WO1993019067A1 - Derives d'imidazopyridine utilises en tant qu'antagonistes d'angiotensine ii - Google Patents

Derives d'imidazopyridine utilises en tant qu'antagonistes d'angiotensine ii Download PDF

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Publication number
WO1993019067A1
WO1993019067A1 PCT/JP1993/000325 JP9300325W WO9319067A1 WO 1993019067 A1 WO1993019067 A1 WO 1993019067A1 JP 9300325 W JP9300325 W JP 9300325W WO 9319067 A1 WO9319067 A1 WO 9319067A1
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Prior art keywords
compound
salt
formula
ethyl
ester
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PCT/JP1993/000325
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English (en)
Inventor
Teruo Oku
Hiroyuki Setoi
Hiroshi Kayakiri
Shigeki Satoh
Takayuki Inoue
Yuki Sawada
Akio Kuroda
Hirokazu Tanaka
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from US07/758,688 external-priority patent/US5215994A/en
Priority claimed from GB929206417A external-priority patent/GB9206417D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP5516425A priority Critical patent/JPH07508260A/ja
Publication of WO1993019067A1 publication Critical patent/WO1993019067A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel heterocyclic derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel imidazole derivatives and a pharmaceutically acceptable
  • one object of the present invention is to provide novel imidazole derivatives and a pharmaceutically acceptable salt thereof, which are useful as a potent and selective antagonist of angiotensin II receptor.
  • Another object of the present invention is to provide process for preparation of said imidazole derivatives or a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said imidazole derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said imidazole derivatives or a pharmaceutically acceptable salt thereof as a medicament such as angiotensin II antagonist useful for treating or preventing angiotensin 11 mediated diseases, for example, hypertension (e. g. essential hypertension, renal hypertension, etc.), heart failure, and the like in human being or animals.
  • angiotensin II antagonist useful for treating or preventing angiotensin 11 mediated diseases, for example, hypertension (e. g. essential hypertension, renal hypertension, etc.), heart failure, and the like in human being or animals.
  • the imidazole derivatives of the present invention are novel and can be represented by the formula (I):
  • R 1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy,
  • R 2 , R 3 and R 4 are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo
  • R 2 and R 3 are linked together to form 1,3 - butadienylene, R 5 is hydrogen or imino - protective group,
  • R 6 is lower alkyl
  • R 7 is lower alkyl
  • R 8 is optionally esterified or amidated carboxy, halogen, cyano, hydroxy (lower) alkyl, or lower alkoxy which may have halogen,
  • A is lower alkylene
  • X is N or CH
  • Y is NH, O or S.
  • the object compound (I) can be prepared by the following processes.
  • Process 1 the object compound (I) can be prepared by the following processes.
  • R 5 a is imino-protective group
  • R 8 a is esterified carboxy
  • R 8 b is amidated carboxy
  • R 8 c is optionally esterified carboxy
  • R 8 d is halogen
  • R 8 e is lower alkoxy which may have halogen
  • R 8 f is amidated carboxy having esterified carboxy
  • Suitable salts of the compound (I) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e. g. sodium salt, potassium salt, cesium salt, etc.), an alkali earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e. g.
  • triethylamine salt pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.
  • an inorganic acid addition salt e. g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic carboxylic or sulfonic acid addition salt e. g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e. g. arginine, aspartic acid, glutamic acid, etc.
  • the preferable example thereof is an acid addition salt.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • Suitable "lower alkyl” and lower alkyl group in the term “lower alkylthio” may include straight or branched one, having 1 to 6 carbon atom (s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 5 carbon atoms, and the like.
  • Suitable "lower alkenyl” may include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 2-pentenyl, and the like, preferably one having 2 to 4 carbon atoms, in which the most preferred one is vinyl.
  • Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, and the like, in which the preferred one is methylene.
  • Suitable "halogen” means fluoro, chloro, bromo and iodo.
  • Suitable "low alkoxy” may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferable one is C 1 -C 4 alkoxy.
  • Suitable acyl group in the term "acylamino" may include carbamoyl, thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, in which the preferable one is aliphatic acyl such as lower alkanoyl (e. g. formyl, acetyl, propionyl, butyryl, hexanoyl, etc. ), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc) and the like.
  • lower alkanoyl e. g. formyl, acetyl, propionyl, butyryl, hexanoyl, etc.
  • lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc
  • Suitable "mono or di or trihalo(lower)alkyl” may include chloromethyl, f luoromethyl , di f luoromethyl, dichloromethyl , tri f l uoromethyl , trifluoromethylpropyl, and the like.
  • Suitable "lower alkoxy which may have halogen” may include lower alkoxy as ment iond above mono- (or di- or tri-) halo (lower) alkoxy (e. g. chloromethoxy, f luoromethoxy, dif luoromethoxy, dichloromethoxy, trifluoroethoxy, trifluoropropoxy and the like.
  • Suitable "hydroxy (lower) alkyl” may include hydroxymethyl, hydroxyethyl, and the like.
  • Suitable “ oxo ( lower)alkyl” may include formyl, formylmethyl, formylethyl, and the like.
  • Suitable "ester moiety" in “esterified carboxy group” may include pharmaceutically acceptable, easily removable one such as lower alkyl ester (e. g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, tert-pentyl ester, hexyl ester, etc. ), lower alkenyl ester (e. g. vinyl ester, allyl ester, etc. ), lower alkynyl ester (e. g. ethynyl ester, propynyl ester, etc.
  • lower alkyl ester e. g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, ter
  • lower alkoxy (lower) alkyl ester e. g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.
  • lower alkylthio (lower) -alkyl ester e. g. methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.
  • carboxy-substituted-lower alkyl ester e. g.
  • acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1(or 2)-acetoxyethyl ester, 1(or 2 or 3)- acetoxypropyl ester, 1(or 2 or 3 or 4)-acetoxybutyl ester, 1(or 2)- propionyloxyethyl ester, 1(or 2 or 3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, 1(or 2)-pivaloyloxyethyl ester, 1(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or
  • heptanoyloxymethyl ester octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, 1(or 2)-heptanoyloxyethyl ester, 1(or 2)-octanoyloxyethyl ester, 1(or 2)-nonanoyloxyethyl ester, 1(or 2)- decanoyloxyethyl ester, 1(or 2)-undecanoyloxyethyl ester, 1
  • cyclohexylcarbonyloxymethyl ester 1(or 2) -cyclopentylcarbonyloxyethyl ester, 1 (or 2) -cyclohexylcarbonyloxyethyl ester, etc,] aroyloxy (lower) alkyl ester such as benzoyloxy(lower)alkyl ester [e. g. 1 (or 2) -benzoyloxyethyl ester, etc,] heterocycliccarbonyloxy(lower)alkyl ester such as lower alkylpiperidylcarbonyloxy(lower)alkyl ester [e.g.
  • lower alkoxycarbonyloxy (lower) alkyl ester [e. g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, isopropoxycarbonyl-oxymethyl ester, tert-butoxycarbonyloxymethyl ester, 1(or 2)-methoxycarbonyloxyethyl ester, 1(or 2)-ethoxycarbonyloxyethyl ester, 1(or 2)-propoxycarbonyloxyethyl ester, 1(or 2)-methoxycarbonyloxyethyl ester, 1(or 2)-ethoxycarbonyloxyethyl ester, 1(or 2)-propoxycarbonyloxyethyl ester, 1(or
  • lower alkanesulfonyl (lower) alkyl ester e.g. mesylmethyl ester, 2-mesylmethyl ester, etc.
  • ar (lower) alkyl ester which may have one or more substituent(s) such as mono- (or di or tri)phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g.
  • benzyl ester 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydryl ester, trityl ester, bis(methoxyphenyl)- methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc. ), aryl ester which may have one or more suitable substituents (e. g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, etc. ), heterocyclic ester (e. g. phthalidyl ester, 1 (or 2)-phthalid-3-ylideneethyl ester, etc. ), and the like.
  • suitable substituents e. g. phenyl ester, tolyl ester, t-
  • Suitable "imino-protective group” may include conventional one, and the preferable example thereof is ar(lower)alkyl such as mono-(or di- or tri-) phenyl (lower) alkyl (e. g. benzyl, benzhydryl, trityl, etc. ), acyl such as lower alkoxycarbonyl (e. g. tert-butoxycarbonyl, etc. ), lower alkanesulfonyl (e. g. mesyl, etc. ), arenesulfonyl (e. g. tosyl, etc. ), and the like, in which the most preferred one is trityl.
  • ar(lower)alkyl such as mono-(or di- or tri-) phenyl (lower) alkyl (e. g. benzyl, benzhydryl, trityl, etc. ), acyl such as lower alkoxycarbonyl (e. g
  • Suitable "acid residue” may include halogen (e. g. fluoro, chloro, bromo, iodo), acyloxy (e. g. acetoxy, tosyloxy, mesyloxy, etc. ) and the like.
  • halogen e. g. fluoro, chloro, bromo, iodo
  • acyloxy e. g. acetoxy, tosyloxy, mesyloxy, etc.
  • Suitable "amidated carboxy” may carbamoyl which may have suitable substituent(s) and may include carbamoyl, mono or di (lower) alkylcarbamoyl (e. g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, etc. ), lower alky larylcarbamoyl (e. g. isobutylphenylcarbamoyl, etc. ), hydroxy (lower)alkylcarbamoyl(e. g. hydroxymethylcarbamoyl, etc.
  • carbamoyl which may have suitable substituent(s) and may include carbamoyl, mono or di (lower) alkylcarbamoyl (e. g. methylcarbamoyl, dimethylcarbamoy
  • N-hydroxy-N-(lower)alkylcarbamoyl e. g. N-hydroxy-N-methylcarbamoyl, etc.
  • acylcarbamoyl such as lower alkylsulfonylcarbamoyl (e. g. mesylcarbamoyl, etc. ), carbamoyl having optionally esterified carboxy such as phenyl(lower)alkylcarbamoyl, in which lower alkyl moiety is substituted by optionally esterified carboxy, for example, 1-carboxyphenethylcarbamoyl, 1- (lower alkoxycarbonyl) phenethylcarbamoyl (e. g. 1- (lower alkoxycarbonyl)phenethylcarbamoyl (e. g. 1-(ethoxycarbonyl)phenethylcarbamoyl, etc. ) and the like.
  • Suitable "amidated carboxy having carboxy” may include phenyl (lower) alkylcarbamoyl, in which lower alkyl moiety is substituted by carboxy, 1-carboxyphenethylcarbamoyl, etc. ), and the like.
  • Suitable "amidated carboxy having esterified carboxy” may include phenyl(lower)alkylcarbamoyl, in which lower alkyl moiety is substituted by esterified carboxy, such as 1-(loweralkoxycarbonyl)phenethylcarbamoyl (e. g. 1-(ethoxycarbonyl)phenethylcarbamoyl, etc.) and the like.
  • Suitable "alkali metal” may include sodium, potassium, cesium, and the like.
  • heterocyclic derivatives (I) of the present invention can be represented by the following chemical formula:
  • the preferred compound (I) of the present invention is represented by the following chemical formula :
  • R 6 , R 7 , R 2 a and R 3 a are each lower alkyl
  • R 8 is carboxy, lower alkoxycarbonyl, carbamoyl, mono - or di (lower) alkylcarbamoyl, N - hydroxy - N - (lower) alkylcarbamoyl, lower alkylsulfonylcarbamoyl , 1 - carboxyphenethylcarbamoyl , 1 - ( lower alkoxycarbonyl) phenethylcarbamoyl, halogen, cyano, hydroxy (lower) alkyl or lower alkoxy which may have halogen.
  • the object compound (I) or a salt thereof can be prepared by subjecting the compound (II) to the formation reaction of a tetrazole group.
  • the agent to be used in the present reaction may include conventional ones which is capable of converting a cyano group to a tetrazolyl group such as metal azide, for example, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. trimethyltin azide, etc. ), triaryltin azide (e. g. triphenyltin azide, etc. ), or the like.
  • metal azide for example, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. trimethyltin azide, etc. ), triaryltin azide (e. g. triphenyltin azide, etc. ), or the like.
  • the present reaction is usually carried out in the presence of a base such as tri(lower)alkylamine(e. g. triethylamine, etc. ), and the like, or 1, 3-dimethyl-2-imidazolidinone, and the like.
  • a base such as tri(lower)alkylamine(e. g. triethylamine, etc. ), and the like, or 1, 3-dimethyl-2-imidazolidinone, and the like.
  • the present reaction is usually carried out in a solvent such as xylene, dioxane, chloroform, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.
  • a solvent such as xylene, dioxane, chloroform, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under warming or heating, preferably under heating.
  • the object compound (I-b) or a salt thereof can be prepared by subjecting the compound (I-a) or a salt thereof to the elimination reaction of the ester moiety.
  • Suitable method for this reaction may include conventional one such as hydrolysis, and the like.
  • the hydrolysis is to be referred to those as explained in process 4.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (III) or a salt thereof with the compound (IV) or a salt thereof.
  • the present reaction is usually carried out in the presence of a base such as alkyl lithium (e. g. n-butyl lithium, etc.), alkali metal hydride (e. g. sodium hydride, potassium hydride, etc.), di(lower)alkylamine (e.g. diisopropylamine, etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine, etc.), pyridine or its derivative (e. g. picoline, lutidine, 4-dimethylaminopyridine, etc.), or the like.
  • alkyl lithium e. g. n-butyl lithium, etc.
  • alkali metal hydride e. g. sodium hydride, potassium hydride, etc.
  • di(lower)alkylamine e.g. diisopropylamine, etc.
  • tri(lower)alkylamine e.g. trimethylamine, triethyl
  • the present reaction is usually carried out in a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.
  • a solvent such as dioxane, dimethyl sulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran, or any other solvent which does not adversely affect the reaction.
  • the base to be used is liquid, it can also be used as a solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (I-d) or a salt thereof can be prepared by subjecting the compound (I-c) or a salt thereof to removal reaction of the imino-protective group.
  • Suitable method for this removal may include conventional one which is capable of removing an imino-protective group on a tetrazolyl group such as hydrolysis, reduction, or the like.
  • the hydrolysis is preferably carried out in the presence of the base or an acid.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e. g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e. g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate, (e. g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e. g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e. g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetate (e. g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e. g.
  • an inorganic base such as alkali metal hydroxide (e. g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e. g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate, (e
  • alkali metal hydrogen phosphate e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • an organic base such as trialkylamine (e. g. trimethylamine, triethylamine, etc. ), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3, 0]non-5-one, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-undecene-5 or the like.
  • the hydrolysis using a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent thereof.
  • Suitable acid may include an organic acid (e. g. formic acid, acetic acid, propionic acid, etc.) and an inorganic acid (e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).
  • organic acid e. g. formic acid, acetic acid, propionic acid, etc.
  • inorganic acid e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the present hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under warming or heating.
  • the object compound (I-e) or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the carboxy group or a salt thereof to amidation reaction.
  • Suitable salt of the compound (I-e) can be referred to
  • the amidating agent to be used in the present amidation reaction may include amine which may have suitable substituent(s).
  • Suitable reactive derivative at the carboxy group of the compound (I-b) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride, an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e. g. dialkylphosphoric acid, phenylphosphoric acid,
  • diphenylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid dialkylphosphorous acid
  • sulforous acid thiosulfuric acid
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e. g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, or trichloroacetic acid, etc.
  • aromatic carboxylic acid e. g. benzoic acid, etc.
  • a symmetrical acid anhydride e. g.
  • N-hydroxy compound e. g. N, N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1 -hydroxy-6-chloro-1H-benzotriazole, etc.
  • N-hydroxy compound e. g. N, N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1 -hydroxy-6-chloro-1H-benzotriazole, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' -dicyclohexylcarbodiimide, N-cycl ohexy l-N ' -morpho l inoethylcarbod i imi de , N-ethyl -N ' - ( 3 -dimethylaminopropyl) carbodiimide, 1, 1 ' -carbonyldi-imidazole, thionyl chloride, oxalyl chloride, lower lower alkoxycarbonyl halide [e. g. ethyl chloroformate, isobutyl chloroformate, etc.], 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotr ⁇ azole, or the like.
  • a conventional condensing agent such as N, N ' -dicyclohexylcarbodiimide, N-
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, acetone, dioxane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • hydrophilic solvents may be used in a mixture with water.
  • reaction in the presence of a condensing agent is usually carried out in an anhydrous, but not critical conditions.
  • the reaction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide (e. g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), tri (lower) alkylamine (e. g. trimethylamine, triethylamine, etc.), pyridine or its derivative (e. g. picoline, lutidine, 4-dimethylaminopyridine, etc.), or the like.
  • an alkali metal hydroxide e. g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • an alkali metal bicarbonate e.g. sodium bicarbonate, potassium bicarbonate, etc.
  • tri (lower) alkylamine
  • the base or the condensing agent to be used is in liquid, it can be used also as a solvent.
  • the reaction temperature is not critical, and the reaction is usually carried out under heating or under warming, preferably under heating.
  • the compound (I-a) or a salt thereof can be prepared by subjecting the compound (I-b) or its reactive derivative at the carboxy thereof, or a salt thereof to esterification.
  • the reaction can be carried out by a conventional esterification.
  • Suitable reactive derivative at the carboxy group of the compound (I-b) may be the same as those exemplified in Process 5.
  • Suitable esterifying agent used in this reaction may include alcohol or its conventional reactive derivative such as halide, (e. g. cyclohexyl 1-iodomethyl carbonate, cycohexyl 1-iodoethyl carbonate, etc. ) sulfonate, and the like. Further, it may include di (lower) alkylsulfate (e. g. dimethylsulfate, etc.), diazo (lower) alkanes (e.g. diazomethane, etc.), 3-lower alkyltriazenes (e. g. 3-methyl-1-tolyltriazene, etc.), and the like.
  • alcohol or its conventional reactive derivative such as halide, (e. g. cyclohexyl 1-iodomethyl carbonate, cycohexyl 1-iodoethyl carbonate, etc. ) sulfonate, and the like. Further, it may include di (lower
  • This reaction is usually carried out in a conventional solvent such as alcohols(e. g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohols(e. g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound (I-c) can be prepared by subjecting the compound (I-d) to introduction reaction of the imino protective group.
  • the introduction reaction of the imino protective group in this step can be carried out by reacting the compound (I-d) with a suitable agent for introducing the imino protective group.
  • Suitable examples of said agent may be ar(lower)alkyl halide which may have aforesaid lower alkoxy such as phenyl(lower)alkyl halide which may have lower alkoxy (e. g. benzyl iodide, 3-methoxybenzyl iodide, benzyl bromide, 4-methoxybenzyl bromide, phenethyl chloride, etc.), diphenyl(lower) alkyl halide (e.g. benzhydryl chloride, etc.), triphenyl(lower)alkyl halide (e. g. tritylchloride, tritylbromide, etc.) or the like.
  • phenyl(lower)alkyl halide which may have lower alkoxy
  • This introduction reaction may be carried out in a suitable solvent such as chloroform, acetonitrile, acetone, nitrobenzene, N,N-dimethylformamide or any other solvent which does not adversely affect the reaction.
  • a suitable solvent such as chloroform, acetonitrile, acetone, nitrobenzene, N,N-dimethylformamide or any other solvent which does not adversely affect the reaction.
  • the reaction temperature is not critical and usually carried out at room temperature, under warming or under heating.
  • the compound (I-g) or a salt thereof can be prepared by subjecting the compound (I-f) or a salt thereof to reduction.
  • This reduction may include, for example, reduction with an alkali metal borohydride (e. g. sodium borohydride, lithium aluminum hydride, and th like.
  • an alkali metal borohydride e. g. sodium borohydride, lithium aluminum hydride, and th like.
  • This reaction is usually carried out in a conventional solvent such as alcohols (e.g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohols (e.g. methanol, ethanol, etc.), dioxane, tetrahydrofuran, or any other organic solvent which does not adversely influence the reaction.
  • the object compound (I-i) or a salt thereof can be prepared by reacting the compound (I-h) or a salt thereof with the compound (V) or a salt thereof.
  • This present reaction is usually carried out in a conventional solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating, preferably under heating.
  • the object compound (I-k) or a salt thereof can be prepared by subjecting the compound (I-j) or a salt thereof to elimination reaction of the ester moiety.
  • Sutable method for this reaction may include conventional one such as hydrolysis, and the like.
  • the hydrolysis is to be referred to those as explained in process 4.
  • the starting compounds (II), (III) and (IV) are new and can be prepared by the methods of Preparations mentioned below or a similar manner thereto or a conventional manner.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, estraction precipitation, fractional crystallization, recrystallization, chromtography, and the like.
  • the object compound (I) thus obtained can be converted to its salt by a conventional method.
  • the object compound (I) of the present invention exhibits angiotensin antagonism such as vasodilating activity and is useful as an angiotensin II antagonist and effective to various angiotensin II mediated diseases such as hypertension (e. g. essential hypertension, renal hypertension, etc.), heart failure, and the like.
  • the object compounds of the present invention are useful as therapeutical and/or preventive agents for cardiopathy (e. g. angina pectoris, arrhythmia, myocardial infarction, etc.), hyperaldosteronism, cerebral vascular diseases, senile dementia, ophthalmic diseases (e. g. glaucoma, etc.), and the like; and diagnostic agents to test the renin angiotensin system.
  • cardiopathy e. g. angina pectoris, arrhythmia, myocardial infarction, etc.
  • hyperaldosteronism e. e. g. angina pectoris, arrhythmia, myocardial infarction, etc.
  • cerebral vascular diseases e. g. senile dementia
  • ophthalmic diseases e. g. glaucoma, etc.
  • diagnostic agents to test the renin angiotensin system e. g. angina pectoris, arrhythmia, myocardial in
  • the object compound(I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and inhalant administration.
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral, external and inhalant administration.
  • the pharmaceutical preparation may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • auxiliary substances stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • the dosage of the compound (I) may vary form and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0. 01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
  • the organic layer was separated and washed successively with saturated sodium cholride.
  • hydrochloric acid was added to the solution until pH4.
  • the suspension was stirred at room temperature for 1 hour, and filtered through a celite powder.
  • reaction mixture was diluted with chloroform and the solution was washed with water and saturated
  • reaction mixture was stirred at 0 °C and then at room temperature for 4 hours. Chloroform and water were added to the solution, and separated. The organic layer was dried over magnesium
  • reaction mixture was stirred at room temperature for one hour, and then 50% aqueous trimethylamine (3ml) was added to the mixture.
  • the reaction mixture was stirred at room temperature for one hour.
  • Water was added to the mixture, and extracted with chloroform twice. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé répondant à la formule (I), dans laquelle R1 représente hydrogène, halogène, nitro, alkyle inférieur, alcoxy inférieur, amino ou acylamino; chacun de R?2, R3 et R4¿ représente hydrogène, halogène, nitro, cyano, alkyle inférieur, alcényle inférieur, alkylthio inférieur, mono, di ou trihaloalkyle (inférieur), oxoalkyle (inférieur), hydroxyalkyle (inférieur) ou carboxy éventuellement estérifié; ou R2 et R3 sont liés l'un à l'autre afin de former 1,3-butadénylène; R5 représente hydrogène ou un groupe protecteur d'imino; R6 représente alkyle inférieur; R7 représente alkyle inférieur; R8 représente carboxy éventuellement estérifié ou amidé, halogène, cyano, hydroxyalkyle (inférieur), ou alcoxy inférieur pouvant posséder un halogène; A représente alkylène inférieur; Q représente CH ou N; X représente N ou CH; et Y représente NH, O ou S; et ses sels pharmaceutiquement acceptables, utilisables comme médicament.
PCT/JP1993/000325 1991-09-12 1993-03-18 Derives d'imidazopyridine utilises en tant qu'antagonistes d'angiotensine ii WO1993019067A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5516425A JPH07508260A (ja) 1992-03-24 1993-03-18 アンジオテンシンｉｉ拮抗剤としてのイミダゾピリジン誘導体

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US07/758,688 US5215994A (en) 1990-09-25 1991-09-12 Angiotenin II antagonizing heterocyclic derivatives
GB9206417.9 1992-03-24
GB929206417A GB9206417D0 (en) 1992-03-24 1992-03-24 Heterocyclic derivatives

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996040634A1 (fr) * 1995-06-07 1996-12-19 Nippon Shinyaku Co., Ltd. Derives du pyrrole et composition medicamenteuse les renfermant
WO1999000372A1 (fr) * 1997-06-27 1999-01-07 Fujisawa Pharmaceutical Co., Ltd. Sulfamides et leur utilisation medicale
EP1136492A1 (fr) * 1998-12-04 2001-09-26 Fujisawa Pharmaceutical Co., Ltd. Composes de sulfamide et utilisations de ces derniers en tant que medicaments
US7297713B2 (en) 2005-07-29 2007-11-20 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426021A1 (fr) * 1989-10-31 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Dérivés condensés d'imidazole et procédés de leur préparation
EP0480204A1 (fr) * 1990-09-25 1992-04-15 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'imidazole, antagonistes sélectives et efficaces du récepteur d'angiotensin II

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0426021A1 (fr) * 1989-10-31 1991-05-08 Fujisawa Pharmaceutical Co., Ltd. Dérivés condensés d'imidazole et procédés de leur préparation
EP0480204A1 (fr) * 1990-09-25 1992-04-15 Fujisawa Pharmaceutical Co., Ltd. Dérivés d'imidazole, antagonistes sélectives et efficaces du récepteur d'angiotensin II

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1090617C (zh) * 1995-06-07 2002-09-11 日本新药株式会社 吡咯衍生物以及医药组合物
WO1996040634A1 (fr) * 1995-06-07 1996-12-19 Nippon Shinyaku Co., Ltd. Derives du pyrrole et composition medicamenteuse les renfermant
WO1999000372A1 (fr) * 1997-06-27 1999-01-07 Fujisawa Pharmaceutical Co., Ltd. Sulfamides et leur utilisation medicale
US6911469B2 (en) 1997-06-27 2005-06-28 Fujisawa Pharmaceutical Co., Ltd. Sulfonamide compounds and pharmaceutical use thereof
US6348474B1 (en) 1997-06-27 2002-02-19 Fujisawa Pharmaceutical Co., Ltd. Sulfonamide compounds and medicinal use thereof
EP1136492A4 (fr) * 1998-12-04 2002-03-27 Fujisawa Pharmaceutical Co Composes de sulfamide et utilisations de ces derniers en tant que medicaments
US6573274B1 (en) 1998-12-04 2003-06-03 Fujisawa Pharmaceutical Co. Ltd. Sulfonamide compounds and uses thereof as medicines
US6890934B2 (en) 1998-12-04 2005-05-10 Fujisawa Pharmaceutical Co., Ltd. Sulfonamide compounds and uses thereof as medicines
EP1136492A1 (fr) * 1998-12-04 2001-09-26 Fujisawa Pharmaceutical Co., Ltd. Composes de sulfamide et utilisations de ces derniers en tant que medicaments
US7973069B2 (en) 2004-07-14 2011-07-05 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7297713B2 (en) 2005-07-29 2007-11-20 Wyeth Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US7652062B2 (en) 2005-07-29 2010-01-26 Wyeth Llc Cyanopyrrole-phenyl amide progesterone receptor modulators and uses thereof
US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US8791141B2 (en) 2008-06-27 2014-07-29 Novartis Ag Organic compounds
US9242963B2 (en) 2008-06-27 2016-01-26 Novartis Ag Organic compounds
US11407733B2 (en) 2016-06-29 2022-08-09 Bristol-Myers Squibb Company Biarylmethyl heterocycles

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