DE1041982T1 - HEMMUNG DER p38 KINASE AKTIVITÄT DURCH SUBSTITUIERTEN HETEROCYCLISCHEN HARNSTOFFEN - Google Patents
HEMMUNG DER p38 KINASE AKTIVITÄT DURCH SUBSTITUIERTEN HETEROCYCLISCHEN HARNSTOFFENInfo
- Publication number
- DE1041982T1 DE1041982T1 DE1041982T DE98964709T DE1041982T1 DE 1041982 T1 DE1041982 T1 DE 1041982T1 DE 1041982 T DE1041982 T DE 1041982T DE 98964709 T DE98964709 T DE 98964709T DE 1041982 T1 DE1041982 T1 DE 1041982T1
- Authority
- DE
- Germany
- Prior art keywords
- butyl
- urea
- tert
- substituted
- pyridinyl
- 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.)
- Pending
Links
- 230000000694 effects Effects 0.000 title claims 2
- 230000005764 inhibitory process Effects 0.000 title 1
- 150000003672 ureas Chemical class 0.000 title 1
- -1 aryl ureas Chemical class 0.000 claims abstract 19
- 201000010099 disease Diseases 0.000 claims abstract 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 9
- 230000001404 mediated effect Effects 0.000 claims abstract 4
- 102000004127 Cytokines Human genes 0.000 claims abstract 3
- 108090000695 Cytokines Proteins 0.000 claims abstract 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract 3
- 108091005804 Peptidases Proteins 0.000 claims abstract 3
- 201000011510 cancer Diseases 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 39
- 150000001875 compounds Chemical class 0.000 claims 21
- 229910052736 halogen Inorganic materials 0.000 claims 19
- 150000002367 halogens Chemical group 0.000 claims 19
- 239000004202 carbamide Substances 0.000 claims 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 17
- 125000003118 aryl group Chemical group 0.000 claims 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 14
- 238000006467 substitution reaction Methods 0.000 claims 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims 12
- 125000000217 alkyl group Chemical group 0.000 claims 11
- 125000004076 pyridyl group Chemical group 0.000 claims 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 11
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 229910052739 hydrogen Inorganic materials 0.000 claims 10
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- 125000001424 substituent group Chemical group 0.000 claims 6
- 239000001257 hydrogen Substances 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 229910052760 oxygen Inorganic materials 0.000 claims 5
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 239000011593 sulfur Substances 0.000 claims 3
- PEZPHMOCGURMEM-UHFFFAOYSA-N (2,3-dichlorophenyl)urea Chemical compound NC(=O)NC1=CC=CC(Cl)=C1Cl PEZPHMOCGURMEM-UHFFFAOYSA-N 0.000 claims 2
- QYYQTVPREWFJTR-UHFFFAOYSA-N (4-pyridin-4-yloxyphenyl)urea Chemical compound C1=CC(NC(=O)N)=CC=C1OC1=CC=NC=C1 QYYQTVPREWFJTR-UHFFFAOYSA-N 0.000 claims 2
- YAXXWOLZFGHUMQ-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-1-(3-pyridin-4-ylsulfanylphenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1N(C(N)=O)C1=CC=CC(SC=2C=CN=CC=2)=C1 YAXXWOLZFGHUMQ-UHFFFAOYSA-N 0.000 claims 2
- HGGBXDNWWLQKFO-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-[4-pyridin-4-ylsulfanyl-3-(trifluoromethyl)phenyl]urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1C(F)(F)F)=CC=C1SC1=CC=NC=C1 HGGBXDNWWLQKFO-UHFFFAOYSA-N 0.000 claims 2
- SCTUFFRENWOJON-UHFFFAOYSA-N C(C)(C)(C)C1=CC(=CS1)N(C(=O)N)C1=CC=C(C=C1)SC1=CC=NC=C1 Chemical compound C(C)(C)(C)C1=CC(=CS1)N(C(=O)N)C1=CC=C(C=C1)SC1=CC=NC=C1 SCTUFFRENWOJON-UHFFFAOYSA-N 0.000 claims 2
- 239000004365 Protease Substances 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims 2
- 125000001544 thienyl group Chemical group 0.000 claims 2
- JVKPSHHYGNWFFP-UHFFFAOYSA-N (3-pyridin-4-ylsulfanylphenyl)urea Chemical compound NC(=O)NC1=CC=CC(SC=2C=CN=CC=2)=C1 JVKPSHHYGNWFFP-UHFFFAOYSA-N 0.000 claims 1
- ORLPLMYCUFHCTN-UHFFFAOYSA-N 1-(2-bromo-5-tert-butylthiophen-3-yl)-3-(4-methylphenyl)urea Chemical compound C1=CC(C)=CC=C1NC(=O)NC1=C(Br)SC(C(C)(C)C)=C1 ORLPLMYCUFHCTN-UHFFFAOYSA-N 0.000 claims 1
- ORIFMUAUSBIDGC-UHFFFAOYSA-N 1-(3-tert-butyl-1,2-oxazol-5-yl)-3-(4-pyridin-4-yloxyphenyl)urea Chemical compound O1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1OC1=CC=NC=C1 ORIFMUAUSBIDGC-UHFFFAOYSA-N 0.000 claims 1
- YSOLQZIGFKVUPX-UHFFFAOYSA-N 1-(3-tert-butyl-1,2-oxazol-5-yl)-3-(4-pyridin-4-ylsulfanylphenyl)urea Chemical compound O1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1SC1=CC=NC=C1 YSOLQZIGFKVUPX-UHFFFAOYSA-N 0.000 claims 1
- NJHHSVCMQSVKLK-UHFFFAOYSA-N 1-(3-tert-butyl-1,2-oxazol-5-yl)-3-[4-(4-methoxyanilino)phenyl]urea Chemical compound C1=CC(OC)=CC=C1NC(C=C1)=CC=C1NC(=O)NC1=CC(C(C)(C)C)=NO1 NJHHSVCMQSVKLK-UHFFFAOYSA-N 0.000 claims 1
- OWVOVWYDNHUGBF-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-1-(4-pyridin-4-yloxyphenyl)urea Chemical compound C(C)(C)(C)C1=CC(=NO1)N(C(N)=O)C1=CC=C(C=C1)OC1=CC=NC=C1 OWVOVWYDNHUGBF-UHFFFAOYSA-N 0.000 claims 1
- GYJWQQJEAAHIIW-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-1-(4-pyridin-4-ylsulfanylphenyl)urea Chemical compound O1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(SC=3C=CN=CC=3)=CC=2)=N1 GYJWQQJEAAHIIW-UHFFFAOYSA-N 0.000 claims 1
- BUEAHSOXZBKYRU-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-1-[4-(pyridin-4-ylmethyl)phenyl]urea Chemical compound C(C)(C)(C)C1=CC(=NO1)N(C(N)=O)C1=CC=C(C=C1)CC1=CC=NC=C1 BUEAHSOXZBKYRU-UHFFFAOYSA-N 0.000 claims 1
- BWYIEKUXLAWWDO-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(3-pyridin-4-ylsulfanylphenyl)urea Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=C(SC=3C=CN=CC=3)C=CC=2)=N1 BWYIEKUXLAWWDO-UHFFFAOYSA-N 0.000 claims 1
- OCVLLNOZMGLZMR-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[3-(3-methylpyridin-4-yl)oxyphenyl]urea Chemical compound CC1=CN=CC=C1OC1=CC=CC(NC(=O)NC2=NOC(=C2)C(C)(C)C)=C1 OCVLLNOZMGLZMR-UHFFFAOYSA-N 0.000 claims 1
- IWCPQASLCDOVME-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[3-[fluoro(pyridin-4-yl)methyl]phenyl]urea Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=C(C=CC=2)C(F)C=2C=CN=CC=2)=N1 IWCPQASLCDOVME-UHFFFAOYSA-N 0.000 claims 1
- DMQFIGFOGVTSFP-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-(4-hydroxyphenoxy)phenyl]urea Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(OC=3C=CC(O)=CC=3)=CC=2)=N1 DMQFIGFOGVTSFP-UHFFFAOYSA-N 0.000 claims 1
- UPTPHBBPQWSUFJ-UHFFFAOYSA-N 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-pyridin-4-ylsulfanyl-3-(trifluoromethyl)phenyl]urea Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=C(C(SC=3C=CN=CC=3)=CC=2)C(F)(F)F)=N1 UPTPHBBPQWSUFJ-UHFFFAOYSA-N 0.000 claims 1
- HFDKZSDVVYXDMY-UHFFFAOYSA-N 1-(5-tert-butyl-1H-pyrazol-3-yl)-1-(4-pyridin-4-yloxyphenyl)urea Chemical compound N1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(OC=3C=CN=CC=3)=CC=2)=N1 HFDKZSDVVYXDMY-UHFFFAOYSA-N 0.000 claims 1
- YOUFVBDDKCYRBT-UHFFFAOYSA-N 1-(5-tert-butyl-1H-pyrazol-3-yl)-1-[4-(pyridin-4-ylmethyl)phenyl]urea Chemical compound N1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(CC=3C=CN=CC=3)=CC=2)=N1 YOUFVBDDKCYRBT-UHFFFAOYSA-N 0.000 claims 1
- PXMZWZHOSUYALM-UHFFFAOYSA-N 1-(5-tert-butyl-1h-pyrazol-3-yl)-3-(3-pyridin-4-yloxyphenyl)urea Chemical compound N1N=C(C(C)(C)C)C=C1NC(=O)NC1=CC=CC(OC=2C=CN=CC=2)=C1 PXMZWZHOSUYALM-UHFFFAOYSA-N 0.000 claims 1
- NISMKTLRQBAMPS-UHFFFAOYSA-N 1-(5-tert-butyl-1h-pyrazol-3-yl)-3-(4-pyridin-4-ylsulfanylphenyl)urea Chemical compound N1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(SC=3C=CN=CC=3)=CC=2)=N1 NISMKTLRQBAMPS-UHFFFAOYSA-N 0.000 claims 1
- VWBAHTCOVBWTMX-UHFFFAOYSA-N 1-(5-tert-butyl-1h-pyrazol-3-yl)-3-[4-(pyridin-4-ylmethyl)phenyl]urea Chemical compound N1N=C(C(C)(C)C)C=C1NC(=O)NC(C=C1)=CC=C1CC1=CC=NC=C1 VWBAHTCOVBWTMX-UHFFFAOYSA-N 0.000 claims 1
- LVXHHBZKFYKYEL-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(2,3-dichlorophenyl)urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC1=CC=CC(Cl)=C1Cl LVXHHBZKFYKYEL-UHFFFAOYSA-N 0.000 claims 1
- FNCGBIQSBMRFGO-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-1-(2,3-dichlorophenyl)urea Chemical compound S1C(C(C)(C)C)=CC(N(C(N)=O)C=2C(=C(Cl)C=CC=2)Cl)=C1 FNCGBIQSBMRFGO-UHFFFAOYSA-N 0.000 claims 1
- DFVUEUQJPMPJMY-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-1-(4-pyridin-4-yloxyphenyl)urea Chemical compound S1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(OC=3C=CN=CC=3)=CC=2)=C1 DFVUEUQJPMPJMY-UHFFFAOYSA-N 0.000 claims 1
- QGNZBPXTRYLNDP-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-1-[4-(4-ethoxyphenoxy)phenyl]urea Chemical compound C1=CC(OCC)=CC=C1OC1=CC=C(N(C(N)=O)C=2C=C(SC=2)C(C)(C)C)C=C1 QGNZBPXTRYLNDP-UHFFFAOYSA-N 0.000 claims 1
- IYQMYSWZQMEBTC-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-1-[4-(4-hydroxyphenoxy)phenyl]urea Chemical compound S1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(OC=3C=CC(O)=CC=3)=CC=2)=C1 IYQMYSWZQMEBTC-UHFFFAOYSA-N 0.000 claims 1
- ZQLOKBHUXHHXNG-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-1-[4-(pyridin-4-ylmethyl)phenyl]urea Chemical compound S1C(C(C)(C)C)=CC(N(C(N)=O)C=2C=CC(CC=3C=CN=CC=3)=CC=2)=C1 ZQLOKBHUXHHXNG-UHFFFAOYSA-N 0.000 claims 1
- WKYHBIQUWHYHAF-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-3-[4-(4-ethoxyphenoxy)phenyl]urea Chemical compound C1=CC(OCC)=CC=C1OC(C=C1)=CC=C1NC(=O)NC1=CSC(C(C)(C)C)=C1 WKYHBIQUWHYHAF-UHFFFAOYSA-N 0.000 claims 1
- OPTYENRVSZMHPJ-UHFFFAOYSA-N 1-(5-tert-butylthiophen-3-yl)-3-[4-(4-propan-2-yloxyphenoxy)phenyl]urea Chemical compound C1=CC(OC(C)C)=CC=C1OC(C=C1)=CC=C1NC(=O)NC1=CSC(C(C)(C)C)=C1 OPTYENRVSZMHPJ-UHFFFAOYSA-N 0.000 claims 1
- RMNIXRMFHYBQQB-UHFFFAOYSA-N 1-[3-(2-methylbutan-2-yl)-1,2-oxazol-5-yl]-3-(3-pyridin-4-ylsulfanylphenyl)urea Chemical compound O1N=C(C(C)(C)CC)C=C1NC(=O)NC1=CC=CC(SC=2C=CN=CC=2)=C1 RMNIXRMFHYBQQB-UHFFFAOYSA-N 0.000 claims 1
- PRUKAVRSMUKMPZ-UHFFFAOYSA-N 1-[3-(3-methylpentan-3-yl)-1,2-oxazol-5-yl]-1-(4-pyridin-4-yloxyphenyl)urea Chemical compound O1N=C(C(C)(CC)CC)C=C1N(C(N)=O)C(C=C1)=CC=C1OC1=CC=NC=C1 PRUKAVRSMUKMPZ-UHFFFAOYSA-N 0.000 claims 1
- AVGDYMIXTWFURX-UHFFFAOYSA-N 1-[3-(3-methylpentan-3-yl)-1,2-oxazol-5-yl]-3-[4-(pyridin-4-ylmethyl)phenyl]urea Chemical compound O1N=C(C(C)(CC)CC)C=C1NC(=O)NC(C=C1)=CC=C1CC1=CC=NC=C1 AVGDYMIXTWFURX-UHFFFAOYSA-N 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- HKQBXLJMQGQRDF-UHFFFAOYSA-N C(C)(C)(C)C1=CC(=CS1)N(C(=O)N)C1=CC=C(C=C1)OC1=CC=C(C=C1)OC Chemical compound C(C)(C)(C)C1=CC(=CS1)N(C(=O)N)C1=CC=C(C=C1)OC1=CC=C(C=C1)OC HKQBXLJMQGQRDF-UHFFFAOYSA-N 0.000 claims 1
- VARNKUIXNDPMRS-UHFFFAOYSA-N C(C)(C)(C)C1=CC(=NO1)N(C(=O)N)C1=CC(=CC=C1)SC1=C(C=NC=C1)C Chemical compound C(C)(C)(C)C1=CC(=NO1)N(C(=O)N)C1=CC(=CC=C1)SC1=C(C=NC=C1)C VARNKUIXNDPMRS-UHFFFAOYSA-N 0.000 claims 1
- NCWIXQOCLSDUPO-UHFFFAOYSA-N C(C)(C)(C)C1=NOC(=C1)N(C(=O)N)C1=CC=C(C=C1)CC1=CC=NC=C1 Chemical compound C(C)(C)(C)C1=NOC(=C1)N(C(=O)N)C1=CC=C(C=C1)CC1=CC=NC=C1 NCWIXQOCLSDUPO-UHFFFAOYSA-N 0.000 claims 1
- VVSDYIZJNRURTB-UHFFFAOYSA-N CN1N=C(C=C1N(C(=O)N)C1=CC=C(C=C1)SC1=CC=NC=C1)C(C)(C)C Chemical compound CN1N=C(C=C1N(C(=O)N)C1=CC=C(C=C1)SC1=CC=NC=C1)C(C)(C)C VVSDYIZJNRURTB-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 108090001005 Interleukin-6 Proteins 0.000 claims 1
- 108090001007 Interleukin-8 Proteins 0.000 claims 1
- 101001013152 Mycobacterium avium Major membrane protein 1 Proteins 0.000 claims 1
- 101001013151 Mycobacterium leprae (strain TN) Major membrane protein I Proteins 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 206010040070 Septic Shock Diseases 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- CKKFAPLZDWYTHG-UHFFFAOYSA-N [3-(4-methylphenoxy)phenyl]urea Chemical compound C1=CC(C)=CC=C1OC1=CC=CC(NC(N)=O)=C1 CKKFAPLZDWYTHG-UHFFFAOYSA-N 0.000 claims 1
- AIOQDSPVQFKKQO-UHFFFAOYSA-N [4-(4-hydroxyphenoxy)phenyl]urea Chemical compound C1=CC(NC(=O)N)=CC=C1OC1=CC=C(O)C=C1 AIOQDSPVQFKKQO-UHFFFAOYSA-N 0.000 claims 1
- WANKHXKMUWCUTK-UHFFFAOYSA-N [4-(4-methoxyphenoxy)phenyl]urea Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(NC(N)=O)C=C1 WANKHXKMUWCUTK-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 244000309464 bull Species 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 238000000021 kinase assay Methods 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 230000036303 septic shock Effects 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 102000035195 Peptidases Human genes 0.000 abstract 1
- 230000003157 cancerolytic effect Effects 0.000 abstract 1
- 235000013877 carbamide Nutrition 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Claims (41)
1. Verfahren zur Behandlung einer von Krebs verschiedenen
Krankheit, welche durch p38 vermittelt wird, umfassend das Verabreichen einer Verbindung der Formel I .·
Ii
A-NH-C-NH-B . &tgr;
worin B ein substituierter oder unsubstituierter, bis zu tricyclischer, Aryl- oder Heteroarylrest mit bis zu 30
Kohlenstoffatomen mit mindestens einer 5- oder 6-gliedrigen
aromatischen Struktur ist, die 0-4 Mitglieder der Gruppe, bestehend aus Stickstoff, Sauerstoff und Schwefel, enthält,
worin B, falls es eine substituierte Gruppe ist, durch einen oder mehrere Substituenten substituiert ist, unabhängig
ausgewählt aus der Gruppe, bestehend aus Halogen, bis zur Perhlogensubstitution, und Xn,
worin &eegr; 0 - 3 ist und jedes X unabhängig ausgewählt ist aus der Gruppe, bestehend aus -CN, -CO2R5, -C(O)NR5R5', -C(O)R5,
-NO2, -OR5, -SR5, -NR5R5', -NR5C(O)OR5', -NR5C(O)R5', C1-C10-Alkyl,
C2-C10-Alkenyl, C1-C10-AIkOXy, C3-C10-Cycloalkyl, C6-C14-Aryl,
C7-C24-Alkaryl, C3-C13-Heteroaryl, C4-C33-
DE/EP 1 041-982 Tl
Alkheteroaryl, substituiertes C1-C10-AIkYl, substituiertes C2-C10-Alkenyl,
substituiertes C1-C10-AIkOXy, substituiertes C3-C10-Cycloalkyl,
substituiertes C4-C23-Alkheteroaryl und -Y-Ar;
worin wenn X eine substituierte Gruppe ist, sie mit einem oder mehreren Substituenten substituiert ist, unabhängig
ausgewählt aus der Gruppe, bestehend aus -CN, -CO2R , -C(O)R5, -C(O)NR5R5',-OR5, -SR5, -NR5R5', -NO9, -NR5C(O)R5',
-NR-5C(O)OR und Halogen bis zur Perhalogensubstitution;
worin R5 und R5' unabhängig ausgewählt sind aus H, C1-C10-Alkyl,
C2-C1Q-Alkenyl, C3-C10-Cycloalkyl, C6-C14-Aryl, C3-C13-Heteroaryl,
C7-C24-Alkaryl, C4-C23-Alkheteroaryl, bis zu
perhalogensubstituiertem C1-C10-AIkYl, bis zu
perhalogensubstituiertem C3-C10-Cycloalkyl, bis zu
perhalogensubstituiertem C2-C10-Alkenyl, bis zu
perhalogensubstituiertem Cg-C14-Aryl, und bis zu
perhalogensubstituiertem C3-C13-Heteroaryl,
worin Y -0-, -S-, -N(R5)-, - (CH2)m-, -C(O)-, -CH(OH)-,
- (CH2)m0-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa,
-NR5C(O)NR5R5'-, -NR5C(O)-, -C(O)NR5-, -CXa 2-, -S-(CH3)m- und
-N(R5)(CH2)m- ist,
m = 1 - 3 und Xa ist Halogen; und
m = 1 - 3 und Xa ist Halogen; und
Ar eine 5-10-gliedrige aromatische Struktur ist mit 0-4
Mitgliedern der Gruppe, bestehend aus Stickstoff, Sauerstoff und Schwefel, welche unsubstituiert oder durch Halogen bis zur
Perhalogensubstitution substituiert ist und gegebenenfalls durch Znl substituiert ist,
worin nl 0 bis 3 ist und jedes Z unabhängig ausgewählt ist
aus der Gruppe, bestehend aus -CN, -CO2R5, -C(O)NR5R5',
-C(O)-NR5, -NO2, =0, -OR5, -SR5, -NR5R5', -C(O)R5, -SO2R5,
-SO2NR5R5', -NR5C(O)OR5', -NR5C(0)R5', C1-C10-AIkYl, C1-C10"
Alkoxy, C3-C10-Cycloalkyl, C6-C14-Aryl, C3-C13-Heteroaryl, C7-C24-Alkaryl,
C4-C23-Alkheteroaryl, substituiertes C1-C10-Alkyl,
substituiertes C3-C10-CyClOaIkYl, substituiertes
C7-C24-Alkaryl und substituiertes C4-C23-Alkheteroaryl;
worin, falls Z eine substituierte Gruppe ist, sie substituiert ist durch einen oder mehrere Substituenten,
&bgr; ·
-3-
DE/EP 1 O41 382 Tl
unabhängig ausgewählt aus der Gruppe, bestehend aus -CN, -CO9R5, -C(O)R5', -C(O)NR5R5', =0, -OR5, -SR5, -NO9, -NR5R5
-NR5C(O)R5', -NR5C(O)OR5', C1-C10-Al]CyI, C1-C10-AIkOXy,
C3-C10-Cycloalkyl, C-C10-Heteroaryl, Cg-C14-Aryl, C4-C24-Alkheteroaryl
und C7-C24-Alkaryl;
A ein Heteroarylrest ist, ausgewählt aus der Gruppe, bestehend aus
R1 R
&Ngr; I. N-
R1
N N-
N-
R1
fAN
Rb
und
worin R1 ausgewählt ist aus der Gruppe, bestehend aus Halogen, C3-C10-Alkyl, C3-C10-CyClOaIkYl, C1-C13-Heteroaryl,
Cg_14-Aryl, C7_24-Al.karyl, bis zu perhalogensubstituiertem C1-C10-Alkyl,
bis zu perhalogensubstituiertem C3-C10-CyClOaIkYl,
bis zu perhalogensubstituiertem C1-C13-Heteroaryl, bis zu
perhalogensubstituiertem Cg_14-Aryl und bis zu
perhalogensubstituiertem C7_24-Alkaryl;
R2 ausgewählt ist aus der Gruppe, bestehend aus H, -C(O)R ,
-CO2R4, -C(O)NR3R3', C1-C10-AIkYl, C3-C10-Cycloalkyl, C7-C24-Alkaryl,
C4-C23~Alkheteroaryl, substituiertem C1-C10
substituiertem C3-C10-Cycloalkyl, substituiertem C7-C24-Alkaryl
und substituiertem C4-C23-Alkheteroaryl,
DE/EP1 O4I 382 Tl
worin R2 eine substituierte Gruppe ist, die substituiert ist
durch einen oder mehreren Substituenten, unabhängig ausgewählt
aus der Gruppe, bestehend aus -CN, -CO2R4, -C(O)-NR3R3', -NO2,
-OR4, -SR4 und Halogen, bis zur Perhalogensubstitution, worin R3 und R3' unabhängig ausgewählt sind aus der Gruppe,
bestehend aus H, -OR4, -SR4, -NR4R4', -C(O)R4, -CO2R4,
-C(O)NR4R4', C1-C10-AIlCyI, C3-C10-Cycloalkyl, C6-C14-Aryl, C3-C13-Heteroaryl,
C7-C24-Alkaryl# C4-C23-Alkheteroaryl, bis zu
perhalogensubstituiertem C1-C^q-Alkyl, bis zu
perhalogensubstituiertem C3-C10-Cycloalkyl, bis zu
perhalogensubstituiertem Cg-C14-Aryl und bis zu
perhalogensubstituiertem C3-C13-Heteroaryl; und
worin R und R unabhängig ausgewählt sind aus der Gruppe,
bestehend aus H, C^C^-Alkyl, C3-C10-Cycloalkyl, C6-C14-Aryl,
C3-C13-Heteroaryl/ C7-C24-Alkaryl, C4-C23-Alkheteroaryl, bis
zu perhalogensubstituiertem C1-C10-Alkyl, bis zu
perhalogensubstituiertem C3-C10-Cycloalkyl, bis zu
perhalogensubstituiertem C6-C14-Aryl und bis zu
perhalogensubstituiertem C3-C13-Heteroaryl,
Ra C1-C10-Alkyl, C3-C10-Cycloalkyl, bis zu
perhalogensubstituiertem C^C^-Alkyl und bis zu
perhalogensubstituiertem C3-C10-Cycloalkyl ist; und
RD Wasserstoff oder Halogen ist,
Rc Wasserstoff, Halogen, C1-C10-Alkyl, bis zu
perhalogensubstituiertem C-^-C^jQ-Alkyl ist oder sich mit R und
den Ringkohlenstoffatomen vereinigt, an welche R1 und Rc
gebunden sind, um einen 5- oder 6-gliedrigen Cycloalkyl-, Aryl- oder Heteroarylring mit 0-2 Mitgliedern, ausgewählt aus
0, N und S zu bilden.
DE/Eh'O41982 T
2. Verfahren nach Anspruch 1, worin B eine bis zu tricyclische aromatische Ringstruktur ist, ausgewählt aus der Gruppe,
bestehend aus
und
welches unsubstituiert oder durch Halogen, bis zur Perhalogensubstitution, substituiert ist, und
worin &eegr; = 0-3 und jedes X unabhängig ausgewählt ist aus der
Gruppe, bestehend aus -CN, -CO9R5, -C(O)NR5R5', -C(O)R5, -NO0,
5 SR5
-NR5R5
NR5C(O)OR5
-NR5C (0) R5
-OR5, SR
C2-10-Alkenyl, C1-10-AIkOXy, C3-C10-Cycloalkyl, Cg-C14-Aryl,
C7-C24-Alkaryl, C3-C13-Heteroaryl, C4-C23-Alkheteroaryl und
substituiertem C1-C10-Alkyl, substituiertem C2-C10-Alkenyl,
substituiertem C1-C10-AIkOXy, substituiertem C3-C10-Cycloalkyl,
substituiertem C4-C23-Alkheteroaryl und -Y-Ar,-
worin X, falls es eine substituierte Gruppe ist, substituiert ist durch einen oder mehreren Substituenten,
unabhängig ausgewählt aus der Gruppe, bestehend aus -CN, -CO2R5, -C(O)R5, -C(O)NR5R5', -OR5,-SR5, -NR5R5', NO2,
-NR5C(O)R5', -NR5C(O)OR5' und Halogen bis zur
Perhalogensubstitution;
worin R5 und R5' unabhängig ausgewählt sind aus H, C1-C10-Alkyl,
C2-10-Alkenyl, C3-C^-Cycloalkyl, Cg-C14-Aryl, C3-C13-Heteroaryl,
C7-C24-Alkaryl, C4-C23-Alkheteroaryl, bis zu
perhalogensubstituiertem C1-C10-Alkyl, bis zu
perhalogensubstituiertem C2-10-Alkenyl, bis zu
perhalogensubstituiertem C3-C10-Cycloalkyl, bis zu
-6-
DE"/EP 1 Oil 982 Tl
perhalogensubstituiertem Cg-C14-Aryl und bis zu
perhalogensubstituiertem C3-C13-Heteroaryl,
worin Y -&Ogr;-, -S-, -N(R5)-, - (CH2)m-, -C(O)-, -CH(OH)-,
-(CH2)mO-, -NR5C(O)NR5R5'-, -NR5C(O)-, -C(O)NR5'-, -(CH2J1nS-,
-(CH2)mN(R5)-, -O(CH2)m-, -CHXa, -CXa 2-, -S-(CH2)m- und
-N(R5) (CH2J1n-, ist,
m = 1-3 und Xa ist Halogen; und
Ar eine 5-10-gliedrige aromatische Struktur ist mit 0-4
Mitgliedern der Gruppe, bestehend aus Stickstoff, Sauerstoff und Schwefel, welche unsubstituiert oder durch Halogen bis zu
Perhalogensubstitution substituiert ist und gegebenenfalls durch znl substituiert ist,
worin nl 0 bis 3 ist und jedes Z unabhängig ausgewählt ist
aus der Gruppe, bestehend aus -CN, -CO2R5, -C(O)R5, =0,
-SO2R5, -SO2, NR5R5', -C(O)NR5R5', -C(O)R5, -NO2, -OR5, -SR5,
-NR5R5', -NR5C(O)OR5', -NR5C(O)R5', C1-C10-AIkYl, C1-C10-Alkoxy,
C3-C10-Cycloalkyl, Cg-C14-Aryl, C3-C13-Heteroaryl, C7-C24-Alkaryl,
C4-C23-Alkheteroaryl, substituiertes C1-C10-Alkyl,
substituiertes C3-C10-CyClOaIkYl, substituiertes
C7-C24-Alkaryl und substituiertes C4-C23-Alkheteroaryl;
worin, falls Z eine substituierte Gruppe ist, es substituiert ist durch einen oder mehrere Substituenten, unabhängig
ausgewählt aus der Gruppe, bestehend aus -CN, -CO2R5,
-C(O)NR5R5', =0, -OR5, -SR5, -NO9, -NR5R5', -NR5C(O)R5',
-NR5C(O)OR5', C1-C10-AIkYl, C1-C10-AIkOXy, C3-C10-Cycloalkyl,
C-C10-Heteroaryl, Cg-C14-Aryl, C4-C24-Alkheteroaryl und
C7-C24-Alkaryl.
3.Verfahren nach Anspruch 1, worin B
—Q— (¥— QVZ111
worin Y ausgewählt ist aus der Gruppe, bestehend aus -0-, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(O)-, -CXa 2, -CXaH-,
it
DE/EPt Ü4T982T1
-CH2O- und -OCH2-, worin Xa Halogen ist,
Q eine sechsgliedrige aromatische Ringstruktur ist, die 0-2 Stickstoffe enthält, unsubstituiert oder substituiert durch
Halogen, bis zur Perhalogensubstitution;
Q1 eine mono- oder bicyclische aromatische Struktur mit
bis 10 Kohlenstoffatomen und 0-4 Mitgliedern der Gruppe, bestehend aus N, 0 und S ist, unsubstituiert oder substituiert
durch Halogen bis zur Perhalogensubstitution, und X, Z, &eegr; und nl wie in Anspruch 1 definiert sind und s 0 oder
ist.
4. Verfahren nach Anspruch 3, worin
Q Phenyl oder Pyridinyl ist, unsubstituiert oder substituiert durch Halogen, bis zur Perhalogensubsitution,
Q1 ausgewählt ist aus der Gruppe, bestehend aus Phenyl,
Pyridinyl, Naphthyl, Pyrimidinyl, Quinolin, Isoquinolin,
Imidazol und Benzothiazolyl, unsubstituiert oder substituiert durch Halogen, bis zur Perhalogensubsitution, oder -Y-Q
Phthalimidinyl, unsubstituiert oder substituiert durch Halogen,, bis zur Perhalogensubstitution und
Z und X unabhängig ausgewählt sind aus der Gruppe, bestehend aus -R6, -OR6 und- NHR7, worin R6 Wasserstoff, C1-C10-AIlCyI
oder C3-C1Q-Cycloalkyl ist und R ausgewählt ist aus der
Gruppe, bestehend aus Wasserstoff, Cj-C-^-Alkyl, C-^-Cg-Cycloalkyl
und Cg-C10-Aryl, worin R6 und R7 mit Halogen oder
bis zur Perhalogensubstitution substituiert sein können.
5. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung der Formel
R1
NH-C-NH-B
worin R1 und R und B wie in Anspruch 1 definiert sind.
DE/EP 1 Ö4iS82Ti
6. Verfahren nach Anspruch 5, worin B 2,3-Dichlorphenyl oder
der Formel y
entspricht,
worin Q Phenyl ist, Q^ Phenyl oder Pyridinyl ist, Y -0-,
-S-, -CH2- oder -SCH0 ist, X CF7 ist und Z -OH, -Cl oder
NHC(O)-C H2 ± ist, worin &rgr; = 2-4, s=0 oder 1, &eegr; = 0 und nl
= 0 oder 1.
7. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung, ausgewählt aus der Gruppe, bestehend aus:
N- (3-tert-Butyl-5-pyrazolyl)-N1-(4-(2, 3-dichlorphenyl)harnstoff;
N-(3-tert-Butyl-5-pyrazolyl)-N1-(3,4-pyridinyl)thiophenyl)harnstoff;
N-(3 -tert-Butyl- 5-pyrazolyl)-N'-(4-(4-pyridinyl)methylphenyl)harnstoff;
N-(3-tert-Butyl-5-pyrazolyl)-N1-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)thiophenyl)harnstoff;
N-(3-tert-Butyl-5-pyrazolyl)-N1-(4-(4-
pyridinyl)methylphenyl)harnstoff; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)
-N' - (2, 3 -dichlorphenyl) harnstoff ,· N-(l-Methyl-3-tert-butyl-S-pyrazolyl)-N'-(4-(4-hydroxyphenyl) thiophenyl)harnstoff;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N1- (4-(4-ethylaminocarbonylphenyl)oxyphenyl)harnstoff;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N1-(4-(4-
isobutylaminocarbonylphenyl)thiophenyl)harnstoff; N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N1-(4-(4-
pyridinyl)thiophenyl)harnstoff; N-(1-Methyl-3 -tert-butyl-5 pyrazolyl)-N1-(3-(4-pyridinyl)thiophenyl)harnstoff;
N-(I-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)thio-3-(trifluormethyl)phenyl)harnstoff;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N1-(4-{(4-pyridinyl)-methyl
thio) phenyl) harnstoff ,· '
DE/EP1041982T1
N-(1-(2,2,2-Trifluorethyl)-3-tert-butyl-S-pyrazolyl)-N'-(2,3-dichlorphenyl)harnstoff;
N-(1-(2-Hydroxyethyl-3-tert- butyl-5-pyrazolyl)-N1-(2, 3-dichlorphenyl)harnstoff; N-(&Igr;&Egr;
thoxycarbonylmethyl-3-tert-butyl-5-pyrazolyl) -N'-(2,3-dichlorphenyl)harnstoff;
N-(1-(2-Cyanoethyl)-3-tert-butyl-5-pyrazolyl) -N1 - (2, 3-dichlorphenyl) harnstoff; N-(I-O-Hydroxyphenyl)-methyl-3-tert-butyl-5-pyrazolyl)-N1
- (2, 3-dichlorphenyl)harnstoff; N-(l-Cyclohexyl-3-tert-butyl-5-pyrazolyl)-N1-(4-(4-pyridinyl)methylphenyl)harnstoff;
N-(1-Methyl-3-phenyl-5-pyrazolyl)-N1-(3-(4-(2-methylcarbamoyl)-pyridyl)thiophenyl)harnstoff;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl-N'-(4-(4-pyridyl)thiophenyl)harnstoff;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N1-(3-(4-pyridyl)-thiophenyl)harnstoff;
N- (l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-trifluormethyl-4-(4-pyridylthio)phenyl)harnstoff;
N-(3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl)harnstoff;
N-O-tertbutyl-5-pyrazolyl)-N'-(4-(4-pyridyl)oxyphenyl)harnstoff;
und pharmazeutisch verträgliche Salze davon.
8. Verfahren nach Anspruch 5, worin R1 t-Butyl ist.
9. Verfahren nach Anspruch I1 umfassend das Verabreichen einer
Verbindung der Formel
worin R und B wie in Anspruch 1 definiert sind.
10. Verfahren nach Anspruch 9, worin B
-&iacgr;&ogr;-
DE/EP1 041982 Tl
worin Q Phenyl ist, Q1 Phenyl oder Pyridinyl ist, Y -0-, -S-
oder -CH2 ist, X CF3 ist, Z OH, CH3, -0-CpH2p+1 ist, worin &eegr; =
2-6 oder -C(O)-NH-CH3 ist, s = 1, &eegr; = 0 oder 1 und nl = 0 oder
1.
11. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung, ausgewählt aus der Gruppe, bestehend aus: N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-
hydroxyphenyl)oxyphenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-isopropoxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-
isobutoxyphenyl)oxyphenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-pentyloxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-methylaminocarbonylphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-pyridinyl)thiophenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-pyridinyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-
-pyridinyl)thiophenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-pyridinyl)methylphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)thio-3- (trifluormethyl)phenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N1-(3-(3-methyl-4-pyridinyl)thiophenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(3-Methyl-4-pyridinyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methyl-4-pyridinyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methyl-4-
pyridinyl)thiophenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N1-(4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl-harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(3-(4-(2-methy1carbamoyl)pyridyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(2-carbamoyl)pyridyl)-oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(3-(4-(2-carbamoyl)pyridyl)-
N-(5-tert-Butyl-3-isoxazolyl)-N1-(3-(4-(2-carbamoyl)pyridyl)-
-11-
DE/EP 1 O41 982 T1
oxyphenyl)harnstoff; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-((4-pyridyl)fluormethyl)phenyl)harnstoff;
N-(5-tert-Butyl-3-isoxazolyl)-N1-(3-((4-pyridyl)oxomethyl)phenyl)harnstoff;
und pharmazeutisch verträgliche Salze davon.
12. Verfahren nach Anspruch 9, worin R1 t-Butyl ist.
13. Verfahren nach Anspruch 1, umfassend das Verabreichen
einer Verbindung der Formel
R1
0 ^NH-C-NH-B
worin R1 und B wie in Anspruch 1 definiert sind.
14. Verfahren nach Anspruch 13, worin B 2,3-Dichlorphenyl ist
oder die Formel
aufweist, worin Q Phenyl ist, Q1 Phenyl, Pyridinyl oder
Benzothiazolyl ist, Y -0-, -S-, -CH0- oder -NH- ist, Z Cl,
-CH3 pder -OCH3 ist,- s=0 oder 1, &eegr; = 0 und nl = 0 oder 1.
15. Verfahren nach Anspruch 13, worin R1 t-Butyl ist.
16. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung, ausgewählt aus der Gruppe, bestehend aus: N-(3-Isopropyl-5-isoxazolyl)-N1-(3-(4-
pyridinyl)thiophenyl)harnstoff; N-(3-tert-Butyl-5-isoxazolyl)-N1-(2,3-dichlorphenyl)harnstoff;
N-(3-tert-Butyl-5-isoxazolyl)-N1-(4-(4-methoxyphenyl)aminophenyl)harnstoff;
N-(3-
-12-
DE/EP1041982T1
tert-Butyl-5-isoxazolyl)-N1-(4-(4-methoxyphenyl)-oxyphenyl)harnstoff;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(3-tert-Butyl-5-isoxa2olyl)-N'-(4-(4-pyridinyl)thiophenyl)harnstoff;
N-(3-tert-Butyl-5-isoxazolyl)-N1-(4-(4-pyridinyl)methylphenyl)harnstoff;
N- (3-(1,1-Dimethylpropyl)-5-isoxazolyl-N'-(4-(4-pyridinyl)-methylphenyl)harnstoff;
N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(3 -(4-pyridinyl)thiophenyl)harnstoff;
N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N1-(4-(2-benzothiazolyl)-oxyphenyl)harnstoff;
N-(3-(1-Methyl-1-ethylpropyl)-5-isoxazolyl-N'-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(3-(1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl)methylphenyl)harnstoff;
N-(3-Cyclobutylyl-5-isoxazolyl)-N1-(4-(4-pyridyl)oxyphenyl)harnstoff;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridyl)thiophenyl)harnstoff;
N-(3-(1-Methyl-1-ethylprop-l-yl)-5-isoxazolyl)-N1-(4-(4-pyridyl)oxyphenyl)harnstoff;
N-(3-tert-butyl-5-isoxazolyl)-N1-(4_(4-pyridyl)methylphenyl)harnstoff;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-methoxyphenyl)aminophenyl)harnstoff;
und pharmazeutisch verträgliche Salze davon.
17. Verfahren nach Anspruch 1, umfassend das Verabreichen
einer Verbindung der Formel
Il
NH-C-NH-B
worin R1, R" und B wie in Anspruch 1 definiert sind.
•TMVi-fji
DE/EP 1 &Ogr;41 982 &Tgr;1
18. Verfahren nach Anspruch 17, worin B die Formel
aufweist, worin Q Phenyl ist, Q1 Phenyl oder Pyridinyl ist, Y,
-O- oder -S- oder -CH2- ist, Z OH, CH3, Cl, -OC2H5 oder -OC3H7
ist s=0 oder 1, &eegr; = 0 und nl = 0 oder 1.
19. Verfahren nach Anspruch 17, worin R1 t-Butyl ist.
20. Verfahren nach Anspruch 17, worin R Wasserstoff ist.
21. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung, ausgewählt aus der Gruppe, bestehend aus: N-(2-Brom-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(2,3-dichlorphenyl)harnstoff; N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-hydroxyphenyl)oxyphenyl)-harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-ethoxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-Isopropoxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N'-(4-(3-pyridinyl)oxyphenyl)-harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridinyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridinyl)thiophenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridinyl)methylphenyl)harnstoff;
N-(5-tert-Butyl-2-(l-thia-3,4-diazolyl))-N1-(4-(4-pyridyl)oxyphenyl)-harnstoff;
N-(5-tert-Butyl-2-(l-thia-3,4-diazolyl))-N1-(3-(4-pyridyl)thiophenyl)harnstoff;
N-(5-tert-Butyl-2-(l-thia-3,4-diazolyl))-N'-(3-(4-methoxyphenyl)oxyphenyl)harnstoff;
N- (5-tert-Butyl-2-(l-thia-3,4-diazolyl))7N1-(3-(4-
methylphenyl)oxyphenyl)harnstoff; N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridyl)oxyphenylharnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridyl)thiophenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-pyridyl)methylphenylharnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(2,3-dichlorphenyl)harnstoff;
N-(5-
DE/EP1 O4I982T1
tert-Butyl-3-thienyl)-N1-(4-(4-hydroxyphenyl)oxyphenyl)-harnstoff;
N-(5-tert-Butyl-3-thienyl)-N1-(4-(4-methoxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-ethoxyphenyl)oxyphenyl)harnstoff;
N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-isopropoxyphenyl)oxyphenyl)harnstoff;
und pharmazeutisch verträgliche Salze davon.
22. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung der Formel
N L—NH-C-NH-B
worin Ra und B wie in Anspruch 1 definiert sind.
23. Verfahren nach Anspruch 22, worin B die Formel
aufweist, worin Q Phenyl ist, Q1 Phenyl oder Pyridinyl ist, Y
-O-, -S- oder CH9-, Cl, -OC9Hc oder -OCtH7 ist, S=O oder I1
&eegr; = 0 und nl ist 0 oder 1.
24. Verfahren nach Anspruch 22, worin Ra CF3- oder t-Butyl
ist.
25.Verfahren nach Anspruch l, umfassend das Verabreichen einer
Verbindung einer der Formeln
R1
/ ^NH-C-NH-B Rb
DE/EP &iacgr; 0itSt2Tt
R'
&ogr; oder &eacgr;—^ Il
NH-C-NH-B NH-CNH-B
worin .R1, R und B wie in Anspruch 1 definiert sind.
26. Verfahren nach Anspruch 25, worin B die Formel
—Q-(Y-
aufweist, worin Q Phenyl ist, Q1 Phenyl oder Pyridinyl ist, Y
-0-, -S- oder CH2- ist, Z OH, CH3, Cl, -OC2H5 oder -OC3H7
ist, s=0 oder 1, n= 0 und nl 0 oder 1 ist.
27. Verfahren nach Anspruch 25, worin R1 t-Butyl ist.
28. Verfahren nach Anspruch 1, worin die Verbindung für Formel I eine p38-Aktivität (IC50) von besser als 10 &mgr;&ngr;&eegr;. gemäß
Bestimmung durch einen in-vitro-Kinaseassay zeigt.
29. Verfahren nach Anspruch 1, worin die Krankheit durch ein Cytokin oder eine Protease, reguliert durch p3 8, vermittelt
wird.
30. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Menge einer Verbindung der Formel I, die effektiv ist,
um p3 8 zu inhibieren.
31. Verfahren nach Anspruch 1, umfassend das Verabreichen
einer Menge einer Verbindung der Formel I, die effektiv ist, um die Erzeugung von krankheitsvermittelndem Cytokin oder
Protease zu inhibieren.
32. Verfahren nach Anspruch 1, worin die Krankheit durch TNFo;,
DE/EP 1 &Ogr;4&iacgr; 982 Tl
MMP-I, &Mgr;&Mgr;&Rgr;-3, IL-I, IL-6 oder IL-8 vermittelt wird.
33. Verfahren nach Anspruch 1, worin die Krankheit eine
entzündliche oder immunmodulatorisc-he Erkrankung ist.
34. Verfahren nach Anspruch 1, worin die Krankheit Rheuma, Arthritis, Osteoporose, Osteoarthritis, Asthma, septischer
Schock, entzündliche Darmerkrankung oder das Ergebnis von Transplantatabstoßungsreaktionen ist.
35. Verbindung nach einer der Formeln
t-Bu
H Il H /=
b)
t-Bu
worin R6 -0-CH2-Phenyl, -NH-C(0)-O-t-Butyl, -O-n-Pentyl,
-O-n-Butyl, -C(O)-N(CH3)2, -0-CH2CH(CH3)2 oder -O-n-Propyl
ist;
c)
R1
worin R1 -CH2-t-Butyl ist;
· J *&idigr;
-17-
d)
t-Bu
Il
-NH-C-NH
R5
R5
Cl
worin R2 -CH2CF3, -C2H4-OH, -CH2-O-HOCgH4),
-CH2C(O)OC2H5, -C2H4CN oder
CH2C(O)NHCH3,
Cl Cl
c ·· t
-18-
DE/EP 1 O41382 Tl
t-Bu
&PSgr; Il &eegr; H &eegr;
/N—^-N-C-N-^ ff
CH3
Il
-C-O-C4H9
t-Bu
NH-C-NH-^ &Lgr;—o-^x
Il /=
NH-C-NH-^ &ohgr; -CH,
CH(CH3)2
NH-C-NH
Cl C!
9 DE/EP 1 O4I 9S2 Tl
ist und pharmazeutisch verträgliche Salze davon.
36. Pharmazeutische Zusammensetzung, umfassend eine Verbindung
nach Anspruch 35 ode'r ein pharmazeutisch verträgliches Salz davon und einen physiologisch verträglichen Träger.
37. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung der Formel
R1
NH-C-NH-B
worin R1 und B wie in Anspruch 1 definiert sind.
38. Verfahren nach Anspruch 1, umfassend das Verabreichen
einer Verbindung der Formel
NH-C-NH-B
worin R1 und B wie in Anspruch 1 definiert sind.
39. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung der Formel
R1
NH-C-NH-B
worin R1, R2 und B wie in Anspruch 1 definiert sind
DE/EP 1 (Ul 98-2 Tt
40. Verfahren nach Anspruch 1, umfassend das Verabreichen
einer Verbindung der Formel
R1
>k NNn
11 Il &igr;? N ^ II
NH-C-NH-B
worin R1 und B wie in Anspruch l definiert sind.
41. Verfahren nach Anspruch 1, umfassend das Verabreichen einer Verbindung der Formel
R1
Il
'NH-C-NH-B
worin R und B wie in Anspruch 1 definiert sind.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US99575097A | 1997-12-22 | 1997-12-22 | |
PCT/US1998/026080 WO1999032111A1 (en) | 1997-12-22 | 1998-12-22 | INHIBITION OF p38 KINASE ACTIVITY USING SUBSTITUTED HETEROCYCLIC UREAS |
Publications (1)
Publication Number | Publication Date |
---|---|
DE1041982T1 true DE1041982T1 (de) | 2001-06-07 |
Family
ID=25542167
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE1041982T Pending DE1041982T1 (de) | 1997-12-22 | 1998-12-22 | HEMMUNG DER p38 KINASE AKTIVITÄT DURCH SUBSTITUIERTEN HETEROCYCLISCHEN HARNSTOFFEN |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1041982B1 (de) |
JP (1) | JP4403482B2 (de) |
AT (1) | ATE529109T1 (de) |
AU (1) | AU739642B2 (de) |
CA (1) | CA2315720A1 (de) |
DE (1) | DE1041982T1 (de) |
ES (1) | ES2154253T3 (de) |
IL (3) | IL136738A0 (de) |
MX (1) | MXPA00006233A (de) |
WO (1) | WO1999032111A1 (de) |
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1998
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- 1998-12-22 EP EP98964709A patent/EP1041982B1/de not_active Expired - Lifetime
- 1998-12-22 WO PCT/US1998/026080 patent/WO1999032111A1/en active Application Filing
- 1998-12-22 AU AU19971/99A patent/AU739642B2/en not_active Ceased
- 1998-12-22 ES ES98964709T patent/ES2154253T3/es not_active Expired - Lifetime
- 1998-12-22 AT AT98964709T patent/ATE529109T1/de not_active IP Right Cessation
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2000
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AU1997199A (en) | 1999-07-12 |
JP2001526223A (ja) | 2001-12-18 |
EP1041982A1 (de) | 2000-10-11 |
MXPA00006233A (es) | 2002-09-18 |
IL136738A (en) | 2007-06-17 |
WO1999032111A1 (en) | 1999-07-01 |
ATE529109T1 (de) | 2011-11-15 |
IL170201A (en) | 2006-12-31 |
EP1041982B1 (de) | 2011-10-19 |
EP1041982A4 (de) | 2006-06-14 |
ES2154253T3 (es) | 2012-01-27 |
IL136738A0 (en) | 2001-06-14 |
JP4403482B2 (ja) | 2010-01-27 |
ES2154253T1 (es) | 2001-04-01 |
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