NZ245741A - 1-biphenylylmethylbenzimidazole derivatives; pharmaceutical compositions and preparatory methods - Google Patents

1-biphenylylmethylbenzimidazole derivatives; pharmaceutical compositions and preparatory methods

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Publication number
NZ245741A
NZ245741A NZ245741A NZ24574193A NZ245741A NZ 245741 A NZ245741 A NZ 245741A NZ 245741 A NZ245741 A NZ 245741A NZ 24574193 A NZ24574193 A NZ 24574193A NZ 245741 A NZ245741 A NZ 245741A
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New Zealand
Prior art keywords
methyl
imidazol
group
benzimidazol
biphenyl
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NZ245741A
Inventor
Norbert Hauel
Berthold Narr
Uwe Ries
Meel Jacques Van
Wolfgang Wienen
Michael Entzeroth
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Thomae Gmbh Dr K
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Publication date
Priority claimed from DE4201554A external-priority patent/DE4201554A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of NZ245741A publication Critical patent/NZ245741A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Toys (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Instructional Devices (AREA)

Abstract

The invention relates to benzimidazoles of the general formuala <IMAGE> in which R1 to R4 are as defined in Claim 1, and their salts, which have useful properties. The novel compounds are, in particular, angiotensin antagonists.

Description

New Zealand Paient Spedficaiion for Paient Number £45741 Priciity Lu:-Jxa): . .. j .k-.i-.f?.?-., ! Complete Specification fiio i: i ci?°>s: .c.cyrtp^Av^.- cct(dv?^os.)v Cfilffcr&W,».«+; . <-9.1 .'Sv. . h-7>f, .U^.S . ,»?>". . .
Publication Dr.r. .?.f J.VL ,8.35 P.O. Jourr.c', K-_: Vft?l«rtr i no d,mnes Patents Form No. 5 Vts*; tx •* NEW ZEALAND >*" 1 1 FEB1993 ~ 1 PATENTS ACT 1953 ^ . ^ r i / COMPLETE SPECIFICATION BENZ IMIDAZOLES , i-'J • -..a - ;*U>»* • '--..As '• WE, DR KARL THOMAE GMBH, a German company of W-7950 Biberach an der Riss, FEDERAL REPUBLIC OF GERMANY hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) *45741 Id BenzimiflazQieg The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.
EP-A-392317 describes benzimidazoles which are valuable angiotensin antagonists.
It has now been found that certain new benzimidazoles are even more useful angiotensin antagonists, particularly angiotensin-II-antagonists.
Thus, according to one aspect the present invention provides compounds of formula I: (wherein Rx represents a C^-alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R2 represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C^.g-alkyl group or by a phenyl group and substituted in the l-position by a Cj^-alkyl group substituted in the terminal position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbony1, (I) (followed by page 2) 245741 morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group, by a C2.4-alkyl group substituted other than in the exposition by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or imidazol-l-yl group, by a Ci.i-alkyl group substituted by a trifluoromethyl group, by a C3.7-cycloalkyl group or by a phenyl group itself mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, or by a C^-alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms; R3 represents a C2.4-alkyl, C2.3-alkoxy, C2-3-alkylthio, cyclopropyl or cyclobutyl group,- and R4 represents a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group); and the compounds (a) 41 -[(2-n-Propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, N.Z. PATENT Oi-'FICE MAR 1995 RECEIVED 2457 (b) 41-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl) benzimidazol-l-yl)-methyl]-biphenyl-2-carboxvlic acid, (c) 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)~ benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (d) 4'-[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (e) 4'-[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid (f) 41 -[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (g) 41 -[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol 4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (h) 4'-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol 4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (i) 4'-[(2-n-Propyl-4-methyl-6-(l-(l-n-propyl-n-butyl) imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (j) 41 -[(2-n-Propyl-4-methyl-6-(l-(l-n-propyl-n-butyl) imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (k) 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid hydrate, V^1L (1) 41 -[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl) -benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (m) 4 '-[ (2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, and (n) 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl and the salts thereof, particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acids or bases.
The term "a group convertable in vivo into a carboxy group" may denote, for example, carboxyl esters such as those of formulae - CO - OR', - CO - 0 - (HCR") - O - CO - R"1 and - CO - 0 - (HCR") - 0 - CO - OR"' (wherein R1 denotes a straight-chained or branched C^-alkyl group or C5.7-cycloalkyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, R" denotes a hydrogen atom or a methyl group, and R"1 denotes a straight-chained or branched C^g-alkyl group or a C5_7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group).
The following are examples of the definitions of groups Rj to R4 given hereinbefore: 2457 R, may represent a hydrogen, fluorine or chlorine atom, a methyl, ethyl, n-propyl or isopropyl group; R; may represent an oxazol-4-yl, 2-methyl-oxazol-4-yl, 2-ethyl-oxazol-4-yl, 2-n-propyl-oxazol-4-yl, 2-isopropyl-oxazol-4-yl, 2-n-butyl-oxazol-4-yl, 2-isobutyl-oxazol-4-yl, 2-n-pentyl-oxazol-4-yl, 2-isoamyl-oxazol-4-yl, 2-n-hexyl-oxazol-4-yl, 2-phenyl-oxazol-4-yl, thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-ethyl-thiazol-4-yl, 2-n~propyl-thiazol-4-yl, 2-isopropyl-thiazol-4-yl, 2-n-butyl-thiazol-4-yl, 2-isobutyl-thiazol-4-yl, 2-n-pentyl-thiazol-4-yl, 2-isoamyl-thiazol-4-yl, 2-n-hexyl-thiazol-4-yl, 2-phenyl-thiazol-4-yl, l-methyl-imidazol-4-yl, l-ethyl-imidazol-4-yl, l-n-propyl-imidazol-4-yl, l-isopropyl-imidazol-4-yl, 1-n-butyl-imidazol-4-yl, l-isobutyl-imidazol-4-yl, 1-n-pentyl-imidazol-4-yl-, l-isoamyl-imidazol-4-yl, 1-n-hexyl-imidazol-4-yl, l-n~hexyl-2-methyl-imidazol-4-yl, 1-(l-methyl-n-pentyl)-imidazol-4-yl, l-(1-ethyl-n-butyl)-imidazol-4-yl, 1-(1-methyl-n-hexyl)-imidazol-4-yl, l-(1-ethyl-n-pentyl)-imidazol-4-yl, 1-(1-n-propyl-n-butyl)-imidazol-4-yl, l-n-heptyl-imidazol-4-yl, 1-ethyl- 2-methyl-imidazo1-4-yl, 1-n-propy1-2-methyl-imidazol-4-yl, l-isopropyl-2-methyl-imidazol-4-yl, l-n-butyl-2-methyl-imidazol-4-yl, 1-isobutyl-2-methyl-imidazol-4-yl, l-n-pentyl-2-methyl-imidazol-4-yl, l-isoamyl-2-methyl-imidazol-4-yl, l-n-hexyl-2-methyl-imidazol-4~yl, l-n-hepty1-2-methyl-imidazol-4-yl, 1-cyclopropylmethyl-imidazol-4-yl, l-cyclobutylmethyl-imidazol-4-yl, 1-cyclopentylmethyl-imidazol-4-yl, 1-cyclohexylmethyl-imidazol-4-yl, l-cycloheptylmethyl-imidazol-4-yl, 1—(2— f^cyclo- propylethyl)-imidazol-4-yl, 1~{2-"*v wlyclobutylethyl)-imidazol-4-yl, 1-(2-cyclopentylethyl)-*midazol-4-yl, l-(2-cyclohexylethyl)-imidazol-4-yl, 1-2-cycloheptyl-ethyl)-imidazol-4-yl, 1-(3-clopropylpropyl)-imidazol-4-yl-, l-(3-clobutylpropyl)-imidazol-4-yl, 1-(3- i 2457 cyclopentylpropyl)-imidazol-4-yl, 1-(3-cyclohexyl-propyl)-imidazol-4-yl, 1-(3-cycloheptylpropyl)-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-imidazol-4-yl, l-(3,3,3-trifluoropropyl)-imidazol-4-yl, l-benzyl-imidazol-4-yl, 1-(2-phenylethyl)-imidazol-4-yl, 1-(3-phenylpropyl)-imidazol-4-yl, 1-(4-fluorobenzyl)-imidazol-4-yl, l-(4-chlorobenzyl)-imidazol-4-yl, 1-(3-chlorobenzyl)-imidazol-4-yl, 1-(4-trifluoromethyl-benzyl)-imidazol-4-yl, 1-(3-methyl-benzyl)-imidazol-4-yl, 1-(4-methyl-benzyl )-imidazol-4-yl, 1-(3-methoxy-benzyl)-imidazol-4-yl, 1-(4-methoxy-benzyl)-imidazol-4-yl, l-(3,4-dimethoxy-benzyl)-imidazol-4-yl, l-(3,5-dimethoxy-benzyl)-imidazol-4-yl, l-cyclopropylmethyl-2-methyl-imidazol-4-yl, l-cyclobutylmethyl-2-methyl-imidazol-4-yl, l-cyclopentylmethyl-2-methyl-imidazol-4-yl, 1-cyclohexylmethyl-2-methyl-imidazol-4-yl, 1-cyclo-heptylmethyl-2-methyl-imidazol-4-yl, 1-(2-cyclopropylethyl)-2-methyl-imidazol-4-yl, l-(2-cyclobutylethyl)-2-methyl-imidazol-4-yl, 1-(2-cyclopentylethyl)-2-methyl-imidazol-4-yl, 1- (2-cyclohexylethyl)-2-methyl-imidazol-4-yl, 1-(2-cycloheptylethyl)-2-methyl-imidazol-4-yl, 1-(3-cyclopropylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cyclobutylpropyl)-2-methyl-imidazol-4-yl, 1- (3-cyclopentylpropyl)-2-methyl-imidazol-4-yl, l-(3-cyclohexylpropyl)-2-methyl-imidazol-4-yl, 1-(3-cycloheptylpropyl)-2-methyl-imidazol-4-yl, 1-(2,2,2-trifluoroethyl)-2-methyl-imidazol-4-yl-, 1-(3,3,3-trifluoropropyl)-2-methyl-imidazol-4-yl-, l-benzyl-2-methyl-imidazol-4-yl, 1-(2-phenylethyl)-2-methyl-imidazol-4-yl, 1-(3-phenylpropyl)-2-methyl-imidazol-4-yl, l-(4-fluorobenzyl)-2-methyl-imidazol-4-yl, l-(4-chlorobenzyl)-2-methyl-imidazol-4-yl, 1-(3-chlorobenzyl) -2-methyl-imidazol-4-yl, l-(4-trifluoromethyl-benzyl)-2-methyl-imidazol-4-yl, 1-(3-methyl-benzyl)-2-ethyl-imidazol-4-yl, 1-(4-methyl-benzyl)-2-methyl-midazol-4-yl, 1-(3-methoxy-benzyl)-2-methyl-imidazol-4- yl, 1-( 4-methoxy-benzyl) -2-methyl-imidazol-4-yl, l-(3,4-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1-(3,5-dimethoxy-benzyl)-2-methyl-imidazol-4-yl, 1-carboxymethyl-imidazol-4-yl, 1-(2-carboxyethyl)-imidazol-4-yl, 1-(3-carboxypropyl)-imidazol-4-yl, l-(4-carboxybutyl)-imidazol-4-y1, 1-(5-carboxypentyl)-imidazol-4-yl, 1-(6-carboxvhexyl)-imidazol-4-yl, l-(7-carboxyheptyl)-imidazol-4-yl, 1-methoxycarbonylmethyl-imidazol-4-yl, 1-(2-methoxycarbonylethyl)-imidazol-4-yl, 1- (3-methoxycarboriylpropyl) -imidazol-4-yl, 1- (4-■methnxyoarbonylbutyl) -imidazol-4-vl, 1- (5-methoxycarbonylpentyl)-imidazol-4-yl, 1-(6-methoxycarbonylhexyl)-imidazol-4-yl, 1-(7-methoxy-carbonylheptyl)-imidazol-4-yl, 1-ethoxycarbonylmethyl-imidazol-4-yl, 1-(2-ethoxycarbonylethyl)-imidazol-4-yl, 1-(3-ethoxycarbonylpropyl)-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-imidazol-4-yl, 1-(5-ethoxycarbonyl-pentyl)-imidazol-4-yl, 1-(6-ethoxycarbonylhexyl)-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-imidazol-4-yl, l-n-propoxycarbonylmethyl-imidazol-4-yl, 1-(2-n-propoxycarbonylethyl)-imidazol-4-yl, 1-(3-n-propoxycarbonylpropyl)-imidazol-4-yl, 1-(4-n-propoxy-carbonylbutyl)-imidazol-4-yl, 1-(5-n-propoxycarbonyl-pentyl)-imidazol-4-yl, 1-(6-n-propoxycarbonylhexyl)-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-imidazol-4-yl, l-isopropoxycarbonylmethyl-imidazol-4-yl, l-(2-isopropoxycarbonylethyl)-imidazol-4-yl, 1-(3-isopropoxycarbonylpropyl)-imidazol-4-yl, 1-(4-isopropoxycarbonylbutyl)-imidazol-4-yl, 1-(5-isopropoxycarbonylpentyl)-imidazol-4-yl, l-(6-isopropoxycarbonylhexyl)-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-imidazol-4-yl, 1-aminocarbonylmethyl-imidazol-4-yl, 1-(2-aminocarbonyl-ethyl)-imidazol-4-yl, 1-(3-aminocarbonylpropyl)-imidazol-4-yl, 1-(4-aminocarbonylbutyl)-imidazol-4-yl, 1-(5-aminocarbonylpentyl)-imidazol-4-yl, 1—(6-aminocarbonylhexyl)-imidazol-4-yl, 1-(7-aminocarbonyl- heptyl) -ijnidazol-4-yl, 1-methylaminocarbonylmethyl-imidazol-4-yl, 1-(2-methylaminocarbonylethyl)-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-methylaminocarbonylbuty1)-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-imidazol-4-yl, l-(6-methylaminocarbonylhexyl)-imidazol-4-yl, 1—(7 — methylaminocarbonylheptyl)-imidazol-4-yl, 1-ethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-ethylamino carbonylethyl)-imidazol-4-yl, 1-(3-ethylaminocarbonyl-propyl) -iiriidazol-4-yl, 1- (4-ethylaminocarbonylbutyl) -imidazol-4-yl, 1-{5-ethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-ethylaminocarbonylhexyl)-imidazol-4-yl, l-(7 ethylaminocarbonylheptyl)-imidazol-4-yl, 1-n-propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-n-propylaminocarbonylethyl)-imidazol-4-yl, 1- (3-n-propylaminocarbonylpropyl)-imidazol-4-yl, l-(4-n-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-n-propylaminocarbonylpentyl)-imidazol-4-yl, l-(6-n-propylaminocarbonylhexyl)-imidazol-4-yl, 1- (7-n-propylaminocarbonylheptyl) -imidazol-4-yl, 1-isopropylaminocarbonylmethyl-imidazol-4-yl, 1- (2-isopropylaminocarbonylethyl)-imidazol-4-yl, 1-(3-isopropylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-isopropylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-isopropylaminocarbonylhexyl)-imidazol-4-yl, 1—(7— isopropylaminocarbonylheptyl)-imidazol-4-yl, 1-dimethylaminocarbonylmethyl-imidazol-4-yl, 1-(2-dimethylaminocarbonylethyl)-imidazol-4-yl, 1-(3-di-methylaminocarbonylpropyl)-imidazol-4-yl, l-(4-dimethylaminocarbonylbutyl)-imidazol-4-yl, 1—(5— dimethylaminocarbonylpentyl)-imidazol-4-yl, l-(6-*^dimethylaminocarbonylhexyl)-imidazol-4-yl, 1-(7- dimethylaminocarbonylheptyl)-imidazol-4-yl, 1-v/ diethylanunocarbonylmethyl-imidazol-4-yl, l-(2-diethylaminocarbonylethyl)-imidazol-4-yl, l-(3-diethylaminocarbonylpropyl)-imidazol-4-yl, 1—(4 — 4 2457 diethylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-diethylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-diethylaminocarbonylhexyl)-imidazol-4-yl, 1-(7-diethylaminocarbonylheptyl)-imidazol-4-yl, 1-di-n-propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-di-n-propylaminocarbonylethyl)-imidazol-4-yl, 1-(3-di-n-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-di-n-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-di-n-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-di-n-propylaminocarbonylhexyl)-imidazol-4-yl, l-(7-di-n-propylaminocarbonylheptyl)-imidazol-4-yl, 1-diiso-propylaminocarbonylmethyl-imidazol-4-yl, 1-(2-diiso-propylaminocarbonylethyl)-imidazol-4-yl, l-(3-diiso-propylaminocarbonylpropyl)-imidazol-4-yl, 1-(4-diiso-propylaminocarbonylbutyl)-imidazol-4-yl, 1-(5-diiso-propylaminocarbonylpentyl)-imidazol-4-yl, 1-(6-diisopropylaminocarbonylhexyl)-imidazol-4-yl, 1—(7 — diisopropylaminocarbonylheptyl)-imidazol-4-yl, 1-morpholinocarbonylmethyl-imidazol-4-yl, 1-(2-morpholinocarbonylethyl)-imidazol-4-yl, 1-(3-morpholinocarbonylpropyl)-imidazol-4-yl, l-(4-morpholinocarbonylbutyl)-imidazol-4-yl, 1-(5-morpholinocarbonylpentyl)-imidazol-4-yl, l-(6-morpholinocarbonylhexyl)-imidazol-4-yl, 1-(7-morpholinocarbonylheptyl)-imidazol-4-yl, 1-thiomorpholinocarbonylmethyl-imidazol-4-yl, 1-(2-thiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-imidazol-4-yl, 1 — (4 — thiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-(5-thiomorpholinocarbonylpentyl)-imidazol-4-yl, l-(6-thiomorpholinocarbonylhexyl)-imidazol-4-yl, l-(7-thiomorpholinocarbonylheptyl)-imidazol-4-yl, 1-oxidothiomorpholinocarbonylmethyl-imidazol-4-yl, 1-(2 oxidothiomorpholinocarbonylethyl)-imidazol-4-yl, 1-(3 oxidothiomorpholinocarbonylpropyl)-imidazol-4-yl, 1-( oxidothiomorpholinocarbonylbutyl)-imidazol-4-yl, 1-(5 oxidothiomorpholinocarbonylpentyl)-imidazol-4-yl, 1-( oxidothiomorpholinocarbonylhexyl)-imidazol-4-yl, l-(7-oxidothiomorpholinocarbonylheptyl)-imidazol-4-yl, 1-carboxymethyl-2-methyl-imidazol-4-yl, 1-(2-carboxyethyl)-2-methyl-imidazol-4-yl, 1- (3-carboxypropyl)-2-methyl-imidazol-4-yl, 1- (4-carboxybutyl) -2-methyl-imidazol-4-yl, 1- (5-carboxypentyl)-2-methyl-imidazol-4-yl, 1- (6-carboxyhexyl)-2-methyl-imidazol-4-yl, 1-(7-carboxyheptyl)-2-methyl-imidazol-4-yl, 1-methoxycarbonylmethyl-2-methyl-iniidazol-4-yl, 1-(2-methoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methoxycarbonylpropyl) -2-inethyl-ifluda2ol-4-yl, 1- (4-methoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-methoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-methoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethoxycarbonylmethyl-2-methyl-imidazol-4-yl, l-(2-ethoxycarbonyl ethyl)-2-methyl-imidazol-4-yl, 1-(3-ethoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-ethoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-ethoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1—(6— ethoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-n-propoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-n-propoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-n-propoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-n-propoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1-isopropoxycarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropoxycarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropoxycarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4 isopropoxycarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-isopropoxycarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6 isopropoxycarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-isopropoxycarbonylheptyl)-2-methyl-imidazol-4-yl, 1- aminocarbonylmethyl-2-methyl-imidazol-4-yl, 1- (2-aminocarbonylethyl)-2-methyl-imidazol-4-yl, 1- (3-aminocarbonylpropyl)-2-methyl-imidazol-4-yl, l-(4-aminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-aminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-aminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-aminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-methylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-methylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-methylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4 methylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-methylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6 methylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, l—(7— methylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-ethylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-ethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-ethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-ethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-ethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-ethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-ethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-n-propylaminocarbonylinethyl-2-methyl-imidazol-4-yl, l- (2-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl 1-(5-n-propylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-n-propylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-isopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-isopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-isopropylaminocarbonyl-propyl)-2-methyl-imidazol-4-yl, l-(4-isopropylamino-carbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-isopropylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1 (6-isopropylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-isopropylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, l-dimethylaminocarbonylmethyl-2-methyl-imidazol-4- p /' K ? A vl, 1-(2-dimethylaminocarbonylethyl)-2-methy1-imidazol-4-yl, 1-(3-dimethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-dimethylaminocarbonylbutyl) -2-methyl-imidazol-4-yl, 1-(5-dimethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-dimethylaminocarbonyl-hexyl) -2-methyl-imidazol-4-yl, 1-(7-dimethylamino-carbonylheptyl)-2-methyl-imidazol-4-yl, 1-diethylaminocarbonylmethy1-2-methyl-imidazol-4-yl, 1-(2-diethylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-diethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-diethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-diethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-diethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-diethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-di-n-propylaminocarbonylmethy1-2-methyl-imidazol-4-yl, 1- (2-di-n-propylaminocarbonylethyl)-2-methy1-imidazol-4-yl, 1-(3-di-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, 1- (4-di-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-di-n-propylaminocarbonyl-pentyl) -2-methyl-imidazol-4-yl, 1-(6-di-n-propylamino-carbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-di-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-diisopropylaminocarbonylmethy1-2-methyl-imidazol-4-yl, 1- (2-diisopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-diisopropylaminocarbonylpropyl)-2-methyl-imidazol-4-yl, l-(4-diisopropylaminocarbonylbutyl)-2-methy l-imidazol-4-yl, 1-(5-diisopropylaminocarbony1-pentyl) -2-methyl-imidazol-4-yl, 1-(6-diisopropylamino-carbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-diisopropyl-aminocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-morpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-morpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, l-(4-morpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-morpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, l-(6-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-morpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, 1- 245741 thiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-thiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-thiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-thiomorpholinocarbonyl-butyl)-2-methyl-imidazol-4-yl, l-(5-thiomorpholinocarbonylpentyl)-2-methyl-imidazol-4-yl, 1-(6-thiomorpholinocarbonyl-hexyl)-2-methyl-imidazol-4-yl, 1-(7-thiomorpholino-carbonylheptyl)-2-methyl-imidazol-4-yl, 1-oxidothio-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl, 1-(2-oxidothiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl, 1-(3-oxidothiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl, 1-(4-oxidothiomorpholinocarbonylbutyl)-2-methyl-imidazol-4-yl, 1-(5-oxidothiomorpholinocarbonyl-pentyl)-2-methyl-imidazol-4-yl, 1-(6-oxidothio-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl, 1-(7-oxidothiomorpholinocarbonylheptyl)-2-methyl-imidazol-4-yl, 1-(2-hydroxyethyl)-imidazol-4-yl, l-(3~ hydroxypropyl)-imidazol-4-yl, 1-(4-hydroxybutyl)-imidazol-4-yl, 1-(2-methoxyethyl)-imidazol-4-yl, 1—(3 — methoxypropyl)-imidazol-4-yl, l-(4-methoxybutyl)-imidazol-4-yl, 1-(2-ethoxyethyl)-imidazol-4-yl, l-(3-ethoxypropyl)-imidazol-4-yl, l-(4-ethoxybutyl)-imidazol-4-yl, 1-(2-n-propoxyethyl)-imidazol-4-yl, 1-(3-n-propoxypropyl)-imidazol-4-yl, 1-(4-n-propoxybutyl)-imidazol-4-yl, 1-(2-isopropoxyethyl)-imidazol-4-yl, 1-(3-isopropoxypropyl)-imidazol-4-yl, 1-(4-isopropoxy-butyl)-imidazol-4-yl, 1-(2-imidazol-l-yl-ethyl)-imidazol-4-yl, 1-(3-Imidazol-l-yl-propyl)-imidazol-4-yl, l-(4-imidazol-l-yl-butyl)-imidazol-4-yl, l-(2,2-diphenyl-ethyl)-imidazol-4-yl, 1-(3, 3-diphenyl-propyl)-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-imidazol-4-yl, 1-(2-hydroxyethyl)-2-methyl-imidazol-4-yl, 1-(3-hydroxy-propyl) -2-methyl-imidazol-4-yl, l-(4-hydroxybutyl)-2-methyl-imidazol-4-yl, 1-(2-methoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-methoxypropyl)-2-methyl-imidazol-4-yl, 1-(4-methoxybutyl)-2-methyl-imidazol-4-yl, l-(2-ethoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-ethoxypropyl)- 9^57 ^ 1 2-methyl-imidazol-4-yl, 1-(4-ethoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-n-propoxyethyl)-2-methyl-imidazol-4-yl, 1-(3-n-propoxypropyl)-2-methyl-imidazol-4-yl, l-(4-n-propoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-isopropoxyethyl)-2-methyl-imidazol-4-yl, 1- (3-isopropoxypropyl)-2-methyl-imidazol-4-yl, l-(4-isopropoxybutyl)-2-methyl-imidazol-4-yl, 1-(2-imidazol-1-yl-ethyl)-2-methyl-imidazol-4-yl, 1-(3-imidazol-l-yl-propyl)-2-methyl-imidazol-4-yl, 1-(4-imidazol-l-yl-butyl)-2-methyl-imidazol-4-yl/ 1-(2,2-diphenyl-ethyl)-2-methyl-imidazol-4-yl. 1 -(3.i-diphenyl-propyl)-2-methyl-imidazol-4-yl, 1-(4,4-diphenyl-butyl)-2-methyl-imidazol-4-yl, 1-[2-(2-methoxyethoxy)-ethyl]-imidazol-4-yl, l-[3-(2-methoxyethoxy)-propyl]-imidazol-4-yl, l-[4-(2-methoxyethoxy)-butyl]-imidazol-4-yl, 1-[2 —(2 — ethoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-ethoxyethoxy)-propyl]-imidazol-4-yl, 1—[4—(2-ethoxyethoxy)-butyl]-imidazol-4-yl, 1-[2-(2-n-propoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-n-propoxyethoxy) -propyl]-imidazol-4-yl, l-[4-(2-n-propoxyethoxy) -butyl]-imidazol-4-yl, 1—[2—(2— isopropoxyethoxy)-ethyl]-imidazol-4-yl, 1-[3-(2-isopropoxyethoxy)-propyl]-imidazol-4-yl, 1-[4-(2-isopropoxyethoxy)-butyl]-imidazol-4-yl, 1-(2-dimethylaminoethyl)-imidazol-4-yl, 1-(2-diethylamino-ethyl)-imidazol-4-yl, 1-(2-di-n-propylamino-ethyl)-imidazol-4-yl, l-(2-diisopropylaminoethyl)-imidazol-4-yl, 1-(3-dimethylaminopropyl)-imidazol-4-yl, l-(3-diethylaminopropyl)-imidazol-4-yl, 1-(3-di-n-propylamino-propyl)-imidazol-4-yl, 1-(3-di-isopropylamino-propyl)-imidazol-4-yl, 1-(4-dimethylamino-butyl)-imidazol-4-yl, 1-(4-diethylamino-butyl)-imidazol-4-yl, 1-(4-di-n-propylamino-butyl)-imidazol-4-yl, l-(4-diisopropylamino-butyl)-imidazol-4-yl, 1-(2-morpholino-ethyl)-imidazol-4-yl, 1—(3 — morpholino-propyl)-imidazol-4-yl, 1-(4-morpholino-butyl)-imidazol-4-yl, 1-(2-pyrrolidino-ethyl)-imidazol-4-yl, l-(3-pyrrolidino-propyl)-imidazc?l-4-yl, l-(4- pyrrolidino-butyl)-imidazol-4-yl, 1-(2-piperidino-ethyl) -imidazol-4-yl, 1-(3-piperidino-propyl)-imidazol-4-yl, 1-(4-piperidino-butyl) -imidazol-4-yl, l-(2-hexamethyleneimino-ethyl)-imidazol-4-yl, 1-(3-hexamethyleneimino-propyl)-imidazol-4-yl, 1-(4-hexamethyleneimino-butyl)-imidazol-4-yl, 1-(2-thiomorpholino-ethyl)-imidazol-4-yl, 1-(3-thio-morpholino-propyl)-imidazol-4-yl, 1-(4-thiomorpholino-butyl)-imidazol-4-yl, 1—[2 —(1-oxido-thiomorpholino)-ethyl]-imidazol-4-yl, 1-[3-(1-oxido-thiomorpholino)-propyl]-imidazol-4-yl or 1-[4-(1-oxido-thiomorpholino)-butyl]-imidazol-4-yl group; R3 may represent an ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, cyclopropyl, cyclobutyl, ethoxy, n-propoxy, isopropoxy, ethylthio, n-propylthio or isopropylthio group; and may represent a hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl, n-hexyloxy-carbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl, 2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl, isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl, n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxy-methoxycarbonyl, cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl, 2-phenylpropionyloxy-methoxycarbonyl, 3-phenyl-propionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl, benzoyloxy-methoxycarbonyl, 1-acetoxyethoxycarbonyl, 1-propionyloxyethoxycarbonyl, 1-n-butyryloxy- 2457 4 1 ethoxycarbonyl, l-isobutyryloxyethoxycarbonyl, 1-n-pentanoyloxyethoxycarbonyl, 1-isopentanoyloxy-ethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl, 1-n-hexanoyloxyethoxycarbonyl, 1-cyclopentanoyl-oxyethoxycarbonyl, l-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl, 1-(1-phenylpropionyloxy)-ethoxycarbonyl, 1-(2-phenylpropionyloxy)-ethoxycarbonyl, 1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl, methoxycarbonyloxymethoxy-carbonyl, ethoxycarbonyloxymethoxycarbonyl, n-propyloxycarbonyloxymethoxycarbonyl, isopropyloxy-carbonyloxymethoxycarbonyl, n-butyloxycarbonyloxy-methoxycarbonyl, isobutyloxycarbonyloxymethoxy-carbonyl, tert.butyloxycarbonyloxymethoxycarbonyl, n-pentyloxycarbonyloxymethoxycarbonyl, isoamyloxycarbonyl-oxymethoxycarbonyl, n-hexyloxycarbonyloxymethoxy-carbonyl, cyclopentyloxycarbonyloxymethoxycarbonyl, cyclohexyloxycarbonyloxymethoxycarbonyl, benzyloxy-carbonyloxymethoxycarbonyl, 1-phenylethoxycarbonyloxy-methoxycarbonyl, 2-phenylethoxycarbonyloxy-methoxycarbonyl, 3-phenylpropyloxycarbonyloxy-methoxycarbonyl, cinnamyloxycarbonyloxymethoxycarbonyl, 1- (methoxycarbonyloxy) -ethoxycarbonyl, 1-(ethoxycarbonyloxy) -ethoxycarbonyl, 1- (n-propyloxycarbonyloxy) -ethoxycarbonyl, 1-(isopropyloxycarbonyloxy) -ethoxycarbonyl, 1- (n-butyloxycarbonyloxy) -ethoxycarbonyl, 1- (isobutyloxy-carbonyloxy) -ethoxycarbonyl, 1- (tert.butyloxy-carbonyloxy) -ethoxycarbonyl, 1- (n-pentyloxycarbonyloxy) -ethoxycarbonyl, l-(isoamyloxycarbonyloxy)-ethoxycarbonyl, 1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl, 1-(cyclopentyloxycarbonyloxy)-ethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl, 1-(benzyloxycarbonyloxy) -ethoxycarbonyl, 1- (1-phenylethoxycarbonyloxy) -ethoxycarbonyl, 1- (2-phenylethoxycarbonyloxy) -ethoxycarbonyl, 1- (3- 245741 phenylpropyloxycarbonyloxy)-ethoxycarbonyl, 1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group.
Preferred compounds according to the invention include those of formula I wherein Rx represents a C^-alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R2 in the G-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C^g-alkyl group or by a phenyl group and substituted in the 1-position by a C^y-alkyl group substituted in the terminal position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl' or l-oxido-thiomorpholinocarbonyl group, by a C2_4-alkyl group substituted other than in the exposition by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or imidazol-1-yl group, by a C^-alkvl group substituted by a trif luoromethyl group, by a C3.7-cycloalkyl group or by a phenyl group itself mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, N.Z.PATBN7 OFFICE ?n MAD 100c; 245741 or by a -alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms ,• R3 represents a C2.4-alkyl, C2_3-alkoxy, C2_3-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group and the salts thereof.
Particularly preferred compounds according to the invention include those of formula I wherein Rx represents a hydrogen or chlorine atom or a methyl group; R- in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a Cj.y-alkyl group substituted in the terminal position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbony1, morpholinocarbonyl, thiomorpholinocarbonyl or l-oxido- 24574 thiomorpholi.no-carbonyl group, by a C2.4-alkyl group substituted other than in the exposition by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-trifluoromethylbenzyl, 3,5-dimethoxybenzyl or 2,2-diphenylethyl group; R3 represents a C2_4-alkyl, C2.3-alkoxy, C2.3-alkylthio cyclopropyl or cyclobutyl group; and R4 represents a carboxy or 1H-tetrazolyl group or a group convertable in vivo into a carboxy group; and the salts thereof.
More particularly preferred compounds of formula I include those wherein Rx represents a hydrogen atom or a methyl group; R2 in the 6-position of the benzimidazole ring represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a C^-alkyl group substituted in the terminal position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholinocarbonyl group, 245741 by a C2.4-alkyl group substituted other than in the exposition by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-l-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, or 4-fluoro-benzyl group; R3 represents a C2.4-alkyl, ethoxy, ethylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy or 1H-tetrazolyl group; and the salts thereof.
The present invention particularly relates to the following compounds of formula I: (a) 4'-[(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (b) 4'-[(2-n-Propyl-4-methyl-6-(1-(2-methoxyethoxy-2 -ethyl)-imidazol-4-yl)-benzimidazol-l-yl) -methyl]-biphenyl-2-carboxylic acid; (c) 41 -[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-l-yl) -methyl] -2-(1H-tetrazol-5-yl)-biphenyl; (d) 41 -[(2 -Ethyl-4-methyl-G-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (e) 4'-[(2-n-Propyl-4-methyl-6-(1-(3- dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-l-yl)- 24574 * methyl]-biphenyl-2-carboxylic acid; (f) 41 -[(2-Ethyl-4-methy1-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (g) 41 -[(2-Ethyl-4-methyl-6-(l-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (h) 41 -[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (i) 41 -[(2-Ethy1-4-methy1-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (j ) 41 -[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (k) 41 -[(2-Ethyl-4-methy1-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid and the salts thereof.
According to a further aspect the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: a) cyclising a compound of formula II * rf- 'A { I y CO *■ * (D r * .ft ^ ^ 4i 22 R 1 (II) (wherein one of the groups X: and Y: represents a group of formula R5 represents a hydrogen atom or an R:.CO group, Ri , R;, R:. and R; are as hereinbefore defined, Z: and Z:, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C:_:-alkyl groups which may be identical or different or Z-. and Z; together represent an oxygen or sulphur atom, an imino group optionally substituted by a C>;.-alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; R and the other group X: or Y-_ represents a group of formula Z- z-/ " NH - C - R-. b) reacting a benzimidazole of formula III (III) (wherein R1; R2 and R:, are as hereinbefore defined) with a biphenyl compound of formula IV (IV) (wherein R4 is as hereinbefore defined and Zy represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxy group); c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V 24 R (V) (wherein Ri, R2 and R:, are as hereinbefore defined, and R41 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; d) (to prepare a compound of formula I wherein R, represents a IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI (wherein R:, Rc and R:, are as hereinbefore defined and R/' represents a IH-tetrazolyl group protected in the 1- or 3-position by a protecting group); (VI) e> (to prepare a compound of formula I wherein R., represents a IH-tetrazolyl group) reacting a compound of formula VII 245741 (VII) (wherein R1( R2 and R3 are as hereinbefore defined) with hydrazoic acid or a salt thereof; f) converting a compound of formula I wherein R4 denotes a carboxy group, by esterification into a corresponding compound of formula I wherein R4 denotes a group convertable in vivo into a carboxy group; g) converting a compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1- position by a C2_4-alkyl group itself substituted other than in the ot-position by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1-position by a C2_4-alkyl group substituted other than in the a-position by a hydroxy group,- h) separating the 1-isomer from a 1-, 3-isomer mixture of a compound of formula I by isomer separation,- i) converting a compound of formula I into a salt thereof, more particularly into a physiologically acceptable addition salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and j) performing a process as defined in any one of steps (a) to (i) above on a corresponding protected compound N.Z.PATEiMT OFFICE 50 MAR 1995 245741 and subsequently removing the protecting groups used.
The cyclisation of step (a) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmono-methylether, diethyleneglycol dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, e.g. at temperatures between 0 and 250 C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphuryl-chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, the cyclisation may also be carried out without a solvent and/or condensing agent.
It is particularly advantageous to carry out the reaction of step (a) by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of formula R-.C00H, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation. The resulting N-oxide is then converted by reduction into a corresponding compound of formula I.
The subsequent reduction of the N-oxide of formula ^>1 obtained is preferably carried out in a solvent such water, water/ethanol, methanol, glacial acetic acid, ithyl acetate or dimethylformamide with hydrogen in the .c presence of a hydrogenation catalyst such as Raney iS c nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid, hydrochloric acid or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50;C, but preferably at ambient temperature.
The reaction of step (b) is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, sodium hydride, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures between 0 and 100°C, e.g. at temperatures between ambient temperature and 50°C.
In the reaction of step (b), a mixture of the 1-and 3- isomers is preferably obtained from which subsequently the 1-isomer is isolated by crystallisation or chromatography using a substrate such as silica gel or aluminium oxide.
In step (c), functional derivatives of the carboxy group such as optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines and anhydrides, and nitrile and tetrazolyl groups may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. tert.butylesters, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.g. benzylesters, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step (c) is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, richloroacetic acid or trifluoroacetic acid or in the resence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, water/dioxane, methylene chloride or chloroform at temperatures between -10 C and 120 C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic acid or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If R.1 in a compound of formula V represents a cyano or aminocarbonyl group, such a group may also be converted into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and 50 C.
If R.; 1 in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, conveniently at temperatures between 40°C and 100°C, preferably at the boiling temperature of the solvent used.
If R.;' in a compound of formula V represents, for example, a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a I nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.
Suitable protecting groups for use in step (d) include, for example, triphenylmethyl, tributyl tin and triphenyl tin groups.
The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, more preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100°C, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150 C, preferably at temperatures between 120 and 14 0°C.
The reaction of step (e) is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150"C, preferably at 125 C. Advantageously, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in the reaction mixture by reacting with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which are also conveniently prepared in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.
The conversion in step (f) of a carboxy1 group into ^574 a group which is metabolically convertable in vivo into a carboxy group is expediently carried out by esterification with a corresponding alcohol or with a corresponding reactive acyl derivative, conveniently in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide or in an excess of an acylating agent as solvent, optionally in the presence of an acid activating or dehydrating agent such as thionyl chloride, with the anhydrides, esters or halides thereof, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously be used as solvent, at temperatures between -25 and 100'C, but preferably at temperatures between -10 and 80"C.
The subsequent ether splitting is conveniently carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydriodic acid or hydrobromic acid, but preferably under the effect of a Lewis acid such as boron trifluoride, boron tribromide, boron trichloride, dimethyl borobromide or aluminium trichloride in a suitable solvent such as dichloromethane or chloroform, or with the aid of bromotrimethylsilane, iodotrimethylsilane or chlorotrimethylsilane/sodium iodide in a suitable solvent such as acetonitrile, dichloromethane or chloroform, at temperatures between 0 and 100C'C, preferably at 20"C, with subsequent aqueous working up.
In the reactions described above, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by means of conventional protecting groups which are split off again after the reaction.
Examples of suitable protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group may include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100cC, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and SO'C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.
An isomer mixture of a compound of formula I thus obtained may if desired be resolved by chromatography using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or IH-tetrazolyl group, may if desired subsequently be converted into the addition salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Some of the compounds of formulae II to VII used as starting materials are known from the literature. Otherwise those compounds may be obtained by methods known from the literature.
Thus, for example, a compound of formula II may be obtained by alkylation of a corresponding o-amino-acylamino compound with a compound of formula IV. The 0-amino-acylamino compound required for this may be obtained by reduction of a corresponding o-nitro-acylamino compound which in turn may be obtained by nitration of a corresponding acylamino-acetophenone, subsequent conversion of the resulting corresponding o-nitro-acylamino-acetophenone into the corresponding co-bromo-acetophenone, subsequent cyclisation of the co-bromo-acetophenone with a corresponding acid amide and subsequent reduction of the nitro group. Before the reduction of the nitro group an oxazol-4-yl compound thus obtained may be converted into the corresponding imidazol-4-yl compound by means of a corresponding amine, preferably with ammonia, under pressure, or an imidazol-4-yl compound unsubstituted in the 1-position obtained in this way may be converted by alkylation into a corresponding imidazol-4-yl compound alkylated in the 1-position.
A starting compound of formula III may be obtained by reduction and cyclisation of an o-nitro-acylamino compound as described hereinbefore.
Starting compounds of formulae V, VI and VII may be obtained by reacting a compound of formula III with a corresponding compound of formula IV.
The new compounds of formula I and the •^7 _ * 1 physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin-antagonists, in particular, angiotensin-II-antagonists.
The compounds of formula I wherein R; represents a group convertable in vivo into a carboxy group, a carboxy or IH-tetrazolyl group have, in particular, useful pharmacological properties since they are angiotensin-antagonists, particularly angiotensin-II-antagonists. The other compounds of formula I are valuable as intermediate products for preparing the compounds mentioned above.
By way of example, the following compounds: A = 41 — [(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl) benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; B = 4'-[(2-n-propyl-4-methyl-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl; C = 41-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-y1)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid ; D = 41 -[(2-ethoxy-6-(l-isopropyl-imidazol-4-yl)- benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid; E = 4'-[(2-n-propyl-4-methy1-6-(1-cyeloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; = 4 * — [(2-n-propyl-4-methyl-6-(l-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphe 2-carboxylic acid; and 24574 G = 4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylamino- propyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid-dihydrochloride-pentahydrate were investigated for their biological activities as follows: Description of method: angiotensin-II-receptor bonding The tissue (rat's lung) is homogenised in tris buffer (50 mMol Tris, 150 mMoi NaCl, 5 mMol EDTA, pH 7.40) and centrifuged twice for 20 minutes each time at 20,000 x g. The finished pellet is resuspended in incubation buffer (50 mMol Tris, 5 mMol MgCl0.2% BSA, pH 7 .40) 1:75, based on the moist weight of the tissue. Each 0.1 ml of homogenate is incubated for 60 minutes at 37 C with 50 pM ['" I]-angiotensin-II (NEN, Dreieich, FRG) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation is ended by rapid filtration through glass fibre filter mats. The filters are each washed with 4 ml of ice cold buffer (25 mMol Tris, 2.5 mMol MgCl:, 0.1% BSA, pH 7.40). The bound radioactivity is measured in a gamma-counter. The corresponding ICs„ value is determined from the dosage-activity curve.
Substances A to G show the following IC- values in the test described: Substance IC- [nM] A 1.2 B 1.5 C 40 D E F 3 . 4 G 1 •3 0 £% R 7 4 e. «<■> -f ' In view of their pharmacological properties, namely a hypotensive effect with a diuretic/saluretic component, the new compounds and the physiologically acceptable addition salts thereof are suitable for the treatment of hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders (e.g. Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases.
Furthermore, the new compounds and the physiologically acceptable salts thereof are suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
Because of the effect of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson's syndrome, as well as disorders of cognitive functions.
Thus viewed from a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with at least one physiologically acceptable carrier or excipient.
Viewed from a still further aspect the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension and cardiac insufficiency and also ^ n. V 36 treating chronic renal insufficiency, ischaemic peripheral circulatory disorders (e.g. Raynaud's syndrome) and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases.
In particular, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout.
More particularly, the present invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for alleviating central nervous system disorders.
Viewed from a yet still further aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension and cardiac insufficiency and also for treating chronic renal insufficiency, ischaemic peripheral circulatory disorders and cerebovascular circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy and retinopathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering In particular, the present invention prov method of treatment of the human or non-human to said body a compound of formula I or a physiologically acceptable salt thereof.
I 37 body to combat pulmonary diseases, for preventing arterial re-sterosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, and for treating arteriosclerosis, diabetic angiopathy, hyperuricaemia and gout, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
More particulary, the present invention provides a method of treatment of the human or non-human animal body to combat central nervous system disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
The dosage required to achieve these effects in adults is appropriately, when administered intravenously, 0.5 to 100 mg, preferably 1 to 70 mg, and, when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 times a day. For this purpose, the compounds of formula I prepared according to the invention, optionally in conjunction with other active substances such as, for example, hypotensive agents, ACE inhibitors, diuretics and/or calcium antagonists, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, micro-crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
Examples of additional active substances which may be used in the combinations mentioned above include bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothia: "V.. {* 14N0w 1994 2457 41 38 cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage of these active substances is conveniently 1/5 of the lowest dose normally recommended up to 1/1 or the normally recommended dosage, that is for example 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 25 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg of nitrendipine.
The following non-limiting Examples are provided to illustrate the invention. All percentages and ratios given are by weight, other than eluant or solvent ratios which are by volume. t Example A 41-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid a) 3-Methy1-4-butyrylamino-5-nitro-acetophenone 32.6 g (148 mMol) of 3-methyl-4-butyrylamino-acetophenone are added in batches to 3 00 ml of fuming nitric acid, with stirring, at -15°C and stirred for a further 3 0 minutes at -15°C. The reaction mixture is then poured onto 3 litres of ice with stirring, the crude product precipitated is suction filtered, washed with 400 ml of water, dried and purified by recrystallisation from ethanol/diethylether (1:1).
Yield: 23.8 g (61.0% of theory), Rf value: 0.32 (silica gel; methylene chloride) Rf value: 0.48 (silica gel; methylene chloride/methanol = 50:1) b) 3-Methvl-4-butvrvlamino-5-nitro-Ci)-bromoacetophenone At ambient temperature, with stirring, a solution of 16.0 g (200 mMol) of bromine in 140 ml of dioxane is slowly added dropwise to a solution of 23.8 g (90 mMol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml of dichloromethane so that the reaction mixture is constantly completely decolorised. It is then stirred for a further two hours, then the reaction mixture is evaporated to dryness in vacuo. the residue thus obtained is triturated with about 20 ml of dichloromethane/diethylether (1:1), suction filtered and then dried. 23 g (74% of theory) of 3-methyl-4-butyrylamino-5-nitro-(o-bromoacetophenone are thus obtained, containing about 10% of starting material. The product is further reacted without any more purification.
R. value: 0.69 (silica gel; methylene chloride/met 24 5741 - = 50:1) R. value: 0.84 (silica gel; methylene chloride/methanol = 9:1) c) 2-Butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene A solution of 6.8 g (20 mMol) of 3-methyl-4-butyrylamino-5~nitro-ci)-bromoacetophenone in 20 ml of formamide is heated to 140 C for 2 hours. The cooled solution is then poured into about 50 ml of 1 N ammonia and stirred for about 15 minutes. The crude product precipitated is suction filtered, washed with about 50 ml of water and dried. In this way, 4.4 g (75% of theory) of the product are obtained, which is further reacted without any more purification.
R,- value: 0.29 (silica gel; methylene chloride/methanol = 9:1) d) 2-Butyrylamino-3-nitro-5-(l-methyl-imidazol-4-yl)- toluene 1.3 g (9.5 mMol) of methyl iodide are added dropwise at ambient temperature to a solution of 2.5 g (8.7 mMol) of 2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mMol) of potassium carbonate dihydrate in ml of dimethylsulphoxide at ambient temperature and then stirred for 2 hours. The reaction mixture is then stirred into about 150 ml of water and then extracted four times with 25 ml of ethyl acetate. The organic extracts are washed with about 30 ml of water, dried and concentrated by evaporation. The crude product thus obtained is purified by column chromatography (300 g silica gel, eluant: methylene chloride/methanol = 30:1). Yield: 640 mg (241 of theory), Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) e) 2-Butyrylamino-3-amino-5- (l-methyl-imidazol-4-y^-^*^fcfc * T toluene 640 mg (2.1 mMol) of 2-butyrylamino-3-nitro-5-(l-methyl imidazol-4-y1)-toluene are hydrogenated at ambient temperature under a hydrogen pressure of 5 bar in 30 ml of methanol after the addition of about 200 mg of 20% palladium/charcoal. After all the water has been absorbed the catalyst is filtered off and the filtrate is evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 600 mg (100% of theory), Rf value: 0.23 (silica gel; methylene chloride/methanol = 9:1) f) 2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazole 600 mg (2.1 mMol) of 2-butyrylamino-3-amino-5-(l-methyl imidazol-4-yl)-toluene are refluxed in 10 ml of glacial acetic acid for one hour. Then the mixture is evaporated to dryness in vacuo r the residue is mixed with about 15 ml of water, made alkaline with ammonia and extracted four times with about 10 ml of ethyl acetate. The organic extracts are washed with about 15 ml of water, dried and finally evaporated down. The crude product thus obtained is further reacted without any more purification.
Yield: 420 mg (79% of theory), R.- value: 0.37 (silica gel; methylene chloride/methanol = 9:1) g) Tert.butyl 41 -[(2-n-propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2- carboxvlate 280 mg (0.8 mMol) of tert.butyl 4'-bromomethyl-biphenyl 2-carboxylate are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl-4-methyl-6-(1-methyl-imidazol 4-yl)-benzimidazole and 90 mg (0.8 mMol) of potassium tert.butoxide in 5 ml of dimethylsulphoxide and t mixture is stirred for 90 minutes at ambient <r j temperature, then stirred into about 40 ml of water, extracted four times with about 10 ml of ethyl acetate, then the organic extracts are washed with 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant; dichloromethane/inethanol = 30:1).
Yield: 230 mg (56% of theory), Rr- value: 0.61 (silica gel; methylene chloride/methanol = 9:1) h) 41 -[(2-n-Propy1-4-methy1-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-vl)-methyl 1-biphenvl-2-carboxylic acid A solution of 230 mg (0.44 mMol) of tert.butyl 4'-[(2-n-propy1-4-methy1-6-(l-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 2 ml of trifluoroacetic acid in 10 ml of dichloromethane is stirred overnight at ambient temperature and then evaporated to dryness. The residue is dissolved in about 5 ml of dilute sodium hydroxide solution, the solution is neutralised with acetic acid, the precipitate formed is suction filtered, washed with water and dried.
Yield: 120 mg (59% of theory), Melting point: 293-295°C R. value: 0.39 (silica gel; methylene chloride/methanol = 9:1) Example B 41 -1(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl) benzimidazol-l-yl) -methyl ]-2- (lH-tetrazol-5-yl) - biphenyl-hydrate ^ 14 NOV 1994 ^ a) 4 ' - [ (2 -n-Propyl - 4 -methy 1-6 - (l-methyl imidazol-4 benzimidazol-l-vl)-methvn-2-cvano-biphenvl l" 14N1A |jj4 "1 245741 218 mg (0.8 mMol) of 4'-bromomethyl-2-cyano-biphenyl are added to a solution of 200 mg (0.79 mMol) of 2-n-propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazole and 90 mg (0.8 mMol) of potassium tert.butoxide in 6 ml of dimethylsulphoxide and the mixture is stirred for 14 hours at ambient temperature. Then it is stirred into about 40 ml of water, extracted four times with about 10 ml of ethyl acetate, the organic extracts are washed ■with about 10 ml of water, dried and evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel; eluant: dichloromethane/ethanol = 50:1).
Yield: 240 mg (67% of theory), Rf value: 0.38 (silica gel; methylene chloride/ethanol = 19:1) b) 4'-[(2-n-Propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate A solution of 222 mg (0.5 mMol) of 41-[(2-n-propyl-4-methyl-6-(l-methyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-cyano-biphenyl, 660 mg (10 mMol) of sodium azide and 540 mg (10 mMol) of ammonium chloride in 12 ml of pure dimethylformamide is heated to 140 C for 18 hours. The solution is then evaporated substantially to dryness and the product is isolated by column chromatography (60 g of silica gel, eluant: dichloromethane with 10% ethanol). The product thus obtained is taken up in about 10 ml of dilute ammonia solution and the solution is then adjusted to pH 6 with acetic acid. A greasy residue is formed which becomes crystalline after the addition of a little ethyl acetate and several hours' stirring. The crystalline product is suction filtered, washed with about 5 ml of water and dried.
Yield: 61.0 mg (24.0% of theory), Melting point: 255-257 C C c.H - N x HO (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.97 22.03 Rf value: 0.24 (silica gel; methylene chloride/methanol = 9:1) Example 1 41 -[(2-n-Propyl-4-methyl-6-(l-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 2 41-[(2-n-Propyl-4-methyl-6-(l-cyclohexylmethyl-imidazol-4—y1)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 41-[(2-n-propyl-4-methyl-6-(l-cyclohexylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 3 41 -[(2-n-Propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6-(l-(4-fluoroben2yl)-imidazol-4 . ¥ * fp yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate Lj and trifluoroacetic acid in methylene chloride. \ i§S4 The following compounds may be obtained analogously Example 3: 41 -[(2-n-propyl-4-methyl-6-(1-(3-chlorobenzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 4'-[(2-n-propyl-4-methyl-6-(1-(3,5~dimethoxybenzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 41-[(2-n-propyl-4-methyl-6-(1-(4-methylbenzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid 41-[(2-n-propyl-4-methyl-6-(1-(4-trifluoromethyl-benzyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Example 4 4•-[(2-n-Propyl-4-methyl-6-(l-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 5 41 -[(2-n-Propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2- 245741 carboxylate and trifluoroacetic acid in methylene chloride.
Example 6 4 1 -[(2-n-Propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl) -imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(3, 3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 7 4 1 -[(2-n-Propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[ (2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 8 41-[(2-n-Propyl-4-methyl-6-(l-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid - Prepared analogously to Example A from tert.butyl 41- "s [(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-^W _ ri4Novm4 yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 9 41 -[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6-(l-cyclopropylmethyl-imidazol-4- yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 59.0% of theory, Melting point: 279-280pC C;,:H3:N.O: (504.64) Calculated: C 76.16 H 6.39 N 11.10 Found: 76.41 6.37 11.20 R. value: 0.44 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 504 Example 10 41 -[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl a) 41 — [(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2- triphenvlmethyl-tetrazol-5-vl)-biphenyl To a solution of 300 mg (1.0 mMol) of 2-n-propyl-4-methyl-6-(l-cyclopropylmethyl-imidazol-4-yl)-benzimidazole and 110 mg (1.0 mMol) potassium tert.butoxide in 20 ml of dimethylsulphoxide are 560 mg (1.0 mMol) of 41-bromomethyl-2-(2- triphenylmethyl-tetrazol-5-yl)-biphenyl and the mixture is stirred for 16 hours at ambient temperature, then stirred into about 120 ml of water and extracted four times with 15 ml of ethyl acetate. The organic extracts are washed with about 30 ml of water, dried and then evaporated to dryness. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: methylene chloride/methanol = 30:1).
Yield: 460 mg (60 % of theory), Rt value: 0.78 (silica gel; methylene chloride/methanol = 9:1) b) 41 -[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benz imidazol-l-yl)-methyl]-2-(1H- tetrazol-5-yl)-biphenyl A mixture of 460 mg (0.6 mMol) of 41 -[(2-n-propyl-4-methyl-6-(1-cyclopropylmethy1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and 10 ml of saturated methanolic hydrochloric acid is stirred for one hour at ambient temperature. The mixture is then evaporated to dryness, the residue is dissolved in dilute ammonia solution and washed with ether. The aqueous phase is adjusted to pH 5 to 6 with acetic acid and subsequently the solid precipitate is suction filtered. The crude product thus obtained is purified by column chromatography (100 g silica gel, eluant: methylene chloride/methanol = 15:1) Yield: 130 mg (41% of theory), Melting point: amorphous C;. H-. N (528.67) Rf value: 0.32 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 528 Example 11 41 -[(2-n-Propyl-4-methyl-6-(1-cyclobutylmethy1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethy1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.
Example 12 4'-[(2-n-Propyl-4-methyl-6-(2-methy1-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6-(2-methy1-oxazol-4-yl)- benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 67.0% of theory, Melting point: 241-243 C C:9H:7N;,0:. (465. 56) Calculated: C 74.82 H 5.85 N 9.03 Found: 74.65 5.98 8.85 Rf value: 0.27 (silica gel; methylene chloride/ethanol = 19:1) ~ V ,! % "A !■ Example 13 1' um 1994 i „ „ y 4' - [ (2-n-Propyl-4-methyl-6- (2-methyl-oxazol-4-yl>j:^f_f v/ benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl I Prepared analogously to Example 10 from 4•-[(2-n-propyl- 4-methy1-6-(2-methy1-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and sodium azide in dimethylformamide.
Example 14 41 -[(2-n-Propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid Prepared analogously to Example A from tert.butyl 4'- [(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)- benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.0% of theory, Melting point: 281-283'C C:,4H:.oN-,0-. (527.63) Calculated: C 77.40 H 5.54 N 7.96 Found: 77.09 5.71 7.76 Rf value: 0.18 (silica gel; methylene chloride/ethanol = 19:1) Example 15 41-[(2-n-Propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methy1-6-(2-pheny1-oxazol-4-yl)-benzimidazol-l-yl)-methyl] -2- (2-triphenylmethyl-tetrazol-5-yl) -biphen^JL-^nd i H sodium azide in dimethylformamide. A* $ ,/n \ I4N0y 1994 2s5741 Example 16 4'-[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 69.0% of theory, Melting point: 175-178°C - N O (504 .61) Calculated: C 69.03 H 5.59 N 22.21 Found: 68.85 5.58 21.97 Rf value: 0.27 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 504 Example 17 4'-[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 41-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl ) -methyl ] -biphenyl-2-carboxylate and trifluoroacetic ^ acid in methylene chloride.
Yield: 38.0% of theory, J Melting point: 220-223°C A C;qH:sNJO:. (480.58) \< ' W'M ' Calculated: C 72.48 H 5.87 N 11.66 V;-Found: 72.36 6.05 llj41 Rf value: 0.26 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 480 41 -[(2-Ethoxy-5-(1-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41 -[(2-ethoxy-5- (l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]- 2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 44.0% of theory, Melting point: amorphous C29H:3N80 (504.61) Rf value: 0.24 (silica gel; methylene chloride/ethanol = 9:1) Mass spectrum: m/e = 504 Example 19 4 1 -[(2-n-Propyl-4-methyl-6-(l-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propy1-4-methy1-6-(1-cyclohepty1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 79.0% of theory, Melting point: from 190°C (decomp.) C35H?sNj02 (54 6.71) Rf value: 0.36 (silica gel; methylene chloride/methan = 9:1) Mass spectrum: m/e =54 6 Example 20 4'-[(2-n-Propyl-4-methyl-6-(l-cycloheptyl-imidazol-4- yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-methyl-6-(l-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl) -methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 27.0% of theory, Melting point: 198-201°C C35H,8N: (57 0.75) Rf value: 0.48 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e =57 0 Example 21 4'-[(2-n-Propy1-4-methy1-6-(1-(1-n-propy1-n-butyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[ (2-n-propyl-4-methyl-6- (1- (l-n-propyl-n-buj^yj.) -imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny carboxylate and trifluoroacetic acid in methyl chloride.
Yield: 28.0% of theory, ■ ^WViqoa Melting point: 236-238°C ^ C35H,,0N4O2 (548.73) Rf value: 0.61 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 548 Example 22 4 1 -[(2-Ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol- 1 4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-ethoxy-4-methy1-6-(l-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl) -methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52.0% of theory, Melting point: 172-173°C C31H30N4Oi (506.61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.36 5.94 11.30 Rf value: 0.52 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 506 Example 23 41 -[(2-Ethoxy-4-methyl-6-(l-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41 -[(2-ethoxy-4-methyl-6-(l-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 42.0% of theory, Melting point: amorphous C31H30NsO (530. 64) Rf value: 0.50 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 530 O L L T1 r-' Example 24 4'~[(2-n-Propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41-[(2-n-propyl- 4-tnethyl-6- (1- (1-n-propyl-n-butyl) -imidazol-4-yl) - benzimidazol-l-yl) -methyl]-2-(2-triphenylmethyl- tetrazol-5-yl)-biphenyl.
Yield: 12.0% of theory, Melting point: from 150 C (sintering) C35H4oN3 (572,76) Rf value: 0.34 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 572 Example 2 5 41 -[(2-n-Propyl-4-methyl-6-(l,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid hydrate a) tert. Butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2- carboxvlate A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6- -(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 agfcf)* * of potassium tert.butoxide in 60 ml of dimethyl- -v • • • 1 £ sulphoxide is stirred for 15 minutes at ambient ^ temperature. Then 5.2 g (15 mMol) of tert.butyl 4.'- ' ^9,94 * bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 14 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (400 g of silica gel; eluant: methylene chloride with 1 to 2% ethanol).
Yield: 3.5 g (61.4% of theory), Melting point: amorphous Rf value: 0.90 (silica gel; methylene chloride/ethanol = 4:1) b) 4 ' — [(2-n-Propyl-4-methyl-6-(l,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid hydrate A mixture of 1.5 g (3 mMol) of tert.butyl 4'-[(2-n-propyl -4 -methy 1-6- (2-methy1-oxazol-4-yl)-benzimidazol-l-yl) -methyl ] -biphenyl-2-carboxylate, 10 ml of 40% N-methylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 200°C in an autoclave. After cooling, the contents of the autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH 6.5 with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in IN sodium hydroxide solution. This solution is washed successively with 25 ml of acetic acid and diethylether, then adjusted to pH 6 with 2 0% citric acid. The product precipitated is suction filtered, washed with about 3 0 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Yield: 950 mg (68% of theory), Melting point: 239-240c,C C30H30N^O: X H;0 (496.62) Calculated: C 72.55 H 6.49 N 11.28 Found: 72.62 6.62 11.54 Rf value: 0.70 (silica gel; methylene chloride/ethanol =', 4:1) Example 2 6 245741 4 ' - [(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-hydrate a) 41 -[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl A solution of 2.8 g (11 mMol) of 2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15 mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide is stirred for 15 minutes at ambient temperature. Then 6.0 g of (11 mMol) of 41-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are added and the mixture is stirred for a further 3 hours at ambient temperature. Then the solution is stirred into about 150 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (500 g of silica gel; eluant: petroleum ether/ethyl acetate = 1:1) Yield: 3.6 g (45% of theory) b) 41 -[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-bipheny1-hydrate A mixture of 3.6 g (4,9 mMol) of 4 *[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 20 ml of 40% N-methylamine solution and 30 ml of N-methylformamide is heated to 200°C for 10 hours in an autoclave. After cooling, the contents of the autoclave are stirred with about 5 0 ml of water, this suspension is adjusted to pH 6.5 with 20% citric acid, then th crude product precipitated is suction filtered and purified by column chromatography (200 g silica ge eluant: methylene chloride with 5 to 20% ethanol). i Yield: 1.0 g (41% of theory), Melting point: from 195'C sintering C30Hv,N:. X H;0 (520.6) Calculated: C 69.21 H 6.19 N 21.52 Found: 68.99 6.26 21.37 Mass spectrum: m/e = 502 Example 27 41 -[(2-Ethyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benz imidazol-1-yl)-methyl]-biphenyl-2-carboxylie acid Prepared analogously to Example A from tert.butyl 41- [(2-ethyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)- benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 49% of theory, Melting point: 165-167cc C^H^NjCK (494.60) Calculated: C 72.85 H 6.11 N 11.33 Found: 72.62 6.27 11.35 Mass spectrum: m/e = 494 Example 28 41 -[(2-Cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-. carboxylic acid Prepared analogously to Example A from tert. butyl 4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene 24574 chloride.
Yield: 78% of theory, Melting point: 179-181°C C31H30N^O3 (506.61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.37 6.02 11.02 Mass spectrum: m/e = 506 Example 29 4 1 -[ (2-n-Propyl-4-inethyl-6- (1-aminocarbonylmethy1-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert. butyl 41- [(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol- 4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 26% of theory, Melting point: 190-192°C C;,0H29NsO;< (507.60) Rf value: 0.44 (silica gel; methylene chloride/methanol = 8:2) Example 3 0 4'-[(2-n-Propyl-4-methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylic acid Prepared analogously to Example A from tert.butyl [(2-n-propyl-4-methyl-6-(l-ethoxycarbonylmethyl- ^ imidazol-4-yl) -benzimidazol-l-yl) -methy 1]-bipheny carboxylate and trifluoroacetic acid in methylene ij, iQftUy jggy chloride. V* Yield: 18% of theory, Melting point: 223-224 C C32H32N404 (536.63) Rf value: 0.69 (silica gel; methylene chloride/methanol = 8:2) Mass spectrum: m/e =53 6 Example 31 41 — [(2-Cyclopropyl-4-methyl-6-(1-(2-hydroxyethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid A solution of 500 mg (1.0 mMol) of 41 -[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-bipheny1-2-carboxylie acid and 1.5 g (6.0 mMol) of boron tribromide in 50 ml of methylene chloride is stirred for 16 hours at ambient temperature, then mixed with about 3 0 ml of water and stirred vigorously for another 10 minutes. This mixture is evaporated to dryness and the residue is refluxed in about 4 0 ml of ethanol for 10 minutes. The mixture is evaporated to dryness once more, the residue is dissolved in about 30 ml of 2N ammonia solution and this solution is adjusted to pH 5-6 with 2N acetic acid. The crude product precipitated is suction filtered and purified by column chromatography (80 g silica gel; eluant: methylene chloride/methanol = 4:1).
Yield: 150 mg (30% of theory), Melting point: 220-222°C CJOHcsNJOV (492.58) Rf value: 0.20 (silica gel; methylene chloride/methanol = 9:1) Mass spectrum: m/e = 492 62 Example 32 4 '-[(2-n-Propyl-4-methyl-6-(l-(2-N-morpholinoethyl) -imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert. butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54% of theory, Melting point: 259-26l°c C34H37NcO:, (563.70) Calculated: C 72.44 H 6.62 N 12.42 Found: 72.68 6.65 12.53 Mass spectrum: m/e = 563 Example 3 3 41 -[(2-n-Propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methylj-bipheny1-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(l-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 49% of theory, Melting point: 192-194°C (552.67) Calculated: C 71.72 H 6.57 N 10.14 Found: 71.52 6.36 10.25 i R. value: 0.36 (silica gel; dichloromethane/methanol = Mass spectrum: m/e = 552 Example 3 4 41-[(2-n-Propy1-4-methyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid dihydrochloride-pentahydrate Prepared analogously to Example A from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 12% of theory, Melting point: from 128°C (decomp.) C33H37N50; x 2 HC1 x 5 H:0 (535.70) Rf value: 0.20 (silica gel; dichloromethane/methanol = 9:1) Mass spectrum: m/e = 535 Example 3 5 41-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'-[ (2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and, trifluoroacetic acid in methylene chloride. ,^ ^ Yield: 32% of theory, i* ia """"" ^ Melting point: 248-250°C \ ^ '994 ^ «/ C29H:7N>0:S (4 31.62) Calculated: C 72.32 H 5.65 N 8.72 Found: 7 2.21 5.83 8.67 Rf value: 0.2 6 (silica gel; dichloromethane/methanol = 9:1) Mass spectrum: m/e = 481 Example 3 6 41-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl) benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl-dihyarochloride Prepared analogously to Example 10 from 41 -[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 91% of theory, Melting point: from 219°C (decomp.) C29H:9C1:N.S (578.58) Calculated: C 60.20 H 5.05 N 16.95 CI 12.25 Found: 59.96 5.19 16.63 12.42 Rf value: 0.32 (silica gel; dichloromethane/methanol = 9:1) Mass spectrum: m/e = 505 Example 37 4'-[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid •< ; '.l -4 Jyot " Prepared analogously to Example A from tert.butyl 4'- ■' [ (2-ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate 245741 and trifluoroacetic acid in methylene chloride.
Yield: 27 % of theory, Melting point: 201-202 C C3;sH35N50, (54 9.65) Calculated: C 72.11 H 6.42 N 12.74 Found: 72.00 6.48 12.62 Rf value: 0.36 (silica gel; methylene chloride/methanol = 9:1) mass spectrum: m/e = 549 Example 38 41 -[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate Prepared analogously to Example 10 from 41 -[(2-ethyl-4- methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)- benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl- tetrazol-5-yl)-biphenyl.
Yield: 14 % of theory, Melting point: above 180°C (decomp.) C;oH;,5N?0 X H-0 (57 3.68) Calculated: C 66.98 H 6.30 N 21.31 Found: 66.87 6.36 21.22 Rf value: 0.31 (silica gel; methylene chloride/methanol = 9:1) mass spectrum: m/e - 57 3 Example 39 4' — £(2-Ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-carboxylic acid Prepared analogously to Example A from tert.butyl 4 9 Ll~ -'-J [(2-ethyl-4-methy1-6-(1-(2-aminocarbonylethyl)-imidazol-^-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66 % of theory, Melting point: above 185°C (decomp.) c:<rjH29NsO;, (507.59) Calculated: C 70.99 H 5.76 N 13.80 Found: 70.73 5.72 13.66 mass spectrum: m/e = 507 Example 40 41-[(2-Ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41 -[(2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 42 % of theory, Melting point: above 191°C (decomp.) C30H29N9O (531.63) Calculated: C 67.78 H 5.50 N 23.71 Found: 67.79 5.40 23.66 Rf value: 0.20 (silica gel; methylene chloride/methanol = 8:2) mass spectrum: m/e =531 r* Example 41 41-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2J 14N0V 1994 T // carboxylic acid , * '' 457 U 1 t ^ L- d I Prepared analogously to Example A from tert.butyl 4'-[(2-ethyl-4-methy1-6-(l-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 60 % of theory, Melting point: 215-217°C C33H35N502 (533.67) Calculated: c 74.27 H 6.61 N 13.12 Found: 74.03 6.85 13.11 Rr- value: 0.30 (silica gel; methylene chloride/methanol = 8:2) mass spectrum: m/e = 533 41-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-ethyl-4-methyl-6-(1- (2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.
Yield: 38 % of theory, Melting point: above 128°C (sintering) C;,;,H35N? (551.71) Calculated: C 71.84 H 6.39 N 22.85 Found: 71.63 6.20 22.49 Rf value: 0.2 3 (silica gel; methylene chloride/methanol = 8:2) TV ^ Example 4 3 „ — • '4N01MSS4 4 (2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)r-imidazol-4-yl)-benzimidazol-l-yl) -methyl] -biphen|yl-2- carboxylic acid-dihydrochloride Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol- 4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 32 % of theory, Melting point: 255-257°C (decomp.) C;oH;0NsO: X 2 HC1 (608.60) Rt- value: 0.24 (silica gel; methylene chloride/methanol = 9:1) mass spectrum: m/e = 535 Example 44 41 -[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 4'-[(2-ethyl-4- methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)- benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl- tetrazol-5-yl)-biphenyl.
Yield: 51 % of theory, Melting point: 191-193°C C33H3-7NC1 (559.70) Calculated: C 70.81 H 6.66 N 22.52 Found: 70.59 6.66 22.58 Rf value: 0.30 (silica gel; methylene chloride/methanol = 8:2) . / Example 4 5 41-[(2-Ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)- ' imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example A from tert.butyl 4'- [(2-ethyl-4-methy1-6-(1-(3-N-piperidinopropyl)-imidazol- 4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 19 % of theory, Melting point: amorphous C35H39N5O2 (561.73) Calculated: C 74.84 H 7.00 N 12.47 Found: 74.61 6.92 12.31 Rf value: 0.34 (silica gel; methylene chloride/methanol = 8:2) Example 46 41 -[(2-Ethyl-4-methy1-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl Prepared analogously to Example 10 from 41 -[(2-ethyl-4- methy1-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)- benzimidazol-l-yl)-methyl]-2-(2-triphenylmethyl- tetrazol-5-yl)-biphenyl.
Yield: 71 % of theory, Melting point: above 140°C (decomp.) C^H^N* (585.76) Calculated: C 71.77 H 6.71 N 21.52 Found: 71.58 6.68 21.44 Rf value: 0.22 (silica gel; methylene chloride/methanol = 8:2) r In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I including the physiologically acceptable salts thereof, particularly those wherein represents a carboxy or IH-tetrazolyl group, may be used as the active substance: Example J Ampoules containing 50 mg of active substance per 5 ml Active substance KH2P0.J NaoHPOj x 2H:0 NaCl Water for injections ad Preparation: The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.
Example II Ampoules containing 100 mg of active substance per 5 ml Active substance 100 mg Methyl glucamine 3 5 mg Glycofurol 1000 mg Polyethyleneglycol-polypropylene- glycol block polymer 250 mg Water for injections ad 5 ml MAlOlf fgg4 4 Preparation: Methyl glucamine is dissolved in some of the water and the active substance is dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.
Example XJI Tablets containing 50 mg of active substance Active substance 50.0 mg Calcium phosphate 7 0.0 mg Lactose 4 0.0 mg Corn starch 3 5.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mg 200.0 mg Preparation: The active substance, CaHPO^, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV Coated tablets containing 50 mg of active substance ??fv< Active substance 50.0 mg Lysine 2 5.0 mg 245741 Lactose 60.0 mg Corn starch 3 4.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mg 180.0 mg Preparation: The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.
Example V Coated tablets containing 100 mg of active substance Active substance Lysine Lactose Corn starch Polyvinylpyrrolidone Microcrystalline cellulose Magnesium stearate Preparation: 100.0 mg 50.0 mg 86.0 mg 50.0 mg 2.8 mg 60.0 mg 1.2 mg 350.0 mg The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at 45°C. After drying, it is screened again and the magnesium f% jf P-' I' L -J' / 1« < I stearate is added. This mixture is compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.
Example VI Capsules containing 250 mg of active substance Active substance 250.0 mg Corn starch 68.5 mg Magnesium stearate 1.5 ma 32 0.0 mg Preparation: The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed magnesium stearate. The final mixture is packed in size 1 hard gelatin capsules.
Example VII . .w- ? ^ Oral suspension containing 50 mg of active substanc^pet" f 5 ml t: .
Active substance 50.0 mg Hydroxyethylcellulose 50.0 mg Sorbic acid 5.0 mg 70% sorbitol 600.0 mg Glycerol 200.0 mg Flavouring 15.0 mg Water ad 5.0 ml Preparation: Distilled water is heated to 70°C. Hydroxyethyl-cellulose is dissolved therein with stirring. By the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One dose of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Active substance 100.0 mg Solid fat 1600.0 ma 1700.0 mg Preparation The hard fat is melted. At 40°c the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds. i 14 My 245741

Claims (11)

WHAT WE CLAIM IS:
1. Compounds of formula I (I) (wherein Rj_ represents a C^-alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R2 represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C^-alkyl group or by a phenyl group and substituted in the 1-position by a Cj.v-alkyl group substituted in the terminal position by a carboxy, alkoxycarbonyl, atninocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group, by a C2-4-alkyl group substituted other than in the exposition by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or imidazol-1-yl group, by a Ci.j-alkyl group substituted by a trif luoromethyl group, by a C3.7-cycloalkyl group or by a phenyl group 245741 - 76 - itself mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, or by a Cj.3-alkyl group substituted by two phenyl groups, where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms; R3 represents a C2_4-alkyl, C2_3-alkoxy, C2.3-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group) and the compounds (a) 41 - [ (2-n-Propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (b) 4'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (c) 41 -[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (d) 41 -[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, r - PATSNT OFFICE - 77 - (e) 41 -[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid (f) 4'-[(2-Ethoxy-6-(l-isopropyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (g) 4 '-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (h) 4 1 - [ (2-n-Propyl-4-methyl-6- (1-cycloheptyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, (i) 41-[(2-n-Propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid, (j) 4'-[(2-n-Propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl, (k) 4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid hydrate, (1) 41 -[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl, i (m) 4 1-[ (2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)'-; < benzimidazol-l-yl)-methyl ]-biphenyl-2-carboxylic acid, and (n) 4•-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-l-yl)-methyl)-2-(lH-tetrazol-5-yl)-biphenyl 245741 - 78 - and the salts thereof.
2. Compounds of formula I as claimed in claim 1, wherein Rj represents a C^-alkyl group, a hydrogen, fluorine, chlorine or bromine atom; R2 is in the 6-position of the benzimidazole ring and represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a C1.6-alkyl group or by a phenyl group and substituted in the 1-position by a C^-alkyl group substituted in the terminal position by a carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group, by a C2-4-alkyl group substituted other than in the exposition by a hydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholino or imidazol-1-yl group, by a Cx.3-alkyl group substituted by a trifluoromethyl group, by a C3.7-cycloalkyl group or by a phenyl group itselH mono- or disubstituted by fluorine or chlorine atoms or by trifluoromethyl, methyl or methoxy groups, or by a Cx.3-alkyl group substituted by two phenyl groups, 245741 - 79 - where unless otherwise specified the above-mentioned alkyl and alkoxy moieties each contain 1 to 3 carbon atoms; R3 represents a C2.4-alkyl, C2_3-alkoxy, C2,3-alkylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group or a group convertable in vivo into a carboxy group and the salts thereof.
3. Compounds of formula I as claimed in claim 1, wherein Rx represents a hydrogen or chlorine atom or a methyl group; R2 is in the 6-position of the benzimidazole ring and represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group, or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a C^v-alkyl group substituted in the terminal position by a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or 1-oxido-thiomorpholi.no-carbonyl group, N.z. PATPENCE IS .SO MAR 1995 *45 "m1 - 80 by a C,..,-alkyl group substituted other than in the a-position by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-1-yl group, or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-raethylbenzyl, 4-trifluoromethylbenzyl, 3,5-dimethoxybenzyl or 2, 2-diphenylethyl group,- R3 represents a C2.4-alkyl, C2_3-alkoxy, C2.3-alkylthio, cyclopropyl or cyclobutyl group,- and R4 represents a carboxy or 1H-tetrazolyl group or a group convertable in vivo into a carboxy group; and the salts thereof.
4. Compounds of formula I as claimed in claim 1, wherein R1( R2 and R3 are as defined in any one of claims 1 to 3; R4 denotes a carboxy group or a group of formula - CO - OR', - CO - 0 - (HCR") - 0 - CO - R"' or - CO - 0 - (HCR") - 0 - CO - OR1" (wherein R1 denotes a straight-chain or branched C^g-alkyl group or a C5.7-cycloalkyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group, R" denotes a hydrogen atom or a methyl group, and N.Z. PATENT OFFICE 3 OMAR 1995 L it \j / 4 i - 81 - ~ ~ R"' denotes a straight-chain or branched C^g-alkyl group or a Cs_7-cycloalkyl, phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group),- and the salts thereof.
5. Compounds of formula I as claimed in claim 1, wherein Rx represents a hydrogen atom or a methyl group; R2 is in the 6-position of the benzimidazole ring and represents an oxazol-4-yl or thiazol-4-yl group substituted in the 2-position by a phenyl group or an imidazol-4-yl group optionally substituted in the 2-position by a methyl group and substituted in the 1-position by a C^-j-alkyl group substituted in the terminal position by a carboxy, methoxycarbonyl, dimethylaminocarbonyl or morpholino-carbonyl group, by a C2_4-alkyl group substituted other than in the exposition by a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino or imidazol-l-yl group,- or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, or 4-fluoro-benzyl group; R3 represents a C2.4-alkyl group, an ethoxy, ethylthio, cyclopropyl or cyclobutyl group; and R4 represents a carboxy or IH-tetrazolyl group° r JP <• x 24574 1. - 82 - and the salts thereof.
6. Compounds of formula I as claimed in claim 1 being: (a) 41 -[(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylie acid; (b) 4'-[(2-n-Propyl-4-methyl-6-(l-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (c) 41-[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (d) 4'-[(2-Ethyl-4-methyl-6-(l-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (e) 4'-[(2-n-Propyl-4-methyl-6-(l-(3- dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (f) 4 (2-Ethy1-4-methy1-6-(l-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (g) 41-[(2-Ethyl-4-methyl-6-(l-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl; (h) 4•-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (i) 4 •-[ (2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidino^hyl) - ovs - 83 245741 imidazol-4-yl)-benzimidazol-l-yl)-methyl] -2-(1H-tetrazol-5-yl)-biphenyl; (j) 4'-[{2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylic acid; (k) 4'-[(2-Ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid or a salt thereof.
7 . 41 - [ (2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl) -imidazol-4-yl)-benzimidazol-l-yl) -methyl] -biphenyl-2-carboxylic acid and the salts thereof.
8. A compound as claimed in any one of claims 1 to 7 being a physiologically acceptable addition salt.
9. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 7 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.
10. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: a) cyclising a compound of formula II 245741 84 R 1 (II) (wherein one of the groups Xx and YL represents a group of formula and the other group Xx or Yx represents a group of the formula R5 represents a hydrogen atom or an R3CO- group, R1( R2, R3 and R4 are as defined in any one of claims 1 to 6, Zx and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by C^g-alkyl groups which may be identical or different or Zx and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C^-alkyl group, or an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms) or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; z, z2 NH - C - R3 245741 85 b) reacting a benzimidazole of formula III R H (III) (wherein R1; R2 and R3 are as defined in any one of claims l to 6) with a biphenyl compound of formula IV (wherein R4 is as defined in any one of claims 1 to 6 and Z3 represents a nucleophilic leaving group); c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of formula V (IV) (V) (wherein Rx, R2 and R3 are as defined in any one of claims 1 to 6 ^45 7 4 1 86 and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; d) (to prepare a compound of formula I wherein R4 represents a IH-tetrazolyl group) cleaving a protecting group from a compound of formula VI (wherein Rlf R2 and R3 are as defined in any one of claims 1 to 6 and R4" represents a 1H-tetrazolyl group protected in the 1-or 3-position by a protecting group) e) (to prepare a compound of formula I wherein R4 represents a IH-tetrazolyl group) reacting a compound of formula VII (VI) (VII) (wherein 245741 - 87 - Ri, R2 and R3 are as defined in any one of claims 1 to 6) with hydrazoic acid or a salt thereof; f) a process as defined in any one of steps a) to e) above wherein the groups R1( R2j R3, R4' , R4", R4 and R5 in formulae II to VII are defined so as to yield any one of compounds (a) to (n) in claim 1; g) converting a compound of formula I wherein R4 denotes a carboxy group by esterification into a corresponding compound of formula I wherein R4 denotes a group convertable in vivo into a carboxy group; h) converting a compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1- position by a C2_4-alkyl group substituted other than in the exposition by an alkoxy or alkoxyalkoxy group, by ether splitting into a corresponding compound of formula I wherein R2 denotes an imidazol-4-yl group substituted in the 1-position by a C2_4-alkyl group substituted other than in the a-position by a hydroxy group; i) separating the 1-isomer from a 1-, 3-isomer mixture of a compound of formula I by isomer separation; j) converting a compound of formula I into a salt thereof with an inorganic or organic acid or base, or converting a salt of a compound of formula I into the free compound; and k) performing a process as defined in any one of steps (a) to (j) above on a corresponding protected compound and subsequently removing the protecting groups used.
11. A compound as claimed in claim 1 substantially as herein disclosed in any one of the Examples 1-46 or a pharmaceutical composition thereof substantially as herein disc! nspH in Evampl pb C-VII. N.Z. PATENT OFFICE 30 MAR 1995 PR KARL THOMAE GmbH -jf / />/ 7^
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