HRP20000724A2 - Pyrazole derivatives as p-38 map kinase inhibitors - Google Patents

Pyrazole derivatives as p-38 map kinase inhibitors Download PDF

Info

Publication number: HRP20000724A2
Authority: HR; Croatia
Prior art keywords: optionally substituted; alkyl; amino; hydrogen; pyrazole
Prior art date: 1998-05-05

Application number

HR20000724A

Other languages

English (en)

Croatian (hr)

Inventor

Sharada

David Mark Rotstein

Eric Brian Sjorgen

Francisco Xavier Talamas

Original Assignee

Hoffmann La Roche

Priority date (The priority date 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 date listed.)

1998-05-05

Filing date

2000-10-25

Publication date

2001-06-30

2000-10-25 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2001-06-30 Publication of HRP20000724A2 publication Critical patent/HRP20000724A2/hr

Links

102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title abstract description 12
108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title abstract description 12
150000003217 pyrazoles Chemical class 0.000 title abstract description 3
239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title abstract 2
150000001875 compounds Chemical class 0.000 claims abstract description 217
238000000034 method Methods 0.000 claims abstract description 42
239000001257 hydrogen Substances 0.000 claims description 197
229910052739 hydrogen Inorganic materials 0.000 claims description 197
-1 individual isomers Substances 0.000 claims description 188
125000000217 alkyl group Chemical group 0.000 claims description 178
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 99
125000004404 heteroalkyl group Chemical group 0.000 claims description 93
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 76
229910052736 halogen Inorganic materials 0.000 claims description 60
150000002367 halogens Chemical class 0.000 claims description 60
239000000203 mixture Substances 0.000 claims description 54
125000000623 heterocyclic group Chemical group 0.000 claims description 49
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 45
125000001072 heteroaryl group Chemical group 0.000 claims description 42
125000003118 aryl group Chemical group 0.000 claims description 30
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
125000003545 alkoxy group Chemical group 0.000 claims description 25
238000006243 chemical reaction Methods 0.000 claims description 25
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
125000004432 carbon atom Chemical group C* 0.000 claims description 20
239000011737 fluorine Chemical group 0.000 claims description 20
229910052731 fluorine Inorganic materials 0.000 claims description 20
239000002253 acid Substances 0.000 claims description 17
150000003839 salts Chemical class 0.000 claims description 17
238000011282 treatment Methods 0.000 claims description 17
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
125000004405 heteroalkoxy group Chemical group 0.000 claims description 15
125000004449 heterocyclylalkenyl group Chemical group 0.000 claims description 14
229910052757 nitrogen Inorganic materials 0.000 claims description 14
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 13
125000001424 substituent group Chemical group 0.000 claims description 13
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 12
125000002252 acyl group Chemical group 0.000 claims description 12
239000000546 pharmaceutical excipient Substances 0.000 claims description 12
239000000460 chlorine Substances 0.000 claims description 11
125000004442 acylamino group Chemical group 0.000 claims description 10
229910052801 chlorine Inorganic materials 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 10
238000002360 preparation method Methods 0.000 claims description 10
230000008569 process Effects 0.000 claims description 10
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 9
239000002585 base Substances 0.000 claims description 8
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 8
125000004663 dialkyl amino group Chemical group 0.000 claims description 8
125000001188 haloalkyl group Chemical group 0.000 claims description 8
MDPZNDLAGKIDFD-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-(3-pyridin-3-ylphenyl)methanone Chemical compound NC1=C(C(=O)C=2C=C(C=CC=2)C=2C=NC=CC=2)C=NN1C1=CC=C(F)C=C1 MDPZNDLAGKIDFD-UHFFFAOYSA-N 0.000 claims description 7
125000003282 alkyl amino group Chemical group 0.000 claims description 7
239000003153 chemical reaction reagent Substances 0.000 claims description 7
229940079593 drug Drugs 0.000 claims description 7
125000005843 halogen group Chemical group 0.000 claims description 7
230000004048 modification Effects 0.000 claims description 7
238000012986 modification Methods 0.000 claims description 7
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
239000000651 prodrug Substances 0.000 claims description 7
229940002612 prodrug Drugs 0.000 claims description 7
229910052799 carbon Inorganic materials 0.000 claims description 6
125000004093 cyano group Chemical group *C#N 0.000 claims description 6
125000002524 organometallic group Chemical group 0.000 claims description 6
125000004001 thioalkyl group Chemical group 0.000 claims description 6
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
NETMPCVQLSKQCS-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(1,2-dihydroxyethyl)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(C=CC=2)C(O)CO)C=NN1C1=CC=C(F)C=C1 NETMPCVQLSKQCS-UHFFFAOYSA-N 0.000 claims description 5
VSBKIQUFBDJXJL-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(3-morpholin-4-ylpropylamino)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(NCCCN3CCOCC3)C=CC=2)C=NN1C1=CC=C(F)C=C1 VSBKIQUFBDJXJL-UHFFFAOYSA-N 0.000 claims description 5
125000004414 alkyl thio group Chemical group 0.000 claims description 5
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
208000027866 inflammatory disease Diseases 0.000 claims description 5
239000000543 intermediate Substances 0.000 claims description 5
XTHHWFJMFDPPPP-UHFFFAOYSA-N 2-[3-[5-amino-1-(4-fluorophenyl)pyrazole-4-carbonyl]phenyl]ethenesulfonamide Chemical compound NC1=C(C(=O)C=2C=C(C=CS(N)(=O)=O)C=CC=2)C=NN1C1=CC=C(F)C=C1 XTHHWFJMFDPPPP-UHFFFAOYSA-N 0.000 claims description 4
FNLHEQLQLSXRBY-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-(3-aminophenyl)methanone Chemical compound NC1=C(C(=O)C=2C=C(N)C=CC=2)C=NN1C1=CC=C(F)C=C1 FNLHEQLQLSXRBY-UHFFFAOYSA-N 0.000 claims description 4
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
239000012458 free base Substances 0.000 claims description 4
125000005844 heterocyclyloxy group Chemical group 0.000 claims description 4
PUBQBMIAESKDQT-UHFFFAOYSA-N 2-[3-[5-amino-1-(4-fluorophenyl)pyrazole-4-carbonyl]phenyl]ethanesulfonamide Chemical compound NC1=C(C(=O)C=2C=C(CCS(N)(=O)=O)C=CC=2)C=NN1C1=CC=C(F)C=C1 PUBQBMIAESKDQT-UHFFFAOYSA-N 0.000 claims description 3
125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
FWYUZBFZDMKZKU-UHFFFAOYSA-N [5-amino-1-(2-methylphenyl)pyrazol-4-yl]-[3-(1-oxidopyridin-1-ium-3-yl)phenyl]methanone Chemical compound CC1=CC=CC=C1N1C(N)=C(C(=O)C=2C=C(C=CC=2)C=2C=[N+]([O-])C=CC=2)C=N1 FWYUZBFZDMKZKU-UHFFFAOYSA-N 0.000 claims description 3
FAOCNBXKNCERRY-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(2-methylsulfonylethyl)phenyl]methanone Chemical compound CS(=O)(=O)CCC1=CC=CC(C(=O)C2=C(N(N=C2)C=2C=CC(F)=CC=2)N)=C1 FAOCNBXKNCERRY-UHFFFAOYSA-N 0.000 claims description 3
AZPXSGWGNRAGOU-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(2-morpholin-4-ylethoxy)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(OCCN3CCOCC3)C=CC=2)C=NN1C1=CC=C(F)C=C1 AZPXSGWGNRAGOU-UHFFFAOYSA-N 0.000 claims description 3
VYZNEDVUQBPGQA-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(3-hydroxy-3-methylbutyl)phenyl]methanone Chemical compound CC(C)(O)CCC1=CC=CC(C(=O)C2=C(N(N=C2)C=2C=CC(F)=CC=2)N)=C1 VYZNEDVUQBPGQA-UHFFFAOYSA-N 0.000 claims description 3
UGLOHEBRMNZKKE-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(3-morpholin-4-ylpropyl)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(CCCN3CCOCC3)C=CC=2)C=NN1C1=CC=C(F)C=C1 UGLOHEBRMNZKKE-UHFFFAOYSA-N 0.000 claims description 3
BSNOOUBZAZNTTC-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-[2-(1-hydroxycyclopentyl)ethyl]phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(CCC3(O)CCCC3)C=CC=2)C=NN1C1=CC=C(F)C=C1 BSNOOUBZAZNTTC-UHFFFAOYSA-N 0.000 claims description 3
238000006073 displacement reaction Methods 0.000 claims description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
125000003107 substituted aryl group Chemical group 0.000 claims description 3
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
PGYCOFUREUQZPC-UHFFFAOYSA-N [3-(2-aminoethyl)phenyl]-[5-amino-1-(4-fluorophenyl)pyrazol-4-yl]methanone Chemical compound NCCC1=CC=CC(C(=O)C2=C(N(N=C2)C=2C=CC(F)=CC=2)N)=C1 PGYCOFUREUQZPC-UHFFFAOYSA-N 0.000 claims description 2
LJHVYEURSIWGNU-UHFFFAOYSA-N [5-amino-1-(2,4-difluorophenyl)pyrazol-4-yl]-[3-(2-hydroxyethylsulfonyl)phenyl]methanone Chemical class NC1=C(C(=O)C=2C=C(C=CC=2)S(=O)(=O)CCO)C=NN1C1=CC=C(F)C=C1F LJHVYEURSIWGNU-UHFFFAOYSA-N 0.000 claims description 2
SQCPBLIPSNRAEA-UHFFFAOYSA-N [5-amino-1-(2,4-difluorophenyl)pyrazol-4-yl]-[3-(3-morpholin-4-ylpropyl)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(CCCN3CCOCC3)C=CC=2)C=NN1C1=CC=C(F)C=C1F SQCPBLIPSNRAEA-UHFFFAOYSA-N 0.000 claims description 2
IJDQETGUEUJVTB-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone Chemical compound NC1=C(C(=O)C=2C=C(OCC(O)CO)C=CC=2)C=NN1C1=CC=C(F)C=C1 IJDQETGUEUJVTB-UHFFFAOYSA-N 0.000 claims description 2
238000010306 acid treatment Methods 0.000 claims description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
125000001309 chloro group Chemical group Cl* 0.000 claims description 2
229910052751 metal Inorganic materials 0.000 claims description 2
239000002184 metal Substances 0.000 claims description 2
RSECCHDABRGVNM-UHFFFAOYSA-N n-[3-(5-amino-1-phenylpyrazole-4-carbonyl)phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C(=O)C2=C(N(N=C2)C=2C=CC=CC=2)N)=C1 RSECCHDABRGVNM-UHFFFAOYSA-N 0.000 claims description 2
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 22
230000002265 prevention Effects 0.000 claims 2
239000012752 auxiliary agent Substances 0.000 claims 1
238000011321 prophylaxis Methods 0.000 claims 1
230000001629 suppression Effects 0.000 claims 1
239000008194 pharmaceutical composition Substances 0.000 abstract description 7
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 276
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
235000019439 ethyl acetate Nutrition 0.000 description 93
239000000243 solution Substances 0.000 description 79
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
239000011541 reaction mixture Substances 0.000 description 74
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 68
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
239000007787 solid Substances 0.000 description 35
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
239000011780 sodium chloride Substances 0.000 description 33
239000000047 product Substances 0.000 description 32
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
238000004587 chromatography analysis Methods 0.000 description 29
239000012044 organic layer Substances 0.000 description 29
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
229910052938 sodium sulfate Inorganic materials 0.000 description 28
235000011152 sodium sulphate Nutrition 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
238000010828 elution Methods 0.000 description 21
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
102100040247 Tumor necrosis factor Human genes 0.000 description 19
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
201000010099 disease Diseases 0.000 description 18
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
238000010992 reflux Methods 0.000 description 17
239000003921 oil Substances 0.000 description 16
235000019198 oils Nutrition 0.000 description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
108060008682 Tumor Necrosis Factor Proteins 0.000 description 15
MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 14
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 13
150000003254 radicals Chemical class 0.000 description 13
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NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
239000004215 Carbon black (E152) Substances 0.000 description 12
229930195733 hydrocarbon Natural products 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 11
229910052786 argon Inorganic materials 0.000 description 10
238000009472 formulation Methods 0.000 description 10
239000004615 ingredient Substances 0.000 description 10
229910052943 magnesium sulfate Inorganic materials 0.000 description 10
235000019341 magnesium sulphate Nutrition 0.000 description 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
125000006413 ring segment Chemical group 0.000 description 9
238000012360 testing method Methods 0.000 description 9
NYPYPOZNGOXYSU-UHFFFAOYSA-N 3-bromopyridine Chemical compound BrC1=CC=CN=C1 NYPYPOZNGOXYSU-UHFFFAOYSA-N 0.000 description 8
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MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
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238000002474 experimental method Methods 0.000 description 8
230000005764 inhibitory process Effects 0.000 description 8
239000003960 organic solvent Substances 0.000 description 8
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 8
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239000010410 layer Substances 0.000 description 7
239000012299 nitrogen atmosphere Substances 0.000 description 7
229910000027 potassium carbonate Inorganic materials 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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206010030113 Oedema Diseases 0.000 description 6
FQOSJTODWKHNRQ-UHFFFAOYSA-N [5-amino-1-(4-fluorophenyl)pyrazol-4-yl]-(3-bromophenyl)methanone Chemical compound NC1=C(C(=O)C=2C=C(Br)C=CC=2)C=NN1C1=CC=C(F)C=C1 FQOSJTODWKHNRQ-UHFFFAOYSA-N 0.000 description 6
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150000002500 ions Chemical class 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
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- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

HR20000724A 1998-05-05 2000-10-25 Pyrazole derivatives as p-38 map kinase inhibitors HRP20000724A2 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US8425098P	1998-05-05	1998-05-05
US12241099P	1999-03-02	1999-03-02
PCT/EP1999/002879 WO1999057101A1 (en)	1998-05-05	1999-04-28	Pyrazole derivatives as p-38 map kinase inhibitors

Publications (1)

Publication Number	Publication Date
HRP20000724A2 true HRP20000724A2 (en)	2001-06-30

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ID=26770756

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HR20000724A HRP20000724A2 (en)	1998-05-05	2000-10-25	Pyrazole derivatives as p-38 map kinase inhibitors

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EP (1)	EP1075467B1 (de)
JP (1)	JP3590586B2 (de)
KR (1)	KR100404256B1 (de)
CN (1)	CN1147476C (de)
AT (1)	ATE292118T1 (de)
AU (1)	AU765030B2 (de)
BR (1)	BR9911013A (de)
CA (1)	CA2329065A1 (de)
DE (1)	DE69924480D1 (de)
HK (1)	HK1037374A1 (de)
HR (1)	HRP20000724A2 (de)
HU (1)	HUP0101581A3 (de)
ID (1)	ID27535A (de)
IL (1)	IL139169A0 (de)
MA (1)	MA26627A1 (de)
NO (1)	NO317985B1 (de)
NZ (1)	NZ507558A (de)
PL (1)	PL344004A1 (de)
RU (1)	RU2000130199A (de)
TR (1)	TR200003256T2 (de)
TW (1)	TW593282B (de)
WO (1)	WO1999057101A1 (de)
YU (1)	YU67600A (de)

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1999
- 1999-04-28 CA CA002329065A patent/CA2329065A1/en not_active Abandoned
- 1999-04-28 JP JP2000547071A patent/JP3590586B2/ja not_active Expired - Fee Related
- 1999-04-28 PL PL99344004A patent/PL344004A1/xx not_active Application Discontinuation
- 1999-04-28 WO PCT/EP1999/002879 patent/WO1999057101A1/en not_active Application Discontinuation
- 1999-04-28 IL IL13916999A patent/IL139169A0/xx unknown
- 1999-04-28 NZ NZ507558A patent/NZ507558A/en unknown
- 1999-04-28 DE DE69924480T patent/DE69924480D1/de not_active Expired - Fee Related
- 1999-04-28 RU RU2000130199/04A patent/RU2000130199A/ru not_active Application Discontinuation
- 1999-04-28 HU HU0101581A patent/HUP0101581A3/hu unknown
- 1999-04-28 AU AU40348/99A patent/AU765030B2/en not_active Ceased
- 1999-04-28 AT AT99923484T patent/ATE292118T1/de not_active IP Right Cessation
- 1999-04-28 KR KR10-2000-7012375A patent/KR100404256B1/ko not_active IP Right Cessation
- 1999-04-28 YU YU67600A patent/YU67600A/sh unknown
- 1999-04-28 BR BR9911013-0A patent/BR9911013A/pt not_active IP Right Cessation
- 1999-04-28 EP EP99923484A patent/EP1075467B1/de not_active Expired - Lifetime
- 1999-04-28 CN CNB998060046A patent/CN1147476C/zh not_active Expired - Fee Related
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- 1999-05-05 TW TW088107268A patent/TW593282B/zh not_active IP Right Cessation
2000
- 2000-10-25 HR HR20000724A patent/HRP20000724A2/hr not_active Application Discontinuation
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2001
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Publication number	Publication date
HK1037374A1 (en)	2002-02-08
KR100404256B1 (ko)	2003-11-01
EP1075467B1 (de)	2005-03-30
DE69924480D1 (en)	2005-05-04
NO317985B1 (no)	2005-01-17
IL139169A0 (en)	2001-11-25
RU2000130199A (ru)	2002-11-10
CN1300282A (zh)	2001-06-20
CA2329065A1 (en)	1999-11-11
CN1147476C (zh)	2004-04-28
TW593282B (en)	2004-06-21
AU4034899A (en)	1999-11-23
JP2002513784A (ja)	2002-05-14
ID27535A (id)	2001-04-12
TR200003256T2 (tr)	2001-04-20
MA26627A1 (fr)	2004-12-20
KR20010043363A (ko)	2001-05-25
JP3590586B2 (ja)	2004-11-17
WO1999057101A1 (en)	1999-11-11
PL344004A1 (en)	2001-09-10
NO20005535D0 (no)	2000-11-02
HUP0101581A3 (en)	2002-07-29
BR9911013A (pt)	2001-02-06
NZ507558A (en)	2003-08-29
EP1075467A1 (de)	2001-02-14
NO20005535L (no)	2000-11-02
HUP0101581A2 (hu)	2002-03-28
AU765030B2 (en)	2003-09-04
ATE292118T1 (de)	2005-04-15
YU67600A (sh)	2003-07-07

Legal Events

Date	Code	Title
2001-06-30	A1OB	Publication of a patent application
2001-12-05	ARAI	Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application
2008-11-21	OBST	Application withdrawn

Publication	Publication Date	Title
HRP20000724A2 (en)	2001-06-30	Pyrazole derivatives as p-38 map kinase inhibitors
US6444696B1 (en)	2002-09-03	Pyrazole derivatives P38 MAP kinase inhibitors
US6143892A (en)	2000-11-07	Process for making 5-substituted pyrazoles
EP0178035B1 (de)	1990-01-03	Antiinflammatorische 1,N-Diarylpyrazol-3-amine, deren Zusammensetzungen und Verfahren zu deren Herstellung
ES2284741T3 (es)	2007-11-16	Derivados de benzoheterociclicos utilizados como moduladores de vasoprsinao de oxitocina.
EP0219193B1 (de)	1992-05-27	Tetrahydrocarbazolonderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
EP2297112A1 (de)	2011-03-23	Pyrazolverbindungen als ccr1-antagonisten
HU208122B (en)	1993-08-30	Process for producing pyrazole derivatives and pharmaceutical compositions comprising same
US6376527B1 (en)	2002-04-23	Pyrazole derivatives-p38 map kinase inhibitors
JPH04243878A (ja)	1992-08-31	１−（置換ピリジニルアミノ）−１ｈ−インドール−５−イル置換カルバメート
US6979693B2 (en)	2005-12-27	Pyrazole derivatives-p38 MAP kinase inhibitors
MXPA00010687A (en)	2001-09-07	Pyrazole derivatives as p-38 map kinase inhibitors
CZ20004058A3 (cs)	2001-03-14	Pyrazolové deriváty jako inhibitory kinázy P-38 MAP
WO2008053764A1 (fr)	2008-05-08	Composé actif anti-prion, agent actif anti-prion et procédé d'inhibition de la production d'une protéine prion anormale