲醯基氧基-2-甲氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(噻吩-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(3-甲氧羰基苯甲醯基氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(4-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(6-甲基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(4-甲基苯甲醯基氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲氧基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(4-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-苯甲醯基氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(噻唑-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(4-甲氧基苯甲醯基氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-溴噻吩-2-基羰氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-溴噻吩-2-基羰氧甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-異丙基羰氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(2-乙醯氧基苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(4-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(2-硝基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-(4-異丙磺醯氧基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-丁磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(2-甲氧基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(2-甲氧基-4-丙磺醯氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(2-甲氧基苯基胺甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(2-甲氧基-4-甲基磺醯氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯基胺甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(3,3,3-三氟丙磺醯氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(2-甲氧基-4-丙磺醯氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-異丙磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-環戊基磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-[N-(2-二甲胺基乙基)-N-乙胺基羰氧基]-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉
‧6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[4-(4-氯苯胺基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉。
‧6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
本化合物可經由以下的方法製造。此外,關於各個具體的製造方法以後述的實施例之『製造例』段落詳細地說明。再者,這些例示只為更理解本發明,並非限定本發明之範圍之物。此外,下述之合成路徑中所示之ha1表示鹵素原子,Fmoc表示9-茀甲氧羰基。
本化合物(I)-(a)(一般式(1)中R2
為-(CO)-R8
之化合物)、本化合物(I)-(b)(一般式(1)中R2
為-(CO)O-R9
之化合物)、本化合物(I)-(c)(一般式(1)中R2
為-(SO2
)-R11
之化合物)、本化合物(I)-(d)(一般式(1)中R2
為-(CO)NR12
R13
之化合物)可依照合成路徑1合成。換言之,化合物(II)於二氯甲烷、吡啶、四氫呋喃(以下稱為「THF」)、N,N-二甲基甲醯胺(以下稱為「DMF」)等之有機溶劑中,三乙胺、二異丙基乙胺(以下稱為「DIEA」)等之鹼基存在下,與對應之酸鹵化物(III)、(IV)、(V)、(VI)在0℃至100℃反應10分鐘至2天,可得到本化合物(I)-(a)、(I)-(b)、(I)-(c)、(I)-(d)。
又本化合物(I)-(a)(一般式(1)中R2
為-(CO)-R8
之化合物)亦可依照合成路徑2合成。換言之,化合物(II)於二氯甲烷、DMF等有機溶劑中,三乙胺、DIEA等鹼基、N,N’-二環己基碳二亞胺、O-(7-吖苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯等之縮合劑存在下,與對應之羧酸(VII)在0℃至室溫反應30分鐘至3天可得到本化合物(I)-(a)。
本化合物(I)-(d)(一般式(1)中R2
為-(CO)NR12
R13
之化合物)亦可依照合成路徑3合成。換言之,化合物(II)與1,1’-羰基二咪唑(以下稱為「CDI」)於二氯甲烷、THF等有機溶劑中,4-二甲胺基吡啶等觸媒存在下,在室溫至50℃反應30分鐘至12小時後,進一步與對應之胺(VIII)在室溫至100℃反應30分鐘至5小時可得到本化合物(I)-(d)。
本化合物(I)-(e)(一般式(1)中R2
為-(CO)NR12
R13
、R13
為氫原子之化合物)可依照合成路徑4合成。換言之,化合物(II)於二氯甲烷、THF、DMF等有機溶劑中,三乙胺、DIEA等鹼基存在下與對應之異氰酸鹽(IX)在0℃至室溫反應30分鐘至1天可得到本化合物(I)-(e)。
本化合物(I)-(f)(一般式(1)中R1
為基(3a)之化合物)亦可依照合成路徑5合成。換言之,將R2
導入依照合成路徑1~4之方法之化合物(X)後,於DMF、二氯甲烷等有機溶劑中,哌啶等鹼基存在下,在0℃至50℃處理5分鐘至24小時可得到本化合物(I)-(f)。
化合物(II)-(a)(化合物(II)中R1
為基(2a)之化合物)、化合物(II)-(b)(化合物(II)中R1
為基(3a)之化合物)、化合物(II)-(c)(化合物(II)中R1
為基(4a)之化合物)、化合物(II)-(d)(化合物(II)中R1
為基(5a)之化合物)可依照合成路徑6合成。換言之,化合物(XI)與甲磺醯氯於二氯甲烷、DMF等有機溶劑中,三乙胺、DIEA等鹼基存在下,在0℃至室溫反應30分鐘至3天可得到化合物(XII)。所得之化合物(XII)與對應之酚類(XIII)、苯胺類(XIV)、苯甲酸類(XV)或噻吩羧酸類(XVI)於DMF、二氯甲烷等有機溶劑中,碳酸鉀、DIEA、氫化鈉等鹼基存在下,在50℃至100℃反應1小時至2天可得到化合物(XVII)-(a)~(XVII)-(d)。所得之化合物(XVII)-(a)~(XVII)-(d)於二氯甲烷或1,4-二烷等有機溶劑中,以氫氯酸或三氟乙酸等酸在0℃至室溫處理1小時至2天可得到化合物(II)-(a)~(II)-(d)。
化合物(II)-(a)(化合物(II)中R1
為基(2a)之化合物)、化合物(II)-(c)(化合物(II)中R1
為基(4a)之化合物)、化合物(II)-(d)(化合物(II)中R1
為基(5a)之化合物)亦可依照合成路徑7合成。換言之,化合物(XI)與對應之酚類(XIII)、苯甲酸類(XV)或噻吩羧酸類(XVI)於苯、THF等有機溶劑中,三苯膦、三丁基膦等膦與偶氮二羧酸二乙酯、偶氮二羧酸二異丙酯、1,1’-(偶氮二羰基)二哌啶等試藥存在下,在室溫反應1小時至2天可得到化合物(XVII)-(a)、(XVII)-(c)、(XVII)-(d)。將所得化合物(XVII)-(a)、(XVII)-(c)、(XVII)-(d)於二氯甲烷或1,4-二烷等有機溶劑中,以氫氯酸或三氟乙酸等酸在0℃至室溫處理1小時至2天可得到化合物(II)-(a)、(II)-(c)、(II)-(d)。
化合物(X)可依照合成路徑8合成。換言之,(II)-(b)與氯化9-茀甲氧羰基於1,4-二烷、水等溶劑中,碳酸氫鈉等鹼基存在下,在0℃至50℃反應1小時至24小時可得到化合物(X)。
化合物(XI)可依照合成路徑9合成。換言之,硼酸(XVIII)與鹵素化合物或三氟甲磺酸化合物(XIX)於DMF、乙醇、甲苯、水等溶劑中,碳酸銫、碳酸鈉或磷酸鉀等鹼基與氯化二(三苯膦)鈀(II)或四(三苯膦)鈀(0)等觸媒存在下,在50℃至120℃反應12小時至2天可得到化合物(XX)。所得化合物(XX)於二氯甲烷、THF等溶劑中,三溴化硼或鹽酸等酸存在下,在-78℃至室溫處理1小時至1天可得到化合物(XXI)。所得化合物(XXI)於甲醇、乙醇、1,4-二烷、THF等有機溶劑中,在氫氣氛下,碳上鈀、二氧化鉑等觸媒存在下,在室溫處理2小時至2天可得到化合物(XXII)。所得化合物(XXII)於丙酮中,在碘存在下,在80℃至130℃處理24小時至5天可得到化合物(XXIII)。所得化合物(XXIII)與氯二甲基醚於二氯甲烷、DMF等有機溶劑中,碳酸鉀、三乙胺、二異丙基乙胺等胺存在下反應可得化合物(XXIV)。所得化合物(XXIV)於二乙基醚、THF等有機溶劑中,在氫化鋰鋁等還原劑存在下,在0℃至50℃處理1小時至1天可得化合物(XXV)。所得化合物(XXV)與對應之鹵化化合物(XXVI)於DMF、乙醇等有機溶劑中,碳酸鉀、DIEA等鹼基存在下,在室溫至100℃反應1小時至24小時可得到化合物(XI)。
此外,關於詳細內容,於後述的實施例「藥理試驗」段落詳細地說明。首先,使用糖皮質激素受體(以下也稱為「GR」)競爭性分析套組(Invitrogen公司製,Cat No.P2816),經由螢光極化分析法(fluorescence polarization assay)進行受體競爭性分析,檢討本化合物對GR之結合活性。結果,本化合物對GR顯示64%以上的GR結合率。
接下來,為評價本化合物作為GR激動劑之作用,在脂多醣(Lipopolysaccharide;以下稱為「LPS」)刺激後的人角膜上皮細胞株中檢討IL-6產生的抑制作用。結果,本化合物顯示優異之IL-6產生的抑制作用。換言之,本化合物具有GR激動劑作用,有用於作為發炎性疾病的預防或治療劑。
此外,為評價經由本化合物之點眼投與,作為前眼部炎症治療劑的可能性,檢討本化合物對小鼠過敏性結膜炎模式之色素漏出量的抑制效果以及本化合物對大鼠角膜病症模式之角膜病症的改善效果。結果,本化合物顯示血管通透性亢進的抑制作用以及角膜病症的改善效果。換言之,本化合物有用作為前眼部發炎性疾病的預防或治療劑,特別是過敏性結膜炎及眼球乾燥症候群(也稱為「乾眼症」)的預防或治療劑。
此外,為評價本化合物作為後眼部發炎性疾病之預防或治療劑的可能性,檢討本化合物經由點眼投與,對大鼠脈絡膜血管新生模式之脈絡膜血管新生的阻害效果。結果,本化合物顯示新生血管的抑制作用。換言之,本化合物有用於作為後眼部發炎性疾病的預防或治療劑,特別是老年黃斑病變或糖尿病視網膜症等視網膜疾病之預防或治療劑。
再者,為評價本化合物作為皮膚炎之預防或治療劑的可能性,檢討本化合物經由塗布投與,對小鼠異位性皮膚炎模式之血管通透性亢進的抑制效果。結果,本化合物於本模式中,也顯示血管通透性亢進的抑制作用。換言之,本化合物有用於作為皮膚炎的預防或治療劑,特別是異位性皮膚炎的預防或治療劑。
由以上的藥理試驗,本化合物有用於含有GR激動劑、該GR激動劑之至少一者為有效成分之醫藥組成物、含有該GR激動劑之至少一者為有效成分之發炎性疾病或免疫疾病的預防或治療劑、含有該GR激動劑之至少一者為有效成分之眼發炎性疾病或皮膚炎的預防或治療劑等。
本化合物亦可經口、非經口投與。作為投與劑型,可舉出錠劑、膠囊劑、顆粒劑、散劑、注射劑、點眼劑、栓劑、經皮吸收製劑、軟膏劑、氣溶膠劑(包括吸入劑)等,此等可使用泛用的技術來製劑化。
舉例而言,視需要可使用必要量之乳糖、甘露糖醇、澱粉、結晶纖維素、輕質無水矽酸、碳酸鈣、磷酸氫鈣等之賦形劑,硬脂酸、硬脂酸鎂、滑石等之潤滑劑,澱粉、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯基吡咯啶酮等之結合劑,羧甲基纖維素、低取代度羥丙基甲基纖維素、檸檬酸鈣等之崩散劑,羥丙基甲基纖維素、聚乙二醇(macrogol)、聚矽氧樹脂等之塗覆劑,對羥基苯甲酸乙酯、苄基醇等之安定劑,甘味料、酸味料、香料等之矯味矯臭劑等來調製錠劑、膠囊劑、顆粒劑、散劑等之徑口劑。
此外,視需要可使用必要量之氯化鈉、濃甘油、丙二醇、聚乙二醇、氯化鉀、山梨醇、甘露糖醇等之等張化劑,磷酸鈉、磷酸氫鈉、醋酸鈉、檸檬酸、冰醋酸、胺丁三醇(Trometamol)等之緩衝劑,聚山梨酸酯80、硬脂酸聚氧酯40、聚氧乙烯氫化蓖麻子油60等之界面活性劑,檸檬酸鈉、EDTA-Na等之安定劑,氯化苯二甲烴銨(benzalkonium chloride)、苯甲酸酯類、氯化苄氧乙銨(benzethonium chloride)、對羥基苯甲酸酯、苯甲酸鈉、氯丁醇、山梨酸等之防腐劑,鹽酸、檸檬酸、磷酸、冰醋酸、氫氧化鈉、碳酸鈉、碳酸氫鈉等之pH調整劑,苄基醇等之無痛化劑等來調製注射劑、點眼劑等非經口劑。
本化合物的投與量可依據症狀、年齡、劑型等適宜地選擇使用。例如經口劑通常每1日為0.01~1000mg,較佳可經由1回或分成數回投與1~100mg。此外,點眼劑通常為0.0001%~10%(w/v),較佳可經由1回或分成數回投與0.01%~5%(w/v)之濃度者。
本發明提供作為醫藥有用之本化合物構成之糖皮質激素受體激動劑、含有至少一該糖皮質激素受體激動劑為有效成分之醫藥組成物、含有至少一該糖皮質激素受體激動劑為有效成分之發炎性疾病之預防或治療劑及含有至少一該糖皮質激素受體激動劑為有效成分之眼發炎性疾病或皮膚炎之預防或治療劑。
特別是本發明之糖皮質激素受體激動劑有用於作為眼發炎性疾病或皮膚炎之預防或治療劑,有用於作為角膜炎、角結膜炎、結膜炎、眼瞼炎、眼球乾燥症候群(也稱為「乾眼症」)、過敏性結膜炎、前部葡萄膜炎、前眼部的手術後炎症、因眼組織移植排斥反應之炎症等之前眼部發炎性疾病、老年黃斑病變、糖尿病視網膜症、糖尿病黄斑浮腫、血管新生黄斑症、突發性黄斑上膜、增殖性玻璃體視網膜症、視網膜色素變性症、視網膜中心靜脈閉塞症、視網膜中心動脈閉塞症、視網膜靜脈分枝閉塞症、視網膜動脈分枝閉塞症、視網膜剝離或外傷造成之炎症或變性、後眼部的手術後炎症、視網膜炎、葡萄膜炎、鞏膜炎、視神經炎等之後眼部發炎性疾病及/或濕疹‧皮膚炎群、癢疹群、蕁麻疹、乾癬及類症、異位性皮膚炎等皮膚炎之預防或治療劑。
以下顯示本化合物之製造例、製劑例及藥理試驗的結果。又這些例示是用於更加理解本發明,但不因此限定本發明之範圍。
將2,4-二甲氧基苯基硼酸(25.0g、137mmol)、2-溴-5-硝基苯甲酸甲酯(35.7g、137mmol)、碳酸銫(89.4g、274mmol)及氯化二(三苯膦)鈀(II)(4.81g、6.85mmol)之混合物懸浮於N,N-二甲基甲醯胺(450mL),氬氮氣氣氛下在80℃攪拌一晚。放冷後添加乙酸乙酯(200mL)、二乙基醚(400mL)及水(1000mL)而分配。以乙酸乙酯(150mL)-二乙基醚(150mL)之混合溶劑萃取水層(2回)。合併有機層,以水(500mL、3回)及飽和食鹽水(500mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下經由餾除溶劑得到褐色油狀物之標記參考化合物。
(定量的)
3-羥基-8-硝基苯并[c]烯-6-酮(參考化合物1-1-(2))
將2-(2,4-二甲氧基苯基)-5-硝基苯甲酸甲酯(參考化合物1-1-(1)、43.5g、137mmol)之無水二氯甲烷(250mL)溶液冷卻至-78℃,滴下三溴化硼(96.2g、384mmol)後,在室溫攪拌1小時。冷卻至-50℃,添加甲醇(300mL)。以甲醇濾取析出物得到黄色固體之標記參考化合物(18.0g)。(產率51%)
8-胺基-3-羥基苯并[c]烯-6-酮(參考化合物1-1-(3))
將3-羥基-8-硝基苯并[c]烯-6-酮(參考化合物1-1-(2)、52.01g、202mmol)溶解於甲醇(150mL)-N,N-二甲基甲醯胺(600mL),添加10%碳上鈀(5.00g),加壓(3kgf/cm2
)氫氣氛下在室溫攪拌一晚。濾去不溶物後,減壓下餾除甲醇。添加水(2L)於殘留物。濾取析出之固體,減壓下在90℃乾燥得到淡黄色固體之標記參考化合物(44.02g)。(產率96%)
8-羥基-2,2,4-三甲基-1,2-二氫-6-氧雜-1-氮雜(azachrysene)-5-酮(參考化合物1-1-(4))
在耐壓管中,將8-胺基-3-羥基苯并[c]烯-6-酮(參考化合物1-1-(3)、40.0g、176mmol)溶解於丙酮(440mL)-N-甲基吡咯啶酮(240mL),添加碘(17.9g、70.5mmol)密封後,在110℃攪拌3天。放冷後,減壓下餾除丙酮。於所得殘留物添加乙酸乙酯(700mL)、己烷(150mL)及1%硫代硫酸鈉水溶液(700mL)而分配。以乙酸乙酯(250mL)-己烷(50mL)之混合溶劑萃取水層(3回)。合併有機層,以水(500mL、3回)及飽和食鹽水(500mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。添加氯仿(150mL)於所得殘留物,濾去不溶物。濃縮濾液後,以矽膠管柱層析(己烷-乙酸乙酯)純化得到黄色固體之標記參考化合物(26.0g)。(產率48%)
8-甲氧基甲氧基-2,2,4-三甲基-1,2-二氫-6-氧雜-1-氮雜-5-酮(參考化合物1-1-(5))
將8-羥基-2,2,4-三甲基-1,2-二氫-6-氧雜-1-氮雜-5-酮(參考化合物1-1-(4)、1.00g、3.25mmol)、氯二甲基醚(420μl、5.53mmol)及碳酸鉀(1.35g、9.77mmol)之混合物懸浮於無水N,N-二甲基甲醯胺(15mL),在50℃攪拌一晚。放冷後,添加乙酸乙酯(100mL)及二乙基醚(100mL)。以水(150mL、100mL)及飽和食鹽水(100mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物得到黄色固體之標記參考化合物(747mg)。(產率66%)
6-(2-羥基-4-甲氧基甲氧基苯基)-5-羥甲基-2,2,4-三甲基-1,2-二氫喹啉(參考化合物1-1-(6))
將氫化鋰鋁(167mg、4.40mmol)懸浮於無水四氫呋喃(3mL)。在0℃滴下8-甲氧基甲氧基-2,2,4-三甲基-1,2-二氫-6-氧雜-1-氮雜-5-酮(參考化合物1-1-(5)、744.1mg、2.12mmol)之無水四氫呋喃(10mL)溶液,同溫下攪拌30分鐘。以乙酸乙酯(2mL)及水(1mL)之順序滴下於反應液後,添加乙酸乙酯(150mL)。添加1當量鹽酸(6mL)後,以水(100mL、2回)及飽和食鹽水(50mL)之順序洗淨,經無水硫酸鎂乾燥。減壓下餾除溶劑得到淡黄色非晶形之標記參考化合物(750.6mg)。(定量的)
5-羥甲基-6-(2-甲氧基-4-甲氧基甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物1-1)
將6-(2-羥基-4-甲氧基甲氧基苯基)-5-羥甲基-2,2,4-三甲基-1,2-二氫喹啉(參考化合物1-1-(6)、746.1mg、2.10mmol)、碘化甲烷(131μl、2.10mmol)及碳酸鉀(582mg、4.21mmol)之混合物懸浮於無水N,N-二甲基甲醯胺(10mL),在50℃攪拌1小時。放冷後,添加乙酸乙酯(50mL)及二乙基醚(50mL)稀釋之。以水(100mL、2回)及飽和食鹽水(50mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到無色固體之標記參考化合物(513.2mg)。(產率66%)
以下使用市售化合物,按照參考化合物1-1之製造方法得到參考化合物1-2。
參考例3
5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-甲氧基甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物3-1)
將5-羥甲基-6-(2-甲氧基-4-甲氧基甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物1-1、511.7mg、1.39mmol)、5-氟-2-甲酚(182μL、1.67mmol)、三正丁基膦(521μL、2.09mmol)、1,1’-(偶氮二羰基)二哌啶(526mg、2.08mmol)溶解於無水苯(8mL),在氬氣氣氛下,在室溫攪拌1小時。添加己烷(15mL)於反應液,濾去不溶物。減壓下濃縮濾液,以矽膠管柱層析(己烷-乙酸乙酯)純化殘留物得到無色非晶形之標記化合物(411.4mg)。(產率62%)
以下使用參考化合物1-1或1-2,按照參考化合物3-1之製造方法得到參考化合物3-2~3-9。
參考例4
6-(2-甲氧基-4-甲氧基甲氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物4-1)
將5-氯甲基-6-(2-甲氧基-4-甲氧基甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物2、262mg、0.675mmol)、2-甲氧基苯胺(84μL、0.74mmol)及碳酸鉀(151mg、1.09mmol)之混合物懸浮於無水N,N-二甲基甲醯胺(4mL),在80℃攪拌一晚。放冷後,添加乙酸乙酯(20mL)及水(20mL)而分配。以飽和食鹽水(20mL)洗淨有機層,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到黄色非晶形之標記參考化合物(196mg)。(產率61%)
以下使用參考化合物2,按照參考化合物4-1之製造方法得到參考化合物4-2。
參考例5
5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1)
將5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-甲氧基甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物3-1、424mg、0.888mmol)溶解於1,4-二烷(5mL),添加4當量氫氯酸/1,4-二烷(666μL),在室溫攪拌一晚。添加乙酸乙酯(150mL)稀釋。以水(100mL、2回)及飽和食鹽水(50mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到無色固體之標記化合物(241.7mg)。(產率63%)
以下使用選自參考化合物3-2~3-9及4-1~4-2之化合物,按照參考化合物5-1之製造方法得到參考化合物5-2~5-11。
參考例6
6-(4-羥基-2-甲氧基苯基)-5-[N-(2-甲氧基苯基)-N-(9-茀甲氧羰基)胺甲基]-2,2,4-三甲基-1,2-二氫喹啉(參考化合物6)
將6-(4-羥基-2-甲氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-10、37.7mg、0.0876mmol)及碳酸氫鈉(9.5mg、0.113mmol)溶解於1,4-二烷(0.5mL)-水(0.5mL),冰冷下添加氯化9-茀甲氧羰基(25.6mg、0.0990mmol)。在室溫攪拌反應液3小時後,添加加乙酸乙酯(10mL)稀釋。以1當量鹽酸(10mL)、水(10mL)及飽和食鹽水(10mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到無色非晶形之標記參考化合物(19.7mg)。(產率34%)
實施例1
6-(4-苯甲醯基氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物1-1)
將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、25.5mg、0.588mmol)溶解於無水四氫呋喃(0.5mL),添加三乙胺(19.7μl、0.141mmol)及苯甲醯氯(8.2μl、0.071mmol)。在室溫攪拌反應液30分鐘。於反應液添加乙酸乙酯(100mL)稀釋。以水(100mL)、飽和食鹽水(50mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到無色固體之標記化合物(26.7mg)。(產率63%)
6-(4-第三丁氧羰基胺基乙醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物1-2)
將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、30.2mg、0.070mmol)、Boc-甘胺酸(15.1mg、0.086mmol)溶解於N,N-二甲基甲醯胺(1ml),添加N,N-二異丙基乙胺(31.4μl、0.18mmol)及O-(7-吖苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸酯(35.4mg、0.093mmol),在室溫攪拌一晚。於反應液添加乙酸乙酯(10ml),以水(10ml)、飽和食鹽水(10ml)之順序洗淨。有機層經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物,得到無色非晶形之標記化合物(35.3mg)。(產率86%)
6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物1-3)
將6-(4-羥基-2-甲氧基苯基)-5-[N-(2-甲氧基苯基)-N-(9-茀甲氧羰基)胺甲基]-2,2,4-三甲基-1,2-二氫喹啉(參考化合物6、17.4mg、0.0267mmol)溶解於二氯甲烷(0.5mL),依順序添加三乙胺(10μL、0.072mmol)及2-呋喃甲醯氯(3.6μL、0.036mmol)。在室溫攪拌反應液3小時後,以矽膠管柱層析(己烷-乙酸乙酯)純化得到無色非晶形(15.6mg)。將所得無色非晶形(11.8mg)溶解於N,N-二甲基甲醯胺(0.3mL),添加哌啶(15.6μL、0.158mmol)。在室溫攪拌反應液1分鐘後,以乙酸乙酯(10mL)稀釋。以水(10mL)及飽和食鹽水(10mL)的順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物得到無色固體之標記化合物(6.0mg)。(產率76%)
以下使用選自參考化合物5-1~5-11及6之化合物,按照化合物1-1~1-3之任一的製造方法得到化合物1-4~1-175。
(實施例2)
6-(5-乙醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物2)
將5-(5-氟-2-甲基苯氧基甲基)-6-(5-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-2、62.5mg、0.14mmol)、三乙胺(154μL、1.11mmol)溶解於無水二氯甲烷(1mL),添加無水乙酸(52μL、0.55mmol),在室溫攪拌1.5小時。於反應液添加氯仿(10mL),以水(10mL)及飽和食鹽水(300mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化殘留物得到無色非晶形之標記化合物(56.6mg)。(產率83%)
(實施例3)
6-(4-胺基乙醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉‧1鹽酸鹽(化合物3-1)
將6-(4-第三丁氧羰基胺基乙醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物1-2、20.1mg、0.034mmol)溶解於1,4-二烷(0.5mL),添加4當量氫氯酸/1,4-二烷溶液(34μL),在室溫攪拌一晚。減壓下濃縮反應液得到無色固體之標記化合物(17.5mg)。(產率98%)
(實施例4)
5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-甲基磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(化合物4-1)
將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、61.0mg、0.141mmol)溶解於二氯甲烷(2mL),添加甲磺醯氯(26μL、0.34mmol)、三乙胺(92μL、0.66mmol),在室溫攪拌一晚。以矽膠管柱層析(己烷-乙酸乙酯)純化反應液得到淡桃色固體之標記化合物(58.0mg)。(產率82%)
以下使用選自參考化合物5-1、5-3~5-6及5-10~5-11之化合物,按照化合物4-1之製造方法得到化合物4-2~4-36。
(實施例5)
5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-甲氧基羰氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(化合物5-1)將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、25.0mg、0.058mmol)溶解於四氫呋喃(0.5mL),添加三乙胺(23μL、0.17mmol)、氯甲酸甲酯(6.8μL、0.088mmol),在室溫攪拌20分鐘。以矽膠管柱層析(己烷-乙酸乙酯)純化反應液得到無色非晶形之標記化合物(28.0mg)。(產率99%)
以下使用選自參考化合物5-1、5-4、5-6及5-10之化合物,按照化合物5-1之製造方法得到化合物5-2~5-11。
(實施例6)
5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-苯胺基羰氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(化合物6-1)
將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、25.0mg、0.058mmol)溶解於四氫呋喃(0.5mL),添加三乙胺(19.3μL、0.138mmol)、異氰酸苯酯(9.5μL、0.087mmol),在室溫攪拌2小時。以矽膠管柱層析(己烷-乙酸乙酯)純化反應液得到無色非晶形之標記化合物(27.3mg)。(產率86%)
6-[4-[N-(2-二甲胺基乙基)-N-甲胺基羰氧基]-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物6-2)
將6-(4-羥基-2-甲氧基苯基)-5-[N-(2-甲氧基苯基)-N-(9-茀基甲氧羰基)胺甲基]-2,2,4-三甲基-1,2-二氫喹啉(參考化合物6、25.0mg、0.0383mmol)、1,1’-羰基二咪唑(62.0mg、0.382mmol)及4-二甲胺基吡啶(0.5mg、0.004mmol)之混合物溶解於無水四氫呋喃(1mL),在室溫攪拌4.5小時。添加N,N,N’-三甲基-乙二胺(39.2mg、0.383mmol),在60℃攪拌2小時。以矽膠管柱層析(己烷-乙酸乙酯)純化反應液。將所得無色非晶形溶解於N,N-二甲基甲醯胺(1mL),添加哌啶(50μL)。在室溫攪拌反應液15分鐘後,以乙酸乙酯(20mL)稀釋。以水(15mL)及飽和食鹽水(15mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(己烷-乙酸乙酯)純化所得殘留物得到無色非晶形之標記化合物(9.9mg)。(產率47%)
6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉(化合物6-3)
將5-(5-氟-2-甲基苯氧基甲基)-6-(4-羥基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉(參考化合物5-1、25mg、0.058mmol)溶解於吡啶(1mL),添加N,N-二甲基胺甲醯氯(6.9μL、0.075mmol),在100℃攪拌3小時。於反應液添加N,N-二甲基胺甲醯氯(3.0μL、0.033mmol),在100℃攪拌1小時。以乙酸乙酯(20mL)稀釋反應液。以0.2當量鹽酸(75mL)、水(50mL)及飽和食鹽水(50mL)之順序洗淨,經無水硫酸鎂乾燥後,減壓下餾除溶劑。以矽膠管柱層析(第1回:己烷-乙酸乙酯、第2回:甲苯-乙酸乙酯)純化所得殘留物得到無色非晶形之標記化合物(8.5mg)。(產率29%)
以下使用選自參考化合物5-1、5-3~5-6及5-10~5-11之化合物,按照化合物6-1~6-3之任一之製造方法得到化合物6-4~6-39。
以下說明含有本化合物之一般製劑例。
本化合物 1mg
乳糖 100mg
玉米澱粉 40mg
羧甲基纖維素鈣 4.5mg
羥丙基纖維素 4mg
硬脂酸鎂 0.5mg
使用3mg塗覆劑(例如羥丙基甲基纖維素、聚乙二醇(macrogol)、聚矽氧樹脂等一般的塗覆劑),於上述處方之錠劑施予塗覆,可得到目的錠劑。又適宜變更本化合物及添加物的種類及/或量,可得到所欲之錠劑。
本化合物 5mg
乳糖 135mg
羧甲基纖維素鈣 4.5mg
羥丙基纖維素 4mg
硬脂酸鎂 1.5mg
適宜變更本化合物及添加劑的種類及或量,可得到所欲之膠囊劑。
本化合物 100mg
氯化鈉 900mg
聚山梨酸酯80 500mg
氫氧化鈉 適量
鹽酸 適量
滅菌純化水 適量
適宜變更本化合物及添加物的種類及/或量,可得到所欲之點眼劑。
為評價本化合物對GR之結合活性,經由螢光極化分析法實施GR受體競爭性分析。分析中使用GR競爭性分析套組(Invitrogen公司製、Cat No.P2816),按照本套組附加之操作手冊進行。以下記載其具體的方法。
GR篩選緩衝液:10mM磷酸鉀(pH 7.4)、20mM鉬酸鈉(Na2
MoP4
)、0.1mM乙二胺四乙酸(以下稱為「EDTA」)、5mM二硫蘇糖醇(DTT)、0.1mM安定化胜肽及2%二甲亞碸所調製成之緩衝液。
4×GS1溶液:以GR篩選緩衝液稀釋螢光糖皮質激素配體FluormoneTM
GS1,調製4nM的溶液。
4×GR溶液:以GR篩選緩衝液稀釋重組人GR,調製16nM的溶液。
將被驗化合物溶解於二甲亞碸後,以GR篩選緩衝液稀釋,調製20μM的被驗化合物溶液。
1)於384井平板,每1井各注入10μL被驗化合物溶液,然後每1井各添加5μL的4×GS1溶液及5μL的4×GR溶液。
2)在暗處及室溫下培育2-4小時。
3)使用含GR篩選緩衝液之井置換被驗化合物溶液及
4×GS1溶液作為空白對照,使用微量盤測讀儀(Microplate Reader)AnalystTM
HT(LJL Biosystems公司製)測定各井之螢光偏光。
4)使用GR篩選緩衝液置換被驗化合物溶液,其他實施與前述1~3)之相同操作,其結果作為陰性對照。
5)使用2mM地塞米松(dexamethasone)置換被驗化合物溶液,其他實施與前述1~3)之相同操作,其結果作為陽性對照。
經由以下之式算出GR結合率(%)。
GR結合率(%)=100×{1-(被驗化合物溶液的螢光偏光-陽性對照溶液的螢光偏光)/(陰性對照溶液的螢光偏光-陽性對照溶液的螢光偏光)}
作為試驗結果之一例,使用化合物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或化合物6-37作為被驗化合物之場合的試驗結果示於以下。
這些化合物全部顯示64%以上的GR結合率。
為評價本化合物作為GR激動劑之作用,在LPS刺激後的人角膜上皮細胞株中檢討IL-6產生的抑制作用。樣品中之IL-6產生量的測定是使用HTRF法(Boehringer-Ingelheim公司製、Cat No.62IL6PEB),按照附加之操作手冊進行。以下記載其具體的方法。
LPS調製液:將LPS溶解於磷酸緩衝生理食鹽液(以下稱為「PBS(-)」)後,以培養液稀釋調製1μg/mL之LPS溶液。
將被驗化合物溶解於二甲亞碸(以下稱為「DMSO」)後,以培養液稀釋調製100μM之被驗化合物溶液。此外,同樣地溶解DEX,調製100μM DEX溶液,測定DEX的IL-6產生抑制率,用於算出效力(Efficacy)(%DEX)。
使用細胞:人角膜上皮細胞株(HCE-T)(理化學研究所)培養方法:
1)以PBS(-)洗淨增殖至次群集(subconfluent)狀態的HCE-T,經由胰蛋白酶-EDTA(trypsin-EDTA)處理將細胞剝離。
2)添加SHEM培養基(補充荷爾蒙之上皮細胞培養基(supplemented hormone epithelial medium):含有15%FBS、5μg/mL胰島素、0.1μg/mL霍亂毒素(choleratoxin)、10ng/mL人EGF、40μg/mL健大黴素(gentamicin)之DMEM/Ham’s F12),使胰蛋白酶去活性化。
3)回收上述懸浮液,以1000rpm離心5分鐘後得到細胞沈渣。
4)以SHEM培養基懸浮細胞沈渣,播種於培養燒瓶後,在CO2
培育箱(溫度:37℃、CO2
濃度:5%)內培養。經由本方法,使用繼代培養之細胞來試驗。
1)回收繼代培養之HCE-T,以2.0×104
細胞/0.1mL/井播種細胞於96井平底培養平板。
2)培養一晚後,除去培養基,以80μL/井添加10% FBS-DMEM/Ham’s F12培養基。
3)以10μL/井添加各被驗化合物溶液。
4)以10μL/井添加LPS溶液。
5)以添加10% FBS-DMEM/Ham’s F12培養基代替各被驗化合物溶液及LPS溶液者,作為陰性對照。
6)以10μL/井添加含有1% DMSO之10% FBS-DMEM/Ham’s F12培養基來代替各被驗化合物溶液者,作為陽性對照。
7)培養4小時終了後,回收上清液,使用HTRF human IL-6套組測定遊離於上清液中的IL-6量。
8)依照以下計算式算出IL-6產生抑制率。
經由以下之式算出IL-6產生抑制率(%)。
IL-6產生抑制率(%)=100X{1-(各樣品之IL-6產生量-陰性對照組的IL-6產生量平均值)/(陽性對照組的IL-6產生量平均值-陰性對照組的IL-6產生量平均值)}(%)
再者,DEX處理組為100時,算出IL-6產生抑制率(效力(%DEX))。
效力(%DEX)=100X{(各樣品之IL-6產生抑制率的平均)/(DEX處理組IL-6產生抑制率的平均值)}(%)
作為試驗結果之一例,使用化合物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或化合物6-37作為被驗化合物時之IL-6產生的抑制作用(%DEX)示於表I。
如表I所示,本化合物顯示優異的IL-6產生的抑制作用。因此,本化合物可使用作為GR激動劑,有用於作為發炎性疾病,特別是前眼部或後眼部發炎性疾病及發炎性的骨、關節疾病之預防或治療劑。
為評價本化合物之抗過敏作用,檢討本化合物對小鼠之過敏性結膜炎模式之血管通透性亢進抑制效果。又,本效果是從基劑投與組(對照組)的色素漏出量與被驗化合物投與組的色素漏出量算出。
於被驗化合物添加0.5%聚山梨酸酯80/生理食鹽液,調製1%(W/V)的被驗化合物懸浮液。
1)將吸着卵白蛋白(ovalbumin)(20μg/mL)之氫氧化鋁凝膠溶解於生理食鹽液,注射500μL於每一6週齡的雄性BALB/c系小鼠的腹腔內進行致敏作用(sensitization)。
2)致敏第6日再度各注射吸着卵白蛋白(20μg/mL)之氫氧化鋁凝膠500μL進行追加致敏。
3)從初回致敏至第11日、第12日、第13日、第14日及第15日,於每一小鼠的右眼點眼投與2μL/眼之含有15%(W/V)卵白蛋白的50%甘油溶液以引起過敏性結膜炎。
4)在致敏第15日之點眼投與卵白蛋白之3小時前、1小時前及15分鐘前(合計3回),於上述小鼠的右眼分別點眼投與2μL/眼之被驗化合物懸浮溶液。又,基劑投與組(對照組)中使用0.5%聚山梨酸酯80/生理食鹽液代替被驗化合物懸浮溶液。
5)致敏第15日,在點眼卵白蛋白之直前從小鼠的尾靜脈注射0.1% Evans Blue溶液,點眼卵白蛋白30分鐘後,摘出色素漏出部位之小鼠的右眼周邊,以色素萃取液萃取色素。然後測定所萃取色素之吸光度,從所得吸光度算出色素漏出量,經由計算式1算出被驗化合物投與組對於過敏性結膜炎伴隨之血管通透性亢進的血管通透性亢進抑制率。
被驗化合物投與組之血管通透性亢進抑制率(%)=(1-Ax/Ao)×100
Ao:基劑投與組(對照組)之色素漏出量
Ax:被驗化合物投與組之色素漏出量
作為試驗結果之一例,使用化合物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或化合物4-18作為被驗化合物時之血管通透性亢進抑制率(%)示於表II。
(又,數值為5-6個體、5-6眼之平均值)
如表II所示,本化合物具有血管通透性亢進阻害效果。因此,本化合物有用於作為前眼部發炎性疾病的預防或治療劑。
評價藥物之脈絡膜血管新生阻害效果的一般方法之一,已知有使用大鼠脈絡膜血管新生模式之新生血管表現試驗,此試驗方法報告於Graefe’s Arch. Cli. Exp. Ophthalmol.,235,313-319(1997)。因此,按照前述文獻記載之方法,進行本化合物之新生血管表現試驗,算出本化合物投與組之新生血管表現率對於基劑投與組(對照組)之新生血管表現率的比例,以此為指標評價本化合物之脈絡膜血管新生阻害效果。
點眼投與之場合,於被驗化合物添加0.5%聚山梨酸酯80/生理食鹽液並懸浮,調製1%(W/V)之被驗化合物懸浮液。結膜下投與之場合,於被驗化合物添加0.5%氫化蓖麻油/生理食鹽液並懸浮,調製20mg/mL之被驗化合物懸浮液。
1)對大鼠(Brown Norway雄性大鼠、7-8週齡、體重140-240g)肌肉內投與5%鹽酸氯胺酮(Ketamine hydrochloride)注射液與2%鹽酸甲苯噻(Xylazine Hydrochloride)注射液之7:1混合液(1mL/kg),全身麻醉。
2)點眼散瞳劑(Tropicamide Phenylephrine Hydrochloride)點眼液(商品名:Mydrin P)散瞳後,使用氪雷射光凝固裝置,光凝固大鼠的Bruch氏膜(Bruch's membrane)。
又,雷射照射,避免眼底後局部的粗視網膜血管,整合其焦點於視網膜深層,每一眼散佈地實施於8-9個位置。此外,該光凝固的條件為100μm的點大小(spot size)、100mM的輸出、0.1秒的凝固時間。
3)光凝固後,進行眼底攝影,確認光凝固(雷射照射)部位。
1)點眼投與之場合,從雷射照射日(第1日)至第8日,連續數日每1日4回點眼投與被驗化合物懸浮溶液。結膜下投與之場合,雷射照射後立即注射50μL一回。
2)使用0.5%聚山梨酸酯80/生理食鹽液或0.5%氫化蓖麻油/生理食鹽液代替被驗化合物懸浮溶液作為基劑投與組(對照組),其他以與1)相同之方法進行試驗,其結果作為對照。
1)在光凝固第7日,從大鼠的尾靜脈注入0.1mL之10%螢光素(fluorescein)水溶液,實施螢光眼底造影。
2)然後以螢光眼底造影,未看到螢光漏出的點為陰性,看到螢光漏出的點為陽性,看到若干螢光漏出之光凝固部位,有2個位置存在這些時判斷為陽性。
3)依照計算式1算出新生血管表現率。從各投與組之新生血管表現率,依照計算式2算出相對於基劑投與組之被驗化合物投與組的新生血管表現率之比例。
新生血管表現率(%)=(陽性光凝固部位數/全部光凝固部位數)×100
被驗化合物投與組的新生血管抑制率(%)=(1-Ax/Ao)×100
Ao:基劑投與組(對照組)的新生血管表現率
Ax:被驗化合物投與組的新生血管表現率
作為試驗結果之一例,使用化合物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或化合物6-35為被驗化合物之場合的新生血管抑制率(%)示於表III。
(又,數值為4個體、7-8眼的平均值)
如表III所示,相較於基劑,本化合物具有抑制新生血管、脈絡膜血管新生阻害效果。因此,本化合物有用於作為後眼部發炎性疾病的預防或治療劑。
為檢討藥物對乾眼症伴隨之角膜病症的改善效果,使用雄性SD大鼠,按照Fujihara等人之方法(Invest. Ophthalmol. Vis. Sci 42(1):96-100(2001))製作角膜病症模式。角膜病症模式作成後,按照村上等人之方法(新眼科21(1):87-90(2004))判定角膜病症的改善率。
於被驗化合物添加聚山梨酸酯80或含一般添加劑之基劑,調製0.03%(W/V)之被驗化合物懸浮液。
1)使用雄性SD大鼠,投與Somnopentyl、施予全身麻醉後,摘出眼窩外淚腺,使於2個月誘發角膜病症。
2)於兩眼1日6回點眼被驗化合物懸浮液14天。此外,對照組同樣地點眼基劑。
3)點眼開始14日後,以螢光素染色角膜的障害部分。至於角膜的上部、中間部及下部各處,依照下述的基準計分判定經由螢光素染色的程度,算出這些計分的合計之平均值。此外,在0、1、2、3之各計分間,設定0.5為中間值。
0:未被染色
1:染色零散,各點狀的染色部分是離散的
2:染色為中程度,點狀之染色部分的一部分鄰接
3:染色是密的,點狀之染色部分是鄰接的
被驗化合物投與組的改善率(%)=(Ao-Ax)/(Ao-An)×100
Ao:基劑投與組(對照組)的角膜病症計分平均值
Ax:被驗化合物投與組的角膜病症計分平均值
An:正常大鼠的角膜病症計分平均值
作為試驗結果之一例,使用化合物1-12、化合物1-13、化合物1-72或化合物4-18為被驗化合物之場合的角膜病症改善率(%)示於表IV。
(又,數值為4個體、8眼的平均值)
如表IV所示,相較於基劑,本化合物具有角膜病症改善效果。因此,本化合物有用於作為乾眼症等伴隨之角膜病症的預防或治療劑。
為評價本化合物對異位性皮膚炎之作用,將已發表之Nagai等人的手法(J. Pharmacol. Exp. Ther.,283:321-327(1997))施以修正之方法作為小鼠的異位性皮膚炎模式,檢討血管通透性亢進抑制效果。又,從基劑投與組(對照組)的色素漏出量與被驗化合物投與組的色素漏出量算出本效果。
於被驗化合物添加白色凡士林,調製1%(W/W)的被驗化合物軟膏。
1)於小鼠的兩耳殼的兩面塗布25μL的0.15%DNFB溶液,每週1回、4週共5回以引起皮膚炎。
2)從初回塗布DNFB的前日至第5回塗布前日之間,在兩耳殼的兩面,於小鼠耳殼的每一面塗布投與各25μL之被驗化合物軟膏每週5回、計21回。此外,在基劑投與組(對照組),同樣地塗布白色凡士林來投與。
3)第5回之DNFB溶液塗布後,立即於小鼠從尾靜脈注射0.2%Evans Blue溶液,尾靜脈注射色素2小時後,摘出色素漏出部位之小鼠的耳殼,以色素萃取液萃取色素。然後測定所萃取色素的吸光度,從所得吸光度算出漏出色素量,經由計算式1算出被驗化合物投與組對於異位性皮膚炎伴隨之血管通透性亢進的血管通透性亢進抑制率。
被驗化合物投與組的血管通透性亢進抑制率(%)=(1-Ax/Ao)×100
Ao:基劑投與組(對照組)的色素漏出量
Ax:被驗化合物投與組的色素漏出量
作為試驗結果之一例,使用化合物1-12、化合物1-13、化合物1-72或化合物4-18作為被驗化合物時之血管通透性亢進抑制率(%)示於表V。
(又,數值為6個體、12耳的平均值)
如表V所示,相較於基劑,本化合物具有異位性皮膚炎伴隨之血管通透性亢進阻害效果。因此,本化合物有用於作為異位性皮膚炎等之皮膚炎的預防或治療劑。
本發明有用於作為糖皮質激素受體激動劑、含有該糖皮質激素受體激動劑為有效成分之醫藥組成物、含有該糖皮質激素受體激動劑為有效成分之發炎性疾病的預防或治療劑及含有該糖皮質激素受體激動劑為有效成分之眼發炎性疾病或皮膚炎的預防或治療劑,特別是有用於作為角膜炎、角結膜炎、結膜炎、眼瞼炎、眼球乾燥症候群(也稱為「乾眼症」)、過敏性結膜炎、前部葡萄膜炎、前眼部之手術後炎症、眼組織移植排斥反應造成之炎症等之前眼部發炎性疾病及/或老年黃斑病變(初期老年黃斑病變、萎縮型老年黃斑病變及/或滲出型老年黃斑病變)、糖尿病視網膜症、糖尿病黄斑浮腫、血管新生黄斑症、突發性黄斑上膜、增殖性玻璃體視網膜症、視網膜色素變性症、視網膜中心靜脈閉塞症、視網膜中心動脈閉塞症、視網膜靜脈分枝閉塞症、視網膜動脈分枝閉塞症、視網膜剝離或外傷造成之炎症或變性、後眼部的手術後炎症、視網膜炎、葡萄膜炎、鞏膜炎、視神經炎等之後眼部發炎性疾病的預防或治療劑。
Claims (35)
- 一種下述一般式(1)所表示之化合物或其鹽所構成之糖皮質激素受體激動劑,
- 如申請專利範圍第1項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中:R1 表示下述一般式(2a)、(3a)、(4a)或(5a);
- 如申請專利範圍第1或2項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R1 表示下述一般式(2a-1)、(2a-2)、(2a-3)、(3a-1)、(3a-2)、(4a-1)、(4a-2)、(4a-3)、(5a-1)或(5a-2);
- 如申請專利範圍第3項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R1 表示下述一般式(2a-1)、(2a-2)、(2a-3)、(3a-1)、(3a-2)、(4a-2)或(5a-1);
- 如申請專利範圍第1或2項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R2 表示-(CO)-R8 、-(CO)O-R9 、-(SO2 )-R11 或-(CO)NR12 R13 。
- 如申請專利範圍第5項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R2 表示-(CO)-R8 或-(SO2 )-R11 。
- 如申請專利範圍第6項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R2 表示-(CO)-R8 。
- 如申請專利範圍第1或2項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R3 表示甲基。
- 如申請專利範圍第1或2項之化合物或其鹽所構成之糖皮質激素受體激動劑,在一般式(1)中R2 -O-為取代於苯環A的4位置。
- 一種選自由下所組群組之化合物或其鹽所構成之糖皮質激素受體激動劑, .6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲氧基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-丁醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-(4-異丁醯氧基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-苯基乙醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[5-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-5-丙醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-5-(吡啶-3-基 羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-乙醯氧基苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(噻唑-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(5-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(3-甲氧羰基苯甲醯基氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(6-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、 .6-(4-第三丁基羰氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氯吡啶-4-基羰氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[4-(3-氟吡啶-4-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(2-甲氧基-5-硝基苯氧基甲基)-6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-苯甲醯基氧基-2-甲氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-氟-2-甲基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基 苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(2-甲氧基苯基胺甲基)-6-[2-甲氧基-4-(噻吩-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(3-甲氧羰基苯甲醯基氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(4-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、 .5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(6-甲基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(4-甲基苯甲醯基氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲氧基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(4-氯苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-苯甲醯基氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻 吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(噻吩-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(呋喃-3-基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲硫基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-甲基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(噻唑-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(吡啶-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(4-甲氧基苯甲醯基氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-溴噻吩-2-基羰氧甲基)-6-[2-甲氧基-4-(吡啶-3-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-溴噻吩-2-基羰氧甲基)-6-[4-(呋喃-2-基羰氧基)-2-甲氧基苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-異丙基羰氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(2-乙醯氧基苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、 .6-[2-甲氧基-4-(2-甲氧基吡啶-3-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(4-氟苯甲醯基氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(2-硝基苯甲醯基氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(3-甲基呋喃-2-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-(4-異丙磺醯氧基-2-甲氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-丁磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(2-甲氧基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(2-甲氧基-4-丙磺醯氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯 氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(2-甲氧基苯基胺甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(2-甲氧基-4-甲基磺醯氧基苯基)-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯基胺甲基)-6-(2-甲氧基-4-丙磺醯氧基苯基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(3,3,3-三氟丙磺醯氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(2-甲氧基-4-丙磺醯氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-異丙磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-環戊基磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-乙磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-環丙基磺醯氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-[N-(2-二甲胺基乙基)-N-乙胺基羰氧基]-2-甲氧基苯基]-5-(5-氟-2-甲基苯氧基甲基)-2,2,4-三甲基-1,2-二 氫喹啉、.6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[4-(4-氯苯胺基羰氧基)-2-甲氧基苯基]-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉、.5-(5-氟-2-甲基苯氧基甲基)-6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-2,2,4-三甲基-1,2-二氫喹啉、.6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(2-甲基-5-硝基苯氧基甲基)-2,2,4-三甲基-1,2-二氫喹啉、.6-[2-甲氧基-4-(嗎福啉-4-基羰氧基)苯基]-5-(2-甲氧基苯基胺甲基)-2,2,4-三甲基-1,2-二氫喹啉、及6-(4-二甲胺基羰氧基-2-甲氧基苯基)-5-(5-甲基噻吩-2-基羰氧甲基)-2,2,4-三甲基-1,2-二氫喹啉。
- 如申請專利範圍第1、2或10項之糖皮質激素受體激動劑,其係使用於發炎性疾病或免疫疾病之預防或治療方法。
- 如申請專利範圍第1、2或10項之糖皮質激素受體激動劑,其係使用於眼發炎性疾病或皮膚炎之預防或治療方法。
- 如申請專利範圍第12項之糖皮質激素受體激動劑,其中眼發炎性疾病是前眼部發炎性疾病。
- 如申請專利範圍第13項之糖皮質激素受體激動劑,其中前眼部發炎性疾病是眼球乾燥症候群或過敏性結膜 炎。
- 如申請專利範圍第12項之糖皮質激素受體激動劑,其中眼發炎性疾病是後眼部發炎性疾病。
- 如申請專利範圍第15項之糖皮質激素受體激動劑,其中後眼部發炎性疾病是老年黃斑病變、糖尿病視網膜症或糖尿病黄斑浮腫。
- 如申請專利範圍第12項之糖皮質激素受體激動劑,其中皮膚炎為異位性皮膚炎。
- 如申請專利範圍第1、2或10項之糖皮質激素受體激動劑,其係使用於自體免疫疾病之預防或治療方法。
- 一種醫藥組成物,其含有如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之至少一種為有效成分。
- 一種發炎性疾病或免疫疾病之預防或治療劑,其含有如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之至少一種為有效成分。
- 一種眼發炎性疾病或皮膚炎之預防或治療劑,其含有如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之至少一種為有效成分。
- 如申請專利範圍第21項之預防或治療劑,其中眼發炎性疾病是前眼部發炎性疾病。
- 如申請專利範圍第22項之預防或治療劑,其中前眼部發炎性疾病是眼球乾燥症候群或過敏性結膜炎。
- 如申請專利範圍第21項之預防或治療劑,其中眼發炎性疾病是後眼部發炎性疾病。
- 如申請專利範圍第24項之預防或治療劑,其中後眼部發炎性疾病是老年黃斑病變、糖尿病視網膜症或糖尿病黄斑浮腫。
- 如申請專利範圍第21項之預防或治療劑,其中皮膚炎是異位性皮膚炎。
- 一種自體免疫疾病之預防或治療劑,其含有如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之至少一種為有效成分。
- 一種如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之用途,其係用於製造發炎性疾病或免疫疾病之預防藥或治療藥。
- 一種如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之用途,其係用於製造眼發炎性疾病或皮膚炎之預防藥或治療藥。
- 如申請專利範圍第29項之用途,其中眼發炎性疾病是前眼部發炎性疾病。
- 如申請專利範圍第30項之用途,其中前眼部發炎性疾病是眼球乾燥症候群或過敏性結膜炎。
- 如申請專利範圍第29項之用途,其中眼發炎性疾病是後眼部發炎性疾病。
- 如申請專利範圍第32項之用途,其中後眼部發炎性疾 病是老年黃斑病變、糖尿病視網膜症或糖尿病黄斑浮腫。
- 如申請專利範圍第29項之用途,其中皮膚炎是異位性皮膚炎。
- 一種如申請專利範圍第1至10項中任一項之糖皮質激素受體激動劑之用途,其係用於製造自體免疫疾病之預防藥或治療藥。
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RU2485104C2 (ru) | 2006-11-14 | 2013-06-20 | Сантен Фармасьютикал Ко., Лтд. | Новые производные 1,2-дигидрохинолина, обладающие активностью связывания глюкокортикоидного рецептора |
TW201309663A (zh) * | 2011-02-09 | 2013-03-01 | 參天製藥股份有限公司 | 3-羥基-6H-苯并[c]□唍烯-6-酮衍生物及其製造方法 |
KR20140117481A (ko) * | 2012-01-20 | 2014-10-07 | 산텐 세이야꾸 가부시키가이샤 | 1,2-디하이드로퀴놀린 유도체 또는 그의 염의 공업적 제조 방법 및 그 제조 중간체 |
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KR20180043329A (ko) * | 2015-08-25 | 2018-04-27 | 산텐 세이야꾸 가부시키가이샤 | [4-(1,3,3-트리메틸-2-옥소-3,4-디히드로-1h-퀴녹살린-7-일)페녹시]에틸옥시 화합물 또는 그의 염 |
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 |
CN110944668A (zh) | 2017-06-16 | 2020-03-31 | 学校法人同志社 | 用于治疗或预防眼部症状、障碍或疾病的包含mTOR抑制剂的药物及其应用 |
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EP2319835A1 (en) | 2011-05-11 |
CN105395550B (zh) | 2018-07-17 |
EA201071296A1 (ru) | 2011-06-30 |
CN105395550A (zh) | 2016-03-16 |
BRPI0912171B1 (pt) | 2020-11-03 |
US8426406B2 (en) | 2013-04-23 |
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ES2574987T3 (es) | 2016-06-23 |
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AU2009247250A1 (en) | 2009-11-19 |
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MX2010012303A (es) | 2011-03-30 |
TW200950781A (en) | 2009-12-16 |
BRPI0912171B8 (pt) | 2021-05-25 |
BRPI0912171A2 (pt) | 2017-10-31 |
BRPI0912171A8 (pt) | 2017-12-12 |
MY158747A (en) | 2016-11-15 |
KR20110010634A (ko) | 2011-02-01 |
EP2319835A4 (en) | 2011-12-28 |
CN102089283A (zh) | 2011-06-08 |
EP2319835B1 (en) | 2016-04-13 |
AU2009247250B2 (en) | 2014-04-10 |
EA019091B1 (ru) | 2014-01-30 |
UA102101C2 (ru) | 2013-06-10 |
CN102089283B (zh) | 2015-11-25 |
CA2724055A1 (en) | 2009-11-19 |
US20110118260A1 (en) | 2011-05-19 |
WO2009139361A1 (ja) | 2009-11-19 |
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