NZ335246A - Substituted carbazole or hydrogenated carbazole derivatives; useful for inhibiting sPLA2 (human non-pancreatic secretory phospholipase A2) mediated release of fatty acids for conditions such as septic shock - Google Patents

Info

Publication number

NZ335246A

NZ335246A NZ335246A NZ33524697A NZ335246A NZ 335246 A NZ335246 A NZ 335246A NZ 335246 A NZ335246 A NZ 335246A NZ 33524697 A NZ33524697 A NZ 33524697A NZ 335246 A NZ335246 A NZ 335246A

Authority

NZ

New Zealand

Prior art keywords

phenyl

alkyl

compound

arthritis

benzyl

Prior art date

1996-10-30

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• 230000002401 inhibitory effect Effects 0.000 title claims description 13
• 230000001404 mediated effect Effects 0.000 title claims description 12
• 235000014113 dietary fatty acids Nutrition 0.000 title claims description 11
• 229930195729 fatty acid Natural products 0.000 title claims description 11
• 239000000194 fatty acid Substances 0.000 title claims description 11
• 150000004665 fatty acids Chemical class 0.000 title claims description 11
• 206010040070 Septic Shock Diseases 0.000 title claims description 10
• 230000036303 septic shock Effects 0.000 title claims description 10
• UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 title description 21
• 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 title description 3
• 102000019054 Group II Phospholipases A2 Human genes 0.000 title description 2
• 108010026929 Group II Phospholipases A2 Proteins 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 193
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 166
• -1 -P(=O)R6R7 Chemical group 0.000 claims abstract description 143
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 134
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 62
• 206010003246 arthritis Diseases 0.000 claims abstract description 50
• 125000001424 substituent group Chemical group 0.000 claims abstract description 28
• 150000003839 salts Chemical class 0.000 claims abstract description 26
• 102000005473 Secretory Phospholipases A2 Human genes 0.000 claims abstract description 25
• 108010031873 Secretory Phospholipases A2 Proteins 0.000 claims abstract description 25
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 25
• 201000010099 disease Diseases 0.000 claims abstract description 17
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
• 239000000651 prodrug Substances 0.000 claims abstract description 17
• 229940002612 prodrug Drugs 0.000 claims abstract description 17
• 241000124008 Mammalia Species 0.000 claims abstract description 16
• 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 14
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
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• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims abstract description 9
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims abstract description 9
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• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims abstract description 8
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 8
• 239000011575 calcium Substances 0.000 claims abstract description 8
• 229910052791 calcium Inorganic materials 0.000 claims abstract description 8
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• 206010020877 Hypertrophic osteoarthropathy Diseases 0.000 claims abstract description 6
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• 125000001475 halogen functional group Chemical group 0.000 claims abstract 7
• 238000002360 preparation method Methods 0.000 claims description 75
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• 238000011282 treatment Methods 0.000 claims description 47
• 238000000034 method Methods 0.000 claims description 40
• 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 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 208000014674 injury Diseases 0.000 claims description 15
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 13
• 206010006448 Bronchiolitis Diseases 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
• 229940114079 arachidonic acid Drugs 0.000 claims description 10
• 235000021342 arachidonic acid Nutrition 0.000 claims description 10
• 230000001684 chronic effect Effects 0.000 claims description 9
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
• 230000008733 trauma Effects 0.000 claims description 9
• 208000004575 Infectious Arthritis Diseases 0.000 claims description 7
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• 230000002939 deleterious effect Effects 0.000 claims description 5
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• 208000036487 Arthropathies Diseases 0.000 claims description 4
• 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 claims description 4
• 208000002849 chondrocalcinosis Diseases 0.000 claims description 4
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• XOTCNYPJDCKTCB-UHFFFAOYSA-N propylphosphonic acid Chemical compound OP(O)(=O)CC=[CH] XOTCNYPJDCKTCB-UHFFFAOYSA-N 0.000 claims description 3
• 159000000000 sodium salts Chemical class 0.000 claims description 3
• PHLMLOIEAYWBBX-UHFFFAOYSA-N 4-[[9-benzyl-5-carbamoyl-2-(2-cyanoethyl)-5,6,7,8-tetrahydrocarbazol-3-yl]oxy]butanoic acid Chemical compound NC(=O)C1CCCC2=C1C1=CC(OCCCC(O)=O)=C(CCC#N)C=C1N2CC1=CC=CC=C1 PHLMLOIEAYWBBX-UHFFFAOYSA-N 0.000 claims description 2
• XMNFDVRHTKIVQK-UHFFFAOYSA-N 2-(9-benzyl-5-carbamoyl-2-methoxycarbazol-4-yl)oxyacetic acid Chemical compound C=1C(OC)=CC(OCC(O)=O)=C(C2=C(C(N)=O)C=CC=C22)C=1N2CC1=CC=CC=C1 XMNFDVRHTKIVQK-UHFFFAOYSA-N 0.000 claims 2
• 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 1
• OCQARBMASQXXGZ-UHFFFAOYSA-N 2-[(9-benzyl-5-carbamoyl-1-methyl-5,6,7,8-tetrahydrocarbazol-4-yl)oxy]acetic acid Chemical compound C1=2C(C)=CC=C(OCC(O)=O)C=2C=2C(C(N)=O)CCCC=2N1CC1=CC=CC=C1 OCQARBMASQXXGZ-UHFFFAOYSA-N 0.000 claims 1
• CRXQYSQDOBKHNV-UHFFFAOYSA-N 2-[(9-benzyl-5-carbamoyl-5,6,7,8-tetrahydrocarbazol-4-yl)oxy]acetic acid Chemical compound NC(=O)C1CCCC2=C1C1=C(OCC(O)=O)C=CC=C1N2CC1=CC=CC=C1 CRXQYSQDOBKHNV-UHFFFAOYSA-N 0.000 claims 1
• SUFLSDPNUYZZTL-UHFFFAOYSA-N 3-[(9-benzyl-5-carbamoyl-2-ethyl-5,6,7,8-tetrahydrocarbazol-3-yl)oxy]propylphosphonic acid Chemical compound C1=2CCCC(C(N)=O)C=2C=2C=C(OCCCP(O)(O)=O)C(CC)=CC=2N1CC1=CC=CC=C1 SUFLSDPNUYZZTL-UHFFFAOYSA-N 0.000 claims 1
• IVUHNJUYWOTYJY-UHFFFAOYSA-N 3-[(9-benzyl-5-carbamoyl-5,6,7,8-tetrahydrocarbazol-3-yl)oxy]propylphosphonic acid Chemical compound NC(=O)C1CCCC2=C1C1=CC(OCCCP(O)(O)=O)=CC=C1N2CC1=CC=CC=C1 IVUHNJUYWOTYJY-UHFFFAOYSA-N 0.000 claims 1
• 230000001969 hypertrophic effect Effects 0.000 claims 1
• 201000001223 septic arthritis Diseases 0.000 claims 1
• 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 5
• 208000029549 Muscle injury Diseases 0.000 abstract 1
• 201000000596 systemic lupus erythematosus Diseases 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 159
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• 241001070944 Mimosa Species 0.000 description 112
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 111
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 89
• 239000000243 solution Substances 0.000 description 84
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 83
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• 239000000203 mixture Substances 0.000 description 64
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• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 60
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• 239000012267 brine Substances 0.000 description 59
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• 238000000921 elemental analysis Methods 0.000 description 53
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• XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical class N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 24
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• 125000005647 linker group Chemical group 0.000 description 21
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• 239000002904 solvent Substances 0.000 description 20
• 239000007787 solid Substances 0.000 description 19
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
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• 239000000543 intermediate Substances 0.000 description 18
• MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
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• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
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• 231100000673 dose–response relationship Toxicity 0.000 description 8
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• ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
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