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WO1997001551A1 - Composes pyrazole et compositions pharmaceutiques - Google Patents

Composes pyrazole et compositions pharmaceutiques Download PDF

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Publication number
WO1997001551A1
WO1997001551A1 PCT/JP1996/001747 JP9601747W WO9701551A1 WO 1997001551 A1 WO1997001551 A1 WO 1997001551A1 JP 9601747 W JP9601747 W JP 9601747W WO 9701551 A1 WO9701551 A1 WO 9701551A1
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WO
WIPO (PCT)
Prior art keywords
salt
compound
preparation
nmr
mixture
Prior art date
Application number
PCT/JP1996/001747
Other languages
English (en)
Inventor
Atsushi Akahane
Satoru Kuroda
Hiromichi Itani
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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.)
Filing date
Publication date
Priority claimed from GBGB9512964.9A external-priority patent/GB9512964D0/en
Priority claimed from AUPN8010A external-priority patent/AUPN801096A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP9504305A priority Critical patent/JPH11508267A/ja
Publication of WO1997001551A1 publication Critical patent/WO1997001551A1/fr

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Classifications

    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a novel pyrazole compound and a salt thereof. More particularly, it relates to a novel pyrazole compound and a salt thereof, which are adenosine antagonists and are useful for the prevention and/or the treatment of ischemic heart diseases (e.g. angina, etc), peripheral vascular diseases (e.g. claudication, etc), cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, or the like; to a process for the preparation of said pyrazole compound or a salt thereof; to a pharmaceutical composition comprising the same; and to a method for using the same therapeutically in a human being or an animal for the prevention and/or the treatment of the aforesaid diseases.
  • ischemic heart diseases e.g. angina, etc
  • peripheral vascular diseases e.g. claudication, etc
  • One object of the present invention is to provide a novel pyrazole compound and a salt thereof, which are useful as adenosine antagonists.
  • Another object of the present invention is to provide a process for the preparation of said pyrazole compound and a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition containing, as an active ingredient, said pyrazole compound or a salt thereof.
  • a still further object of the present invention is to provide use of said pyrazole compound or a salt thereof as a medicament such as an adenosine antagonist useful for the prevention and/or the treatment of the aforesaid diseases; to provide a method for using the same therapeutically in a human being or an animal for the prevention and/or the treatment of the aforesaid diseases.
  • novel pyrazole compound of the present invention can be shown by the following formula (I) :
  • R 1 and R 3 are the same or different and each is independently hydrogen, lower alkyl, ar(lower)alkyl, heterocyclic group, or aryl which may have one or more suitable substituent(s),
  • R 2 is hydrogen, lower alkyl, or ar(lower)alkyl which may have one or more suitable substituent(s), and
  • R 4 is hydrogen or lower alkyl.
  • the object compound (I) or a salt thereof can be prepared according to the following schemes. Process 1
  • the object compound (I) may include the geometrical isomer(s) due to the double bond(s) and/or the stereo isomer(s) due to the asymmetric carbon atom(s).
  • one isomer can be converted to another in a manner conventional in this field of the art.
  • Suitable salts of the object compound (I) are pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc), an organic acid salt (e.g.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc), an organic acid
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc
  • a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc
  • Suitable "lower alkyl” may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl or the like, in which the preferred one may be (C 1 -C5) alkyl and the more preferred one may be methyl, ethyl, isobutyl or pentyl.
  • Suitable "aryl” may include phenyl, naphthyl, indenyl, anthryl and the like, in which the preferred one may be (C 6 -C ⁇ 0 )aryl and the more preferred one may be phenyl.
  • This "aryl” may have one or more (preferably 1 to 3) suitable substituent(s) selected from the group consisting of halogen (e.g. fluoro, chloro, bromo, iodo), lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc), hydroxy, lower alkyl-silyloxy (e.g. trimethylsilyloxy, t-butyldimethylsilyloxy, etc), phenyl(lower)alkoxy (e.g.
  • Suitable "ar(lower)alkyl” may include phenyl(lower)alkyl (e.g. benzyl, phenethyl, benzhydryl, trityl, 2-phenylpropyl, 3,4- diphenylbutyl, 2-phenylpentyl, 6-phenylhexyl, etc), and the like.
  • phenyl(lower)alkyl e.g. benzyl, phenethyl, benzhydryl, trityl, 2-phenylpropyl, 3,4- diphenylbutyl, 2-phenylpentyl, 6-phenylhexyl, etc
  • aromatic alkyl may have one or more (preferably 1 to 3) suitable substituent(s) such as lower alkoxy as mentioned above, and the like.
  • Suitable “heterocyclic group” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl (e.g. lH-azepinyl, etc), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.
  • heterocyclic group the preferred one may be unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, and the more preferred one may be furyl.
  • Suitable “a leaving group” may include halogen as mentioned above, acyloxy such as sulfonyloxy (e.g. mesyloxy, tosyloxy, etc), and the like.
  • the preferred one may be the compound (I) wherein
  • R 1 and R 3 are the same or different and each is independently hydrogen; lower alkyl; phenyl(lower)alkyl; unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom; or phenyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, lower alkyl-silyloxy, phenyl(lower)alkoxy, and phenyl which may have halo(lower)alkyl;
  • R 2 is hydrogen, lower alkyl, or phenyl(lower)alkyl which may have lower alkoxy, and
  • R 4 is hydrogen or lower alkyl.
  • the more preferred one may be the compound which is shown by the formula (I 1 )!
  • R 1 , R 2 , R 3 and R 4 are each as defined for the above-mentioned preferred compound (I).
  • the still more preferred one may be the compound (I') wherein
  • R 1 and R 3 are the same or different and each is independently phenyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy, and
  • R 2 and R 4 are the same or different and each is independently hydrogen or lower alkyl.
  • R 1 and R 3 are the same or different and each is independently phenyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy, and
  • R 2 and R 4 are each hydrogen.
  • the pharmacological test data of the representative test compound is shown in the following in order to show the utility of the pyrazole compound (I).
  • a radioligand binding assay at the cloned human A ⁇ . adenosine receptor was carried out with 3 H-CGS 21680 (commercially available).
  • the inhibition (%) was more than 80% at the dose of 1.0 x IO" 6 (M)
  • the pyrazole compound (I) and a salt thereof of this invention are useful as adenosine antagonists and for the prevention and/or the treatment of ischemic heart diseases (e.g. angina, etc), peripheral vascular diseases (e.g. claudication, etc), cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, and the like.
  • ischemic heart diseases e.g. angina, etc
  • peripheral vascular diseases e.g. claudication, etc
  • cerebral ischemia migraine, diabetes, depression, Parkinson's disease, and the like.
  • the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyrazole compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administration or insufflation.
  • a pharmaceutical preparation for example, in a solid, semisolid or liquid form, which contains the pyrazole compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administration or insufflation.
  • the active ingredient may be compounded, for example, with the usual non ⁇ toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. Where necessary, any number of auxiliary agents, stabilizing agents, thickening agents, coloring agents and perfumes may be additionally used.
  • the pyrazole compound (I) or a pharmaceutically acceptable salt thereof is included in the pharmaceutical composition in an amount sufficient to produce the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
  • the composition is preferably applied to a human being or an animal by intravenous, intramuscular, pulmonary, or oral administration, or insufflation. While the therapeutically effective amount of the pyrazole compound (I) varies depending on the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 100 mg of the pyrazole compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1 - 100 mg of the pyrazole compound (I) per kg weight of a human being or an animal, in case of oral administration, a daily dose of 0.5 - 100 mg of the pyrazole compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.
  • Trifluoromethanesulfonic anhydride (0.27 ml) was added dropwise to a mixture of 4-acetyl-3-(3-hydroxyphenyl)-5-phenylpyrazole, triethylamine (0.50 ml) and dry 1,2-dichloroethane (4 ml) at below 10°C under nitrogen atmosphere. The mixture was warmed up to room temperature and stirred for 18 hours. The mixture was partitioned between water and chloroform. The separated organic layer was evaporated in vacuo.
  • Example 2 The following compounds (Examples 2 to 4) were obtained according to a manner similar to that of Example 1.
  • Example 2
  • Example 6 The following compounds (Examples 6 to 8) were obtained according to a manner similar to that of Example 1.
  • Example 6

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé pyrazole de la formule (I). Dans cette formule, R1 et R3 sont les mêmes ou différents et chacun est, d'une manière indépendante, un hydrogène, un alkyle inférieur, un arylalkyle inférieur, un groupe hétérocyclique ou aryle, portant éventuellement un ou plusieurs substituants appropriés, R2 est un hydrogène, un alkyle inférieur ou un arylalkyle inférieur, portant éventuellement un ou plusieurs substituants appropriés et R4 est un hydrogène ou un alkyle inférieur. L'invention concerne également les sels de ces composés. Le composé pyrazole (1) et ses sels selon l'invention sont des antagonistes de l'adénosine et ils sont utiles pour la prévention et/ou le traitement des maladies cardiaques ischémiques (angine, etc.), de maladies du système vasculaire périphérique (claudication, etc.), des ischémies cérébrales, des migraines, du diabète, de la dépression, de la maladie de Parkinson et similaire.
PCT/JP1996/001747 1995-06-26 1996-06-24 Composes pyrazole et compositions pharmaceutiques WO1997001551A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP9504305A JPH11508267A (ja) 1995-06-26 1996-06-24 ピラゾール化合物および医薬組成物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9512964.9 1995-06-26
GBGB9512964.9A GB9512964D0 (en) 1995-06-26 1995-06-26 New compound
AUPN8010A AUPN801096A0 (en) 1996-02-12 1996-02-12 New compound
AUPN8010 1996-02-12

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WO1997001551A1 true WO1997001551A1 (fr) 1997-01-16

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PCT/JP1996/001747 WO1997001551A1 (fr) 1995-06-26 1996-06-24 Composes pyrazole et compositions pharmaceutiques

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JP (1) JPH11508267A (fr)
WO (1) WO1997001551A1 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998052937A3 (fr) * 1997-05-22 1999-03-11 Searle & Co PYRAZOLES 3(5)-HETEROARYL SUBSTITUEES UTILISEES COMME INHIBITEURS DE KINASE p38
WO1999024424A1 (fr) * 1997-11-07 1999-05-20 Fujisawa Pharmaceutical Co., Ltd. Composes de pyrazole et utilisation de ces composes en tant que medicaments
WO1999035147A1 (fr) * 1998-01-05 1999-07-15 Eisai Co., Ltd. Derives de purine et antagonistes du recepteur a2 d'adenosine utiles comme moyens de prevention/traitement du diabete
US6087381A (en) * 1997-05-22 2000-07-11 G. D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US6087496A (en) * 1998-05-22 2000-07-11 G. D. Searle & Co. Substituted pyrazoles suitable as p38 kinase inhibitors
WO2000007996A3 (fr) * 1998-08-07 2000-08-31 Chiron Corp Modulateurs de recepteurs d'oestrogenes
US6262098B1 (en) 1998-08-07 2001-07-17 Chiron Corporation Estrogen receptor modulators
US6423713B1 (en) 1997-05-22 2002-07-23 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
WO2002066020A3 (fr) * 2001-02-21 2003-01-03 Can Fite Biopharma Ltd Modulation de l'activite de gsk-3beta et ses differentes utilisations
WO2004022540A2 (fr) * 2002-09-06 2004-03-18 Fujisawa Pharmaceutical Co., Ltd. Compose de pyridazinone et son utilisation pharmaceutique
WO2004056782A1 (fr) * 2002-12-19 2004-07-08 Vernalis (Cambridge) Limited Composes de pyrazole
US6841549B1 (en) 1999-07-02 2005-01-11 Eisai Co., Ltd. Condensed imidazole compounds and a therapeutic agent for diabetes mellitus
US6897318B2 (en) 2001-09-25 2005-05-24 Pharmacia Corporation Process for making substituted pyrazoles
US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
EP1615895A1 (fr) * 2003-04-03 2006-01-18 Merck & Co., Inc. Pyrazoles biaryle substitue utilises en tant que bloqueurs de canaux sodiques
US7057049B2 (en) 2001-09-25 2006-06-06 Pharmacia Corporation Process for making substituted pyrazoles
EP1765335A2 (fr) * 2004-07-07 2007-03-28 Merck & Co., Inc. Derives de pyrazole amide, compositions contenant de tels composes et procedes d'utilisation
USRE39708E1 (en) 1998-08-07 2007-06-26 Chiron Corporation Estrogen receptor modulators
US7763625B2 (en) 2004-01-28 2010-07-27 Kyowa Hakko Kirin Co., Ltd. Agents for treating migraine
US9296741B2 (en) 2011-12-30 2016-03-29 Abbvie Inc. Bromodomain inhibitors
US10633379B2 (en) 2016-04-15 2020-04-28 Abbvie Inc. Bromodomain inhibitors
JP2020516672A (ja) * 2017-04-18 2020-06-11 セルジーン クオンティセル リサーチ，インク． 治療用化合物

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EP0220735A2 (fr) * 1985-10-30 1987-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Dérivés de 3(2H)-pyridazinones, procédé et intermédiaires pour les préparer et médicaments les contenant et/ou d'autres dérivés de 3(2H)-pyridazinone

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EP0175363A2 (fr) * 1984-09-21 1986-03-26 CASSELLA Aktiengesellschaft 4,5-Dihydro-3(2H)-pyridazinones, procédé pour leur préparation et leur usage
EP0220735A2 (fr) * 1985-10-30 1987-05-06 Richter Gedeon Vegyeszeti Gyar R.T. Dérivés de 3(2H)-pyridazinones, procédé et intermédiaires pour les préparer et médicaments les contenant et/ou d'autres dérivés de 3(2H)-pyridazinone

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579873B2 (en) 1997-05-22 2003-06-17 Pharmacia Corporation 3 (5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
US6852740B2 (en) 1997-05-22 2005-02-08 G. D. Searle & Co. Pyrazole derivatives as p38 kinase inhibitors
US5932576A (en) * 1997-05-22 1999-08-03 G. D. Searle & Company 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors
US6087381A (en) * 1997-05-22 2000-07-11 G. D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US6503930B1 (en) 1997-05-22 2003-01-07 G.D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US7153959B2 (en) 1997-05-22 2006-12-26 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
US6617324B1 (en) 1997-05-22 2003-09-09 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6423713B1 (en) 1997-05-22 2002-07-23 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6335336B1 (en) 1997-05-22 2002-01-01 G.D. Searle & Company 3(5)-Heteroaryl substituted pyrazoles as p38 kinase inhibitors
WO1998052937A3 (fr) * 1997-05-22 1999-03-11 Searle & Co PYRAZOLES 3(5)-HETEROARYL SUBSTITUEES UTILISEES COMME INHIBITEURS DE KINASE p38
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
WO1999024424A1 (fr) * 1997-11-07 1999-05-20 Fujisawa Pharmaceutical Co., Ltd. Composes de pyrazole et utilisation de ces composes en tant que medicaments
USRE39112E1 (en) * 1998-01-05 2006-05-30 Eisai Co., Ltd. Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes
US6579868B1 (en) 1998-01-05 2003-06-17 Eisai Co., Ltd. Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes
WO1999035147A1 (fr) * 1998-01-05 1999-07-15 Eisai Co., Ltd. Derives de purine et antagonistes du recepteur a2 d'adenosine utiles comme moyens de prevention/traitement du diabete
EP1300147A1 (fr) * 1998-01-05 2003-04-09 Eisai Co. Ltd Dérivés de purine et antagoniste de récepteur d'adénosine A2 en tant qu'agent prophylactique ou thérapeutique pour le diabète sucre
US6087496A (en) * 1998-05-22 2000-07-11 G. D. Searle & Co. Substituted pyrazoles suitable as p38 kinase inhibitors
US6262098B1 (en) 1998-08-07 2001-07-17 Chiron Corporation Estrogen receptor modulators
US6869969B2 (en) 1998-08-07 2005-03-22 Chiron Corporation Estrogen receptor modulators
US6387920B2 (en) 1998-08-07 2002-05-14 Chiron Corporation Estrogen receptor modulators
USRE39708E1 (en) 1998-08-07 2007-06-26 Chiron Corporation Estrogen receptor modulators
US6727273B2 (en) 1998-08-07 2004-04-27 Chiron Corporation Estrogen receptor modulators
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
WO2000007996A3 (fr) * 1998-08-07 2000-08-31 Chiron Corp Modulateurs de recepteurs d'oestrogenes
US6291505B1 (en) 1998-08-07 2001-09-18 Chiron Corporation Estrogen receptor modulators
US6525059B1 (en) 1998-11-20 2003-02-25 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6841549B1 (en) 1999-07-02 2005-01-11 Eisai Co., Ltd. Condensed imidazole compounds and a therapeutic agent for diabetes mellitus
WO2002066020A3 (fr) * 2001-02-21 2003-01-03 Can Fite Biopharma Ltd Modulation de l'activite de gsk-3beta et ses differentes utilisations
US7057049B2 (en) 2001-09-25 2006-06-06 Pharmacia Corporation Process for making substituted pyrazoles
US6897318B2 (en) 2001-09-25 2005-05-24 Pharmacia Corporation Process for making substituted pyrazoles
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