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WO1993018030A1 - Benzimidazole derivatives as angiotensin ii antagonists - Google Patents

Benzimidazole derivatives as angiotensin ii antagonists Download PDF

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Publication number
WO1993018030A1
WO1993018030A1 PCT/JP1993/000261 JP9300261W WO9318030A1 WO 1993018030 A1 WO1993018030 A1 WO 1993018030A1 JP 9300261 W JP9300261 W JP 9300261W WO 9318030 A1 WO9318030 A1 WO 9318030A1
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WIPO (PCT)
Prior art keywords
compound
salt
pyrrolyl
benzyl
ethyl
Prior art date
Application number
PCT/JP1993/000261
Other languages
French (fr)
Inventor
Teruo Oku
Hiroyuki Setoi
Hiroshi Kayakiri
Shigeki Satoh
Takayuki Inoue
Yuki Sawada
Akio Kuroda
Hirokazu Tanaka
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 GB929204564A external-priority patent/GB9204564D0/en
Priority claimed from GB929206421A external-priority patent/GB9206421D0/en
Priority claimed from GB929208418A external-priority patent/GB9208418D0/en
Priority claimed from GB929213825A external-priority patent/GB9213825D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP5515525A priority Critical patent/JPH07507271A/en
Publication of WO1993018030A1 publication Critical patent/WO1993018030A1/en

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    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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 salt thereof which have pharmaceutically activities such as angiotensin II antagonism and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
  • 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, amino or acylamino
  • R ⁇ , R° and R are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R ⁇ and R ⁇ are linked together to form 1, 3-butadienylene, R ⁇ is hydrogen or imino-protective group,
  • R" is lower alkyl
  • R 7 is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene, Q is CH or N,
  • the object compound (I) can be prepared by the following processes. Process 1
  • R 1 R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , A, Q, X, Y and Z are each as defined above, R
  • K is lower alkoxycarbonylamino
  • R 8 is acid residue
  • 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.
  • 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
  • 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.
  • halogen means fluoro, chloro, bromo and iodo.
  • Suitable “lower 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 Cj-C ⁇ 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, hexanoyl, etc. ), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc) and the like.
  • lower alkanoyl e. g. formyl, acetyl, propionyl, hexanoyl, etc.
  • lower alkoxycarbonyl methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc
  • Suitable "mono or di or trihalo (lower) alkyl” may include chloromethyl, f luoromethyl, dif luoromethyl, dichloromethyl, trifluoromethyl, trifluoromethylpropyl, 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. carboxymethyl ester, 2-carboxyethyl ester, 3-carboxypropyl ester, etc.
  • protected carboxy-substituted-lower alkyl ester such as lower alkoxycarbonyl-substituted-lower alkyl ester (e. g. methoxycarbonylmethyl ester, tert-butoxycarbonyl ethyl ester, 2-tert-butoxycarbonyl-ethyl ester, 3-tert-butoxycarbonylpropyl ester, etc. ), protected carboxy- substituted-lower alkenyl ester such as lower alkoxycarbonyl-substituted -lower alkenyl ester (e. g. 2-isobutoxycarbonyl-2-pentenyl ester, etc.
  • protected carboxy-substituted-lower alkyl ester such as lower alkoxycarbonyl-substituted-lower alkyl ester (e. g. 2-isobutoxycarbonyl-2-pentenyl ester, etc.
  • halo (lower) alkyl ester e. g. 2-iodoethyl ester, 2, 2, 2- trichloroethyl ester, etc.
  • lower alkanoyloxy (lower) alkyl ester e. g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or
  • heptanoyloxymethyl ester octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethy l es ter, s tearoy loxymethyl es ter , nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, Kor 2)- heptanoyloxyethyl ester, Kor 2)-octanoyloxyethyl ester, Kor 2)- nonanoyloxyethyl ester, Kor 2)-decanoyloxyethyl ester, Kor 2) - undecanoyloxyethyl ester, Kor 2)
  • cycloalkylcarbonyloxy(lower)alkyl ester [e. g. cyclohexylcarbonyloxymethyl ester, Kor 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, ] heterocycliccarbonylox (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-butoxycarbony loxymethy 1 ester, Kor 2)- methoxycarbonyloxyethyl ester, Kor 2)-ethoxycarbonyloxyethyl ester, Kor
  • (lower)alkyl ester e.g. cyclohexyloxycarbonyloxymethyl ester, Kor 2)- cyc 1 o pent y 1 oxy ca rbony 1 oxye t hy 1 ester, 1 (or 2)- cyclohexyloxycarbonyloxyethyl ester, etc.]
  • (5-lower alkyl-2-oxo-l, 3- dioxol-4-yl)(lower)alkyl ester e.g.
  • 1,3-dioxolen-4-yl)(lower)alkyl ester e.g. (5-phenyl-2-oxo-l,3-dioxolen-
  • 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, Kor 2)-phthalid-3-ylideneethyl ester, etc. ), and the like.
  • suitable substituents e.g. phenyl ester, tolyl ester, t-butylpheny
  • 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-butoxycarbony 1, 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 alkylarylcarbamoyl (e. g. isobutylphenylcarbamoyl, etc. ), N-hydroxy-N-, (lower)alkylcarbamoyl(e. g. N-hydroxy-N-methylcarbamoyl, etc. ) and the like.
  • carbamoyl which may have suitable substituent(s) and may include carbamoyl, mono or di (lower) alkylcarbamoyl (e. g.
  • Suitable "substituted amino” is conventional one used in a pharmaceutical field and may include mono or di (lower) alky lamino (e. g. methy lamino, dimethylamino, ethylamino, butylamino, etc. ), lower alkenylamino (e. g. viny lamino, propenylamino, etc. ), lower alkynylamino (e. g. ethynylamino, propyny lamino, etc. ), hydroxy (lower) alkylamino (e. g. hydroxymethy lamino, hydroxyethylamino, hydroxypropy lamino etc.
  • mono or di (lower) alky lamino e. g. methy lamino, dimethylamino, ethylamino, butylamino, etc.
  • lower alkenylamino e. g. viny lamino, propeny
  • lower alkoxy (lower) alkylamino e. g. methoxymethylamino, etc.
  • mono or di (lower) alkylamino (lower) alkylamino e. g. methy laminomethylamino, dimethylaminoethy lamino, etc.
  • protected amino such as acylamino, in which acyl is as mentioned above.
  • l ower a lkoxycarb ony lam ino may inc lud e methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, and the like.
  • heterocyclic derivatives (I) of the present invention can be represented by the following chemical formula:
  • R 5 , R 6 , R 7 and A are each as defined above, RI , Rb and Ri are each lower alkyl, and RE, Ri. and Ra are each hydrogen, halogen, or lower alkyl.
  • the preferred embodiment of the compound (I) can be represented by the following formula :
  • R 5 , R 6 , R ⁇ and A are each as defined above, RI , RI and Ra are each lower alkyl, and Rb, Ro and Ra are each hydrogen, halogen, or lower alkyl.
  • the preferred compound (I) of the present invention is represented by the following formula :
  • R 3 and R 6 are each lower alkyl
  • R 7 is carboxy, lower alkoxycarbonyl, lower alkoxycarbonyl(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl, benzoyloxy(lower)alkoxycarbonyl, lower alkylpiperidylcarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkyloxycarbonyloxy(lower)alkoxycarbonyl, (5-lower alkyl-2-oxo-l, 3-dioxolen-4-yl)(lower)- alkoxycarbonyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)(lower)alkoxycarbonyl or phthalid-3
  • 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 examle, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. tri ethyltin azide, etc.), triaryltin azide (e. g. triphenyltin azide, etc.), or the like.
  • metal azide for examle, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. tri ethyltin azide, etc.), triaryltin azide (e. g. trip
  • the present reaction is usually carried out in the presence of a base such as tri(lower)alkylamine(e.g. triethyla ine, etc.), and the like, or 1, 3-dimethyl-2-imidazolidinone, and the like.
  • a base such as tri(lower)alkylamine(e.g. triethyla ine, 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.
  • 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 (
  • 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
  • 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
  • alkali metal hydrogen phosphate e.g. diisodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine
  • 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, sulfurie acid, etc.).
  • organic acid e. g. formic acid, acetic acid, propionic acid, etc.
  • inorganic acid e. g. hydrochloric acid, hydrobromic acid, sulfurie 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 salt exemplified for the compound (I).
  • 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, sulforous acid, thiosulfuric acid, sulfurie 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, l-hydroxy-2- (lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6- chloro-lH-benzotriazole, etc.
  • N-hydroxy compound e. g. N,N-dimethylhydroxylamine, l-hydroxy-2- (lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6- chloro-lH-benzotriazole, etc.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N' - dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, 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
  • 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.
  • pyridine e.g. trimethylamine, triethylamine, etc.
  • pyridine or its derivative e.g. picoline, lutidine, 4-dimethylaminopyridine, etc.
  • 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, 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-l-tolyltriazene, etc.), and the 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.
  • 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 a foresaid 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.
  • 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.
  • reaction temperature is not critical and usually carried out at room temperature, under warming or under heating.
  • the compound (I-f) 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 the. conversion reaction of carboxy to lower alkoxycarbonylamino.
  • This reaction can be carried out in a conventional manner, for example, (1) azidation, (2)Curtius type rearrangement to an isocyanate, and then (3) addition of alcohol, the details of which are explained in the below example.
  • the object compound (I) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to ring closure. This reaction is usually carried out in the presence of acetic acid.
  • This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e. g. methanol, ethanol, etc. ), chloroform, acetonitrile, acetone, nitrobenzene, N, N-dimethylf ormamide or a mixture thereof.
  • a conventional solvent which does not adversely influence the reaction such as water, alcohol (e. g. methanol, ethanol, etc. ), chloroform, acetonitrile, acetone, nitrobenzene, N, N-dimethylf ormamide or a mixture thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out at room temperature, under warming or under heating.
  • the starting compounds (I I), (I I I) 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 puri fied in a conventional manner, for example, extract ion precipitation, fractional crystallization, recrystallization, chromatography, 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 I I antagonist and effective to various angiotensin I I 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, yocardial 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, yocardial infarction, etc.
  • hyperaldosteronism e. e. g. angina pectoris, arrhythmia, yocardial 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,
  • 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, s ' tearic 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.
  • Example 2 Ethyl 2-ethoxy-3- [4- [l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxylate(223mg) was dissolved in 0. IN aqueous solution of sodium hydroxide (4. 46ml). The solution was lyophilized to afford sodium salt of ethyl 2-ethoxy-3-[4- [l-ethyl-5- methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (217mg) as an amorphous powder.
  • N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxamide(16mg) was dissolved in 0. IN sodium hydroxide (0.33ml) and water (1ml). The solution was lyophilized to afford sodium salt of N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH -tetrazol-5-yl)-2-pyrrolyl] benzyl] -4-benzimidazolecarboxamide as amorphous powder.
  • Example 7 A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (85mg), diphenylphosphoryl azide (149mg), triethylamine (0.1ml), and ethanol
  • Example 10 N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid (llmg) was dissolved in 0.01N sodium hydroxide (4ml) and lyophilized to afford disodium salt of N-methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid as white powder.
  • NMR(D 2 0, ⁇ N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid as white
  • Example 14 • The following compound was obtained according to a similar manner to that of Example 1.
  • Example 18 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 21 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 22 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 23 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 30 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 33 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 44 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 45 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 46 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 47 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 48 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 49 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 50 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 51 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 52 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 56 The following compound was obtained according to a similar manner to that of Example 3.
  • Example 60 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 61 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 64 The following compound was obtained according to a similar manner to that of Example 1.
  • Example 68 The following compound was obtained according to a similar manner to that of Example 13.
  • Example 76 The following compound was obtained according to a similar manner to that of Example 74.
  • Example 77 The following compound was obtained according to a similar manner to that of Example75.
  • Example 78 The following compound was obtained according to a similar manner to that of Example 2.
  • Example 100 The following compound was obtained according to a similar manner to that of Example 75.
  • Example 75 The following compound can be obtained according to a similar manner to that of Example 75.
  • Example 75 The following compound can be obtained according to a similar manner to that of Example 75.
  • Example 106 The following compound can be obtained according to a similar manner to that of Example 75. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
  • Example 107 The following compound can be obtained according to a similar manner to that of Example 75. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
  • Example 107 The following compound can be obtained according to a similar manner to that of Example 75. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarbox
  • Example 75 The following compound can be obtained according to a similar manner to that of Example 75.
  • Example 112 The following compound was obtained according to a similar manner to that of Example 75.
  • Example 113 The following compounds can be obtained according to a similar manner to that of Example 74.

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Abstract

The object compound of formula (I) wherein R1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R?2, R3 and R4¿ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R?2 and R3¿ are linked together to form 1,3-butadienylene, R5 is hydrogen or imino-protective group, R6 is lower alkyl, R7 is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylen, Q is CH or N, X is N or CH, Y is NH, O or S, and Z is S, SO¿2? or 0, and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

BENZIMIDAZOLE DERIVATIVES AS ANGIOTENSIN II ANTAGONISTS
TECHNICAL FIELD 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 salt thereof which have pharmaceutically activities such as angiotensin II antagonism and the like, to process for preparation thereof, to a pharmaceutical composition comprising the same and to a use of the same as a medicament.
Accordingly, 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.
DISCLOSURE OF INVENTION
The imidazole derivatives of the present invention are novel and can be represented by the formula (I):
Figure imgf000004_0001
wherein R1 is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, Rώ, R° and R are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, R^ is hydrogen or imino-protective group,
R" is lower alkyl,
R7 is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene, Q is CH or N,
X is N or CH, Y is NH, 0 or S, and Z is S, S02 or 0. According to the present invention, the object compound (I) can be prepared by the following processes. Process 1
Figure imgf000005_0001
(π)
Figure imgf000005_0002
(I) or a salt thereof Process 2
Elimination of the ester moiety
Figure imgf000006_0001
(I-a) or a salt thereof
Figure imgf000006_0002
(I-TD) or a salt thereof Process 3
Figure imgf000007_0001
(III) (IV) or a salt thereof or a salt thereof
Figure imgf000007_0002
(I) or a salt thereof Process 4
Removal of the imino-protective group
Figure imgf000008_0001
Figure imgf000008_0002
(I-d) or a salt thereof Process 5
Amidation
Figure imgf000009_0001
or its reactive derivative at the carboxy group or a salt thereof
-
Figure imgf000009_0002
(I - e) or a salt thereof Process 6
Esterification
Figure imgf000010_0001
or its reactive derivative at the carboxy group or a salt thereof
Figure imgf000010_0002
or a salt thereof Process 7
Figure imgf000011_0001
(I-d) or a salt thereof
Figure imgf000011_0002
(I-c) or a salt thereof Process 8
Conversion of carboxy to lower alkoxycarbonylamino
Figure imgf000012_0001
or its reactive derivative at the carboxy group or a salt thereof
Figure imgf000012_0002
(i - f) or a salt thereof
Figure imgf000013_0001
Figure imgf000013_0003
Figure imgf000013_0002
(I) or a salt thereof Wherein R1 R2, R3, R4, R5, Rδ, R7, A, Q, X, Y and Z are each as defined above, R| is imino-protective group, R is esterified carboxy, RS is amidated carboxy,
K is lower alkoxycarbonylamino, and R8 is acid residue.
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. );and the like, and the preferable example thereof is an acid addition salt.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "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 "lower 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 Cj-C^ 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, hexanoyl, etc. ), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc) and the like.
Suitable "mono or di or trihalo (lower) alkyl " may include chloromethyl, f luoromethyl, dif luoromethyl, dichloromethyl, trifluoromethyl, trifluoromethylpropyl, 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 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. carboxymethyl ester, 2-carboxyethyl ester, 3-carboxypropyl ester, etc. ), protected carboxy-substituted-lower alkyl ester such as lower alkoxycarbonyl-substituted-lower alkyl ester (e. g. methoxycarbonylmethyl ester, tert-butoxycarbonyl ethyl ester, 2-tert-butoxycarbonyl-ethyl ester, 3-tert-butoxycarbonylpropyl ester, etc. ), protected carboxy- substituted-lower alkenyl ester such as lower alkoxycarbonyl-substituted -lower alkenyl ester (e. g. 2-isobutoxycarbonyl-2-pentenyl ester, etc. ), mono (or di or tri) halo (lower) alkyl ester (e. g. 2-iodoethyl ester, 2, 2, 2- trichloroethyl ester, etc. ), lower alkanoyloxy (lower) alkyl ester [e. g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or
3 or 4)-acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or
3)-propionyloxypropyl ester, Kor 2)-butyryloxyethyl ester, Kor 2)- isobutyryloxyethyl ester, Kor 2)-pivaloyloxyethyl ester, Kor 2)- hexanoyloxyethyl es ter, i sobu tyryl oxyme thy l es ter, 2 - ethylbutyryloxymethyl ester, 3, 3-dimethylbutyryloxymethyl ester, 1 (or 2) -pentanoyloxyethyl ester, etc. ], higher alkanoyloxy (lower) -alkyl ester [e. g. heptanoyloxymethyl ester, octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester, lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethy l es ter, s tearoy loxymethyl es ter , nonadecanoyloxymethyl ester, eicosanoyloxymethyl ester, Kor 2)- heptanoyloxyethyl ester, Kor 2)-octanoyloxyethyl ester, Kor 2)- nonanoyloxyethyl ester, Kor 2)-decanoyloxyethyl ester, Kor 2) - undecanoyloxyethyl ester, Kor 2)~lauroyloxyethyl ester, Kor 2)- tridecanoyloxyethyl ester, Kor 2)-myristoyloxyethyl ester, Kor 2)- pentadecanoyloxyethyl ester, Kor 2)-palmitoyloxyethyl ester, Kor 2)- heptadecanyloxyethyl ester, Kor 2)-stearoyloxyethyl ester, Kor 2)- nonadecanoyl-oxyethyl ester, Kor 2)-eicosanoyloxyethyl ester, etc. ], cycloalkylcarbonyloxy(lower)alkyl ester [e. g. cyclohexylcarbonyloxymethyl ester, Kor 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, ] heterocycliccarbonylox (lower) alkyl ester such as lower alkylpiperidylcarbonyloxy(lower)alkyl ester [e.g. 1 (or 2) -Q- methylpiperidyDcarbonyloxyethyl, etc.], lower alkoxycarbonyloxy (lower) alkyl ester [e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, isopropoxycarbonyl-oxymethyl ester, tert-butoxycarbony loxymethy 1 ester, Kor 2)- methoxycarbonyloxyethyl ester, Kor 2)-ethoxycarbonyloxyethyl ester, Kor
2)-propoxycarbonyloxyethyl ester, Kor 2)-isopropoxycarbonyloxyethyl ester, Kor 2)-butoxycarbonyloxyethyl ester, Kor 2)- isobutoxycarbonyloxyethyl ester, Kor 2)-tert-butoxycarbonyloxyethyl ester, Kor 2)-hexyloxycarbonyloxy-ethyl ester, Kor 2 or 3)- methoxycarbonyloxypropyl ester, Kor 2 or 3)-ethoxycarbonyloxypropy1 ester, Kor 2 or 3)-isopropoxycarbonyloxypropyl ester, Kor 2 or 3 or 4) -ethoxycarbonyloxybutyl ester, Kor 2 or 3 or 4)-butoxycarbonyloxybutyl ester, Kor 2 or 3 or 4 or 5)-pentyloxycarbonyloxypentyl ester, Kor 2 or 3 or 4 or 5)-neopentyloxycarbonyloxypentyl ester, Kor 2 or 3 or 4 or 5 or 6)-ethoxycarbonyloxyhexyl ester, ,etc.], cycloalkyloxycarbonyloxy
(lower)alkyl ester [e.g. cyclohexyloxycarbonyloxymethyl ester, Kor 2)- cyc 1 o pent y 1 oxy ca rbony 1 oxye t hy 1 ester, 1 (or 2)- cyclohexyloxycarbonyloxyethyl ester, etc.], (5-lower alkyl-2-oxo-l, 3- dioxol-4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-propyl-2- oxo-1,3-dioxol-4-yl)ethyl ester, etc.], (5-lower alkyl-2-oxo-l,3-dioxolen -4-yl)(lower)alkyl ester [e.g. (5-methyl-2-oxo-l, 3-dioxolen-4-yl)methyl ester, (5-tert-butyl-2-oxo-l, 3-dioxolen-4-yl)methyl ester, etc. ], (5- aryl-2-oxo-l,3-dioxolen-4-yl)(lower)alkyl ester such as (5-phenyl-2-oxo-
1,3-dioxolen-4-yl)(lower)alkyl ester [e.g. (5-phenyl-2-oxo-l,3-dioxolen-
4-yl)methyl ester, etc.], 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, Kor 2)-phthalid-3-ylideneethyl ester, etc. ), and the like.
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-butoxycarbony 1, etc. ), lower alkanesulfonyl (e. g. mesyl, etc. ), arenesulfonyl (e. g. tosyl, etc. ), and the like, in which the most preferred one is trityl.
Suitable "acid residue" may include halogen (e. g. fluoro, chloro, bromo, iodo), acyloxy (e. g. acetoxy, tosyloxy, mesyloxy, etc. ) and the like.
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 alkylarylcarbamoyl (e. g. isobutylphenylcarbamoyl, etc. ), N-hydroxy-N-, (lower)alkylcarbamoyl(e. g. N-hydroxy-N-methylcarbamoyl, etc. ) and the like.
Suitable "substituted amino" is conventional one used in a pharmaceutical field and may include mono or di (lower) alky lamino (e. g. methy lamino, dimethylamino, ethylamino, butylamino, etc. ), lower alkenylamino (e. g. viny lamino, propenylamino, etc. ), lower alkynylamino (e. g. ethynylamino, propyny lamino, etc. ), hydroxy (lower) alkylamino (e. g. hydroxymethy lamino, hydroxyethylamino, hydroxypropy lamino etc. ), lower alkoxy (lower) alkylamino (e. g. methoxymethylamino, etc. ), mono or di (lower) alkylamino (lower) alkylamino (e. g. methy laminomethylamino, dimethylaminoethy lamino, etc. ), protected amino such as acylamino, in which acyl is as mentioned above.
Su itable " l ower a lkoxycarb ony lam ino " may inc lud e methoxycarbonylamino, ethoxycarbonylamino, butoxycarbonylamino, and the like.
The preferred embodiment of the heterocyclic derivatives (I) of the present invention can be represented by the following chemical formula:
Figure imgf000019_0001
(1-1)
Figure imgf000019_0002
(1-3)
wherein R5, R6, R7 and A are each as defined above, RI , Rb and Ri are each lower alkyl, and RE, Ri. and Ra are each hydrogen, halogen, or lower alkyl. Further, the preferred embodiment of the compound (I) can be represented by the following formula :
Figure imgf000020_0001
(I-4)
Figure imgf000020_0002
Figure imgf000020_0003
(1-6)
wherein R5, R6, Rτ and A are each as defined above, RI , RI and Ra are each lower alkyl, and Rb, Ro and Ra are each hydrogen, halogen, or lower alkyl.
Particularly, the preferred compound (I) of the present invention is represented by the following formula :
Figure imgf000021_0001
wherein R3 and R6 are each lower alkyl,
R7 is carboxy, lower alkoxycarbonyl, lower alkoxycarbonyl(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl, benzoyloxy(lower)alkoxycarbonyl, lower alkylpiperidylcarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkyloxycarbonyloxy(lower)alkoxycarbonyl, (5-lower alkyl-2-oxo-l, 3-dioxolen-4-yl)(lower)- alkoxycarbonyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)(lower)alkoxycarbonyl or phthalid-3-yϋdene(lower)alkoxycarbonyl.
The processes for preparing the object compound (I) of the present invention are explained in detail in the following. . Process 1 :
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 examle, alkali metal azide(e. g. , potassium azide, sodium azide etc. ), tri(lower)alkyltin azide(e. g. tri ethyltin 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. triethyla ine, 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.
The reaction temperature is not critical and the reaction is usually carried out under warming or heating, preferably under heating.
Process 2 :
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.
Process 3 :
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. 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. In case that 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.
Process 4 :
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. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g.disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and 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, sulfurie 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.
Process 5:
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 salt exemplified for the compound (I).
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, sulforous acid, thiosulfuric acid, sulfurie acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, or trichloroacetic acid, etc. ) or aromatic carboxylic acid (e. g. benzoic acid, etc.); a symmetrical acid anhydride; or an activated ester (e.g. cyano ethyl ester, methoxymethyl ester, dimethyliminomeihyl [(CH3)2N+=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4- dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresylthioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc. ), or an ester with a N-hydroxy compound (e. g. N,N-dimethylhydroxylamine, l-hydroxy-2- (lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-6- chloro-lH-benzotriazole, etc. ), and the like.
When the compound (I-b) is used in a free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N' - dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N
-ethyl-N'-(3-dimethylaminopropyl) carbodiimide, 1, l'-carbonyldi- imidazole, thionyl chloride, oxalyl chloride, lower lower alkoxycarbonyl halide [e.g. ethyl chloroformate, isobutyl chloroformate, etc.], l-(p- chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, or the like.
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. Among these solvents, hydrophilic solvents may be used in a mixture with water.
The 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.
In case that 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.
Process 6
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, 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-l-tolyltriazene, etc.), and the 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.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
Process 7
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 a foresaid 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. 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.
The reaction temperature is not critical and usually carried out at room temperature, under warming or under heating. Process 8
The compound (I-f) 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 the. conversion reaction of carboxy to lower alkoxycarbonylamino.
This reaction can be carried out in a conventional manner, for example, (1) azidation, (2)Curtius type rearrangement to an isocyanate, and then (3) addition of alcohol, the details of which are explained in the below example.
Process 9
The object compound (I) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to ring closure. This reaction is usually carried out in the presence of acetic acid.
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e. g. methanol, ethanol, etc. ), chloroform, acetonitrile, acetone, nitrobenzene, N, N-dimethylf ormamide or a mixture thereof.
The reaction temperature is not critical, and the reaction is usually carried out at room temperature, under warming or under heating.
The starting compounds (I I), (I I I) 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 puri fied in a conventional manner, for example, extract ion precipitation, fractional crystallization, recrystallization, chromatography, 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 I I antagonist and effective to various angiotensin I I mediated diseases such as hypertension (e. g. essential hypertension, renal hypertension, etc. ), heart failure, and the like.
Further, it is expected that the object compounds of the present invention are useful as therapeutical and/or preventive agents for cardiopathy (e. g. angina pectoris, arrhythmia, yocardial 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.
For therapeutic or preventive administration, 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. 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.
If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, s'tearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
While 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 following Preparations and Examples are given for the purpose of illustrating the present invention.
Preparation 1 To a solution of ethyl 2-tert-butoxycarbonylamino-3-nitro- benzoate(2. 94g) in dimethylformamide(30ml) was added sodium hydride (379mg, 60% in oil) in an ice-water bath, and the mixture was stirred at ambient temperature for 25 minutes. Therein l -ethyl-2- (4- methanesulfonyloxymethylphenyl) pyrrole-3-carbonitrile(2. 87g) was added. After stirring for 3 hours, the mixture was poured into brine and extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted by n-hexane/ethyl acetate) to afford ethyl 2-[N-tert-butoxycarbonyl-[4-(3-cyano-l-ethyl-5- methyl-2-pyrrolyl)benzyl] amino] -3-nitrobenzoate (4. 36g) as amorphous powder.
NMR(CDClg, δ : 1. 19(3H, t, J=7Hz), 1. 33(3H, t, J=7Hz), 1. 34(9H, s), 2. 28(3H, s), 3. 87(2H, q, J=7Hz), 4. 23(2H, q, J=7Hz), 4.49QH, d, J=14Hz), 4. 94(lH, d, J=14Hz), 6. 19(lH, s), 7. 24(4H, s), 7. 48QH, t, J=8Hz), 7. 87(lH, dd, J=8, 2Hz), 8. 09(lH, dd, J=8, 2Hz)
Preparation 2
To a solution of ethyl 2-[N-tert-butoxycarbonyl-[4-(3-cyano-l-ethyl
-5-methyl-2-pyrrolyl)benzyl]amino] -3-nitrobenzoate (4. 36g) in dichloromethane (5ml) was added trifluoroacetic acid (7. 5ml). After
•standing at ambient temperature for 40 minutes, the reaction mixture was evaporated in vacuo. The residue was crystallized from methanol to afford ethyl 2-[[4-(3-cyano-l-ethyl-5-methyl -2-pyrrolyl) benzyl] amino] -3
-nitrobenzoate (3. 18g) as yellow crystals. mp: 119-120°C
NMR(CDClg, δ : 1. 20C3H, t, MHz), 1. 40(3H, t, J=7Hz), 2. 30(3H, s),
3.86(2H, q, J=7Hz), 4. 23(2H, s), 4. 37(2H, q, J=7Hz), 6. 2K1H, s),
6. 74(1H, t, J=8Hz), 7- 40(4H, s), 8. OKlH. dd, J=8. 2Hz), 8. 12(lH, dd, J=8. 2Hz)
Preparation 3
A mixture of ethyl 2-[[4-(3-cyano-l-ethyl-5-methyl -2-pyrrolyl) benzyl]amino]-3-nitrobenzoate (3.18g), 10% palladium on carbon (1. Og), methanol(20ml) and dioxane(20ml) was stirred at 40°C for 7 hours under hydrogen atmosphere (4atm). After removal of the catalyst by vacuum filtration, the filtrate was evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 3-amino-2-[[4-(3-cyano-l-ethyl-5- methyl -2-pyrrolyl)benzyl]amino]benzoate (2.43g) as an amorphous powder.
NMR(CDC13, 5) : 1.19(3H,t, J=7Hz), 1.36(3H, t, J=7Hz), 2.29(3H,s), 3.87(2H,q,J=7Hz), 4.2K2H,s), 4.28(2H,q, J=7Hz), 6.21(lH,s), 6.86-6.94 (2H), 7.30-7.50(5©
Preparation 4
A mixture of ethyl 3-amino-2-[[4-(3-cyano-l-ethyl-5-methyl -2- pyrrolyl)benzyl]amino]benzoate (2.43g), tetraethoxymethaneQ.5ml), and acetic acid (24ml) was stirred at ambient temperature for 2 hours and evaporated in vacuo. The residue was crystallized from ethyl acetate-n- hexane to afford ethyl 3-[4-(3-cyanp-l-ethyl-5-methyl-2-pyrrolyl)benzyl] -2-ethoxy-4-benzimidazolecarboxylate (2.015g) as yellow crystals. mp:153-155O NHR(CDClg, 5) : 1.13C3H,t, J=7Hz), 1.24(3H,t, J=7Hz), 1.49(3H,t, J=7Hz), 2.26(3H,s), 3.80(2H,q,J=7Hz), 4.23(2H,q,J=7Hz), 4.67(2H,q>J=7Hz), 5.70(2H,s), 6.19(1H,s), 7.08C2H,d,J=8Hz), *7.19QH, t,J=8Hz), 7.28(2H,d,J=8Hz), 7.58QH,dd,J=8, 1Hz), 7.73(lH,dd,J=8, 1Hz)
Preparation 5
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl]-N-tert- butoxycarbonylamino]-3-nitrobenzoate. NMR(CDC13, 5) :1.29C3H,t,J=7.5Hz), 1.35(9H,s),3.70(3H,s),4.03-4.22(2H,m), 4.70(2H,s),7.22(2H,d,J=8.5Hz),7.30C1H,s), 7.4K2H,d, J=8.5Hz), 7.46(1H,t,J= 8.0Hz),7.9K1H,dd,J=8.0, 1.0Hz), 8.04QH,dd,J=8.0, 1.0Hz)
Preparation 6 The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl]amino]-3- nitrobenzoate. m.p.124-126.5°C NMR(CDC13, d) :1.39(3H, t, J=7.5Hz), 3.70C3H,s),4.20(2H,s),4.37C2H,q, J=7. 5Hz), 6. 73(1H, t, J=8. OHz), 7. 32(1H, s), 7. 39(2H, d, J=8. 5Hz), 7. 56(2H, d, J=8. 5Hz), 8. 02(1H, dd, J=8. 0, 1. OHz), 8. 12(1H, dd, J=8. 0, 1. OHz)
Preparation 7 The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[[4-(2-bromo-4-cyano-l-methyl-3-pyrrolyl)benzyl] amino]-3-nitrobenzoate.
NMR(CDC13, δ ) :1.30(3H,t, J=7.5Hz), 3.70C3H, s),4.24(2H,q, J=7.5Hz),4.32(2H, s),6.90-7.0K2H,m),7.31-7.42(1H,m),7.33(1H,s),7.36(2H,d,J=8.5Hz),7.52(2H, d,J=8.5Hz)
Preparation 8
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-bromo-4-cyano-l-methy1-3-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate .
NMR(CDC13, 5) :1.22(3H,t,J=7.5Hz), 1.50(3H,t, J=7.5Hz), 3.68(3H,s),4.2K2H, q,J=7.5Hz),4.72(2H,q,J=7.5Hz),5.68C2H,s),7.05(2H,d, J=8.5Hz), 7.20(1H, t,J= 8.OHz), 7.30(1H,s),7.44(2H,d,J=8.5Hz), 7.58(1H,dd, J=8.0, 1.OHz),7.79(1H,dd, J=8.0, 1.OHz)
Preparation 9
The following compound was obtained according to.a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(4-chloro-2-cyano-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate.
NMR(CDClg, <5) :1.35(9H,s), 1.35(3H,t, J=7.5Hz),4.24(2H,q, J=7.5Hz),4.48C1H, d,J=14.5Hz),4.93(1H,d,J=14.5Hz),6.89(1H,d,J=l.OHz),7.02(1H,d,J=l.OHz),7. 3K4H,s), 7.50(1H, t,J=8.OHz),7.89(1H,dd, J=8.0, 1. OHz),8.09(1H,dd, J=8.0, 1. OHz)
Preparation 10
The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2- [ [4-(4-chloro-2-cyano-l-pyrrolyl) benzyl] amino] -3- nitrobenzoate.
m. p. 131-133 NMR(CDC13, δ ) : 1. 39(3H, t, J=7. 5Hz)4. 23(2H, s), 4. 35(2H, q, J=7. 5Hz), 6. 75(1H, t, J=8. OHz), 6. 90QH, d, J=l. OHz), 7. 05QH, d, J=l. OHz), 7. 39(2H, d, J=8. 5Hz), 7. 48 (2H, d, J=8. 5Hz), 7. 99(1H, dd, J=8. 0, 1. OHz), 8. 16(1H, dd, J=8. 0, 1. OHz)
Preparation 11 The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2- [[4-(4-chloro-2-cyano-l-pyrrolyl)benzyl] amino] nitrobenzoate.
NMR(CDC13, S) :1. 32(3H, t, J=7. 5Hz), 3. 92(2H, s), 4. 27 (2H, q, J=7. 5Hz), 6. 86-6. 94 (3H, m), 7.02QH, d, J=l. OHz), 7. 32-7. 42(1H, m), 7. 35(2H, d, J=9. OHz), 7. 47 (2H, d, J =9. OHz)
Preparation 12
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(4-chloro-2-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzi idazolecarboxylate . m.p.151-154'O
NHR(CDC13, S) : 1. 27 (3H, t, J=7. 5Hz), 1. 9(3H, t, J=7. 5Hz), 4. 23C2H, q, J=7. 5Hz), 4. 70(2H, q, J=7. 5Hz), 5. 72(2H, s), 6. 88(1H, d, J=l. 5Hz), 6. 97QH, d, J=l. 5Hz), 7. 14
(2H, d, J=9. OHz), 7. 2K1H, t, J=8. 5Hz), 7. 3K2H, d, J=9. OHz), 7. 62C1H, dd, J=8. 5, 1.
0Hz), 7. 77(lH, dd, J=8. 5, 1. 0Hz)
Preparation 13 The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-5-methyl-l-pyrroly1) benzyl]amino]-3-nitrobenzoate.
NMR(CDC13, δ ) : 1.35(9H,s), 1.36(3H,t,J=8Hz), 2.15(3H,s), 4.28Q.5HX2, q 2, J=8Hz each), 4.45 (IH,d, J=15Hz), 5. OlQH.d,J=15Hz), 6.05C1H,d, J= 4Hz), 6. 48(lH, d, J=4Hz), 7. 15(2H, d, J=9Hz), 7. 29 (2H, d, J=9Hz), 7. 48( lH, t, J =7Hz), 7. 86(lH, dd, J=7, 1Hz), 8. 10(1H, dd, J=7, 1Hz)
Preparation 14 The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate.
NMR(CDC13, δ ) : 1.39(3H, t,J=7.5Hz), 2.14(3H, s), 2.35(3H,s), 4.25 (2H,s), 4.37(2H,q,J=7.5Hz), 6.06( IH,d, J=5Hz), 6.76QH, t, J=8Hz), 6.86QH, d,J=5Hz), 7.28(2H,d,J=9Hz), 7.45(2H,d,J=9Hz), 7.99(lH,dd, J=8 and 1Hz), 8.13(1H,dd, J=8 and 1Hz) Preparation 15
The following compound was obtained according to a similar manner to that of Preparation.3.
Ethyl 3-amino-2-[[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]amino] benzoate.
NMR(CDC13, δ ) : 1.34(3H,t,J=7.5Hz), 2.12(3H,s), 3.97(2H,br,s), 4. 25(2H,br,s), 4.27(2H,q,J=7.5Hz), 6.07(lH,d,J=5Hz), 6.49(lH,br,s), 6.79-6. 96(3H,m), 7.25(2H,d, J=9Hz), 7.39(lH,dd, J=7 and 5Hz), 7,49(2H,s, J=9Hz) Preparation 16
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-5-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate.
NMR(CDC13, δ ) : 1.25(3H, t, J=7.5Hz), 1.48(3H,t, J=7.5Hz), 2.09(3H, s), 4.22(2H,q,J=7.5Hz), 4.66 (2H,q, J=7.5Hz), 5.74(2H,s), 6.04(lH,d,J= 5Hz), 6.84(lH,d,J=5Hz), 7.03-7.25(5H,m), 7.60C1H,dd, J=7.5 and 1Hz), 7.75 (IH,dd,J=7.5 and 1Hz)
Preparation 17
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-[4-(2-cyano-4-methyl-l-pyrrolyl]benzyl]-N-tert- butoxycarbonyl-amino]-3-nitrobenzoate. NMR(CDC13, δ ) : 1.33(3H,t, J=7.5Hz), 1.79(9H,s), 2.13C3H, s), 4.15 -4.29(2H,m). 4.53QH,d, J=14.5Hz), 4.88QH, d, J=14.5Hz), 6.80(1H,d, J=0. 5Hz), 6.87QH, d,J=0.5Hz), 7.28(4H,s), 7.49QH,t, J=8.OHz). 7.90(lH,dd. J= 8.0.0.5Hz). 8.09(IH,dd, J=8.0,0.5Hz) Preparation 18
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:124.5-128
NMR(CDC13, δ ) : 1.39(3H,t,J=7.5Hz), 2.13(3H,s), 4.21(2H,s), 4.35 (2H,q,J=7.5Hz), 6.75(lH,t, J=8.0Hz), 6.82(1H,d, J=0.5Hz), 6.88QH,d, J=0. 5Hz), 7.41(4H,s), 8.OOQH.dd, J=8.0, 1. OHz), 8.14QH,dd, J=8.0,1.0Hz)
Preparation 19
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. NMR(CDC13, δ ) : 1.32C3H,t,J=7.5Hz), 2.13(3H,s), 3.94(2H,bs), 4.21 (2H,bs), 4.26(2H,q,J=7.5Hz), 6.45(lH,bs), 6.80(lH,d, J=0.5Hz), 6.84(lH,d, J=0.5Hz), 6.86-6.93(2H,m), 7.31-7.40(3H,m), 7.43(2H,d, J=8.5Hz)
Preparation 20 The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2- ethoxy-4- benzimidazolecarboxylate. mp:152.5-154.5 °C NHR(CDClg, δ ) : 1.26(3H,t,J=7.5Hz), 1.49(3H,t, J=7.5Hz), 2.1K3H, s), 4.24(2H,q,J=7.5Hz), 4.67C2H,q,J=7.5Hz), 5.70(2H,s), 6.79(2H,s), 7.09 (2H,d, J=8.5Hz), 7.19QH,t,J=8.0Hz), 7.3K2H, d,J=8.5Hz), 7.60(lH,dd, J=8. 0,0.5Hz), 7.74(lH,dd, J=8.0,0.5Hz)
Preparation 21 The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]-N-tert- butoxycarbonylamino]-3-nitrobenzoate. N R(CDClg, δ ) : 1.34(3H, t, J=7.5Hz), 1.37(9H,s), 4.15-4.33(2H,m), 4.56(lH,d,J=14.5Hz), 4.91(lH,d, J=14.5Hz), 6.36QH,d, J=4.5Hz), 6.9K1H, d, J=4.5Hz), 7.19(2H,d,J=8.5Hz), 7.34(2H,d, J=8.5Hz), 7.49QH,t,J=8.OHz), 7.90(lH,!dd, J=8.0, 0.5Hz), 8.09(1H,dd, J=8.0, 0.5Hz)
Preparation 22
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:105-109 V
NMR(CDClg, δ ) : 1.39(3H,t, J=7.5Hz), 4.29(2H,d, J=5. OHz), 4.35C2H, q,J=7.5Hz), 6.38(lH,d,J=4.5Hz), 6.76QH, t, J=8. OHz), 6.93(lH,d, J=4.5Hz), 7.34(2H, d,J=8.5Hz), 7.48C2H,d, J=8.5Hz), 8.01(IH,dd, J=8.0, 0.5Hz), 8.14 (IH,dd,J=8.0, 0.5Hz), 8.91(lH,bt, J=5. OHz)
Preparation 23
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]amino] benzoate.
NMR(CDClg, δ ) : 1.34(3H,t,J=7.5Hz), 3.93(2H,bs), 4.24(2H,s), 4.27 (2H,q,J=7.5Hz), 6.37(lH,d, J=4.5Hz), 6.49(lH,bs), 6.84-6.95(3H,m),.7.29 (2H, d,J=8.5Hz), 7.40(lH,dd,J=5.5,4.5Hz), 7.51(2H,d, J=8.5Hz)
Preparation 24
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-bromo-5-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. . NMR(CDC13, δ ) : 1.23(3H,t,J=7.5Hz), 1.46(3H,t, J=7.5Hz), 4.20(2H, q,J=7.5Hz), 4.64(2H,q, J=7.5Hz), 5.75(2H,s), 6.35(lH,d, J=4.5Hz), 6.89C1H, d, J=4.5Hz), 7.13C2H,d,J=8.5Hz), 7.23C2H,d, J=8.5Hz), 7.18-7.30(lH,m), 7. 61(IH.dd,J=8.0,0.5Hz),7.74(1H, dd,J=8.0,0.5Hz)
Preparation 25
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-[4-(4-bromo-2-cyano-l-pyrrolyl)benzyl]-N- tert- butoxycarbonylamino]-3-nitrobenzoate. NMR(CDC13, δ ) : 1.35(3H.t,J=7.5Hz), 1.35(9H,s), 4.17-4.3K2H,m), 4.49QH,d,J=14.5Hz), 4.93(lH,d, J=14.5Hz), 6.94QH,d, J=0.5Hz), 7.07QH,d, J=0.5Hz), 7.28(2H,d,J=8.5Hz), 7.32(2H,d,J=8.5Hz), 7.50QH,t, J=8.0Hz), 7. 88(IH,dd, J=8.0, 0.5Hz), 8.09(IH,dd,J=8.0,0.5Hz)
Preparation 26
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(4-bromό-2-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. mp:119-123
NMR(CDC13, δ ) : 1.39(3H, t, J=7.5Hz), 4.23(2H,s), 4.36(2H,q, J=7. 5Hz), 6.76QH,t,J=8.OHz). 6.97QH, d,J=0.5Hz), 7.09(lH.d,J=0.5Hz). 7.40 (2H.d. J=8.5Hz), 7.47(2H,d,J=8.5Hz), 7.99QH,dd,J=8.0, 0.5Hz), 8.16QH, dd,J=8.0,0.5Hz)
Preparation 27
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[[4-(4-bromo-2-cyano-l-pyrrolyl)- benzyl]amino]-3-nitrobenzoate.
NMR(CDC13, δ ) : 1.33(3H,t,J=7.5Hz), 3.93(2H,bs), 4.22(2H,bs), 4. 26(2H,q,J=7.5Hz). 6.48QH,bs). 6.82-6.93(2H,m), 6.94QH,d,J=0.5Hz), 7. 04QH,d, J=0.5Hz), 7.29-7.41(lH,m), 7.35(2H,d, J=8.5Hz), 7.47(2H,d. J=8. 5Hz) Preparation 28 The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(4-bromo-2-cyano-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. mp:148-152 °C
NMR(CDC13, δ ) : 1.27(3H, t,J=7.5Hz), 1.47(3H,t, J=7.5Hz), 4.23(2H, q,J=7.5Hz), 4.67(2H,q.J=7.5Hz), 5.72(2H,s), 6.95(lH,d, J=0.5Hz), 7. OKIH, d, J=0.5HZ), 7.13C2H,d,J=8.5Hz), 7.20QH,t,J=8.OHz), 7.3K2H,d,J=8.5Hz), 7.6K1H,dd, J=8.0, 0.5Hz), 7.76QH,dd, J=8.0, 0.5Hz)
Preparation 29
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(5-chloro-2-cyano-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate.
NMR(CDC13, δ ) : 1.32(3H, t, J=7.5Hz), 1.35(9H,s). 4.06-4.35(2H,m), , 4.57(lH,d,J=14Hz), 4.89(lH,d, J=14Hz), 6.26(lH,d, J=5Hz), 6.90(lH,d,J= 5Hz), 7.2K2H.d,J=9Hz), 7.35(2H,d.J=9Hz), 7.49(lH,t, J=8Hz), 7.90(lH,dd, J=8,lflz), 8.09(lH,dd,J=8,lHz) Preparation 30
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[[4-(5-chloro-2-cyano-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate. (This product was used for the next step without further purification)
Preparation 31
The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[[4-(5-chloro-2-cyano-l-pyrrolyl)benzyl]amino] benzoate.
NMR(CDC13, δ ) : 1.32(3H,t,J=7.5Hz), 3.94(2H,br.s), 4.24(2H,s), 4. 27(2H,q,J=7.5Hz), 6.25(lH,d,J=5Hz), 6.50QH.br.s), 6.83-6.95(3H,m), 7.30 (2H,d,J=9Hz), 7.39QH,dd,J=6,5Hz), 7.50(2H,d,J=9Hz), Preparation 32
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(5-chloro-2-cyano-1-pyrroly1)benzyl]-2-ethoxy-4- benzimidazolecarboxylate. mp:102-104 °C
NMR(CDC13, δ ) : 1. 25(3H, t, J=7. 5Hz), 1.46(3H, t, J=7. 5Hz), 4. 20(2H, q, J=7.5Hz), 4. 65(2H, q, J=7. 5Hz), 5. 75(2H, s), 6. 24QH, d, J=5Hz), 6. 89(lH, d, J=5Hz), 7. 06-7. 30(5H, m), 7. 60QH, dd, J=8, 0. 5Hz), 7. 76QH, dd, J=8, 0. 5Hz).
Preparation 33
A mixture of ethyl 3-amino-2-[4-(3-cyano-l-ethyl-5-methyl-2- pyrrolyl)benzyl]aminobenzoate(937.4mg), trimethyltin azideQ.44g) and xylene (lθml)was stirred at 125 °C for 40 hours and concentrated in vacuo. The residue was dissolved in a mixture of methanol and chloroform Q:4v/v90(10ml).Then silica gel(2g) was added to the solution and the mixture was stirred at room temperature for an hour. The suspension was filtered through a celite pad,and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (methanol-chloroform)to give ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3-(lH
-tetrazol-5-yl)-2-pyrrolyl]benzyl]amino]benzoate (777.4mg)as pale brown amorphous.
NHR(CDC13, δ ) : 1. 13 (3H, t, J=7.5Hz), 1. 30(3H, t, J=7. 5Hz), 2. 33(3H. s), 3. 73(2H. q. J=7. 5Hz), 4. 21(2H, q, J=7. 5Hz), 4. 24(2H, s), 6. 67QH, s), 6.
90-6. 99(2H, m), 7. 19-7. 37(5H, )
Preparation 34
Ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl] benzyl] amino] benzoa te (1. 38g), triethylamine(859. 0 μDand dichloromethane (14ml)were combined under nitrogen atmosphere. Then trityl chloride (906. 7mg)was added to the solution at 0 °C. The reaction mixture was stirred at room temperature for 1. 5 hours, and di luted in dichloromethane. The organic solution was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by a silica gel column chromatography(n-hexane-ethy acetate)to afford pale yellow amorphous which solidified with isopropyl ether to give ethyl 3- amino-2-[[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2-pyrrolyl] benzyl]amino]benzoate(824. Omg) as pale yellow solid, mp:141-145 V NMR(CDC13, δ ) : 1.1K3H,t,J=7.5Hz), 1.33(3H, t, J=7.5Hz), 2.32C3H, s), 3.78(2H,q,J=7.5Hz), 3.92(2H,bs), 4.17(2H,bs), 4.30(2H,q,J=7.5Hz), 6.40(lH,bs), 6.53(lH,s), 6.87(1H,d,J=5. OHz), 6.88(1H,d,J=4.5Hz), 6.92- 7.04(6H,m), 7.16-7.34 (13H,m), 7.39QH,dd, J=5.0.4.5Hz)
Preparation 35
The following compound was obtained according to a similar manner to that of Preparation 4. Ethyl 3-[4-(3-cyano-l-ethyl-5-methyl-2-pyrrolyl)benzyl]-2-propyloxy-4 -benzimidazolecarboxylate. mp:168-169.5 V
NMR(CDC13, δ ) : 0.98C3H,t, J=7.5Hz). 1.13(3H. t, J=7.5Hz). 1.25(3H. t,J=7.0Hz), 1.85(2H,sextet, J=7.0Hz). 2.27(3H,s), 3.79(2H,q,J=7.5Hz), 4.
23(2H, q. J=7.5Hz). 4.56C2H, t, J=7. OHz). 5. 70(2H. s), 6. 19QH, s). 7. 09C2H, d. J=8. 5Hz), 7. 18(lH, t. J=8.0Hz), 7.27(2H, d, J=8. 5Hz), 7. 59(1H, dd, J=8. 0, 0. 5Hz), 7. 73(lH, dd, J=8. 0, 0. 5Hz)
Preparation 36
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4, 5-dimethyl-l- pyrrolyl)benzyl]amino]-3-nitrobenzoate.
NMR (CDClg, δ : 1.36(9H,s), 1.36(3H, t, J=7.5Hz), 2.06(6H,s), 4.17-4.34 (2H,m), 4.45QH,d.J=14.5Hz). δ.OOQH.d.J=14.5Hz), 6.71(lH,s), 7.12(2H,d, J=8.0Hz), 7.29(2H,d,J=8.0Hz), 7.49C1H, t, J=7.5Hz), 7.87(1H, dd, J=7.5, 0. 5Hz), 8.11(lH,dd,J=7.5,0.5Hz)
Preparation 37
The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2-[N-[4-(2-cyano-4, 5-dimethyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate
NMR (CDClg, d) : 1.39(3H, t,J=7.5Hz), 2.06(6H,s), 4.25C2H,d, J=5.OHz), 4. 37(2H,q,J=7.5Hz), 6.73QH,s), 6.77QH.t, J=8.OHz), 7.26(2H,d, J=8.5Hz), 7. 44(2H,d,J=8.5Hz), 8.OKIH,dd,J=8.0,0.5Hz), 8.16(lH,dd,J=8.0,0.5Hz), 8.90 (IH,bt,J=5. OHz)
Preparation 38
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[N-[4-(2-cyano-4,5-dimethyl-l-pyrrolyl)benzyl]amino] benzoate
NMR (CDClg, 5) : 1.33(3H,t,J=7.5Hz), 2.03(3H,s), 2.06(3H,s), 4.25(2H,d,
J=4.0Hz), 4.28(2H,q,J=7.5Hz), 6.72(lH,s), 6.90(lH,d, J=5.5Hz), 6.91(lH,d, J=4.5Hz). 7.2K2H,d,J=8.5Hz), 7.39QH,dd,J=5.5,4.5Hz), 7.48C2H,d,J=8.5Hz)
Preparation 39
The following compound was obtained according to a similar manner to that of Preparation 4. Ethyl 3-[4-(2-cyano-4, 5-dimethyl-l-pyrrolyl)benzyl] 2-ethoxy-4- benzimidazolecarboxylate mp : 121-122.5°C
NMR (CDClg, 5) : 1.25(3H. t, J=7.5Hz), 1.48(3H. t, J=7.5Hz), 1.98(3H,s), 2.
04(3H,s). 4.22(2H.q.J=7.5Hz), 4.65(2H.q, J=7.5Hz). 5.73(2H,s), 6.71(lH,s). 7.10(2H.d.J=8.5Hz). 7.16(2H, d, J=8.5Hz), 7.20QH, t, J=8. OHz), 7.60(lH,dd,
J=8.0, 0.5Hz), 7.76(1H, dd, J=8.0, 0.5Hz)
Preparation 40
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(5-chloro-2-cyano-4-methyl-l- pyrrolyl)benzyl]amino]-3-nitrobenzoate
NMR (CDClg, 5) : 1.3K3H, t. J=7.5Hz). 1.37(9H,s). 2.09(3H.s). 4.09-4.30
(2H,m), 4.59QH, d, J=14.5Hz), 4.86QH, d, J=14.5Hz), 6.78(lH,s), 7.20(2H,d. J=&5Hz), 7.33(2H,d. J=8.5Hz), 7.49QH, t,J=8.0Hz), 7.90QH, dd, J=8.0, 0. 5Hz), 8. 09C1H, dd, J=8. 0, 0. 5Hz)
Preparation 41
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[N-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-3 -nitrobenzoate
NMR (CDClg, δ ) : 1.39(3H.t,J=7.5Hz), 2.10(3H, s), 4.27(2H,s), 4.36C2H,q, J=7.5Hz), 6.76GH,t, J=8.OHz), 6.79(lH,s), 7.33(2H,d, J=8.5Hz), 7.47(2H,d, J=8.5Hz), 8.02QH,dd, J=8.0, 0.5Hz), 8.16(lH,dd, J=8.0, 0.5Hz)
Preparation 42
The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[N-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl] amino]benzoate
NMR (CDClg, <5) : 1.34(3H,t.J=7.5Hz). 2.10(3H,s), 3.94(2H.bs). 4.24(2H, bs), 4.28(2H,q,J=7.5Hz), 6.47(lH,bs), 6.79(lH,s), 6.84-6.95(2H,m), 7.29 (2H,d,J=8.5Hz), 7.40(lH,dd,J=5.5,4.5Hz), 7.5K2H,d,J=8.5Hz)
Preparation 43
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(5-chloro-2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4 -benzimidazolecarboxylate
NMR (CDClg, <5) : 1.23(3H,t,J=7.5Hz), 1.47(3H, t, J=7.5Hz), 2.09(3H.s), 4. 20(2H,q,J=7.5Hz), 4.66(2H.q,J=7.5Hz), 5.75(2H,s). 6.77QH.s), 7.12(2H,d, J=8.5Hz), 7.19(lH,t, J=8. OHz), 7.2K2H, d, J=8.5Hz), 7.60(1H, dd. J=8.0, 0. 5Hz). 7.74(lH.dd.J=8.0,0.5Hz)
Preparation 44
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(4-chloro-2-cyano-5-methyl-l- pyrrolyDbenzyl]amino]-3-nitrobenzoate NMR (CDClg, δ~) : 1.35(9H,s), 1.37(3H,t, J=7.5Hz), 2.13(3H,s), 4.21-4.38 (2H,m), 4.41(lH,d,J=14.5Hz), 5.OδQH.d,J=14.5Hz), 6.82QH,s), 7.13(2H,d, J=8.5Hz), 7.3K2H,d, J=8.5Hz), 7.50(1H, t, J=8. OHz), 7.87(1H,dd, J=8.0, 0. 5Hz), 8.12(lH,dd,J=8.0,0.5Hz)
Preparation 45
The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[N-[4-(4-chloro-2-cyano-5-methyl-l-ρyrroly1)benzyl]amino]-3 -nitrobenzoate
NMR (CDClg, S) : 1.39(3H. t,J=7.5Hz), 2.12(3H,s). 4.29(2H,d,J=5.OHz), 4. 36(2H,q,J=7.5Hz), 6.77QH,t, J=8.OHz), 6.85(lH,s), 7.29(2H,d, J=8.5Hz), 7. 49(2H,d,J=8.5Hz), 7.99(lH,dd,J=8.0, 0.5Hz), 8.16QH,dd, J=8.0,0.5Hz), 8.91 (IH,bt.J=5.OHz)
Preparation 46
The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[N-[4-(4-chloro-2-cyano-5-methyl-l-pyrrolyl)benzyl] amino]benzoate
NMR (CDClg, 5) : 1.34C3H,t,J=7.5Hz), 2.10C3H,s), 3.95(2H,bs). 4.24(2H. s). 4.26(2H,q,J=7.5Hz), 6.84(lH,s), 6.90QH,d,J=5.5Hz), 6.9K1H,d, J=4. OHz), 7.22(2H,d. J=8.5Hz), 7.39(1H.dd,J=5.5,4. OHz), 7.50(2H,d,J=8.5Hz)
Preparation 47
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(4-chloro-2-cyano-5-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4 -benzimidazolecarboxylate NMR (CDClg, 5) : 1.25(3H,t,J=7.5Hz), 1.48(3H,t,J=7.5Hz), 2.04(3H,s), 4. 22(2H,q,J=7.5Hz), 4.66(2H,q,J=7.5Hz), 5.74(2H,s), 6.81(lH,s), 7.14(4H,s), 7.20QH,t,J=8.OHz), 7.6K1H,d,J=8. OHz), 7.76(lH,d, J=8.OHz)
Preparation 48 . A mixture of ethyl 4-(2-cyano-4-vinyl-l-pyrrolyl)benzoate (864.6mg), platinum(IV) oxide(90mg) and ethyl acetate(8.6ml) was stirred at room temperature for 2 hours under hydrogen atmosphere (atmospheric pressure). After removal of the catalyst by vacuum filtration, the filtrate was evaporated in vacuo. The residue was purified by a silica gel column chromatography(ethyl acetate-hexane) to give ethyl 4-(2-cyano-4-ethyl-l- pyrrolyl)benzoate (833.6mg). mp : 64-69°C
NMR (CDClg, δ : 1.23(3H,t,J=7.5Hz), 1.42(3H, t,J=6.5Hz), 2.57(2H,q,J=7. 5Hz), 4.4K2H,q,J=6.5Hz), 6.90(lH,d, J=0.5Hz), 6.94(lH,d,J=0.5Hz), 7.53 (2H,d,J=9. OHz), 8, 18(2H,d, J=9.OHz)
Preparation 49
Ethyl 4-(2-cyano-4-ethyl-l-pyrrolyl)benzoate(830mg) , lithium borohydride (134. 6mg) and tetrahydrofuran (8. 3ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 2 hours. After cooled to room temperature, saturated aqueous ammonium chloride was added to the mixture at 0°C, and stirred at room temperature for 2 hours, and ethyl acetate and water were added to the mixture. The separated organic layer was washed with water and sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted by a mixture of ethy l ace ta te and n -hexane ( 1 : 2 ) t o g i ve 4-e thy l- l - ( 4 - hydroxymethylphenyl)-2-pyrrolecarbonitrile (644. 9mg). NMR (CDClg, 5 ) : 1. 23(3H, t, J=7. 5Hz), 1. 84(1H, t, J=5. 5Hz), 2. 53C2H, q, J=7. 5Hz), 4. 76(2H, d, J=5. 5Hz), 6. 84QH, d, J=0. 5Hz), 6. 89(1H, d, J=0. 5Hz), 7. 43 (2H, d, J=7. 5Hz), 7.50 (2H, d, J=9.5Hz)
Preparation 50
4-Ethyl-l-(4-hydroxymethylphenyl)-2-pyrrolecarbonitrile (622. 3mg) was dissolved in dichloromethane (6. 2ml) under nitrogen atmosphere. Triethylamine (460ml) was added to the mixture, and cooled to -30 °C. Then, methanesulfonyl chloride (223. 5 # 1) was added at -30CC for 5 minutes. The reaction mixture was stirred at -10°C for 15 minutes and poured into water. The organic layer was washed with water (2 times), sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo to give 4-ethyl-l-(4- methanesulf onyloxymethylphenyl) -2-pyrrolecarbonitrile (860.9mg) . NMR (CDClg, δ) : 1.23(3H, t, J=7.5Hz), 2.53(2H, q, J=7.5Hz), 3.01(3H,s), 5. 29(2H,s), 6.86(lH,d,J=0.5Hz), 6.90(1H. d, J=0.5Hz), 7.49(2H, d, J=9.5Hz), 7.57 (2H, d, J=9.5Hz)
Preparation 51
The following compound was obtained according to a similar manner to that of Preparation 1. Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-ethyl-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate
NMR (CDClg, 5) : 1.2K3H,t, J=7.5Hz), 1.33(3H,t, J=7.5Hz), 1.36(6H,s), 1. 58(3H,s), 2.52(2H,q,J=7.5Hz), 4.14-4.32(2H,m), 4.53QH,d, J=14.5Hz), 4.90 QH,d,J=14.5Hz), 6.82QH,d,J=0.5Hz), 6.87QH,d, J=0.5Hz), 7.29(4H,s), 7.49 QH,d,J=0.5Hz), 7.90(lH,dd,J=7.5,0.5Hz), 8.09C1H,dd,J=7.5,0.5Hz)
Preparation 52
The following compound was obtained according to a similar manner to that of Preparation 2. Ethyl 2-[N-[4-(2-cyano-4-ethyl-l~pyrrolyl)benzyl]amino]-3~ nitrobenzoate
NMR (DMSO-dg, 5) : 1.22C3H, t, J=7.5Hz), 1.39(3H, t, J=7.5Hz), 2.53(2H,q,J =7.5Hz), 4.21(2H,s), 4.37(2H,q, J=7.5Hz), 6.75QH, t, J=8. OHz), 6.85QH,d,J =0.5Hz), 6.89(lH,d,J=0.5Hz), 7.42(4H,s), 8.01(lH,dd, J=8.0, 0.5Hz), 8.13 (IH, dd, J=8.0, 0.5Hz)
Preparation 53
The following compound was obtained according to a similar manner to that of Preparation 3. Ethyl 3-amino-2-[N-[4-(2-cyano-4-ethyl-l-pyrrolyl)benzyl]amino] benzoate
NMR (CDClg, £) : 1.22C3H, t, J=7.5Hz), 1.33(3H,t,J=7.5Hz), 2.53(2H,q, J=7. 5Hz), 4.2K2H,bs), 4.27(2H,q, J=7.5Hz), 6.82-6.93(4H,m), 7.33-7.4K3H,m), 7.45(2H,d,J=9.0Hz) Preparation 54
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-4-ethyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazole-4-carboxylate mp : 121-124°C
NMR (CDClg, 5) : 1.20C3H, t,J=7.5Hz), 1.26(3H, t, J=7.5Hz), 1.48(3H, t, J=7. 5Hz), 2.50(2H,q,J=7.5Hz), 4.27(2H,q, J=7.5Hz), 4.66(2H,q, J=7.5Hz), 5.70 (2H,s), 6.79(lH,d,J=0.5Hz), 6.8K1H,d, J=0.5Hz), 7.10(2H,d, J=9.5Hz), 7.20 (IH,t,J=7.5Hz), 7.3K2H,d,J=9.5Hz), 7.60(lH,dd, J=7.5Hz), 7.76(1H,dd, J=7. 5Hz)
Preparation 55
Bromo(ethyl)triphenylphosphorane(3.3g) was dissolved in dimethyl sulfoxide (20ml) under nitrogen atmosphere, and sodium hydride (355.5mg) was added to the solution at room temperature. The mixture was stirred at 50°C for an hour. After cooled to room temperature, ethyl 4-(2-cyano
-4-formyl-l-pyrrolyl)benzoate (2. Og) was added to the solution, and stirred at room temperature for 16 hours. Water and ethyl acetate were added to the mixture and separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (2 times) and brine, and dried over magnesium sulfate, and concentrated in vacuo to give a mixture of ethyl 4-[2-cyano-4-[(Z)-l-propenyl]-l- pyrrolyl]benzoate and ethyl 4-[2-cyano-4-[(E)-l-propeηyl]-l-pyrrolyl] benzoate (1.42g).
NMR (CDClg, δ ) : 1.4K3H, t, J=7.5Hz), 1.82-1.97(3H,m), 4.42(2H,q, J=7. 5Hz), 5.63-6.29(2H,m), 7.01-7.17(2H,m), 7.49-7.6K2H,m), 8.12-8.25(2H,m)
Preparation 56 The following compound was obtained according to a similar manner to that of Preparation 48.
Ethyl 4-(2-cyano-4-propyl-l-pyrrolyl)benzoate NMR (CDClg, 5) : 0.97(3H,t, J=7.5Hz), 1.4K3H,t,J=7.5Hz), 1.62(2H, sextet, J=7.5Hz), 2.47(2H,t,J=7.5Hz), 4.41(2H,q,J=7.5Hz), 6.88QH,d,J=0.5Hz), 6. 94(lH,d,J=0.5Hz), 7.53(2H,d, J=9.5Hz), 8.19(2H,d,J=9.5Hz) Preparation 57
The following compound was obtained according to a similar manner to that of Preparation 49. 1-(4-Hydroxymethylpheny1)-4-propyl-2-pyrrolecarbonitrile
NMR (CDClg, <5) : 0.98(3H,t,J=7.5Hz), 1.62(2H,sextet, J=7.5Hz), 1.83(lH,t, J=5.5Hz), 2.46(2H,t,J=7.5Hz), 4.76(2H,d, J=5.5Hz), 6.83QH,d,J=0.5Hz), 6. 88C1H,d,J=0.5Hz), 7.42(2H,d,J=9.5Hz), 7.50(2H,d, J=9.5Hz)
Preparation 58
The following compound was obtained according to a similar manner to that of Preparation 50.
1-(4-Methanosulfonyloxy ethylphenyl)-4-propy1-2-pyrrolecarbonitrile NMR (CDClg, 5) : 0.97(3H,t,J=7.5Hz), 1.6K2H,sextet, J=7.5Hz), 2.47C2H, t,J=7.5Hz), 3.0K3H,t), 5.29(2H,s), 6.85QH,d, J=0.5Hz), 6.90QH,d, J=0. 5Hz), 7.49(2H,d,J=9.5Hz), 7.57(2H,d,J=9.5Hz)
Preparation 59
The following compound was obtained according to a similar manner to that of Preparation 1.
Ethyl 2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-propyl-l-pyrrolyl) benzyl]amino]-3-nitrobenzoate
NMR (CDClg, δ : 0.97(3H,t,J=7.5Hz), 1.33(3H, t, J=7.5Hz), 1.36(6H,s), 1.
49-1.72(2H,m), 1.58(3H,s), 2.46(2H, t, J=7.5Hz), 4.13-4.31(2H,m), 4.53QH, d,J=14.5Hz), 4.89(lH,d,J=14.5Hz), 6.8K1H,d,J=0.5Hz), 6.86(lH,d,J=0.5Hz),
7.29(4H,s), 7.48C1H,t,J=7.5Hz), 7.89(1H,dd,J=7.5, 0.5Hz), 8.09(1H,dd,J=7.
5,0.5Hz)
Preparation 60 The following compound was obtained according to a similar manner to that of Preparation 2.
Ethyl 2-[N-[4-(2-cyano-4-propyl-l-pyrrolyl)benzyl]amino]-3- nitrobenzoate
NMR (CDClg, δ : 0.97(3H,t,J=7.5Hz), 1.40(3H,t,J=7.5Hz), 1.61(2H, sextet, J=7:5Hz), 2.47(2H,t,J=7.5Hz), 4.21(2H,s), 4.37(2H,q, J=7.5Hz), 6.75(lH,t, J=7. 5Hz), 6. 83C1H. d, J=0. 5Hz), 6. 89(1H, d, J=0. 5Hz), 7. 42(4H, s), 8. OOQH, dd, J=7. 5, 0. 5Hz), 8. 13(1H, dd, J=7. 5, 0. 5Hz)
Preparation 61 The following compound was obtained according to a similar manner to that of Preparation 3.
Ethyl 3-amino-2-[N-[4-(2-cyano-4-propy1-1-pyrrolyl)benzyl] aminobenzoate
NMR (CDClg, δ ) : 0.96(3H,t, J=7.5Hz), 1.32(3H,t, J=7.5Hz), 1.61(2H,sextet, J=7.5Hz), 2.47(2H,t, J=7.5Hz), 3.9K2H,bs), 4.2K2H,bs), 4.26(2H,q, J=7. 5Hz), 6.47(lH,bs), 6.80QH,d,J=0.5Hz), 6.85(1H,d, J=0.5Hz), 6.87-6.92C2H, m), 7.30-7.48(5H,m)
Preparation 62 The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-4-propyl-l-pyrrolyl)benzyl]-2-ethoxy-4- benzimidazolecarboxylate mp : lOδ.δ-HO'C NMR (CDClg, 5) : 0.94(3H, t,J=7.5Hz), 1.27(3H, t, J=7.5Hz), 1.49(3H, t, J=7.
5Hz), 1.59(2H,sextet,J=7.5Hz), 2.43(2H,t,J=7.5Hz), 4.25(2H,q, J=7.5Hz), 5.
70(2H,s), 6.80(2H,s), 7.09(2H,d, J=9.5Hz), 7.19C1H,t, J=7.5Hz), 7.30(2H,d,
J=9.5Hz), 7.60QH,dd,J=7.5,0.5Hz), 7.74QH,dd,J=7.5,0.5Hz)
Preparation 63
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-propoxy-4- benzimidazolecarboxylate mp : 106-108°C
NMR (CDClg, δ : 0.99C3H, t, J=7.5Hz), 1.27(3H, t, J=7.5Hz), 1.77-1.98C2H, m), 2.10(3H,s), 4.24(2H,q, J=7.5Hz), 4.56(2H, t, J=7.5Hz), 5.7K2H,s), 6.78 (2H,s), 7.11(2H,d,J=9.0Hz), 7.19(1H,t, J=7.5Hz), 7.30(2H,d, J=9. OHz), 7.61 (IH,dd, J=7.5,0.5Hz), 7.75(1H,dd,J=7.5, 0.5Hz) Preparation 64
The following compound was obtained according to a similar manner to that of Preparation 4.
Ethyl 3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-methoxy-4- benzimidazolecarboxylate
Figure imgf000048_0001
NMR (CDClg, .,$) : 1.26(3H, t,J=7.5Hz), 2.12(3H,s), 4.23C2H,q, J=7.5Hz), 4. 25(3H,s), 5.70(2H,s), 6.79(2H,s). 7.10(2H,d.J=9.OHz), 7.20QH,t, J=8.OHz), 7.30(2H,d,J=9.OHz), 7.61(IH,dd,J=8.0,0.5Hz), 7.77(IH,dd, J=8.0, 0.5Hz)
Preparation 65
The following compound was obtained according to a similar manner to that of Example 3.
2-[N-tert-butoxycarbonyl-N-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl] amino]-3-nitrobenzoic acid
NMR (CDClg, δ : 1.29(6H,s), 1.53(3H,s), 2.09(3H,s), 4.45-5.00(2H,m), 6. 75(lH,s), 6.81(lH,s), 7.09-7.29(4H,m), 7.38(lH,bt,J=8.OHz), 7.83(lH,bd,J =8.OHz), 8.08QH,bd,J=8.0Hz)
Preparation 66
The following compound was obtained according to a similar manner to that of Example 7.
3-(tert-Butoxycarbon lamino)-2-[N-tert-butoxycarbonyl-N-[4-(2-cyano -4-methyl-l-pyrrolyl)benzyl]amino]-1-nitrobenzene NMR (CDClg, £) : 1.35(9H,s), 1.4K9H,s), 2.12(3H,s), 4.33QH,d, J=14. 5Hz). 5.04QH,d,J=14.5Hz), 6.59(lH,bs), 6.80(lH.d,J=0.5Hz), 6.84(lH,d,J= 0.5Hz), 7.19-7.46(lH,m), 7.34(4H,s), 7.60QH,dd, J=8.0,0.5Hz), 8.33QH,dd, J=8.0,0.5Hz)
Preparation 67
The following compound was obtained according to a similar manner to that of Preparation 2.
3-Amino-2-[N-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]amino]-1- nitrobenzene NMR (CDClg, 5) : 2.13(3H,s), 4.10(2H,bs), 4.28(2H,d, J=8.OHz), 6.07(lH,t, J=8. 0Hz), 6. 80(lH, d, J=0. 5Hz), 6. 86(lH, d, J=0. 5Hz), 6. 89-7. 0K2H, m), 7. 37 (4H, s), 7. 40(1H, dd, J=6. 5, 2. OHz)
Preparation 68 The following compound was obtained according to a similar manner to that of Preparation 4.
3-[4-(2-cyano-4-methyl-l-pyrrolyl)benzyl]-2-ethoxy-4-nitro- benzimidazole mp : 166-169°C NMR (CDClg, 5) : 1.53(3H, t,J=7.5Hz), 2.12(3H, s), 4.72(2H,q, J=7.5Hz), 5. 57(2H,s), 6.78QH,d, J=0.5Hz), 6.81(lH,d,J=0.5Hz), 7.10(2H,d, J=9. OHz), 7. 23(1H, t, J=8. OHz), 7.3K2H,d, J=9. OHz), 7.73(1H,dd, J=8.0,0.5Hz), 8.82QH, dd, J=8.0, 0.5Hz)
Example 1
A mixture of ethyl 3- [4-(3-cyano.-l-ethyl-5-methyl-2-pyrrolyl) benzyl] -2-ethoxy-4-benzimidazolecarboxy late (2. 356g), trimethyltin azide (3. 19g) and xylene (24ml) was stirred at 120 °C for 39 hours and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted by dichloromethane/methanol) twice to give ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]- 4-benzimidazolecarboxylate(l. 87g) as an amorphous powder. NMR(CDClg, δ) : 1. 12C3H, t, J=7Hz), 1. 3K3H, t, J=7Hz), 1. 52(3H, t, J=7Hz), 2. 33(3H, s), 3. 73(2H, q, J=7Hz), 4. 24(2H, q, J=7Hz), 4. 70(2H, q, J=7Hz), 5. 69(2H, s), 6. 63(lH, s), 7. 10(2H, d, J=8Hz), 7. 1K1H, t, J=8Hz), 7. 16(2H, d, J=8Hz), 7. 56(lH, dd, J=8, 1Hz), 7. 73(1H, dd, J=8, 1Hz).
Example 2 Ethyl 2-ethoxy-3- [4- [l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxylate(223mg) was dissolved in 0. IN aqueous solution of sodium hydroxide (4. 46ml). The solution was lyophilized to afford sodium salt of ethyl 2-ethoxy-3-[4- [l-ethyl-5- methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (217mg) as an amorphous powder. NMR(D20, δ : 0.76(3H, t,J=7Hz), 0.96C3H,t, J=7Hz), 1.37(3H, t,J=7Hz), 2.17(3H,s), 3.38(2H,q,J=7Hz), 3.98(2H,q, J=7Hz), 4.50(2H,q, J=7Hz), 5.35(2H,s), 6.30(lH,s), 6.79(2H,d, J=8Hz), 6.97(2H,d, J=8Hz), 7.03(lH,t, J=8Hz), 7.28(1H,d,J=8Hz), 7.58C1H,d,J=8Hz).
Example 3
A mixture of ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol- 5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (465mg), IN aqueous solution of sodium hydroxide (2.8ml) and ethanol (7.5ml) was stirred at 80 °C for 1 hour. The reaction mixture was evaporated in vacuo, and the residue was dissolved in water (6ml). The pH value of the solution was adjusted to 4 with IN hydrochloric acid. Resulting precipitate was collected, washed with water and recrystallized from ethanol to afford 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5- yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (330mg) as colorless crystals, mp 2U-212°C
NMR(DMS0-d6, <5) : 0.98(3H,t, MHz), 1.39(3H,t, J=7Hz), 2.28(3H,s), 3.69(2H,q,J=7Hz), 4.60(2H,q, J=7Hz), 5.69(2H,s), 6.32(lH,s), 7.02(2H,d, J=8Hz), 7.18QH,t,J=8Hz), 7.24(2H,d, J=8Hz), 7.5K1H,dd, J=8, 1Hz). 7.68QH,dd,J=8,lHz).
Example 4
The following compound was obtained according to a similar manner to that of Example2.
Disodium salt of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5- yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylie acid. NMR(D20, 5) : 1.0K3H,t,J=7Hz), 1.43(3H,t, J=7Hz), 2.32(3H,s), 3.74(2H,q,J=7Hz), 4.58(2H,q, J=7Hz), 5.60(2H,s), 6.37(lH,s), 7.10-7.33(6H), 7.54(lH,dd, J=8, 1Hz).
Example 5
To a mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)
-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (47mg), triethylamine (0.3ml), and tetrahydrofuran(2ml) was added ethyl chloroformate(0.1ml) dropwise in an ice-water bath. The mixture was stirred for.15 minutes in an ice-water bath and then for 1 hour at ambient temperature. An 40% aqueous solution of methylamine (0.05ml) was added therein and stirring was continued for 3 hours at ambient temperature. After removal of the solvent, the residue was purified by preparative thin layer chromatography to afford N-methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH- tetrazol-5-yl)pyrrolyl] benzyl] -4-benzimidazolecarboxamide (18mg) as colorless glass
NMR(CDClg-CDgOD) : , 1.13(3H, t, MHz), 1.52(3H, t, MHz), 2.32(3H,s),
2.64(3H,s), 3.78(2H,q,MHz), 4.68(2H,q, MHz), 5.50(2H,s), 6.36(lH,s), 6.98(2H, d, J=8Hz), 7.10-7.23(4H), 7.60(1H, dd, J=8, 2Hz).
Example 6
N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl] benzyl] -4-benzimidazolecarboxamide(16mg) was dissolved in 0. IN sodium hydroxide (0.33ml) and water (1ml). The solution was lyophilized to afford sodium salt of N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH -tetrazol-5-yl)-2-pyrrolyl] benzyl] -4-benzimidazolecarboxamide as amorphous powder. NMR(D20, <5):
0.78(3H, t, MHz), 1.45(3H, t, MHz), 2.13(3H, s), 2.47(3H,s), 3.58(2H,q,MHz), 4.6K2H, q, MHz), 5.42(2H,s), 5.80(lH,s), 6.81(2H,d, J=8Hz),
6.94(2H, d, J=8Hz), 7.17-7.31 (2H), 7.67C1H, dd, J=8, 2Hz).
Example 7 A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (85mg), diphenylphosphoryl azide (149mg), triethylamine (0.1ml), and ethanol
(2ml) was heated under reflux for 3 hours. After removal of the solvent under reduced pressure, the residue was purified by preparative thin layer chromategraphy to afford 2-ethoxy-4-ethoxycarbonylamino-3-[4-[l- ethyl-5-methyl-3-QH-tetrazol-5~yl)-2-pyrrolyl] benzyl] benzimidazole (41mg) as amorphous powder. NMR(CDClg, <5 ) :
1. 12(3H, t, J=7Hz), 1. 16(3H, t, MHz), 1. 51(3H, t, MHz), 2. 32(3H, s), 3. 65-3. 90 (4H),
4. 70(2H, q, MHz), 5. 47(2H, s), 6. 68(lH, s), 6. 93-7.40C6H), 7. 53QH, d, J=8Hz).
Example 8 2-Ethoxy-4-ethoxycarbonylamino-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol- 5-yl)-2-pyrrolyl]benzyl]benzimidazole (41mg) was dissolved in 0. IN sodium hydroxide (0.8ml) and water (1ml). The solution was filtered through a milipor filter and lyophilized to yield sodium salt of 2-ethoxy-4- ethoxycarbonylamino-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]benzimidazole as amorphous powder. NMR(D20, 5):
0.85(3H,t,MHz), 1.10(3H,t, MHz), 1.32(3H,t,MHz), 2.19(3H,s), 3.5K2H,q,MHz), 3.90(2H,q,MHz), 4.48(2H,q,MHz), 5.2K2H,s), 6.31QH,s), 6.82-7.17(6H), 7.40(lH,d, J=8Hz).
Example 9
The following compound was obtained according to a similar manner to that of Example 5. N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid. NMR(CDClg-CDgOD):
1.10(3H,t,MHz), 1.50(3H,t,MHz), 2.32(3H,s)„ 3.75C3H,t,MHz), 3.80(3H,s), 4.67(2H,q,MHz), 5.65(2H,s), 6.48(lH,s), 7.09(2H,d, J=8Hz), 7.17-7.33(3H), 7.59(1H,dd,J=8, 1Hz), 7.75(lH,dd,J=8,lHz).
Example 10 ' ■ N-Methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid (llmg) was dissolved in 0.01N sodium hydroxide (4ml) and lyophilized to afford disodium salt of N-methyl-2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarbohydroxamic acid as white powder. NMR(D20, δ :
0.74(2.2H,t,MHz), 0.98(0.8H, t, MHz),
1.36(2.2H,t,MHz), 1.40(0.8H,t,MHz),
2.17(2.2H,s), 2.30(0.8H,s), 3.40(1.4H,q, MHz), 3.49(3H,s), 3.69(0.6H,q,MHz), 4.49(1.4H,q,MHz), 4.56(0.6H,q, MHz), 5.32(1.4H,s), 5.58(0.6H,s), 6.31(0.7H, s), 6.37(0.3H,s), 6.78(2H,d,J=8Hz), 6.96(2H,d, J=8Hz), 7.02C1H,t, J=8Hz), 7.13-7.33(2H), 7.51-7.6K1H).
Example 11
A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (158mg), triethylamine (0.06ml), trityl chloride (lOOmg), and dichloromethane (3ml) was stirred at ambient temperature for 3 hours. The mixture was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) to afford 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-4-bezimidazolecarboxylic acid (121mg) as white solid. mp : 188-190°C NMP(CDC13, <5): 1.03(3H,t,MHz), 1.47(3H,t,MHz), 2.27(3H,s), 3.70(2H,q,MHz), 4.67(2H,q,MHz), 5.63(2H,s), 6.44(lH,s), 6.92(2H,d,J=8Hz), 6.96-7.34Q8H), 7.50(lH,dd,J=8,lHz), 7.73(1H,dd, J=8, 1Hz)
Example 12
A mixture of 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(l-trityl-lH-tetrazol-
5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (llδmg), cyclohexyl 1-iodoethyl carbonate (465mg), potassium carbonate (72mg), and dimethylformamide (3ml) was stirred at ambient temperature for 3 hours. The mixture was portioned into a mixture of ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sultate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane- ethyl acetate) to afford 1-cyclohexyloxycarbonyloxyethyl 2-ethoxy-3-[4-[l -ethyl-5-methyl-3-(l-trityl-lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-4- benzimidazolecarboxylate (74mg) as pale yellow oil. NMR(CDC13, 5): 0.82-2.00(19H), 2.29(3H,s), 3.68(2H,q,MHz), 4.54-4.72C3H), 5.58(lH,d,J=15Hz), 5.74QH,d,J=15Hz), 6.50(lH,s), 6.86-7.03(8H), 7.11-7.33Q2H), 7.60(1H,dd,J=8, 1Hz), 7.76(1H,dd, J=8, 1Hz)
Example 13
A mixture of 1-cyclohexyloxycarbony loxyethyl 2-ethoxy-3-[4-[l-ethyl-5
' -methyl-3- (l-trityl-lH-tetrazol-5-yl) -2-pyrrolyl] benzyl] -4- benzimidazolecarboxylate (74mg), silica gel (370mg), and methanol (7.4ml) was heated under reflux for 18 hours. After removal of the silica gel by vacuum filtration, the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromathane - methanol) and pulverized with water to afford 1-
(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[l-ethyl-5-methyl-3-(lH- tetrazol-5-yl)-2-pyrrolyl]benzyl]-4-benzimidazolecarboxylate (39mg) as amorphous powder.
NMR(CDC13, 5) : 1. 05-1. 97Q9H), 2. 32(3H, s), 3. 73(2H, q, MHz), 4. 55QH, m), 4. 70(2H, q, MHz), 5. 68QH, d, M5Hz), 5. 80(lH, d, J=15Hz),
6. 63(lH, s), 6. 88QH, q, J=5Hz), 7. 10-7. 30 (5H), 7. 66(1H, dd, J=8, 1Hz), 7. 78(1H, dd, J=8, 1Hz)
Example 14 • The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3-pyrrolyl]benzyl] -2-ethoxy-4-benzimidazolecarboxylate. mp: 177-181°C NMR(DMS0-dg, δ ) : 1. 13(3H, t, M. 5Hz), 1. 4K3H, t, M. 5Hz), 3. 70(3H, s),
4. 19C2H, q, J=7. 5Hz), 4. 62C2H, q, J=7. 5Hz), 5. 53(2H, s), 6. 9K2H, q, J=7. 5Hz), 7. 16 (2H, d,J=8. 5Hz), 7. 18(1H, t, J=8. OHz), 7. 46(1H, dd, J=8. 0, 1. OHz), 7. 62(1H, s), 7. 70 (IH, dd, J=8. 0, 1. OHz)
Example 15
The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of ethyl 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylate. NMR(DMS0-d6, δ ) :1.17(3H,t,M.5Hz), 1.42(3H,t,M.5Hz),3.6K3H,s),
4.20(2H,q,M.5Hz),4.6K2H,q,J=7.5Hz),5.50(2H,s),6.80(2H,q,J=8.5Hz),7.18 (IH,t, J=8.OHz),7.18(1H,s),7.27(2H,d, J=8*.5Hz),7.43(1H,dd,J=8.0,0.5Hz), 7.69 (IH,dd,J=8.0,0.5Hz)
Example 16
The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[2-Bromo-l-methyl-4-(lH-tetrazol-5-yl)-3-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid. mp:178-180<€
NMR(DMS0-d6, δ ) :1.40(3H,t,M.5Hz),3.69(3H,s),4.59(2H,q,M.5Hz),
5.66(2H,s), 6.97(2H,d,J=8.5Hz), 7.16(2H,d, J=8.5Hz), 7.19(1H,t, J=8. OHz), 7.53 (IH,dd,J=8.0,0.5Hz),7.61(IH,s),7.67(1H,dd,J=8.0,0.5Hz),
Example 17
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[2-bromo-l-methyl-4-(lH-tetrazol-5-yl)-3- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. • NMR(D20, δ) :1.40(3H, t, J=7.5Hz), 3.67C3H, s),4.53(2H,q,J=7.5Hz), 5.52 (2H, s), 7. 04(2H, d, J=8. 5Hz), 7. 12(2H, d, J=8. 5Hz), 7. 2K1H, t, J=8. OHz), 7. 24-7. 37 (2H, m), 7. 5K1H, dd, J=8. 0. 1. OHz)
Example 18 ..The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate. mp:149-153°C NMR(DMS0-dg, δ ) :1.18(3H,t,M.5Hz), 1.4K3H, t, M.5Hz),4.19(2H,q, M.5Hz),4.6K2H,q,M.5Hz).5.56(2H,s),6.87(1H.d, J=l. OHz), 6.97(2H,d, J=9. OHz),7.20(IH,t,J=8.OHz),7.2K2H,d,J=9.OHz),7.39(IH,d, J=l.OHz),7.49(IH,dd, J=8.0,0.5Hz),7.70(IH,dd,J=8.0,0.5Hz)
Example 19
The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of ethyl 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate. NMR(DMSO-dg, δ ) :1.17(3H,t,M.5Hz), 1.4K3H,t,M.5Hz),4.19(2H,q, M.5Hz),4.6K2H,q,J=7.5Hz),5.5K2H,s),6.33(1H,d,J=l.OHz).6.85(2H,d,J=8. 5Hz),7.03(1H,d,J=l.OHz),7.09(2H,d,J=8.5Hz),7.20(1H,t,J=8.OHz),7.47(IH,dd, J=8.0,0.5Hz),7.69(IH,dd, J=8.0,0.5Hz)
Example 20
The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid. mp:182-184eO
NMR(DMS0-d6, δ ) :1.38(3H,t,J=7.5Hz),4.59(2H,q,J=7.5Hz),5.69(2H,s), 6.90(IH,d,J=l.OHz), 7.04(2H,d, J=8.5Hz),7.18(IH, t,J=8.OHz), 7.23(2H,d, J=8. 5Hz).7.44(1H,d,J=l.OHz),7.56(IH,d,J=8.OHz).7.69(1H,d.J=8.OHz)
Example 21 The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[4-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. NMR(D20, δ ):1.40(3H, t,J=7.5Hz),4.56(2H,q, J=7.5Hz), 5.53(2H,s), 6.68(1H, d, J=l.OHz), 6.98(2H,d, J=8.5Hz), 7.06(2H,d, J=8.5Hz), 7.1K1H,d, J=l. OHz), 7.22 (IH,t,J=8. OHz), 7.28(1H,dd, J=8.0, 1. OHz), 7.53C1H,dd, J=8.0, 1. OHz)
Example 22 The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl] -4-benzimidazolecarboxylate.
NMR(CDC13, δ ) : 1.30(3H, t,M.5Hz), 1.49(3H,t, M.5Hz), 2.07(3H,s), 4.22(2H,q, M.5Hz), 4.65 (2H,q,M.5Hz), 5.69(2H,s), 6.17(1H,d, J=5Hz), 6.99-7.25(6H,m), 7.55(1H,dd,M, 0.5Hz). 7.66QH, dd,M,0.5Hz)
Example 23 The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of ethyl 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate.
NMR(DMS0-d6, δ ) : 1.15(3H,t,M.5Hz), 1.40(3H,t, M.5Hz), 1.92(3H,s), 4.14(2H,q,M.5Hz), 4.61 (2H,q,M.5Hz), 5.53(2H,s), 5.91(lH,d, J=5Hz), 6.21(lH,d,J=5Hz), 6.85(2H,d,J=9Hz), 7.04(2H,d, J=9Hz), 7.20(lH,d,M.5Hz), 7.44QH,dd,M.5, 1Hz), 7.70QH,dd, M.5, 1Hz)
Example 24
The following compound was obtained according to a similar manner to that of Example 3.
2-Ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid. mp:141-144 °C
NMR(DMS0-d6, δ ) : 1.38C3H, t,M.5Hz), 1.95(3H,s), 4.60(2H,q,M.5Hz), 5.70(2H,s), 6.66QH,d, J=5Hz), 6.80QH,d, J=5Hz), 7.04 (2H,d,J=9Hz), 7.16(2H,d, J=9Hz), 7.19(lH,d, J=8Hz), 7.52QH.dd,J=8, 0.5Hz), 7.69(IH,dd,J=8,0.5Hz)
Example 25
The following compound was obtained according to a similar manner to that of Example 2. Disodium salt of 2-ethoxy-3-[4-[5-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid. mp:>285°C(dec.)
NMR(DMS0-d6, δ ) : 1.28(3H,t.J=7.5Hz). 1.9K3H.s). 4.47(2H.q.M.5Hz), 5.85-5.95(3H,m), 6.20(lH,d. J=5Hz). 6.96(lH.d.J=8Hz). 6.98(2H,d.J=9Hz),
7.11(2H,d.J=9Hz). 7.30QH,dd,J=8.0.5Hz), 7.35QH, dd,J=8,0.5Hz)
Example 26
The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate. mp:161-162.5 °C
NMR(DMS0-dg, δ ) : 1.17(3H, t,M.5Hz), 1.4K3H,t, • J=7.5Hz), 2.10(3H,s), 4.19C2H,q,M.5Hz). 4.6K2H.q,M.5Hz). 5.56(2H.s). 6.69(lH.d, J=0.5Hz), 6.94(2H,d,J=8.5Hz), 6.97QH.d.J=0.5Hz). 7.13(2H,d,J=8.5Hz), 7. 19(IH,t,J=8.OHz), 7.48(IH, dd, J=8.0, 0.5Hz), 7.70(IH,dd, J=8.0, 0.5Hz)
Example 27
The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[4-Methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid. - mp:183-184 °C NMR(DMS0-dg, δ ) : 1.39C3H,t,M.5Hz), 2.09(3H,s), 4.59(2H,q,M.5Hz), 5.67(2H,s). 6.70(lH,d, J=0.5Hz), 6.99(lH,d,J=0.5Hz), 7.01(2H,d, J=8.5Hz), 7.15(2H,d, J=8.5Hz), 7. 19(1H,t, J=8.OHz), 7.54QH, dd, J=8.0, 0.5Hz), 7.68(lH,dd, J=8.0, 0.5Hz)
Example 28
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C
NMR(DMSO-dg, δ ) : 1.35(3H,t, M.5Hz), 2.03(3H,s), 4.48(2H,q,M.5Hz), 5.86(2H,s), 6.14(lH,d,
J=0.5Hz), 6.66(lH,d,J=0.5Hz), 6.95QH,t,J=8.OHz), 6.96(2H,d,J=8.5Hz), 7. 06(2H,d,J=8.5Hz). 7.28GH, dd, J=8.0, 0.5Hz), 7.3K1H,dd, J=8.0, 0.5Hz)
Example 29
The following compound was obtained according to a similar manner to that of Example 1. Ethyl 3-[4-[5-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate.
NMR(CDC13, δ ) : 1.29(3H,t, M.5Hz), 1.47(3H,t, M.5Hz), 4.21(2H,q,M.5Hz), 4.59(2H,q, M.5Hz), 5.68(2H,s), 6.48(lH,d, J=4.5Hz), 7.04(2H,d,
J=8.5Hz), 7.11-7.23(4H,m), 7.55(lH,dd, J=8.0, 0.5Hz), 7.63(lH,dd,J=8.0,0.5Hz)
Example 30 The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[5-Bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:172.5-177 °C • NMR(DMSO-dg, δ ) : 1.37(3H. t,J=7.5Hz), 4.59(2H,q, M.5Hz), 5.72(2H,s), 6.59QH,d, J=4.5Hz), 6.93 (IH,d, J=4.5Hz), 7.07(2H, d,J=8.5Hz), 7.14-7.28C3H, ), 7.56(1H,dd, J=8.0, 0.5Hz), 7.69(lH,dd, J=8.0, 0.5Hz)
Example 31
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[5-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C
NMR(DMS0-dg, δ ) : 1.29(3H,t,M.5Hz), 4.48(2H,q, J=7.5Hz), 5.93(2H,s), 6.30(lH.d.J=4.OHz).
6.40(lH,d,J=4.0Hz), 6.99QH, t.J=8.0Hz), 7.02(2H, d,J=8.5Hz), 7.16(2H,d, J=8.5Hz), 7.30QH,dd.J=8.0, 0.5Hz), 7.36(lH,dd,J=8.0,0.5Hz)
Example 32
The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4-bromo-2-(lH-tetrazol-5-yl)-1-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate. mp:157-160 °C NMR(DMS0-dg, δ ) : 1.17C3H, t,M.5Hz), 1.40(3H,t,
M.5Hz), 4.I9(2H,q,M.5Hz), 4.62(2H,q.M.5Hz), 5.57(2H,s), 6. 90QH,d,J=l.OHz), 6.97(2H,d, J=8.5Hz), 7.20QH,t,J=8.0Hz), 7.21(2H,d,J=8.5Hz), 7.42(lH,d, J=l.OHz), 7. 49QH,dd.J=8.0.0.5Hz), 7.71QH,dd.J=8.0,0.5Hz)
Example 33 The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[4-Bromo-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:176-180 - NMR(DMS0-d6, δ ) : 1.39(3H,t,M.5Hz). 4.59(2H,q, M.5Hz), 5.68(2H,s), 6.83(lH,d,M.5Hz), 7.01(2H,d.J=8.5Hz), 7.18(1H,t,J=8. OHz), 7.20C2H, d,J=8.5Hz), 7.39(lH,d. M.5Hz), 7.55QH.dd,J=8.0, 0.5Hz), 7.69(lH,dd,J=8.0, 0.5Hz) Example 34 The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[4-bromo-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C NMR(DMSO-dg, δ ) : 1.34(3H,t,M.5Hz), 4.48(2H,q, J=7.5Hz), 5.88(2H.s), 6.34(1H,d, J=0.5Hz),
6.96QH,t,J=8.OHz), 7.02(2H,d,J=8.5Hz), 7.07(1H, d,J=0.5Hz). 7.10(2H,d, J=8.5Hz). 7.29(lH,dd,J=8.0, 0.5Hz), 7.32QH,dd, J=8.0, 0.5Hz)
Example 35
The following compound was obtained according to a similar manner to that of Example 1. .
Ethyl 3-[4-[5-chloro-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylate. NMR(DMSO-dg, δ ) : 1.13(3H,t, J=7.5Hz), 1.38(3H,t,
M.5Hz), 4.14(2H,q,M.5Hz), 4.60(2H,q, M.5Hz), 5.60(2H,s), 6. 50(1H,d, J=5Hz), 6.9K1H,d, J=5Hz),
7.00(2H,d.J=9Hz). 7.10-7.37(3H,m), 7.46(1H,d, J=8Hz). 7.70(lH,d.J=8Hz)
Example 36
The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[5-Chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy-4- benzimidazolecarboxylic acid, mp:156-161 °C
NMR(DMSO-dg, δ ) : 1.46(3H.t,M.5Hz), 4.59(2H,q, M.5Hz), 5.71(2H,s), 6.5K1H,d, J=5Hz), 6.95QH, d, J=5Hz), 7.08(2H,d,J =9Hz), 7.14-7.30(3H,m), 7.56(1H,d,J=8Hz), 7.70(1H,d,J=8Hz) Example 37
The following compound was obtained according to a similar manner to that of Example 2. Disodium salt of 3-[4-[5-chloro-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid. mp:>280°C(dec.)
NMR(DMS0-dg, δ ) : 1.29(3H, t,J=7.5Hz), 4.47(2H,q, M.5Hz), 5.92(2H,s), 6.22(lH,d, J=5Hz), 6.46QH, d, J=5Hz), 6.98QH,t,J =8Hz). 7.04(2H,d,J=9Hz). 7.16C2H,d, J=9Hz), 7.31(lH,br.d.J=8Hz), 7.35QH, br.d,J=5Hz)
Example 38
A mixture of ethyl 3-amino-2-[[4-[l-ethyl-5-methyl-3~(l-trityl-lH- tetrazol-5-yl)-2-pyrrolyl]benzyl]amino]benzoate(803. Img),acetic acid (12ml) and tetramethyl orthocarbonate(186.5μl)was stirred at room temperature for 2 hours under nitrogen atmosphere. Then water(lml) and chloroform(6ml) were added to the mixture,and stirred at 50°C for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by a silica gel column chromatography(ethyl acetate)to give ethyl 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-methoxy-4-benzimidazolecarboxylate (529.7mg)as pale orange amorphous
NMR(CDC13, δ ) : 1.1K3H,t, M.5Hz), 1.30(3H,t, M.5Hz), 2.32(3H,s), 3.72(2H,q, M.5Hz), 4.23(2H,q,J=7.5Hz), 4.29(3H,s), 5.68(2H,s). 6.64(lH,s), 7.08(2H.d,J=8.5Hz), 7.2KlH,t, J=7.5Hz), 7.26(2H,d, J=8.5Hz), 7.58(lH.dd, M.5. 0.5Hz). 7.76(lH.dd,J=7.5,0.5Hz)
Example 39
The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2- methoxy-4-benzimidazolecarboxylic acid. mp:175-178 °C
NMR(DMS0-dg, δ ) : 0.98(3H,t,M.5Hz), 2.27(3H,s), 3.69(2H,q,M.5Hz), 4.18(3H,s), 5.70(2H,s), 6.32(lH,s), 7.00(2H.d,J=8.5Hz), 7.19(lH.t, J=8.0Hz), 7.25(2H,d,J=8.5Hz)i 7.53(1H,dd, J=8.0, 0.5Hz), 7.69C1H.dd,J=8.0.0.5Hz)
Example 40
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-methoxy-4-benzimidazolecarboxylic acid. mp:>280°C
NMR(DMS0-dg. δ ) : 1.00(3H,t,J=7.5Hz), 2.29(3H,s), 3.73(2H,q,M.5Hz), 4.19(3H,s), 5.59(2H,s), 6.37(1H,s), 7.12(2H,d.J=8.5Hz), 7.19(2H.d, ' J=8.5Hz), 7.23(lH,t,J=8.0Hz), 7.3K1H,dd, J=8.0, 0.5Hz), 7.56(IH,dd,J=8.0,0.5Hz)
Example 41
The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl] -2-propyloxy-4-benzimidazolecarboxylate. NMR(CDC13, δ ) : 1.02(3H, t, M.5Hz), 1. ll(3H,t, M.5Hz), 1.3K3H,t, M.5Hz), 1.90(2H,sextet, M.5Hz). 2.3K3H.S), 3.7K2H,q, M.5Hz),
4.24(2H,q,J=7.5Hz), 4.57(2H, t, M.5Hz), 5.68(2H, s), .6.6K1H,s), 7.10 (2H,d,J=8.5Hz), 7.20(lH,t, J=8.0Hz), 7.25(2H,d,J=8.5Hz), 7.56(lH,dd, J=8.0, 0.5Hz), 7.72(lH,dd,J=8.0,0.5Hz)
Example 42
The following compound was obtained according to a similar manner to that of Example 3. 3-[4-[l-Ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2-pyrrolyl]benzyl]-2- propyloxy-4-benzimidazolecarboxylic acid. mp:135-144 °C
NMR(DMSO-dg, δ ) : 0.89(3H, t,M.0Hz), 0.98(3H,t, M.5Hz), 1.76(2H,sextet, M.OHz), 2.28(3H,s),
3.69(2H,q,J=7.5Hz), 4.49(2H,t. M.OHz), 5.70C2H, s), 6.32(lH,s), 7.03 (2H,d,J=8.5Hz), 7.17(lH,t, J=8.OHz), 7.23(2H,d,J=8.5Hz), 7.52(1H,dd,J=8.0, 0.5Hz), 7.63(IH,dd,J=8.0, 0.5Hz)
Example 43
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[l-ethyl-5-methyl-3-(lH-tetrazol-5-yl)-2- pyrrolyl]benzyl]-2-propyloxy-4-benzimidazolecarboxylic acid. mp:>266 °C(dec.)
NMR(DMSO-dg. δ ) : 0.82(3H,t,J=7.5Hz), 0.96(3H,t, J=7.5Hz), 1.69(2H,sextet,J=7.5Hz), 2.23(3H,s),
3.64(2H.q,M.5Hz), 4.39(2H, t, M.5Hz), 5.92C2H, s), 6.09(lH,s), 6.98 (IH,t,J=8.OHz), 7.08(2H,d, J=8.5Hz), 7.20(2H,d,J=8.5Hz), 7.30QH,dd,J=8. 0, 0.5Hz). 7.35(lH.dd.J=8.0.0.5Hz)
Example 44 The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4, 5-dimethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylate
NMR (CDClg, 5) : 1.30(3H,t,J=7.5Hz), 1.50(3H,t, M.5Hz), 1.98(3H,s), 2. ll(3H,s), 4.23(2H,q,M.5Hz), 4.66(2H,q,M.5Hz). 5.68(2H,s), 6.98(lH,s), 7.08(2H,d,J=8.5Hz), 7.14(2H,d,J=8.5Hz), 7.19QH,t, J=8.OHz), 7.57QH,dd, J=8.0,0.5Hz), 7.69(IH,dd,J=8.0, 0.5Hz)
Example 45 The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[4, 5-Dimethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-ethoxy -4-benzimidazolecarboxylic acid. mp:> 260°C NMR (DMSO-dg, 5) : 1.25(3H,t,M.5Hz), 1.8K3H,s), 1.98(3H,s), 4.49(2H, q,M.5Hz), 5.91(2H,s), 6.18(lH,s), 7.00(4H,s), 7.08(1H,t, J=8. OHz), 7.48 (IH,dd,J=8.0, 0.5Hz), 7.56(1H,dd, J=8.0, 0.5Hz)
Example 46 The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[5-chloro-4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate
NMR (CDClg, 5) : 1.27(3H, t.M.5Hz). 1.45(3H,t,M.5Hz), 2.13(3H,s), 4. 17(2H,q,M.5Hz), 4.57(2H,q,M.5Hz), 5.66(2H,s), 7.00(lH,s), 7.0K2H,d, J=8.5Hz), 7. ll(2H,d,J=8.5Hz), 7.18(1H, t, J=8. OHz), 7.53(1H, dd, J=8.0, 0. ' 5Hz), 7.60(lH,dd,J=8.0,0.5Hz)
Example 47 The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[5-Chloro-4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid mp : lδO-lθO'C NMR (DMSO-dg, 5) : 1.35(3H,t, J=7.5Hz), 2.07(3H, s), 4.59(2H,q, J=7.5Hz), 5.70(2H,s), 6.82(lH,s), 7.04(2H,d,J=8.5Hz), 7.17(1H, t, J=8. OHz), 7.20(2H, d,J=8.5Hz), 7.55(lH,dd,J=8.0,0.5Hz), 7.68(1H,dd, J=8.0, 0.5Hz)
Example 48 The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[5-chloro-4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid mp:> 260°C NMR (DMSO-dg, δ ) : 1.30(3H,t,J=7.5Hz), 2.0K3H,s), 4.48(2H,q,J=7.5Hz), 5. 92(2H, s), 6. 29(lH, s), 6. 97QH, t, J=8. OHz), 7. 0K2H, d, J=8. 5Hz), 7. 14(2H, d, J=8. 5Hz), 7. 30(lH, dd, J=8. 0, 0. 5Hz), 7. 34QH, dd, J=8. 0, 0. 5Hz)
Example 49 The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4-chloro-5-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-ethoxy-4-benzimidazolecarboxylate
NMR (CDClg, 5) : 1.29(3H,t,M.5Hz), 1.45(3H,t,M.5Hz), 2.03(3H,s), 4. 21(2H,q,M.5Hz), 4.6K2H,q,M.5Hz), 5.67(2H,s), 7.05(lH,s), 7.08(2H,d, J=8.5Hz), 7.12(2H,d,J=8.5Hz), 7.20(1H, t, J=8.OHz), 7.57QH, dd, J=8.0, 0. 5Hz), 7.66QH,dd,J=8.0,0.5Hz)
Example 50 The following compound was obtained according to a similar manner to that of Example 3.
3-[4-[4-Chloro-5-methyl-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-2- ethoxy-4-benzimidazolecarboxylic acid mp : 156-159X NMR (CDgOD-CDCl3, δ : 1.47(3H, t, M.5Hz), 2.04(3H,s), 4.62(2H,q,M. -5Hz), 5.69(2H,s), 6.87(lH,s), 7.09(4H,s), 7.20QH,t,J=8.OHz), 7.64C1H,dd, J=8.0,0.5Hz), 7.72(1H,dd,J=8.0, 0.5Hz)
Example 51 The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[4-chloro-5-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid mp:> 260 NMR (DMSO-dg, S) : 1.28(3H,t,J=7.5Hz), 1.88(3H,s), 4.48(2H,q,M.5Hz), 5.93(2H,s), 6.29QH,s), 6.98(lH,t,J=8.0Hz), 7.03(2H,d,J=8.5Hz), 7.15(2H, d,J=8.5Hz), 7.30(lH,dd,J=8.0,0.5Hz), 7.35QH,dd, J=8.0,0.5Hz)
Example 52 . The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 2-ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl] -4-benzimidazolecarboxylate
NMR (CDClg, <5) : 1.19(3H, t,M.5Hz), 1.26(3H, t, M.5Hz), 1.46(3H, t, J=7. 5Hz), 2.58(2H,q,M.5Hz), 4.09(2H,q, J=7.5Hz), 4.43(2H,q, J=7.5Hz), 5.59 (2H,s), 6.71(lH,d,J=0.5Hz), 6.81(2H,d, J=9.5Hz), 6.90(2H,d, J=9.5Hz), 7.00 (IH,d,J=0.5Hz), 7.09C1H,t, J=8. OHz), 7.21(lH,dd, J=8.0, 0.5Hz), 7.48(lH,dd, J=8.0,0.5Hz)
Example 53
The following compound was obtained according to a similar manner to that of Example 3.
2-Ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 178.5-180.5
NMR (CDClg-CDgOD, <5) : 1.23(3H,t,J=7.5Hz), 1.48(3H,t, J=7.5Hz), 2.54(2H, q,M.5Hz), 4.62(2H,q,M.5Hz), 5.68(2H,s), 6.82(2H,s), 7.04(2H,d, J=9. 5Hz), 7.11(2H,d,J=9.5Hz), 7.2K1H,t, J=8.0Hz), 7.66(lH,dd,J=8.0,0.5Hz), 7. 70(lH,dd,J=8.0,0.5Hz)
Example 54
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 2-ethoxy-3-[4-[4-ethyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid τnp:> 250°C
NMR (DMSO-dg, δ) : 1.14(3H,t, J=7.5Hz), 1.34(3H, t,J=7.5Hz), 2.42(2H,q, J= 7.5Hz), 4.48(2H,q, M.5Hz), 5.84(2H,s), 6.19(1H,d,J=0.5Hz), 6.67(lH,d,J= 0.5Hz), 6.95QH,t, M.5Hz), 6.96C2H,d, J=9.5Hz), 7.06(2H,d, J=9.5Hz), 7.29 (lH,dd,M.5,0.5Hz), 7.32QH,dd, M.5, 0.5Hz)
Example 55
The following compound was obtained according to a similar manner to that of Example 1. • Ethyl 2-ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-4-benzimidazolecarboxylate mp : 123-128°C
NMR (CDClg, δ ) : 1.00C3H,t,J=7.5Hz), 1.18C3H,t, M.5Hz), 1.46(3H,t,M. 5Hz), 1.67(2H,sextet, M.5Hz), 2.5K2H,t,M.5Hz), 4.09(2H,q, M.5Hz), 4. 40(2H,q,M.5Hz), 5.60(2H,s), 6.7K1H,d,J=0.5Hz), 6.80(2H,d,J=9.5Hz), 6. 92(2H,d,J=9.5Hz), 6.99(lH,d, J=0.5Hz), 7.07(IH,t,M.5Hz), 7.2K1H,dd, M. 5, 0.5Hz), 7.48C1H,dd,J=7.5, 0.5Hz)
Example 56 The following compound was obtained according to a similar manner to that of Example 3.
2-Ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yD-1-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 170.5-173O NMR (CDClg-CDgOD, δ > : 0.98(3H,t,J=7.5Hz), 1.49(3H,t, M.5Hz), 1.63C2H, sextet,M.5Hz), 2.49C2H,t,M.5Hz), 4.63(2H,q,M.5Hz), 5,68(2H,s), 6.80 (2H,s), 7.04(2H,d,J=9.0Hz), 7. ll(2H,d,J=90Hz), 7.2K1H,t, J=8.OHz), 7.64 (IH,dd,J=8.0,0.5Hz), 7.70C1H,dd,J=8.0,0.5Hz)
Example 57
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 2-ethoxy-3-[4-[4-propyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid mp:> 250^
NMR (DMSO-dg, <5) : 0.92(3H, t, J=7.5Hz), 1.34(3H, t, J=7.5Hz), 1.55C2H, sextet,M.5Hz), 2.37(2H,t,J=7.5Hz), 4.48C2H,q,J=7.5Hz), 5.85(2H,s),.6.17 (IH,d, J=0.5Hz), 6.66QH,d, J=0.5Hz), 6.95(1H,t, J=8. OHz), 6.96C2H,d, J=8. 5Hz),7.04(2H,d,J=8.5Hz), 7.29QH,d,J=8.OHz), 7.31(lH,d,J=8.OHz)
Example 58
A mixture of 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol-5-yl)-
1-pyrrolyl] benzyl] -4-benzimidazolecarboxylic acid (500. Omg), 1, 1 '- carbonyldiimidazole (354. 6mg) and tetrahydrofuran (5mg) was stirred at room temperature for 23 hours under nitrogen atmosphere. Then triethylamine (650.3ml) and glycine ethyl ester hydrochloride (610.5ml) were added to the mixture. The resulting suspension was stirred at room temperature for 11.5 hours and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate-n-hexane to give N-ethoxycarbonylmethyl-2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxamide(352.4mg) as a white amorphous.
NMR (CDClg, δ ) : 1.2K3H,t, J=7.5Hz), 1.49(3H, t, J=7.5Hz), 2.13(3H, s), 3. 83(2H,d,J=6.0Hz), 4.12(2H,q,M.5Hz), 4.67(2H,q,M.5Hz), 5.46(2H,s), 6. 12(lH,t,J=6.0Hz), 4.67(lH,d,J=0.5Hz), 6.78-6.83(3H,m), 6.91-7.00(9H,m), 7.07-7. ll(2H,m), 7.19-7.68(9H,m)
Example 59
The following compound was obtained according to a similar manner to that of Example 13.
N-Ethoxycarbonylmethyl-2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)
-l-pyrrolyl]benzyl]-4-benzimidazolecarboxamide mp : 178-180.5°C
NMR (DMSO-dg, 5) : 1.19(3H,t, J=7.5Hz), 1.40(3H,t, M.5Hz), 2.09(3H,s), 3.9K2H,d,J=5.5Hz), 4. ll(2H,q,M.5Hz), 4.59(2H,q,M.5Hz),' 5.4K2H, s),
6.68(lH,d,J=0.5Hz), 6.97QH,d,J=0.5Hz), 7.05(2H,d,J=9. OHz), 7.09-7.26(2H, m), 7.12(2H,d,J=9.0Hz), 7.57C1H,dd,J=8.0,0.5Hz), 8.82QH,t,J=5.5Hz)
Example 60 The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 184-194°C
NMR (DMSO-dg, δ : 1.17(3H,t, J=7.5Hz), 1.4K3H,t, M.5Hz), 2.05(3H,s), 4.19(2H,q,J=7.5Hz), 4.6K2H,q,J=7.5Hz), 5.48(2H,s), 6.16(1H, d, J=0.5Hz), 6.65(lH,d,J=0.5Hz), 6.80(2H,d,J=9.0Hz), 7.02(2H,d,J=9. OHz), 7.19(lH,t,J= 8.0Hz), 7.46(lH,dd,J=8.0,0.5Hz), 7.69(lH,dd,J=8.0, 0.5Hz)
Example 61 The following compound was obtained according to a similar manner to that of Example 1.
Ethyl 3-[4-[4-methy1-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2- propoxy-4-benzimidazolecarboxylate mp : 156-157.5°C
NMR (DMSO-dg, δ) : 0.92(3H,t,M.5Hz), 1.17(3H,t,M.5Hz), 1.70-1.90(2H, m), 2.09(3H,s), 4.19C2H,q, M.5Hz), 4.5K2H, t, M.5Hz), 5.53(2H,s), 6.70 QH,d,J=0.5Hz), 6.96C2H,d, J=9. OHz), 6.97QH,d, J=0.5Hz), 7.14C2H,d, J=9. 0Hz, 7.20(1H, t, J=8. OHz), 7.49(1H,dd, J=8.0, 0.5Hz), 7.70QH,dd, J=8.0, 0. 5Hz)
Example 62
The following compound was obtained according to a similar manner to that of Example 3. 3-[4-[4-Methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-2-propoxy-4- benzimidazolecarboxylic acid mp : 169-1711:
NMR (DMSO-dg, S) : 0.92C3H,t,M.5Hz), 1.69-1.90(2H,m), 2.08(3H,s), 4.49
(2H,t,M.5Hz), 5.68(2H,s), 6.70QH,d,J=0.5Hz), 6.99(lH,d,J=0.5Hz), 7.00 (2H,d,J=9.OHz), 7.16(2H,d,J=9.0Hz), 7.19QH, t,J=8.OHz), 7.56(lH,dd,J=8.0,
0.5Hz), 7.67(lH,dd,J=8.0,0.5Hz)
Example 63
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-2-propoxy-4-benzimidazolecarboxylic acid
NMR (DMSO-dg, 5) : 0.89C3H,t,M.5Hz), 1.64-1.85(2H,m), 2.04(3H,s), 4.39
(2H,t,M.5Hz), 5.85(2H,s), 6.14QH,d, J=0.5Hz), 6.64(lH,d,J=0.5Hz), 6.97 (IH,t, J=8.OHz), 6.97(2H,d,J=9.0Hz), 7.07(2H,d,J=9.OHz), 7.28QH,dd,J=8.0,
0.5Hz), 7.32(1H,dd,J=8.0,0.5Hz)
0.5Hz), 7.67(1H,dd,J=8.0, 0.5Hz)
Example 64 - The following compound was obtained according to a similar manner to that of Example 1.
■■ ■ Ethyl 2-methoxy-3- [4- [4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl] benzyl]-4-benzimidazolecarboxylate mp : 151-153°C NMR (DMSO-dg, δ : 1. 15(3H, t, M. 5Hz), 2. 08(3H, s), 4. 18(3H, s), 4. 18(2H, q, M. 5Hz), 5. 54(2H, s), 6. 68QH, d, J=0. 5Hz), 6. 93(2H, d, J=9. OHz), 6. 96(1H, d, J=0. 5Hz), 7. 14(2H, d, J=9. OHz), 7. 20(1H, t, J=8. OHz), 7. 48(1H, dd, J=8. 0, 0. 5Hz), 7. 7K1H, dd, J=8. 0, 0. 5Hz)
Example 65
The following compound was obtained according to a similar manner to that of Example 3.
2-Methoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- benzimidazolecarboxylic acid mp : 181-184.5
NMR (DMSO-dg, <5) : 2.08(3H,s), 4.18(3H,s), 5.69(2H,s), 6.70C1H,d, J=0. 5Hz), 6.98(2H,d,J=9.0Hz), 7. OOQH, d, J=0.5Hz), 7.14(2H, d,J=9. OHz), 7.20 (IH,t,J=8.OHz), 7.57(1H,dd,J=8.0,0.5Hz), 7.70(1H,dd, J=8.0,0.5Hz)
Example 66
The following compound was obtained according to a similar manner to that of Example 2.
Disodium salt of 2-methoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg, <5) : 2.03(3H,s), 4.07(3H, s). 5.88(2H,s), 6.14QH,d, J=0. 5Hz). 6.65(lH,d,J=0.5Hz), 6.97QH.t, J=8.OHz), 6.98(4H,s), 7.30QH,dd, J=8. 0,0.5Hz), 7.32(lH,dd,J=8.0,0.5Hz)
Example 67 The following compound was obtained according to a similar manner to that of Example 12. l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ) : 1.15-2. OOdOH,m), 1.43(3H,d,J=4Hz). 1.44(3H,t, J=7.5Hz), 2-12(3H,s), 4.57(lH.m), 4.62(2H,q, M.5Hz), 5.56QH,d, J=20Hz), 5.65(1H, d, J=20Hz), 6. 63QH. br, s), 6. 79-7. 42(21H, m), 7.49(lH, dd, J=7. 5 and 1Hz), 7. 75(lH, dd, J=8 and 1Hz)
Example 68 The following compound was obtained according to a similar manner to that of Example 13.
l-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, 5) : 0.83-2.02(10H,m), 1.45(3H,t,M.5Hz), 1.54(3H,d,J=4Hz), 2.18(3H,s), 4.39-4.76(3H,m), 5.60QH,d, M7.5Hz), 5.72QH,d, M7.5Hz), 6.74(lH,m), 6.78(1H,q,J=4Hz), 6.94(lH,m), 6.95(2H,d, J=9Hz), 7.02(2H,d,J= 9Hz), 7.18(1H,t,M.5Hz), 7.58C1H,dd. M.5 and 0.5Hz), 7.62(1H.dd.J=7.5 and 0.5Hz)
Example 69
The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of l-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3~[4-[4- methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg. δ ) : 1.11-1.9K16H.m), 2.03(3H.s), 4.37-4.62(lH.m). 4.62 (2H.q,M.5Hz). 5.49(2H.s), 6.17QH.d,J=0.5Hz). 6.64(lH.d,J=0.5Hz), 6.79 QH,q,J=5.0Hz), 6.82(2H,d,J=9. OHz), 7.02(2H,d, J=9.OHz), 7.20(1H, t, J=7. 5Hz), 7.46(lH,dd,M.5.0.5Hz). 7.73QH.dd, M.5, 0.5Hz) :
Example 70
The following compound was obtained according to a similar manner to that of Example 12. l-(Ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyi-2-(1-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, δ : 1.28C3H, t, J=7.5Hz), 1.45(3H, t,M.5Hz), 1.46C3H,d, J= 5Hz),2.12(3H,s), 4.19(2H,q, M.5Hz), 4.63(2H,q,M.5Hz). 5.50(s,0.8H), 5. 61(s,1.2H), 6.53-6.65(2H,m), 6.78-7.44(2IH,m), 7.60QH,dd, J=9, IHz), 7.76 (IH,dd,J=9, IHz) Example 71
The following compound was obtained according to a similar manner to that of Example 13. l-(Ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)- l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, δ) : 1.22(3H,t,M.5Hz), 1.47(3H,t,M.5Hz), 1.54(3H,d,
J=5.5Hz). 2.17(3H,s), 4.13(2H,q, M.5Hz), 4.57(2H,q, M.5Hz), 5.60(lH,d,
J=15.5Hz), 5.77(lH,d,M5.5Hz), 6.70-6.83(2H,m), 6.94(2H,d,J=9.OHz), 6.95
(lH,d,J=0.5Hz), 7.02(2H.d,J=9.OHz). 7.17(1H, t, M.5Hz), 7.59C1H,dd,M.5, 0.5Hz), 7.63(lH,dd.M.5.0.5Hz)
Example 72
The following compound was obtained according to a similar manner to that of Example 2. Sodium salt of l-(ethoxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2 -(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (DMSO-dg, δ ) : 1.20(3H,t,J=7.5Hz), 'l.40(3H,d,J=5.5Hz), , 1.4K3H, t, J= 7.5Hz), 2.04(3H,s). 4.16(2H,q,M.5Hz), 4.6K2H,q,M.5Hz), 5.49(2H.s), 6.16(lH.d,J=0.5Hz), 6.63(lH,d,J=0.5Hz), 6.79(lH,q,J=5.5Hz), 6.8K2H,d,J= 8.5Hz), 7.00(2H,d,J=8.5Hz), 7.2K1H,t,M.5Hz), 7.47(lH,dd,M.5, 0.5Hz), 7.73(1H,dd,J=7.5, 0.5Hz)
Example 73
To a stirred suspension of 3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-2-ethoxy-4-benzimidazolecarboxylic acid (400mg) in dichloromethane (5ml) was added triethylamine (150 μl) and trityl chloride (302mg) at ambient temperature and the resulting suspension was stirred for 12 hours at the same temperature. The mixture was diluted with dichloromethane and washed with water and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-Ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (706mg) as a amorphous solid. This compound was used in the next step without further purification. NMR (CDClg, δ ) : 1.30(3H, t,M.5Hz), 2.07(3H,s), 4.5K2H,q, M.5Hz), 5. 65(2H. s), 6. 41-8. 00(24H, m)
Example 74
To a stirred solution of 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylic acid (706mg) in N,N-dimethylformamide (10ml) was added potassium carbonate (373mg) and iodomethyl pivalate (327mg) at ambient temperature and the resulting heterogeneous mixture was stirred at the same temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with saturated ammonium chloride and saturated sodium chloride. After dried over magnesium sulfate, the organic layer was concentrated in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate- n-hexane (1:3→1:2V/V) to give pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl -2-(l-trityl-lH-tetrazol-5-yl) -l-pyrrolyl]benzyl]-4- benzimidazolecarboxylate (647mg) as a colorless amorphous.
NMR (CDClg. S : 1.18(9H,s), 1.33(3H.t, M.5Hz), 2.13(3H,s), 4.62(2H,d, . M.5Hz). 5.65(2H.br.s), 6.80(2H.s), 6.56-7.44(20H.m). 7.63QH.dd. J=8 and 0.5Hz), 7.77(1H,dd.J=8 and 0.5Hz)
Example 75
To a stirred solution of pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl-
2-(1-trityl-lH-tetrazol-5-yl)-l-pyrrolyl] benzyl] -4- benzimidazolecarboxylate (788mg) in a mixed solvent (tetrahydrofuran- acetic acid-water=2:4:1 14ml) was stirred at ambient temperature for three hours and then at 50°C for 2 hours. The solvent was evaporated in vacuo and the residual solvent was removed azeotropically with toluene.
The residue was purified by flash chromatography eluting with ethyl acetate-n-hexane (1:1V/V) -ethyl acetate (2 times) to afford an amorphous solid which was suspended in water (10ml) and stirred vigorously at ambient temperature for three hours. The solid was filtered and dried to give pivaloyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate (216mg) as a pale brown amorphous solid. mp : 81-90.5 NMR- (CDClg, δ ) : 1.18(9H,s), 1.46QH,t, M.5Hz), 2.18(3H.s), 4.56(2H.q. M.5Hz), 5.6K2H,s), 5.79(2H,s), 6.78QH, br, s), 6.94(1H, s), 6.97(2H,d, J =9Hz), 7.05(2H,d,J=9Hz), 7.17(1H, t, MHz), 7.59(2H, d, MHz)
Example 76 The following compound was obtained according to a similar manner to that of Example 74.
(5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3- [4- [4-methyl-2- (l-trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, δ : 1.45(3H, t, M.5Hz), 2.04(3H,s), 2.17(3H,s), 4.63(2H,q, M.5Hz), 4.81(2H,s), 5.63(2H,s), 6.69(lH,s), 6.77-6.85(2H,m), 6.93-7.09 (8H,m). 7.18-7.36C11H, m), 7.60<1H, dJ=7.5Hz), 7.80(lH,dM.5Hz)
Example 77 The following compound was obtained according to a similar manner to that of Example75.
(5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3- [4- [4-methyl-2- (lH-tetrazol-5-yl)-l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate NMR (CDClg, 5) : 1.43(3H, t, M.5Hz), 2.17(6H.s), 4.54(2H,q, J=7.5Hz), 4. 90(2H.s), 5.16(2H,s), 6.79(lH,d, J=0.5Hz), 6.91(lH,d, J=0.5Hz), 6.93(2H,d, J=8.5Hz), 7.04(2H, d, J=8.5Hz), 7.17(1H, t, M.5Hz), 7.56QH, d. M.5Hz), 7. 58(lH.d.M.5Hz)
Example 78 The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of (5-Methyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-
[4- [4-methy 1-2- (lH-tetrazol-5-yl)- l-pyrrolyl] benzyl] -4- benzimidazolecarboxylate mp : 153-174<
NMR (DMSO-dg, 5) : 1.4K3H, t, M.5Hz), 2.06(3H,s), 2.18(3H,s), 4.62(2H, q,M.5Hz), 5.13(2H,s), 6.17QH, d, J=0.5Hz), 6.66(lH,d, J=0.5Hz), 6.8K2H, d,J=8.5Hz), 7.0K2H, d, J=8.5Hz), 7.20(1H, t, J=8. OHz), 7.48(1H, dd, J=8.0, 0.
5Hz), 7.72(lH,dd,J=8.0,0.5Hz) Example 79
The following compound was obtained according to a similar manner to that of Example 74.
2-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-Q- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg. δ : 1.29-1.96(13H.m). 2.13(3H.s). 4.22-4.38(2H.m). 4.48-4. 70(4H,m), 5.49(4/3H,s), 5.61(2/3H,s), 6.53-6.69(4H,m), 6.77-7.46C17H,m), 7.57-7.64(lH,m), 7.72-7.82(2H,m), 8.OKIH,dd,J=8.0,0.5Hz)
Example 80
The following compound was obtained according to a similar manner to that of Example 75.
2-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 81.5-90.5°C
NMR (CDC13, δ : 1.14-2.21(10H,m), 1.47C3H,t,M.5Hz), 2.16(3H,s), 4.23 -4.32(2H,m). 4.34-4.43(2H,m), 4.47-4.69(lH.m), 4.6K2H,q, M.5Hz), 5.61 (2H,s), 6.76QH,s), 6.92(lH,s), 6.98(2H,d,J=8.5Hz), 7.07(2H.d.J=8.5Hz), 7.19(1H,t,J=8.OHz), 7.57C1H,d,J=8.OHz), 7.68(1H,d.J=8.OHz)
Example 81
The following compound was obtained according to a similar manner to that of Example 74. l-(Propionyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2 l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, δ : 1.1K3H,t,M.5Hz). 1.40(3H,d, J=5.5Hz), 1.43(3H,t,M. 5Hz), 2.13(3H,s), 2.30(2H,q.M.5Hz), 4.62(2H,q, M.5Hz), 5.50(2/5H,s). 5.6K8/5H.S). 6.55-6.64(lH,m). 6.78-7.04(llH.m). 7.10-7.42(llH.m), 7.58 (IH,dd,J=8.0,0.5Hz), 7.77C1H,dd,J=8.0,0.5Hz)
Example 82
The following compound was obtained according to a similar manner to that of Example 75. l-(Propionyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)- l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 88-96°C
NMR (CDClg, 5 ) : 1. 0K3H, t, M. 5Hz), 1. 47C3H, t, J=5. 5Hz), 1. 5K3H, d, J=5. 5Hz), 2. 17(3H, s), 2. 29(2H, q, M. 5Hz), 4. 58(2H, q, M. 5Hz), 5. 59QH, d, M6. 5Hz), 5. 83(lH, d, M6. 5Hz), 6. 74(lH, .d, J=0. 5Hz), 6. 88QH, q, J=5. 5Hz), 6. 93 (lH, d, J=0. 5Hz), 6. 97(2H, d, J=9. 0Hz), 7. 04(2H, d, J=9. OHz), 7. 18(1H, t, J=8. OHz), 7. 56-7. 68(2H, m)
Example 83
The following compound was obtained according to a similar manner to that of Example 1.
2-Ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4- nitrobenzimidazole
NMR (CDClg, δ : 1.54(3H, t,M.5Hz). 2.13(3H,s), 4.70(2H.q, M.5Hz), 5. 52(2H,s), 6.77(lH.d,J=0.5Hz), 6.93QH,d, J=0.5Hz), 7.00(2H,d,J=9. OHz), 7. 12(2H,d,J=9.0Hz), 7,22(1H,t,J=8. OHz), 7.67(1H,dd, J=8.0,0.5Hz), 7.78QH, dd,J=8.0,0.5Hz)
Example 84
The following compound was obtained according to a similar manner to that of Example 2.
Sodium salt of 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-nitrobenzimidazole
NMR (DMSO-dg, <5) : 1.43(3H,t, M.5Hz), 2.04(3H,s), 4.65(2H,q, J=7.5Hz), 5.39(2H,s), 6.17(lH,d,J=0.5Hz), 6.69(lH,d,J=0.5Hz), 6.84(2H,d,J=9.OHz), 7.03(2H,d,J=9.0Hz), 7.30(1H,t,J=8.OHz), 7.74(lH,dd,J=8.0, 0.5Hz), 7.88(1H, dd, J=8.0,0.5Hz)
Example 85
The following compound was obtained according to a similar manner to that of Example 74. l-(Pivaloyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.18(9H,s), 1.39(3H,d, J=5.5Hz), 1.43(3H, t, M.5Hz), 2. 12(3H,s), 4.63(2H.q.M.5Hz). 5.62(2H.s). 6.61(lH,s), 6.78-7.06(12H,m), 7.11-7.43(10H,m), 7.57(1H,dd,J=8.0,0.5Hz), 7.76(1H,dd, J=8.0, 0.5Hz) Example 86
The following compound was obtained according to a similar manner to that of Example 75. l-(Pivaloyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l -pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 91-99
NMR (CDClg, 5) : 1.12C9H,s), 1.45(3H,t, M.5Hz), 1.47(3H,d, J=5.5Hz), 2. 17(3H,s), 4.43-4.65(2H,m), 5.60(lH,d,J=15.5Hz), 5.78(lH,d, 5.5Hz), 6.74 (IH,d,J=0.5Hz), 6.83(1H,g, J=5.5Hz), 6.93(1H,d,J=0.5Hz)6.96(2H,d, J=9.OHz), 7.02(2H,d,J=9.OHz),7.17(IH,t, J=7.5Hz), 7.56(IH,dd,M.5,0.5Hz),7.60(IH, dd,J=7.5,0.5Hz) Example 87
The following compound was obtained according to a similar manner to that of Example 74. l-(Cyclohexylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl- lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.10-1.49(6H,m), 1.39(3H,d, J=5.5Hz), 1.43(3H, t, J=7. 5Hz), 1.54-1.96(4H,m), 2.12(3H,s), 2.20-2.38QH,m), 4.6K2H,q,J=7.5Hz), 5.60(2H,s), 6.60QH,d,J=0.5Hz), 6.80(2H,d, J=9.0Hz), 6.87-7.05(8H,m), 7.12 -7.43(12H.m), 7.56QH,dd,J=7.5.0.5Hz). 7.76(lH,dd,M.5,0.5Hz) Example 88
The following compound was obtained according to a similar manner to that of Example 75. l-(Cyclohexylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(1H- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 89-98°C
NMR (CDC13, δ : 1.05-1.36(6H,m), 1.47(3H,t,M.5Hz), 1.49(3H,d,J=5.5Hz), 1.53-1.89(4H,m),2.11-2.3K1H,m),2.16(3H,s),4.58C2H,q,M.5Hz), 5.59C1H,d. J=16.OHz),5.80(IH,d,M6.OHz), 6.76(1H,d,J=0,5Hz), 6.87(1H,q,J=5,5Hz), 6. 92C1H,d,J=0,5Hz), 6.94(2H,d, J=9. OHz), 7.02(2H,d,J=9.0Hz)7.18C1H, t, J=7. 5Hz), 7.60(IH,dd, M.5, 0.5Hz),7.61(IH,dd,J=7.5,0.5Hz) Example 89
The following compound was obtained according to a similar manner to that of Example 74. - l-(Isobutyryloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, δ ) : 1.15(3H,d, J=6.5Hz), 1.17C3H, d, J=6.5Hz), 1.40(3H, d, J=5.
5Hz), 1.45(3H,t,M.5Hz), 2.13(3H,s),2.52QH,septet, J=6.5Hz), 4.6K2H,q,
M.5Hz), 5.61(2H,s), 6.60(lH,d, J=0..5Hz), 6.82(2H,d, J=9. OHz), 6.83(lH,d, J=0.5Hz),6.87-7.06(9H,m), 7.10-7.44C10H,m,), 7.59(lH,dd,J=8.0,0.5Hz),7.76
(IH,dd, J=8.0, 0.5Hz)
Example 90
The following compound was obtained according to a similar manner to that of Example 75. l-(Isobutyryloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)
-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 79-83.5°C
NMR (CDClg, 5) : 1.08(3H,d, J=6.5Hz), 1.09(3H,d, J=6.5Hz), 1.45(3H, t, J=7.
5Hz), 1.48(3H.d,J=5.5Hz), 2.16(3H,s),2.50QH,septet,J=6.5Hz), 4.49-4.64 (2H.m). 5.59(lH,d.J=16.0Hz). 5.80(lH,d.M6.OHz). 6.74(1H,d, J=0.5Hz), 6.
86(lH,q,J=5.5Hz). 6.95(lH,d,J=0.5Hz), 6.96(2H.d,J=9.OHz). 7.03(2H,d,J=9.
OHz), 7.18QH,t, J=8.OHz), 7.61(2H,d.J=8. OHz)
Example 91
The following compound was obtained according to a similar manner to that of Example 74. l-(Acetoxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol-5- yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg. δ : 1.40(3H,d. J=5.5Hz). 1.43(3H,t,M.5Hz).2.03C3H,s), 2.11
(3H,s), 4.62(2H,q,J=7.5Hz), 5.62(2H,s), 6.62(lH,d, J=0..5Hz), 6.78-7.06 (12H,m), 7.12-7.4K10H,m), 7.60QH,dd,M.5,0.5Hz), 7.77(1H,dd, M.5,0.
5Hz)
Example 92
The following compound was obtained according to a similar manner to that of Example 75. l-(Acetoxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 85-93.5°C
NMR (CDClg. 5) : 1.46(3H.t.J=7.5Hz), 1.52(3H,d.J=5.5Hz), 2.00(3H,s), 2.
15(3H,s), 4.60(2H,q.M.5Hz). 5.59(1H,d, J=16. OHz), 5.88(lH,d, M6. OHz), 6.75(lH,d,J=0.5Hz), 6.83(lH,q,J=5.5Hz), 6.95(1H,d,J=0.5Hz), 6.95(2H,d,J= 9.OHz). 7.03(2H,d,J=9.OHz),7.19C1H,t,J=7.5Hz),7.6K1H,dd,J=7.5,0.5Hz), 7.
65(lH,dd,M.5,0.5Hz)
Example 93
The following compound was obtained according to a similar manner to that of Example 74. l-(Butytyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ) : 0.91(3H,t, J=7.5Hz), 1.41(3H,d, J=5.5Hz), 1.43(3H,t, J=7. 5Hz), 1.53-1.75(2H,m), 2.12(3H, s), 2.29(2H, t, J=7.5Hz), 4.62(2H.q, J=7. 5Hz), 5.61(2H,s), 6.61(lH,d, J=0.5Hz), 6.76-7.07C12H,m), 7.10-7.43C10H,m), 7.58C1H,dd, J=7.5.0.5Hz). 7.77(IH,dd, J=7.5, 0.5Hz) Example 94
The following compound was obtained according to a similar manner to that of Example 75. l-(Butytyloxy) thyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yD-1- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 77-81O
NMR (CDClg, δ) : 0.84(3H,t,M.5Hz), 1.41-1.62(2H,m).1.47(3H.t,J=7.5Hz), 1.5K3H,d,J=5.5Hz), 2.17(3H,s), 2.23(2H,t,J=7.5Hz), 4.58C2H,q,J=7.5Hz), 5.60(lH,d,J=16.0Hz),5.84(lH,d,J=16.0Hz), 6.76QH,d, J=0.5Hz), 6.87QH.q, J=5.5Hz), 6.95(2H,d.J=9.0Hz), 6.97QH,d, J=0.5Hz), 7.02(2H,d,J=9. OHz), 7. 18(1H,t,J=7.5Hz), 7.6K2H,d, J=7.5Hz) Example 95
The following compound was obtained according to a.similar manner to that of Example 74. l-(Benzoyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl-lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NHR (CDClg, δ : 1.44(3H, t,M.5Hz), 1.57(3H,d, J=5.5Hz), 2.13(3H,s), 4. 63(2H,q,M.5Hz), 5.62(2H,s), 6.57(1H,d,J=0.5Hz), 6.77(2H,d,J=9. OHz). 6. 81-6.97(9H,m), 7.11-7.57(14H,m), 7.63QH.dd, M.S.0.5Hz), 7.76QH,dd, M. 5,0.5Hz), 8.00(2H,dd,M.5,0.5Hz) Example 96
The following compound was obtained according to a similar manner to that of Example 75. • l-(Benzoyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate mp : 93-103.5°C
NMR (CDClg, δ ) : 1.44C3H, t, M.5Hz), 1.60C3H,d, J=5.5Hz), 2.20(3H,s), 4. 49(2H,q,J=7.5Hz). 5.57(1H,d,J=17.OHz),5.79(1H,d,J=17.OHz), 6.70(1H,d,J=0. 5Hz), 6.84(2H,d,J=8.5Hz).6.89(2H.d,J=8.5Hz), 6.95(1H,d, J=0.5Hz), 7.09-7. 22(2H,m), 7.29-7.41(2H,m) 7.47(1H,d, M.5Hz), 7.57QH, t, M.5Hz), 7.64QH, d,M.5Hz), 7.89(2H,d,M.5Hz) Example 97
The following compound was obtained according to a similar manner to that of Example 74.
Propionyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.1K3H,t,M.5Hz), 1.43(3H,t, M.5Hz), 2.12(3H,s), 2.31 (2H,q,M.5Hz),4.63(2H,q.M.5Hz). 5.62(2H,s), 5.80(2H,s), 6.56-7.06Q2H, m), 7.10-7.43(10H,m), 7.64(lH,dd,M.5,0.5Hz), 7.77C1H,dd,M.5,0.5Hz) Example 98
The following compound was obtained according to a similar manner to that of Example 75.
Propionyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl]benzyl]-4-benzimidazolecarboxylate
NMR (CDClg, <5) : 1.10(3H,t,M.5Hz), 1.47C3H,t,M.5Hz), 2.17(3H,s), 2. 37(2H.q,M.5Hz), 4.56(2H,q,M.5Hz), 5.62(2H,s), 5.79(2H,s), 6.77(lH,d, J=0.5Hz), 6.94(lH,d,J=0.5Hz), 6.96(2H,d,J=9. OHz), 7.06(2H,d,J=9. OHz). 7. 18C1H,t, J=7.5Hz). 7.60X1H,dd, J=7.5,0.5Hz), 7.62(1H,dd, J=7.5, 0.5Hz) Example 99
The following compound was obtained according to a similar manner to that of Example 74.
Cyclohexylcarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ : 1.12-1.51(6H,m), 1.43(3H, t,J=7.5Hz), 1.52-1.78(2H,m), 1.79-1.96C2H,m), 2.13(3H,s), 2.20-2.38(lH,m), 4.62(2H,q, M.5Hz), 5.62 (2H,s), 5.79(2H,s), 6.66(1H,d, J=0.5Hz), 6.8K2H,d,J=9. OHz), 6.83(lH,d,J= 0.5Hz), 6.87-6.99(6H,m), 7.03(2H,d, J=9.OHz), 7.12-7.44(10H.m), 7.630H, dd, M.5,0.5Hz), 7.78QH,dd, M.5, 0.5Hz) Example 100 The following compound was obtained according to a similar manner to that of Example 75.
Cyclohexylcarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, S) : 1.08-1.52C4H,m), 1.44(3H,t,M.5Hz), 1.56-1.78(4H,m), 1.79-1.93(2H,m), 2.17(3H,s), 2.20-2.39(lH,m). 4.56(2H,q,M.5Hz), 5.61 (2H.s), 5.76(2H,s), 6.77(lH,d, J=0.5Hz), 6.93(lH,d,J=0.5Hz), 6.94(2H,d,J= 9.0Hz), 7.03(2H,d,J=9.OHz), 7.17QH, t,M.5Hz), 7.57(lH,dd,M.5,0.5Hz), 7.59QH,dd,M.5,0.5Hz) Example 101
The following compound can be obtained according to a similar manner to that of Example 74.
Cyclohexyloxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl- lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 102
The following compound can be obtained according to a similar manner to that of Example 75.
Cyclohexyloxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 103
The following compound can be obtained according to a similar manner to that of Example 74.
Ethoxycarbonyloxymethyl 2-ethoxy-3~[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 104
The following compound can be obtained according to a similar manner to that of Example 75.
Ethoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl) -l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 105
The following compound can be obtained according to a similar manner to that of Example 74. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-Q-trityl-lH -tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 106 The following compound can be obtained according to a similar manner to that of Example 75. tert-Butoxycarbonyloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol -5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 107
The following compound can be obtained according to a similar manner to that of Example 74.
2-(Phthalid-3-ylidene)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl-lH- tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 108
The following compound can be obtained according to a similar manner to that of Example 75.
2-(Phthalid-3-ylidene)ethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol- 5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 109
The following compound can be obtained according to a similar manner to that of Example 74. l-(l-Methylpiperidyl)carbonyloxyethyl 2-ethoxy-3-[4-[4-methyl-2-(l- trityl-lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 110
The following compound can be obtained according to a similar manner to that of Example 75. l-(l-Methylpiperidyl)carbonyloxyethyl 2-ethoxy-3-[4-[4-methyl-2-(lH -tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate Example 111
The following compound was obtained according to a similar manner to that of Example 74. l-(Cyclopentylcarbonyloxy)ethyl 2-ethoxy-3-[4-[4-methyl-2-(l-trityl -lH-tetrazol-5-yl)-l-pyrrolyl]benzyl]-4-benzimidazolecarboxylate NMR (CDClg, δ ) : 1.40(3H,d. J=5.5Hz), 1.44(3H.t, M.5Hz), 1.50-1.90C8H, m). 2.13(3H.s), 2.61-2.77(lH,m), 4.62(2H,q,M.5Hz), 5.62(2H, s), 6.63QH, d,J=0.5Hz). 6.77-7.05(12H,m). 7.11-7.43C10H,m), 7.59(lH,dd,M.5,0.5Hz), 7.77(lH,dd,M.5,0.5Hz) Example 112 The following compound was obtained according to a similar manner to that of Example 75. l-(Cyclopentylcarbonyloxy) ethyl 2-ethoxy-3- [4- [4-methyl-2-(lH- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate NHR (CDClg, S) : 1. 39-1. 9K8H, m), 1. 46(3H, t, M. 5Hz), 1. 50C3H, d, J=7. 5Hz), 2. 16(3H, s), 2. 57-2. 75(lH, m), 4. 57(2H, q, J=7. 5Hz), 5. 60QH, d, J=16. 5Hz), 5. 81(lH, d, M6. 5Hz), 6. 75QH, d, J=0. 5Hz), 6. 87(lH, q, J=5. 5Hz), 6. 94 (IH, d, J=0. 5Hz), 6. 96C2H. d, J=9. OHz), 7. 02(2H, d, J=9. OHz), 7. 18(1H, t, J=7. 5Hz), 7. 60 (IH, dd, J=7. 5, 0. 5Hz), 7. 62 (IH, dd. J=7. 5, 0. 5Hz) Example 113 The following compounds can be obtained according to a similar manner to that of Example 74.
(1) Isobutyryloxymethyl 2-ethoxy-3- [4-[4-methyl-2-(l-trityl-lH-tetrazol -5-yl)-l -pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(2) Butyryloxymethyl 2-ethoxy-3- [4- [4-methyl-2-(l-trityl-lH-tetrazol-5- yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(3) (5-tert-Butyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl -2- ( l -tri tyl - l H-tet ra zol -5 -yl ) - l -pyrro ly l ] benzy l ] -4 - benzimidazolecarboxylate
(4) (5-Phenyl-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl-2- (l-trityl-lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazόlecarboxylate
(5) Hethoxycarbonylmethyl 2-ethoxy-3- [4- [4-methyl-2-(l-trityl-lH- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(6) 2-1 sobutoxycarbonyl-2-pentenyl 2-ethoxy-3- [4- [4-methyl-2-Q-trityl- lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate Example 114
The following compounds can be obtained according to a similar manner to that of Example 75.
(1) Isobutyryloxymethyl 2-ethoxy-3-[4-[4-methyl-2-(lH-tetrazol-5-yl)-l- pyrrolyl] benzyl] -4-benzimidazolecarboxylate (2) Butyryloxymethyl 2-ethoxy-3-[4-[4-methyl-~2-(lH-tetrazol-5-yl)-l- pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(3) (5-tert-Butyl-2-oxo-l. 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl -2-(lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(4) (5-Pheny 1-2-oxo-l, 3-dioxolen-4-yl)methyl 2-ethoxy-3-[4-[4-methyl-2- (lH-tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate (5) Methoxycarbonylmethyl 2-ethoxy-3- [4- [4-methyl-2-(lH-tetrazol-5-yl)- 1-pyrrolyl] benzyl] -4-benzimidazolecarboxylate
(6) 2- I sobutoxycarbonyl-2-penteny 1 2-ethoxy-3- [4- [4-methy 1-2- (1H- tetrazol-5-yl) -l-pyrrolyl] benzyl] -4-benzimidazolecarboxylate

Claims

What we claim is :
1. A compound of the formula
Figure imgf000086_0001
wherein R is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R , R3 and R^ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form
1,3-butadienylene, R^ is hydrogen or imino-protective group, R" is lower alkyl,
R7 is nitro,optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene,
Q is CH or N,
X is N or CH, Y is NH, 0 or S, and Z is S, S02 or 0,
and pharmaceutically acceptable salt thereof.
2. A compound of claim 1, which is represented by the formula
Figure imgf000087_0001
wherein R6 and A are each as defined in claim 1, R7 is optionally esterified carboxy, R9 is a group of the formula :
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000088_0001
in which R5 is as defined in claim 1,
RI, RI and RI are each lower alkyl, and
Rb , R? and RI are each hydrogen, halogen or lower alkyl.
3.A compound of claim 2, which is represented by the formula
Figure imgf000088_0002
wherein R6, R7 and R9 are each as defined in claim 2.
4.A compound of claim 3, which is Rτ is carboxy, lower alkoxycarbonyl, lower alkoxycarbonyl(lower)alkoxycarbonyl, lower alkoxycarbonyl(lower)alkenyloxycarbonyl, lower alkanoyloxy(lower)alkoxycarbonyl, cycloalkylcarbonyloxy(lower)alkoxycarbonyl, benzoyloxy(lower)alkoxycarbonyl, lower alkylpiperidylcarbonyloxy(lower)alkoxycarbonyl, lower alkoxycarbonyloxy(lower)alkoxycarbonyl, cycloalkyloxycarbonyloxy(lower)alkoxycarbonyl, (5-lower alkyl-2-oxo-l, 3-dioxolen-4-yl)(lower)alkoxycarbonyl, (5-phenyl-2-oxo-l,3-dioxolen-4-yl)(lower)alkoxycarbonyl, phthalid-3-ylidene(lower)alkoxycarbonyl.
5.A compound of claim 4, which is represented by the formula :
Figure imgf000089_0001
wherein R6 and R7 are each as defined in claim 4, and RI is lower alkyl.
6. A process for preparing a compound of formula :
Figure imgf000089_0002
wherein R^ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R% R and R^ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono or di or trihalo(lower)alkyl, oxo(lower)alkyl, hydroxy(lower)alkyl or optionally esterified carboxy; or R^ and R^ are linked together to form 1, 3-butadienylene, R^ is hydrogen or imino-protective group,
Rb is lower alkyl,
R7 is nitro, optionally esterified or amidated carboxy or optionally substituted amino, A is lower alkylene, Q is CH or N,
X is N or CH, Y is NH, 0 or S, and Z is S, S02 or 0, or a salt thereof, which comprises
a) subjecting a compound of formula :
Figure imgf000090_0001
wherein R1, R2, R3, R\ R6, R7, \,Q,X,Y and Z are each as defined above, to- formation reaction of a tetrazole group, to give a compound of the formula
Figure imgf000091_0001
wherein R1, R2, R3, R4, R5, R6, R7, A,Q,X,Y and Z are each as defined above, or a salt thereof, or b) subjecting a compound of the formula:
Figure imgf000091_0002
wherein R1, R2, R3, R4, R5, R6, A,Q,X,Y and Z are each as defined above, and RI is esterified carboxy, or a salt thereof, to elimination of the ester moiety, to give a compound of the formula :
Figure imgf000092_0001
wherein R1, R2, R3, R4, R5, R6, A,Q,X,Y and Z are each as defined above, or a salt thereof, or
C) reacting a compound of the formula :
Figure imgf000092_0002
wherein Rs, R7 and Z are each as defined above, or a salt thereof, with a compound of the formula :
Figure imgf000093_0001
wherein R\ R2, R3, R4, R5, A,Q,X,and Y are each as defined above, and R8 is acid residue, or a salt thereof, to give a compound of the formula :
Figure imgf000093_0002
wherein R1, R2, R3, R4, R5, R6, R7, A,Q,X and Z are each as defined above, or a salt thereof, or d) subjecting a compound of the formula:
Figure imgf000094_0001
wherein R1, R2, R3, R4, R6, R7, A,Q,X,Y and Z are each as defined above, and RI is imino-protective group, or a salt thereof, to removal of the imino-protective group, to give a compound of the formula :
Figure imgf000094_0002
wherein R1, R2, R3, R4, RB, R7, A,Q,X,Y and Z are each as defined above, or a salt thereof, or e) subjecting a compound of the formula:
Figure imgf000095_0001
wherein R1, R2, R3, R4, R5, R6, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to amidation, to give a compound of the formula :
Figure imgf000095_0002
wherein R1, R2, R3, R4, R5, R\ A,Q,X,Y and Z are each as defined above, and b is amidated carboxy, or a salt thereof, or f) subjecting a compound of the formula:
Figure imgf000096_0001
wherein R1, R2, R3, R4, R5, RB, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to esterification, to give a compound of the formula
Figure imgf000096_0002
wherein R\ R2. R3, R4. R5. R6, A,Q,X,Y and Z are each as defined above, and RI is esterified carboxy, or a salt thereof, or g) subjecting a compound of the formula:
Figure imgf000097_0001
wherein R1, R2, R3, R4, R6, R7,A,Q,X,Y and Z are each as defined above, or a salt thereof, to introduction of the imino-protective group, to give a compound of the formula :
Figure imgf000097_0002
wherein R1, R2, R3, R\ R6, R7,A,Q,X,Y and Z are each as defined above, and RI is imino-protective group, or a salt thereof, or h) subjecting a compound of the formula:
Figure imgf000098_0001
wherein R R2, R3, R4, R5, R6, A,Q,X,Y and Z are each as defined above, or its reactive derivative at the carboxy group, or a salt thereof, to the conversion reaction of carboxy to lower alkoxycarbonylamino to give a compound of the formula :
Figure imgf000098_0002
wherein R1, R2, R3, R4, R5, Ra, A,Q,X.Y and Z are each as defined above, and RI is lower alkoxycarbonylamino, or a salt thereof, or i) subjecting a compound of the formula:
Figure imgf000099_0001
wherein R\ R2, R3, R4, R5, R7,A,Q,X and Y are each as defined above, or a salt thereof, to ring closure, to give a compound of the formula
Figure imgf000099_0002
wherein R\ R2, R3, R4, R5. R6, R7, A,Q,X,Y and Z are each as defined above, or a salt thereof.
7. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
8. A method for treating or preventing angiotensin II mediated diseases, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or • animals.
9. A method for treating or preventing hypertension or heart failure, which comprises administering a compound of claim 1 or pharmaceutically acceptable salt thereof to human being or animals.
10. A compound of-claim 1 or pharmaceutically acceptable salt thereof for use as a medicament.
11. A compound of claim 1 or pharmaceutically acceptable salt thereof for use as an angiotensin II antagonist.
12. Use of a compound of claim 1 for manufacturing a medicament for treating or preventing angiotensin II mediated diseases.
13. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 with a pharmaceutically acceptable substantially non-toxic carrier or excipient.
PCT/JP1993/000261 1992-03-03 1993-03-01 Benzimidazole derivatives as angiotensin ii antagonists WO1993018030A1 (en)

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EP0577023A3 (en) * 1992-07-01 1996-12-18 Hoechst Ag Angiotensin-ii receptor-antagonists for the treatment of arrhythmices
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RU2152941C1 (en) * 1994-11-14 2000-07-20 Дайити Фармасьютикал Ко., Лтд. Crystalline 3[-2[4-(3-chloro-2-methylphenyl)-1- piperazinyl]ethyl]-5,6-dimethoxy-1-[4-imidazolylmethyl]- 1h-indazole dehydrochloride and 3,5-hydrate thereof, and methods of preparation thereof
JP3294616B2 (en) 1995-08-10 2002-06-24 メルク エンド カンパニー インコーポレーテッド 2-Substituted arylpyrroles, compositions containing such compounds and methods of use
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