NO312240B1 - Substituerte tricykliske forbindelser, preparater inneholdende forbindelsene samt forbindelsenes anvendelse - Google Patents

Info

Publication number

NO312240B1

NO312240B1 NO19991822A NO991822A NO312240B1 NO 312240 B1 NO312240 B1 NO 312240B1 NO 19991822 A NO19991822 A NO 19991822A NO 991822 A NO991822 A NO 991822A NO 312240 B1 NO312240 B1 NO 312240B1

Authority

NO

Norway

Prior art keywords

methyl

oxyacetic acid

carbamoylcarbazol

acid

arthritis

Prior art date

1998-04-17

Links

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• 150000001875 compounds Chemical class 0.000 title claims description 127
• 238000002360 preparation method Methods 0.000 title claims description 63
• -1 diethyl glycolamide ester Chemical class 0.000 claims description 65
• 239000002253 acid Substances 0.000 claims description 48
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
• 238000011282 treatment Methods 0.000 claims description 26
• 102000005473 Secretory Phospholipases A2 Human genes 0.000 claims description 23
• 108010031873 Secretory Phospholipases A2 Proteins 0.000 claims description 23
• 150000003839 salts Chemical class 0.000 claims description 21
• 159000000000 sodium salts Chemical class 0.000 claims description 21
• 239000011734 sodium Substances 0.000 claims description 17
• YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 15
• 206010003246 arthritis Diseases 0.000 claims description 14
• 201000010099 disease Diseases 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 239000000651 prodrug Substances 0.000 claims description 14
• 229940002612 prodrug Drugs 0.000 claims description 14
• 230000002401 inhibitory effect Effects 0.000 claims description 10
• 235000014113 dietary fatty acids Nutrition 0.000 claims description 9
• 229940079593 drug Drugs 0.000 claims description 9
• 239000000194 fatty acid Substances 0.000 claims description 9
• 229930195729 fatty acid Natural products 0.000 claims description 9
• 150000004665 fatty acids Chemical class 0.000 claims description 9
• 230000001404 mediated effect Effects 0.000 claims description 9
• KWBVGNHCBQIRTN-UHFFFAOYSA-N 2-[5-carbamoyl-9-[(3-fluorophenyl)methyl]carbazol-4-yl]oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC(F)=C1 KWBVGNHCBQIRTN-UHFFFAOYSA-N 0.000 claims description 8
• 229940114079 arachidonic acid Drugs 0.000 claims description 8
• 235000021342 arachidonic acid Nutrition 0.000 claims description 8
• LOEUKRWGLDWONT-UHFFFAOYSA-N 2-(9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl)oxyacetic acid Chemical compound C12=C(F)C=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC=C1 LOEUKRWGLDWONT-UHFFFAOYSA-N 0.000 claims description 7
• YFTJSPAAYBFQNI-UHFFFAOYSA-N 2-[5-carbamoyl-9-(cyclopentylmethyl)carbazol-4-yl]oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1CCCC1 YFTJSPAAYBFQNI-UHFFFAOYSA-N 0.000 claims description 7
• UIMGRPXPFBJHJJ-UHFFFAOYSA-N 2-[5-carbamoyl-9-[(3-chlorophenyl)methyl]carbazol-4-yl]oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC(Cl)=C1 UIMGRPXPFBJHJJ-UHFFFAOYSA-N 0.000 claims description 7
• 208000006673 asthma Diseases 0.000 claims description 7
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• 229910052708 sodium Inorganic materials 0.000 claims description 7
• WVVBMMFAUGIIJM-UHFFFAOYSA-N 2-(9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl)oxyacetic acid Chemical compound C12=C(Cl)C=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC=C1 WVVBMMFAUGIIJM-UHFFFAOYSA-N 0.000 claims description 6
• UFJILQXRMNERCL-UHFFFAOYSA-N 2-(9-benzyl-5-carbamoylcarbazol-4-yl)oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC=C1 UFJILQXRMNERCL-UHFFFAOYSA-N 0.000 claims description 6
• UJSZZKJIGGAMHM-UHFFFAOYSA-N 2-[5-carbamoyl-9-[(2-methylphenyl)methyl]carbazol-4-yl]oxyacetic acid Chemical compound CC1=CC=CC=C1CN1C2=CC=CC(C(N)=O)=C2C2=C(OCC(O)=O)C=CC=C21 UJSZZKJIGGAMHM-UHFFFAOYSA-N 0.000 claims description 6
• 208000012659 Joint disease Diseases 0.000 claims description 6
• 206010040070 Septic Shock Diseases 0.000 claims description 6
• 239000003085 diluting agent Substances 0.000 claims description 6
• 125000001495 ethyl group Chemical class [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 230000036303 septic shock Effects 0.000 claims description 6
• 239000012453 solvate Substances 0.000 claims description 6
• XQHXEBCEJGFYFD-UHFFFAOYSA-N 2-[5-carbamoyl-9-(cyclohexylmethyl)carbazol-4-yl]oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1CCCCC1 XQHXEBCEJGFYFD-UHFFFAOYSA-N 0.000 claims description 5
• IKVWXTBYJHSVHF-UHFFFAOYSA-N 2-[5-carbamoyl-9-[(3-methylphenyl)methyl]carbazol-4-yl]oxyacetic acid Chemical compound CC1=CC=CC(CN2C3=CC=CC(=C3C3=C(OCC(O)=O)C=CC=C32)C(N)=O)=C1 IKVWXTBYJHSVHF-UHFFFAOYSA-N 0.000 claims description 5
• GCOWGWQVPARYNI-UHFFFAOYSA-N 2-[5-carbamoyl-9-[[3-(trifluoromethoxy)phenyl]methyl]carbazol-4-yl]oxyacetic acid Chemical compound C12=CC=CC(OCC(O)=O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC(OC(F)(F)F)=C1 GCOWGWQVPARYNI-UHFFFAOYSA-N 0.000 claims description 5
• 206010033645 Pancreatitis Diseases 0.000 claims description 5
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 5
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• 208000036487 Arthropathies Diseases 0.000 claims description 4
• 206010006448 Bronchiolitis Diseases 0.000 claims description 4
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
• 201000003883 Cystic fibrosis Diseases 0.000 claims description 4
• 208000004575 Infectious Arthritis Diseases 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 4
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 4
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
• 206010006451 bronchitis Diseases 0.000 claims description 4
• 125000000484 butyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000001449 isopropyl group Chemical class [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
• 208000002574 reactive arthritis Diseases 0.000 claims description 4
• 230000035939 shock Effects 0.000 claims description 4
• 239000011575 calcium Substances 0.000 claims description 3
• 229910052791 calcium Inorganic materials 0.000 claims description 3
• 125000001436 propyl group Chemical class [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 206010000599 Acromegaly Diseases 0.000 claims description 2
• 208000008190 Agammaglobulinemia Diseases 0.000 claims description 2
• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
• 206010003256 Arthritis gonococcal Diseases 0.000 claims description 2
• 206010003267 Arthritis reactive Diseases 0.000 claims description 2
• 206010003274 Arthritis viral Diseases 0.000 claims description 2
• 206010006458 Bronchitis chronic Diseases 0.000 claims description 2
• 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 claims description 2
• 235000008733 Citrus aurantifolia Nutrition 0.000 claims description 2
• 201000011275 Epicondylitis Diseases 0.000 claims description 2
• 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 2
• 201000005569 Gout Diseases 0.000 claims description 2
• 208000018565 Hemochromatosis Diseases 0.000 claims description 2
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
• 201000002980 Hyperparathyroidism Diseases 0.000 claims description 2
• 206010020877 Hypertrophic osteoarthropathy Diseases 0.000 claims description 2
• 206010020983 Hypogammaglobulinaemia Diseases 0.000 claims description 2
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
• 208000034624 Leukocytoclastic Cutaneous Vasculitis Diseases 0.000 claims description 2
• 208000032514 Leukocytoclastic vasculitis Diseases 0.000 claims description 2
• 206010065159 Polychondritis Diseases 0.000 claims description 2
• 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
• 208000033464 Reiter syndrome Diseases 0.000 claims description 2
• 206010040047 Sepsis Diseases 0.000 claims description 2
• 208000006045 Spondylarthropathies Diseases 0.000 claims description 2
• 201000002661 Spondylitis Diseases 0.000 claims description 2
• 208000006011 Stroke Diseases 0.000 claims description 2
• 208000002240 Tennis Elbow Diseases 0.000 claims description 2
• 235000011941 Tilia x europaea Nutrition 0.000 claims description 2
• 208000027418 Wounds and injury Diseases 0.000 claims description 2
• 208000021240 acute bronchiolitis Diseases 0.000 claims description 2
• 230000006907 apoptotic process Effects 0.000 claims description 2
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• 208000002849 chondrocalcinosis Diseases 0.000 claims description 2
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• 239000013078 crystal Substances 0.000 claims description 2
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• 230000008021 deposition Effects 0.000 claims description 2
• 230000002538 fungal effect Effects 0.000 claims description 2
• 208000002085 hemarthrosis Diseases 0.000 claims description 2
• 208000034737 hemoglobinopathy Diseases 0.000 claims description 2
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• 230000002458 infectious effect Effects 0.000 claims description 2
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• 239000004571 lime Substances 0.000 claims description 2
• 206010025135 lupus erythematosus Diseases 0.000 claims description 2
• 125000006203 morpholinoethyl group Chemical class [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
• 201000011201 multicentric reticulohistiocytosis Diseases 0.000 claims description 2
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• 201000006292 polyarteritis nodosa Diseases 0.000 claims description 2
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• 230000009885 systemic effect Effects 0.000 claims description 2
• 230000003156 vasculitic effect Effects 0.000 claims description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 244
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 114
• 239000000243 solution Substances 0.000 description 98
• 239000000203 mixture Substances 0.000 description 96
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 94
• 235000019439 ethyl acetate Nutrition 0.000 description 85
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 80
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 65
• 238000000921 elemental analysis Methods 0.000 description 64
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 63
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• 239000000741 silica gel Substances 0.000 description 57
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
• 229910001868 water Inorganic materials 0.000 description 52
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• 235000019341 magnesium sulphate Nutrition 0.000 description 44
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
• 238000000034 method Methods 0.000 description 35
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• 239000000284 extract Substances 0.000 description 31
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• 125000000217 alkyl group Chemical group 0.000 description 30
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
• HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 28
• 239000002585 base Substances 0.000 description 28
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• UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 23
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 21
• 239000000543 intermediate Substances 0.000 description 20
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• 239000001257 hydrogen Substances 0.000 description 19
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• 229910000104 sodium hydride Inorganic materials 0.000 description 19
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• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
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• YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 13
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• 125000002837 carbocyclic group Chemical group 0.000 description 8
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• 125000001424 substituent group Chemical group 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
• 239000002168 alkylating agent Substances 0.000 description 7
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• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
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• DWIAYAAEVRBFGW-UHFFFAOYSA-N methyl 5-hydroxy-9-[(2-methylphenyl)methyl]carbazole-4-carboxylate Chemical compound C12=CC=CC(O)=C2C=2C(C(=O)OC)=CC=CC=2N1CC1=CC=CC=C1C DWIAYAAEVRBFGW-UHFFFAOYSA-N 0.000 description 3
• LPGOWPXYSCNOID-UHFFFAOYSA-N methyl 5-hydroxy-9-[[3-(trifluoromethoxy)phenyl]methyl]carbazole-4-carboxylate Chemical compound C12=CC=CC(O)=C2C=2C(C(=O)OC)=CC=CC=2N1CC1=CC=CC(OC(F)(F)F)=C1 LPGOWPXYSCNOID-UHFFFAOYSA-N 0.000 description 3
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• HXURTMLFEIDBBQ-UHFFFAOYSA-N methyl 9-[(3-methylphenyl)methyl]-5-oxo-7,8-dihydro-6h-carbazole-4-carboxylate Chemical compound C1=2CCCC(=O)C=2C=2C(C(=O)OC)=CC=CC=2N1CC1=CC=CC(C)=C1 HXURTMLFEIDBBQ-UHFFFAOYSA-N 0.000 description 3
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• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
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• GLUGRMILFITQLF-UHFFFAOYSA-N 5-hydroxy-9-[[3-(trifluoromethoxy)phenyl]methyl]carbazole-4-carboxamide Chemical compound C12=CC=CC(O)=C2C=2C(C(=O)N)=CC=CC=2N1CC1=CC=CC(OC(F)(F)F)=C1 GLUGRMILFITQLF-UHFFFAOYSA-N 0.000 description 2
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• PENJYQTYSNGYMY-UHFFFAOYSA-N methyl 2-[5-carbamoyl-9-[[3-(trifluoromethyl)phenyl]methyl]carbazol-4-yl]oxyacetate Chemical compound C12=CC=CC(C(N)=O)=C2C=2C(OCC(=O)OC)=CC=CC=2N1CC1=CC=CC(C(F)(F)F)=C1 PENJYQTYSNGYMY-UHFFFAOYSA-N 0.000 description 1
• ZBSOAAIJVOCBEH-UHFFFAOYSA-N methyl 2-bromo-3-[(3-oxocyclohexen-1-yl)amino]benzoate Chemical compound COC(=O)C1=CC=CC(NC=2CCCC(=O)C=2)=C1Br ZBSOAAIJVOCBEH-UHFFFAOYSA-N 0.000 description 1
• GRNUVEMCUGCDDO-UHFFFAOYSA-N methyl 7-methyl-5-oxo-6,7,8,9-tetrahydrocarbazole-4-carboxylate Chemical compound C1C(C)CC(=O)C2=C1NC1=C2C(C(=O)OC)=CC=C1 GRNUVEMCUGCDDO-UHFFFAOYSA-N 0.000 description 1
• KISUBDQINFFPAU-UHFFFAOYSA-N methyl 9-(cyclohexylmethyl)-5-oxo-7,8-dihydro-6h-carbazole-4-carboxylate Chemical compound C1=2CCCC(=O)C=2C=2C(C(=O)OC)=CC=CC=2N1CC1CCCCC1 KISUBDQINFFPAU-UHFFFAOYSA-N 0.000 description 1
• QZRSFEAXAOKXCG-UHFFFAOYSA-N methyl 9-(cyclopentylmethyl)-5-oxo-7,8-dihydro-6h-carbazole-4-carboxylate Chemical compound C1=2CCCC(=O)C=2C=2C(C(=O)OC)=CC=CC=2N1CC1CCCC1 QZRSFEAXAOKXCG-UHFFFAOYSA-N 0.000 description 1
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