IE912822A1 - Imidazoles - Google Patents

Imidazoles

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Publication number
IE912822A1
IE912822A1 IE282291A IE282291A IE912822A1 IE 912822 A1 IE912822 A1 IE 912822A1 IE 282291 A IE282291 A IE 282291A IE 282291 A IE282291 A IE 282291A IE 912822 A1 IE912822 A1 IE 912822A1
Authority
IE
Ireland
Prior art keywords
group
methyl
butyl
biphenyl
pyridin
Prior art date
Application number
IE282291A
Original Assignee
Thomae Gmbh Dr K
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19904025358 external-priority patent/DE4025358A1/en
Priority claimed from DE19904031601 external-priority patent/DE4031601A1/en
Priority claimed from DE19914105827 external-priority patent/DE4105827A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of IE912822A1 publication Critical patent/IE912822A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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

Abstract

The invention relates to heterocyclic imidazoles of the general formula in which A1 to A4 and R1 to R5 are as defined in Claim 1, their 1- and 3-isomer mixtures, their tautomers, their enantiomers and their acid addition salts, which have useful pharmacological properties. The novel compounds are angiotensin antagonists, in particular angiotensin II antagonists.

Description

The present invention relates to novel heterocyclic imidazoles, processes for their preparation and pharmaceutical compositions containing them.
We have found that certain new heterocyclic imidazoles possess interesting and valuable pharmacological activities making them particularly suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
Thus, according to one aspect the present invention provides compounds of formula I (wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of Av A2, A3 and A4 each represent a methine group; R1 represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, - 2 an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a CV6-alkyl, phenyl, C5.7-cycloalkyl, phenyl (C1.3-alkyi) or (C5.7-cycloalkyl) C^j-alkyl group, which substituents may be identical or different and which acyl group is a Cv7-alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (CV3-alkoxy)carbonyl group, a C16-alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl (C1.3-alkanesulphonyl) , naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2aminocarbonyl-cyclohexylcarbonyl, (C5.7-cycloalkyl) carbonyl, phenyl (C14-alkanoyl) or (C5.7-cycloalkyl)C14~alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, a C3.5-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a Cv3-alkyl or hydroxycarbonyl(C^j-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula - N - CO - N [in which R6, R7 and Rg, which may be identical or different, represent hydrogen atoms, Cv8-alkyl groups, C5.7-cycloalkyl, phenyl, (C5.7-cycloalkyl)CV3-alkyl or phenyl(Cv3-alkyl) groups, and - 3 R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3chloro-propyl or 3-bromo-propyl group, and where R6 and R? together represent an ethylene or propylene group, R8 may also represent a di(C^j-alkyl)aminocarbonyl group, or R6 and R? together represent an ethylene or propylene group and in which the phenyl nucleus of the above-mentioned phenyl and phenyl (C1.3~alkyl) groups may in each case be mono- or disubstituted by hydroxy or C13-alkoxy groups which substituents may be identical or different], and R1 may also represent a hydrogen atom, except where R2 represents a hydrogen atom, R3 represents an n-butyl group, R4 represents a carboxy group and R5 represents a hydrogen atom, and (i) one of the groups A1, A2, A3 and A4 represents a nitrogen atom and the remaining groups A1, A2, A3 or A4 each represent methine groups, or (ii) A2 and A4 or A1 and A3 each represent a nitrogen atom and the remaining groups A1 and A3 or A2 and A4 each represent a methine group, or (iii) A4 represents a nitrogen atom and A3 represents a methine group substituted by a hydroxy or methoxy group and the remaining groups A1 and A2 each represent a methine group, or (iv) A4 represents a nitrogen atom, A, represents a methine group substituted by a methyl group and the remaining groups A2 and A3 each represent a methine group; - 4 R2 represents a hydrogen atom or a C13-alkyl group; R3 represents a CV6-alkyl group; R4 represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C14~alkoxy)carbonyl group; and R^ represents a hydrogen, fluorine, chlorine or bromine atom); and isomers and salts, particularly the 1-, 3-isomer mixtures, tautomers, enantiomers and addition salts thereof, and more particularly for pharmaceutical use the physiologically acceptable addition salts thereof with organic or inorganic acids or bases.
Examples of heteroaromatic groups covered by the definition of the groups Av A2, A3 and A4 hereinbefore include pyrido, pyrimido, pyrazino or pyridazino groups.
The following are examples of the definitions of the groups Rv R2, R3, R4 and R5 as mentioned hereinbefore: R, may represent a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, forroylamino, acetylamino, propionylamino, nbutanoylamino, isobutanoylamino, n-pentanoylamino, 2methyl-n-butanoylamino, 3-methyl-n-butanoylamino, nhexanoylamino, n-heptanoylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino, cyclopentylmethylcarbonylamino, cyclohexylmethylcarbonylamino, cycloheptylmethylcarbonylamino, (2cyclopentylethyl)-carbonylamino, (2-cyclohexylethyl)carbonylamino, (2-cycloheptylethy1)-carbonylamino, benzoylamino, phenylacetylamino, 2-phenylpropionylamino, - 5 naphthyl-(1)-carbonylamino, naphthyl-(2)-carbonylamino, methoxycarbonylamino, ethoxycarbonylamino, npropoxycarbonylamino, methanesulphonylamino, ethanesulphonylamino, n-propanesulphonylamino, isopropanesulphonylamino, n-butanesulphonylaroino, n-pentanesulphonylamino, n-hexanesulphonylamino, benzenesulphonylamino, 2-methylbenzenesulphonylamino, 4methylbenzenesulphonylamino, 2-methoxybenzenesulphonylamino, 4-methoxybenzenesulphonylamino, 2-fluorobenzenesulphonylamino, 4-fluorobenzenesulphonylamino, 2chlorobenzenesulphonylamino, 4-chlorobenzenesulphonylamino, 2-bromobenzenesulphonylamino, 4-bromobenzenesulphonylamino, 2,4-dimethoxybenzenesulphonylamino, benzylsulphonylamino, naphthalene-(1)-sulphonylamino, naphthalene-(2)-sulphonylamino, propanesultam-(1)-yl, n butanesultam-(1)-yl, n-pentanesultam-(1)-yl, amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, n-pentylamino, nhexylamino, dimethylamino, diethylamino, di-npropylamino, methyl-ethylamino, methyl-isopropylamino, methyl-n-butylamino, ethyl-n-propylamino, methyl-npentylamino, ethyl-n-hexylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, (2-cyclopentylethyl)-amino, (2-cyclohexylethyl)-amino, (2-cycloheptylethyl)-amino, (3-cyclopentylpropyl)-amino (3-cyclohexylpropyl)-amino, (3-cycloheptylpropyl)-amino benzylamino, 2-phenylethylamino, 3-phenylpropylamino, phenylamino, dicyclohexylamino, dicyclohexylmethylamino dibenzylamino, N-methyl-cyclopropylamino, N-methylcyclopentylamino, N-ethyl-cyclohexylamino, N-(n-propyl) cycloheptylamino, N-methyl-cyclopentylmethylamino, Nethyl-cyclohexylmethylamino, N-(n-propyl)-cycloheptylmethylamino, N-methyl-(2-cyclopentylethyl)-amino, Nethyl-(2-cyclohexylethyl)-amino, N—(n-propyl)-(2cycloheptylethyl)-amino, N-methyl-(3-cyclopentylpropyl) amino, N-ethyl-(3-cyclohexylpropyl)-amino, N-methylIE 912822 benzylamino, N-ethyl-benzylamino, N-isopropylbenzylamino, N-methyl-(2-phenylethyl)-amino, N-methylphenylamino, N-(n-propyl)-phenylamino, N-acetylmethylamino, N-acetyl-ethylamino, N-acetylisopropylamino, N-acetyl-n-butylamino, N-acetyl-nhexylamino, N-propionyl-methylamino, N-propionylethylamino, N-propionyl-n-butylamino, N-n-butanoylmethylamino, N-n-butanoyl-ethylamino, N-n-butanoyl-npentylamino, N-isobutanoyl-methylamino, N-isobutanoylethylamino, N-isobutanoyl-isopropylamino, N-isobutanoyl n-butylamino, N-isobutanoyl-n-pentylamino, N-npentanoyl-methylamino, N-n-pentanoyl-ethylamino, N-npentanoyl-isopropylamino, N-n-pentanoyl-n-pentylamino, N-n-hexanoyl-methylamino, N-n-hexanoyl-ethylamino, N-nhexanoyl-isopropylamino, N-n-hexanoyl-n-pentylamino, Νονοί openty1carbonyl-methylamino, N-cyclohexy1carbonylmethylamino, N-cyclohexylcarbonyl-ethylamino, Ncycloheptylcarbonyl-methylamino, N-cyclopentylmethylcarbonyl-methylamino, N-cyclohexylmethylcarbonylmethylamino, N-cycloheptylmethylcarbonyl-methylamino, N (2-cyclopentylethylcarbonyl)-methylamino, N-(2cyclohexylethylcarbonyl)-methylamino, N-(2-cycloheptylethylcarbonyl)-methylamino, N-benzoyl-methylamino, Nbenzoyl-ethylamino, N-benzoyl-isopropylamino, N-benzoyl n-butylamino, N-benzoyl-n-pentylamino, N-benzoyl-nhexylamino, N-phenylacetyl-methylamino, N-naphthyl-(1)carbonyl-methylamino, N-naphthyl-(2)-carbonylmethylamino, N-methoxycarbonyl-methylamino, Nmethoxycarbonyl-ethylamino, N-methoxycarbonyl-nbutylamino, N-methoxycarbonyl-isobutylamino, Nethoxycarbonyl-methylamino, N-ethoxycarbonyl-ethylamino N-ethoxycarbonyl-isopropylamino, N-ethoxycarbonyl-nbutylamino, N-n-propoxycarbonyl-methylamino, Nmethanesulphonyl-methylamino, N-ethanesulphonylisopropylamino, N-(n-propanesulphonyl)-methylamino, isopropanesulphonylmethylamino, N-(n-butanesulphonyl)methylamino, N-(n-pentanesulphonyl)-methylamino, N-(nIE 912822 - 7 hexanesulphonyl)-methylamino, benzenesulphonylmethylamino, N- (2methylbenzenesulphonyl)-methylamino, N-(4methylbenzenesulphonyl)-methylamino, N-(2-methoxybenzenesulphonyl)-methylamino, N-(4-methoxybenzenesulphonyl) -methylamino, N-(2-fluorobenzenesulphonyl)methylamino, N-(4-fluorobenzenesulphonyl)-methylamino, N-(2-chlorobenzenesulphonyl)-methylamino, N-(4chlorobenzene-sulphonyl)-methylamino, N-(2bromobenzenesulphonyl)-methylamino, N-(4bromobenzenesulphonyl)-methylamino, N-(2,4dimethoxybenzenesulphonyl)-methylamino, N-benzylsulphonyl-methylamino, N-(naphthalene-(1)-sulphonyl)methylamino, N-(naphthalene-(2)-sulphonyl)-methylamino, N-benzoyl-cyclopentylamino, N-benzoyl-cyclohexylamino, N-benzoyl-cycloheptylamino, N-phenylacetyl-cyclopentylamino, N-phenylacetyl-cyclohexylamino, N-phenylacetylcycloheptylamino, N-benzoyl-cyclopentylmethylamino, Nbenzoyl-cyclohexylmethylamino, N-benzoyl-cycloheptylmethylamino, N-phenylacetyl-cyclopentylmethylamino, Nphenylacetyl-cyclohexylmethylamino, N-phenylacetylcycloheptylmethylamino, N-(3-phenylpropionyl)methylamino, N-(3-phenylpropionyl)-ethylamino, N-(3phenylpropionyl)-isopropylamino, N-(3-phenylpropionyl)isobutylamino, N-benzoyl-(2-cyclopentylethyl)-amino, Nbenzoyl-(2-cyclohexylethyl)-amino, N-benzoyl-(2cycloheptylethyl)-amino, N-phenylacetyl-(2cyclopentylethyl)-amino, N-phenylacetyl-(2-cyclohexylethyl) -amino, N-phenylacetyl-(2-cycloheptylethyl)-amino N-benzoyl-(3-cyclopentylpropyl)-amino, N-benzoyl-(3cyclohexylpropyl)-amino, N-benzoyl-(3-cycloheptylpropyl)-amino, N-phenylacetyl-(3-cyclopentylpropyl)amino, N-phenylacetyl-(3-cyclohexylpropyl)-amino, Nphenylacetyl-(3-cycloheptylpropyl)-amino, N-acetylcyclopentylamino, N-acetyl-cyclohexylamino, N-acetylcycloheptylamino, N-acetyl-cyclopentylmethylamino, Nacetyl-cyclohexylmethylamino, N-acetyl-cycloheptylmethylamino, N-acetyl-(2-cyclopentylethyl)-amino, NIE 912822 — 8 acetyl-(2-cyclohexylethyl)-amino, N-acetyl-(2cycloheptylethyl)-amino, N-acetyl-(3-cyclopentylpropyl)amino, N-acetyl-(3-cyolohexylpropyl)-amino, N-acetyl-(3cycloheptylpropyl)-amino, N-acetyl-benzylamino, Nacety1-(2-phenylethy1)-amino, N-acetyl-(3-phenylpropy1) amino, N-benzoyl-benzylamino, N-benzoyl-(2-phenylethyl)amino, N-benzoyl-(3-phenylpropy1)-amino, 2-carboxycyclohexylcarbonylamino, 2-aminocarbonyl-cyclohexylcarbonylamino, phthalimido, tetrahydrophthalimido, hexahydrophthalimido, cis-hexahydrophthalimido, transhexahydrophthalimido, pyrrolidino, methylpyrrolidino, ethyl-pyrrolidino, isopropylpyrrolidino, piperidino, methylpiperidino, ethylpiperidino, isopropylpiperidino, hexamethyleneimino, methylhexamethyleneimino, ethylhexamethyleneimino, isopropylhexamethyleneimino, 2carboxymethyl-pyrrolidino, 2-oxo-pyrrolidino, 2-oxopiperidino, 2-oxo-hexamethyleneimino, aminocarbonylamino, methylaminocarbonylamino, dimethylaminocarbonylamino, N-methylaminocarbonyl-methylamino, N-(dimethylaminocarbonyl) -methylamino, N-dimethylaminocarbonylethylamino, N-dimethylaminocarbonyl-isopropylamino, N(dimethylaminocarbonyl)-n-pentylamino, N-methylaminocarbonyl-ethylamino, N-methylaminocarbonyl-npentylamino, N-methylaminocarbonyl-n-hexylamino, Nmethylaminocarbonyl-n-octylamino, N-methylaminocarbonyl-cyclohexylamino, ethylaminocarbonylamino, Nethylaminocarbonyl-methylamino, N-ethylaminocarbonylethylamino, N-ethylaminocarbonyl-n-hexylamino, Nethylaminocarbonyl-n-heptylamino, N-ethylaminocarbonylcyclohexylamino, diethylaminocarbonylamino, N(diethylaroinocarbonyl)-methylamino, N-(diethylaminocarbonyl) -ethylamino, N-(diethylaminocarbonyl)-nbutylamino, N-(diethylaminocarbonyl)-n-hexylamino, N(diethylaminocarbonyl)-n-octylamino, isopropylarainocarbonylamino, N-isopropylaminocarbonyl-methylamino, nbutylaminocarbonylamino, N-(n-butylaminocarbonyl)methylamino, N-(n-butylaminocarbonyl)-ethylamino, N-(nIE 912822 - 9 butylaminocarbonyl)-isopropylamino, N-(n-butylaminocarbony1)-n-butylamino, N-(n-butylaminocarbonyl)-nhexylamino, N-(n-butylaminocarbonyl)-cyclohexylamino, N (di-(n-butyl)-aminocarbonyl)-amino, N-(di-(n-butyl)aminocarbonyl)-methylamino, N-(di-(n-butyl) aminocarbonyl)-ethylamino, N-(di-(n-butyl)aminocarbonyl)-n-butylamino, N-(di-(n-butyl)aminocarbonyl)-n-hexylamino, N-(n-pentylaminocarbony1) ethylamino, N-(n-hexylaminocarbonyl)-ethylamino, nhexylaminocarbonylamino, n-heptylaminocarbonylamino, noctylaminocarbonylamino, N-(n-hexylaminocarbonyl)-nbutylamino, N-(n-hexylaminocarbonyl)-n-pentylamino, N(n-hexylaminocarbonyl)-n-hexylamino, N-(n-hexylaminocarbonyl) -cyclohexylamino, di-(n-hexyl)-aminocarbonylamino, N-(di-(n-hexyl)-aminocarbonyl)-methylamino, N((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylaminocarbonylamino, N-cyclohexylaminocarbonyl-methylamino, N cyclohexylaminocarbonyl-ethylamino, N-cyclohexylaminocarbonyl-n-butylamino, N-cyclohexylaminocarbonylisobutylamino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-hexylamino, Ncyclohexylaminocarbonyl-cyclohexylamino, N-(ethylcyclohexylaminocarbonyl)-methylamino, N-(propyl-cyclohexylaminocarbonyl)-methylamino, N-(n-butyl-cyclohexylaminocarbonyl)-methylamino, N-benzylaminocarbonylisobutylamino, 2(1H)-imidazolidinon-l-yl, 3-methyl2(1H)-imidazolidinon-l-yl, 3-ethyl-2(1H)-imidazolidinon 1-yl, 3-n-propyl-2(1H)-imidazolidinon-l-yl, 3-isopropyl 2(1H)-imidazolidinon-l-yl, 3-n-butyl-2(1H)imidazolidinon-l-yl, 3-isobutyl-2(1H)-imidazolidinon-lyl, 3-n-pentyl-2(1H)-iroidazolidinon-l-yl, 3-n-hexyl2(1H)-imidazolidinon-l-yl, 3-cyclopentyl-2(1H)imidazolidinon-l-yl, 3-cyclohexyl-2(1H)-imidazolidinonl-yl, 3-cycloheptyl-2(1H)-imidazolidinon-l-yl, 3-benzyl 2(1H)-imidazolidinon-l-yl, 3-(3-hydroxybenzyl)-2(1H)imidazolidinon-l-yl, 3-(4-hydroxybenzyl)-2(1H)imidazolidinon-l-yl, 3-(3-methoxybenzyl)-2(1H)IE 912822 - 10 imidazolidinon-l-yl, 3-(4-methoxybenzyl)-2(1H)imidazolidinon-l-yl, 3-(3,4-dihydroxybenzyl)-2(1H)imidazolidinon-l-yl, 3-(3,4-dimethoxybenzyl)-2(1H)imidazolidonon-l-yl, 3-cyclopentylmethyl-2(1H)imidazolidinon-l-yl, 3-cyclohexylmethyl-2(1H)imidazolidinon-l-yl, 3-cycloheptylmethyl-2(1H)imidazolidinon-l-yl, 3-(2-phenylethyl)-2(1H)imidazolidinon-l-yl, 3-(2-cyclopentylethyl)-2(1H)imidazolidinon-l-yl, 3-(2-cyclohexylethyl)-2(1H)imidazolidinon-l-yl, 3-(2-cycloheptylethyl)-2(1H)imidazolidinon-l-yl, 3-(3-phenylpropyl)-2(1H)imidazolidinon-l-yl, 3-(3-cyclopentylpropyl)-2(1H)imidazolidinon-l-yl, 3-(3-cyclohexylpropyl)-2(1H)imidazolidinon-l-yl, 3-(3-cycloheptylpropyl)-2(1H)imidazolidinon-l-yl, 3,4,5,6-tetrahydro-2(1H)-pyrimidon 1-yl, 3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-l-yl, 3-npropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3isopropyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-l-yl, 3-nbutyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-l-yl, 3isobutyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-l-yl, 3-npentyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-nhexyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3cyclopentyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3cyclohexyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3cycloheptyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidon-l-yl, 3benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3hydroxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(4-hydroxybenzyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidonl-yl , 3-(3-methoxybenzyl)-3,4,5,6-tetrahydro-2(1H)pyrimidon-l-yl, 3-(4-methoxybenzyl)-3,4,5,6-tetrahydro2(1H)-pyrimidon-l-yl, 3-(3,4-dihydroxybenzyl)-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3,4-dimethoxybenzyl )-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3cyclohexylmethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-lyl , 3-cycloheptylmethyl-3,4,5,6-tetrahydro-2(1H)pyrimidon-l-yl, 3-(2-phenylethy1)-3,4,5,6-tetrahydroIE 912822 - 11 2(ΙΗ)-pyrimidon-l-yl, 3-(2-cyclopentylethyl)-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-(2-cyclohexylethyl) 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(2cycloheptylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-lyl , 3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)pyrimidon-l-yl, 3-(3-cyclopentylpropyl)-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3-cyclohexylpropyl) 3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3-(3cycloheptylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1 yl, 2-chloroethylaminocarbonylamino, 3-chloropropylaminocarbonylamino, 2-bromoethylaminocarbonylamino, 3bromopropylaminocarbonylamino, (N-2-chloroethylmethylaminocarbonyl)-amino, (N-2-bromoethyl-methylamino carbonyl)-amino, (N-2-chloropropylmethylaminocarbonyl)amino, tert.butylcarbonylamino, (N-2-bromopropylmethylaminocarbonyl)-amino, 2-oxo-isoindolin-l-yl, 3dimethylaminocarbonyl-2(1H)-imidazolidinon-l-yl, 3diethylaminocarbonyl-2(1H)-imidazolidinon-l-yl, 3-di-npropylaminocarbonyl-2(1H)-imidazolidinon-l-yl, 3dimethylaminocarbonyl-3,4,5,6-tetrahydro-2 (1H)pyriroidon-l-yl, 3-diethylaminocarbonyl-3,4,5,6tetrahydro-2(1H)-pyrimidon-l-yl, 3-diisopropylaminocarbonyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-l-yl, 3chloro-propionylamino, 4-chloro-butanoylamino, 5chloropentanoylamino, 6-chloro-hexanoylamino, 7-chloroheptanoylamino, 3-hydroxy-propionylamino, 4-hydroxybutanoylamino, 5-hydroxy-pentanoylamino, 6-hydroxyhexanoylamino, 7-hydroxy-heptanoylamino, 2,2-dimethylpropionylamino or tert.-butylamino group; R2 may represent a hydrogen atom, a methyl, ethyl, npropyl or isopropyl group; R3 may represent a methyl, ethyl, n-propyl, isopropyl, r butyl, isobutyl, tert.-butyl, n-pentyl, n-hexyl, 1methylpropyl, 1-methylbutyl, 2-methylbutyl, 3methylbutyl, 1-methylpentyl, 2-methylpentyl, 3IE 912822 - 12 methylpentyl, 4-methylpentyl, 1-ethylpropyl or 1,1diethylethyl group; R4 may represent a carboxy, cyano, ΙΗ-tetrazolyl, 1triphenylmethyl-tetrazolyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl or tert.butoxycarbonyl group; and R^ may represent a hydrogen, fluorine, chlorine or bromine atom.
Preferred compounds according to the invention include those of formula I wherein one or two of A,, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A1, A2, A3 and A4 each represent a methine group; R1 represents a fluorine atom, an amino or C^-aIkylamino group substituted at the nitrogen atom by a phenyl, C5.7-cycloalkyl, phenyl (CV3alkyl) or (C5.7-cycloalkyl) Cv3-alkyl group, an amino group disubstituted by a phenyl, C5.7-cycloalkyl, phenyl (CV3alkyl) or (C5.7-cycloalkyl)CV3-alkyl group which substituents may be identical or different, or an acylamino group optionally substituted at the nitrogen atom by a Cv6-alkyl group or by a phenyl, C5.7-cycloalkyl, phenyl (CV3-alkyl) or (C5_7-cycloalkyl) C^-alkyl group, wherein the acyl group is a C2.7-alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C^j-alkoxy)carbonyl group, a C1.6-alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl (C^.j-alkanesulphonyl) , naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2aminocarbonyl-cyclohexylcarbonyl, (C5.7-cycloalkyl) IE 912822 - 13 carbonyl, phenylalkanoyl or (C5_7-cycloalkyl) C^-alkanoyl group, in which the above-mentioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, a C3.5-alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C1.3-alkyl or hydroxycarbonyl (Cv3-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiroinone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula - N - CO - N [in which R6, R7 and Rfl, which may be identical or different, represent hydrogen atoms, C^g-alkyl groups, C5.7-cycloalkyl, phenyl, (C5.7-cycloalkyl)C13~alkyl or phenyl(C^j-alkyl) groups, and Rg may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3 chloro-propyl or 3-bromo-propyl group, and where R6 and R7 together represent an ethylene or propylene group, Rg may also represent a di(CV3-alkyl)aminocarbonyl group, or R6 and R? together represent an ethylene or propylene group, and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(Cv3-alkyl) groups may be mono- or disubstituted by hydroxy or CV3-alkoxy groups which substituents may be identical or different]; R2 represents a hydrogen atom or a CV3-alkyl group; R3 represents a CV6-alkyl group; R4 represents a carboxy, cyano, IH-tetrazolyl, 1triphenylmethyl-tetrazolyl group or a (C1.4-alkoxy)carbonyl group; and represents a hydrogen, fluorine, chlorine or bromine atom; and the isomers and salts thereof especially the 1-, 3isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic acids or bases.
Particularly preferred compounds according to the invention include those of formula I wherein one or two of Av A2, A3 and A4 represent a nitrogen atom and the remaining two or three of Av A2, A3 and A4 each represent a methine group; R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or CV4alkylamino group substituted by a C2_6-alkanoyl group, by a C1.4-alkanesulphonyl group, by a C2.4-alkoxycarbonyl group or by a cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a Cj.4alkylsultam group, a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-l-yl or piperidin-2-on-l-yl group, an optionally wholly hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula R, N - CO - N R. - 15 [in which R6, R? and Rg, which may be identical or different, represent hydrogen atoms, CV4-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and R8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3 chloro-propyl or 3-bromo-propyl group, and where R6 and R? together represent an ethylene or propylene group, Rg may also represent a dimethylaminocarbonyl group, or R6 and R? together represent an ethylene or propylene group]; R2 represents a hydrogen atom or a methyl or ethyl group R3 represents a C^j-alkyl group; R4 represents a carboxy or ΙΗ-tetrazolyl group; and R5 represents a hydrogen atom; and the isomers and salts thereof, especially the 1-, 3isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic acids or bases.
More particularly preferred compounds according to the invention include those of formula I wherein one or two of A1, A2, A3 and A4 represent a nitrogen atom and the remaining two or three of A,, A2, A3 and A4 each represent a methine group; R1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C2.6-alkanoyl group, by a CV4alkanesulphonyl group, by a C2.4-alkoxycarbonyl group, by a benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C14alkylamino group substituted by a C14-alkanesulphonyl, cyclohexylcarbonyl, 2aminocarbonyl-cyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C3.4-alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-1-yl or piperidin-2-on-l-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula L6 N - CO - N R. [in which one of the groups R6, R7 or R8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R6, R? or Rg, which may be identical or different, represent hydrogen atoms, CV4-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R? represents a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloropropyl or 3-bromo-propyl group, and R6 and Rg, which may be identical or different, represent hydrogen atoms, C1.4-alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R6 and R7 together represent an ethylene or propylene group, and R8 represents a hydrogen atom, a CV4-alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, - 17 methoxybenzyl, hydroxybenzyl, 2-chloro-ethyl, 2-bromoethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylaminocarbonyl group]; R2 represents a hydrogen atom or a methyl or ethyl group R3 represents a C15-alkyl group; R4 represents a carboxy or ΙΗ-tetrazolyl group; and R5 represents a hydrogen atom; and the isomers and salts thereof, especially the 1-, 3isomer mixtures, tautomers, enantiomers and addition salts thereof with organic or inorganic acids or bases.
Although the present invention relates to new compounds of formula I, the corresponding cyano, alkoxycarbonyl and triphenylmethyl compounds, in particular, are valuable intermediates which can readily be converted to one of the pharmacologically active compounds and thus form further aspects of the present invention.
According to a still 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 (wherein - 18 R1, R2, A1, A2, A3 and A4 are as hereinbefore defined; one of the groups X1 or Y1 represents a group of formula and the other group X1 or Y1 represents a group of formula Z. z? \ / - NH - C - R3 R3 and Rg are as hereinbefore defined; R9 represents a hydrogen atom or an R3CO group; and R3 is as hereinbefore defined; Z1 and Z2, which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower (eg. CV6)alkyl groups, or Z, and Z2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C1.3-alkyl group, or a C2.3-alkylenedioxy or C2.3-alkylenedithio group, with the proviso that one of the groups X1 or Y1 must represent a group of formula or \or3 NH - C - R3 ) or an N-oxide thereof and if necessary subsequently reducing the cyclized Noxide; b) reacting a compound of formula III H (Hl) (wherein R1, R2, R3, A1, A2, A3 and A4 are as hereinbefore defined) with a biphenyl compound of formula IV (wherein R4 and R5 are as hereinbefore defined; and Z3 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 ptoluenesulphonyloxy group); c) (to prepare a compound of formula I wherein R4 represents a carboxy group) converting a compound of - 20 formula V (wherein R1, R2, R3, R5, Av A2, A3 and A4 are as hereinbefore defined; and R4' represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; d) (to prepare a compound of formula I wherein R4 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI (wherein R1, R2, r3, Rj, A1, A2, A3 and A4 are as hereinbefore defined; and R4 represents a ΙΗ-tetrazolyl group protected in the 1position by a protecting group); - 21 e) (to prepare a compound of formula I wherein R4 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII (wherein R1, R2, R3, R5, A,, A2, A3 and A4 are as hereinbefore defined) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R1 represents an amino group optionally substituted by a (C^-alkyl) group or by a phenyl, C5.7-cycloalkyl, phenyl (C1.3-alkyl) or (C5.7-cycloalkyl) C1.3-alkyl group) converting a compound of formula VIII (wherein R2, R3, R4, Rj, A1, A2, A3 and A4 are as hereinbefore defined; and R10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a C1.6-alkyl group or by a phenyl, C5 7-cycloalkyl, phenyl(C^-alkyl) or - 22 (C5.7-cycloalkyl) C13-alkyl group) ; g) (to prepare compounds of formula represents a group of formula I wherein R, (wherein R2, R3, R4, Rj, A1, A2, A3 and A4 are as hereinbefore defined; and Rn represents an R6NH group, wherein R6 is as hereinbefore defined) with a compound of formula X CO (X) (wherein R7 and Rfl are as hereinbefore defined; Z4 represents a nucleophilic leaving group such as a chlorine or bromine atom, or Z4 together with R? represents a nitrogen-carbon bond) h) (to prepare compounds of formula I wherein R1 - 23 represents an N-acylamino group optionally substituted at the nitrogen atom by a CV6-alkyl, phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group) acylating a compound of formula XI (wherein R2, R3, R4, Rg, A1# A2, A3 and A4 are as hereinbefore defined; and R12 represents an amino group optionally substituted by a C^g-alkyl, phenyl, C5.7-cycloalkyl, phenyl (C^-alkyl) or (C5.7-cycloalkyl) C1.3-alkyl group) with a compound of formula XII R13 - W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R13 represents a CV6-alkyl group, a C1.3-alkoxy group, a phenyl (CV3-alkyl) , Cg 7-cycloalkyl or (C5.7-cycloalkyl) CV3alkyl group, a phenyl, naphthyl, 2-carboxy-cyclohexyl or 2-aminocarbonyl-cyclohexyl group, in which the abovementioned phenyl nuclei may be mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, or, if W represents a carbonyl group, R13 may also represent a hydrogen atom) or with a reactive derivative thereof, such as an acid halide, acid ester or acid anhydride; - 24 i) (to prepare a compound of formula I wherein R6 and R? together represent an ethylene or n-propylene group) cyclising a compound of formula XIII (wherein R2, R3, R4, R5, R8, A1, A2, A3 and A4 are as hereinbefore defined; Hal represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV Rg - Hal (XIV) (wherein R8 is as hereinbefore defined, with the exception of the hydrogen atom; and Hal represents a chlorine, bromine or iodine atom); j) resolving a 1-, 3- isomer mixture of a compound of formula I by isomer separation into the 1- and 3isomers thereof; k) converting a compound of formula I into an addition salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an organic or inorganic acid or base, or converting a salt of a compound of formula I into the free compound; and l) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound - 25 and subsequently removing the protecting group used.
The cyclisation of step (a) may conveniently be carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, 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. The reaction is conveniently effected at temperatures between 0 and 250°C, preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, ptoluenesulphonic 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, 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 general formula R3COOH, or by acylating 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 I obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, - 26 ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric 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, preferably at ambient temperature.
The reaction of step (b) may conveniently be carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, acetone, tetrahydrofuran, dioxane, dimethylsulphoxide, 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, conveniently at temperatures between 0 and 100°C, preferably at temperatures between ambient temperature and 50°C. A mixture of the 1- and 3- isomers is preferably obtained.
In step (c) functional derivatives of the carboxy group such as the optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides or the nitrile group may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. the tert.butylester, may be converted by thermolysis into a carboxy group and esters with aralkanols, e.g. the benzylester, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step (c) may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such - 27 as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10°C and 120°C, preferably at temperatures between ambient temperature and the boiling temperature of the reaction mixture. When the hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may optionally simultaneously be converted into a corresponding acyloxy group such as the trifluoroacetoxy group.
If R4' in a compound of formula V represents a cyano or aminocarbonyl group, these groups may also be converted into the 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 R4' 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 trifluoroacetic acid, 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 R4' 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, - 28 dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, more preferably 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 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 phenylpropionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
If R1 in a compound of formula V represents one of the above mentioned hydrolysable groups, it may be converted during the reaction into a corresponding amino compound.
Suitable protecting groups for use in step (d) include, for example, the triphenylmethyl, trimethyl tin, tributyl tin, triphenyl tin, propionic acid nitrile or p-nitrobenzyl groups. The cleaving of a protecting group used is preferably carried out in the presence of a hydrohalic acid, 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, conveniently at temperatures between 0 and 100°C, 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 140°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. Appropriately, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. sodium azide in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in - 29 the reaction mixture from the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced 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 or 2N sulphuric acid.
In the reagent of formula VIII used in step (f), acylamino groups, e.g. the valeroylamino, benzoylamino or phthalimido group, may be converted by hydrolysis into an amino group, and imino groups, e.g. the phthalimino group, may be converted by transamidation into an amino group.
The hydrolysis of step (f) may conveniently be carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/iso-propanol or water/dioxane conveniently at temperatures of between -10’C and 120°C, preferably 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 the trifluoroacetoxy group. If Rw represents a phthalimido group, this group may, to particular advantage, be converted into an amino group in the presence of a primary organic base such as methylamine, ethylamine or propylamine or with hydrazine optionally in a suitable solvent such as methanol, ethanol, isopropanol, dimethylformamide, methanol/diIE 912822 - 30 methylformamide or methanol/water by transamidation at temperatures between 0 and 50°C, preferably at ambient temperature.
The reaction of step (g) is preferably carried out in a solvent such as tetrahydrofuran, dioxane, ethylene chloride or benzene, optionally in the presence of an acid binding agent such as triethylamine or pyridine, conveniently at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.
Examples of reactive derivatives of a compound of formula XII in step (h) include, for example, the esters thereof such as the methyl, ethyl or benzylesters, the thioesters such as the methylthio or ethylthioesters, and the halides such as the acid chloride, the anhydrides or imidazolides thereof.
The reaction of step (h) may conveniently be carried out in a solvent or mixture of solvents such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide with a corresponding carboxylic acid in the presence of an acid-activating or dehydrating agent such as thionyl chloride, with the anhydrides thereof such as acetic acid anhydride, with the esters thereof such as ethyl acetate, with the halides thereof such as acetyl chloride or methanesulphonyl chloride, 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 serve as solvent, conveniently at temperatures between -25 and 100°C, preferably at temperatures between -10 and 80°C.
The cyclisation of step (i) and, if necessary, the subsequent alkylation are expediently carried out in a solvent such as methanol, ethanol, benzene or - 31 dimethylsulphoxide, optionally in the presence of a phase transfer catalyst such as benzyltriethylammoniuin bromide in the presence of an acid binding agent such as sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride or potassium tert.-butoxide at temperatures between 20 and 100°, preferably at temperatures between 30 and 70°C.
The isomer separation of step (j) is preferably carried out 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 the physiologically acceptable salts thereof with organic or inorganic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or tetrazolyl group, may, if desired, subsequently be converted into the addition salts thereof with organic or inorganic bases, more particularly for pharmaceutical use into the physiologically acceptable addition salts thereof. Suitable bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolaraine, diethanolamine and triethanolamine.
Some of the compounds of formulae II to XIV used as starting materials are known from the literature. Otherwise these compounds may be obtained by methods known from the literature.
Thus, for example, a compound of general formula II is - 32 obtained by alkylation of a corresponding o-amino-nitro compound and subsequent reduction of the nitro group.
Compounds of formulae III, V, VI, VII, VIII, IX, XI or XIII used as starting materials are obtained by alkylation of a corresponding o-diamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino compound thus obtained, or by NHalkylation of a corresponding ΙΗ-compound, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography.
The new compounds of general formula I and the physiologically acceptable addition salts thereof have valuable pharmacological properties. They are angiotensin antagonists, in particular, angiotensin-IIantagonists. Compounds of formula I which are of particular value are those wherein R4 represents an alkoxycarbonyl, carboxy or ΙΗ-tetrazolyl group.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable addition salt thereof together with at least one pharmaceutical carrier or excipient.
In 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, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases. - 33 In a still yet further aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), cardiac insufficiency progression after myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I or a physiologically acceptable addition salt thereof.
By way of example, the following compounds: A = 4’-[(2—n—butyl—5—methyl—6—phthalimido—3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid; B = 41-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3y1) methyl]bipheny1-2-carboxylic acid; C = 4'—[(2—benzylamino—8—n—butyl—9H—purin—9—yl)—methyl]— biphenyl-2-carboxylic acid; D = 4’-[[2-n-butyl-5-methyl-6-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid; E = 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid; F = 4'-[[2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2carboxylic acid; G = 4'-[(2-n-butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3yl) methyl]-2-(lH-tetrazol-5-yl) biphenyl; - 34 Η = 41-[[2-n-butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(ΙΗ)pyrimidinon-l-yl)-3H-imidazo[4, 5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid; I = 4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5yl)biphenyl; J = 4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol5-yl)biphenyl; and K = 41-[[2—n-propyl—5—(2—methyl—propylamino)—3H—imidazo— [4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl were tested for their biological effects as follows: Rats (male, 180-220 g) are anaesthetised with sodium hexobarbital (150 mg/kg i.p.). After they have become unconscious, a tracheal cannula is inserted, the animals are pithed and then immediately artificially respirated with a ventilator pump. The arterial blood pressure is recorded by means of a cannula in the carotid artery using a Bell & Howell pressure recorder. The substances are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, 20 and 30 mg/kg i.v.), with one dose of substance being tested on each animal. Three minutes after the intravenous administration of the test substance, angiotensin-II is administered intravenously in increasing doses and in this way a cumulative doseactivity relationship is achieved for angiotensin-II in the presence of the test substances. The increase in arterial blood pressure is measured. - 35 These dose-activity curves are compared with standard curves for angiotensin-II without the use of any test substances. Using a computer program, the shifts to the right in the dose-activity curves for angiotensin-II as a result of the administration of the test substances are determined and corresponding pA2-values are calculated for the test substances.
The pA2 values of the above-mentioned test compounds A to K are between 5.1 and 7.9.
Moreover, when the above-mentioned compounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or heart rhythm diosorders, were observed. Accordingly, the compounds are well tolerated.
The new compounds and their physiologically acceptable addition salts are suitable for their treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptable addition salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl choline and dopamine in the brain, the new angiotensin antagonists are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's - 36 disease, Parkinson syndrome, bulimia and disorders of cognitive function.
The dosage required to achieve these effects is conveniently, when administered intravenously, 20 to 100 mg, preferably 30 to 70 mg, and, when administered orally, 50 to 200 mg, preferably 75 to 150 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, may be incorporated together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline 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.
The following non-limiting Examples are provided to illustrate the invention. Unless otherwise specified all percentages and ratios given are by weight. - 37 Example A 2-n-Butyl-7-methyl-imidazo[4,5-b]pyridine 3.6 g (29 mMol) of 2,3-diamino-4-methyl-pyridine and 3 ml of valeric acid are refluxed for 2 hours in 30 ml of phosphorusoxytrichloride. The reaction mixture is evaporated down in vacuo and the residue is mixed with 100 ml of ice water. By adding 20% sodium hydroxide solution, the mixture is neutralised and then extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulphate and evaporation of the solvent, an oil is obtained.
Yield: 4.8 g (87% of theory), Rf value: 0.40 (silica gel, eluant: ethylmethylketone/ xylene = 1:1 by volume) C^H^Nj (189.26) Calculated: C 69.81 H 7.99 N 22.20 Found: 69.60 7.91 21.96 The following compounds are obtained analogously: 8-n-buty1-2-benzylamino-purine Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-buty1-2-n-butylamino-purine Melting point: 111-114 °C 8-n-butyl-2-cyclohexylamino-purine Oil, Rf value: 0.60 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) 8-n-buty1-2-ethoxy-purine Melting point: 181-182 °C 8-n-butyl-2-methoxy-purine Melting point: 166°C - 38 8-n-buty1-purine Melting point: 178-180°C 2-n-butyl-5-bromo-imidazo[4,5-b]pyridine Melting point: 223-225’C Example B 2-n-Butyl-5-valeroylamino-imidazo[4,5-b]pyridine Prepared from 2,6-bis(n-pentanoylamino)-3-nitro-pyridine analogously to Example 1.
Yield: 83% of theory, Melting point: 148-150°C The following compounds are obtained analogously: 2-n-butyl-5-dimethylamino-imidazo[4,5-b]pyridine Melting point: 128-129°C 2-n-butyl-5-methyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0.23 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-butyl-6-amino-imidazo[4,5-b]pyridine Oil, Rf value: 0.15 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) Example C 2-n-Butyl-5-(cis-hexahydrophthalimido)-imidazo[4,5-b] pyridine Prepared by reacting 2-n-butyl-5-amino-imidazo[4,5-b]pyridine with cis-hexahydrophthalic acid anhydride analogously to Example 4.
Yield: 63% of theory, Oil, Rf value: 0.50 (silica gel; eluant: methylene - 39 chloride/ ethanol = 9:1 by volume) The following compounds are obtained analogously: 2-n-butyl-5-methyl-6-phthalimido-imidazo[4,5-b]pyridine Oil, Rf value: 0.77 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) 2-n-butyl-6-phthalimido-imidazo[4,5-b]pyridine Oil, Rf value: 0.68 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 2-n-propyl-5-(2,2-dimethylpropionylamino)-imidazo[4,5-b]pyridine Oil, Rf value: 0.42 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1 by volume) 2-n-propyl-5-cyclohexylcarbonylamino-imidazo[4,5-b]pyridine Oil, Rf value: 0.67 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1 by volume) - 40 Example 1 Tert.-butyl 4(2-n-butyl-5-methylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate 1.8 g (3.5 raMol) of 2-[N-4-(2-tert.butoxycarbonylphenyl )benzyl-N-pentanoylamino]-3-nitro-6-methylaminopyridine are dissolved in 200 ml of ethanol, mixed with 1.0 g of 10% palladium on activated charcoal and hydrogenated for 2 hours at ambient temperature under 5 bars of hydrogen pressure. After the uptake of hydrogen has ended the catalyst is filtered off and the residue is concentrated by evaporation. The residue is dissolved in 20 ml of glacial acetic acid and heated for 30 minutes over a steam bath. Then the reaction mixture is evaporated down, the residue is dissolved in 100 ml of ethyl acetate and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. After drying over magnesium sulphate, evaporation of the solvent and column chromatography on silica gel (particle size: 0.06-0.2 mm, eluant: petroleum ether/ethyl acetate = 1:1 by volume) a colourless oil is obtained.
Yield: 1.4 g (86% of theory), Oil, Rf value: 0.27 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) C29H34N4O2 (470.61) Calculated: C 74.01 H 7.28 N 11.91 Found: 73.86 7.35 12.13 The following compounds are obtained analogously: tert.butyl 4’-[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyridin-3-y1) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4·-[(2-n-butyl-5-n-butylamino-3H-imidazoIE 912822 -41[4,5-b]pyridin-3-y1) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-ethylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant; petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-cyclohexylmethylamino-3Himidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) 41-[[2-n-propyl-5-(2-methylpropylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(l-triphenylmethyltetrazol-S-yl) biphenyl Melting point: 132-135°C tert.butyl 4'-[[2-n-butyl-5-(2,4-dimethoxybenzyl)amino3H-imidazo[4,5-b]pyridin-3-yl]-methyl]bipheny1-2carboxylate Oil, Rf value: 0.40 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-benzylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4'—[(2-n-butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-l-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.44 (silica gel; eluant: ethylmethylketone/xylene = 1:2 by volume) 4'-[[2-n-butyl-5-(4-methyl-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethylIE 912822 - 42 tetrazol-5-yl)-biphenyl Melting point: 147-149’C Example 2 Tert.butyl 4'-[(2-n-butyl-5-valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylate (I) and Tert.butyl 4'—[(2-n-butyl-5-valeroylamino-lH-imidazo[4,5-b]pyridin-l-yl)methyl]-biphenyl-2-carboxylate (II) 8.9 g (10.6 mMol) of 2-n-butyl-5-valeroylamino-3Himidazo[4,5-b]pyridine are dissolved in 400 ml of acetone, mixed with 7.3 g (53 mMol) of potassium carbonate and with 5.5 g (15.9 mMol) of tert.butyl 4’bromomethyl-biphenyl-2-carboxylate and refluxed for 6 hours with stirring. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is purified over a silica gel column (particle size: 0.063-0.2 mm), using a mixture of petroleum ether and ethyl acetate in the ratio 3:1 by volume as eluant. The uniform fractions are evaporated to dryness and triturated with diethylether. The solids thus crystallised are washed with ether and dried.
I: Yield: 4.2 g (73% of theory), Melting point: 102-104 °C C33H39N4°3 (539.70) Calculated: C 73.20 H 7.46 N 10.36 Found: 73.18 7.72 10.19 II: Yield: 1.1 g (20% of theory), Melting point: 107-108°C C33H39N4°3 (539.70) Calculated: C 73.20 H 7.46 N 10.36 Found: 73.14 7.44 10.38 The following compounds are obtained analogously: - 43 tert.butyl 4’-[(2-n-propyl-5-butanoylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]bipheny1-2-carboxylate Melting point: 157-158 °C tert.butyl 4'-((2-n-propyl-5-butanoylamino-lH-imidazo[4,5-b]pyridin-l-yl) methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.38 (silica gel, eluant: ethyl acetate) tert.butyl 4'-[(2-n-propyl-5-butanoylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2carboxylate Oil, Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) tert.butyl 4'—[(2-n-butyl-5-dimethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.37 (aluminium oxide; eluant: ethyl acetate/petroleum ether = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylethylketone/xylene = 1:2 by volume) tert.butyl 4'(2-n-butyl-5-bromo-lH-imidazo[4,5-b]pyridin-l-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.20 (silica gel; eluant: methylethylketone/xylene = 1:2 by volume) tert.butyl 4’-[(2-n-butyl-5-methyl-6-phthalimido-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylethylketone/xylene = 1:4 by volume) tert.butyl 4(2-n-butyl-5-methyl-6-phthalimido-lHimidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylate - 44 Oil, Rf value: 0.18 (silica gel; eluant: methylethylketone/xylene = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.62 (silica gel; eluant: methylethylketone/xylene = 1:1 by volume) tert.butyl 4’—[(2-n-butyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-l-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.43 (silica gel; eluant: methylethylketone/xylene = 1:1 by volume) tert.butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-3Himidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2carboxylate Oil, Rf value: 0.58 (silica gel; eluant: methylethylketone/xylene = 1:1 by volume) tert. butyl 4'-[(2-n-butyl-6-hexahydrophthalimido-lHimidazo[4,5-b]pyridin-l-yl)-methyl]biphenyl-2carboxylate Oil, Rf value: 0.31 (silica gel; eluant: methylethylketone/xylene = 1:1 by volume) 4'-[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyltetrazol-5-yl)biphenyl Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: ethyl acetate) methyl 4’-[(2-n-butylamino-8-n-butyl-9H-purin-9yl)methyl]biphenyl-2-carboxylate Melting point: 125-126°C - 45 methyl 4'-[(2-cyclohexylamino-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.52 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) methyl 4'-[(2-ethoxy-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) methyl 4'—[(2-methoxy-8-n-butyl-9H-purin-9-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol = 95:5 by volume) 4'-[[2-n-propyl-5-(2,2-dimethylpropionylamino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl Melting point: 177-178 °C *-[(2-n-propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl Melting point: 183-184 °C Example 3 Tert.butyl 4'—[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylate 3.4 g (6.3 mMol) of tert.butyl 4’-[(2-n-butyl-5valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate are dissolved in 75 ml of ethanol, mixed with 35 ml of 2N sodium hydroxide solution and heated to 80°C for 8 hours with stirring. The reaction mixture is concentrated by evaporation, taken up in ethyl acetate and extracted with water. The aqueous phase is re-extracted twice with about 100 ml of ethyl acetate. The organic phases are combined, washed - 46 with saturated saline solution and dried over magnesium sulphate. After evaporation of the solvent the residue is crystallised by triturating with petroleum ether. Yield: 2.1 g (73% of theory), Melting point: 112-124'C C28H32N4°2 (456.59) Calculated: C 73.66 H 7.07 N 12.21 Found: 73.72 7.20 12.12 The following compounds are obtained analogously: tert.butyl 4'-[(2-n-propyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.50 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.56 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6-amino-lH-imidazo[4,5-b]pyridin-l-yl) methyl]bipheny1-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) Example 4 4'-[[2-n-Butyl-5-(N-acetyl-cyclohexylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid 0.3 g (0.62 mMol) of 4'-[(2-n-butyl-5-cyclohexylamino3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2carboxylic acid are dissolved in 3.0 g (38 mMol) of acetyl chloride and refluxed for 2 hours. The reaction mixture is evaporated down, the residue is mixed with water and neutralised with aqueous ammonia solution.
The precipitate formed after acidification with glacial acetic acid is suction filtered, washed with water and - 47 dried.
Yield: 0.22 g (68% of theory), Melting point: 121-123 °C C32H36N4°3 (524.67) Calculated: C 73.26 H 6.92 N 10.68 Found: 72.43 6.93 10.96 The following compounds are obtained analogously: tert, butyl 4'-[(2-n-propyl-5-benzylcarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate Oil, Rf value: 0.36 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert, butyl 4 '-[ [ 2-n-but,yl-5-(cis-hexahydrophthalimido) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate Oil, Rf value: 0.66 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-(N-acetyl-n-butylamino)-3Himidazo(4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.21 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 41 — [[2-n-butyl-5-(N-ethoxycarbonylethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.45 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 41-[[2-n-butyl-5-(N-cyclohexylcarbonylethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.34 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4’-[[2-n-butyl-5-N-[(2-methyl-propionyl)-nIE 912822 - 48 butylamino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 4’-[[2-n-butyl-5-(N-ethoxycarbonyl-nbutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.53 (silica gel; eluant: petroleum ether/ethyl acetate = 1:1 by volume) tert.butyl 41-[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-lH-imidazo[4,5-b]pyridin-l-yl) methylbiphenyl-2-carboxy late Amorphous, Rf value: 0.55 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 80:20:2 by volume) tert.butyl 4'-[(2-n-butyl-5-methyl-6dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3yl) methyl]biphenyl-2-carboxylate Amorphous, Rf value: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) tert.butyl 4·-[[2-n-butyl-5-methyl-6-(N-ethylcyclohexylcarbonylamino)-3H-imidazo[4,5-b]pyridin-3yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.46 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(5-chloropentanoyl amino)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2carboxylate Oil, Rf value: 0.63 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(N-acetyl-nbutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]IE 912822 - 49 biphenyl-2-carboxylate Oil, Rf value: 0.48 (silica gel; eluant: methyl ketone/ethanol = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5-(4-chlorophenylsulphonylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate Oil, Rf value: 0.39 (silica gel; eluant: methylene chloride/ethanol = 9:1 by volume) Example 5 4’-[[2-n-Butyl-5-(N-acetyl-cyclohexylmethylamino)-3Himidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4'-[(2-n-butyl-5 cyclohexylmethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid and acetylchloride. Yield: 93% of theory, Melting point: 180-185°C C33H38N4°3 (53θ·2θ) Calculated: C 73.58 H 7.11 N 10.40 Found: 73.56 7.37 10.46 Example 6 41-[(2-n-Butyl-5-propionylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4'-[(2-n-butyl-5 amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2carboxylate and propionic acid anhydride.
Yield: 66% of theory, Melting point: 278-281’C C27H28N4O3 (456.55) Calculated: C 71.03 H 6.18 N 12.27 Found: 70.86 6.23 12.40 - 50 Example 7 '-[[2-n-Butyl-5-(2-methylpropionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4’-[(2-n-butyl-5amino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2carboxylic acid and isobutyric acid chloride.
Yield: 49% of theory, Melting point: 250°C C28H30N4°3 (430.58) Calculated: C 71.47 H 6.43 N 11.91 Found: 71.26 6.31 11.66 Example 8 Tert.butyl 4'-[[2-n-butyl-5-(N—(3-chloropropylaminocarbonyl) -amino) -3H-imidazo[4,5-b ] pyr idin-3-yl ] methylbiphenyl-2-carboxylate 1.3 g (2.9 mMol) of tert.butyl 4'(2-n-butyl-5-amino3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2carboxylate are dissolved in 10 ml of dimethylformamide, mixed with 1.4 g (12 mMol) of 3-chloropropylisocyanate and stirred for 40 hours at ambient temperature. After the addition of 200 ml of ice water the mixture is extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulphate the solvent is evaporated and the residue is triturated with ether. The precipitate formed is suction filtered and dried.
Yield: 1.5 g (90% of theory), Melting point: 207-209°C C32H38C1N5°3 (646.17) Calculated: C 66.71 H 6.65 N 12.16 Found: 66.71 6.72 12.47 The following compounds are obtained analogously: - 51 tert.butyl 4 [2-n-propyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b ] pyr idin-3-yl] methylbiphenyls-carboxy late Oil, Rf value: 0.20 (silica gel; eluant: ethyl acetate) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonylethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.30 (silica gel; eluant: ethyl acetate/petroleum ether = 1:1 by volume) tert.butyl 4'-[[2-n-butyl-5-(N-cyclohexylaminocarbonyln-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.55 (silica gel; eluant: ethyl acetate/petroleum ether = 1:2 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-[N-(3-chloropropylaminocarbonyl)amino]-3H-imidazo[4,5-b]pyridin-3yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.58 (silica gel; eluant: ethyl acetate/ethanol/ammonia = 90:10:1 by volume) 4'-[[2-n-propyl-6-(N-benzylaminocarbonyl-isobutylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl) biphenyl Oil, Rf value: 0.67 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) 4'-[[2-n-propyl-5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1triphenylmethyl-tetrazol-5-yl)biphenyl Oil, Rf value: 0.62 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) - 52 Example 9 4'-[(2-n-Butyl-5-cyclohexylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 8 from 4'-[(2-n-butyl-5amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2carboxylic acid and cyclohexylisocyanate.
Yield: 46% of theory, Melting point: 287-291’C C31H35N5°3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 69.01 6.66 13.18 Example 10 Tert.butyl 41-[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate 0.26 g (5.3 mMol) of sodium hydride are dissolved in 20 ml of tert.butanol. After 5 minutes at ambient temperature, 0.58 g (1.0 mMol) of tert.-butyl 4'-[[2-nbutyl-5-(N-(3-chloropropylaminocarbonyl)-amino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate are added in batches. The mixture is stirred for 10 hours at ambient temperature. By adding 2N hydrochloric acid the pH is adjusted to 5 and the tert.-butanol is evaporated off in vacuo. The residue is stirred with 100 ml of ethyl acetate and 100 ml of water, the organic phase is separated off and the aqueous phase is extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. After evaporation of the solvent the residue is triturated with ether, the precipitate formed is suction filtered and dried. - 53 Yield: 0.4 g (74% of theory), Rf value: 0.33 (silica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) C32H37N5°3 (539.68) Calculated: C 71.22 H 6.91 N 12.98 Found: 70.99 6.98 12.81 The following compounds are obtained analogously: tert.butyl 41-[[2-n-propyl-5-(3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl] biphenyl-2-carboxylate Melting point: 175°C tert.butyl 4’-[[2-n-butyl-5-methyl-6-(3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b] pyridin-3-yl]methyl]biphenyl-2-carboxylate Melting point: 200-202 °C tert.butyl 4[2-n-butyl-5-methyl-6-(2-oxo-piperidin-l yl)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2carboxylate Rf value: 0.49 (silica gel; eluant: methylene chloride/ ethanol = 9:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(n-butanesultam-lyl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate Rf value: 0.50 (silica gel; eluant: methylene chloride/ ethanol = 19:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-l yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate Rf value: 0.60 (silica gel; eluant: methylene chloride/ ethanol = 19:1 by volume) - 54 Example 11 Tert.butyl 4'-[[2-n-butyl-5-(3-benzyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate 0.4 g (0.74 mMol) of tert.butyl 4'-[[2-n-butyl-5-(N-(3chloropropylaminocarbonyl)-amino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate are suspended in 20 ml of dimethylformamide and mixed with 0.04 g (0.85 mMol) of sodium hydride. The mixture is stirred for 10 minutes at 60°C, 0.5 ml (4.25 mMol) of benzylbromide are added and the resulting mixture is stirred for 3 hours at ambient temperature. The reaction mixture is poured onto ice and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated saline solution and dried over magnesium sulphate. After the solvent has been evaporated, a colourless oil is obtained.
Yield: 0.35 g (75% of theory), Rf value: 0.41 (silica gel; eluant: methylene chloride/ethyl acetate = 1:1 by volume) Mass spectrum: M+ = 629 The following compounds are obtained analogously: tert.butyl 4'-[[2-n-butyl-5-(3-methyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.41 (silica gel; eluant: ethyl acetate/ethanol = 9:1 by volume) tert.butyl 4'-[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate Oil, Rf value: 0.44 (silica gel; eluant: methylene chloride/ethanol = 19:1 by volume) - 55 Example 12 4·-[(2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2 (1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid 0.35 g (0.55 mMol) of tert.butyl 4'[2-n-butyl-5-(3benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3Himidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2carboxylate are dissolved in 10 ml of methylene chloride and mixed with 5 ml of trifluoroacetic acid. The mixture is stirred for 65 hours at ambient temperature. The solvent is evaporated off, the residue is taken up in ice water and acidified with glacial acetic acid.
The precipitate thus formed is filtered off, washed with water and dried at 60°C.
Yield: 0.26 g (82% of theory), Melting point: 168-l70°C C35H35N5°3 (573.70) Calculated: C 73.28 H 6.15 N 12.21 Found: 73.37 6.51 12.12 Example 13 '-[[2-n-Butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64% of theory, Melting point: 249-252 °C C29H31N5°3 (497.60) Calculated: C 70.00 H 6.28 N 14.00 Found: 69.85 6.40 13.89 - 56 Example 14 4'-[[2-n-Butyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 300-302 °C C28H29N5°3 (483.58) Calculated: C 68.27 H 6.14 N 14.22 Found: 68.47 6.11 14.28 Example 15 41~[[2-n-Propyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon1-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-(3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 92% of theory, Melting point: 265-268 °C C27H27N5°3 (469.55) Calculated: C 69.07 H 5.80 N 14.92 Found: 68.87 5.78 15.00 Example 16 4'-[(2-n-Butyl-5-cyclohexylmethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’IE 912822 - 57 [(2-n-butyl-5-cyclohexylmethylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 23.6% of theory, Melting point: 202-205’C (496.66) Calculated: C 74.97 H 7.31 N 11.28 Found: 74.82 7.84 10.98 Example 17 4' — [(2-n-Butyl-5-ethylamino-3H-imidazo[4,5-b]pyridin-3y1) methyl]biphenyl-2-carboxy1ic acid Prepared analogously to Example 12 from tert.butyl 4·[(2-n-butyl-5-ethylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 76% of theory, Melting point: 245-247 °C C26H28N4°2 (428.54) Calculated: C 72.87 H 6.59 N 13.09 Found: 72.72 6.65 12.84 Example 18 4’-((2-n-Butyl-5-n-butylamino-3H-imidazo[4,5-b]pyridin3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4‘[(2-n-butyl-5-n-butylamino-3H-imidazo[4,5-b]pyridin-3yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 217-219°C C28H32N4°2 (456.59) Calculated: C 73.66 H 7.06 N 12.27 Found: 73.46 7.03 12.17 - 58 Example 19 ’ (2-n-Butyl-5-cyclohexylamino-3H-imidazo[4,5-b] pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyridin3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 221-224”C C30H34N4O2 (482.63) Calculated: C 73.29 H 7.18 N 11.40 Found: 73.51 6.95 11.25 Example 20 4'-f(2-n-Butyl-5-methylamino-3H-imidazo[4,5-b]pyridin-3yl)-methyl]biphenyl-2-carboxylie acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-methylamino-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 61% of theory, Melting point: 274-277ec C25H26N4°2 (414.51) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.26 6.26 13.30 Example 21 4'-[(2-n-Butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic - 59 acid.
Yield: 35% of theory, Melting point: 238-240’C C24H24N4O2 (400.48) Calculated: C 71.98 H 6.04 N 13.99 Found: 71.90 5.96 13.86 Example 22 4'-[(2-n-Butyl-5-dimethylamino-3H-imidazo[4,5-b]pyridin 3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-dimethylamino-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 213-215’C C26H28N4°2 (428.54) Calculated: C 72.87 H 6.57 N 13.08 Found: 72.82 6.73 12.90 Example 23 4'-[(2-n-Butyl-5-benzylamino-3H-imidazo[4,5-b]pyridin-3 yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-benzylamino-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 67% of theory, Melting point: 224-225’C C31H30N4O2 (490.61) Calculated: C 75.89 H 6.16 N 11.42 Found: 75.70 6.24 11.37 - 60 Example 24 4’-[[2-n-Butyl-5-(2,4-dimethoxybenzylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(2,4-dimethoxybenzylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 223-226°C C33H34N4°4 (490.61) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.70 6.21 10.16 Example 25 4'-[[2-n-Butyl-5-(N-isobutyryl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(N-isobutyryl-n-butylamino-3H-imidazo[4,5-b]pyridin-3-yl]methyl]bipheny1-2-carboxylate and trifluoroacetic acid.
Yield: 33% of theory, Melting point: 186-189°C C32H38N4O3 (490.61) Calculated: C 72.98 H 7.27 N 10.64 Found: 73.09 7.45 10.53 - 61 Example 26 4’-[[2-n-Butyl-5-(N-acetyl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(N-acetyl-n-butylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 36% of theory, Melting point: 173-175°C C30H34N4°3 (498.63) Calculated: C 72.26 H 6.87 N 11.24 Found: 72.39 7.00 11.07 Example 27 41 -[[2-n-Butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo-[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 203-205°C C33H38N4°3 (538.70) Calculated: C 73.58 H 7.11 N 10.40 Found: 73.66 7.19 10.35 Example 28 4’-[[2-n-Butyl-5-(N-acetyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]bipheny1-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'IE 912822 [[2-n-butyl-5-(N-acetyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 89-93 °C C33H38N4°3 (470.58) Calculated: C 70.99 H 6.47 N 11.79 Found: 70.79 6.47 11.52 Example 29 4'-[(2-n-Butyl-5-valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-valeroylamino-3H-imidazo-[4,5-b]pyridin-3 yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% of theory, Melting point: 240-242°C C33H38N4°3 (484.60) Calculated: C 71.88 H 6.66 N 11.56 Found: 71.61 6.72 11.47 Example 30 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin3-yl)methyl]biphenyl-2—carboxylate and trifluoroacetic acid.
Yield: 68% of theory, Melting point: 254-255*C (456.55) I: C 71.03 H 6.18 N 12.27 C27H28N4°3 I Calculated Found 70.98 6.25 12.36 - 63 Example 31 4'-[(2-n-Propyl-5-butanoylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-4-bromo-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-butanoylamino-3H-imidazo-[4,5-b]pyridin3-yl)methyl]biphenyl-4-bromo-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 244-245°C C27H27N4O3Br (53 5.54) Calculated: C 60.56 H 5.08 N 10.46 Br 14.92 Found: 60.42 5.07 10.41 14.82 Example 32 4'-[[2-n-Propyl-5-(2-methyl-valeroylamino)-3Himidazo[4,5-b]-pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-(2-methyl-valeroylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 97% of theory, Melting point: 244-245°C C29H32N4°3 (484.61) Calculated: C 71.88 H 6.66 N 11.56 Found: 71.77 6.79 11.51 Example 33 4'-[(2-n-Propyl-5-benzylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-benzylcarbonylamino-3H-imidazoIE 912822 - 64 [4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93% of theory, Melting point: 252-254 °C C31H28N4°3 (504.60) Calculated: C 73.79 H 5.59 N 11.10 Found: 73.85 5.78 10.93 Example 34 4'-[(2-n-Propyl-5-butanoylamino-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-butanoylamino-lH-imidazo-[4,5-b]pyridinl-yl) methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% of theory, Melting point: 120°C C27H28N4°3 (456.55) Calculated: C 70.34 H 6.23 N 12.15 Found: 70.14 6.24 12.34 Example 35 41-([2-n-Butyl-5-(N-ethoxycarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylie acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-(N-ethoxycarbonyl-ethylamino)-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185°C C29H32N4°4 (500.61) Calculated: C 69.58 H 6.44 N 11.19 Found: 69.72 6.57 11.13 - 65 Example 36 4'-[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 95% of theory, Melting point: 182-185°C C33H39N5°3 (500.61) Calculated: C 71.58 H 7.10 N 12.65 Found: 71.77 7.22 12.59 Example 37 4'-[[2-n-Butyl-5-(N-ethoxycarbonyl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-(N-ethoxycarbonyl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 37% of theory, Melting point: 154-156’C C31H36N4O4 (528.66) Calculated: C 70.43 H 6.86 N 10.60 Found: 70.68 7.10 10.50 - 66 Example 38 4'-[[2-n-Butyl-5-(N-cyclohexylaminocarbonyl-n-butylam ino) -3 H-imidazo[4,5-b]pyr idin-3-y1]methy1]bipheny1-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-(N-cyclohexylaminocarbonyl-n-butylamino)3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 89% of theory, Melting point: 195-198 °C C35HA°3 (581.47) Calculated: C 72.26 H 7.45 N 12.04 Found: 72.29 7.66 11.81 Example 39 4'-[[2-n-Butyl-5-(n-butylaminocarbonylamino)-1Hiraidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(n-butylaminocarbonylamino)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 290-295°C C29H33N5°3 (499.62) Calculated: C 69.72 H 6.66 N 14.02 Found: 69.62 6.76 13.98 - 67 Example 40 4'-[[2-n-Butyl-5-(cis-hexahydrophthalimido)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4·[[2-n-butyl-5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84% of theory, Melting point: 113-115°C C32H32N4O4 (53 6.64) Calculated: C 62.76 H 5.11 N 8.61 Found: 62.79 5.21 8.48 Example 41 41-[(2-n-Butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-1yl)methyl]biphenyl-2-carboxylic acid-trifluoroacetatehydrate Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-lyl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 126-128°C C25H25N3°3 x CFjCOOH X H2o (547.54) Calculated: C 59.23 H 5.15 N 7.68 Found: 59.46 4.99 7.63 Example 42 4'(2-n-Butyl-6-bromo-lH-imidazo[4,5-b]pyridin-lyl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-6-bromo-lH-imidazo[4,5-b]pyridin-lIE 912822 - 68 yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Melting point: 239-240°C C24H22BrN3O2 (464.36) Calculated: C 62.08 H 4.77 N 9.05 Br 17.21 Found: 61.83 4.71 8.92 17.43 Example 43 41 -[(2-n-Butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [(2-n-butyl-6-bromo-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85% of theory, Melting point: 221-223°C C24H22BrN3O2 (4 64.3 6) Calculated: C 62.08 H 4.77 N 9.05 Br 17.21 Found: 61.95 4.84 8.96 17.38 Example 44 4'-[(2-n-Butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 75% of theory, Melting point: 336-340’C C33H28N4°4 (544.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.59 5.18 10.26 - 69 Example 45 4’-[(2-n-Butyl-5-methyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [(2-n-butyl-5-methyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 301-303 °C C33H28N4°4 (54 4.62) Calculated: C 72.78 H 5.18 N 10.29 Found: 72.71 5.25 10.18 Example 46 4'-[(8-n-Butyl-2-methoxy-9H-purin-9-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’ [(8-n-butyl-2-methoxy-9H-purin-9-yl) methyl]bipheny1-2 carboxylate and trifluoroacetic acid.
Yield: 73% of theory, Melting point: 146-148 °C C24H24N4O3 (416.48) Calculated: C 69.21 H 5.81 N 13.45 Found: 68.97 5.84 13.17 Example 47 4'-[(8-n-Butyl-2-methoxy-7H-purin-7-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [(8-n-butyl-2-methoxy-7H-purin-7-yl)methyl]biphenyl-2 carboxylate and trifluoroacetic acid.
Yield: 73% of theory, - 70 Melting point: 146-148°C C24H24N4O3 (416.48) Calculated: C 69.21 H 5.81 N 13.45 Found: 69.07 5.94 13.27 Example 48 4'-[(2-Benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-benzylamino-8-n-butyl-9H-purin-9-yl)methyl]bipheny12-carboxylate and trifluoroacetic acid.
Yield: 13% of theory, Melting point: 232-234°C C30H29N5°2 (491.60) Calculated: C 73.20 H 5.95 N 14.25 Found: 73.16 6.05 14.44 Example 49 4(2-n-Butyl-5-methyl-6-(N-acetyl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4·[(2-n-butyl-5-methyl-6-(N-acetyl-n-butylamino)-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% of theory, Melting point: 144-146’C C31H36N4°3 (512.65) Calculated: C 72.63 H 7.08 N 10.93 Found: 72.39 7.15 10.79 - 71 Example 50 4'-[(2-n-Butyl-5-methyl-6-amino-3H-imidazo[4,5-b] pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-methyl-6-amino-3H-imidazo[4,5-b]pyridin-3yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80% of theory, Melting point: 168-170°C C26H26N4°2 (414.57) Calculated: C 72.44 H 6.32 N 13.52 Found: 72.40 6.50 13.32 Example 51 41-[(2-n-Butyl-6-hexahydrophthalimido-3H-imidazo[4,5-bJpyridin-3-yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-6-hexahydrophthalimido-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 179-181°C C32H32N4°4 (536.64) Calculated: C 71.62 H 6.01 N 10.44 Found: 71.87 6.00 10.36 Example 52 41-[(2-n-Butyl-5-methyl-6-butyrylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]bipheny1-2-carboxylie acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-methyl-6-butyrylamino-3H-imida zo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and - 72 trifluoroacetic acid.
Example 53 4'-[[2-n-Butyl-5-methyl-6-(2-oxo-piperidin-l-yl)-1Himidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-l-yl)-1Himidazo[4,5-b]pyridin-l-yl]methyl]bipheny1-2-carboxylate and trifluoroacetic acid.
Yield: 91% of theory, Melting point: 171-173 °C C30H32N4°3 x CF3COOH (610.65) Calculated: C 62.94 H 5.45 N 9.18 Found: 62.74 5.49 8.98 Example 54 4'-([2-n-Butyl-5-methyl-6-(2-methyl-propionylamino)-3Himidazo(4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(2-methyl-propionylamino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 55 [2-n-Butyl-5-methyl-6-(N-cyclohexylcarbonylethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-methyl-6-(N-cyclohexylcarbonylethylamino)-3H-imidazo(4,5-b J pyridin-3-yl]-methyl]IE 912822 - 73 biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 164-166’C C34H40N4O3 (552.72) Calculated: C 73.88 H 7.29 N 10.14 Found: 73.58 7.29 10.04 Example 56 4'-[[2-n-Butyl-5-methyl-6-(cis-hexahydrophthalimido)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(cis-hexahydrophthalimido)-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 261-263°C C33H34N4°4 (550.67) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.78 6.25 9.95 Example 57 4'-[(2-n-Butyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylic aciddihydrate Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-6-(cis-hexahydrophthalimido)-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 70% of theory, Melting point: 203-205°C C32H32N4°4 X 2 H2° (572.68) Calculated: C 67.11 H 6.33 N 9.78 Found: 67.25 6.30 9.78 - 74 Example 58 ’ - [[2-n-Butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 77% of theory, Melting point: 168-170’C C36H37N5°3 x CF3COOH (701.76) Calculated: C 65.04 H 5.46 N 9.98 Found: 64.98 5.67 9.91 Example 59 4'-[[2-n-Butyl-5-[3-(4-methoxy)benzyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b] pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-[3-(4-methoxy)benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 60 4'-[[2-n-Butyl-5-[3-(4-hydroxy)benzyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-[3-(4-hydroxy)-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3yl]methyl]biphenyl-2-carboxylate and trifluoroacetic - 75 acid.
Example 61 41 -[[2-n-Butyl-5-(3-cyclohexylmethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]-pyridin-3yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(3-cyclohexylmethyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 62 4’-[[2-n-Propyl-5-[(2-carboxymethyl)pyrrolidino]-3Himidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-[(2-carboxymethyl)pyrrolidino]-3Himida zo[4,5-b]pyridin-3-y1]methyl]bipheny1-2-carboxylate and trifluoroacetic acid.
Yield: 37% of theory, Melting point: 137-139°C C29H30N4O4 (498.62) Calculated: C 69.86 H 6.06 N 11.24 Found: 69.59 6.20 11.04 Example 63 4·-[(2-n-Butyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-lyl )-methyl]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-lyl)-methyl]biphenyl-2-carboxylate and trifluoroacetic - 76 acid.
Yield: 74% of theory, Melting point: 168-170°C C32H26N4°4 x CFjCOOH (644.61) Calculated: C 63.35 H 4.22 N 8.96 Found: 63.50 4.53 9.06 Example 64 4'-[[8-n-Butyl-2-(n-butylamino)-9H-purin-9-yl]methyl]biphenyl-2-carboxylic acid 0.45 g (0.95 mMol) of methyl 4’-[[8-n-butyl-2-(nbutylamino)-9H-purin-9-yl]methyl)biphenyl-2-carboxylate are dissolved in 20 ml of methanol and 10 ml of water, mixed with 0.4 g of powdered potassium hydroxide and refluxed for 3 hours. The reaction mixture is then concentrated by evaporation and the residue is dissolved in 30 ml of water. It is filtered over charcoal and acidified with glacial acetic acid. The precipitate formed is suction filtered, washed with water and dried. Yield: 0.4 g (92% of theory), Melting point: 213-215°C C27H31N5°2 (457.58) Calculated: C 70.87 H 6.83 N 15.31 Found: 70.70 6.89 15.19 Example 65 41-[(8-n-Butyl-2-cyclohexylamino-9H-purin-9-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl 4'-[(8-nbuty1-2-cyclohexylamino-9H-purin-9-yl)methyl]biphenyl-2carboxylate and methanolic potassium hydroxide solution. Yield: 55% of theory, Melting point: 213-215’C C29H33N5°2 (483.62) - 77 Calculated: C 72.02 H 6.88 N 14.48 Found: 71.84 6.98 14.62 Example 66 4'-[(8-n-Butyl-2-ethoxy-9H-purin-9-yl)methyl]biphenyl-2carboxylic acid Prepared analogously to Example 64 from methyl 4’-[(8-nbutyl-2-ethoxy-9H-purin-9-yl)methyl]biphenyl-2carboxylate and methanolic potassium hydroxide solution. Yield: 48% of theory, Melting point: 190-192 °C C25H26N4°3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.75 6.13 12.83 Example 67 4'-[(8-n-Butyl-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2carboxylic acid Prepared analogously to Example 64 from methyl 4'-[(8-nbuty1-2-ethoxy-7H-purin-7-yl)methyl]biphenyl-2carboxylate and methanolic potassium hydroxide solution. Yield: 10% of theory, Melting point: 155-158°C C25H26N4°3 (430.51) Calculated: C 69.75 H 6.09 N 13.01 Found: 69.95 6.10 11.83 Example 68 4'-[[2-n-Propyl-5-(2-methylpropylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-y1) biphenyl 0.32 g (0.42 mMol) of 4'-[[2-n-propyl-5-(2-methylpropylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lIE 912822 -78triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in 20 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature. The solvent is concentrated by evaporation, the residue is triturated with 20 ml of water, suction filtered and dried. After column chromatography on silica gel (particle size: 0.06-0.2 mm, eluant: methylene chloride/ethanol 0-10%) a white solid is obtained.
Yield: 0.1 g (51% of theory), Melting point: 128-130’C C27H30N8 (466.60) Calculated: C 69.50 H 6.48 N 24.02 Found: 69.44 6.73 24.04 Example 69 4·-[[2-n-Butyl-5-(2-aminocarbonyl-cyclohexylcarbonylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1Htetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl5-(2-aminocarbonyl-cyclohexylcarbonylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethy1tetrazol-5-yl)biphenyl and methanolic hydrochloric acid. Yield: 37% of theory, Melting point: 165-175°C C32H35N9°2 (577.70) Calculated: C 66.53 H 6.11 N 21.82 Found: 65.73 6.13 21.84 Example 70 4'-[[2-n-Butyl-5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'[2-n-butyl5-(cis-hexahydrophthalimido)-3H-imidazo[4,5-b]pyridin-3IE 912822 -79yl]methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and glacial acetic acid.
Yield: 30% of theory, Melting point: 127°C C32H32N8°2 (560.66) Mass spectrum: M* = 560 Example 71 41-[[2-n-Butyl-5-(4-methyl-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4’-[[2-n-buty15-(4-methyl-piperidino)-3H-imidazo[4,5-b]pyridin-3yl]methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 39% of theory, Melting point: 187-189°C C30H34N8 (506.70) Mass spectrum: M+ = 506 Example 72 4·-[[2-n-Propyl-5-[N-(3-phenylpropionyl)isobutylamino]3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl 5-[N-(3-phenylpropionyl)-isobutylamino]-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl and methanolic hydrochloric acid. - 80 Example 73 41-[[2-n-Propyl-5-(N-benzylaminocarbonyl-isobutylamino) 3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl 5-(N-benzylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 37% of theory, Melting point: 195-196°C C35H37N9° (599.75) Calculated: C 70.09 H 6.22 N 21.02 Found: 69.95 6.32 20.86 Example 74 4'-[[2-n-Propyl-5-(N-cyclohexylaminocarbonylisobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4·-[[2-n-propyl 5-(N-cyclohexylaminocarbonyl-isobutylamino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyltetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 38% of theory, Melting point: 112-113 °C C34H41N9O (591.77) Calculated: C 69.01 H 6.98 N 21.30 Found: 68.86 6.88 21.18 - 81 Example 75 4’-[[2-n-Butyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 76 41-[(2-n-Butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 65% of theory, Melting point: 233-235°C C25H25N3°2 (399.50) Calculated: C 75.16 H 6.31 N 10.52 Found: 75.06 6.35 10.46 Example 77 4'-[[2-n-Butyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(ΙΗ-tetrazol-5-y1)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-butyl5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3yl]methyl]-2-(l-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid. - 82 Example 78 4'[[2-n-Propyl-5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl5-(2-oxo-pyrrolidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 79 4'[[2-n-Butyl-5-(2-oxo-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4’-[[2-n-butyl5-(2-oxo-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 80 4’[[2-n-Propyl-5-(2-oxo-piperidino)-3H-imidazo[4 ,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl5-(2-oxo-piperidino)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(1-triphenyl-methyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Example 81 4’-[[2-n-Butyl-5-methyl-6-(cis-hexahydrophthalimido)-1Himidazo(4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4‘[[2-n-butyl-5-methyl-6-(cis-hexahydrophthalimido)-1Himidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylate - 83 and trifluoroacetic acid.
Yield: 79% of theory, Melting point: 188-190°C C33H34N4°4 x CFjCOOH (664.68) Calculated: C 63.24 H 5.31 N 8.42 Found: 63.52 5.65 8.69 Example 82 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-lHimidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-lHimidazo[4,5-b]pyridin-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 147-149°C C28H31N5°3 x CF3COOH (599.61) Calculated: C 60.09 H 5.37 N 11.68 Found: 60.31 5.39 11.51 Example 83 4'-[(2-n-Butyl-5-methyl-lH-imidazo[4,5-b]pyridin-l-yl)methyl]bipheny1-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-methyl-lH-imidazo[4,5-b]pyridin-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 77% of theory, Melting point: 230-232°C C25H25N3°2 (399.50) Calculated: C 75.16 H 6.31 N 10.52 Found: 74.86 6.39 10.46 - 84 Example 84 4'-[(2-n-Butyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3yl)-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-6-phthalimido-3H-imidazo[4,5-b]pyridin-3yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 271-272 °C C32H26N4°4 (53 0.59) Calculated: C 72.44 H 4.94 N 10.56 Found: 72.37 4.99 10.48 Example 85 4'-[[2-n-Butyl-5-(4-chlorophenyl)sulphonylamino-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid-hydrate Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-(4-chlorophenyl)sulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63% of theory, Melting point: 158-160°C C30H27N4O4ClS X H2O (593.10) Calculated: C 60.75 H 4.93 N 9.45 Found: 60.62 4.76 9.27 Example 86 4'-[(2-n-Butyl-5-n-butylsulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4'-[(2-n-butyl-5amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2IE 912822 - 85 carboxylic acid and butanesulphonyl chloride in pyridine.
Yield: 16% of theory, Melting point: > 250°C C28H32N4°4S (520.70) Calculated: C 65.59 H 6.19 N 10.76 Found: 65.41 6.28 10.58 The following compounds are obtained analogously: 41-[(2-n-butyl-5-n-propylsulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid 4'-[(2-n-butyl-5-isopropylsulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5-(3-chloropropylsulphonylamino)-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid 4'-[(2-n-butyl-5-n-hexylsulphonylamino-3H-imidazo[4,5-b]pyridin-3-yl) methyl]bipheny1-2-carboxy1ic acid 4'-[(2-n-butyl-5-benzylsulphonylamino-3H-imidazo[4,5-b] pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Example 87 4'[2-n-Butyl-5-(n-butanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl) biphenyl Prepared analogously to Example 68 from 4’-[[2-n-butyl5-(n-butanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
The following compounds are obtained analogously: - 86 4'-[[2-n-propyl-5-(n-butanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 41 -[[2-n-butyl-5-(n-propanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5yl)biphenyl 4'-[[2-n-propyl-5-(n-propanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl 4'-[[2-n-butyl-5-(n-butanesultam-l-yl)-3H-imidazo[4 ,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid 4’-[[2-n-propyl-5-(n-butanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-butyl-5-(n-propanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid 4'-[[2-n-propyl-5-(n-propanesultam-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Example 88 4’-[(2-n-Butyl-5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[(2-n-butyl5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(1triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 43% of theory, Melting point: 206-207 °C C25H25N7° (439.52) Calculated: C 68.32 H 5.73 N 22.31 Found: 68.11 5.88 22.19 - 87 Example 89 4'-[(2-n-Butyl-3H-imidazo[4,5-b]pyridin-5-on-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[(2-n-butyl3H-imidazo[4,5-b]pyridin-5-on-3-yl)methyl]—2—(l— triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 18% of theory, Melting point: amorphous C24H23N7° (42 5.50) Calculated: C 67.75 H 5.45 N 23.04 Found: 67.54 5.42 22.91 Example 90 ' - [[2-n-Propyl-5-(2,2-dimethylpropionylamino)-3Himidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4[2-n-propyl5-(2,2-dimethylpropionylamino)-3H-imidazo[4,5-b]pyridin3-yl]methyl]-2-(l-triphenylmethyl-tetrazol-5-yl) biphenyl and methanolic hydrochloric acid.
Yield: 81% of theory, Melting point: 217-220°C C28H30N8° (494.60) Calculated: C 67.99 H 6.11 N 22.66 Found: 67.82 6.22 22.46 Example 91 4'-[(2-n-Propyl-5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[(2-n-propylIE 912822 - 88 5-cyclohexylcarbonylamino-3H-imidazo[4,5-b]pyridin-3yl)methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and methanolic hydrochloric acid.
Yield: 89% of theory, Melting point: 229-231°C C30H32N8° (52 0.64) Calculated: C 69.21 H 6.20 N 21.52 Found: 69.14 6.20 21.32 Example 92 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl) methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[(2-n-butyl-5-methyl-6-dimethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 74% of theory, Melting point: 220-221°C C28H31N5°3 (485.58) Calculated: C 69.26 H 6.44 N 14.42 Found: 69.08 6.47 14.25 Example 93 4'-[(2-n-Butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-4-chloro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 85% of theory, Melting point: 221-222’C C24H22C1N3°2 (419.92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.66 5.15 10.19 - 89 Example 94 41-[(2-n-Butyl-4-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-4-chloro-lH-imidazo[4,5-c]pyridin-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 85% of theory, Melting point: 221-222°C C24H22C1N3O2 (419.92) Calculated: C 68.65 H 5.28 N 10.00 Found: 68.56 5.18 10.09 Example 95 41-[(2-Ethyl-5-propionylamino-3H-imidazo[4,5-b]pyridin3-yl) methyl]bipheny1-2-carboxylie acid Prepared analogously to Example 12 from tert.butyl 4'[(2-ethyl-5-propionylamino-3H-imidazo[4,5-b]pyridin-3yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 99% of theory, Melting point: 283-293 °C C25H24N4°3 (428.50) Calculated: C 70.08 H 5.65 N 13.08 Found: 69.87 5.68 13.05 Example 96 4[2-n-Propyl-5-(5-hydroxy-valeroylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-(5-hydroxy-n-valeroylamino)-3Himidazo(4,5-b]pyridin-3-yl)-methyl]biphenyl-2IE 912822 - 90 carboxylate and trifluoroacetic acid. Yield: 80% of theory, Melting point: 220°C C28H30N4°4 (486.60) Calculated: C 69.12 H 6.22 N 11.52 Found: 68.97 6.44 11.39 Example 97 41-[[2-Ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 12 from tert.butyl 4'[[2-ethyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 62% of theory, Melting point: from 250°C (decomp.) C27H27N5°3 X 1/2 H2° (478.60) Calculated: C 67.77 H 5.90 N 14.64 Found: 67.98 5.84 14.66 Example 98 1 -[[2-n-Propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4·[[2-n-propyl-5-(3-methyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 74% of theory, Melting point: 202-205’C C28H29N5°3 (483.57) Calculated: C 69.55 H 6.04 N 14.48 Found: 69.30 5.98 14.62 - 91 Example 99 4'-[[2-Ethyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid-semihydrate Prepared analogously to Example 12 from tert.butyl 4'[[2-ethyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 66% of theory, Melting point: 137-138°C C33H31N5°3 X V2 H20 (545.70) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.40 5.76 12.88 Example 100 · — [[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 77% of theory, Melting point: 149-152 °C C34H33N5°3 (559.67) Calculated: C 72.97 H 5.94 N 12.51 Found: 73.11 5.91 12.39 - 92 Example 101 4'-[[2-n-Propyl-5-(N-cyclohexylaminocarbonylethylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [[2-n-propyl-5-(N-cyclohexylaminocarbonyl-ethylamino) 3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 10% of theory, Melting point: 166-167 °C C34H33N5°3 (539.69) Calculated: C 71.22 H 6.91 N 12.98 Found: 71.37 6.70 12.80 Example 102 4’-([2-Ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino) 3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [(2-ethyl-5-(N-cyclohexylaminocarbonyl-ethylamino)-3H imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 25% of theory, Melting point: 95-100°C (decomp.) C31H35N5°3 (525.66) Calculated: C 70.83 H 6.71 N 13.32 Found: 70.69 6.65 13.30 - 93 Example 103 [2-n-Propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 112-115°C C32H36N4°3 (524.67) Calculated: C 73.26 H 6.92 N 10.68 Found: 73.18 7.19 10.67 Example 104 4'-[[2-Ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-ethyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 91% of theory, Melting point: 223-224 °C C^H^Oj (510.65) Calculated: C 72.92 H 6.71 N 10.97 Found: 72.97 6.65 10.93 Example 105 4' — [[2-(N-Isobutyryl-n-butylamino)-8-n-butyl-9H-purin-9yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 4 from 4’-[[2-(nIE 912822 - 94 butylamino)-8-n-butyl-9H-purin-9-yl]-methyl]-biphenyl-2 carboxylic acid and isobutyric acid chloride.
Yield: 38% of theory, Melting point: 80°C C31H37N5°3 (527.68) Calculated: C 70.56 H 7.07 N 13.27 Found: 70.45 7.22 13.06 Example 106 4'-[[2-n-Butyl-5-methyl-6-(2-oxo-piperidin-l-yl)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4‘[[2-n-butyl-5-methyl-6-(2-oxo-piperidin-l-yl)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 77% of theory, Melting point: 266-268 °C C30H32N4°3 (496.62) Calculated: C 72.56 H 6.50 N 11.23 Found: 72.46 6.73 11.10 Example 107 4'-[[2-n-Butyl-5-methyl-6-(n-butanesultam-l-yl)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(n-butanesultam-l-yl)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 78% of theory, Melting point: 287-288 °C C29H32N4°4S (532.67) Calculated: C 65.39 H 6.06 N 10.52 - 95 Found: 65.26 6.25 10.37 Example 108 4'-[[2-n-Butyl-5-methyl-6-(N-cyclohexylaminocarbonylethylamino)-lH-imidazo[4,5-b]pyridin-l-yl]-methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-methy1-6-(N-cyclohexylarainocarbonylethylamino)-lH-imidazo[4,5-b]pyridin-l-yl]-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88% of theory, Melting point: 177-179 °C C34H31N5O3 (567.74) Calculated: C 71.93 H 7.28 N 12.34 Found: 71.76 7.20 12.13 Example 109 4'-[[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4·[[2,5-dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 74% of theory, Melting point: 277-280°C C33H31N5°3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.87 5.57 12.66 - 96 Example 110 4'-[[2,5-Dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2,5-dimethyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-lH-imidazo[4,5-b]pyridin-l-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 77% of theory, Melting point: 142-144 °C C33H31N5°3 (545.65) Calculated: C 72.64 H 5.73 N 12.84 Found: 72.59 5.51 12.60 Example 111 4’-[[2-Ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-ethyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 73% of theory, Melting point: 272-274 °C C34H33N5°3 (559.68) Calculated: C 72.97 H 5.94 N 12.51 Found: 72.87 5.97 12.37 - 97 Example 112 4'-[(2-n-Butyl-5-ethyl-6-dimethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl) methyl]-biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-ethyl-6-dimethylaminocarbonylaroino-3Himidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 72% of theory, Melting point: 180-182 °C C29H33N5°3 x CF3COOH (613.65) Calculated: C 60.67 H 5.58 N 11.41 Found: 60.81 5.81 11.65 Example 113 4'(2-n-Propyl-5-methyl-6-dimethylaminocarbonylamino3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-methyl-6-dimethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 81% of theory, Melting point: 243-245°C C27H29N5°3 x CF3COOH (585.60) Calculated: C 59.48 H 5.16 N 11.96 Found: 59.68 5.26 11.99 - 98 Example 114 4'-[(2-n-Propyl-5-methyl-6-dimethylaminocarbonylaminoΙΗ-imidazo[4,5-b]pyridin-l-yl) methyl]-biphenyl-2carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4’[(2-n-propyl-5-methyl-6-dimethylaminocarbonylamino-lHimidazo[4,5-b]pyridin-l-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 213-216°C C27H29N5°3 X CFjCOOH (585.60) Calculated: C 59.48 H 5.16 N 11.96 Found: 59.61 5.13 11.77 Example 115 4’-[(2-n-Butyl-5-methyl-6-diethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-methyl-6-diethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 90% of theory, Melting point: 137-140eC C30H35N5°3 X CFjCOOH (627.67) Calculated: C 61.23 H 5.78 N 11.16 Found: 60.97 5.93 10.98 - 99 Example 116 4'-[[2-n-Butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’[[2-n-butyl-5-ethyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 85% of theory, Melting point: 173-175°C C37H39N5O3 (601.76) Calculated: C 73.85 H 6.53 N 11.64 Found: 73.63 6.40 11.41 Example 117 4’-[[2-n-Propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro 2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-propyl-5-methyl-6-(3-benzyl-3,4,5,6-tetrahydro2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid Yield: 64% of theory, Melting point: 199-201°C C35H35N5°3 (573.69) Calculated: C 73.27 H 6.05 N 12.21 Found: 73.20 6.19 12.08 - 100 Example 118 4'-[[2-n-Butyl-5-methyl-6-(3-dimethylaminocarbonyl3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2-carboxy1ic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(3-dimethylaminocarbonyl-3,4,5,6tetrahydro-2(1H)-pyrimidinon-l-yl)-3H-imidazo[4,5-b] pyridin-3-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Example 119 41-[[2-n-Butyl-5-methyl-6-(3-benzyl-3,4,5-trihydro2(1H)-imidazolinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[[2-n-butyl-5-methyl-6-(3-benzyl-3,4,5-trihydro-2(1H)imidazolinon-l-yl)-3H-imidazo[4,5-b]-pyridin-3-yl]methyl]-biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 92% of theory, Melting point: 149-151’C C35H35N5°3 (573.70) Calculated: C 73.28 H 6.15 N 12.21 Found: 73.16 5.98 12.07 Example 120 4'-[(2-n-Propyl-5-methyl-6-(cis-hexahydrophthalimido)3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-3Himidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid. - 101 Yield: 77% of theory, Melting point: 269-270’C C32H32N4°4 (53 6.64) Calculated: C 71.62 H 6.01 N 10.44 Found: 71.48 6.24 10.31 Example 121 4'-[(2-n-Propyl-5-methyl-6-(cis-hexahydrophthalimido) 1H-imidazo[4,5-b]pyridin-l-yl) methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4’ [(2-n-propyl-5-methyl-6-(cis-hexahydrophthalimido)-1H imidazo[4,5-b]-pyridin-l-yl)-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 79% of theory, Melting point: 219-221’C C32H32N4°4 (536.64) Calculated: C 71.62 H 6.01 N 10.44 Found: 71.45 5.86 10.21 Example 122 4'-[[2-n-Butyl-5-(N-phenylsulphonyl-methylamino)-3Himidazo[4,5-b]pyridin-3-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example 12 from tert.butyl 4' [[2-n-butyl-5-(N-phenylsulphonyl-methylamino)-3Himidazo[4,5-b]-pyridin-3-yl]-methyl]-biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 83% of theory, Melting point: 226-227 °C C31H30N4O4S (554.60) Calculated: C 67.14 H 5.45 N 10.10 S 5.79 Found: 67.00 5.51 10.25 5.78 - 102 Example 123 4'-[[2-n-Propyl-5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[(2-n-propyl5-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-l-yl)3H-imidazo[4,5-b]pyridin-3-ylJ-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 72% of theory, Melting point: amorphous C34H33N9° (583.70) Calculated: C 69.96 H 5.70 N 21.60 Found: 70.11 5.57 21.49 Example 124 4,_[[2-n-Propyl-5-(2-oxo-indolin-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4'-[[2-n-propyl5-(2-oxo-indolin-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 11% of theory, Melting point: sinters from 190°C C31H26N8° (526.61) Mass spectrum: (M+H)+ = 527 - 103 Example 125 4'-[(2-n-Butyl-5-methyl-6-dimethylaminocarbonylamino-3Himidazo[4,5-b]pyridin-3-yl)methyl]-2-(lH-tetrazol-5-yl)biphenyl Prepared analogously to Example 68 from 4’-[(2-n-butyl5-methyl-6-dimethylaminocarbonylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-2-(l-triphenylmethyl-tetrazol-5yl)-biphenyl and methanolic hydrochloric acid.
Example 126 4'-[[2-Ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5-yl)biphenyl-hydrochloride Prepared analogously to Example 68 from 4’-[[2-ethyl-5(2,2-dimethyl-propionylamino)-3H-imidazo[4,5-b]pyridin3-yl]-methyl]-2-(l-triphenylmethyl-tetrazol-5-yl) biphenyl and methanolic hydrochloric acid.
Yield: 52% of theory, Melting point: sinters from 188 °C C27H28N8° x HC1 (517.04) Calculated: C 62.95 H 5.65 N 21.90 Cl 6.85 Found: 62.73 5.47 21.75 6.67 Example 127 4'-[(2-n-Butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-l-yl)-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 12 from tert.butyl 4'[(2-n-butyl-5-ethyl-6-phthalimido-lH-imidazo[4,5-b]pyridin-l-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 56% of theory Melting point: 277-279°C - 104 C34H30N4°4 (558.64) Calculated: C 73.10 H 5.41 N 10.03 Found: 72.97 5.52 10.16 Example 128 4’-[(2-n-Butyl-5-methoxy-lH-imidazo[4,5-b]pyridin-l-yl) methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 68 from 4'-[(2-n-butyl5-methoxy-lH-imidazo[4,5-b]pyridin-l-yl)-methyl]-2-(1triphenylmethyl-tetrazol-5-yl)-biphenyl and methanolic hydrochloric acid.
Yield: 60% of theory, Melting point: 170-171’C C25H25N7° (439.53) Calculated: C 68.32 H 5.73 N 22.31 Found: 68.19 5.53 22.06 - 105 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly compounds A to K of the pharmacological test report, may be used as the active substance: Example I Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg kh2po4 2 mg Na2HPO4 x 2H2O 50 mg NaCl 12 mg Water for injections ad 5 ml Preparation: The buffer substances and isotonic substance are dissolved in some of the water. The active substance is added and, once it has 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 Preparation: Methyl glucamine is dissolved in some of the water and - 106 the active substance is dissolved with stirring and heating. After the addition of solvents, water is added to make up the desired volume.
Example III Tablets containing 50 mg of active substance Active substance 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mg 200.0 mg Preparation: The active substance, CaHPO4, 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 Active substance 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 mg Gelatin 10.0 mg Magnesium stearate 1.0 mg - 107 180.0 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 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline cellulose 60.0 mg Magnesium stearate 1.2 mq 350.0 mg Preparation: 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 filtered again and the magnesium stearate is added. This mixture is then compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating - 108 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 mq 320.0 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 with magnesium stearate. The final mixture is packed into size 1 hard gelatin capsules.
Example VII Oral suspension containing 50 mg of active substance per 5 ml 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. Hydroxyethylcellulose is dissolved therein with stirring. By the - 109 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 Solid fat 100.0 mg 1600.0 mq 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.

Claims (12)

Claims
1. A compound of formula I (wherein one or two of A 1 , A 2 , A 3 and A 4 represent a nitrogen atom and the remaining two or three of A v A 2 , A 3 and A 4 each represent a methine group; represents a fluorine, chlorine or bromine atom, a hydroxy, alkyl or alkoxy group, an amino group optionally mono- or disubstituted, or an N-acylamino group optionally monosubstituted, at the nitrogen atom by a C.,. 6 -alkyl, phenyl, C 5 . 7 -cycloalkyl, phenyl(C 13 ~alkyl) or (C 5 . 7 -cycloalkyl)C^-alkyl group, which substituents may be identical or different and which acyl group is a C v7 -alkanoyl group optionally substituted in the 3-, 4-, 5-, 6- or 7-position by a halogen atom or a hydroxy group, a (C^j-alkoxy)carbonyl group, a C V6 -alkylsulphonyl group, a benzoyl, benzenesulphonyl, phenyl(C^-alkanesulphonyl), naphthalenesulphonyl, 2-carboxy-cyclohexylcarbonyl, 2aminocarbonyl-cyclohexylcarbonyl, (C 5 . 7 -cycloalkyl) carbonyl, phenyl (C 1 . 4 -alkanoyl) or (C 5 . 7 -cycloalkyl) C v4 alkanoyl group, in which the above-mentioned phenyl nuclei are optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or - Ill methoxy group which substituents may be identical or different, a C 3 . 5 -alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C^j-alkyl or hydroxycarbonyl(C^j-alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally totally or partially hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula - N - CO - N [in which R 6 , R ? and Rg, which may be identical or different, represent hydrogen atoms, C^g-alkyl groups, C 5 . 7 -cycloalkyl, phenyl, (C 5 . 7 -cycloalkyl) C 1 . 3 -alkyl or phenyl-(C V3 -alkyl) groups, and Rg may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3 chloro-propyl or 3-bromo-propyl group, and where R 6 and R 7 together represent an ethylene or propylene group, R 8 may also represent a di(C^-alkyl)aminocarbonyl group, or R 6 and R ? together represent an ethylene or propylene group, and in which the phenyl nucleus of the above-mentioned phenyl and phenyl (C^j-alkyl) groups may in each case be mono- or disubstituted by hydroxy or C V3 -alkoxy groups which substituents may be identical or different], and R, may also represent a hydrogen atom, except where R 2 represents a hydrogen atom, R 3 represents an n-butyl - 112 group, R 4 represents a carboxy group and Rg represents a hydrogen atom, and (i) one of the groups A 1 , A 2 , A 3 and A 4 represents a nitrogen atom and the remaining groups A v A 2 , A 3 or A 4 each represent methine groups, or (ii) A 2 and A 4 or A 1 and A 3 each represent a nitrogen atom and the remaining groups A, and A 3 or A 2 and A 4 each represent a methine group, or (iii) A 4 represents a nitrogen atom and A 3 represents a methine group substituted by a hydroxy or methoxy group and the remaining groups A 1 and A 2 each represent a methine group, or (iv) A 4 represents a nitrogen atom, A 1 represents a methine group substituted by a methyl group and the remaining groups A 2 and A 3 each represent a methine group; R 2 represents a hydrogen atom or a C v3 -alkyl group; R 3 represents a C 16 -alkyl group; R 4 represents a carboxy, cyano, ΙΗ-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C 1 . 4 -alkoxy)carbonyl group; and R^ represents a hydrogen, fluorine, chlorine or bromine atom); and the isomers and addition salts thereof.
2. A compound of formula I as claimed in claim 1, wherein - 113 one or two of A 1 , A 2 , A 3 and A 4 represent a nitrogen atom and the remaining two or three of A 1 , A 2 , A 3 and A 4 each represent a methine group; R 1 represents a fluorine atom, an amino or C 16 -alkylamino group substituted at the nitrogen atom by a phenyl, C 5 . 7 -cycloalkyl, phenyl (C^jalkyl) or (C 5 _ 7 -cycloalkyl)C^-alkyl group, an amino group disubstituted by a phenyl, C 5 . 7 -cycloalkyl, phenyl(C v3 alkyl) or (C 5 . 7 -cycloalkyl) C p3 -alkyl group which substituents may be identical or different, or an acylamino group optionally substituted at the nitrogen atom by a C v6 -alkyl, phenyl, C 5 . 7 -cycloalkyl, phenyl (Chalky 1) or (C 5 _ 7 -cycloalkyl) C 1 . 3 -alkyl group and in which the acyl group is a C 2 . 7 -alkanoyl group substituted in the terminal position by a chlorine atom or by a hydroxy group, a (C.,_ 3 -alkoxy)carbonyl group, a C 1 . 6 -alkylsulphonyl group, a formyl, benzoyl, benzenesulphonyl, phenyl(C V3 alkanesulphonyl), naphthalenesulphonyl, 2-carboxycyclohexylcarbonyl, 2-aminocarbonyl-cyclohexylcarbonyl, (C 5 . 7 -cycloalkyl)carbonyl, phenylalkanoyl or (C 5 . 7 cycloalkyl) C 1 . 4 -alkanoyl group, in which the abovementioned phenyl nuclei is optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, a C 3 . 5 -alkylsultam group, a pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by a C^j-alkyl or hydroxycarbonyl(C V3 -alkyl) group, a pyrrolidinone, piperidinone or hexamethyleneiminone group, an optionally wholly or partially hydrogenated phthalimido group or a group of formula - 114 - [in which R 6 , R ? and Rg, which may be identical or different, represent hydrogen atoms, C^g-alkyl groups, C 5 _ 7 -cycloalkyl, phenyl, (C 5 . 7 -cycloalkyl)C^j-alkyl or phenyl(C^j-alkyl) groups, and R 8 may also represent a 2-chloro-ethyl, 2-bromo-ethyl,
3. Chloro-propyl or 3-bromo-propyl group, and where R 6 and R ? together represent an ethylene or propylene group, Rg may also represent a di(C^-alkyl)aminocarbonyl group, or R 6 and R ? together represent an ethylene or propylene group), and in which the phenyl nucleus of the above-mentioned phenyl and phenyl(C V3 -alkyl) groups may be mono- or disubstituted by hydroxy or C^j-alkoxy groups which substituents may be identical or different], and R 2 represents a hydrogen atom or a C 13 ~alkyl group; R 3 represents a C 16 -alkyl group; R 4 represents a carboxy, cyano, ΙΗ-tetrazolyl, 1triphenylmethyl-tetrazolyl group or a (C w -alkoxy)carbonyl group; and Rj represents a hydrogen, fluorine, chlorine or bromine atom; and the isomers and addition salts thereof. - 115 3. A compound of formula I as claimed in claim 1 or claim 2, wherein one or two of A 1 , A 2 , A 3 and A 4 represent a nitrogen atom and the remaining two or three of A v A 2 , A 3 and A 4 each represent a methine group; R 1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl, cyclohexylmethyl, benzyl or dimethoxybenzyl group, an amino, cyclohexylamino, cyclohexylmethyl or C V4 -alkylamino group substituted by a C 2 . 6 -alkanoyl, C v4 -alkanesulphonyl, C 2 _ 4 -alkoxycarbonyl, cyclohexylcarbonyl, benzylcarbonyl, 2-aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C 3 . 4 ~alkylsultam group a pyrrolidino or piperidino group optionally substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2-on-l-yl or piperidin-2-on-l-yl group, an optionally fully hydrogenated phthalimido or 2-oxoisoindolin-l-yl group or a group of formula [in which R 6 , R 7 and Rg, which may be identical or different, represent hydrogen atoms, C 1 . 4 -alkyl groups, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, and Rg may also represent a 2-chloro-ethyl, 2-bromo-ethyl, 3chloro-propyl or 3-bromo-propyl group, and where R 6 and R 7 together represent an ethylene or propylene group, R s may also represent a dimethylaminocarbonyl group, or R 6 and R 7 together represent an ethylene or propylene group]; - 116 R 2 represents a hydrogen atom or a methyl or ethyl group; R 3 represents a C^-alkyl group; R 4 represents a carboxy or ΙΗ-tetrazolyl group; and R 5 represents a hydrogen atom; and the isomers and salts thereof.
4. A compound as claimed in any one of claims 1 to 3 wherein one or two of A 1 , A 2 , A 3 and A 4 represent a nitrogen atom and the remaining two or three of A 1 , A 2 , A 3 and A 4 each represent a methine group; R 1 represents an amino, methylamino or ethylamino group substituted by a cyclohexyl or cyclohexylmethyl group, a cyclohexylamino or cyclohexylmethylamino group substituted by a C 2 6 -alkanoyl, C 1 . 4 -alkanesulphonyl, C 2 . 4 alkoxycarbonyl, benzylcarbonyl, 2aminocarbonylcyclohexylcarbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a cyclohexylcarbonylamino group, a cyclohexylamino, cyclohexylmethylamino or C V4 -alkylamino group substituted by a C v4 alkanesulphonyl, cyclohexylcarbonyl, 2-aminocarbonylcyclohexyl-carbonyl, benzenesulphonyl or chlorobenzenesulphonyl group, a C 3 . 4 - alkylsultam group, a pyrrolidino or piperidino group substituted by a methyl or hydroxycarbonylmethyl group, a pyrrolidin-2on-l-yl or piperidin-2-on-l-yl group, an optionally fully hydrogenated phthalimido or 2-oxo-isoindolin-l-yl group or a group of formula 117 [in which one of the groups R 6 , R 7 or R 8 represents a cyclopentyl, cyclohexyl or cyclohexylmethyl group, and the remaining groups R 6 , R ? or R 8 , which may be identical or different, represent hydrogen atoms or C 1 . 4 -alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R 7 represents a 2-chloro-ethyl, 2-bromo-ethyl, 3-chloropropyl or 3-bromo-propyl group, and R 6 and R 8 , which may be identical or different, represent hydrogen atoms or C V4 -alkyl, cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl or hydroxybenzyl groups, or R 6 and R ? together represent an ethylene or propylene group, and R 8 represents a hydrogen atom, a C 1 . 4 -alkyl group, a cyclohexyl, phenyl, cyclohexylmethyl, benzyl, methoxybenzyl, hydroxybenzyl, 2-chloro-ethyl, 2-bromoethyl, 3-chloro-propyl, 3-bromo-propyl or dimethylaminocarbonyl group]; R 2 represents a hydrogen atom or a methyl or ethyl group? R 3 represents a C v5 -alkyl group; R 4 represents a carboxy or IH-tetrazolyl group; and Rg represents a hydrogen atom; and the isomers and addition salts thereof.
5. A compound as claimed in any one of claims 1 to 4 being - 118 4’-[(2-n-butyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid; 4'-[(2-n-butyl-5-methyl-6-phthalimido-3H-imidazo[4,5-b] pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid; 4'-[(2-n-butyl-lH-imidazo[4,5-c]pyridin-l-yl)methyl]biphenyl-2-carboxylic acid; 4'-[(2-n-butyl-5-amino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]-biphenyl-2-carboxylic acid; 4’-[(2-benzylamino-8-n-butyl-9H-purin-9-yl)-methyl]biphenyl-2-carboxylic acid; 4(2-n-butyl-5-methyl-6-propionylamino-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]biphenyl-2-carboxylic acid; 4'-[(2-n-butyl-5-cyclohexylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid; 4’-[(2-n-butyl-5-(N-cyclohexylcarbonyl-ethylamino)-3Himidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid; 4’-[(2-n-butyl-5-methyl-6-valeroylamino-3H-imidazo[4,5-b]pyridin-3-yl)methyl]biphenyl-2-carboxylic acid; 4'-[(2-n-butyl-5-[3-benzyl-3,4,5,6-tetrahydro-2(1H)pyrimidinon-l-yl]-3H-imidazo[4,5-b]pyridin-3-yl)methyl] biphenyl-2-carboxylic acid; 4'-[(2-n-propyl-5-cyclohexylcarbonylamino-3Himidazo[4,5-b]pyridin-3-yl) methyl]-2-(lH-tetrazol-5yl)biphenyl; 4'-[[2-ethyl-5-(2,2-dimethyl-propionylamino)-3H-imidazo - 119 [4,5-b]pyridin-3-yl]-methyl]-2-(lH-tetrazol-5yl)biphenyl; or 4'-[(2-n-propyl-5-(2-methyl-propionylamino)-3H-imidazo[4,5-b]pyridin-3-yl)-methyl]-2-(lH-tetrazol-5yl) biphenyl; or an addition salt thereof.
6. A compound as claimed in any one of claims 1 to 5 being a physiologically acceptable addition salt of a compound of formula I.
7. 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 (wherein R 1 , R 2 , A,, A 2 , A 3 and A 4 are as defined in claims 1 to 5; one of the groups X 1 or Y, represents a group of formula - 120 and the other group X, or Y 1 represents a group of formula Z K z Zz - NH - C - R, R 3 and 1*5 are as defined in claims 1 to 5; R? represents a hydrogen atom or an R 3 CO group; and R 3 is as hereinbefore defined; Z 1 and Z 2 , which may be identical or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z 1 and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C v3 -alkyl group, or a C 2 . 3 ~alkylenedioxy or C 2 . 3 -alkylenedithio group, with the proviso that one of the groups X 1 or Y 1 must represent a group of formula \or 3 - NH - C - R 3 ) or an N-oxide thereof and if necessary subsequently reducing the cyclised Noxide; b) reacting a compound of formula III 121 R H (III) (wherein R 1 , R 2 , R 3 , A v A 2 , A 3 and A 4 are as defined in claims 1 to 5) with a biphenyl compound of formula IV (iv) (wherein R 4 and Rg are as defined in claims 1 to 5; and Z 3 represents a nucleophilic leaving group), c) (to prepare a compound of formula I wherein R 4 represents a carboxy group) converting a compound of formula V (wherein R 1 , r 2 , R 3 , Rg, A 1 , A 2 , Aj and A 4 are as defined in claims 1 to 5; and R 4 1 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or - 122 hydrogenolysis) into a corresponding carboxy compound; d) (to prepare a compound of formula I wherein R 4 represents a ΙΗ-tetrazolyl group) cleaving a protecting group from a compound of formula VI (wherein R 1 , R 2 , R 3 , Rg, A 1 , A 2 , A 3 and A 4 are as defined in claims 1 to 5; and R 4 represents a ΙΗ-tetrazolyl group protected in the 1position by a protecting group); e) (to prepare a compound of formula I wherein R 4 represents a ΙΗ-tetrazolyl group) reacting a compound of formula VII (wherein R 1 , R 2 , R 3 , Rg, A 1 , A 2 , A 3 and A 4 are as defined in claims 1 to 5) with hydrazoic acid or the salts thereof; 123 f) to prepare compounds of formula I wherein R 1 represents an amino group optionally substituted by a C V6 -alkyl, phenyl, C 5 . 7 -cycloalkyl, phenyl (C^j-alkyl) or (C 57 -cycloalkyl)C^j-alkyl group) converting a compound of formula VIII (wherein R 2 , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 and A 4 are as defined in claims 1 to 5; and R 10 represents a group which can be converted by hydrolysis, hydrogenolysis or transamidation into an amino group optionally substituted by a C^-alkyl, phenyl, C 5 . 7 -cycloalkyl, phenyl (C 1 . 3 -alkyl) or (C 5 . 7 cycloalkyl)C^j-alkyl group) into a corresponding compound; g) (to prepare compounds of formula I wherein R 1 represents a group of formula ‘6 N - CO - N R. reacting a compound of formula IX - 124 - (wherein R 2 , R 3 , R 4 , Rj, A 1# A 2 , A 3 and A 4 are as defined in claims 1 to 5; and R n represents an R 6 NH group, wherein R 6 is as defined in claims 1 to 5) with a compound of formula X (X) (wherein R 7 and R a are as defined in claims 1 to 5; Z 4 represents a nucleophilic leaving group, or Z 4 together with R ? represents a nitrogen-carbon bond); h) (to prepare compounds of formula I wherein R 1 represents an N-acylamino group optionally substituted at the nitrogen atom by a C^g-alkyl, phenyl, cycloalkyl, phenylalkyl or cycloalkylalkyl group) acylating a compound of formula XI - 125 (wherein R 2 , R 3 , R 4 , R^, A 1 , A 2 , A 3 and A 4 are as defined in claims 1 to 5; and R 12 represents an amino group optionally substituted by a C 1 . 6 -alkyl, phenyl, C 5 . 7 -cycloalkyl, phenyl (C 13 -alkyl) or (C 5 7 ~cycloalkyl) C 13 -alkyl group) with a compound of formula XII R 13 - W - OH (XII) (wherein W represents a carbonyl or sulphonyl group; and R 13 represents a C 16 ~alkyl group, a C 13 ~alkoxy group, a phenyl (C 13 -alkyl) , C 5 _ 7 -cycloalkyl or (C 5 . 7 -cycloalkyl) Chalky 1 group, a phenyl, naphthyl, 2-carboxy-cyclohexyl or 2-aminocarbonyl-cyclohexyl group, in which the abovementioned phenyl nuclei may be mono- or disubstituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group which substituents may be identical or different, or, if W represents a carbonyl group, R 13 may also represent a hydrogen atom) or with a reactive derivative thereof; i) (to prepare a compound of formula I wherein R 6 and R 7 together represent an ethylene or n-propylene group) cyclising a compound of formula XIII (wherein - 126 R 2 , R 3 , R 4 , Rg, R a , A 1 , A 2 , A 3 and A 4 are as defined in claims 1 to 5; Hal represents a chlorine, bromine or iodine atom; and n represents the number 2 or 3) and if necessary subsequently reacting with a compound of formula XIV Rg - Hal (XIV) (wherein Rg is as defined in claims 1 to 5, with the exception of the hydrogen atom; and Hal represents a chlorine, bromine or iodine atom); j) resolving a 1-, 3-isomer mixture of a compound of formula I by isomer separation into the 1- and 3-isomers thereof; k) converting a compound of formula I into an addition salt thereof, more particularly for pharmaceutical use into a physiologically acceptable 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 l) performing a process as defined in any one of steps (a) to (k) above on a corresponding protected compound and subsequently removing the protecting group used.
8. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable addition salt thereof together with at least one pharmaceutical carrier or excipient.
9. Use of a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac 127 insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
10. A method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), cardiac insufficiency progression after myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable addition salt thereof.
11. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples.
12. Each and every novel compound, composition, process, use and method as herein disclosed.
IE282291A 1990-08-10 1991-08-09 Imidazoles IE912822A1 (en)

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