FR2902428A1 - NOVEL DIAZENIUMDIOLATE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

Compounds of formula (I): in which: R1 represents an alkanoyl group, R2 represents an alkyl group substituted by a G group, or R1 and R2 together with the nitrogen atom carrying them a substituted imidazolyl or benzimidazolyl group; by a group G, and G represents a group - (CH2) nA- (CH2) m- (CR4R5) p- (CH2) o -R3 in which n, m, p, o, R4, R5 and A are such that defined in the description, and R3 represents a group Drug.

Description

The present invention relates to novel diazeniumdiolate derivatives, their

  method of preparation and pharmaceutical compositions containing them.

  These compounds have original structures and find their application in the field of hypertension and cardiovascular diseases.

  Hypertension carries a high risk of vascular accidents, especially at the cerebral and coronary level. It is increasingly associated with other conditions such as atherosclerosis or metabolic diseases such as obesity, diabetes or kidney failure, which greatly increases the risk of spasm and thrombosis.

  Angiotensin II is a cardiovascular mediator whose overproduction is involved in the development of hypertension. The physiological and physiopathological effects of angiotensin II, such as sodium retention, vasoconstriction, and pro-oxidant effect, are mediated by the activation of receptors, the angiotensin receptors. Several antagonists of these receptors are thus effective in humans, by lowering the arterial pressure and the risk of vascular accidents (Goodfriend TL et al., 1996, New Eng., J. Med., 334 (25), 1649-1654 Sierra C. et al., 2005, Curr Opin Nephrol, Hypertens., 14, 435-441). Since the discovery in 1980 of its cardiovascular action, nitric oxide (NO) is recognized as a vasodilator and vasoprotective molecule capable of preventing vasospasms, atherosclerosis and thrombosis, this endogenous mediator thus offering protection against cardiovascular disease. . NO is mainly produced by endothelial cells, and in cardiovascular pathologies, endothelial dysfunction causes endogenous NO deficiency. Nitrovasodilator compounds, such as nitroglycerin, have long been used to treat angina pectoris and heart failure. The beneficial effect of these products is related to their ability to form (spontaneously or metabolically) NO. The use of these products also led to the observation that in the hypertensive subject, these NO donors cause a predominant decrease in systolic blood pressure. Uncontrolled systolic blood pressure is an important risk factor for stroke and heart failure and is often resistant to antihypertensive drugs. Indeed, despite demonstrated antihypertensive and vasoprotective effects of products such as angiotensin receptor antagonists and other classes of antihypertensive products, blood pressure, in particular -2 systolic, remains difficult to control and the rate morbidity and mortality remains high. Adding a NO-donor property to angiotensin receptor antagonist products would improve its antihypertensive, cardio- and vasculoprotective properties and add direct antithrombotic action, NO having an anti-platelet and antithrombotic effect ( Walford, G. et al., 2003, J. Thromb, Haemost., 1, 2112-2118).

  The compounds of the present invention, in addition to their structural originality, have this double pharmacological activity conferring on them properties quite surprising and interesting in the field of hypertension and cardiovascular pathologies.

  More specifically, the present invention relates to the compounds of formula (I): ## STR1 ## in which:

  R1 represents a linear or branched alkanoyl group,

  R2 represents a linear or branched (C1-C6) alkyl group substituted by a group G,

  Or R1 and R2 together with the nitrogen atom carrying them an imidazolyl or benzimidazolyl group, these groups being substituted by a group G and optionally substituted by one or two other additional groups selected from linear (C1-C6) alkyl or branched, linear or branched (C1-C6) alkoxy, and halogen atoms, (I) and G represents - (CH2) n-A- (CH2) n (CR4R5) p (CH2) O- R3 wherein n is 0, 1, 2 or 3, is 0, 1,2 or 3, or 0 is 0, 1 or 2, R4 and R5, the same or different, each represents a hydrogen atom or an alkyl group ( C1-C6) linear or branched, A represents a group R6 ~ IN Nù / NO or / N Nù \ R6 in which R6 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, and R3 represents a group O I + N NR 'N 0 + O \ OR ~ NN R9 R8 where R7, R8 and R9, identical or different, each represent a hydrogen atom or an alkyl group (C1 -C6) linear or branched, or R7 and R8 together form a linear or branched (C1-C6) alkylene chain,

  their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

  Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methane sulphonic, camphoric, etc ...

  Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. More specifically, the invention relates to compounds of formula ( I) for which R1 and R2 together with the nitrogen atom carrying them an imidazolyl group and even more preferably a 2-butyl-4-chloro-1H-imidazolyl group. A advantageously represents a group -C (O) O-.

  The preferred R3 group according to the invention is the group -O-N = N (O) -NR7R8. Even more particularly, the invention relates to the compounds of formula (I) which are: • 2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] {(Z) -2-oxido-2-pyrrolidin-1-yldiazenyl] oxy} methyl methyl} -1H-imidazole-5-carboxylate, • 2-butyl-4-chloro-1- {[2 1- {2H-Tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazo le-5-carboxylate from {[(Z) -2- (3,5-dimethylpiperidin-1-yl)} 2-Oxidodiazienyl] oxy} methyl • 2-butyl-4-chloro-{[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5- {[(Z) -2- (3,5-dimethylpiperidin-1-yl) -2-oxidodiazenyl] oxy} methyl carboxylate, • 2-butyl-4-chloro-1 - {[2 '- (2H- {(Z) -2-oxido-2-piperidin-1-yldiazenyl] oxy} methyl tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate, 15 • 2 butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from {[(Z) -2-oxido} 2- (4-phenylpiperazin-1-yldiazenyl) oxy} methyl, • N-pentanoyl-N - {[2 '- (2H-t {[(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} methyl betzol-5-yl) biphenyl-4-yl] methyl} -L-valinate, • N-pentanoyl-N - {[ 2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl] -L-valinate of {[(2) - (3,5-dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl, 2-ethoxy-1 - {{2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from {[(Z) -2-oxido} 2-pyrrolidin-1-yldiazenyl] oxy} methyl, 2-ethoxy-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole; {(Z) -2- (3,5-dimethylpiperidin-1-yl) -2-oxidodiazenyl] oxy} methyl 7-carboxylate,

  2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate of 2- {[(Z)} 2-oxido-2-pyrrolidin-1-yldiazenyl] oxy} ethyl, (2-butyl-4-chloro-1-yl) -benzoylpyrrolidin-1-yl (diazenyl) oxy] acetate; {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl,

1 - [(2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) carbonyl] - 4 - [(Z) -methoxy-NNO-azoxy] piperazine,

  • N - [(1S ') - 1 - ({4 - [(Z) -methoxy-NNO-azoxy] piperazin-1-yl} carbonyl) -2-methylpropyl] -N - {[2' - (2H) tetrazol-5-yl) biphenyl-4-yl] methyl pentanamide

[(2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methylcarbamate [(Z) - (3,5-dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl,

[(2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methylcarbamate [(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} methyl,

  • (2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4 - 4 - [(Z) -methoxy-NNO-azoxy] piperazine-1-carboxylate yl] methyl} -1H-imidazol-5-yl) methyl.

  The invention also relates to the process for preparing the compounds of formula (I), characterized in that the compound of formula (II) used is the starting material: R'2 R'1 \ NCH in which R '1 represents a linear or branched alkanoyl group, R'2 represents a linear or branched alkyl group, or R '1 and R'2 form together with the nitrogen and carbon atoms which carry them an imidazolyl or benzimidazolyl group, these groups being optionally substituted; by a linear or branched alkyl group, linear or branched alkoxy or halogen atoms, and Tr represents a trityl group, which is converted by oxidation reaction, reduction or reductive amination into a compound of formula (III) R'2 A'uH R, 1 \ (CH2) n wherein n is as defined in formula (I), R'1, R'2 and Tr are as defined above, and A 'represents a grouping C (O) O-, -O-, or -NH-, 6 -7 on which a co compound of formula (IV): ## STR5 ## wherein m, p, o, R, R and R are as defined in formula (I) ) and A "represents a halogen atom or a hydroxy or carboxy group, to give the compound of formula (V): (V) in which Tr is as defined above and R1 and R2 are as defined in the formula ( I), which is heated under reflux to give the compound of formula (I), compound of formula (I) which is purified, if appropriate, according to a conventional purification technique, the isomers are optionally separated, according to a conventional separation technique, and that it is converted, if desired, in its addition salts, to a pharmaceutically acceptable acid or base.

  The compounds of formula (II) as defined above are commercially available or obtained by conventional reactions of organic chemistry.

  The compounds of the present invention, by virtue of their pharmacological properties, are useful in the treatment of hypertension and cardiovascular pathologies and its complications such as retinopathy, cerebral accidents, dementia, left ventricular hypertrophy, insufficiency heart disease, angina pectoris, myocardial infarction -8 and nephropathy. The compounds according to the invention are also useful in cardiovascular pathologies associated with atherothrombosis such as cerebral and coronary events, arteritis and vasculopathies as well as in the vascular complications of a number of diseases such as diabetes, obesity, metabolic syndrome, cancer, liver fibrosis etc. The compounds are also useful in pulmonary, ocular or portal hypertension.

  The subject of the present invention is also pharmaceutical compositions containing, as active principle, at least one compound of formula (I), one of its isomers, or one of its addition salts with an acid or a pharmaceutically acceptable base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

  Among the pharmaceutical compositions according to the invention, mention will be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular, or subcutaneous), per-or trans-cutaneous, intravaginal, rectal, nasal, perlingual, oral administration. , ocular or respiratory.

  The pharmaceutical compositions according to the invention for parenteral injections comprise, in particular, aqueous and non-aqueous sterile solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstituting injectable solutions or dispersions.

  The pharmaceutical compositions according to the invention, for solid oral administrations, comprise, in particular, single or coated tablets, sublingual tablets, sachets, capsules, granules, and for oral, nasal, oral or ocular liquid administrations, especially comprising emulsions, solutions, suspensions, drops, syrups and aerosols.

  The pharmaceutical compositions for rectal or vaginal administration are preferably suppositories, and those for per-trans-cutaneous administration include, in particular, powders, aerosols, creams, ointments, gels and patches. The pharmaceutical compositions cited above illustrate the invention but do not limit it in any way.

  Among the inert, non-toxic, pharmaceutically acceptable inert excipients or carriers, mention may be made, by way of indication and without limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, blowing agents, disintegrating agents, retardants, lubricants, absorbents, suspending agents, dyes, flavoring agents, etc.

  The dosage varies depending on the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the condition, and the taking of any associated treatments. The dosage ranges from 10 mg to 1 g in one or more doses per day.

  The following preparations and examples illustrate the invention but do not limit it in any way.

  The starting materials used are known products or prepared according to known procedures. The structures of the compounds, described in the examples, were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).

  Preparation 1: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] -3,5-dimethylpiperidine Step A: 3,5-Dimethyl-1 - {(Z) - [(methylthio) methoxy] -NNO-azoxy } Piperidine Sodium 3,5-dimethyl-1 - [(Z) -oxido-NNO-azoxy] piperidine (1.54 × 10 -2 mol) is suspended in tetrahydrofuran (30 ml). Place under a stream of nitrogen and cool to 0 C. Add sodium carbonate (1.54 × 10 -2 mol) at once and stir vigorously. Add dropwise chloromethyl methylsulfide (2.10-2 mol) and then dimethylformamide (11 ml) all at once. Leave stirring at 0 ° C. for 10 minutes and then return to ambient temperature. Then add potassium iodide (8.91.104 mol). The reaction medium is stirred for 20 hours at room temperature and then diluted with diethyl ether (200 ml) and washed with water. The aqueous phase is extracted with diethyl ether and the combined organic phases are washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The oily residue is chromatographed on a silica column eluting with a 95/5 then 90/10 n-heptane / ethyl acetate mixture to yield the title product in the form of a yellow oil.

  Stage B: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] -3,5-dimethylpiperidine

  In a bicol placed under a stream of nitrogen, solubilize the compound obtained in Step A (3.43 × 10 -3 mol) in dichloromethane (90 ml). Cool the solution to 0 C and stir. Add dropwise a 1M solution of sulfuryl chloride in dichloromethane (3.43 × 10 -3 mol). After the addition, wait 10 minutes then return to room temperature. After stirring for 2 hours, the reaction medium is evaporated to dryness under reduced pressure. The title product is obtained in the form of a yellowish oil.

  Preparation 2: N - [(Z) - (Chloromethoxy) -NNO-azoxy] -N-ethylethanamine Step A: N-Ethyl-N- {(Z) - [(methylthio) methoxy] -NNO-azoxy} ethanamine

  Procedure identical to Stage A of Preparation 1, replacing sodium 3,5-dimethyl-1 - [(Z) -oxido-NNO-azoxy] piperidine with sodium 1 - (Z) -3,3-diethyltriaz-1 1-olate 2-oxide. The title product is obtained in the form of an orange oil.

  Stage B: N - [(Z) - (Chloromethoxy) -NNO-azoxy] -N-ethylethanamine Procedure identical to Stage B of Preparation 1 starting from the compound obtained in Stage A. The title product is obtained in the form an orange oil. Preparation 3: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] piperidine Step A: 1 - {(Z) - [(Methylthio) methoxy] -NNO-azoxy} piperidine

  Procedure identical to Step A of Preparation 1, replacing sodium 3,5-dimethyl-1 - [(Z) -oxido-NNO-azoxy] piperidine with sodium 1 - [(Z) -oxido-NNO-azoxy] piperidine. The title product is obtained in the form of an orange oil.

  Stage B: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] piperidine

  Procedure identical to Stage B of Preparation 1 using the compound obtained in Stage A. The title product is obtained in the form of an orange oil.

  Preparation 4: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] -4-phenylpiperazine Step A: 4-Phenyl-1 - {(Z) - [methylthio] methoxy] -NNO-azoxy} piperazine

  Procedure identical to Stage A of Preparation 1, replacing sodium 3,5-dimethyl-1 - [(Z) -oxido-NNO-azoxy] piperidine with sodium 4-phenyl-1 - [(Z) -oxido] -NNO-azoxy] piperazine. The title product is obtained in the form of an orange oil.

  Stage B: 1 - [(Z) - (Chloromethoxy) -NNO-azoxy] -4-phenylpiperazine Procedure identical to Stage B of Preparation 1 using the compound obtained in Stage A. The title product is obtained in the form of of a brown oil.

  Preparation 5: 2 - {[(Z) -Oxido (pyrrolidin-1-yl) diazenyl] oxy} ethanol

  Sodium 1 - [(Z) -oxido-NNO-azoxy] pyrrolidine (3.26 × 10.2 mol) is suspended in tetrahydrofuran (40 ml). Place the medium under stirring and under a slight flow of nitrogen.

  Add 2-bromoethanol (3.18 × 10 -2 mol) and heat to reflux. After 20 hours, evaporate the reaction medium to dryness under reduced pressure. The oily brown residue obtained is chromatographed on a silica column, eluting with a 95/5 dichloromethane / methanol mixture. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure. The yellowish oily residue is then filtered off on Sephadex LH-20 gel, eluting with a dichloromethane / acetone 1/1 mixture.

  The title product is obtained in the form of a yellow oil.

  Preparation 6: {[(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} acetic acid Step A: {[(Z) -Oxido (pyrrolidin-1-yl) diazenyl] oxy} acetonitrile

  Sodium 1 - [(Z) -oxido-NNO-azoxy] pyrrolidine (3.26 × 10 -2 mol) is suspended in tetrahydrofuran (40 ml). Place under a stream of nitrogen and cool to 0 C. Add sodium carbonate (3.26 × 10 -2 mol) at a time and stir vigorously. Add dropwise chloroacetonitrile (3.92 × 10 -2 mol) and then dimethylformamide (14.6 ml) all at once. Leave stirring at 0 ° C. for 10 minutes and then return to ambient temperature. Then add potassium iodide (1.90 × 10 -3 mol). Leave overnight stirring at room temperature and then dilute the reaction medium in water and extract with ethyl acetate. The various organic phases are combined, washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue obtained is chromatographed on a silica column, eluting with dichloromethane. The title product is obtained in the form of a white solid.

Melting point: 82-83 ° C

  Step B: {[((Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} acetic acid Solubilize {[(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} acetonitrile (0.01 mol) in dioxane (70 ml). Place with stirring and add concentrated hydrochloric acid (8 ml). Reflux for 2 hours then dilute the reaction medium with water and extract with ethyl acetate and dichloromethane. The combined organic phases are washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The orange oily residue is purified by gel filtration on Sephadex LH-20, eluting with a dichloromethane / acetone 1/1 mixture. The title product is obtained in the form of a white solid. Melting point: 70-71 ° C

EXAMPLE 1 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from {[(Z)} -2-oxido-2-pyrrolidin-1-yldiazenyl] oxy} methyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylic acid

Solubilize 2-butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carbaldehyde (7, 54.10-3 mol) in acetonitrile (11) and water (150 ml). Place with stirring at ambient temperature then add 2-methyl-2-butene (0.3 mol), sodium chlorite (5.95 × 10 -2 mol) and sodium hydrogen phosphate (4.5 × 10 -2 mol) . Leave the reaction medium stirring at room temperature for 20 hours and then add a saturated aqueous solution of sodium sulfite (500 ml). After separation of the two phases, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water and brine, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The title product is obtained in the form of a white solid and used without further purification.

Step B: 2-Butyl-4-chloro-1- {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate of [(Z) -2-oxido-2-pyrrolidin-1-yl-diazenyl] oxy} methyl

  Solubilize 1 - [(Z) - (chloromethoxy) -NNO-azoxy] pyrrolidine (4.64 × 10 -3 mol) in dimethylformamide (90 ml) and place the solution with stirring. Add at once a solution of the compound obtained in Step A (4.42 × 10 -3 mol) in dimethylformamide (60 ml) and then cesium carbonate (4.42 × 10 -3 mol). Leave the reaction mixture vigorously stirring at room temperature for 4 hours and then dilute with water and extract with diethyl ether. The organic phase is washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The title product is obtained in the form of an orange oil.

  Stage C: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from {[(Z)] 2-oxido-2-pyrrolidin-1-yldiazenyl] oxy} methyl

  Solubilize the compound obtained in Step B (4.38 × 10 -3 mol) in methanol (100 ml) and dichloromethane (50 ml). Place under agitation and heat under reflux for 2 hours. Evaporate the reaction medium to dryness under reduced pressure and chromatograph the oily residue obtained on a silica column eluting with a dichloromethane / methanol 99/01, 97/03 and 90/10. The residue is taken up in a n-heptane / ethyl acetate 7/3 mixture allowing crystallization of the product in the form of a white solid.

  Melting point: 176-177 ° C. Elemental microanalysis: C H N Cl% theoretical: 55.91 5.21 21.73 6.11% experimental: 55.79 5.22 20.49 6.50

Example 2: 2-Butyl-4-chloro-1- {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from {[(Z 2 - ( 3,5-dimethylpiperidin-1-yl) -2-oxodiazenyl] oxy} methyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from [[ (Z) -2- (3,5-dimethylpiperidin-1-yl) -2-oxodiazenyl] oxy} methyl

  The product obtained in Stage A of Example 1 is reacted with the compound obtained in Preparation 1 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a solid. white after purification by chromatography on a silica column eluting with n-heptane / ethyl acetate 9/1, 8/2 then 7/3. Melting point: 64-65 ° C. Step B: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H {(2) -2- (3,5-dimethylpiperidin-1-yl) -2-oxidodiazenyl] oxy} methyl imidazole-5-carboxylate

  Procedure identical to Stage C of Example 1 starting from the compound obtained in Stage A. The title product is obtained in the form of a white solid. Melting point: 78-80 CCHN Cl Elemental microanalysis:% theoretical: 57.92 5.83 20.26 5.70% experimental: 57.87 5.80 19.46 5.79 Example 3: 2-Butyl 4-Chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate of ({(1Z) -2,2-diethyl- 1-oxidohydrazono] amino} oxy) methyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate [(1Z) -2,2-Diethyl-1-oxidohydrazono] amino} oxy) methyl

  The product obtained in Stage A of Example 1 is reacted with the compound obtained in Preparation 2 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a solid. white after purification by chromatography on a silica column eluting with n-heptane / ethyl acetate 75/25. CHN Cl Melting point: 53-55 C Elemental microanalysis:% theoretical: 67.02 5.62 15.29 4.30% experimental: 67.01 5, 75 14.33 3.66 - 16 - Stage B: 2 -Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from ({[(1Z) -2,2 diethyl-1-oxidohydrazono] amino} oxy) methyl

  Procedure identical to Stage C of Example 1 starting from the compound obtained in Stage A. The title product is obtained in the form of a white solid.

  Melting point: 63-65 ° C. Elemental microanalysis: C H N Cl% theoretical: 55, 72 5.54 21, 66 6.09 experimental: 55.35 5.53 20.10 6.35

Example 4: 2-Butyl-4-chloro-1- {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl) -1H-imidazole-5-carboxylate of {[(Z)] 2-oxido-2-piperidin-1-yldiazenyl] oxy} methyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from [[ (Z) -2-Oxido-2-piperidin-1-yldiazenyl] oxy} methyl

  The product obtained in Stage A of Example 1 is reacted with the compound obtained in Preparation 3 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a solid. white after purification by chromatography on a silica column eluting with a 75/25 n-heptane / ethyl acetate mixture. Melting point: 59-60 ° C

Step B: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from {[(Z)] 2-oxido-2-piperidin-1-yldiazenyl] oxy} methyl Procedure identical to Step C of Example 1 using the compound obtained in Step A. The title product is obtained in the form of a white solid. Melting point: 81-82 CCHN Cl Elemental microanalysis:% theory: 56.61 5.43 21.22 5.97% experimental: 56.14 5.43 21.42 6.45 Example 5: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H imidazole-5-carboxylate of {[(Z) -2-oxido} 2- (4-phenylpiperazin-1-yldiazenyl) oxy} methyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from [[ (Z) -2-oxido-2- (4-phenylpiperazin-1-yldiazenyl) oxy} methyl

  The product obtained in Stage A of Example 1 is reacted with the compound obtained in Preparation 4 according to the operating conditions described in Stage B of Example 1.

  Step B: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate from [(Z) - 2-oxido-2- (4-phenylpiperazin-1-yldiazenyl) oxy} methyl

  Procedure identical to Stage C of Example 1 from the compound obtained in Stage A. The title product is obtained in the form of an off-white solid.

  Melting point: 84-85 ° C. Elemental microanalysis: CHN% theoretical: 59.06 5.26 20.87% experimental: 56.67 5.00 18.59 Example 18: N-Pentanoyl-N- 2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl] -L-valinate of {[(2-oxido (pyrrolidin-1-yl) diazenyl] oxy} methyl

Step A: N - Pentanoyl-N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valinate from {[(Z) -oxido (pyrrolidine) 1-yl) diazenyl] oxy} methyl N-pentanoyl-N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valine is reacted with 1 - [(Z) - (chloromethoxy) -NNO-azoxy] pyrrolidine according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a white solid after purification by chromatography on a silica column eluting with n-heptane / ethyl acetate 7/3.

Melting point: 58-59 ° C

Step B: N - Pentanoyl N - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valinate from {[(Z) -oxido (pyrrolidin-1-yl)} diazényl] oxy} methyl

  Procedure identical to Stage C of Example 1 using the product obtained in Stage A. The title product is obtained in the form of a white solid.

  Melting point: 61-63 CCHN Elemental microanalysis:% theoretical: 60.19 6.62 19.36% experimental: 60.07 6.61 18.69 Example 1: N Pentanoyl-N - {[2 '- (2H {(Z) - (3,5-Dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl -tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valinate

Step A: N-Pentanoyl-N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valinate from {[(Z) - (3.5 dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl

  N-Pentanoyl-N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valine is reacted with the compound obtained in Preparation 1 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a white solid after purification by chromatography on a silica column, eluting with a n-heptane / acetate mixture. ethyl 9/1, 8/2 then 7/3. Melting point: 54-55 ° C

  Stage B: {[(Z) - (3,5-dimethylpiperidin-1) -N-pentanoyl-N- {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valinate -yl) (oxido) diazenyl] oxy} methyl Procedure identical to Step C of Example 1 using the compound obtained in Step A. The title product is obtained in the form of a white solid.

  Melting point: 60-64 CCHN Elemental microanalysis:% theory: 61.92 7.14 18.05% experimental: 61.60 7.18 17.31 Example 8: 2-Ethoxy-1 - {[2 '- ( 1 - [(2-oxido-2-pyrrolidin-1-yldiazenyl) oxy] methyl [1-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate

  Step A: 2-Ethoxy-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid

  Solubilize 2-ethoxy-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (1.36 × 10 -3 mol) in tetrahydrofuran ( 5 ml). Place with stirring, add triethylamine (2.72 × 10 -3 mol) and heat to reflux. Then add a solution of trityl chloride (1.36.10-3 mol) in tetrahydrofuran (2 ml). After heating for 3 hours, allow the temperature of the reaction medium to reach room temperature and dilute the medium with water. Extract with ethyl acetate.

  The organic phase is then washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The yellowish solid residue obtained is recrystallized from a mixture of ethyl acetate / n-heptane / petroleum ether. The title product is obtained in the form of an off-white solid. Melting point: 132-133 ° C

  Stage B: 2-Ethoxy-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from {[(Z)] 2-oxido-2-pyrrolidin-1-ydiazenyl] oxy} methyl

  2-Ethoxy-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid is reacted with 1 - [(Z) - (chloromethoxy) -NNO-azoxy] pyrrolidine according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a colorless oil.

  Stage C: 2-Ethoxy-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from {[(Z) -2-oxido- 2-pyrrolidin-1-yldiazenyl] oxy} methyl Procedure identical to Stage C of Example 1 from the product obtained in Stage B. The title product is obtained in the form of a white solid.

  Melting point: 100-101 C Elemental microanalysis: CHN% theory: 59.68 5.01 21.60% Experimental: 59.62 5.01 20.43 Example 9: 2-Ethoxy-1 [ 2-tert-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from {[O- (3,5-dimethylpiperidin-1-yl) -2-oxodiazenyl] oxy } methyl

  Step A: 2-Ethoxy-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from [(2) - 2- (3,5-Dimethylpiperidin-1-yl) -2-oxodiazenyl] oxy} methyl

  2-Ethoxy-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid is reacted with the compound obtained in Preparation 1 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a white solid after purification by chromatography on a silica column, eluting with a n-heptane / ethyl acetate 7/3. Melting point: 70-72 C

  Step B: 2-Ethoxy-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate from {[(Z) -2- (3 5-dimethylpiperidin-1-yl) -2-oxodiazenyl] oxy} methyl

  Procedure identical to Stage C of Example 1 using the compound obtained in Stage A. The title product is obtained in the form of a white solid.

  Melting point: 80 ° -82 ° C. Elemental microanalysis: CHN% theoretical: 61.43 5.64 20.15% experimental: 61.34 5.65 19.33 Example 10: 2-Butyl-4-chloro 2- {[(2-oxido-2-pyrrolidin-1-yl] -2-tetrazol-5-yl) biphenyl-4-yl] methyl} -1HT imidazole-5-carboxylate yldiazenyl] oxy} ethyl

Step A: 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate {[(Z) -2-oxido-2-pyrrolidin-1-yldiazenyl] oxy} ethyl

  Solubilize 1,1'-carbonyldiimidazole (1.1010-3 mol) in dichloromethane (4 ml). Place the solution under a gentle stream of nitrogen with stirring and cool to 0 C. Add 1-butyl-4-chloro-1 - {[2 '- (2-trityl-2H) tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylic acid (1.10 × 10 -3 mol), allow the temperature of the reaction medium to return to ambient temperature and maintain stirring for 1 hour. Then add a solution of the compound obtained in Preparation 5 (1.10 × 10 -3 mol) in dichloromethane (2 ml) After stirring for 24 hours at room temperature, the reaction medium is evaporated to dryness under reduced pressure. is purified by chromatography on a column of silica eluting with n-heptane / ethyl acetate 7/3 The title product is recovered in the form of a white solid Melting point: 61-62 ° C

  Step B: 2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carboxylate of 2 - {[(Z ) -2-oxido-2-pyrrolidin-1-yldiazényl] oxy} ethyl

  Procedure identical to Stage C of Example 1 using the compound obtained in Stage A. The title product is obtained in the form of a white solid.

  Melting point: 72-73 ° C. Elemental microanalysis: CHN Cl% theoretical: 56.61 5.43 21.22 5.97% experimental: 54.30 5.19 18.92 6.54 -23-Example 11: [(Z) -Oxido (pyrrolidin-1-yl) diazenyl] oxy] (2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] acetate Methyl} -1H-imidazol-5-yl) Methyl

  Step A: (2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-) - {[(Z) -Oxido (pyrrolidin-1-yl) diazenyl] oxy} acetate yl) Biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl

Solubilize (2-butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methanol ( 1.09 × 10 -3 mol) and the compound obtained in Preparation 6 (1.63 × 10 -3 mol) in tetrahydrofuran (11 ml). Place the solution with stirring and add a catalytic amount of 4- (dimethylamino) pyridine (0.011 g). Then add a solution of 1,3-dicyclohexylcarbodiimide (1.09 × 10 -3 mol) in tetrahydrofuran (7 ml). After 20 hours, the reaction medium is filtered. The filtrate is evaporated to dryness under reduced pressure. The oily orange residue obtained is purified by chromatography on a silica column, eluting with a n-heptane / ethyl acetate mixture 7/3 and 5/5. All the fractions containing the expected product are evaporated under reduced pressure and the residue obtained is then passed over Sephadex LH-20 gel, eluting with a dichloromethane / acetone 1/1 mixture. The title product is obtained in the form of a white solid.

  Step B: (2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl) - {[(Z) -Oxido (pyrrolidin-1-yl) diazenyl] oxy} acetate 4-yl] methyl} -1H-imidazol-5-yl) methyl

  Procedure identical to Stage C of Example 1 using the compound obtained in Step A above. The title product is obtained in the form of a white solid after chromatography on a silica column, eluting with a 99/1 and then 96/4 dichloromethane / methanol mixture and a Sephadex LH-20 gel passage, eluting with a dichloromethane / acetone mixture 1/1. Melting point: 75-76 CCHN Cl Elemental microanalysis:% theory: 56.61 5.43 21.22 5.97% experimental: 56.45 5.32 20.74 6.07 Example 12: 1- [(2-Butyl-4-chloro-1 {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) carbonyl] -4 (Z) -methoxy-NNO-azoxy] piperazine

Step A: 1 - [(2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5 yl) carbonyl] -4- [(Z) -methoxy-NNO-azoxy] piperazine The compound obtained in Step A of Example 1 (7.36 × 10 4 mol) is solubilized in thionyl chloride (3 ml). The solution is heated at 80 ° C. for 1 hour and then the excess of thionyl chloride is removed by evaporation under reduced pressure and the oily residue obtained is dried under vacuum. Solubilize 1 - [(Z) -methoxy-NNO-azoxy] piperazine (7.87 × 10 4 mol) in dichloromethane (10 ml) and cool the resulting solution to 0 ° C.

  Add triethylamine (7.87 × 10 -4 mol) and then the residue obtained previously in solution in dichloromethane (2 ml). After the addition is complete, let the temperature of the medium return to room temperature and continue stirring for 3 hours. Hydrolyze the reaction medium with water and extract with dichloromethane. The organic phase is washed with water and brine then dried over magnesium sulfate, filtered and evaporated under reduced pressure. The oily residue is purified by chromatography on a silica column, eluting with a n-heptane / ethyl acetate mixture 5/5. The title product is obtained in the form of an orange solid. Melting point: 80-81 C

Step B: 1 - [(2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -25H-imidazol-5-yl) carbonyl ] -4 - [(Z) -methoxy-NNO-azoxy] piperazine

  Procedure identical to Stage C of Example 1 starting from the compound obtained in Stage A. The title product is obtained in the form of an off-white solid after chromatography on a silica column, eluting with a mixture of dichloromethane / methanol 99/1 then 98/02.

  Melting point: 79-81 ° C. Elemental microanalysis: C H N Cl% theoretical: 56.00 5.40 24.19 6.12% experimental: 56.89 6.14 21.23 5.99

  Example 13: N - [(1S) -1 - ({4 - [(Z) -Methoxy-N, N-α-oxy] piperazin-1-yl} carbonyl) -2-methylprapyl] -N- {[2'- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} pentanamide Step A: N - [(18) -1 - ({4 - [(Z) -Methoxy-NNO-azoxy] piperazin-1-yl carbonyl) -2-methylpropyl] -N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} pentanamide

  N-Pentanoyl-N - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -L-valine is reacted with 1 - [(Z) - methoxy-NNO-azoxy] piperazine according to the operating conditions described in Step A of Example 10. The title product is obtained after chromatography on a silica column eluting with a 99/01 dichloromethane / methanol Sephadex LH-20 eluting with a 1/1 dichloromethane / acetone mixture. M.p. - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} pentanamide

  Procedure identical to Stage C of Example 1 starting from the compound obtained in Stage A. The title product is obtained in the form of a white solid after chromatography on a silica column, eluting with a dichloromethane / methanol mixture. / 01 then 98/02. Melting point: 85-86 CCHN Elemental microanalysis:% theoretical: 60.30 6.80 21.82% experimental: 60.42 6.81 21.09 Example 14: [(2-Butyl-4-chloro) 1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methylcarbamate of {[(Z) - (3,5-dimethylpiperidine) -1-yl) (oxido) diazenyl] oxy} methyl

  Step A: [(2-Butyl-4-ethyl-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5 yl) methyl] methylamine 2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazole-5-carbaldehyde (7.54 × 10 -3 mol) is dissolved in dichloromethane (50 ml). Add a 2 M solution of methylamine (11.31 × 10 -3 mol) in tetrahydrofuran and place the reaction medium with stirring at ambient temperature and a gentle stream of nitrogen. After 30 minutes, add a suspension of sodium triacetoxyborohydride (10.55 × 10 -3 mol) in dichloromethane (50 ml) in one go. After 2 days, the reaction medium is hydrolysed with water and extracted with dichloromethane. The organic phase is washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue obtained is purified by chromatography on a silica column, eluting with a 98/2 dichloromethane / methanol mixture and then passed on Sephadex LH-20 gel, eluting with a 1/1 dichloromethane / acetone mixture. The title product is thus obtained in the form of an off-white solid. Melting point: 64-65 ° C

Step B: [(2-Butyl-4-chloro-1-1 [2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) {[(Z) - (3,5-dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl methyl] methylcarbamate

  The product obtained in Stage A is reacted with the compound obtained in Preparation 1 according to the operating conditions described in Stage B of Example 1. The title product is obtained in the form of a white solid after purification by chromatography on a silica column, eluting with a dichloromethane / methanol mixture 98/02 then 95/05 and passage over Sephadex LH-20 gel, eluting with a dichloromethane / acetone 1/1 mixture.

Melting point: 65-66 ° C

Step C: [(2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methyl arbamate of {[(Z) - (3,5-dimethylpiperidin-1-yl) (oxido) diazenyl] oxy} methyl

  Procedure identical to Stage C of Example 1 from the product obtained in Stage B.

  The expected product is obtained in the form of a white solid after chromatography on a silica column, eluting with a dichloromethane / methanol 98/02 then 95/05 and passage over Sephadex LH-20 gel, eluting with a dichloromethane mixture. 1/1 acetone.

  Melting point: 79-80 ° C. Elemental microanalysis: CHN Cl% theory: 57.78 6.21 21.06 5.33% experimental: 57.22 6.18 20.49 5.97 Example 15: [(2- Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methylcarbamate of {[(Z) -oxido} (pyrrolidin-1-yl) diazenylmethylmethyl

Step A: [(2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) {[(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} methyl methyl] methylcarbamate

  The product obtained in Stage A of Example 14 is reacted with 1 - [(Z) - 25 (chloromethoxy) -NNO-azoxy] pyrrolidine according to the operating conditions described in Stage B of Example 1. The product The title is obtained in the form of a white solid after purification by chromatography on a silica column, eluting with a mixture of n-28-heptane / ethyl acetate 9/1 and passage over Sephadex LH-20 gel, eluting with with a dichloromethane / acetone 1/1 mixture. Melting point: 66-67 ° C

Step B: [(2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl] methylcarbamate {[(Z) -oxido (pyrrolidin-1-yl) diazenyl] oxy} methyl

  Procedure identical to Stage C of Example 1, using the compound obtained in Stage A. The title product is obtained in the form of a white solid after chromatography on a silica column, eluting with a dichloromethane / methanol mixture. / 01 then 96/04 and passage over Sephadex LH-20 gel eluting with a 1/1 dichloromethane / acetone mixture.

  Melting point: 80-81 C Elemental microanalysis: C H N Theoretical: 55.90 5.66 22.48% Experimental: 56.24 5.96 20.74

  Example 16: (2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4 - 4 - [(Z) -Methoxy-NNO-azoxy] piperazine-1-carboxylate -yl] methyl} -1H-imidazol-5-yl) methyl

  Step A: 4 (2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) - 4 - [(Z) -Methoxy-NNO-azoxy] piperazine-1-carboxylate ) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methyl

  Solubilize 1,1'-carbonyldiimidazole (7.52.10 -4 mol) in dichloromethane (3 ml) Place the solution under a gentle stream of nitrogen, stir and cool to 0 C. Then add a solution dropwise (2-Butyl-4-chloro-1 - {[2 '- (2-trityl-2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1H-imidazol-5-yl) methanol (7.52.104) mol) in dichloromethane (3 ml), allow the temperature of the reaction medium to return to room temperature and stir for 1 hour, then add a solution of 1 - [(Z) -methoxy-29-NNO-azoxy] piperazine (7, 52.104 mol) in dichloromethane (3 ml) After 20 hours, the reaction medium is evaporated to dryness under reduced pressure The residue is purified by chromatography on a silica column eluting with a n-heptane / ethyl acetate mixture. 3. The title product is obtained in the form of a white solid.

Melting point: 68-69 ° C

  Step B: (2-Butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4 - [(Z) -Methoxy-NNO-azoxy] piperazine-1-carboxylate yl] methyl} -1H-imidazol-5-yl) methyl

  Procedure identical to Stage C of Example 1, using the compound obtained in Stage A. The title product is obtained in the form of a white solid after chromatography on a silica column, eluting with a dichloromethane / methanol mixture. / 01 then 95/05.

  Melting point: 90-91 C Elemental microanalysis: CHN Cl% theoretical: 55,22 5,46 23,00 5,82% experimental: 55, 77 5,44 22,67 6,08 -30- PHARMACOLOGICAL STUDY OF PRODUCTS EXAMPLE A: Antagonist effect of angiotensin II receptors

  In vitro The femoral artery and the aorta are taken from anaesthetized Neo-Zelandian rabbits, and cut into 2 mm rings which are then suspended between 2 hooks, one of which is a tension sensor in chambers filled with physiological solution. The femoral artery rings are used, in the presence of a guanylate cyclase inhibitor, ODQ (1H- [1,2,4] oxalodiazolo [4,3-a] quinoxalin-1) to 10 M. After stabilization a first range of increasing concentrations of angiotensin II is performed, followed after washing and addition of a dose of the test compound of a second range of angiotensin II. The results are expressed in% of the maximum effect of angiotensin II in the first range. The concentration-dependent response curves are analyzed to determine the EC50 values and calculate the pA2 value (Arunlakshana and Schild, 1959).

  Results: The compounds of the invention show an excellent antagonist activity of these receptors with pA2 values obtained greater than 8.5.

  In vivo The antagonistic effect of the compounds of the invention is evaluated on spinalised rats. Angiotensin II is injected twice at 0.1 g / kg i.v. and its hypertensive effect is measured in delta (mmHg). Angiotensin II is then administered repeatedly at the same dose after increasing doses of the test compound. The% inhibition curve of the angiotensin II pressure effect as a function of the dose is constructed and the effect of the molecule is determined by the D50 (50% inhibiting dose effect of Angiotensin II ). Results: The compounds of the invention show excellent antagonistic effects of angiotension II receptors with D50 values obtained lower than 0.6 mg / kg. EXAMPLE B NO Donor Activity

  In vitro Aorta rings without endothelium are used. After a first contraction induced by 60 mM KC1 to characterize the sensitivity of the ring and a wash, stable contraction is induced by noradrenaline (0.1-0.3 M) in the presence or absence of ODQ. A range of cumulative concentration is achieved and the activity of the product to be tested is calculated by an IC50 (dose inhibiting 50% maximum effect). Results: The compounds according to the invention have a quite significant relaxing effect with IC50 values below 11.tM.

  In vivo The NO donor effect of the molecule is evaluated by the pressure drop caused when the angiotensin II receptors are previously blocked. In spontaneously hypertensive rats anesthetized with pentobarbital, a reference antagonist is injected at a high dose (candesartan 0.1 mg / kg); after 40 minutes the blood pressure is stable and the product to be tested is administered i.v. in increasing doses. The dose causing 20 or 50% hypotension is determined. Results: A decrease of at least 50% in blood pressure is observed with the compounds of the invention for doses less than 0.3 mg / kg.

  EXAMPLE C Pharmaceutical Composition Preparation formula for 1000 tablets dosed with 100 mg of 2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} -1 {[(Z) -2-Oxido-2-pyrrolidin-1-yldiazenyl] oxy} methyl H-imidazole-5-carboxylate (Example 1) 100 g Hydroxypropycellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g

Claims (8)

  Compounds of formula (I): wherein R1 represents a linear or branched alkanoyl group, R2 represents a linear or branched (C1-C6) alkyl group substituted by a group G, or R1 and R2 together with the nitrogen atom carrying an imidazolyl or benzimidazolyl group, these groups being substituted with a group G and optionally substituted with one or two other additional groups selected from linear or branched (C1-C6) alkyl, alkoxy (C1-C6) linear or branched, and halogen atoms, and G represents a group - (CH2), - A- (CH2), n (CR4R5) p- (CH2) o -R3 in which: - n is 0, 1, 2 or 3, - mute 0, 1,2 or 3 - p is 0 or 1 - ovaut 0, 1 or 2 R4 and R5, identical or different, each represent a hydrogen atom or a (C1-C6) alkyl group ) linear or branched, - A represents a group where R 6 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, and R3 represents a group where R7, R8 and R9, which may be identical or different, each represent a group hydrogen atom or a linear or branched (C1-C6) alkyl group, or R7 and R8 together form a linear or branched (C1-C6) alkylene chain, their enantiomers and diastereoisomers as well as their addition salts with an acid or to a pharmaceutically acceptable base.   2. Compounds of formula (I), according to claim 1, for which R1 and R2 together with the nitrogen atom carrying them an imidazolyl group, their enantiomers and diastereoisomers and their addition salts with an acid or to a pharmaceutically acceptable base. 15   3. Compounds of formula (I) according to claim 1, wherein A represents a group C (O) O-, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.   4. Compounds of formula (I) according to claim 1, wherein R3 represents a group -O-N = N (O) -NR7R8, their enantiomers and diastereoisomers and also their addition salts with an acid or a base. pharmaceutically acceptable.   A compound of formula (I) according to claim 1 which is 2-butyl-4-chloro-1 - {[2 '- (2H-tetrazol-5-yl) biphenyl-4-yl] methyl} - {(Z) -2-oxido-3,4-pyrrolidin-1-yldiazenyl] oxy} methyl 1H-imidazole-5-carboxylate and its addition salts with a pharmaceutically acceptable acid or base.   6. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that the compound of formula (II) used is the starting material: R'2 R'1 \ / \ ONCH in which R '1 represents a linear or branched alkanoyl group, R'2 represents a linear or branched alkyl group, or R' 1 and R'2 form together with the nitrogen and carbon atoms which carry them an imidazolyl or benzimidazolyl group these groups being optionally substituted by a linear or branched alkyl group, linear or branched alkoxy or halogen atoms, and Tr represents a trityl group, which is converted by oxidation reaction, reduction or reductive amination into a formula (III): ## STR5 ## wherein n is as defined in formula (I), R'1, R'2 and Tr are such that defined above, and A 'represents a group -C (O) O-, -O-, or -NH-, on which one condenses a compound of formula (IV): ## STR2 ## wherein m, p, o, R 4, R 5 and R 3 are as defined in formula (I) ) and A "represents a halogen atom or a hydroxy or carboxy group, to give the compound of formula (V): (V) in which Tr is as defined above and R1 and R2 are as defined in the formula (I), which is heated under reflux to give the compound of formula (I), compound of formula (I) which is purified, if appropriate, according to a conventional purification technique, which is optionally separated off. isomers, according to a conventional separation technique, and which is converted, if desired, into its addition salts, a pharmaceutically acceptable acid or base.   7. Pharmaceutical compositions containing as active ingredient a compound according to any one of claims 1 to 5 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.   8. Pharmaceutical compositions according to claim 7 containing at least one active principle according to any one of claims 1 to 5, as a drug, in the treatment of hypertension and cardiovascular pathologies and its complications such as retinopathy. , stroke, dementia, left ventricular hypertrophy, heart failure, angina pectoris, myocardial infarction and nephropathy; in the treatment of cardiovascular pathologies associated with atherothrombosis such as cerebral and coronary accidents, arteritis and vasculopathies; in the treatment of vascular complications of many diseases such as diabetes, obesity, metabolic syndrome, cancer or liver fibrosis; and in the treatment of pulmonary, ocular or portal hypertension.