KR20030040419A - 단백질 키나아제 억제제인 융합된 피라졸 유도체 - Google Patents
단백질 키나아제 억제제인 융합된 피라졸 유도체 Download PDFInfo
- Publication number
- KR20030040419A KR20030040419A KR10-2003-7002634A KR20037002634A KR20030040419A KR 20030040419 A KR20030040419 A KR 20030040419A KR 20037002634 A KR20037002634 A KR 20037002634A KR 20030040419 A KR20030040419 A KR 20030040419A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- formula
- fluorophenyl
- pyrazolo
- pyridin
- 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.)
- Withdrawn
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title abstract description 3
- 239000003909 protein kinase inhibitor Substances 0.000 title abstract description 3
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 413
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 239000012453 solvate Substances 0.000 claims abstract description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 206
- -1 C 1-6 alkylsulphenyl Chemical group 0.000 claims description 182
- 238000000034 method Methods 0.000 claims description 82
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 48
- 201000010099 disease Diseases 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 39
- 102000002569 MAP Kinase Kinase 4 Human genes 0.000 claims description 38
- 108010068304 MAP Kinase Kinase 4 Proteins 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 37
- 230000001404 mediated effect Effects 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 102000004127 Cytokines Human genes 0.000 claims description 24
- 108090000695 Cytokines Proteins 0.000 claims description 24
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 23
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 23
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 12
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 5
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical group C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 5
- 108091000080 Phosphotransferase Proteins 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 5
- 102000020233 phosphotransferase Human genes 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 claims description 4
- 102000019145 JUN kinase activity proteins Human genes 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- JIIWFBWSAHKMIA-UHFFFAOYSA-N 3-[[4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl]amino]propan-1-ol Chemical compound OCCCNC1=NC=CC(C2=C3C=CC(=CN3N=C2C=2C=CC(F)=CC=2)C(F)(F)F)=N1 JIIWFBWSAHKMIA-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 130
- 239000000243 solution Substances 0.000 description 130
- 239000007787 solid Substances 0.000 description 114
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 110
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 108
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 94
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 150000001412 amines Chemical class 0.000 description 66
- 239000002904 solvent Substances 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 235000002639 sodium chloride Nutrition 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000001914 filtration Methods 0.000 description 44
- 230000008569 process Effects 0.000 description 42
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 40
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
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- 239000000843 powder Substances 0.000 description 15
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
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- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 description 10
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| GB0020576A GB0020576D0 (en) | 2000-08-22 | 2000-08-22 | Fused pyrazole derivatives |
| GB0020576.5 | 2000-08-22 | ||
| GB0020556.7 | 2000-08-22 | ||
| GBGB0020556.7A GB0020556D0 (en) | 2000-08-22 | 2000-08-22 | Fused pyrazole derivatives |
| PCT/GB2001/003783 WO2002016359A1 (en) | 2000-08-22 | 2001-08-22 | Fused pyrazole derivatives being protein kinase inhibitors |
Publications (1)
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| KR20030040419A true KR20030040419A (ko) | 2003-05-22 |
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| KR10-2003-7002634A Withdrawn KR20030040419A (ko) | 2000-08-22 | 2001-08-22 | 단백질 키나아제 억제제인 융합된 피라졸 유도체 |
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-
2001
- 2001-08-21 PE PE2001000842A patent/PE20020506A1/es not_active Application Discontinuation
- 2001-08-22 PL PL36213001A patent/PL362130A1/xx not_active Application Discontinuation
- 2001-08-22 DE DE60117568T patent/DE60117568T2/de not_active Expired - Fee Related
- 2001-08-22 IL IL15440201A patent/IL154402A0/xx unknown
- 2001-08-22 US US10/362,146 patent/US7166597B2/en not_active Expired - Fee Related
- 2001-08-22 KR KR10-2003-7002634A patent/KR20030040419A/ko not_active Withdrawn
- 2001-08-22 EP EP01960928A patent/EP1311507B1/en not_active Expired - Lifetime
- 2001-08-22 WO PCT/GB2001/003783 patent/WO2002016359A1/en not_active Ceased
- 2001-08-22 MX MXPA03001593A patent/MXPA03001593A/es unknown
- 2001-08-22 BR BR0113448-5A patent/BR0113448A/pt not_active Application Discontinuation
- 2001-08-22 AR ARP010104007A patent/AR034261A1/es unknown
- 2001-08-22 ES ES01960928T patent/ES2259331T3/es not_active Expired - Lifetime
- 2001-08-22 HU HU0400757A patent/HUP0400757A2/hu unknown
- 2001-08-22 UY UY26899A patent/UY26899A1/es unknown
- 2001-08-22 CA CA002420024A patent/CA2420024A1/en not_active Abandoned
- 2001-08-22 AU AU2001282318A patent/AU2001282318A1/en not_active Abandoned
- 2001-08-22 AT AT01960928T patent/ATE318814T1/de not_active IP Right Cessation
- 2001-08-22 JP JP2002521460A patent/JP2004506736A/ja active Pending
-
2003
- 2003-02-19 NO NO20030779A patent/NO20030779L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA03001593A (es) | 2003-06-04 |
| ES2259331T3 (es) | 2006-10-01 |
| UY26899A1 (es) | 2002-03-22 |
| IL154402A0 (en) | 2003-09-17 |
| ATE318814T1 (de) | 2006-03-15 |
| CA2420024A1 (en) | 2002-02-28 |
| HUP0400757A2 (hu) | 2004-07-28 |
| EP1311507A1 (en) | 2003-05-21 |
| AU2001282318A1 (en) | 2002-03-04 |
| WO2002016359A1 (en) | 2002-02-28 |
| US20040053942A1 (en) | 2004-03-18 |
| DE60117568D1 (de) | 2006-04-27 |
| PL362130A1 (en) | 2004-10-18 |
| US7166597B2 (en) | 2007-01-23 |
| NO20030779L (no) | 2003-04-07 |
| AR034261A1 (es) | 2004-02-18 |
| PE20020506A1 (es) | 2002-07-09 |
| NO20030779D0 (no) | 2003-02-19 |
| DE60117568T2 (de) | 2006-08-24 |
| JP2004506736A (ja) | 2004-03-04 |
| BR0113448A (pt) | 2003-06-17 |
| EP1311507B1 (en) | 2006-03-01 |
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