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WO1999024424A1 - Composes de pyrazole et utilisation de ces composes en tant que medicaments - Google Patents

Composes de pyrazole et utilisation de ces composes en tant que medicaments Download PDF

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Publication number
WO1999024424A1
WO1999024424A1 PCT/JP1998/004892 JP9804892W WO9924424A1 WO 1999024424 A1 WO1999024424 A1 WO 1999024424A1 JP 9804892 W JP9804892 W JP 9804892W WO 9924424 A1 WO9924424 A1 WO 9924424A1
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WIPO (PCT)
Prior art keywords
group
alkyl
formula
salt
alkyl group
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Application number
PCT/JP1998/004892
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English (en)
Japanese (ja)
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.)
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Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1999024424A1 publication Critical patent/WO1999024424A1/fr

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    • 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

Definitions

  • the present invention relates to a novel pyrazole compound useful as a medicament, a salt thereof, and a use thereof. More specifically, the present invention relates to the prevention of ischemic heart disease (eg, angina), peripheral vascular disease (eg, claudication), cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, etc. And z or a novel pyrazole compound useful for treatment and a salt thereof, and a use thereof.
  • ischemic heart disease eg, angina
  • peripheral vascular disease eg, claudication
  • cerebral ischemia migraine
  • diabetes depression
  • Parkinson's disease Parkinson's disease
  • Adenosine receptors to date (hereinafter, A, receptor) antagonists or adenosine emissions
  • a 2 receptor (hereinafter, A 2 receptor)
  • Various compounds have been proposed as antagonists. However, the compounds proposed to date have not always been effective enough.
  • An object of the present invention is to provide a novel pyrazole compound useful as an adenosine antagonist and a salt thereof.
  • Another object of the present invention is to provide a medicament comprising the pyrazole compound or a salt thereof.o
  • the present inventors have result of intensive studies, the general formula (I) novel pyrazole represented by - strength have antagonism against both receptors Le compound or a salt thereof receptors and A 2 receptors Yes
  • the compound of the present invention can be used as a preventive and / or therapeutic agent for ischemic heart disease such as angina, peripheral vascular disease such as claudication, cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, and the like. And completed the present invention.
  • R 1 and R 2 may be the same or different and each is an aryl group which may have a substituent, and R 3 may have a hydrogen, a lower alkyl group or a substituent
  • An ar (lower) alkyl group, and R 4 has the formula:
  • R 5 represents an ar (lower) alkyl group which may have a substituent, or a lower alkanoyl (lower) alkyl group), or a formula:
  • R 6 represents a carboxy group which may be protected
  • R 6 represents a carboxy group which may be protected
  • the birazol compound of the present invention or a salt thereof can be produced as follows.
  • R 1 , R 2 , R 3 and R 5 are as defined above, X is a leaving group, R 3a is an ar (lower) alkyl group, R 3b is a lower alkyl group and R 6a is protected. Means a carboxyl group)
  • the reactions of the above Production Methods 1 to 5 can be carried out according to the methods described in Examples of the present specification or conventional methods in this technical field.
  • the pyrazole compound (I) may include a geometric isomer based on a double bond and a stereoisomer based on Z or an asymmetric carbon atom.
  • the isomer can be converted into another isomer by a conventional method in this technical field.
  • Examples of the salt of the pyrazole compound (I) include, for example, metal salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), and ammonium salts.
  • metal salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), and ammonium salts.
  • organic base salts eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt, etc.
  • organic acid salts eg, acetate, trifluoroacetic acid
  • inorganic acid salts eg, hydrochloride, hydrobromide, iodide
  • Hydrochloride sulfate, phosphate, etc.
  • amino acid alginic acid, aspartic acid, glutamic acid, etc.
  • salts of Ru and the like are preferably used as pharmaceutically acceptable salts of the pyrazole compounds (I).
  • “Lower” means 1 to 6 carbon atoms unless otherwise noted.
  • Aryl includes, for example, phenyl, naphthyl, indenyl, anthryl and the like, preferably phenyl, naphthyl and more preferably phenyl.
  • the “aryl” is a halogen (eg, fluoro, chloro, bromo, halide)-a lower alkyl, as described below, a lower alkoxy, a hydroxy group, a tri (lower) alkylsilyloxy (eg, trimethylsilyloxy, t-methyl). Butyldimethylsilyloxy, etc.), phenyl (lower) alkoxy (for example, phenylmethoxy, phenylethoxy, phenylpropoxy, fuunylbutoxy, phenylpentyloxy, phenylhexyloxy, etc.), and halo (lower) alkyl. Phenyl (eg, trifluoromethylphenyl), heterocyclic (lower) alkoxy And one or more (preferably 1 to 3) suitable substituents selected from the above.
  • a halogen eg, fluoro, chloro, bromo, halide
  • heterocyclic (lower) alkoxy examples include a saturated or unsaturated monocyclic or polycyclic heterocyclic ring.
  • Unsaturated 3- to 8-membered (more preferably 5- to 7-membered) complex monocyclic group containing 1 to 4 nitrogen atoms such as azepinyl (eg, 1 H-azepinyl etc.), pyrrolyl, pyrrolinyl, imidazolyl, Birazolyl, pyridyl and its N-oxides, dihydric pyridyl, pyrimidinyl, virazinyl, pyridazinyl, triazolyl (eg, 4H-1, 2,4,1-triazolyl, 1H-1,2,3—triazolyl, 2H-1, 2,3_triazolyl), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl, etc.);
  • azepinyl eg, 1 H-azepinyl etc.
  • pyrrolyl pyrrolinyl
  • imidazolyl Birazo
  • Saturated 3 to 8 membered (more preferably 5 to 7 membered) heterocyclic group containing 1 to 4 nitrogen atoms for example perhydroazepinyl (for example, perhydro-1H-azepinyl etc.), pyrrolidinyl, imidazolidinyl, Piperidyl, piperazinyl, etc .;
  • Unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (for example, Imidazo [4, 5-c] pyridyl, etc.), tetrahydroimidazo pyridyl (for example, 4, 5, 6, 7-tetrahydro [4, 5-c] pyridyl, etc.);
  • a saturated condensed heterocyclic group containing 1 to 4 nitrogen atoms for example, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl, and the like;
  • Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms such as oxazolyl, isoxazolyl, oxaziazolyl (eg, 1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);
  • Saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms such as morpholinyl (2-morpholinyl) Nil, 3-morpholinyl), morpholino, sydnoyl, etc .;
  • Unsaturated condensed heterocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms such as benzoxazolyl, benzoxodiazolyl and the like;
  • Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic monocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms such as thiazolyl, isothiazolyl, thiadiazolyl (eg, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .;
  • Unsaturated fused heterocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms such as benzothiazolyl, benzothiaziazolyl, and the like;
  • Unsaturated condensed heterocyclic groups containing one or two sulfur atoms such as benzodienyl, benzodithiynyl and the like;
  • Unsaturated condensed heterocyclic groups containing one oxygen atom and one or two sulfur atoms such as benzoxoxathiinyl
  • heterocyclic group an unsaturated 3 to 8-membered heteromonocyclic group containing one oxygen atom is preferable, and more preferably furyl.
  • alkoxy in the “heterocycle (lower) alkoxy” examples include methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t_pentyloxy, hexyloxy and the like.
  • “Lower alkyl” includes straight-chain or branched alkyl such as methyl, ethyl Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. Preferably it is (d—C 5 ) alkyl, more preferably methyl, ethyl, isobutyl or pentyl.
  • lower alkoxy examples include the alkoxy in the above-mentioned heterocyclic (lower) alkoxy.
  • alk (lower) alkyl examples include, for example, phenyl (lower) alkyl (specifically, benzyl, phenethyl, benzhydryl, trityl, 2-phenylpropyl, 3,4-diphenylbutyl, 2-phenylpentyl). , 6-phenylhexyl and the like).
  • the “ar (lower) alkyl” may have one or more (preferably 1 to 3) suitable substituents, for example, lower alkyl, lower alkoxy, nitro group and the like as described above. .
  • lower alkanoyl in the “lower alkanoyl (lower) alkyl” examples include acetyl, propanoyl, butanol, isobutanol, pentanoyl, hexanoyl and the like.
  • Examples of the lower alkyl in the “lower alkanoyl (lower) alkyl” include the same as those described above.
  • the “optionally protected carboxy group” is a carboxy group or a protected carboxy group.
  • the protected carboxy group include an esterified carboxy group and an amidated carboxy group.
  • the esterified carboxy group include lower alkyl esters (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.). However, these may have at least one substituent.
  • substituted lower alkyl ester examples include lower alkanoyloxy (lower) alkyl esters [eg, acetyloxymethyl ester, propionyloxy) Cimethyl ester, Butyryloxymethyl ester, Valeryloxymethyl ester, Bivaloyloxymethyl ester, Hexanoyloxymethyl ester,
  • lower alkanoyloxy (lower) alkyl esters eg, acetyloxymethyl ester, propionyloxy) Cimethyl ester, Butyryloxymethyl ester, Valeryloxymethyl ester, Bivaloyloxymethyl ester, Hexanoyloxymethyl ester,
  • lower alkoxycarbonyloxy (lower) alkyl ester eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl Ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, one (or two) methoxycarboxyloxyethyl ester, one (or two _) ethoxycarbonyloxyethyl ester, one (Or 2-) isopropoxycarbonyl oxethyl ester, etc.].
  • amidated carboxy group examples include a carbazole group, a carbamoyl group, and an N-lower alkylcarbamoyl group.
  • Examples of the leaving group include the above-mentioned halogen and sulfoxy, such as sulfonyloxy (eg, mesiloxy, tosiloxy, etc.).
  • R 1 and R 2 are the same or different and each represents a hydroxy group or a tri (lower) alkyl group.
  • R 5 is an ar (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol ( Lower) which means an alkyl group) or a group represented by the formula:
  • R 6 represents a carboxy group or an amidated carboxy group
  • R 1 and R 2 are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group.
  • An optionally substituted phenyl group, R 3 is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1-3 lower alkoxy groups, and R 4 is a group represented by the formula:
  • R 5 is a group consisting of a lower alkyl group, a lower alkoxy group, and a nitro group.
  • R 6 represents a carboxy group or a carbazolyl group
  • R 1 and R 2 are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group.
  • a phenyl group (optionally) is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1 to 3 lower alkoxy groups, and R 4 is a group represented by the formula:
  • R 5 is a phenyl (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol (lower group)
  • R 5 is a phenyl (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol (lower group)
  • A a compound or a salt thereof, which is a group represented by
  • R 1 and R 2 may be the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group
  • R 3 is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1 to 3 lower alkoxy groups
  • R 4 is a group represented by the formula:
  • R 6 represents a carboxy group
  • Therapeutic drugs for heart failure inotropic drugs, antihypertensive drugs, renal failure drugs, nephrotoxic drugs, renal protective drugs, renal function improvers, diuretics, edema drugs, antiobesity drugs, antiasthmatic drugs, bronchodilators Antipyretic, Gout, Hyperuricemia, Sudden Infant Death Syndrome (SIDS), Immunosuppressive Adenosine, Antidiabetic, Antiulcer, Knee, Meniere Syndrome, anti-anemic, thrombosis, myocardial infarction, embolism, obstructive atherosclerosis, thrombophlebitis, cerebral infarction, transient ischemic therapy It is useful as a remedy, a drug for treating angina, etc., depression, dementia (eg, Alzheimer's disease, cerebrovascular dementia, dementia associated with Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (eg, essential Hypertension, renal hypertension, etc.), ischemia / reper
  • the medicament of the present invention comprises, as an active ingredient, a pyrazole compound (I) or a salt thereof, for rectal administration, pulmonary inhalation (nasal inhalation or oral mucosal inhalation), nasal instillation, ophthalmic instillation, topical administration (topical administration), oral or non-oral administration.
  • Pharmaceutically acceptable carriers excipients, binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, dissolutions, suitable for oral (including subcutaneous, intravenous and intramuscular) administration or infusion Adjuvants).
  • it can be used as a solid, semi-solid or liquid form of a pharmaceutical preparation.
  • Such active ingredients include, for example, tablets, granules, troches, capsules, suppositories, creams, ointments, aerosols, powders for inhalation, solutions, emulsions, suspensions and any other suitable for use.
  • active ingredients include, for example, tablets, granules, troches, capsules, suppositories, creams, ointments, aerosols, powders for inhalation, solutions, emulsions, suspensions and any other suitable for use.
  • the auxiliaries, stabilizers, thickeners, coloring agents and fragrances may be further used.
  • the medicament of the present invention can be produced by a conventional method in this technical field. If necessary, a drug bioavailability improvement technique commonly used in this technical field can be applied.
  • Intravenous (including intravenous)-intramuscular, pulmonary or oral administration, or inhalation or insufflation of aerosol from a metered dose inhaler, nebulizer or dry powder inhaler when applying the drug to humans or animals It is preferably applied by
  • the therapeutically effective amount of the Pyrazol Compound (I) can vary depending on the age and condition of each individual treated patient.
  • the daily dose of pyrazole compound (I) is 0.01 to 100 mg per kg body weight of human or animal, and for intramuscular administration, human or animal kg
  • the daily dose of the pyrazole compound (I) per body weight is 0.1 to 10 O mg; in the case of oral administration, the daily dose of the pyrazole compound (I) is 0.5 to 10 per kg body weight of human or animal. O mg is commonly given for prevention and Z or treatment of the disease.
  • Pyrazole Ichiru compound or a salt thereof of the present invention has a strong antagonistic action against both receptors receptors and A 2 receptor, ischemic heart diseases such as angina pectoris, peripheral vascular diseases claudication, etc. And prophylactic and / or therapeutic agents for cerebral ischemia, migraine, diabetes, depression, Parkinson's disease and the like.
  • This application is based on Japanese Patent Application No. 3061671 filed in Japan, the contents of which are incorporated in full herein.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de pyrazole représentés par la formule générale (I), ou des sels de ces composés, qui font preuve d'un antagonisme intense à la fois contre les récepteurs A1 et A2, et peuvent ainsi servir pour le traitement préventif et/ou thérapeutique des maladies cardiaques ischémiques telles que l'angine de poitrine, des acrosyndromes vasculaires tels que la claudication, de l'ischémie cérébrale, de la migraine, du diabète, de la mélancolie, de la maladie de Parkinson, etc. R1 et R2 peuvent être identiques ou différents et représentent chacun l'hydrogène, un alkyle inférieur ou un arlakyle (inférieur) éventuellement substitué; et R4 représente soit un groupe de formule (A) (dans laquelle R5 représente l'aralkyle (inférieur) éventuellement substitué ou l'alcanoyle-alkyle (inférieur) inférieur) ou un groupe de formule (B) (dans laquelle R6 représente le carboxyle éventuellement protégé).
PCT/JP1998/004892 1997-11-07 1998-10-28 Composes de pyrazole et utilisation de ces composes en tant que medicaments WO1999024424A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP30616797 1997-11-07
JP9/306167 1997-11-07

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WO1999024424A1 true WO1999024424A1 (fr) 1999-05-20

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001551A1 (fr) * 1995-06-26 1997-01-16 Fujisawa Pharmaceutical Co., Ltd. Composes pyrazole et compositions pharmaceutiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001551A1 (fr) * 1995-06-26 1997-01-16 Fujisawa Pharmaceutical Co., Ltd. Composes pyrazole et compositions pharmaceutiques

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