BG64447B1 - Indazole derivatives, pharmaceutical compositions and application thereof - Google Patents
Indazole derivatives, pharmaceutical compositions and application thereof Download PDFInfo
- Publication number
- BG64447B1 BG64447B1 BG103195A BG10319599A BG64447B1 BG 64447 B1 BG64447 B1 BG 64447B1 BG 103195 A BG103195 A BG 103195A BG 10319599 A BG10319599 A BG 10319599A BG 64447 B1 BG64447 B1 BG 64447B1
- Authority
- BG
- Bulgaria
- Prior art keywords
- indazole
- ethyl
- mmol
- carboxylic acid
- cyclopentyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 238000002360 preparation method Methods 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 22
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 22
- 230000005764 inhibitory process Effects 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 241000124008 Mammalia Species 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- -1 -NR 12 R 13 Chemical group 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 150000002473 indoazoles Chemical class 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 17
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 208000030507 AIDS Diseases 0.000 claims description 11
- 206010040070 Septic Shock Diseases 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- ISIQAMHROGZHOV-UHFFFAOYSA-N 3,5-dichloropyridin-4-amine Chemical compound NC1=C(Cl)C=NC=C1Cl ISIQAMHROGZHOV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 206010040047 Sepsis Diseases 0.000 claims description 7
- 206010006895 Cachexia Diseases 0.000 claims description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 6
- 230000001684 chronic effect Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 230000036303 septic shock Effects 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- VQXPUWAIJHXSON-UHFFFAOYSA-N 2-amino-N-phenylmethoxypropanamide Chemical compound CC(N)C(=O)NOCC1=CC=CC=C1 VQXPUWAIJHXSON-UHFFFAOYSA-N 0.000 claims description 4
- 208000005314 Multi-Infarct Dementia Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 201000004810 Vascular dementia Diseases 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000007943 implant Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- CDNUDVJNYLASKG-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-6-phenylindazole Chemical compound C12=CC(C=3C=CC=CC=3)=CC=C2C(CC)=NN1C1CCCC1 CDNUDVJNYLASKG-UHFFFAOYSA-N 0.000 claims description 3
- USBYMDFDMFTLDN-LLVKDONJSA-N 1-cyclopentyl-3-ethyl-n-[(2r)-1-(hydroxyamino)-1-oxopropan-2-yl]indazole-6-carboxamide Chemical compound C12=CC(C(=O)N[C@H](C)C(=O)NO)=CC=C2C(CC)=NN1C1CCCC1 USBYMDFDMFTLDN-LLVKDONJSA-N 0.000 claims description 3
- RTVOEYUKLWNRFB-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-n-[2-(hydroxyamino)-2-oxoethyl]indazole-6-carboxamide Chemical compound C12=CC(C(=O)NCC(=O)NO)=CC=C2C(CC)=NN1C1CCCC1 RTVOEYUKLWNRFB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 206010001513 AIDS related complex Diseases 0.000 claims description 3
- 208000006386 Bone Resorption Diseases 0.000 claims description 3
- 206010063094 Cerebral malaria Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010014824 Endotoxic shock Diseases 0.000 claims description 3
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 208000000112 Myalgia Diseases 0.000 claims description 3
- 206010029132 Nephritis haemorrhagic Diseases 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 206010041591 Spinal osteoarthritis Diseases 0.000 claims description 3
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 3
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 230000002052 anaphylactic effect Effects 0.000 claims description 3
- 230000002917 arthritic effect Effects 0.000 claims description 3
- 230000024279 bone resorption Effects 0.000 claims description 3
- 208000019664 bone resorption disease Diseases 0.000 claims description 3
- 230000008993 bowel inflammation Effects 0.000 claims description 3
- 210000000589 cicatrix Anatomy 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 201000006549 dyspepsia Diseases 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 208000024798 heartburn Diseases 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 208000011379 keloid formation Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 230000003211 malignant effect Effects 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 201000003651 pulmonary sarcoidosis Diseases 0.000 claims description 3
- 208000024981 pyrosis Diseases 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000005801 spondylosis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 230000009772 tissue formation Effects 0.000 claims description 3
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims description 2
- JMOMIZNLLRYUDW-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-6-thiophen-2-ylindazole Chemical compound C12=CC(C=3SC=CC=3)=CC=C2C(CC)=NN1C1CCCC1 JMOMIZNLLRYUDW-UHFFFAOYSA-N 0.000 claims description 2
- QCRZIHACFORZTO-UHFFFAOYSA-N 1-cyclopentyl-n-(2,6-dichlorophenyl)-3-ethylindazole-6-carboxamide Chemical compound C12=CC(C(=O)NC=3C(=CC=CC=3Cl)Cl)=CC=C2C(CC)=NN1C1CCCC1 QCRZIHACFORZTO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004606 5,6,7,8-tetrahydroisoquinolinyl group Chemical group C1(=NC=CC=2CCCCC12)* 0.000 claims description 2
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 claims description 2
- WSBICWGRBSUVLN-UHFFFAOYSA-N C1=CC2=C(C=C1NC(=O)C3=C(C(=C(C=C3)O)O)O)NN=C2 Chemical compound C1=CC2=C(C=C1NC(=O)C3=C(C(=C(C=C3)O)O)O)NN=C2 WSBICWGRBSUVLN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 206010022000 influenza Diseases 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims 2
- 230000004054 inflammatory process Effects 0.000 claims 2
- 230000000414 obstructive effect Effects 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- BOZIUZKHHXMJPH-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-n-[2-(hydroxyamino)-2-oxoethyl]-n-methylindazole-6-carboxamide Chemical compound C12=CC(C(=O)N(C)CC(=O)NO)=CC=C2C(CC)=NN1C1CCCC1 BOZIUZKHHXMJPH-UHFFFAOYSA-N 0.000 claims 1
- ZNXUMZCAXJXCGI-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-3-ethyl-1-propan-2-ylindazole-6-carboxamide Chemical compound C=1C=C2C(CC)=NN(C(C)C)C2=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl ZNXUMZCAXJXCGI-UHFFFAOYSA-N 0.000 claims 1
- 210000002345 respiratory system Anatomy 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 199
- 239000011541 reaction mixture Substances 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- 235000019439 ethyl acetate Nutrition 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 63
- 239000007787 solid Substances 0.000 description 62
- 239000000203 mixture Substances 0.000 description 59
- 238000004458 analytical method Methods 0.000 description 52
- 239000007858 starting material Substances 0.000 description 46
- 239000011734 sodium Substances 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 238000004896 high resolution mass spectrometry Methods 0.000 description 37
- 239000012267 brine Substances 0.000 description 36
- 239000000706 filtrate Substances 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 238000001914 filtration Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
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- 239000000741 silica gel Substances 0.000 description 32
- 229910002027 silica gel Inorganic materials 0.000 description 32
- 239000002585 base Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- 238000003756 stirring Methods 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- QUKDARNAEGBEOY-UHFFFAOYSA-N 1-cyclopentyl-3-ethylindazole-6-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2C(CC)=NN1C1CCCC1 QUKDARNAEGBEOY-UHFFFAOYSA-N 0.000 description 19
- 239000000843 powder Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- 239000013078 crystal Substances 0.000 description 15
- 239000000284 extract Substances 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- 239000003054 catalyst Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- CSQGAIUWKCKTHI-UHFFFAOYSA-N methyl 3-ethyl-2h-indazole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(CC)=NNC2=C1 CSQGAIUWKCKTHI-UHFFFAOYSA-N 0.000 description 9
- LQBQDLNKPVZVGB-UHFFFAOYSA-N 1-cyclopentyl-3-ethylindazole-6-carbonyl chloride Chemical compound C12=CC(C(Cl)=O)=CC=C2C(CC)=NN1C1CCCC1 LQBQDLNKPVZVGB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000004533 oil dispersion Substances 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
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- DNCVTVVLMRHJCJ-UHFFFAOYSA-N 1h-indazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C=NNC2=C1 DNCVTVVLMRHJCJ-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
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- XADIHHWTQYSWCS-UHFFFAOYSA-N methyl 1-cyclopentyl-3-ethylindazole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(CC)=NN1C1CCCC1 XADIHHWTQYSWCS-UHFFFAOYSA-N 0.000 description 7
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 7
- 238000001308 synthesis method Methods 0.000 description 7
- MJFDEQYMXUJFQE-UHFFFAOYSA-N 3-amino-4-propylbenzoic acid Chemical compound CCCC1=CC=C(C(O)=O)C=C1N MJFDEQYMXUJFQE-UHFFFAOYSA-N 0.000 description 6
- GXRWLPVXYJGNTK-UHFFFAOYSA-N 3-nitro-4-propylbenzoic acid Chemical compound CCCC1=CC=C(C(O)=O)C=C1[N+]([O-])=O GXRWLPVXYJGNTK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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- 241001465754 Metazoa Species 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
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- 239000006260 foam Substances 0.000 description 6
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- FCLDDXMLCBBXKS-UHFFFAOYSA-N 6-bromo-1-cyclopentyl-3-ethylindazole Chemical compound C12=CC(Br)=CC=C2C(CC)=NN1C1CCCC1 FCLDDXMLCBBXKS-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
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- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
- NWNSMAXWOXQTNY-UHFFFAOYSA-N 3-ethyl-2h-indazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(CC)=NNC2=C1 NWNSMAXWOXQTNY-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000005484 gravity Effects 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
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- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- CVNKFOIOZXAFBO-UHFFFAOYSA-J tin(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Sn+4] CVNKFOIOZXAFBO-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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- Veterinary Medicine (AREA)
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- Engineering & Computer Science (AREA)
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- Pulmonology (AREA)
- Diabetes (AREA)
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- Virology (AREA)
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- Rheumatology (AREA)
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- Pain & Pain Management (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Endocrinology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Applications Claiming Priority (1)
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| US2544696P | 1996-09-04 | 1996-09-04 |
Publications (2)
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| BG103195A BG103195A (en) | 1999-09-30 |
| BG64447B1 true BG64447B1 (en) | 2005-02-28 |
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| GT (1) | GT199700102A (es) |
| HN (1) | HN1997000126A (es) |
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Families Citing this family (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2258728C (en) | 1996-06-19 | 2011-09-27 | Rhone Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
| EA200000385A1 (ru) * | 1997-11-04 | 2000-10-30 | Пфайзер Продактс Инк. | Терапевтически активные соединения на основе индазольной биоизостерической замены катехина в ингибиторах фосфодиэстеразы типа vi (pde4) |
| EA200000488A1 (ru) * | 1997-11-04 | 2000-10-30 | Пфайзер Продактс Инк. | Замена катехина на биоизостеру индазола в терапевтически активных соединениях |
| JP2000198734A (ja) * | 1998-12-30 | 2000-07-18 | Pfizer Inc | 胃運動性減弱および関連疾患の治療のための運動性増強薬 |
| US6191300B1 (en) | 1999-04-16 | 2001-02-20 | Eastman Chemical Company | Process for the preparation of cyclopropylacetonitrile |
| UA71971C2 (en) | 1999-06-04 | 2005-01-17 | Agoron Pharmaceuticals Inc | Diaminothiazoles, composition based thereon, a method for modulation of protein kinases activity, a method for the treatment of diseases mediated by protein kinases |
| TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
| US7141581B2 (en) | 1999-07-02 | 2006-11-28 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| PE20010306A1 (es) * | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
| AU777012B2 (en) | 1999-08-21 | 2004-09-30 | Takeda Gmbh | Synergistic combination of PDE inhibitors and beta 2 adrenoceptor agonist |
| US6362213B1 (en) | 1999-12-23 | 2002-03-26 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
| PT1244649E (pt) * | 1999-12-23 | 2005-06-30 | Icos Corp | Inibidores de fosfodiesterase especificos de mfa ciclica |
| US7217722B2 (en) * | 2000-02-01 | 2007-05-15 | Kirin Beer Kabushiki Kaisha | Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same |
| CA2398446A1 (en) | 2000-04-18 | 2001-10-25 | Agouron Pharmaceuticals, Inc. | Pyrazoles for inhibiting protein kinases |
| US7153871B2 (en) | 2001-01-22 | 2006-12-26 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs |
| US7205320B2 (en) | 2001-01-22 | 2007-04-17 | Memory Pharmaceuticals Corp. | Phosphodiesterase 4 inhibitors |
| US20040180900A1 (en) * | 2001-05-23 | 2004-09-16 | Masaharu Takigawa | Therapeutic composition for repairing chondropathy |
| KR20040007596A (ko) * | 2001-05-23 | 2004-01-24 | 다나베 세이야꾸 가부시키가이샤 | 골절 치료 촉진용 조성물 |
| TWI221838B (en) | 2001-08-09 | 2004-10-11 | Tanabe Seiyaku Co | Pyrazinoisoquinoline compound or naphthalene compound |
| PE20030701A1 (es) | 2001-12-20 | 2003-08-21 | Schering Corp | Compuestos para el tratamiento de trastornos inflamatorios |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| KR20050000400A (ko) * | 2002-04-12 | 2005-01-03 | 셀진 코포레이션 | 줄기 및 전구 세포 분화의 조절, 측정 및 이들의 용도 |
| EP1525308A4 (en) * | 2002-05-30 | 2006-11-02 | Celgene Corp | METHODS OF USING JNK OR MKK INHIBITORS TO MODULATE CELL DIFFERENTIATION AND TREAT MYELOPROLIFERATIVE DISORDERS AND MYELODYSPLASIC SYNDROMES |
| MXPA05000827A (es) | 2002-07-19 | 2005-08-29 | Memory Pharm Corp | Inhibidores de fosfodiesterasa 4, incluyendo analogos de anilina y difenilamina n-sustituidos. |
| JP2006502995A (ja) * | 2002-07-19 | 2006-01-26 | メモリー・ファーマシューティカルズ・コーポレイション | ホスホジエステラーゼ４阻害剤としての６−アミノ−１ｈ−インダゾール及び４−アミノベンゾフラン化合物 |
| EP1569908B1 (en) * | 2002-11-19 | 2010-09-15 | Memory Pharmaceuticals Corporation | Pyridine n-oxide compounds as phosphodiesterase 4 inhibitors |
| AU2003285614B2 (en) | 2002-12-20 | 2009-05-14 | Pfizer Products, Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| US7109337B2 (en) | 2002-12-20 | 2006-09-19 | Pfizer Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
| US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
| JP2006522151A (ja) | 2003-04-01 | 2006-09-28 | アプライド リサーチ システムズ エーアールエス ホールディング ナームロゼ フェンノートシャップ | 不妊症におけるホスホジエステラーゼ阻害剤 |
| US7297709B2 (en) * | 2003-05-22 | 2007-11-20 | Abbott Laboratories | Indazole, benzisoxazole, and benzisothiazole kinase inhibitors |
| US20090048255A1 (en) * | 2003-07-21 | 2009-02-19 | Schumacher Richard A | Phosphodiesterase 4 inhibitors, including n-substituted aniline and diphenylamine analogs |
| JP2005089457A (ja) | 2003-09-03 | 2005-04-07 | Yung Shin Pharmaceutical Industry Co Ltd | 骨成長を促進するまたは骨吸収を阻害するための薬剤組成物 |
| MY141255A (en) * | 2003-12-11 | 2010-03-31 | Memory Pharm Corp | Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs |
| CN1926139A (zh) | 2004-02-27 | 2007-03-07 | 霍夫曼-拉罗奇有限公司 | 稠合吡唑衍生物 |
| JP2007523937A (ja) | 2004-02-27 | 2007-08-23 | エフ．ホフマン−ラ ロシュ アーゲー | インダゾール誘導体およびそれを含む医薬組成物 |
| EP1720878A1 (en) | 2004-02-27 | 2006-11-15 | F.Hoffmann-La Roche Ag | Heteroaryl-fused pyrazolo derivatives |
| WO2005111024A1 (en) | 2004-05-14 | 2005-11-24 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| JP2007537230A (ja) | 2004-05-14 | 2007-12-20 | ファイザー・プロダクツ・インク | 異常細胞増殖の処置用のピリミジン誘導体 |
| JP2007537238A (ja) | 2004-05-14 | 2007-12-20 | ファイザー・プロダクツ・インク | 異常細胞増殖の治療のためのピリミジン誘導体 |
| AU2005271841A1 (en) * | 2004-07-12 | 2006-02-16 | Merck & Co., Inc. | Inhibitors of histone deacetylase |
| US7601847B2 (en) | 2004-10-26 | 2009-10-13 | Wyeth | Preparation and purification of 4-(indazol-3-yl)phenols |
| TW200621237A (en) | 2004-11-01 | 2006-07-01 | Wyeth Corp | [(1-h-indazol-3-yl)methyl]phenols and (hydroxyphenyl)(1h-indazol-3-yl)methanones |
| WO2006129158A2 (en) * | 2005-05-30 | 2006-12-07 | Ranbaxy Laboratories Limited | 3 - indazolyl - isoxazoline derivatives as inhibitors of phosphodiesterase type - i |
| WO2007023111A2 (en) | 2005-08-25 | 2007-03-01 | F. Hoffmann-La Roche Ag | P38 map kinase inhibitors and methods for using the same |
| EP1928866A1 (en) | 2005-09-05 | 2008-06-11 | Ranbaxy Laboratories Limited | Substituted indazoles as inhibitors of phosphodiesterase type-iv |
| US7915286B2 (en) | 2005-09-16 | 2011-03-29 | Ranbaxy Laboratories Limited | Substituted pyrazolo [3,4-b] pyridines as phosphodiesterase inhibitors |
| PL1981851T3 (pl) | 2006-01-31 | 2012-07-31 | Array Biopharma Inc | Inhibitory kinazy i sposoby ich stosowania |
| WO2008026687A1 (en) | 2006-09-01 | 2008-03-06 | Kyorin Pharmaceutical Co., Ltd. | Pyrazolopyridine carboxamide derivative and phosphodiesterase (pde) inhibitor comprising the derivative |
| AU2007329480A1 (en) * | 2006-12-05 | 2008-06-12 | National Chio Tung University | Indazole compounds |
| DK2124944T3 (da) | 2007-03-14 | 2012-04-23 | Ranbaxy Lab Ltd | Pyrazolo[3,4-b]pyridinderivater som phosphodiesteraseinhibitorer |
| WO2010003084A2 (en) * | 2008-07-02 | 2010-01-07 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors |
| ES2660892T3 (es) * | 2009-03-23 | 2018-03-26 | Merck Sharp & Dohme Corp. | Antagonistas del receptor P2X3 para el tratamiento del dolor |
| ES2545811T3 (es) | 2010-04-22 | 2015-09-16 | Janssen Pharmaceutica Nv | Compuestos de indazol útiles como inhibidores de quetohexoquinasa |
| EP2681216B1 (en) | 2011-02-28 | 2017-09-27 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| EP3137454A1 (en) | 2014-04-28 | 2017-03-08 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
| KR20190078646A (ko) * | 2016-11-18 | 2019-07-04 | 머크 샤프 앤드 돔 코포레이션 | 디아실글리세리드 o-아실트랜스퍼라제 2의 억제제로서 유용한 인다졸 유도체 |
| US11427558B1 (en) | 2019-07-11 | 2022-08-30 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as LRRK2 inhibitors |
| CN112694474B (zh) * | 2019-10-23 | 2022-03-18 | 四川大学 | 吲唑类衍生物及其制备方法和用途 |
| US20240279828A1 (en) * | 2021-05-31 | 2024-08-22 | Genscript Usa Inc. | Electrografted films for dna synthesis |
| CN116003325B (zh) * | 2023-01-09 | 2025-04-25 | 南方医科大学 | 吲唑类化合物或其药学上可接受的盐及其制备方法和应用 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE531433A (es) | 1953-06-17 | |||
| US4665397A (en) | 1983-11-01 | 1987-05-12 | Universal Photonics, Inc. | Apparatus and method for a universal electronic locking system |
| GB8524157D0 (en) * | 1984-10-19 | 1985-11-06 | Ici America Inc | Heterocyclic amides |
| JPH061350B2 (ja) * | 1985-07-26 | 1994-01-05 | コニカ株式会社 | ハロゲン化銀写真感光材料 |
| JPS6250751A (ja) * | 1985-08-29 | 1987-03-05 | Konishiroku Photo Ind Co Ltd | ハロゲン化銀写真感光材料 |
| GB8609175D0 (en) * | 1986-04-15 | 1986-05-21 | Ici America Inc | Heterocyclic carboxamides |
| DK0381422T3 (da) * | 1989-02-02 | 1997-03-10 | Yamanouchi Pharma Co Ltd | Tetrahydrobenzimidazolderivater |
| KR100188801B1 (ko) | 1990-05-18 | 1999-06-01 | 엥겔하르트 라피체 | 이속사졸-4카복스아미드 및 하이드록시알킬리덴 시아노아세트아미드 및 이들 화합물을 함유하는 약제학적 조성물 |
| US5444038A (en) * | 1992-03-09 | 1995-08-22 | Zeneca Limited | Arylindazoles and their use as herbicides |
| BR9406946A (pt) * | 1993-07-06 | 1996-08-06 | Pfizer | Tetra-hidro-pirazolpiridinas bicíclicas |
| GB9401460D0 (en) * | 1994-01-26 | 1994-03-23 | Rhone Poulenc Rorer Ltd | Compositions of matter |
| ATE178046T1 (de) * | 1994-02-17 | 1999-04-15 | American Home Prod | Substituierte biphenyl-derivate mit phosphodiesterase inhibierender wirkung |
| WO1995027692A1 (en) | 1994-04-08 | 1995-10-19 | Smithkline Beecham Corporation | Subtituted biphenyl tnf inhibitors |
| JPH08143525A (ja) * | 1994-11-21 | 1996-06-04 | Banyu Pharmaceut Co Ltd | ヒドロキシ安息香酸アミド誘導体を有効成分とする骨疾患の予防・治療剤 |
| ES2201299T3 (es) * | 1996-06-25 | 2004-03-16 | Pfizer Inc. | Derivados sustituidos de indazol y su uso como inhibidores de fosfodiesterasa (pde) de tipo iv y factor de necrosis tumoral (tnf)`. |
| DE69709493T2 (de) * | 1996-06-27 | 2002-10-31 | Pfizer Inc., New York | Substituierte Indazolderivate |
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1997
- 1997-08-25 BR BR9712005A patent/BR9712005A/pt not_active Application Discontinuation
- 1997-08-25 TR TR1999/00481T patent/TR199900481T2/xx unknown
- 1997-08-25 NZ NZ334213A patent/NZ334213A/xx unknown
- 1997-08-25 CN CN97199022A patent/CN1234031A/zh active Pending
- 1997-08-25 EA EA199900183A patent/EA002113B1/ru not_active IP Right Cessation
- 1997-08-25 US US09/254,346 patent/US6262040B1/en not_active Expired - Fee Related
- 1997-08-25 WO PCT/IB1997/001023 patent/WO1998009961A1/en not_active Ceased
- 1997-08-25 JP JP51240998A patent/JP3554337B2/ja not_active Expired - Fee Related
- 1997-08-25 PL PL97332187A patent/PL332187A1/xx unknown
- 1997-08-25 AU AU37813/97A patent/AU724549B2/en not_active Ceased
- 1997-08-25 EP EP97934678A patent/EP0931075A1/en not_active Withdrawn
- 1997-08-25 CA CA002264798A patent/CA2264798A1/en not_active Abandoned
- 1997-08-25 KR KR1019997001779A patent/KR100338610B1/ko not_active Expired - Fee Related
- 1997-08-25 HU HU9903248A patent/HUP9903248A3/hu unknown
- 1997-08-25 YU YU11299A patent/YU11299A/sh unknown
- 1997-08-25 IL IL12864297A patent/IL128642A0/xx unknown
- 1997-08-25 SK SK272-99A patent/SK27299A3/sk unknown
- 1997-08-29 HN HN1997000126A patent/HN1997000126A/es unknown
- 1997-09-01 TW TW086112518A patent/TW402595B/zh not_active IP Right Cessation
- 1997-09-02 PE PE1997000777A patent/PE107998A1/es not_active Application Discontinuation
- 1997-09-02 AR ARP970104001A patent/AR008162A1/es unknown
- 1997-09-03 DZ DZ970153A patent/DZ2303A1/xx active
- 1997-09-03 GT GT199700102A patent/GT199700102A/es unknown
- 1997-09-03 PA PA19978437301A patent/PA8437301A1/es unknown
- 1997-09-03 ZA ZA977903A patent/ZA977903B/xx unknown
- 1997-09-03 TN TNTNSN97148A patent/TNSN97148A1/fr unknown
- 1997-09-03 MA MA24783A patent/MA26439A1/fr unknown
- 1997-09-03 ID IDP973065A patent/ID18157A/id unknown
- 1997-09-04 CO CO97051473A patent/CO4600636A1/es unknown
- 1997-09-04 AP APAP/P/1997/001080A patent/AP795A/en active
- 1997-09-04 HR HR970478A patent/HRP970478B1/xx not_active IP Right Cessation
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1999
- 1999-02-16 IS IS4979A patent/IS4979A/is unknown
- 1999-02-22 BG BG103195A patent/BG64447B1/bg unknown
- 1999-03-01 OA OA9900046A patent/OA10985A/en unknown
- 1999-03-03 NO NO991048A patent/NO991048L/no unknown
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2004
- 2004-03-23 JP JP2004083812A patent/JP2004217668A/ja active Pending
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