DE4233590A1 - New benzimidazole cpds. - are useful as angiotensin antagonists for treatment of, e.g., hypertension, bronchitis or CNS disorders - Google Patents

Abstract

Benzimidazoles of formula (I), and their 1,3-isomer mixts. and salts, are new. In (I), Ra = 1-3C alkyl, CF3, H, F, Cl or Br; Rb = RCXNR or a gp. of formula (i); R = 1-5C alkyl, TO, TS, R2R3N, PLO or PhS; X = nitromethylene, NR5 or cyanomethylene (opt. substd. by one R4 gp.); R1, R3 = H or T; R2 = H, 1-10C alkyl (opt. substd. in positions 2-, 3- or 4- by one OH, TO, NH2, TNH or (T)2N gp.) 1-4C alkyl (substd. by a phenyl or pyridyl gp. and opt. substd. in position 2-, 3- or 4 by an OH gp.), 3-4C cycloalkyl, 5-8C cycloalkyl (in which an ethylene bridge is opt. replaced by an o-phenylene gp.), or a 6-8C bicycloalkyl gp. (opt. substd. by 1-3 alkyl); or NR2R3 = a 4-6C cyclic alkyleneimino (in which an ethylene bridge in the 3,4-position is opt. replaced by an o-phenylene gp., and which is opt. substd. by 1-2 alkyl or by a phenyl gp.), a morpholino gp., or a piperazino gp. (opt. substd. in position 4 by a gp. T or Ph); R4 = COOH, CN, NR2R3CO or 1-4C alkoxy-carbonyl; R5 = CN, TSO2, PhSO2, PhT'SO2, NH2SO2, TNHSO2, (S)2NSO2, TCO, PhCO, NH2CO, TNHCO, (T)2NHCO; T = 1-3C alkyl; T' = 1-3C alkylene; Ph = phenyl; Rc = 2-4C alkyl, 2-3C alkoxy, 2-3C alkylthio, cyclopropyl or cyclobutyl; Rd = COOH, CN, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl, 2-triphenylmethyl- tetrazolyl, or a gp. convertible in vivo to carboxy. USE - (I) are angiotensin-antagonists, esp. angiotensin II-antagonists, and are useful in treatment of hypertension, coronary insufficiency, ischaemic peripheral circulation disorders, angina, diabetic nephropathy, glaucoma, gastrointestinal disorders, bladder disorders, lung oedema, chronic bronchitis, restenosis, diabetic angiopathy, arteriosclerosis, CNS disorders (such as Parkinson's disease or Alzheimer's disease) or cognitive disorders. Admin. is esp. oral or intravenous. Dosage is, e.g., 0.5-100 (esp. 1-100) mg 1-3 times daily.

Description

The present invention relates to novel benzimidazoles of general formula

their 1, 3-isomer mixtures and their salts, in particular for the pharmaceutical application whose physiologically ver Suitable salts with inorganic or organic acids or bases which are valuable angiotensin antagonists, in special angiotensin II antagonists, represent these Compounds containing drugs and their use and process for their preparation.

In the above general formula I means
R _{a is} an alkyl group having 1 to 3 carbon atoms, a tri fluoromethyl group, a hydrogen, fluorine, chlorine or bromine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula

in which
R is an alkyl group having 1 to 5 carbon atoms, an alkoxy or alkylthio group each having 1 to 3 carbon atoms, a phenoxy or phenylthio group or a (R ₂ NR ₃ ) group and
X is a nitromethylene group, an optionally substituted by an R ₄ group cyanomethylene group or a group of the formula = NR ₅ , in which

• R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
• R _{2 is} a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, which may be substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, in which Alkyl moiety each containing 1 to 3 carbon atoms, an alkyl group having 1 to 4 carbon atoms, which is substituted by a phenyl or pyridyl group and may additionally be substituted in the 2-, 3- or 4-position by a hydroxy group, a cycloalkyl group with 3 or 4 Kohlenstoffato men, a cycloalkyl group having 5 to 8 carbon atoms, in which an ethylene bridge may be replaced by an o-phenylene group, an optionally substituted by 1, 2 or 3 alkyl groups Bicycloalkylgruppe having 6 to 8 carbon atoms or
• R ₂ and R ₃ together with the intermediate nitrogen atom, a cyclic Alkyleniminogruppe having 4 to 6 carbon atoms, which may be substituted by one or two alkyl groups or by a phenyl group and in addition an ethylene bridge in 3,4-position by an o-phenylene group may be substituted, a morpholino group or a piperazino group optionally substituted in the 4-position by an alkyl group having 1 to 3 carbon atoms or by a phenyl group,
• R _{4 is} a carboxy, cyano, R ₂ NR ₃ -CO- or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, where R ₂ and R ₃ are defined as mentioned above, and
  R _{5 is} a cyano, alkanesulfonyl, phenylsulfonyl, Phe nylalkansulfonyl-, aminosulfonyl, Alkylaminosulfonyl-, Dialkylaminosulfonyl-, alkylcarbonyl, phenylcarbonyl, aminocarbonyl, alkylaminocarbonyl or Dialkylaminocar bonylgruppe, in which the alkyl moiety each 1 to 3 Koh lenstoffatome may contain

R _{c is} an alkyl group having 2 to 4 carbon atoms, an alkoxy or alkylthio group each having 2 or 3 carbon atoms in the alkyl moiety, a cyclopropyl or cyclobutyl group and
R _{d is} a carboxy group convertible in vivo, a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-trazolyl or 2-triphenylmethyl-tetrazolyl group.

Under the above-mentioned term "a group which is in vivo is converted into a carboxy group, "are example example, their esters of the formulas

-CO-OR ',
-CO-O- (HCR '') - O-CO-R '''and
-CO-O- (HCR '') - O-CO-OR '''

in which
R 'is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group,
R '' is a hydrogen atom or a methyl group and
R '"is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group.

Preferred compounds of the above general formula I are those in which
R _{a represents} a methyl group, a hydrogen, fluorine, chlorine or bromine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula

in which
R is an alkyl group having 1 to 3 carbon atoms, a methoxy, methylthio, phenoxy or phenylthio group or a (R ₂ NR ₃ ) group and
X is a nitromethylene or dicyanomethylene group or a group of formula = NR ₅ in which

• R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
• R _{2 is} an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms or
• R ₂ and R ₃ together with the intermediate nitrogen atom, a cyclic Alkyleniminogruppe with 4 or 5 carbon atoms, which may be substituted by one or two methyl groups, and
• R _{5 represents} a cyano or aminosulfonyl group,

R _{c is} an alkyl group having 2 to 4 carbon atoms and
R _{d represents} a carboxy, 1H-tetrazolyl, 1-triphenylmethyl-trazolyl or 2-triphenylmethyl-tetrazolyl group,
their 1, 3-isomer mixtures and their salts.

Particularly preferred compounds of the above general formula I are those in which
R _{a represents} a methyl group or a chlorine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula

in which
R is an (R ₂ NR ₃ ) group or an alkyl group having 1 to 3 carbon atoms and
X is a nitromethylene or dicyanomethylene group or a group of formula = NR ₅ in which

• R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
• R _{2 is} an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms or
• R ₂ and R ₃ together with the intermediate nitrogen atom, a pyrrolidino or piperidino group and
• R _{5 represents} a cyano or aminosulfonyl group,

R _{c is} an alkyl group having 2 to 4 carbon atoms and
R _{d represents} a carboxy or 1H-tetrazolyl group,
in particular the compounds

• a) 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -] 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid,
• b) 4 '- [(2-n-Propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanine dino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl,
• c) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl- 2-carboxylic acid,
• d) 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitro- ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl- 2-carboxylic acid and
• e) 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl) guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-car bonsäure,

their 1, 3-isomer mixtures and their salts.

According to the invention, the compounds are obtained according to the following Method:

• a) For the preparation of compounds of the general formula I, in which R represents an alkoxy or alkylthio group each having 1 to 3 carbon atoms or a phenyloxy or phenylthio group:
  Reaction of a compound of the general formula in the
  R _a , R _c , R _d and R _{1 are} as defined above, with a compound of general formula (Y ') ₂ C = X (III) in the
  X as defined above,
  the radicals Y ', which may be identical or different, depending Weil provide an alkoxy or alkylthio group each having 1 to 3 carbon atoms, a phenoxy or phenylthio group.
• The reaction is preferably carried out in a solvent such as Methanol, ethanol, isopropanol, dioxane, tetrahydrofuran or Chloroform optionally in the presence of an acid-binding By means such as potassium carbonate, triethylamine or pyridine, wherein the latter two are also used as solvents can, conveniently at temperatures between 0 and 50 ° C, but preferably at room temperature.
• b) For the preparation of compounds of general formula I in which R represents a (R ₂ NR ₃ ) group:
  Reaction of a compound of the general formula in the
  R _a , R _c , R _d , R ₁ and X are as defined above and Y "is an alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl group each having 1 to 3 carbon atoms, a phenyl oxy, phenylthio, phenylsulfinyl or phenylsulfonyl group, with an amine of the general formula R ₂ R ₃ NH (V) in the
  R ₂ and R _{3 are} as defined above.
  The reaction is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane or benzene or in an excess of the amine used of the general formula V optionally in a pressure vessel and optionally in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine Temperatures between 0 and 125 ° C, preferably at temperatures between 50 and 100 ° C performed.
  If Y "in an compound of the general formula IV denotes an alkylthio or phenylthio group, the corresponding sulfinyl compound is advantageously obtained by oxidation with an oxidizing agent or by prior oxidation
  Y "in a compound of the general formula IV is an alkylthio, alkylsulfinyl, phenylthio or phenylsulfinyl group, it is expedient to obtain the corresponding de sulfonyl compound by preceding oxidation with an oxidizing agent.
  The previous oxidation is treated with an oxidizing agent such as a peracid, e.g. B. with 3-chloroperbenzoic acid, in a solvent such as methylene chloride, ethanol, isopropanol, tetrahydrofuran, dioxane or benzene at temperatures between 0 and 50 ° C, preferably at room temperature, performed.
• c) For the preparation of compounds of general formula I in which R represents an alkyl group having 1 to 5 carbon atoms:
  Reaction of a compound of the general formula in the
  R _a , R _c , R _d and R _{1 are} as defined above, with a compound of the general formula in the
  X as defined above,
  R 'represents an alkyl group having 1 to 5 carbon atoms and Y''' represents an alkylthio group having 1 to 3 carbon atoms.
  The reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran or chloroform optionally in the presence of an acid-binding agent such as potassium carbonate, triethylamine or pyridine, the latter two also being useful as a solvent, conveniently at temperatures between 0 and 50 ° C, but preferably at room temperature.
• d) For the preparation of a compound of general formula I in which R _{d represents} a carboxy group:
  Transfer of a compound of the general formula in the
  R _a to R _{c are} as defined above and
  R _d 'represents a group convertible into a carboxy group by hydrolysis, thermolysis or hydrogenolysis.

For example, functional derivatives of Carboxygrup pe such as their unsubstituted or substituted amides, esters, Thiol esters, orthoesters, imino ethers, amidines or anhydrides, the nitrile group or the tetrazolyl group by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. B. the tert. Butyl ester, by thermolysis in a Carboxygrup pe and esters with aralkanols, eg. B. the benzyl ester, by means Hydrogenolysis be converted into a carboxy group.

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, tri chloroacetic acid or trifluoroacetic acid or especially  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 / isopropanol or water / dioxane at temperatures between -10 ° C and 120 ° C, z. B. at temperatures between room temperature and the boiling point temperature of the reaction mixture, carried out.

If R _d 'in a compound of the general formula VII is a cyano or aminocarbonyl group, these groups may also be reacted with a nitrite, eg. As sodium nitrite, in the presence of an acid such as sulfuric acid, this is suitably used simultaneously as a solvent, be converted at temperatures between 0 and 50 ° C in the carboxy group.

R _d 'in a compound of general formula VII, for example, the tert. Butyloxycarbonylgruppe, so the tert. Butyl also thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in Ge presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid preferably at the boiling point of the used Solvent, e.g. B. at temperatures between 40 ° C and 100 ° C, are split off.

If R _d 'in a compound of general formula VII, for example, the benzyloxycarbonyl group, the Ben zylgruppe can hydrogenolytically in the presence of a hydrogenation tion catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, ice acetic, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, z. B. at room temperature, and a hydrogen pressure of 1 to 5 bar are split off. In the hydrogenolysis can simultane- ously other radicals, for. A nitro group to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, mitreduziert or by hydrogen atoms, eg. As a halogen atom by a What hydrogen atom, be replaced.

• e) For the preparation of a compound of general formula I in which R _{d represents} a 1H-tetrazolyl group:
  Cleavage of a protecting moiety from a compound of the general formula in the
  R _a to R _{c are} as defined above and
  R _d "represents a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protecting group.
  As a protective group is, for example, the triphenylmethyl, tributyltin or Triphenylzinngruppe into consideration.

The cleavage of a used protective moiety takes place preferably in the presence of a hydrogen halide, preferably in the presence of hydrogen chloride, in the presence of a Base such as sodium hydroxide or alcoholic ammonia in one suitable solvents such as methylene chloride, methanol, Me ethanol / ammonia, ethanol or isopropanol at temperatures between 0 and 100 ° C, but preferably at room temperature, or also, if the reaction in the presence of alcohol ischemic ammonia, at elevated temperatures, z. B. at temperatures between 100 and 150 ° C, preferably at temperatures between 120 and 140 ° C.  

In the reactions described above can give If present, reactive groups such as hydroxyl, amino or alkylamino groups during the reaction by conventional Protecting groups are protected, which after the reaction be split off again.

For example, comes as a protective group for a hydroxy group the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and as Protecting group for an amino, alkylamino or imino group Acetyl, benzoyl, ethoxycarbonyl or benzyl group in Be costume.

The optional subsequent cleavage of a use The protective moiety is preferably carried out hydrolytically in one aqueous solvents, for. In water, isopropanol / water, Tetrahydrofuran / water or dioxane / water, in the presence of egg ner acid such as hydrochloric acid or sulfuric acid or in the presence an alkali base such as sodium hydroxide or potassium hydroxide Temperatures between 0 and 100 ° C, preferably at the you Detemperatur of the reaction mixture. The splitting off of a Benzylrestes is preferably hydrogenolytically, z. With hydrogen in the presence of a catalyst such as Palladium / carbon in a solvent such as methanol, ethanol, Ethyl acetate or glacial acetic acid, if appropriate under Zu Set an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and a Hydrogen pressure of 1 to 7 bar, but preferably of 3 up to 5 bar.

An inventively obtained isomer mixture of a Compound of the general formula I can, if desired preferably chromatographically using a Support such as silica gel or alumina are separated.

Furthermore, the obtained compounds of the general nen formula I in their acid addition salts, in particular for the pharmaceutical application in their physiologically compatible  salts with inorganic or organic acids, over be guided. As acids come for example for this Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid fumaric acid, succinic acid, lactic acid, citric acid, Tartaric acid or maleic acid into consideration.

In addition, the new compounds thus obtained can be general formula I, if this is a carboxy or 1H-Te trazolyl group, if desired subsequently in their salts with inorganic or organic bases, in particular especially for the pharmaceutical application in their physiolo cially acceptable salts. As bases come here for example, sodium hydroxide, potassium hydroxide, cyclo hexylamine, ethanolamine, diethanolamine and triethanolamine in Consideration.

The compounds used as starting materials of the general NEN Formulas II to VIII are partially known from the literature or This is obtained by literature methods, such as these for example in EP-A 0 253 310, EP-A 0 291 969, EP-A 0 392 317, EP-A 0 468 470 and EP-A 0 502 314 to be discribed.

For example, one obtains a compound of the general Formula II by cleavage of a protective residue of an ent correspondingly substituted amino compound, which is one of their on the other hand by acylation of a corresponding o-phenylenediamine followed by cyclization or by acylation of a corresponding o-amino-nitro compound, followed by Re Nitro group and cyclization, with such a gege optionally obtained NH-benzimidazole by alkylation with a corresponding biphenyl derivative in a 1-position appropriately substituted compound to be converted can, and if appropriate, subsequent spin-off of a ver used protective remainder.  

A compound of general formula IV used as starting material is obtained by reacting a compound of general formula II with a corresponding compound of general formula III,
a compound of general formula VII and VIII by imple mentation of a corresponding 1H-benzimidazole with an ent speaking biphenyl derivative.

A compound used as starting material of the general Formula VI is obtained by implementing a corresponding sub substituted dialkylthio compound with a corresponding Alkylmagnesium.

The novel compounds of the general formula I in which R _{d is} a carboxy group convertible in vivo group, a carboxy or a 1H-tetrazolyl group, and their physiologically acceptable salts have valuable phar makologische properties. They are angiotensin antagonists, in particular angiotensin II antagonists. The remaining compounds of general formula I represent valuable intermediates for the preparation of the abovementioned compound.

For example, the compounds were
A = 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid,
B = 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3,3-dimethylguanidine) -1H-benzimidazol-1-yl] methyl] -2- (1H tetrazol-5-yl) - biphenyl,
C = 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid .
D = 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid and
E = 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid
examined for their biological effects as follows:

Method description of angiotensin II receptor binding

The tissue (rat lung) is homogenized in Tris buffer (50 mM Tris, 150 mM NaCl, 5 mM EDTA, pH 7.40) and centrifuged twice at 20,000 × g for 20 minutes each. The final pellet is resuspended in incubation buffer (50 mM Tris, 5 mM MgCl ₂ , 0.2% BSA, pH 7.40) 1:75 based on tissue wet weight. Per 0.1 ml of homogenate is incubated for 60 min. At 37 ° C with 50 pM [ ¹²⁵ I] -angiotensin II (NEN, Dreieich, FRG) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation is terminated by rapid filtration through glass fiber filter mats. The filters are each 4 ml of ice-cold buffer (25 mmol Tris, 2.5 mmol MgCl ₂ , 0.1% BSA, pH 7.40) ge wash. The bound radioactivity is determined in a gamma counter. From the dose-response curve, the corresponding IC ₅₀ value is determined.

The substances A to F show the following IC ₅₀ values in the described test:

Furthermore, in the application of the above Ver up to a dose of 30 mg / kg i.v. no tox side effects, eg. B. no negative inotropic effect and no arrhythmia can be observed. The Ver Accordingly, bonds are well tolerated.

Due to their pharmacological properties are suitable the new compounds and their physiologically acceptable Salts for the treatment of hypertension and heart failure, also for the treatment of ischemic peripheral blood circulation disorders, myocardial ischemia (angina), for prevention Cardiac insufficiency progression after myocardial infarction Treatment of diabetic nephropathy, glaucoma, of gastrointestinal diseases and bladder disease.

Furthermore, the new compounds and their phy are physiologically acceptable salts for the treatment of pulmonary Diseases, eg. From pulmonary edema and chronic Bronchitis, for the prevention of arterial re-stenosis after Angioplasty, from thickening of the vessel wall to vessel operations, arteriosclerosis and diabetic angio pathy. Due to the influence of acetylcholine and Dopamine release by angiotensin in the brain are suitable the new angiotensin antagonists also central to remedy nervous disorders, z. Depression, 'Alzheimer's disease' disease, Parkinson's syndrome, bulimia, and of disorders of cognitive functions.  

The for achieving a corresponding effect on the adult required dosage is expediently at intra venous administration 0.5 to 100 mg, preferably 1 to 70 mg, and when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 times a day. For this purpose, the invention can be according to compounds of general formula I prepared, optionally in combination with other active substances such as z. Hypertensives, ACE inhibitors, diuretics and / or calcium Antagonists, along with one or more inert ov carriers and / or diluents, eg. B. with Corn starch, milk sugar, cane sugar, microcrystalline cell lulose, magnesium stearate, polyvinylpyrrolidone, citric acid, Tartaric acid, water, water / ethanol, water / glycerine, water / Sorbitol, water / polyethylene glycol, propylene glycol, cetylste aryl alcohol, carboxymethyl cellulose or fatty sub punching such as hard fat or their suitable mixtures, in üb galenic preparations such as tablets, dragees, ch prepare powders, suspensions or suppositories.

For the above-mentioned combinations thus come as white tere active substances, for example bendroflumethiazide, chlorine thiazide, hydrochlorothiazide, spironolactone, benzthiazide, Cyc lothiazide, ethacrynic acid, furosemide, metoprolol, prazosin, Atenolol, propranolol, (di) hydralazine hydrochloride, Diltia zem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendi pin, captopril, enalapril, lisinopril, cilazapril, quina pril, fosinopril and ramipril. The dose for this active substance is expediently 1/5 the usually recommended lowest dosage up to 1/1 of the normally recommended dosage, so for example 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorine thiazide, 15 to 200 mg ethacrynic acid, 5 to 80 mg furosemide, 20 to 480 mg propranolol, 5 to 60 mg felodipine, 5 to 60 mg Nifedipine or 5 to 60 mg nitrendipine.

The following examples are intended to illustrate the invention in more detail purify:

example 1 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H- benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole-1] yl] methyl] -biphenyl] -2-carboxylic acid methylester.

3.27 g (10.0 mmol) of 2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole are dissolved in 50 ml of dimethyl sulfoxide, por tionwise with 1.23 g (11.0 mmol) of potassium tert . Butylate ver and stirred for 30 minutes at room temperature. Then who added the 3.38 g (11.0 mmol) of 4'-bromomethyl-biphenyl-2-carboxylic acid methyl ester in portions. Subsequently, the reaction mixture is stirred for 3 hours at room temperature, stirred into ice-water and extracted 3 × with ethyl acetate. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), starting with petroleum ether, later mixtures of petroleum ether and ethyl acetate of increasing polarity (9: 1, 4: 1 and 7: 3) as eluent. be used. The uniform fractions are combined and evaporated.
Yield: 2.15 g (38% of theory),
Melting point: sinters from 118 ° C

b) 4 '- [[2-n-propyl-4-chloro-6-amino-1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid methylester.

2.05 g of methyl 4 '- [[2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate are dissolved in 125 ml of ethanol and washed with 5 ml of a 40% aqueous Me methylamine solution. The reaction mixture is stirred for 3 hours at room temperature and then stirred into brine. After 3-fold extraction with ethyl acetate, the combined organic phases are dried over sodium sulfate and evaporated. The residue is stirred for 24 hours with petroleum ether / ether (1: 4), the solid material formed is filtered off with suction and dried.
Yield: 745 mg (50% of theory),
Melting point: 120-121 ° C.

c) 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -] 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid methylester.

0.7 g (1.6 mmol) of methyl 4 '- [[2-n-propyl-4-chloro-6-amino-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate and 395 mg (1.6 mmol) of diphenyl Cyancarbamidsäure are dissolved in 75 ml of isopropanol and stirred for 18 hours at room temperature. Thereafter, the resulting turbidity is filtered off. The filtrate is mixed in a pressure vessel with about 1 ml of gaseous methylamine and heated to 100 ° C for 4 hours he. After cooling, the reaction mixture is evaporated and the residue is mixed with 100 ml of brine. After 3-fold extraction with ethyl acetate, the combined organic phases are dried over sodium sulfate. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) chromatographed using initially as eluent methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1 and 9: 1). The uniform fractions are combined and evaporated.
Yield: 205 mg (21% of theory),
Melting point <250 ° C (decomp.)

d) 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) - 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid.

175 mg (0.34 mmol) of 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H-benzimidazol-1-yl] -methyl] - Biphenyl-2-carbo-methyl ester are dissolved in 20 ml of ethanol, treated with 2 ml of 2N sodium hydroxide solution and stirred for 16 hours at room temperature. After evaporation of the solvent in vacuo, the viscous residue is taken up in 50 ml of bicarbonate solution, filtered through activated charcoal and treated at 0 ° C with 2N acetic acid. The precipitate formed is filtered off with suction, washed with water and dried.
Yield: 95 mg (56% of theory),
Melting point: 251-254 ° C
C₂₇H₂₅ClN₆O₂ (500,99)
Calculated:
C, 64.50, H, 5.00, N, 16.80, Cl, 7.10%;
Found:
C, 64.33, H, 5.13, N, 16.77, Cl, 7.21%.

Example 2 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -1H- benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole] 1-yl] methyl] -biphenyl-2-carboxylic acid methylester.

Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and methyl 4'-bromomethyl-biphenyl-2-carboxylate.
Yield: 35% of theory,
Melting point: 176-177 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] -me thyl] biphenyl-2-carboxylic acid methylester.

Prepared analogously to Example 1b from 4 '- [[2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carbo-methyl ester and methylamine.
Yield: 78% of theory,
R _f value: 0.40 (silica gel, ethyl acetate / petroleum ether = 4: 1).

c) 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -] 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid methylester.

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid methyl ester, cyanecarboxydiphenyl ester and methylamine.
Yield: 44% of theory,
Melting point: 117-119 ° C.

d) 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -] 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid.

Prepared analogously to Example 1d from 4 '- [(2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -1H-benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 40% of theory,
Melting point: 247-249 ° C
C ₂₈ H ₂₈ N ₆ O ₂ (480.57)
Mass spectrum: M⁺ = 480.

Example 3 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanidino) - 1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-Propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanine dino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid methylester.

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid methyl ester, Cyancarbamidsäure diphenylester and dimethyl amine.
Yield: 34% of theory,
R _f value: 0.60 (silica gel, methylene chloride / ethanol = 9: 1).

b) 4 '- [[2-n-Propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanine dino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid.

Prepared analogously to Example 1d from 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl 2-carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 9.5% of theory,
Melting point: sinters from 180 ° C
C ₂₉ H ₃₀ N ₆ O ₂ (494.60)
Mass spectrum: M⁺ = 494.

Example 4 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3,3-dimethyl-guanidino) - 1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl

a) 4 '- [(2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole] 1-yl) methyl] -2- (1-triphenylmethyl-tetrazol-5-yl) biphenyl.

Prepared analogously to Example 1a from 2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazole and 4'-bromomethyl-2- (1-triphenylmethyl-tetrazol-5-yl) -biphenyl.
Yield: 35% of theory,
R _f value: 0.55 (silica gel, methylene chloride / ethanol = 19: 1).

b) 4 '- [(2-n-propyl-4-chloro-6-amino-1H-benzimidazol-1-yl) -me thyl] -2- (1-triphenylmethyl-tetrazol-5-yl) biphenyl.

Prepared analogously to Example 1b from 4 '- [[2-n-propyl-4-chloro-6-phthalimido-1H-benzimidazol-1-yl] methyl] -2- (1-tri-phenylmethyltetrazol-5-yl) biphenyl and methylamine.
Yield: 72% of theory,
Melting point: 209-210 ° C.

c) 4 '- [[2-n-Propyl-4-chloro-6- (2-cyano-3,3-dimethyl-guanine dino) -1H-benzimidazol-1-yl] methyl] -2- (1-triphenylmethyl tetrazol-5-yl) biphenyl.

Prepared analogously to Example 1c from 4 '- [(2-n-propyl-4-chloro-6-amino-1H-benzimidazol-1-yl) methyl] -2- (1-triphenylmethyltetrazol-5-yl) -biphenyl , Cyanobenzamide diphenyl ester and dimethylamine.
Yield: 50% of theory,
Melting point: sinters from 134 ° C.

In addition, 18% of 4 '- [[2-n-propyl-4-chloro-6- (2-cyano) 3,3-dimethyl-guanidino) -1H-benzimidazol-1-yl) methyl] -2- (1 H tetrazol-5-yl) biphenyl.  

d) 4 '- [[2-n-Propyl-4-chloro-6- (2-cyano-3,3-dimethyl-guanine dino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - biphenyl.

225 mg (0.29 mmol) of 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3,3-dimethyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -2- (1-tri phenylmethyl-tetrazol-5-yl) -biphenyl are dissolved in 10 ml absolu tem ethanol, with 2.5 ml of methanolic hydrochloric acid ver and stirred for 90 minutes at room temperature. The solvent is then removed in vacuo and the residue taken up in methylene chloride / ethanol (4: 1) and adjusted to pH 8 with methano lischem ammonia. After addition of 5 g of silica gel is evaporated to dryness. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1, 19: 1 and 9: 1). The uniform fractions are combined and evaporated.
Yield: 15 mg (10% of theory),
Melting point: 204-206 ° CC ₂₈ H ₂₇ ClN ₁₀ (539.05)
Mass spectrum: (M + H) ⁺ = 539/541 (Cl).

Example 5 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H- benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl

a) 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H- benzimidazol-1-yl] methyl] -2- (1-triphenylmethyl-tetrazol- 5-yl] biphenyl.

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-chloro-6-amino-1H-benzimidazol-1-yl] methyl] -2- (1-triphenylmethyltetrazol-5-yl) -biphenyl , Cyanecarbamic acid diphenyl ester and methylamine.
Yield: 32% of theory,
Melting point: 222-224 ° C.

b) 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H- benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl.

Prepared analogously to Example 4d from 4 '- [[2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -2- (1 -triphenylmethyl-tetrazol-5-yl) -biphenyl and methanoic hydrochloric acid.
Yield: 11% of theory,
Melting point: <250 ° C
C ₂₇ H ₂₅ ClN ₁₀ (525.02)
Mass spectrum: (M + H) ⁺ = 525/527 (Cl).

Example 6 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-cyclohexyl-guanidino) - 1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl

a) 4 '- [[2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole] 1-yl] methyl] -2-cyano-biphenyl.

Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and 4'-bromomethyl-2-cyano-biphenyl.
Yield: 49% of theory,
Melting point 243-244 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl) - methyl] -2- (1H-tetrazol-5-yl] biphenyl.

4.75 g (12.5 mmol) of 4 '- [[2-n-propyl-4-methyl-6-phthalimido- 1H-benzimidazol-1-yl] methyl] -2-cyano-biphenyl are dissolved in 200 ml Dissolved absolute toluene and treated with 20.8 g (62.5 mmol) of tributyltin azide. The reaction mixture is heated to reflux for 5 days with stirring. The solvent is then distilled off, the residue taken up in brine and extracted 3 times with 100 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1 and 9: 1) is used. The unitary fractions are combined and evaporated. The residue is triturated with ether / petroleum ether (1: 1) and filtered off with suction.
Yield: 4.05 g (77% of theory),
Melting point: sinters from 177 ° C.

c) 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -] 1H-benzimidazol-1-yl] -2- (1H-tetrazol-5-yl) biphenyl.

1.70 g (4.0 mmol) of 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] methyl] -2- (1H-tetrazole-5 -yl) -biphenyl are taken up in 150 ml of isopropanol and mixed with 30 ml of methylene chloride and 3.1 g (13 mmol) of diphenyl Cyancarbamidsäure. The reaction solution is stirred for 3 days at room temperature and then evaporated. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), where as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1 and 9: 1) is used. The uniform fractions are combined and evaporated. The residue is triturated with ether / petroleum ether (1: 1) and filtered off with suction.
Yield: 905 mg (40% of theory),
Melting point <250 ° C.

d) 4 '- [[2-n-Propyl-4-methyl-6- (2-cyano-3-cyclohexyl-guanine dino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - biphenyl.

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyanoisoureido) -1H-benzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl and cyclohexylamine in boiling isopropanol.
Yield: 44% of theory,
Melting point: sinters at 188 ° C
C ₃₃ H ₃₆ N ₁₀ (572.72)
Mass spectrum: (M + H) ⁺ = 573.

Example 7 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanidino) - 1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl and dimethylamine in it in the isopropanol.
Yield: 24% of theory,
Melting point: sinters from 292 ° C
C ₂₉ H ₃₀ N ₁₀ (518.63)
Mass spectrum: M⁺ = 518.

Example 8 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-isopropyl-guanidino) - 1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) biphenyl

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl and isopropylamine in boiling isopropanol.
Yield: 39% of theory,
Melting point: sinters from 198 ° C
C ₃₀ H ₃₂ N ₁₀ (532.66)
Mass spectrum: M⁺ = 532.

Example 9 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3,3-diisopropyl-Guani dino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) -bi phenyl

Prepared analogously to Example 1c from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl and diisopropylamine in boiling isopropanol.
Yield: 19% of theory,
Melting point: sinters from 185 ° C
C ₃₃ H ₃₈ N ₁₀ (574.74)
Mass spectrum: (M + H) ⁺ = 575.

Example 10 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-pyrrolidino-ethene ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole] 1-yl] methyl] -biphenyl-2-carboxylic acid tert-butyl ester.

Prepared analogously to Example 1a from 2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazole and 4'-bromomethyl-biphenyl-2-car bonsäure tert.butylester.
Yield: 68% of theory,
Melting point: 153-154 ° C.

b) 4 '- [(2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl) -me thyl] biphenyl-2-carboxylic acid tert-butyl ester.

Prepared analogously to Example 1b from 4 '- ((2-n-propyl-4-methyl-6-phthalimido-1H-benzimidazol-1-yl) -methyl] -biphenyl-2-carboxylic acid tert-butyl ester and methylamine.
Yield: 94% of theory,
Melting point 118-119 ° C.

c) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid tert-butyl ester.

2.70 g (6.1 mmol) of 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid tert. butyl ester are dissolved in 125 ml of isopropanol, treated with 2.38 g (14 mmol) of 2,2-dicyano-1,1-dimethylmercapto-ethene and heated under reflux for 4 days. Thereafter, the solvent is evaporated, the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1 and 25: 1) ver used. The uniform fractions are combined and evaporated. The residue is triturated with ether and filtered with suction.
Yield: 2.15 g (62% of theory),
Melting point: 186-188 ° C.

d) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-pyrrolidino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid tert-butyl ester.

425 mg (0.75 mmol) of 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl ] -biphenyl-2-carboxylic acid tert-butyl ester are dissolved in 25 ml of methylene chloride. Subsequently, at 0 ° C under nitrogen, a solution of 380 mg (1.1 mmol) of 3-chloro-peroxy benzoic acid (50%) in 5 ml of methylene chloride was added dropwise. The solution is stirred for 5 hours at room temperature, followed by ßend with 1.17 g (16.5 mmol) of pyrrolidine and stirred for a further 12 hours at room temperature. Thereafter, the solvent is evaporated off, the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1 and 19: 1). The uniform fractions are combined and evaporated.
Yield: 185 mg (41% of theory),
R _f value: 0.40 (silica gel, methylene chloride / ethanol = 19: 1).

e) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-pyrrolidino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

185 mg (0.31 mmol) of 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-pyrrolidino-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] - Biphenyl-2-carboxylic acid tert-butyl ester are dissolved in 10 ml of methylene chloride and treated with 1.5 ml of trifluoroacetic acid. After 3 hours at room temperature, the solution is evaporated, the residue is taken up in 25 ml of sodium bicarbonate solution and filtered through activated charcoal. The precipitate formed after the addition of 2N acetic acid at 5 ° C is filtered off with suction and dried.
Yield: 37 mg (22% of theory),
Melting point: 188-190 ° C
C ₃₃ H ₃₂ N ₆ O ₂ (544.66)
Mass spectrum: (M + H) ⁺ = 545.

Example 11 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylamino-ethene ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- ([2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylamino ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid tert-butyl ester.

Prepared analogously to Example 10d from 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] - tert-butyl biphenyl-2-carboxylate, 3-chloroperoxybenzoic acid and methylamine.
Yield: 45% of theory,
Melting point: 240-242 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylamino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

Prepared analogously to Example 10e from 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylamino-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl 2-carboxylic acid tert-butyl ester and trifluoroacetic acid.
Yield: 43% of theory,
Melting point: sinters at 178 ° C
C ₃₀ H ₂₈ N ₆ O ₂ (504.60)
Mass spectrum: M⁺ = 504.

Example 12 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino-ethene ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid tert-butyl ester.

Prepared analogously to Example 10d from 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] - biphenyl-2-carboxylic acid tert-butyl ester and dimethylamine.
Yield: 38% of theory,
Melting point: sinters from 138 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

Prepared analogously to Example 10e from 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino-ethenyleneamino) -1H-benzimidazol-1-yl] methyl] -biphenyl -2-carboxylic acid tert-butyl ester and trifluoroacetic acid.
Yield: 49% of theory,
Melting point: 178 ° C
C ₃₁ H ₃₀ N ₆ O ₂ (518.62)
Mass spectrum: M⁺ = 519.

Example 13 4 - [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino-ethene ylenamino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - biphenyl

a) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto) ethenylenamino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetra zol-5-yl) biphenyl.

Prepared analogously to Example 10c from 4 '- [[2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl] methyl] -2- (1H-tetrazol-5-yl) -biphenyl and 2,2-dicyano-1,1-dimethylmercapto-ethene.
Yield: 79% of theory,
Melting point: 184-185 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino) ethenylenamino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetra zol-5-yl) biphenyl.

Prepared analogously to Example 10d from 4 '- [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] - 2- (1H-tetrazol-5-yl) -biphenyl and dimethylamine.
Yield: 29% of theory,
Melting point: sinters from 208 ° C
C ₃₁ H ₃₀ N ₁₀ (542.65)
Mass spectrum: (M + H) ⁺ = 543.

Example 14 4 '- [[2-n-propyl-4-methyl-6- 1-dimethylamino-2-nitro-ethene ( ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-methyl-6- (1-methylmercapto-2-nitro- ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl- 2-carboxylic acid methylester.

826 mg (2.0 mmol) of methyl 4 '- [[2-n-propyl-4-methyl-1-amino-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate are dissolved in 75 ml of isopropanol, treated with 0.97 g (6.0 mmol) of 1,1-bis (methylmercapto) -2-nitro-ethene and heated under reflux for 6 hours. Thereafter, the solvent is evaporated, the residue is recrystallized from isopropanol / petroleum ether (3: 1) with the addition of activated carbon.
Yield: 745 mg (70% of theory),
Melting point: 173-174 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitrobenzene) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid methylester.

250 mg (0.47 mmol) of 4 '- [[2-n-propyl-4-methyl-6- (1-methylmercapo-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] - methyl biphenyl-2-carboxylate are dissolved in 50 ml of isopropanol, admixed with 1.0 ml of dimethylamine and heated to 60 ° C. in a pressure vessel for 3 hours. After cooling to room temperature, the precipitate formed is filtered off, washed with water and ether and dried.
Yield: 195 mg (79% of theory),
Melting point: 127-128 ° C.

c) 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitrobenzene) ethenylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

Prepared analogously to Example 1d from 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 34% of theory,
Melting point: sinters from 200 ° C
C ₂₉ H ₃₁ N ₅ O ₄ (513.60)
Mass spectrum: M⁺ = 513.

Example 15 4 '- [[2-n-propyl-4-methyl-6- ethenylene 1-methylamino-2-nitro-( amino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-Propyl-4-methyl-6- (1-methylamino-2-nitro-ethene ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-car bonsäure-methylester.

Prepared analogously to Example 14b from 4 '- [[2-n-propyl-4-methyl-6- (1-methylmercapto-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid methyl ester and methylamine.
Yield: 68% of theory,
R _f value: 0.15 (silica gel, methylene chloride / ethanol = 9: 1).

b) 4 '- [[2-n-Propyl-4-methyl-6- (1-methylamino-2-nitro-ethene ylenamino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-car bonsäure.

Prepared analogously to Example 1d from 4 '- [[2-n-propyl-4-methyl-6- (1-methylamino-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2- carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 30% of theory,
Melting point: sinters at 188 ° C
C ₂₈ H ₂₉ N ₅ O ₄ (499.57)
Mass spectrum: M⁺ = 499.

Example 16 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl-Guani dino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-Propyl-4-methyl-6- (3-methyl-2-amidosulfonyl guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid methylester.

413 mg (1.0 mmol) of methyl 4 '- [[2-n-propyl-4-amino-1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate are dissolved in the 50th ml of isopropanol dissolved, treated with 1.17 g (4.0 mmol) of diphenyl Amidosulfonylcarbamidsäure and stirred for 2 days at room temperature. After addition of 1.5 ml of methylamine, the reaction mixture is heated in a pressure vessel for 3 hours at 60 ° C. Thereafter, the solvent is evaporated, the residue is chromatographed on silica gel (particle size 0.032-0.063 mm), using as eluent initially methylene chloride, later methylene chloride / ethanol (50: 1, 25: 1 and 19: 1) is used. The uniform fractions are combined and evaporated, the residue is triturated from ether / petroleum ether (1: 1) and filtered off with suction.
Yield: 235 mg (43% of theory),
Melting point 115-117 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl) guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

Prepared analogously to Example 1d from 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 31% of theory,
Melting point: 208 ° C
C ₂₇ H ₃₀ N ₆ O ₄ S (534.64)
Mass spectrum: (M + H) ⁺ = 535.

Example 17 4 '- [[2-n-propyl-4-methyl-6- (3,3-dimethyl-2-amidosulfonyl guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid

a) 4 '- [[2-n-propyl-4-methyl-6- (3,3-dimethyl-2-amidosulfonyl guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid methylester.

Prepared analogously to Example 16a from 4 '- [(2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl) methyl] -biphenyl-2-carboxylic acid methyl ester, diphenyl Amidosulfonylcarbamidsäure and dimethylamine.
Yield: 56% of theory,
Melting point: 188-189 ° C.

b) 4 '- [[2-n-propyl-4-methyl-6- (3,3-dimethyl-2-amidosulfonyl guanidino) -1H-benzimidazol-1-yl] methyl] -biphenyl-2- carboxylic acid.

Prepared analogously to Example 1d from 4 '- [[2-n-propyl-4-methyl-6- (3,3-dimethyl-2-amidosulfonyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylic acid methyl ester and 2N sodium hydroxide solution in ethanol.
Yield: 26% of theory,
Melting point: sinters from 165 ° C
C ₂₈ H ₃₂ N ₆ O ₄ S (548.67)
Mass spectrum: (M + H) ⁺ = 549.

Example 18 4 '- [[2-n-propyl-4-methyl-6- [2-cyano-3- (2-dimethylamino-ethyl) - 3-methyl-guanidino] -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetra zol-5-yl) biphenyl

Prepared analogously to Example 6d from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] -methyl] -2- (1H tetrazol-5-yl) -biphenyl and N- (2-dimethylamino-ethyl) -methylamine in isopropanol.
Yield: 40% of theory,
Melting point: 220 ° C (sinters from 115 ° C)
C ₃₂ H ₃₇ N ₁₁ (575.74)
Mass spectrum: (M + H) ⁺ = 576.

Example 19 4 '- [[2-n-propyl-4-methyl-6- [2-cyano-3- (2-hydroxy-ethyl) -3-me thyl-guanidino] -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol- 5-yl) biphenyl

Prepared analogously to Example 6d from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] -methyl] -2- (1H tetrazol-5-yl) -biphenyl and N- (2-hydroxy-ethyl) -methylamine in isopropanol.
Yield: 47.5% of theory,
Melting point: 230 ° C (sinters from 108 ° C)
C ₃₀ H ₃₂ N ₁₀ O (548.67)
Mass spectrum: (M + H) ⁺ = 549.

Example 20 4 '- [[2-n-propyl-4-methyl-6- [2-cyano-3- (bis-2-methoxy-ethyl) - guanidino] -1H-benzimidazol-1-yl] -2- (1H-tetrazol-5-yl) -bi phenyl

Prepared analogously to Example 6d from 4 '- [[2-n-propyl-4-methyl-6- (2-phenoxy-3-cyano-isoureido) -1H-benzimidazol-1-yl] methyl] -2- ( 1H-tetrazol-5-yl) -biphenyl and bis (2-methoxy) -ethylamine in isopropanol.
Yield: 27.5% of theory,
Melting point 104-106 ° C (sinters from 70 ° C),
C ₃₃ H ₃₈ N ₁₀ O ₂ (606.74)
Mass spectrum: M⁺ = 606.

Example 21 4 '- [[2-n-propyl-4-methyl-6- (N- (2-methyl-1-cyanimino-propyl) - amino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol-5-yl) - biphenyl

a) (1-Methyl-ethyl) - (methylmercapto) -methyleniminonitrile.

A Grig nardlösung prepared from 28.0 g (0.23 mol) of isopropyl bromide and 5.5 g (0.23 mol) of magnesium in 10 ml of diethyl ether is added within 30 minutes under ice cooling to a solution of 22.0 g (0, 15 mol) Cyanimidodithiokohlensäu redimethyl ester in 150 ml of tetrahydrofuran. The solution is stirred for 24 hours at room temperature and then treated with 100 ml of 4N hydrochloric acid. After separation of the phases, the aqueous phase is extracted 3 × with 50 ml of ethyl acetate. The combined organic phases are washed with brine and dried with sodium sulfate. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm), initially using petroleum ether, later mixtures of petroleum ether / ethyl acetate (19: 1, 9: 1 and 4: 1) who the. The uniform fractions are combined and evaporated.
Yield: 4.65 g (22% of theory),
R _f : 0.40 (silica gel, petroleum ether / ethyl acetate = 9: 1).

b) 4 '- [[2-n-propyl-4-methyl-6- (N- (2-methyl-1-cyanimino-pro pyl) amino) -1H-benzimidazol-1-yl] -methyl] -2- (1H-tetrazol- 5-yl) biphenyl.

Prepared analogously to Example 1c from 4 '- [(2-n-propyl-4-methyl-6-amino-1H-benzimidazol-1-yl) methyl] -2- (1H-tetrazol-5-yl) -bi-phenyl and (1-methyl-ethyl) - (methylmercapto) -methylen-imino-nitrile in isopropanol.
Yield: 20.3% of theory,
Melting point: 208-210 ° C (sinters from 162 ° C),
C ₃₀ H ₃₁ N ₉ (517.65)
Mass spectrum: M⁺ = 517.

In the following pharmaceutical application examples, the active substance used may be any suitable compound of the formula I, in particular those in which R _{d represents} a carboxy or 1H-tetrazolyl group:

Example I

Ampoules containing 50 mg of active ingredient per 5 ml active substance 50 mg KH₂PO₄ 2 mg Na₂HPO₄ × 2 H₂O 50 mg @ NaCl 12 mg @ Water for injections ad 5 ml

manufacturing

In a part of the water the buffer substances and the Isotonans solved. The active ingredient is added and after full permanent solution with water to the nominal volume.

Example II

Ampoules containing 100 mg of active ingredient per 5 ml active substance 100 mg methylglucamine 35 mg glycofurol 1000 mg @ Polyethylene glycol-polypropylene glycol block polymer 250 mg @ Water for injections ad 5 ml

manufacturing

In a part of the water is dissolved methylglucamine and the Active ingredient with stirring and heating brought into solution. To Add the solvent with water to the nominal volume refilled.

Example III

Tablets containing 50 mg of active ingredient 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

manufacturing

The active ingredient, CaHPO ₄ , lactose and corn starch are evenly moistened with an aqueous PVP solution. The mass is passed through a 2-mm sieve, dried in a convection oven at 50 ° C and sieved again.

After admixing the lubricant, the granules on a Tabletting machine pressed.  

Example IV

Dragees containing 50 mg of active ingredient 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 @ 180.0 mg

manufacturing

The active ingredient is mixed with the excipients and with an aqueous gelatin solution moistened. After screening and Drying, the granules are mixed with magnesium stearate and pressed into cores.

The cores thus produced are prepared by known methods covered with a shell. The coating suspension or solution Dye can be added.

Example V

Dragees containing 100 mg of active ingredient 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 mg @ 350.0 mg

manufacturing

The active ingredient is mixed with the excipients and with an aqueous PVP solution moistened. The wet mass is passed through a 1.5 mm sieve and dried at 45 ° C. After drying, sieved again and the magnesium stea advice. This mixture is pressed into cores.

The cores thus produced are prepared by known methods covered with a shell. The coating suspension or solution Dyes can be added.

Example VI

Capsules containing 250 mg of active ingredient active substance 250.0 mg corn starch 68.5 mg magnesium stearate 1.5 mg @ 320.0 mg

manufacturing

Active ingredient and cornstarch are mixed and treated with water moistens. The moist mass is sieved and dried. The dry granules are screened and ge with magnesium stearate mixed. The final mixture is in hard gelatin capsules size 1 bottled.  

Example VII

Oral suspension containing 50 mg of active ingredient per 5 ml active substance 50.0 mg hydroxyethyl 50.0 mg sorbic acid 5.0 mg @ Sorbitol 70% 600.0 mg @ glycerin 200.0 mg @ Aroma 15.0 mg @ Water ad 5.0 ml

manufacturing

Distilled water is heated to 70 ° C. This is under Stirring dissolved hydroxyethyl cellulose. By adding sorbitol Solution and glycerol is cooled to room temperature. at Room temperature, sorbic acid, flavor and drug are added give. To vent the suspension is evaku with stirring ated. One dose = 50 mg is contained in 5.0 ml.

Example VIII

Suppositories containing 100 mg of active ingredient active substance 100.0 mg Adeps solidus 1600.0 mg 1700.0 mg

manufacturing

The hard fat is melted. At 40 ° C, the ground Active substance homogeneously dispersed in the melt. It will open Cooled to 38 ° C and in slightly pre-cooled suppository forms poured out.

Claims (18)

1. Benzimidazoles of the general formula in the
R _{a is} an alkyl group having 1 to 3 carbon atoms, a tri fluoromethyl group, a hydrogen, fluorine, chlorine or bromine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula in which
R is an alkyl group having 1 to 5 carbon atoms, an alkoxy or alkylthio group each having 1 to 3 carbon atoms, a phenoxy or phenylthio group or a (R ₂ NR ₃ ) group and
X is a nitromethylene group, an optionally substituted by an R ₄ group cyanomethylene group or a group of the formula = NR ₅ , in which
R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
R _{2 is} a hydrogen atom, a branched or unbranched alkyl group having 1 to 10 carbon atoms, which may be substituted in the 2-, 3- or 4-position by a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, in which Alkyl moiety each containing 1 to 3 carbon atoms, an alkyl group having 1 to 4 carbon atoms, which is substituted by a phenyl or pyridyl group and may additionally be substituted in the 2-, 3- or 4-position by a hydroxy group, a cycloalkyl group with 3 or 4 Kohlenstoffato men, a cycloalkyl group having 5 to 8 carbon atoms, in which an ethylene bridge may be replaced by an o-phenylene group, an optionally substituted by 1, 2 or 3 alkyl groups Bicycloalkylgruppe having 6 to 8 carbon atoms or
R ₂ and R ₃ together with the intermediate nitrogen atom, a cyclic Alkyleniminogruppe having 4 to 6 carbon atoms, which may be substituted by one or two alkyl groups or by a phenyl group and in addition an ethylene bridge in 3,4-position by an o-phenylene group may be substituted, a morpholino group or a piperazino group optionally substituted in the 4-position by an alkyl group having 1 to 3 carbon atoms or by a phenyl group,
R _{4 is} a carboxy, cyano, R ₂ NR ₃ -CO- or alkoxycarbonyl group having a total of 2 to 5 carbon atoms, where R ₂ and R ₃ are defined as mentioned above, and
R _{5 represents} a cyano, alkanesulfonyl, phenylsulfonyl, phenylalkanesulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonyl, phenylcarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylamino carbonyl group in which the alkyl portion contains from 1 to 3 carbon atoms each can, represent,
R _{c is} an alkyl group having 2 to 4 carbon atoms, an alkoxy or alkylthio group each having 2 or 3 carbon atoms in the alkyl moiety, a cyclopropyl or cyclobutyl group and
R _{d is} a group convertible in vivo to a carboxy group, a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group,
their 1, 3-isomer mixtures and their salts. 2. Benzimidazoles of the general formula I according to claim 1, in which
R _a to R _{c are} as defined above and
R _{d is} a 1H-tetrazolyl group, a carboxy group or a group of the formulas -CO-OR ',
-CO-O- (HCR '') - O-CO-R '''and
-CO-O- (HCR '') - O-CO-OR '''in which
R 'is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, methoxymethyl or cinnamyl group,
R '' is a hydrogen atom or a methyl group and
R '''is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or 3-phenylpropyl group,
their 1, 3-isomer mixtures and their salts. 3. Benzimidazoles of the general formula I according to claim 1, in which
R _{a represents} a methyl group, a hydrogen, fluorine, chlorine or bromine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula in which
R is an alkyl group having 1 to 3 carbon atoms, a methoxy, methylthio, phenoxy or phenylthio group or a (R ₂ NR ₃ ) group and
X is a nitromethylene or dicyanomethylene group or a group of formula = NR ₅ in which

• R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
  R _{2 is} an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms or
  R ₂ and R ₃ together with the intermediate nitrogen atom, a cyclic Alkyleniminogruppe with 4 or 5 carbon atoms, which may be substituted by one or two methyl groups, and
  R _{5 represents} a cyano or aminosulfonyl group,

R _{c is} an alkyl group having 2 to 4 carbon atoms and
R _{d represents} a carboxy, 1H-tetrazolyl, 1-triphenylmethyl-trazolyl or 2-triphenylmethyl-tetrazolyl group,
their 1, 3-isomer mixtures and their salts. 4. Benzimidazoles of the general formula I according to claim 1, in which
R _{a represents} a methyl group or a chlorine atom,
R _{b is} an R-CX-NR ₁ group or a group of the formula in which
R is an (R ₂ NR ₃ ) group or an alkyl group having 1 to 3 carbon atoms and
X is a nitromethylene or dicyanomethylene group or a group of formula = NR ₅ in which

• R ₁ and R ₃ , which may be the same or different, are hydrogen atoms or alkyl groups each having 1 to 3 carbon atoms,
  R _{2 is} an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms or R ₃ together with the intervening nitrogen atom is a pyrrolidino or piperidino group and
  R _{5 represents} a cyano or aminosulfonyl group,

R _{c is} an alkyl group having 2 to 4 carbon atoms and
R _{d represents} a carboxy or 1H-tetrazolyl group,
their 1, 3-isomer mixtures and their salts. 5. The following benzimidazoles of the general formula I according to claim 1:

• a) 4 '- [[2-n-propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid,
• b) 4 '- [[2-n-Propyl-4-methyl-6- (2-cyano-3,3-dimethyl-guanidine) -1H-benzimidazol-1-yl] -methyl] -2- (1H tetrazol-5-yl) - biphenyl,
• c) 4 '- [[2-n-Propyl-4-methyl-6- (2,2-dicyano-1-dimethylamino-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid .
• d) 4 '- [[2-n-propyl-4-methyl-6- (1-dimethylamino-2-nitro-ethenyleneamino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid and
• e) 4 '- [[2-n-propyl-4-methyl-6- (3-methyl-2-amidosulfonyl-guanidino) -1H-benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylic acid,

their 1, 3-isomer mixtures and their salts. 6. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 5 with inorganic or organic acids or bases.   7. A pharmaceutical composition containing a compound after at least one of claims 1 to 5 or a physiologically acceptable Lich salt according to claim 6 in addition to optionally one or several inert carriers and / or diluents. 8. Use of a compound according to at least one of Claims 1 to 6 for the manufacture of a medicament with An giotensin-antagonistic action. 9. A process for the preparation of a medicament according to An claim 7, characterized in that non-chemical Ways a connection according to at least one of claims 1 to 6 in one or more inert carriers and / or Ver is incorporated. 10. A process for the preparation of benzimidazoles according to the Claims 1 to 6, characterized in that a) for the preparation of compounds of general formula I in which R is an alkoxy or alkylthio group each having 1 to 3 carbon atoms or a phenyloxy or Phenylthiogrup PE, a compound of the general formula in the
R _a , R _c , R _d and R _{1 are} as defined in claims 1 to 5, with a compound of general formula (Y ') ₂ C = X, (III) in the
X is as defined in claims 1 to 5, the radicals Y ', which may be identical or different, depending Weil's an alkoxy or alkylthio group each having 1 to 3 carbon atoms, a phenoxy or phenylthio group is reacted or b) for the preparation of compounds of the general formula I in which R represents an (R ₂ NR ₃ ) group, a compound of the general formula in the
R _a , R _c , R _d , R ₁ and X are as defined in claims 1 to 5 and
Y '' is an alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl group each having 1 to 3 carbon atoms, a phenyl oxy, phenylthio, phenylsulfinyl or phenylsulfonyl group, with an amine of the general formula R ₂ R ₃ NH, (V) in the
R ₂ and R _{3 are} as defined in claims 1 to 5, is reacted or c) for the preparation of compounds of the general formula I in which R represents an alkyl group having 1 to 5 carbon atoms, a compound of the general formula in the
R _a , R _c , R _d and R _{1 are} as defined in claims 1 to 5, with a compound of the general formula in the
X as defined in claims 1 to 5,
R 'is an alkyl group having 1 to 5 carbon atoms and
Y '''represents an alkylthio group having 1 to 3 carbon atoms, is reacted or d) for the preparation of a compound of the general formula I, in which R _{d represents} a carboxy group, a compound of the general formula in the
R _a to R _{c are} as defined in claims 1 to 5 and
R _d 'represents a group convertible into a carboxy group by hydrolysis, thermolysis or hydrogenolysis, converted into a corresponding carboxy compound, or e) for the preparation of a compound of the general formula I in which R _{d represents} a 1H-tetrazolyl group, a protective residue of a compound of the general formula in the
R _a to R _{c are} as defined in claims 1 to 5 and
R _d '' represents a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protective radical, is split off, and
if necessary, a protective moiety used during reactions a) to e) to protect reactive groups will be cleaved and / or
if desired, then a thus obtained 1-, 3-Isome rengemisch a compound of general formula I is separated by isomer separation in its 1- and 3-isomer, or
a compound of the general formula I thus obtained is converted into its salt, in particular for the pharmaceutical application in its physiologically tolerated salt with an inorganic or organic acid or base.