JP2008526790A - スクアリン酸誘導体 - Google Patents
スクアリン酸誘導体 Download PDFInfo
- Publication number
- JP2008526790A JP2008526790A JP2007549807A JP2007549807A JP2008526790A JP 2008526790 A JP2008526790 A JP 2008526790A JP 2007549807 A JP2007549807 A JP 2007549807A JP 2007549807 A JP2007549807 A JP 2007549807A JP 2008526790 A JP2008526790 A JP 2008526790A
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- JP
- Japan
- Prior art keywords
- dione
- cyclobut
- ene
- hydroxy
- ethylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical class OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 title abstract 2
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 206010016654 Fibrosis Diseases 0.000 claims abstract description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
- 208000017169 kidney disease Diseases 0.000 claims abstract description 11
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 230000004761 fibrosis Effects 0.000 claims abstract description 7
- 208000019622 heart disease Diseases 0.000 claims abstract description 7
- 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 5
- 230000009885 systemic effect Effects 0.000 claims abstract description 5
- 208000037905 systemic hypertension Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 111
- 150000003839 salts Chemical class 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 60
- 239000004480 active ingredient Substances 0.000 claims description 38
- 239000012453 solvate Substances 0.000 claims description 31
- -1 4-hydroxy-3-aminosulfonylphenylamino Chemical group 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 108091000080 Phosphotransferase Proteins 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 102000020233 phosphotransferase Human genes 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 206010053567 Coagulopathies Diseases 0.000 claims description 8
- 208000015294 blood coagulation disease Diseases 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 201000009101 diabetic angiopathy Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
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- 230000002924 anti-infective effect Effects 0.000 claims description 5
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 230000011664 signaling Effects 0.000 claims description 5
- 210000004881 tumor cell Anatomy 0.000 claims description 5
- WECVNCVLORISOS-SECBINFHSA-N 3-(3-chloro-4-hydroxyanilino)-4-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C(Cl)=C1 WECVNCVLORISOS-SECBINFHSA-N 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 4
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 4
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
- 208000006029 Cardiomegaly Diseases 0.000 claims description 4
- 208000002177 Cataract Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 208000032056 Radiation Fibrosis Syndrome Diseases 0.000 claims description 4
- 206010067953 Radiation fibrosis Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 230000009787 cardiac fibrosis Effects 0.000 claims description 4
- 208000007451 chronic bronchitis Diseases 0.000 claims description 4
- 230000007882 cirrhosis Effects 0.000 claims description 4
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 4
- RGBVWCQARBEPPW-UHFFFAOYSA-N cyclobut-3-ene-1,2-dione Chemical compound O=C1C=CC1=O RGBVWCQARBEPPW-UHFFFAOYSA-N 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- 201000002249 diabetic peripheral angiopathy Diseases 0.000 claims description 4
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- 230000029142 excretion Effects 0.000 claims description 4
- 230000003176 fibrotic effect Effects 0.000 claims description 4
- 206010061989 glomerulosclerosis Diseases 0.000 claims description 4
- 201000008383 nephritis Diseases 0.000 claims description 4
- 201000009925 nephrosclerosis Diseases 0.000 claims description 4
- 230000008587 neuronal excitability Effects 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 231100000241 scar Toxicity 0.000 claims description 4
- UGYGPNWZMYEHMR-UHFFFAOYSA-N 3,4-bis(4-hydroxyanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=CC(O)=CC=C1NC(C(C1=O)=O)=C1NC1=CC=C(O)C=C1 UGYGPNWZMYEHMR-UHFFFAOYSA-N 0.000 claims description 3
- KNKACFPVPONSJT-LLVKDONJSA-N 3-(4-hydroxy-3-methylanilino)-4-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C(C)=C1 KNKACFPVPONSJT-LLVKDONJSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010054044 Diabetic microangiopathy Diseases 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 3
- WBYHARPCBIDFCG-UHFFFAOYSA-N 2-hydroxy-5-[[2-[(3-hydroxyphenyl)methylamino]-3,4-dioxocyclobuten-1-yl]amino]benzoic acid Chemical compound C1=C(O)C(C(=O)O)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 WBYHARPCBIDFCG-UHFFFAOYSA-N 0.000 claims description 2
- PBRWZGPDUQCEIM-UHFFFAOYSA-N 2-hydroxy-5-[[2-[(3-hydroxyphenyl)methylamino]-3,4-dioxocyclobuten-1-yl]amino]benzonitrile Chemical compound OC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(C(O)=CC=2)C#N)=O)=C1 PBRWZGPDUQCEIM-UHFFFAOYSA-N 0.000 claims description 2
- FUDISYOINDBUKW-SECBINFHSA-N 2-hydroxy-5-[[2-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzenesulfonamide Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C(S(N)(=O)=O)=C1 FUDISYOINDBUKW-SECBINFHSA-N 0.000 claims description 2
- UQAAGYVNYFPRLF-SECBINFHSA-N 2-hydroxy-5-[[2-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzoic acid Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C(C(O)=O)=C1 UQAAGYVNYFPRLF-SECBINFHSA-N 0.000 claims description 2
- NQUUHJLODZMXKW-UHFFFAOYSA-N 3,4-bis(4-hydroxy-3-methylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NC=2C=C(C)C(O)=CC=2)=O)=C1 NQUUHJLODZMXKW-UHFFFAOYSA-N 0.000 claims description 2
- MKWZZCCGJPDXIQ-UHFFFAOYSA-N 3-(3-chloro-4-hydroxyanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound OC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(Cl)C(O)=CC=2)=O)=C1 MKWZZCCGJPDXIQ-UHFFFAOYSA-N 0.000 claims description 2
- MZLPSLRLISIJBY-UHFFFAOYSA-N 3-(3-chloro-4-hydroxyanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(Cl)C(O)=CC=2)=O)=C1 MZLPSLRLISIJBY-UHFFFAOYSA-N 0.000 claims description 2
- CMJFMUAKVMCJLE-UHFFFAOYSA-N 3-(3-ethyl-4-hydroxyanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(CC)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 CMJFMUAKVMCJLE-UHFFFAOYSA-N 0.000 claims description 2
- MLFMBEDHBPIYNV-UHFFFAOYSA-N 3-(3-ethyl-4-hydroxyanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(CC)=CC(NC=2C(C(=O)C=2NCC=2C=C(OC)C=CC=2)=O)=C1 MLFMBEDHBPIYNV-UHFFFAOYSA-N 0.000 claims description 2
- REMMTQUPVWNVPK-LLVKDONJSA-N 3-(3-ethyl-4-hydroxyanilino)-4-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(CC)=CC(NC=2C(C(=O)C=2N[C@H](C)C=2C=C(O)C=CC=2)=O)=C1 REMMTQUPVWNVPK-LLVKDONJSA-N 0.000 claims description 2
- CZMHRCBLXVCPFE-UHFFFAOYSA-N 3-(3-hydroxyanilino)-4-(4-hydroxy-3-methylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NC=2C=C(O)C=CC=2)=O)=C1 CZMHRCBLXVCPFE-UHFFFAOYSA-N 0.000 claims description 2
- XDSQILRRFJSORK-UHFFFAOYSA-N 3-(4-hydroxy-2-methylanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound CC1=CC(O)=CC=C1NC(C(C1=O)=O)=C1NCC1=CC=CC(O)=C1 XDSQILRRFJSORK-UHFFFAOYSA-N 0.000 claims description 2
- TUMVDPRAWPPWJD-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound CC1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 TUMVDPRAWPPWJD-UHFFFAOYSA-N 0.000 claims description 2
- CHIZMKCDTVMZIW-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(C)C(O)=C(C)C=2)=O)=C1 CHIZMKCDTVMZIW-UHFFFAOYSA-N 0.000 claims description 2
- YIAKSDPANHFYKV-GFCCVEGCSA-N 3-(4-hydroxy-3,5-dimethylanilino)-4-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC(C)=C(O)C(C)=C1 YIAKSDPANHFYKV-GFCCVEGCSA-N 0.000 claims description 2
- QLPSZBPHBYZYOZ-CYBMUJFWSA-N 3-(4-hydroxy-3,5-dimethylanilino)-4-[[(1r)-1-(3-methoxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC([C@@H](C)NC=2C(C(=O)C=2NC=2C=C(C)C(O)=C(C)C=2)=O)=C1 QLPSZBPHBYZYOZ-CYBMUJFWSA-N 0.000 claims description 2
- AZAQNCJXRLJAMQ-UHFFFAOYSA-N 3-(4-hydroxy-3,5-dimethylanilino)-4-[[1-(3-hydroxyphenyl)cyclopropyl]amino]cyclobut-3-ene-1,2-dione Chemical compound CC1=C(O)C(C)=CC(NC=2C(C(=O)C=2NC2(CC2)C=2C=C(O)C=CC=2)=O)=C1 AZAQNCJXRLJAMQ-UHFFFAOYSA-N 0.000 claims description 2
- DWKVFSPRMDBZGX-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[(2-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C(=CC=CC=2)O)=O)=C1 DWKVFSPRMDBZGX-UHFFFAOYSA-N 0.000 claims description 2
- KAAALFWNCZMUIE-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[(2-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC=C1CNC(C(C1=O)=O)=C1NC1=CC=C(O)C(C)=C1 KAAALFWNCZMUIE-UHFFFAOYSA-N 0.000 claims description 2
- TXSMMWCBYNQSIC-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 TXSMMWCBYNQSIC-UHFFFAOYSA-N 0.000 claims description 2
- NODDZPGQURGUDV-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(C)C(O)=CC=2)=O)=C1 NODDZPGQURGUDV-UHFFFAOYSA-N 0.000 claims description 2
- VJDRFZIFYVXRMK-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[(3-nitrophenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(C=CC=2)[N+]([O-])=O)=O)=C1 VJDRFZIFYVXRMK-UHFFFAOYSA-N 0.000 claims description 2
- XGDBMUPRJFOSCV-GFCCVEGCSA-N 3-(4-hydroxy-3-methylanilino)-4-[[(1r)-1-(3-methoxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC([C@@H](C)NC=2C(C(=O)C=2NC=2C=C(C)C(O)=CC=2)=O)=C1 XGDBMUPRJFOSCV-GFCCVEGCSA-N 0.000 claims description 2
- KNKACFPVPONSJT-NSHDSACASA-N 3-(4-hydroxy-3-methylanilino)-4-[[(1s)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound N([C@@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C(C)=C1 KNKACFPVPONSJT-NSHDSACASA-N 0.000 claims description 2
- UUHKVWFEMOSFET-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[[1-(3-hydroxyphenyl)cyclopropyl]amino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NC2(CC2)C=2C=C(O)C=CC=2)=O)=C1 UUHKVWFEMOSFET-UHFFFAOYSA-N 0.000 claims description 2
- WCTMCWZDFGOQHC-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[[1-(3-methoxyphenyl)cyclopropyl]amino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(C2(CC2)NC=2C(C(=O)C=2NC=2C=C(C)C(O)=CC=2)=O)=C1 WCTMCWZDFGOQHC-UHFFFAOYSA-N 0.000 claims description 2
- FARPHOIPZHGUFZ-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[[3-(trifluoromethoxy)phenyl]methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(OC(F)(F)F)C=CC=2)=O)=C1 FARPHOIPZHGUFZ-UHFFFAOYSA-N 0.000 claims description 2
- VVBGBVGMCCWYEO-UHFFFAOYSA-N 3-(4-hydroxy-3-methylanilino)-4-[[3-(trifluoromethyl)phenyl]methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(C=CC=2)C(F)(F)F)=O)=C1 VVBGBVGMCCWYEO-UHFFFAOYSA-N 0.000 claims description 2
- IXMZYHNNTLIGQR-UHFFFAOYSA-N 3-(4-hydroxy-3-nitroanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound OC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(C(O)=CC=2)[N+]([O-])=O)=O)=C1 IXMZYHNNTLIGQR-UHFFFAOYSA-N 0.000 claims description 2
- RPIIQCCKUSPFJF-SECBINFHSA-N 3-(4-hydroxy-3-nitroanilino)-4-[[(1r)-1-(3-hydroxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound N([C@H](C)C=1C=C(O)C=CC=1)C(C(C1=O)=O)=C1NC1=CC=C(O)C([N+]([O-])=O)=C1 RPIIQCCKUSPFJF-SECBINFHSA-N 0.000 claims description 2
- NLOKHCNBDIBUTJ-UHFFFAOYSA-N 3-(4-hydroxy-3-propan-2-ylanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=C(C(O)=CC=2)C(C)C)=O)=C1 NLOKHCNBDIBUTJ-UHFFFAOYSA-N 0.000 claims description 2
- QLLBJJIARIMBAD-CYBMUJFWSA-N 3-(4-hydroxy-3-propan-2-ylanilino)-4-[[(1r)-1-(3-methoxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC([C@@H](C)NC=2C(C(=O)C=2NC=2C=C(C(O)=CC=2)C(C)C)=O)=C1 QLLBJJIARIMBAD-CYBMUJFWSA-N 0.000 claims description 2
- HNVYGNJSPXXFMQ-UHFFFAOYSA-N 3-(4-hydroxy-3-propanoylanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C(=O)CC)=CC(NC=2C(C(=O)C=2NCC=2C=C(OC)C=CC=2)=O)=C1 HNVYGNJSPXXFMQ-UHFFFAOYSA-N 0.000 claims description 2
- MUCIFNQXIXZMEE-GFCCVEGCSA-N 3-(4-hydroxy-3-propanoylanilino)-4-[[(1r)-1-(3-methoxyphenyl)ethyl]amino]cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C(=O)CC)=CC(NC=2C(C(=O)C=2N[C@H](C)C=2C=C(OC)C=CC=2)=O)=C1 MUCIFNQXIXZMEE-GFCCVEGCSA-N 0.000 claims description 2
- FLPGVWNUYOPJRQ-UHFFFAOYSA-N 3-(4-hydroxyanilino)-4-[(3-hydroxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound C1=CC(O)=CC=C1NC(C(C1=O)=O)=C1NCC1=CC=CC(O)=C1 FLPGVWNUYOPJRQ-UHFFFAOYSA-N 0.000 claims description 2
- LAAGELQKGFTRAQ-UHFFFAOYSA-N 3-(4-hydroxyanilino)-4-[(3-methoxyphenyl)methylamino]cyclobut-3-ene-1,2-dione Chemical compound COC1=CC=CC(CNC=2C(C(=O)C=2NC=2C=CC(O)=CC=2)=O)=C1 LAAGELQKGFTRAQ-UHFFFAOYSA-N 0.000 claims description 2
- ZDZLAEPGKJOTMH-UHFFFAOYSA-N 3-[(3-chlorophenyl)methylamino]-4-(4-hydroxy-3-methylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C)=CC(NC=2C(C(=O)C=2NCC=2C=C(Cl)C=CC=2)=O)=C1 ZDZLAEPGKJOTMH-UHFFFAOYSA-N 0.000 claims description 2
- WZSOHUXUVFMMRD-UHFFFAOYSA-N 3-[(3-chlorophenyl)methylamino]-4-(4-hydroxyanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=CC(O)=CC=C1NC(C(C1=O)=O)=C1NCC1=CC=CC(Cl)=C1 WZSOHUXUVFMMRD-UHFFFAOYSA-N 0.000 claims description 2
- KULSXZDKAIDCDJ-UHFFFAOYSA-N 3-[(3-hydroxyphenyl)methylamino]-4-(4-hydroxy-3-propan-2-ylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C(C)C)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 KULSXZDKAIDCDJ-UHFFFAOYSA-N 0.000 claims description 2
- KIQRVZVWCXKOBA-UHFFFAOYSA-N 3-[(3-hydroxyphenyl)methylamino]-4-(4-hydroxy-3-propanoylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(C(=O)CC)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 KIQRVZVWCXKOBA-UHFFFAOYSA-N 0.000 claims description 2
- LZERSGNZDUUEGL-UHFFFAOYSA-N 3-[(3-hydroxyphenyl)methylamino]-4-(4-hydroxy-3-propylanilino)cyclobut-3-ene-1,2-dione Chemical compound C1=C(O)C(CCC)=CC(NC=2C(C(=O)C=2NCC=2C=C(O)C=CC=2)=O)=C1 LZERSGNZDUUEGL-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
本発明は、価値ある特性を有する新規化合物、特に医薬の製造に用いることができる化合物を見出す目的を有していた。
本発明は、キナーゼシグナル伝達の阻害、調節および/または調整、特に細胞容積調節ヒトキナーゼh−sgk(ヒト血清およびグルココルチコイド依存性キナーゼまたはSGK)によるものが一因となる化合物に関し、さらにこれらの化合物を含む医薬組成物に関し、ならびにSGK誘発疾患の処置に対する化合物の使用に関する。
本発明の化合物は、好ましくはSGK−1の選択的阻害剤である。それらはさらに、SGK−2および/またはSGK−3の阻害剤であってもよい。
本発明の化合物をさらに、例えば、フィブリノゲン異常症、低プロコンバーチン血症、血友病B、スチュアートプラウアー因子欠乏症、プロトロンビン複合体欠乏症、消費性凝固障害、線溶亢進、免疫凝固障害または複合性凝固障害などの凝固障害の処置に対して、また、神経細胞の興奮性、例えば、てんかんにおいて使用する。本発明の化合物をまた、緑内障または白内障の処置において、治療に用いることができる。
本発明の化合物をさらに、細菌感染の処置および抗感染療法において使用する。本発明の化合物はまた、学習能力および注意を増加させるために治療に用いることができる。加えて、本発明の化合物は、細胞の老化およびストレスに対抗し、したがって寿命および高齢者の健康を増加させる。
特にこれらは、SGK阻害作用を示す。
US 5,466,712およびUS 5,605,909は、他のN−アリール−およびN−ヘテロアリール−1,2−ジアミノシクロブテン−3,4−ジオン類を平滑筋弛緩薬として記載している。
合成樹脂の安定剤としてスクアリン酸アミド類が、US 4,170,588およびDE 1669798に記載されている。
WO 02/083624、WO 02/076926、US 2003/0204085およびWO 03/080053は、炎症または癌などのケモカイン誘発疾患の処置のための3,4−置換シクロブテン−1,2−ジオン類をCXCケモカイン受容体リガンドとして記載している。
ケモカイン(特にIL−8)誘発疾患の処置のための他の3,4−置換シクロブテン−1,2−ジオン類は、WO 01/92202およびWO 01/64208からIL−8受容体拮抗剤として知られている。
抗感染療法におけるキナーゼ阻害剤の使用が、C.Doerigにより、Cell. Mol. Biol. Lett. Vol.8, No. 2A, 2003, 524-525に記載されている。
肥満におけるキナーゼ阻害剤の使用が、N.Perrottiにより、J. Biol. Chem. 2001, March 23; 276(12):9406-9412に記載されている。
1: Chung EJ, Sung YK, Farooq M, Kim Y, Im S, Tak WY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells. 2002;14:382-7.
2: Brickley DR, Mikosz CA, Hagan CR, Conzen SD. Ubiquitin modification of serumand glucocorticoid-induced protein kinase-1(SGK-1). J Biol Chem. 2002;277:43064-70.
4: Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001;21:952-65
6: Zuo Z, Urban G, Scammell JG, Dean NM, McLean TK, Aragon I, Honkanen RE. Ser/Thr protein phosphatase type 5 (PP5) is a negative regulator of glucocorticoid receptor-mediated growth arrest. Biochemistry. 1999;38:8849-57.
8: M. Hertweck, C. Gobel, R. Baumeister: C.elegans SGK-1 is the critical component in the Akt/PKB Kinase complex to control stress responseおよびlife span. Developmental Cell, Vol. 6, 577-588, April, 2004.
Rは、HまたはAを示し、
R1、R1’はそれぞれ、互いに独立して、H、A、Hal、CN、NO2、C(=O)A、CHO、CH(OH)A、NH2、NH(C=O)A、COOH、COOAまたはSO2NH2、CONH2またはCONA2を示し、
R2は、OH、OA、Hal、CF3、NO2またはSO2NH2を示し、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜7個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2、CHA、CA2または
Halは、F、Cl、BrまたはIを示し、
nは、1、2、3または4を示し、
ここでbis(4−ヒドロキシフェニルアミノ)シクロブト−3−エン−1,2−ジオンは除外される、
で表される化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物に関する。
Aは、1、2、3または4個のC原子を有するアルキルを示し、
R、R1およびR1’は、請求項1に示した意味を有する、
で表される化合物が、式III
XおよびR2は、請求項1に示した意味を有する、
で表される化合物と反応する、
または
および/または式Iの塩基または酸を、その塩の1つに変換する
ことを特徴とする、式Iの化合物ならびにそれらの薬学的に使用可能な誘導体、互変異性体、溶媒和物、塩および立体異性体の製造方法に関する。
プロドラッグ誘導体とは、例えば、アルキルまたはアシル基、糖またはオリゴペプチドにより修飾され、本発明の活性な化合物を生じさせるために、生物内で急速に開裂する、式Iの化合物の意味に解釈される。
これらはまた、例えば、Int. J. Pharm. 115, 61-67 (1995)中に記載されているように、本発明の化合物の生物分解可能なポリマー誘導体も含む。
加えて、表現「治療有効量」は、この量を受けていない対応する対象に比べて、以下の結果を有する量を意味する:
疾患、症候群、状態、病状、疾患または副作用の改善された処置、治癒、防止または除去、あるいはまた、疾患、状態または疾患の進行の低減。
表現「治療有効量」はまた、正常な生理機能を増加させるのに効果的な量も包含する。
これらは、特に好ましくは立体異性化合物の混合物である。
2回以上現れる全ての基について、それらの意味は、それぞれ独立している。
本明細書中、基またはパラメーターR、R1、R1’、R2およびXは、他にとくに明記しない限り、式Iにおいて定義したとおりである。
非常に特に好ましくは、1、2、3、4、5または6個のC原子を有するアルキルを示し、好ましくはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、トリフルオロメチル、ペンタフルオロエチルまたは1,1,1−トリフルオロエチルである。
R1は好ましくは、H、A、Hal、CN、NO2、CH(OH)A、C(=O)A、COOH、COOAまたはSO2NH2;特に好ましくはHまたはAを示す。
R1’は好ましくは、HまたはAを示す。
R2は好ましくは、OHまたはOAを示す。
Iaにおいて、R1は、H、A、Hal、CN、NO2、CH(OH)A、C(=O)A、COOH、COOAまたはSO2NH2を示し;
R1’は、HまたはAを示す;
Ibにおいて、Rは、Hを示し、
R1、R1’はそれぞれ、互いに独立して、HまたはAを示し、
R2は、OHまたはOAを示す;
R1は、H、A、Hal、CN、NO2、CH(OH)A、C(=O)A、COOH、COOAまたはSO2NH2を示し、
R1’は、HまたはAを示し、
R2は、OH、OA、Hal、CF3、NO2またはSO2NH2を示し、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜7個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2、CHA、CA2または
Halは、F、Cl、BrまたはIを示し、
nは、1、2、3または4を示す;
Ieにおいて、Rは、Hを示し、
R1、R1’はそれぞれ、互いに独立して、HまたはAを示し、
R2は、OHまたはOAを示し、
Aは、1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜5個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2またはCHAを示す;
ならびに、それらの薬学的に使用可能な誘導体、互変異性体、溶媒和物、塩および立体異性体、またはそれらの全ての比率での混合物である。
出発化合物は、一般に知られている。しかしながら、それらが新規の場合は、それらは本来知られている方法により製造することができる。
反応は、当業者に既知の方法により行われる。
反応は、一般的に不活性溶媒中で行われる。
エーテルの開裂は、当業者に既知の方法を使って行われる。
エーテル開裂の標準方法は、三臭化ホウ素の使用である。
本発明の前記化合物は、それらの最終的な、塩ではない形態で使用することができる。他方では、本発明はまた、それらの化合物の、当業者に既知の手順により様々な有機および無機の酸および塩基から生成され得るそれらの薬学的に許容しうる塩の形態での使用を包含する。式Iの化合物の薬学的に許容しうる塩の形態は、大部分が、従来の方法により製造される。
口内で局所適用に適した医薬製剤は、ローゼンジ、トローチおよびマウスウォッシュを包含する。
直腸投与に適した医薬製剤を、坐薬またはかん腸剤の形状で投与することができる。
膣内投与に適した医薬製剤を、ペッサリー、タンポン、クリーム、ゲル、ペースト、泡またはスプレー製剤として投与することができる。
処方に従って調製する注射溶液および懸濁液は、無菌粉剤、顆粒および錠剤から調製することができる。
しかしながら、処置に対する本発明の化合物の有効量は一般的に、1日あたり受容体(哺乳動物)あたり0.1〜100mg/kg(体重)の範囲、特に典型的に1日あたり1〜10mg/kg(体重)の範囲である。したがって、体重70kgの成熟した哺乳動物に対する実際の1日あたりの量は通常、70〜700mgであり、この量を、1日量の合計が同じであるように、1日あたり個々の用量として、あるいは通常、1日あたり一連の部分用量(例えば、2、3、4、5または6など)で投与することができる。塩または溶媒和物またはそれらの生理学的機能性誘導体の有効量を、それ自体、本発明の化合物の有効量の画分として、決定することができる。同様の用量が、上記の他の状態の処置に対して好適であることが、想定され得る。
(a)本発明の化合物、および/またはそれらの薬学的に使用できる誘導体、互変異性体、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物の有効量
および
(b)更なる医薬活性成分の有効量
の分離パックからなるセット(キット)に関する。
本発明の化合物は、SGK誘発疾患の処置において、哺乳動物、特にヒトにとって医薬活性成分として好適である。
本発明の化合物をさらに、凝固障害、例えば、フィブリノゲン異常症、低プロコンバーチン血症、血友病B、スチュアートプラウアー因子欠乏症、プロトロンビン複合体欠乏症、消費性凝固障害、線溶亢進、免疫凝固障害または複合性凝固障害などの処置に対して、また、神経細胞の興奮性、例えば、てんかんにおいて使用する。本発明の化合物をまた、緑内障または白内障の処置において、治療に用いることができる。本発明の化合物をさらに、細菌感染の処置および抗感染療法において使用する。本発明の化合物はまた、学習能力および注意を増加させるために治療に用いることができる。
心疾患は、好ましくは心筋梗塞後の心線維症、心臓肥大、心不全および動脈硬化症である。
線維症および炎症過程は、好ましくは肝硬変、肺線維症、線維性膵炎、リウマチおよび関節症、クローン病、慢性気管支炎、放射線線維症、硬化性皮膚炎、嚢胞性線維症、瘢痕、アルツハイマー病である。
例に記載の本発明の化合物を、以下に記載のアッセイで試験し、キナーゼ阻害活性を有することを見出した。さらなるアッセイが、文献から知られており、当業者によって容易に行われ得る(例えば、Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538-549参照)。
定量分析(MS):EI(電子衝撃イオン化)M+
FAB(高速原子衝撃)(M+H)+
ESI(エレクトロスプレーイオン化)(M+H)+(特に明記しない限り)
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「1」)の製造は、以下のスキームと同様に行なわれる:
3,4−bis(4−ヒドロキシフェニルアミノ)シクロブト−3−エン−1,2−ジオン(「2」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「3」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「4」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「5」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ヒドロキシフェニルアミノ)シクロブト−3−エン−1,2−ジオン(「7」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「8」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−クロロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「9」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−クロロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「10」)、
3−(4−ヒドロキシ−2−メチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「12」)、
3−(4−ヒドロキシ−3−エチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「13」)、MS−FAB(M+H+)=339;
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(S)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「14」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「15」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「17」)、MS−FAB(M+H+)=360;
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「18」)、MS−FAB(M+H+)=360;
3−(4−ヒドロキシ−3−シアノフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「19」)、MS−FAB(M+H+)=336;
3−(4−ヒドロキシ−3−ニトロフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「20」)、MS−FAB(M+H+)=356;
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「23」)、
3−(3−クロロ−4−ヒドロキシフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「24」)、MS−FAB(M+H+)=346;
3−(4−ヒドロキシ−3−ニトロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「25」)、MS−FAB(M+H+)=370;
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「27」)、MS−FAB(M+H+)=367;
3−[4−ヒドロキシ−3−(1−ヒドロキシプロピル)フェニルアミノ]−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「28」)、
3−[4−ヒドロキシ−3−(1−ヒドロキシプロピル)フェニルアミノ]−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「29」)、
3−(4−ヒドロキシ−3−プロピルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「30」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「32」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「33」)、MS−FAB(M+H+)=379;
3−(4−ヒドロキシ−3−アミノスルホニルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「34」)、
3−(4−ヒドロキシ−3−アミノスルホニルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「35」)、
3−(4−ヒドロキシ−3−カルボキシフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「37」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「38」)、MS−FAB(M+H+)=353;
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「39」)、MS−FAB(M+H+)=339;
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[1−(3−ヒドロキシフェニル)シクロプロピルアミノ]シクロブト−3−エン−1,2−ジオン(「40」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−トリフルオロメトキシ−ベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「42」)、MS−FAB(M+H+)=393;
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)−エチルアミノ]シクロブト−3−エン−1,2−ジオン(「43」)、MS−FAB(M+H+)=367;
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「44」)、MS−FAB(M+H+)=353;
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「45」)、MS−FAB(M+H+)=381;
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「47」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「48」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「49」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「50」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「52」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「53」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−トリフルオロメチルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「54」)、MS−FAB(M+H+)=377;
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ニトロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「55」)、MS−FAB(M+H+)=354;
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(2−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「57」)、MS−FAB(M+H+)=339;
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「58」)、MS−FAB(M+H+)=374;
3−(4−ヒドロキシ−3−エチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「59」)、MS−FAB(M+H+)=353。
例A:注射バイアル
3リットルの二回蒸留水中に100gの本発明の活性成分および5gのリン酸水素二ナトリウムを含有する溶液を、2N塩酸を使ってpH6.5に調整し、滅菌濾過し、注射バイアルに移し、無菌条件下で凍結乾燥し、無菌条件下で封をする。各注射バイアルは、5mgの活性成分を含む。
例B:坐薬
20gの本発明の活性成分の混合物を、100gの大豆レシチンおよび1400gのココアバターと共に溶かし、鋳型に注ぎ、冷ます。各坐薬は、20mgの活性成分を含む。
溶液を、二回蒸留水940ml中1gの本発明の活性成分、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2Oおよび0.1gの塩化ベンザルコニウムから調製する。pHを、6.8に調整し、溶液を、1リットルにそろえ、照射により殺菌する。本溶液は、目薬の形で使用することができる。
例D:軟膏
500mgの本発明の活性成分を、無菌条件下で99.5gのワセリンと混合する。
1kgの本発明の活性成分、4kgの乳糖、1.2kgのじゃがいもデンプン、0.2kgのタルクおよび0.1kgのステアリン酸マグネシウムの混合物を、各錠剤が10mgの活性成分を含むように、従来の方法で、圧縮して錠剤とする。
例F:被覆錠
錠剤を、例Eと同様に圧縮し、その後にショ糖、じゃがいもデンプン、タルク、トラガカントおよび染料のコーティング剤で、従来の方法でコーティングする。
2kgの本発明の活性成分を、硬質ゼラチンカプセルに、各カプセルが20mgの活性成分を含むように、従来の方法で導入する。
例H:アンプル
二回蒸留水60リットル中に1kgの本発明の活性成分を含有する溶液を滅菌濾過し、アンプルに移し、無菌条件下で凍結乾燥し、無菌条件下で封をする。各アンプルは、10mgの活性成分を含む。
Claims (19)
- 式I
Rは、HまたはAを示し、
R1、R1’はそれぞれ、互いに独立して、H、A、Hal、CN、NO2、C(=O)A、CHO、CH(OH)A、NH2、NH(C=O)A、COOH、COOAまたはSO2NH2、CONH2またはCONA2を示し、
R2は、OH、OA、Hal、CF3、NO2またはSO2NH2を示し、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜7個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2、CHA、CA2または
Halは、F、Cl、BrまたはIを示し、
nは、1、2、3または4を示し、
ここでbis(4−ヒドロキシフェニルアミノ)シクロブト−3−エン−1,2−ジオンは除外される、
で表される化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - R1は、H、A、Hal、CN、NO2、CH(OH)A、C(=O)A、COOH、COOAまたはSO2NH2を示し、
R1’は、HまたはAを示す、
請求項1に記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - Rは、Hを示し、
R1、R1’はそれぞれ、互いに独立して、HまたはAを示し、
R2は、OHまたはOAを示す、
請求項1または2に記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - Rは、HまたはAを示し、
R1は、H、A、Hal、CN、NO2、CH(OH)A、C(=O)A、COOH、COOAまたはSO2NH2を示し、
R1’は、HまたはAを示し、
R2は、OH、OA、Hal、CF3、NO2またはSO2NH2を示し、
Aは、1〜10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜7個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2、CHA、CA2または
Halは、F、Cl、BrまたはIを示し、
nは、1、2、3または4を示す、
請求項1〜3のいずれかに記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - Aは、1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜5個のH原子は、Fにより置き換えられてもよい、
請求項1〜4のいずれかに記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - Rは、Hを示し、
R1、R1’はそれぞれ、互いに独立して、HまたはAを示し、
R2は、OHまたはOAを示し、
Aは、1〜6個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1〜5個のH原子は、Fにより置き換えられてもよく、
Xは、不在であるか、またはCH2またはCHAを示す、
請求項1〜5のいずれかに記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - 群
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「1」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「3」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「4」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「5」)、
3,4−bis(4−ヒドロキシ−3−メチルフェニルアミノ)シクロブト−3−エン−1,2−ジオン(「6」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ヒドロキシフェニルアミノ)シクロブト−3−エン−1,2−ジオン(「7」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「8」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−クロロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「9」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−クロロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「10」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「11」)、
3−(4−ヒドロキシ−2−メチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「12」)、
3−(4−ヒドロキシ−3−エチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「13」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[(S)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「14」)、
3−(4−ヒドロキシフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「15」)、
3−(4−ヒドロキシ−3−エチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「16」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「17」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「18」)、
3−(4−ヒドロキシ−3−シアノフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「19」)、
3−(4−ヒドロキシ−3−ニトロフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「20」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[1−(3−メトキシフェニル)シクロプロピルアミノ]シクロブト−3−エン−1,2−ジオン(「21」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(2−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「22」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「23」)、
3−(3−クロロ−4−ヒドロキシフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「24」)、
3−(4−ヒドロキシ−3−ニトロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「25」)、
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「26」)、
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「27」)、
3−[4−ヒドロキシ−3−(1−ヒドロキシプロピル)フェニルアミノ]−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「28」)、
3−[4−ヒドロキシ−3−(1−ヒドロキシプロピル)フェニルアミノ]−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「29」)、
3−(4−ヒドロキシ−3−プロピルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「30」)、
3−(4−ヒドロキシ−3−プロピルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「31」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「32」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「33」)、
3−(4−ヒドロキシ−3−アミノスルホニルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「34」)、
3−(4−ヒドロキシ−3−アミノスルホニルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「35」)、
3−(4−ヒドロキシ−3−カルボキシフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「36」)、
3−(4−ヒドロキシ−3−カルボキシフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「37」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「38」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「39」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[1−(3−ヒドロキシフェニル)シクロプロピルアミノ]シクロブト−3−エン−1,2−ジオン(「40」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−[1−(3−ヒドロキシフェニル)シクロプロピルアミノ]シクロブト−3−エン−1,2−ジオン(「41」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−トリフルオロメトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「42」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「43」)、
3−(4−ヒドロキシ−3,5−ジメチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「44」)、
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「45」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−(3−ヒドロキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「46」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「47」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「48」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「49」)、
3−(4−ヒドロキシ−3−イソプロピルフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「50」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「51」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「52」)、
3−(4−ヒドロキシ−3−トリフルオロメチルフェニルアミノ)−4−(3−アミノスルホニルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「53」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−トリフルオロメチルベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「54」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(3−ニトロベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「55」)、
3−(4−ヒドロキシ−3−プロピオニルフェニルアミノ)−4−[(R)−1−(3−メトキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「56」)、
3−(4−ヒドロキシ−3−メチルフェニルアミノ)−4−(2−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「57」)、
3−(4−ヒドロキシ−3−クロロフェニルアミノ)−4−[(R)−1−(3−ヒドロキシフェニル)エチルアミノ]シクロブト−3−エン−1,2−ジオン(「58」)、
3−(4−ヒドロキシ−3−エチルフェニルアミノ)−4−(3−メトキシベンジルアミノ)シクロブト−3−エン−1,2−ジオン(「59」)、
から選択される、請求項1に記載の化合物、ならびにそれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物、および立体異性体、またはそれらの全ての比率での混合物。 - 請求項1〜7のいずれかに記載の化合物および/またはこれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物および立体異性体、またはそれらの全ての比率での混合物、ならびに任意の賦形剤および/または補助剤を含む医薬。
- キナーゼシグナル伝達の阻害、調節および/または調整が一因となる疾患の処置および/または予防に対する医薬の製造のための、請求項1〜7のいずれかに記載の化合物、ならびにそれらの薬学的に使用できる誘導体、塩、互変異性体、溶媒和物および立体異性体、またはそれらの全ての比率での混合物の使用。
- キナーゼがSGKである、請求項10に記載の使用。
- 請求項1〜21のいずれかに記載の化合物によるSGKの阻害に影響を受ける疾患の処置に対する医薬の製造のための、請求項1〜7のいずれかに記載の化合物、ならびにこれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物および立体異性体、またはそれらの全ての比率での混合物の請求項11に記載の使用。
- 糖尿病、肥満、代謝症候群(異常脂質血症)、全身性および肺高血圧症、心疾患および腎疾患の、一般的にあらゆる種類の線維症および炎症過程、癌、腫瘍細胞、腫瘍転移、凝固障害、神経細胞の興奮性、緑内障、白内障、細菌感染における、ならびに抗感染療法における、学習能力および注意を増加させるための、処置または防止に対する、ならびに細胞の老化およびストレスの処置および予防に対する、医薬の製造のための請求項1〜7のいずれかに記載の化合物、ならびにこれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物および立体異性体、またはそれらの全ての比率での混合物の請求項12に記載の使用。
- 糖尿病が、真性糖尿病、糖尿病性ネフロパシー、糖尿病性神経障害、糖尿病性血管症および細小血管症である、請求項13に記載の使用。
- 心疾患が、心筋梗塞後の心線維症、心臓肥大、心不全および動脈硬化症である、請求項13に記載の使用。
- 腎疾患が、糸球体硬化症、腎硬化症、腎炎、ネフロパシーおよび電解質***障害である、請求項13に記載の使用。
- 線維症および炎症過程が、肝硬変、肺線維症、線維性膵炎、リウマチおよび関節症、クローン病、慢性気管支炎、放射線線維症、硬化性皮膚炎、嚢胞性線維症、瘢痕およびアルツハイマー病である、請求項13に記載の使用。
- 請求項1〜7のいずれかに記載の化合物および/またはこれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物および立体異性体、またはそれらの全ての比率での混合物の少なくとも1種、ならびに少なくとも1種の更なる医薬活性成分を含む医薬。
- (a)請求項1〜7のいずれかに記載の化合物および/またはこれらの薬学的に使用できる誘導体、互変異性体、塩、溶媒和物および立体異性体、またはそれらの全ての比率での混合物の有効量
および
(b)更なる医薬活性成分の有効量
の分離パックからなるセット(キット)。
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EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
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- 2005-12-09 WO PCT/EP2005/013225 patent/WO2006072354A1/de active Application Filing
- 2005-12-09 JP JP2007549807A patent/JP2008526790A/ja active Pending
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- 2005-12-09 US US11/813,475 patent/US20080262096A1/en not_active Abandoned
- 2005-12-09 EP EP05849991A patent/EP1838662A1/de not_active Withdrawn
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