RU2249591C2 - 3(5)-гетероарилзамещенные пиразолы в качестве ингибиторов киназы p38 - Google Patents

Info

Publication number

RU2249591C2

RU2249591C2 RU99126510/04A RU99126510A RU2249591C2 RU 2249591 C2 RU2249591 C2 RU 2249591C2 RU 99126510/04 A RU99126510/04 A RU 99126510/04A RU 99126510 A RU99126510 A RU 99126510A RU 2249591 C2 RU2249591 C2 RU 2249591C2

Authority

RU

Russia

Prior art keywords

pyrazol

fluorophenyl

pyridinyl

ness

methyl

Prior art date

1997-05-22

Links

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• Global Dossier
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• 150000003217 pyrazoles Chemical class 0.000 title abstract description 19
• 108091000080 Phosphotransferase Proteins 0.000 title abstract description 15
• 102000020233 phosphotransferase Human genes 0.000 title abstract description 15
• 239000012826 P38 inhibitor Substances 0.000 title abstract 3
• -1 amino, aminocarbonylamino Chemical group 0.000 claims abstract description 251
• 150000001875 compounds Chemical class 0.000 claims abstract description 100
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 55
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 45
• 150000003839 salts Chemical class 0.000 claims abstract description 45
• 150000004678 hydrides Chemical group 0.000 claims abstract description 32
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 23
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
• 125000005843 halogen group Chemical group 0.000 claims abstract description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
• 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims abstract description 7
• 239000001257 hydrogen Substances 0.000 claims abstract description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims abstract description 5
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
• 125000003386 piperidinyl group Chemical group 0.000 claims abstract 2
• 238000000034 method Methods 0.000 claims description 38
• 102100040247 Tumor necrosis factor Human genes 0.000 claims description 33
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 30
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 30
• 208000035475 disorder Diseases 0.000 claims description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
• 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 claims description 23
• 230000001404 mediated effect Effects 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 125000003282 alkyl amino group Chemical group 0.000 claims description 16
• 206010061218 Inflammation Diseases 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
• 230000004054 inflammatory process Effects 0.000 claims description 15
• 206010003246 arthritis Diseases 0.000 claims description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
• UCYCFYFNBWRJIL-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-1h-pyrazol-5-yl]pyridine Chemical compound C1=CC(F)=CC=C1C1=CNN=C1C1=CC=NC=C1 UCYCFYFNBWRJIL-UHFFFAOYSA-N 0.000 claims description 9
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• FNEJUCNPMRBTLD-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-1-methylpyrazol-3-yl]pyridine Chemical compound N=1N(C)C=C(C=2C=CC(F)=CC=2)C=1C1=CC=NC=C1 FNEJUCNPMRBTLD-UHFFFAOYSA-N 0.000 claims description 8
• ZVCFVJLZJGIPAY-UHFFFAOYSA-N n-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-pyrazol-3-yl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=NNC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 ZVCFVJLZJGIPAY-UHFFFAOYSA-N 0.000 claims description 7
• LZTNKQMWDZLVCY-UHFFFAOYSA-N 2-[4-(4-fluorophenyl)-3-pyridin-4-ylpyrazol-1-yl]ethanol Chemical compound N=1N(CCO)C=C(C=2C=CC(F)=CC=2)C=1C1=CC=NC=C1 LZTNKQMWDZLVCY-UHFFFAOYSA-N 0.000 claims description 6
• DKUGHDSTBVGJJW-UHFFFAOYSA-N 4-(5-methyl-4-phenyl-1h-pyrazol-3-yl)pyridine Chemical compound CC1=NNC(C=2C=CN=CC=2)=C1C1=CC=CC=C1 DKUGHDSTBVGJJW-UHFFFAOYSA-N 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• ZTVUVHMVLWWIAS-UHFFFAOYSA-N 1-[4-(4-fluorophenyl)-5-pyridin-4-yl-1h-pyrazol-3-yl]-3-methylurea Chemical compound CNC(=O)NC1=NNC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 ZTVUVHMVLWWIAS-UHFFFAOYSA-N 0.000 claims description 5
• JSFYQSJJVQMXLF-UHFFFAOYSA-N 2-[4-(4-fluorophenyl)-3-pyridin-4-ylpyrazol-1-yl]-n,n-dimethylethanamine Chemical compound N=1N(CCN(C)C)C=C(C=2C=CC(F)=CC=2)C=1C1=CC=NC=C1 JSFYQSJJVQMXLF-UHFFFAOYSA-N 0.000 claims description 5
• FXTBNPRXFDHPMN-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-methyl-5-pyridin-4-ylpyrazol-3-amine Chemical compound NC=1N(C)N=C(C=2C=CN=CC=2)C=1C1=CC=C(Cl)C=C1 FXTBNPRXFDHPMN-UHFFFAOYSA-N 0.000 claims description 5
• ZKMHYJQCWPWZFC-UHFFFAOYSA-N 4-(4-fluorophenyl)-n-(methylsulfamoyl)-5-pyridin-4-yl-1h-pyrazol-3-amine Chemical compound CNS(=O)(=O)NC1=NNC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 ZKMHYJQCWPWZFC-UHFFFAOYSA-N 0.000 claims description 5
• JCJQRHJXLMGLSV-UHFFFAOYSA-N 4-[2-[4-(4-fluorophenyl)-3-pyridin-4-ylpyrazol-1-yl]ethyl]morpholine Chemical compound C1=CC(F)=CC=C1C(C(=N1)C=2C=CN=CC=2)=CN1CCN1CCOCC1 JCJQRHJXLMGLSV-UHFFFAOYSA-N 0.000 claims description 5
• WLHUGRQFOOXJEW-UHFFFAOYSA-N 4-[4-(4-chlorophenyl)-1h-pyrazol-5-yl]pyridine Chemical compound C1=CC(Cl)=CC=C1C1=CNN=C1C1=CC=NC=C1 WLHUGRQFOOXJEW-UHFFFAOYSA-N 0.000 claims description 5
• WUFIEVBIPYUAGD-UHFFFAOYSA-N 4-[4-(4-fluorophenyl)-3-(sulfamoylamino)-1h-pyrazol-5-yl]pyridine Chemical compound NS(=O)(=O)NC1=NNC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 WUFIEVBIPYUAGD-UHFFFAOYSA-N 0.000 claims description 5
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 5
• RLBDPHUIKKSEPY-UHFFFAOYSA-N [4-(4-fluorophenyl)-5-pyridin-4-yl-1h-pyrazol-3-yl]urea Chemical compound NC(=O)NC1=NNC(C=2C=CN=CC=2)=C1C1=CC=C(F)C=C1 RLBDPHUIKKSEPY-UHFFFAOYSA-N 0.000 claims description 5
• 230000002401 inhibitory effect Effects 0.000 claims description 5
• 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 5
• 230000010410 reperfusion Effects 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
• 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 230000006378 damage Effects 0.000 claims description 4
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
• 230000002757 inflammatory effect Effects 0.000 claims description 4
• 208000006386 Bone Resorption Diseases 0.000 claims description 3
• 206010006895 Cachexia Diseases 0.000 claims description 3
• 201000005569 Gout Diseases 0.000 claims description 3
• 208000019693 Lung disease Diseases 0.000 claims description 3
• 230000024279 bone resorption Effects 0.000 claims description 3
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 3
• 201000008482 osteoarthritis Diseases 0.000 claims description 3
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
• 201000001320 Atherosclerosis Diseases 0.000 claims description 2
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
• 208000011231 Crohn disease Diseases 0.000 claims description 2
• 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
• 201000004681 Psoriasis Diseases 0.000 claims description 2
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
• 208000007536 Thrombosis Diseases 0.000 claims description 2
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
• 230000003683 cardiac damage Effects 0.000 claims description 2
• 230000001684 chronic effect Effects 0.000 claims description 2
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
• 208000024908 graft versus host disease Diseases 0.000 claims description 2
• 210000003734 kidney Anatomy 0.000 claims description 2
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 206010018364 Glomerulonephritis Diseases 0.000 claims 1
• 206010065390 Inflammatory pain Diseases 0.000 claims 1
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 1
• 125000001246 bromo group Chemical group Br* 0.000 claims 1
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims 1
• 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims 1
• 230000002207 retinal effect Effects 0.000 claims 1
• 201000010099 disease Diseases 0.000 abstract description 20
• 229910052736 halogen Inorganic materials 0.000 abstract description 19
• 150000002367 halogens Chemical class 0.000 abstract description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 13
• 230000000694 effects Effects 0.000 abstract description 7
• 239000000126 substance Substances 0.000 abstract description 4
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 2
• 150000003254 radicals Chemical group 0.000 description 89
• 239000000203 mixture Substances 0.000 description 45
• 125000004432 carbon atom Chemical group C* 0.000 description 37
• 235000002639 sodium chloride Nutrition 0.000 description 37
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
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• 210000004027 cell Anatomy 0.000 description 26
• 125000000623 heterocyclic group Chemical group 0.000 description 24
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
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• 125000001188 haloalkyl group Chemical group 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
• 239000013543 active substance Substances 0.000 description 19
• 125000003545 alkoxy group Chemical group 0.000 description 19
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• 229920006008 lipopolysaccharide Polymers 0.000 description 17
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
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• 238000000921 elemental analysis Methods 0.000 description 16
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• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 12
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