AU669736B2 - Benzimidazoles - Google Patents

Description

111" 1111,

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

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*0 S.

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0 0 TO BE COMP'LETED BY APPLICANT Name of Applicant: DR. KARL THOMAE GMBH Actual Inventor(s): Uwe RIES, Norbert I-AUEL, Jacques VAN MEEL, Wolfgang WIENEN and Michael ENTZEROTH Address for Service: CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Invention Title: "BENZIMI[DAZOLES" The following statement is a full description of this invention, including the best method of performing it known to me:- 1 60300/000.588 Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.

We have now found that certain new benzimidazoles have valuable pharmaceutical properties, in particular angiotensin antagonistic effects, especially against angiotensin-IT.

Thus, viewed from one aspect the present invention provides compounds of formula I:

R

RbtI R(I) (wherein: 2 Ra denotes a methyl group or a hydrogen, fluorine, chlorine or bromine atom; Rb denotes an RiNRe- group in which Re denotes an R-CXgroup or a 3,4-dioxo-l-cyclobuten-l-yl group substituted in the 2-position by a C 1 .3-alkoxy gro'ip or by an (RINR 3 group), or Re denotes a 3-nitro-pyrrol-2-yl group optionally substituted in the 1-position by a methyl group; R denotes a C1.

3 -alkyl or an (R 2

NR

3 group; oe o* o o o ooeo o o ooeo oo X denotes an N0 2

(NC)

2 C= or R 6 group; RI denotes a hydrogen atom or a Ci.3-alkyl group;

R

2 denotes a C_.

3 -alkyl group optionally substituted in the 2- or 3-position by a hydroxy, C 1 _3-alkoxy, amino,

C

1 .3-alkylamino, di (Ci.3-alkyl) amino, or C 5 s 7 -cycloalkyl group, and

R

3 denotes a hydrogen atom or C1.3-alkyl, 2-methoxyethyl, 3 2-dimethylaminoethyl or 2-diethylaminoethyl group, or

R

2 and R3 together with the intervening nitrogen atom denote a cyclic C4.

5 -alkyleneimino group optionally substituted by one or two methyl groups, a morpholino group or a piperazino group optionally substituted in the 4-position by a C 1 _3-alkyl group;

R

6 denotes a C 1 3 -alkylsulphonyl, cyano, aminosulphonyl or phenylsulphonyl group; RC denotes a C 2 _4-alkyl group; and Rd denotes a carboxy, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyltetrazolyl group) and the 3-isomer mixtures and salts thereof.

Particularly preferred compounds according to the invention include those of formula I wherein: o o 4 Ra in the 4-position denotes a methyl group or a chlorine atom; Rb in the 6-position denotes an RiNR e group in which Re denotes an R-CX- group, a 3,4-dioxo-l-cyclobuten-l-yl group substituted in the 2-position by an (RiNR 3 group, or a 3-nitro-pyrrol-2-yl group optionally substituted in the 1-position by a methyl group; R denotes an (R 2

NR

3 or C 1 _3-alkyl group; X denotes an NO2-CH=, (NC) 2 C= or R6-N= group; RI denotes a hydrogen atom or a methyl group;

R

2 denotes a C 1 -3-alkyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl or C5.

7 cycloalkyl group, and

R

3 denotes a hydrogen atom or a C 1 _3-alkyl, 2methoxyethyl, 2-dimethylaminoethyl or 2diethylaminoethyl group, or

S*

a

R

2 and R 3 together with the intervening nitrogen atom denote a pyrrolidino, piperidino, morpholino or 4methyl-piperazino group; RE denotes a cyano, aminosulphonyl, methylsulphonyl or phenylsuiphonyl group; Rc denotes a C 2 4 -alkyl group; and Rd denotes a carboxy or ii--tetrazol-5-yl group; and the isomers, isomer mixtures and salts thereof.

Especially preferred compounds according to the invention include: [[2-n-propyl-4-methyl-6- (2-cyano-3-methylguanidino) -lH-benzimidazol-1-yl] -methyll -biphenyl- 2-carboxylic acid, S S S S S S S S

S..

55S555 S S -6 [[2-n-propyl-4-methyl-G- (2-cyano-3,3-dimethylguanidino) -lH-benzimidazol-l-yl] -methyl] (lH- -biphenyl, [[2-n-propyl-4-methyl-6- 2-dicyano-ldimethylamino-ethenylamino) -1H-benzimidazol-lyl] methyl] -biphenyl-2-carboxylic acid, [[2-n-propyl-4-methyl-6- (l-dimethylamino-2nitro-ethenylamino) -lII-benzimidazol---yl] -methyl] biphenyl-2-carboxylic acid, [[2-n-propyl-4-methyl-6- (3-methyl-2amidosuiphonyl-guanidino) -lH-benzimidazol-l-yll methyl] -biphenyl-2-c-arboxylic acid, [[2-n-propyl-4-methyl-6- (l-dimethylamino-2nitro-ethenylamino) -1H-benzimidazol-1-yll -methyl] 2- (lH-tetrazol-5-yl) -biphenyl, -7 (g E2-ethyl-4-methyl-6-[ (2-dimethylamino-3,4dioxo-l-cyclobuten-l-yl) -amino] -lH-benzimidazol-lyl] -methyl] -biphenyl-2-carboxylic acid and 4'-[[2-ethyl-4-methyl-6-(3,3-dimethyl-2methylsuiphonyl-guanidino) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl, and the 3-isomer mixtures and salts thereof.

Viewed from a further aspect, the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R denotes a C 13 -alkoxy, C 1 3 -alkylthio, phenyloxy or phenylthio group) reacting a compound of formula II H N n copon of foml III (wherein X is as hereinbefore defined, the groups which may be identical or different, each denote a C 13 -alkoxy, Cl- 3 -alkylthio, phenoxy or phenylthio

I

8 group); b) (to prepare compounds of formula I wherein R denotes an (R 2

NR

3 group) reacting of a compound of formula IV xR R/ (IV) S* Rd *0 So (wherein Ra, Re, Rd, R 1 and X are as hereinbefore defined and Y" denotes a C1_-alkoxy, C 1 _,-alkylthio, C 1 3 alkylsulphinyl or C 1 3 -alkylsulphonyl, phenyloxy, phenylthio, phenylsulphinyl or phenylsulphonyl group) with an amine of formula V

R

2

R

3 NH (V) (wherein

R

2 and R3 are as hereinbefore defined; c) (to prepare compounds of formula I wherein R denotes a C 1 5 -alkyl group) reacting of a compound of formula II H N R -"N 1 (i) (wherein 9 Ra, R Rd and R, are as hereinbefore defined) with a c<-mpound of formula VI

X

II

R' C (VI) wherein X is as hereinbefore defined, R' denotes a C 1 alkyl group and denotes a C 1 3 -alkylthio group; d) (to prepare compounds of formula I wherein Rd denotes i. 99 a carboxy group) converting of a compound of formula VII R N

(VII)

Rd' (wherein

CQ

R to R C are as hereinbefore defined and Rd' denotes a group which may be converted into a carbo y 0group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; e) (to prepare compounds of formula I wherein Rd represents a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula

VIII

I

10 R N Rb1CN -Rc Rd" (wherein Ra to R c are defined as hereinbefore and Ra" represents a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protecting group); f) (to prepare compounds of formula I wherein Rb denotes an RiNRe- group in which Re denotes one of the abovementioned 3-nitro-pyrrol-2-yl groups) cyclising a compound of formula IX *H NO H-N N R* (I Rd (wherein RI, R 3 Ra, R c and Rd are as hereinbefore defined and the groups which may be identical or different, each represent a Ci_ 3 -alkoxy group); g) (to prepare compounds of formula I wherein Rb denotes an RiNRe- group wherein Re denotes one of the abovementioned 3,4-dioxo-l-cyclobuten-l-yl groups) reacting a compound of formula II 11 1 L7 (II) Rd (wherein Ra, Rc, Rd and R, are as hereinbefore defined) with a 3,4-dioxo-l,2-di(C 1 _3-alkoxy)-1-cyclobutene and, if desired, to prepare a corresponding 2-amino compound subsequently reacting a 2-alkoxy compound thus obtained with an amine of formula V

R

2

R

3 NH (V) wherein

R

2 and R 3 are as hereinbefore defined; h) (to prepare compounds of formula I wherein R d denotes 9 a 1H-tetrazolyl group)

S.

reacting a compound of formula X

R

R

b

R

c

NC

A

.d (wherein

R

a to R c are as hereinbefore defined) with hydrazoic acid or the salts thereof; i) performing a process as defined in any one of steps to above on a corresponding protected compound Sand subsequently removing the protecting group used; 12 j) resolving a compound of formula I by isomer separation from a 3-isomer mixture into the individual isomers; and k) converting a compound of formula I into a salt thereof, more particularly for pharmaceutical use into a physiologically acceptable salt thereof with an inorganic or organic acid or base.

The reaction of step is preferably carried out in a solvent such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran or chloroform, optionally in the 0 presence of an acid-binding agent such as potassium carbonate, triethylamine or pyridine, whilst the latter two may also be used as solvents, appropriately at temperatures between 0 and 50"C, but preferably at ambient temperature.

The reaction of step is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane or benzene or in an excess of the amine of formula V used, optionally in a pressurised vessel and optionally in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine at temperatures between 0 and 125*C, preferably at temperatures between 50 and 100 C.

If Y" in a compound of formula IV denotes an alkylthio or phenylthio group, the corresponding sulphinyl compound is conveniently obtained by prior oxidation with an oxidising agent and if Y" in a compound of formula IV denotes an alkylthio, alkylsulphinyl, phenylthio or phenylsulphinyl group, the corresponding sulphonyl compound is conveniently obtained by prior oxidation with an oxidising agent.

The prior oxidation may be carried out with an oxidising 13 agent such as a peracid, e.g. 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 ambient temperature.

The reaction of step 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 S. carbonate, triethylamine or pyridine, whilst the latter two may also be used as solvents, appropriately at temperatures between 0 and 50"C, but preferably at ambient temperature.

SIn step functional derivatives of the carboxy group such as the unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, a nitrile group or a tetrazolyl group may be converted by hydrolysis into a carboxy group; esters with tertiary alcohols, e.g. tert.butylesters, may be converted by thermolysis into a carboxy group; and esters with aralkanols, e.g. benzylesters, may be converted by hydrogenolysis into a carboxy group.

The hydrolysis in step is appropriately carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid or, most advantageously, 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, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

-14 If Rd' in a compound of formula VII represents a cyano or aminocarbonyl group, these groups may also be converted into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and If Rd' in a compound of formula VII represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, b benzene, toluene, tetrahydrofuran or dioxane and "preferably in the presence of a catalytic amount of an acid such as trifluoroacetic acid, p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40*C and 100"C.

If Rd' in a compound of formula VII represents, for 0, example, a benzyloxycarbonyl group, the benzyl group may 3e I also be hydrogenolytically cleaved in the presence of a *AGO hydrogenation catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50°C, e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar. During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group to a hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenyl-propionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen atom may be replaced by a hydrogen atom.

In step suitable protecting groups include, for

I)

S- 15 example, the triphenylmethyl, tributyl tin or triphenyl tin groups.

The cleaving of a protecting group is preferably carried out in the presence of a hydrohalic acid, preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia, in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100°C, but preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 150*C, preferably at temperatures between 120 and 140'C.

The cyclisation of step is preferably carried out in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or water or in aqueous mixtures thereof, in the presence of an acid such as hydrochloric acid or sulphuric acid at temperatures between 0 and 125*C, preferably at temperatures between 50 and 100"C.

"The compound of formula IX required for this is conveniently obtained by reacting a corresponding compound of formula IV with a 2-amino-acetaldehyde diacetal in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane or benzene or in an excess of the 2-amino-acetaldehyde diacetal used, optionally in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine at temperatures between 0 and 125"C, preferably at temperatures between 50 and 100*C.

The reaction of step 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, whilst the latter 16 two may also be used as solvent, appropriately at temperatures between 0 and 50"C, but preferably at ambient temperature.

The subsequent reaction of a 2-alkoxy compound thus obtained with an amine of formula V is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane or benzene or in an excess of the amine of formula V used, optionally in a pressurised vessel and optionally in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine or pyridine at temperatures between 0 and 125"C, preferably at temperatures between 50 and 100*C.

The reaction of step is preferably carried out in a solvent such as benzene, toluene or dimethylformamide, at temperatures between 80 and 150"C, preferably at 125°C. Advantageously, either the hydrazoic acid is liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt S* obtained in the reaction mixture by reacting with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which are also conveniently prepared in the reaction mixture by reacting aluminium chloride or tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.

In the reaction steps to described hereinbefore, any reactive groups present such as hydroxy, amino or alkylamino groups may be protected during the reaction by means of conventional protecting groups which are split off again after the reaction.

I 0 17 Examples of protecting groups for a hydroxy group include trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl and tetrahydropyranyl groups and protecting groups for an amino, alkylamino or imino group include acetyl, benzoyl, ethoxycarbonyl or benzyl groups.

The optional subsequent cleaving of a protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100*C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group is preferably cleaved by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

An isomer mixture of a compound of formula I thus obtained may if desired be resolved by chromatography using a substrate such as silica gel or aluminium oxide.

a Moreover, the compounds of formula I obtained may be converted into the acid addition salts thereof, more S* particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, S- 18 lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the new compounds of formula I thus obtained, if they contain a carboxy or 1H-tetrazolyl group, may if desired subsequently be converted into the salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of formulae II to X used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature, such as those described for example in EP-A-253310, EP-A-291969, EP-A-392317, EP-A-468470 and EP-A-502314.

S Thus, for example, a compound of formula II may be obtained by cleaving a protecting group from a correspondingly substituted amino compound, which is in turn obtained by acylating a corresponding ophenylenediamine and subsequent cyclisation or by acylating a corresponding o-amino-nitro compound, subsequent reduction of the nitro compound and S. cyclisation, whilst an NH-benzimidazole optionally obtained in this manner may be converted by alkylation with a corresponding biphenyl derivative into a compound which is correspondingly substituted in the 1-position, with optional subsequent cleaving of any protecting group used.

.9 9 A compound of formula IV used as starting material may be obtained by reacting a compound of formula II with a corresponding compound of formula III, and a compound of formulae VII and VIII may be obtained by reacting a 1 19 corresponding 1H-benzimidazole with a corresponding biphenyl derivative.

If the group Rb in a starting compound of formula VII or VIII contains one of the above-mentioned 3-nitro-pyrrole groups, this may be obtained by reacting a corresponding l-alkylmercapto-2-nitro-ethenyleneamino compound with a corresponding 2-amino-acetaldehyde acetal and subsequent cyclisation in the presence of an acid (see also J. Med.

Chem. 31, 669 (1988)).

If the group Rb in a starting compound of formula VII or VIII contains one of the above-mentioned 3,4-dioxo-lcyclobutene groups, it may be obtained by reacting a corresponding amino compound with a 1,2-dialkoxy-3,4dioxo-l-cyclobutene and subsequently reacting with a corresponding amine (see also J. Med. Chem. 35, 4720 *0 0 *0 (1992)) 00 A starting compound of formula IX may be obtained by Sreacting a corresponding l-alkylmercapto-2-nitroethenyleneamine of formula I with a 2-amino-acetaldehyde diacetal.

A compound of formula VI used as starting material may be obtained by reacting a correspondingly substituted S* dialkylthio compound with a corresponding alkylmagnesium *0 halide.

The monoalkylation of amines which may be necessary to 0* prepare the starting compounds is described in J. Chem.

Soc. Chem. Com. 1984, 1335.

The new compounds of formula I wherein Rd denotes a group which can be converted into a carboxy group in vivo, or a carboxy or 1H-tetrazolyl group, and the physiologically acceptable salts thereof have valuable 20 pharmacological properties. They are angiotensin antagonists, particularly angiotensin-II-antagonists.

The other compounds of formula I are valuable intermediates for preparing the above-mentioned compounds.

By way of example, the following compounds: A [[2-n-propyl-4-methyl-6- (2-cyano-3-methylguanidino) -lH-benzimidazol-l-yl) -methyl] -biphenyl- 2-carboxylic acid, B I[2-n-propyl-4-methyl-6- (2-cyano-3,3-dimethylguanidino) -lH-benzimidazol-l-yl] -methyl] (lH- -biphenyl, C [[2-n-propyl-4-methyl-6- (2,2-dicyano-1dimethylamino-ethenylamino) -lH-benzimidazol-l-yll methyl] -biphenyl-2-carboxylic acid, D [[2-n-propyl-4-methyl-6- (l-dimethylamino-2nitro-ethenylamino) -lI--benzimidazol-l-yll -methyl] biphenyl-2 -carboxylic acid, E [[2-n-propyl-4-methyl-6- (3-methyl-2- S amidosulphonylguanidino) -lH-benzimidazol-l-yl] methyl] -biphenyl-2-carboxylic acid, F [[2-n-propyl-4-methyl-6- (l,l-dimethylamino-2nitro-ethenylami-no) -lH,-benzimidazol-l-yll -methyl] 2- (lH-tetrazol-5-yl) -biphenyl, G =4'-II 12-ethyl-4-methyl-6- II(2-dimethylamino-3, 4dioxo-1-cyclobuten-l-yl) -amino] -lH-benzimidazol-lyll -methyl] -biphenyl-2-carboxylic acid and H [[2-ethyl-4-methyl-6- (3,3-dimethyl-2is 1 21 methylsulphonyl-guanidino)-1H-benzimidazol-1-yl]were investigated for their biological activities as follows: Description of method: anqiotensin-II-receptor binding The tissue (rat's lung) is homogenised in Tris buffer mM Tris, 150 mM NaCl, 5 mM EDTA, pH 7.40) and centrifuged twice for 20 minutes at 20,000 x g. 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 the wet weight of the tissue. Each 0.1 ml of homogenate is incubated for 60 minutes at 37 C with 50 pM [125I]angiotensin-II (NEN, Dreieich, Germany) and increasing concentrations of the test substance in a total volume of 0.25 ml. The incubation is ended by rapid filtration through glass fibre filter mats. The filters are each S, "washed with 4 ml of ice-cold buffer (25 mM Tris, 2.5 mM MgCl 2 0.1% BSA, pH 7.40). The bound radioactivity is measured in a gamma-counter. The cor'esponding IC 50 value is determined from the dosage-activity curve.

Substances A to H show the following IC 50 values in the test described: e Substance IC 50 [nM] A 11 B 3 C 64 D 13 c i I 22 Moreover, when the above compounds were administered in doses of up to 30 mg/kg i.v. no toxic side effects were observed, e.g. negative inotropic effects or heart rhythm disorders. The compounds are therefore well tolerated.

In view of their pharmacological properties, the new compounds and the physiologically acceptable salts thereof are suitable for the treatment of hypertension and cardiac insufficiency and for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

Furthermore, the new compounds and the physiologically

Q

acceptable salts thereof are suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of the vascular walls after vascular operations, arteriosclerosis and diabetic angiopathy. Because of the effect of angiotensin on the release of acetylcholine and dopamine in the brain, the new angiotensin antagonists are also S. suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson's syndrome and bulimia, as well as disorders 9090 -of cognitive functions.

emcee2 Thus, viewed from a further aspect the present invention S "provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients.

Viewed from a still further aspect the invention 1 I 23 provides the use of a compound of formula I or physiologically acceptable salt thereof for the manufacture of a therapeutic agent for combatting hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia, diabetic nephropathv, glaucoma, gastrointestinal disease, bladder disease, pulmonary disease, vascular wall thickening, arteriosclerosis, diabetic angiopathy, central nervous system disorders and cognitive fuction disorders.

Viewed from a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia, diabetic nephropathy, glaucoma, gastrointestinal disease, bladder disease, pulmonary disease, vascular wall thickening, arteriosclerosis, diabetic angiopathy, central nervous system disorders and cognitive fuction disorders, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

The dosage required to achieve these effects in adults is appropriately, when administered intravenously, to 100 mg, preferably 1 to 70 mg, and, when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3 times a day. For this purpose, the compounds of formula I or salts thereof, optionally in conjunction with other active substances such as, for example, hypotensive agents, ACE inhibitors, diuretics and/or calcium antagonists, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g.

with corn starch, lactose, glucose, micro-crystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, 24 water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat, or suitable mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

Examples of additional active substances which may be used in the combinations mentioned above include bendroflumethiazide, chlorothiazide, hydrochlorothiazide, spironolactone, benzothiazide, cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosin, atenolol, propranolol, (di)hydralazinehydrochloride, diltiazem, felodipine, nicardipine, nifedipine, nisoldipine, nitrendipine, captopril, enalapril, lisinopril, cilazapril, quinapril, fosinopril and ramipril. The dosage of these active substances is conveniently 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dosage, that is for example 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg of chlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg of furosemide, 20 to 480 mg of propranolci, 5 to 60 mg of felodipine, 5 to 60 mg of nifedipine or 5 to 60 mg of nitrendipine.

0* I I The following non-limiting Examples are provided to illustrate the invention: Example 1 4'-[[2-n-Propyl-4-chloro-6-(2-cyano-3-methyl-guanidino)- 1H-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid a) Methyl 4'-[(2-n-propyl-4-chloro-6-phthalimido-lHbenzimidazol-l-yl)-methyll-biphenyl-2-carboxylate 3.27 g (10.0 mMol) of 2-n-propyl-4-chloro-6-phthalimido- 1H-benzimidazole are dissolved in 50 ml of dimethylsulphoxide, 1.23 g (11.0 mMol) of potassium tert.butoxide are added in batches thereto and the resulting mixture is stirred for 30 minutes at ambient temperature. Then 3.38 g (11.0 mMol) of methyl 4'- S" bromomethyl-biphenyl-2-carboxylate are added in batches thereto. The reaction mixture is then stirred for 3 hours at ambient temperature, stirred into ice water and extracted 3 times with ethyl acetate. The combined organic phases are washed with saline solution and dried over magnesium sulphate. Then the solvent is removed in vacuo and the residue is chromatographed on silica gel (particle size 0.032-0.063 mm), using as eluant first petroleum ether and then mixtures of petroleum ether and ethyl acetate of increasing polarity 4:1 and 7:3).

Similar fractions are combined and evaporated down.

Yield: 2.15 g (38% of theory), Melting point: sintering from 118°C b) Methyl 4'-[(2-n-propyl-4-chloro-6-amino-lHbenzimidazol-l-yl)-methyll-biphenyl-2-carboxylate 2.05 g of methyl 4'-[(2-n-propyl-4-chloro-6-phthalimido- 1H-benzimidazol-l-yl)-methyl]-biphenyl-2-carboxylate are dissolved in 125 ml of ethanol and mixed with 5 ml of a aqueous methylamine solution. The reaction mixture is stirred for 3 hours at ambient temperature and then 26 stirred into saline solution. After extracting 3 times with ethyl acetate the combined organic phases are dried over sodium sulphate and evaporated down. The residue is stirred with petroleum ether/ether for 24 hours, the solids formed are suction filtered and dried.

Yield: 745 mg (50% of theory), Melting point: 120-121°C c) Methyl 4'-[[2-n-propyl-4-chloro-6-(2-cyano-3-methylguanidino)-1H-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate 0.7 g (1.6 mMol) of methyl 4'-[[2-n-propyl-4-chloro-6amino-lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate and 395 mg (1.6 mMol) of diphenyl cyanocarbamidate are dissolved in 75 ml of isopropanol and stirred for 18 hours at ambient temperature. Then the mixture is filtered to remove the turbidity. The 9 filtrate is combined with about 1 ml of gaseous S'.9 methylamine in a pressurised vessel and heated to 100°C for 4 hours. After cooling, the reaction mixture is evaporated down and the residue is combined with 100 ml of saline solution. After extracting 3 times with ethyl acetate, the combined organic phases are dried over sodium sulphate. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1 and The uniform fractions are combined and evaporated down.

999 •Yield: 205 mg (21% of theory), Melting point: 250*C (decomp.) d) 4'-[[2-n-Propyl-4-chloro-6-(2-cyano-3-methylguanidino)-1H-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 175 mg (0.34 mMol) of methyl 4'-[(2-n-propyl-4-chloro-6- (2-cyano-3-methyl-guanidino)-1H-benzimidazol-l-yl)methyl]-biphenyl-2-carboxylate are dissolved in 20 ml of F -27 ethanol, combined with 2 ml of 2N sodium hydroxide solution and stirred for 16 hours at ambient temperature. After the solvent has been evaporated of f in vacuo the viscous residue is taken up in 50 ml of bicarbonate solution, filtered over activated charcoal and 2N acetic acid are added at 0CC. The precipitate formed is suction filtered, washed with water and dried.

Yield: 95 mg (56% of theory), Melting point: 251-254*C

C

27

H

25 C1N 6 0 2 (500.99) Calculated: C 64.50 H 5.00 N 16.80 Cl 7.10 Found: 64.3:2 5.13 16.77 7.21 Example 2 [2-n-Propyl-4-methyl-6- (2-cyano-3-methyl-guanidino) lH-benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylic acid 4 a) Methyl 4' (2-n-propyl-4-methyl-6-phthalimido-lHbenzimidazol-1-yl) -methyll -biphenyl-2-carboxylate Prepared analogous".y to Example la from 2-n-propyl-4methyl-6-phthialimido-lH-benzimidazole and methyl 4'bromomethyl-biphenyl-2 -carboxylate.

Yield: 35% of theory, Melting point: 176-177*C ,to b) Methyl 4' (2-n-propyl-4-methyl-6-amino-lHbenzimidazol-1-yl) -methyll-biphenvl-2-carboxylate Prepared analogously to Example lb from methyl propyl-4methyl-6phthalimido-lHbenzimidazoll1yl) methyl] -biphenyl-2-carboxylate and methylamine.

Yield: 78% of theory, Rf value: 0.40 (silica gel; ethyl acetate/pc troleum ether 4:1) 28 c) Methyl 4 [2-n-propyl-4-methyl-6-(2-cyalo--3-methylguanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylate Prepared analogously to Example 1c from methyl propyl-4-methyl-6-amino-lH-benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate, diphenyl cyanocarbamidate and methylamine.

Yield: 44% of theory, Melting point: 117-119*C d) 4 [2-n-Propyl-4-methyl-6-(2-cyano-3-methylguanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example id from methyl 4'-[112-npropyl-4-methyl-6- (2-cyano-3-methyl-gualidino) -lHbenzimidazol-l-yl] -methyl] -biphenyl-2-carboxy..ate and 2N 00.sodium hydroxide solution in ethanol.

.0.Yield: 40% of theory, 000 Melting point: 247-249'C 000C 28

H

28

N

6 0 2 (480.57) 0 00Mass spectrum: M+ 480 Example 3 [2-n-Propyl-4-methyl-6- (2-cyano-3 ,3-dimethyl- 0000 guanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid 0 0 a) Methyl [2-n-propyl-4-methyl-6-(2-.cyano- 3 ,3dimethyl-guanidino) -lH-benz imidazol-l-yl] -methyl] b iphenyl -2 -carboxylate Prepared analogously to Example lc from methyl 4'-L[2-npropyl-4-methyl-6-amino-lH-benzimidazol1yl] -methyl] biphenyl-2-carboxylate, diphenyl cyanocarbamidate and dimethylamine.

Yield: 34% of theory, 29 Rf value: 0.60 (silica gel; methylene chloride/ethanol 9:1) b) 4 [2-n-propyl-4-methyl-6-(2-cyano-3, 3-dimethylguanidino) -lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid Prepared analogously to Example ld from methyl 4'-[42-npropyl-4-methyl-6- (2-cyano-3 ,3-dimethyl-guanidino) -lHbenzimidazol-l-yl] -methyl] -biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 9.5% of theory, Melting point: sintering from 180*C

C

29

H

30

N

6 0 2 (494.60) Mass spectrum: M+ 494 0 Example-4 [2-n-Propyl-4-chloro-6- (2-cyano-3, 3-dimethylguanidino)-lH-benzimidazol-l-yl]-methyl]-2- (lH-tetrazol- 0 5-yl) -biphenyl a) 4' (2-n-Propyl-4-chloro-6-phthalimido-lHbenziinidazol-1-yl) -methyl] -2-(1-triphenylmethyl- -biphenyl *see Prepared analogously to Example la from 2-n-propyl-4- :chloro-6-phthalimido-lH-benzimidazole and 4'bromomethyl-2- (l-triphenylmethyl-tetrazol-5-yl) biphenyl.

900000Yield: 35% of theory, Rf value: 0.55 (silica gel; methylene chloride/ethanol- 000 19:1) b) 4' (2-n-Propyl-4-chloro-6-amino-lH-benzimidazol-lyl) -methyl] (l-triphenylmethyl-tetrazol-5-yl) b iphenyl Prepared analogously to Example lb from 4'-[(2-n-propyl- 30 0 so *00 o *so *a o* 4-chloro-6-phthalimido-lH-benzimidazol-1-yl) -methyl]-2- -biphenyl and methylamine.

Yield: 72% of theory, Melting point: 209-210*C c) (2-n-Propyl-4--chloro-6-(2-cyano-3 ,3-dimethylguanidino) -lH-benzimidazol-l-yl] -methyl 1-2- (1- Prepared analogously to Example 1c from 4'-[(2-n-propyl- 4-chloro-6-amino-lH-benzimidazol-l-yl) -methyl] (1- -biphenyl, diphenyl cyanocarbamidate and dimethylamine.

Yield: 50% of theory, Melting point: sintering from 134 0

C

This produces 18% of 4'-[[2-n-propyl-4-chloro-6-(2cyano-3 ,3-dimethyl-guanidino) -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl d) 4'-[[2-n-Propyl-4-chloro-6-(2-cyano-3,3-dimethylguanidino) -lH-benzimidazol-l-yl 1-methyl] (11- -biphenyl.

225 mg (0.29 mMol) of 4'-[[2-n-propyl-4-chloro-6-(2cyano-3, 3-dimethyl-guanidino)-111-benz imidazol-l-yl] methyl] (l-triphenylmethyl-tetrazol-5-yl) -biphenyl are dissolved in 10 ml of absolute ethanol, mixed with ml of methanolic hydrochloric acid and stirred for minutes at ambient temperature. The solvent is then removed in vacuo and the residue is taken up in methylene chloride/ethanol and adjusted to pH 8 with methanolic ammonia. After the addition of 5 g of silica gel the mixture is evaporated to dryness. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1, 19:1 and Similar fractions are combined and evaporated 311 down.

Yield: 15 mg (10% of theory), Melting point: 204-206'C

C

28 H 27 C1N 10 (539.05) Mass spectrum: 539/541 (Cl) Example 4' ['-n-Propyl-4-chloro-6- (2-cyano-3-methyl-guanidino) 1H-benzimidazol-l-yl] -methyl] (1H-tetrazol-5-yl) b iphenyl a) 4 [2-n-Propyl-4-chloro-6-(2-cyano-3-methyl- -biphenyi Prepared analogously to Example lc from 4'-[(2-n-propyl- 4 -chloro-6-amino-lH-benzimidazol-l-yl) -methyl] (1- -biphenyl, diphenyl cyanocarbamidate and methylamine.

Yield: 32% of theory, Melting point: 222-224*C b) 4 [2-n-Propyl-4-chloro-6-(2-cyano-3-methylguanidino) -lH-benzimidazol-l-yl] -methyl] (lH- -biphenyl Prepared analogously to Example 4d from 4'-[(2-n-propyl- 4-chloro-6- (2-cyano-3-methyl-guanidino) -lH-benzimidazol- 1-yl]-methyl]-2-(l-triphenylmethyl-tetrazol-5-yl) biphenyl and methanolic hydrochloric acid.

Yield: 11'- of theory, Melting point: >250'C C 27

H

25 C1N 10 (525.02) Mass spectrum: 525/527 (Cl) 32 Example 6 4 '-[[2-n-Propyl-4-methyl-6-(2-cyano-3-cyclohexylguanidino) -lH-benzimidazol-l-yl]-methyl] (lH-tetrazol- -biphenyl a) 4' (2-n-Propyl-4-methyl-6-phthalimido-lHbenzimidazol-l-l)-methyll -2-cyano-biphenyl Prepared analogously to Example la from 2-n-propyl-4methyl-6-phthalimido-lH-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.-lH-benizimnidazol-lvll -methyli (lH-tetrazol-5-vl) -biphenyl 4.75 g (12.5 mMol) of 4'-[(2-n-propyl-4-methyl-6phthalimido-lH-benzimidazol-l-yl) -methyll -2-cyanobiphenyl are dissolved in 200 ml of absolute toluene and combined with 20.8 g (62.5 mMol) of tributyl tin azide.

The reaction mixture is ref luxed for 5 days with stirring. Then the solvent is distilled off, the residue is taken up in saline solution and extracted 3 times with 100 mol of ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as sees eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1 and The uniform 55.55.fractions are combined and evaporated down. The residue is triturated3 with ether/petroleum ether and suction filtered.

Yield: 4.05 g (77% of theory), Melting point: sintering from 177*C 33 c) 4 t[ L2-n-Phenyl-4-methyl-6-(2-phenoxy-3-cyanoisoureido) -lH-benzimidazol-l-yl] VP) -biphenyl 1.70 g (4.0 mMol) of 4'-[[2-n-propyl-4-methyl-6-amino- 1H-benzimidazol-l-yl]-methyl]-2-(lH-tetrazol-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 cyanocarbamidate. The reaction solution is stirred at' ambient temperature for 3 days and then evaporated down. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1 and The uniform fractions are combined and evaporated down. The residue is triturated with ether/petroleum ether and suction filtered.

*'Yield: 905 mg (40% of theory), Melting point: >250*C d) 4'-i [2-i--Propyl-4-methyl-6- (2-cyano-3-cyclohexyl- S guanidino) -lH-benzimidazol-l-yl] -methyl] (lH- -biphenyl Prepared analogously to Example 1c from 4'-[[2-n-propyl- 4-methyl-6- (2-phenoxy-3-cyano-isoureido) -lHbenzimidazol-l-ylJ-methyl]-2- (lH-tetrazol-5-yl) -biphenyl and cyclohexylamine in boiling isopropanol.

Yield: 44% of theory, Melting point: sintering from 188*C sop*.

C

33

H

36

N

1 a (572.72) Mass spectrum: 573 w 34 Example 7 4' -[[j2-n-Propyl-4-methyl-6-(2-cyano-3 ,3-dirnethylguanidino) -lH-benzimidazol-1-yl]-methyll-2-(lH-tetrazol- -biphenyl Prepared analogously to Example lc from 4'-[[2-n-propyl- 4-methyl-6- (2-phenoxy-3-cyano-isoureido) -lHbenzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl and dimethylamine in boiling isopropanol.

Yield: 24% of theory, Melting point: sintering from 202'C

C

29

H

30

N

10 (518.63) Mass spectrum: M+ 518 Example 8 e 4 [2-n-Propyl-4-methyl-6-(2-cyano-3-isopropylguanidino) -lH-benzimidazol-l-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) -lHbenzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl fees and isopropylamine in boiling isopropanol.

Yield: 39% of theory, SO Melting point: sintering from 198'C

*C

30

H

32

N

10 (532.66) Mass spectrum: M+ 532

I

33 Example 9 [[2-n-Propyl-4-methyl-6- (2-cyano-3 ,3-diisopropylguanidino) -1H-benzimidazol-l-yl] -methyl] (lH-tetrazol- -biphenyl Prepared analogously to Example lc from 41-[[2-n-propyl- 4-methyl-6- (2-phenoxy-3-cyano-isoureido) -lHbenzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -bip~henyl and diisopropylamine in boiling isopropanol.

Yield: 19%* of theory, Melting point: sintering from 185 0

C

C

33

H

38

NI

0 (574.74) Mass spectrum: 575 Example [[2-n-Propyl-4-methyl-6- 2-dicyano-l-pyrrolidinoethenylamino) -1I-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylic acid a) Tert.butyl 41-1 (2-n-propyl-4-methyl-6-phthalimidol1H-benzimidazol-l-yl) -methyl] -bi-phenyl-2- Prprdanlgul to Example la from 2-n-pr~opyl-4methyl-6-phthalimido-l1I-benzimidazole and tLert .butyl 4' bromomethyl -biphenyl carboxylate.

Yield: 68*- of theory, Melting point: 153-154 0

C

b) Tert.butyl I(2-n-propyl-4-methyl-6-amino-lHbenzimidazol-l-v l) -methyl] -bilphenyl-2-carboxylate Prepared analogously to Example lb from tert.butyl 4'- [(2-n-propyl-4-methyl-6-phthalimido-lH-benzimidazol-lyl) -methyl] -biphenyl-2-carboxylate and methylamine.

Yield: 94%; of theory, R Melting point: 118-119 0

C

36 c) Tert.butyl [[2-n-propyl-4-methyl-6-(2,2-dicyano- 1-methylmercapto-ethenylamino)-1H-benzimidazol-lyll-methyll-biphenyl-2-carboxylate 2.70 ml (6.1 mMol) of Lert.butyl 4'-[[2-n-propyl-4methyl-6-amino-1H-benzimidazol-l-yl]-methyl]-biphenyl-2carboxyla'.a are dissolved in 125 ml of isopropanol, mixed with 2.38 g (14 mMol) of 2,2-dicyano-l,1dimethylmercapto-ethene and refluxed for 4 days. The solvent is evaporated off, the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant first methylene chloride and then methylene chloride/ethanol (50:1 and 25:1). Similar fractions are combined and evaporated down. The residue is triturated with ether and suction filtered.

Yield: 2.15 g (62% of theory), Melting point: 186-188 0

C

d) Tert.butyl 4'-[[2-n-propyl-4-methyl-b-(2,2-dicyano- 1-pyrrolidino-ethenylamino)-1H-benzimidazol-l-yl]methyll-biphenyl-2-carboxylate 425 mg (0.75 mMol) of tert.butyl 4'-[[2-n-propyl-4methyl-6-(2,2-dicyano-l-methylmercapto-ethenyleneamino)- 1 H-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 25 ml of methylene chloride. Then at 0 C under nitrogen a solution of 380 mg (1.1 mMol) of 50% 3chloro-peroxybenzoic acid in 5 ml of methylene chloride is added dropwise. The solution is stirred for 5 hours ambient temperature, then 1.17 g (16.5 mMol) of pyrrolidine are added and the mixture is stirred for a further 12 hours at ambient temperature. Then the solvent is evaporated off, the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant first methylene A chloride and then methylene chloride/ethanol (50:1, 25:1 37 and 19:1) Similar fractions are combined and evaporated down.

Yield: 185 mg (41k of theory), Rf value: 0.40 (silica gel; methylene chloride/ethanol 19:1) e) 41-[P' pyl-4-methyl-6-(2,2-dicyano-lpyrrolidinio-ethenylamino) -lH-benzimidazol-l-yll methyll -bilphenyl-2-carboxylic acid 185 mg (0.31 mMol) of tert.butyl 4'-[[2-n-propyl-4methyl-6- 2-dicyano-l-pyrrolidino-ethenyleneamino) -1Hbenzimidazol-l-yl] -methyl] -biphenyl-2-carboxylate are dissolved in 10 ml of methylene chloride and mixed with ml of trifluoroacetic acid. After 3 hours at ambient temperature, the solution is evaporated down, the residue is taken up in 25 ml of sodium bicarbonate solution and filtered over activated charcoal. The precipitate formed after the addition of 2N acetic acidl at 5 0 C is suction filtered and dried.

Yield: 37 mg (22% of theory), Melting point: 188-190*C

*C

33

H

32

N

6 0 2 (544.66) Mass spectrum: (M+H)l 545 Examnle 11 4 II[2-n-Propyl-4-methyl-6- (2,2-dicyano-l-methylaminoethenylamino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid a) Tert.butyl 4'-[[12-n-propyl-4-methyl-6- 2-dicyano- 1-methylamino-ethenylamino) -lH-benzimidazol-1-yll methyll -biphenyl-2-carboxylate Prepared analogously to Example 10d from tert.butyl 4'- [(2-n-propyl-4-methyl-6- 2-dicyano-1-methylmercaptoethenyleneamino) -I-benzimidazol-1-yl) -methyl] -biphenyl- 38 2-carboxylate, 3-chloro-peroxybenzjic acid and methylamine.

Yield: 44%. of theory, Melting point: 240-242*C b) [[2-n-Propyl-4-methyl-6-(2,2-dicyano-lmethylamino-ethenylamino) -lI-benzimidazol-l-yll methvll -biphenyl-2-carboxylic acid Prepared analogously to Example l0e from tert.butyl [[2-n-propyl-4-methyl-6-(2, 2-dicyano-l-methylaminoethenyleneamino) -1H-benzimidazol-l-yl] -methyl] -biphenyl- 2-carboxylate and trifluoroacetic acid.

Yield: 43% of theory, Melting point: sintering from 178 0

C

C

3 oH 2 8N6O 2 (504.60) Mass spectrum: M+ 504 Examiple 12 [[2-n-Propyl-4-methyl-6- (2,2-dicyano-1-dimethylaminoethenylamino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid a) Tert.butyl [[2-n-propyl-4-methyl-6- (2,2-dicyano- 1-dimethylamino-ethenylamino) -1H-benzimidazol-1yvi -methyl] -bipohenyl-2-carboxylate Prepared analogously to Example l0d from tert.butyl 4'- II[2-n-propyl-4-methyl-6- 2-dicyano-l-methylmercaptoethenyleneanino) -I--benzimidazol-1-yl] -methyl] -biphenyl- 2-carboxylate and dimethylamine.

Yield: 38% of theory, Melting point: sintering from 138'C b) [t2-n-Propyl-4-methyl-6- (2,2-dicyano-ldimethylamino-ethenylamino) -lH-benzimidazol-l-yl] ,44 methyll -bihenyl-2-carboxlic acid Prepared analogously to Example 10e from tert.butyl 4'- 39 [[2-n-propyl-4-methyl-6- (2,2-dicyano-1-dimethylaminoethenyleneamino) -I--benzimidazol-l-yl] -methyl] -biphenyl- 2-carboxylate and trifluoroacetic acid.

Yield: 49*% of theory, Melting point: 178*C

C

31

H

30

N

6 0 2 (518.62) Mass spectrum: M+ 519 Examiple 13 [[2-n-Propyl-4-methyl-6-(2,2-dicyano-1-dimethylaminoethenylamino) -lH-benzimidazol-1-yll -methyl] (lH- -biphenyl a) 4'-1 [2-n-Propyl-4-methyl-6- (2,2-dicyano-lmethylmercapto-ethenylamino) -lH-benzimidazol-l-yl] methl- (lH-tetrazol-5-yl) -bipohenyl Prepared analogously to Example 10c from 41-[[2-npropyl-4-methyl-6-amino-lH--benzimidazol-l-yl] -methyl] -2- -biphenyl and 2, 2-dicyano-l, 1dimethylmercapto-ethene.

*Yield: 79%* of theory, Melting point: 184-185 0

C

b) [[2-n-Propyl-4-methyl-G- (2,2-dicyano-l- 0:00dimethylamino-ethenylamino) -lH-benzimidazol-1-yll methyll (lH-tetrazol-5-yl) -biiphenyl Prepared analogously to Example lod from propyl-4-methyl-6- (2,2-dicyano-1-methylmercapto- 9: ethenyleneamino) -lH-benzimidazol-1-yl] -methyl] (lH- -biphenyl and dimethylamine.

Yield: 29% of theory, Melting point: sintering from 208 0

C

31

H

30

N

10 (542.65) Mass spectrum: 543 40 Example 14 [[2-n-Propyl-4-methyl-G- (l-dimethylamino-2-nitroethenylamino) -1H-benzimidazol-l-yll -methyl] -biphenyl-2carboxylic acid a) Methyl [[2-n-propyl-4-methyl-6- (1methylmercapto- 2-nitro-ethenylamino) Kbenzimidazol-l-yll -methyll -biphenyl-2-carboxylate 826 mg (2.0 mMol) of methyl 41-[(2-n-propyl-4-methyl-6amino-lH--benzimidazol-1-yl) -methyl] -biphenyl-2carboxylate are dissolved in 75 ml of isopropanol, mixed with 0.97 g (6.0 m~vol) of l,l-bis-(methylmercapto)-2nitro-ethene and ref luxed for 6 hours. Then the solvent is evaporated off, the residue is recrystallised from isopropanol/petroleum ether with the addition of activated charcoal.

Yield: 745 mg of theory), Melting point: 173-174 0

C

b) Methyl [[2-n-propyl-4-methyl-6- (1-dimethylamino- 2-nitro-ethenylamino) -1H-benzimidazol-1-yl] methyll -biphenyl-2 -carboxylate **250 mg (0.47 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6- (1-methylmercapto-2-nitro-ethenyleneamino) -liibenzimidazol-l-yl) -methyl] -biphenyl-2-carboxylate are dissolved in 50 ml of isopropanol, mixed with 1.0 ml of dimethylamine and heated to 60 0 C for 3 hours in a pressurised vessel. After cooling to ambient temperature the precipitate formed is filtered off, washed with water and ether and dried.

Yield: 195 mg of theory), Melting point: 127-128 0

C

41 C) [[2-n-Propyl-4-methyl-G- (l-dimethylamino-2nitro-ethenylamino) -lH-benzimidazol-l-yl] -methyl] bipohenyl-2 -carboxylic acid Prepared analogously to Example id from methyl propyl-4-ret-hyl-6- (l-dimethylamino-2-nitroethenyleneamino) -lH-benzimtidazo1-l-yl] -methyl] -biphenyl- 2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 34*1 of theory, Melting point: sintering from 200 0

C

C

29 Ii 31

N

5

O

4 (513.60O) Mass spectrum: M+ 513 Examiple 4? I[2-n-Propyl-4-methyl-G- (1-methylamino-2-nitroethenylamino) lH-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylic acid a) Methyl [[12-n-propyl-4-methyl-G- (1-methylamino-2nitro-ethenylamino) -lH--benzimidazol-1-yl] -methyl] bip~henyl carboxylate Prepared analogously to Example 14b from methyl 0 0.

n-propyl-4-methyl-6- (l-methylmercapto-2-nitroethenyleneamino) -lH-benzimidazol-l-yl] -methyl] -biphenyl- 2-carboxylate and methylamine.

Yield: 68*1 of theoiy, Rf value: 0.15 (silica gel; methylene chloride/ethanol= 9:1) b) 2-n-propyl-4-methyl-6-(l-methylamino-2-nitroethenylamino) -±n-benzimidazol-1-' ii -methyl] biphenyl-2-carboxcylic acid Prepared analogously to Example ld from methyl propyl-4-methyl-6- (1-methylamino-2-nitroethenyleneamino) -11-benzimidazol-l-yl] -methyl] -biphenyl- 42 2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 30% of theory, Melting point: sintering from 188°C

C

28

H

29

N

5 0 4 (499.57) Mass spectrum: M 499 Example 16 4'-[[2-n-Propyl-4-methyl-6-(3-methyl-2-amidosulphonylguanidino)-1H-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid 9 9 9.

a) Methyl 4'-[[2-n-propyl-4-methyl-6-(3-methyl-2amidosulphonyl-guanidino)-lH-benzimidazol-l-yl]methyl -biphenyl-2-carboxylate 413 mg (1.0 mMol) of methyl 4'-[(2-n-propyl-4-methyl-6amino-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate are dissolved in 50 ml of isopropanol, mixed with 1.17 g (4.0 mMol) of diphenyl amidosulphonylcarbamidate and stirred for 2 days at ambient temperature. After the addition of 1.5 ml of methylamine the reaction mixture is heated to 60°C for 3 *hours in a pressurised vessel. Then the solvent is evaporated off, the residue is chromatographed on silica gel (particle size: 0.032-0.063 mm), using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1 and 19:1). Similar fractions are combined and evaporated down, the residue is triturated from ether/petroleum ether and suction filtered.

Yield: 235 mg (43% of theory), Melting point: 115-117°C 43 b) [2-n-propyl-4-methyl-6--(3-methyl-2aiidosuiphonyl-guanidino) -lH-benzimidazol-l-yl] methyll1-biphenvl-2-carboxylic acid Prepared analogously to Example id from methyl propyl-4-methyl-6- (3-mettyl-2-amidosulphonyl-guanidino) lH-benzimidazol-l-yl]-methyl] -biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 31% of theory, Melting point: 208'C

C

27

H

30

N

6 0 4 S (534.64) Mass spectrum: 535 Example 17 4'-[[2-n--Propyl-4-methyl-6-(3,3-dimethyl-2amidosulphonyl-guanidino) -lH-benzimidazol---yl] -methyl] 5.55.biphenyl-2-carboxylic acid a) Methyl 4'-[(2-n-propyl-4-methyl-6-(3,3-dimethyl-2amidosulphonyl-guanidino)-111-benz imidazol-l-yl] methyll1-biphenyl-2-carboxylate Prepared analogously to Example 16a from methyl n-propyl-4-methyl-6-amino-lH-benzimidazol-l-yl) -methyl] some biphenyl-2-carboxylate, diphenyl amidosuiphonylcarbamidate and dimethylamine.

Yield: 56% of theory, Melting point: 188-189*C b) -Propyl-4-methyl-6-(3,3-dimethyl-2amidosuiphonyl-guanidino) -lH-benzimidazol-l-yl] methyll -biphenyl-2-carboxylic acid Prepared analogously to Example id from methyl propyl-4-methyl-6- 3-dimethyl-2-amidosulphonylguanidino) -lH-benzimidazol-l-yl]-methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 26% of theory, 44 0. 00 0* 0 0 00 0 00 *0 00 *0* 00 00 0£ £0 a OS hO 0£ to ~0 a 0 0000 0* .0 0 &I00 0 *000 006000 0 44 00 0 *09 0 Melting point: sintering from 165'C

C

28

H

32

N

6 0 4 S (548. 67) Mass spectrum: 549 Example 18 4' [2-n-Propyl-4-methyl-6-[2-cyano-3- (2-dimethylaminoethyl) -3-methyl-guanidino] -lH-benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 6d from 4'-[[2-n-propyl- 4-methyl-6- (2-phenoxy-3-cyano-isoureido) -lHbenzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl and N-(2-dimethylamino-ethyl) -methylamine in isopropanol.

Yield: 40% of theory, Melting point: 22000 (sintering from 1lS*C) C 32

H

37

N

11 (575.74) Mass spectrum: 576 Example 19 4 [2-n-Propyl-4-methyl-6-[2-cyano-3- (2-hydroxy-ethyl) 3-methyl-guanidino] -lH-benzimidazol-1-yl] -methyl] (lHtetrazol-5-yl) -biphenyl Prepared analogously to Example 6d from 4'-[[2-n-propyl- 4-methyl-6- (2-phenoxy-3-cyano-isoureido) -lH- -biphenyl and N- (2-hydroxy-ethyl) -methylamine in isopropanol.

Yield: 47.5% of theory, Meclting point: 23000 (sintering from 108*C) C 30

H

32

NI

0 0 (548.67) Mass spectrum: (M+H) 4 549 I I S- 45 Example 4'-[[2-n-Propyl-4-methyl-6-[2-cyano-3-(bis-2-methoxyethyl)-guanidino]-lH-benzimidazol-l-yl]methyl]-2-(lH- Prepared analogously to Example 6d from 4'-[[2-n-propyl- 4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1Hand bis-(2-methoxy)-ethylamine in isopropanol.

Yield: 27.5% of theory, Melting point: 104-106°C (sintering from

C

33

H

38

N

10 0 2 (606.74) Mass spectrum: M+ 606 p Example 21 4 4'-[[2-n-Propyl-4-methyl-6-(N-(2-methyl-l-cyaniminoe.8 propyl)-amino)-1H-benzimidazol-l-yl]-methyl]-2-(lHa) (1-Methyl-ethyl)-(methylmercapto)-methyleneiminonitrile A Grignard solution prepared from 28.0 g (0.23 mol) of too. isopropylbromide and 5.5 g (0.23 mol) of magnesium in 10 ml of diethylether is added dropwise within minutes, whilst cooling with ice, to a solution of .22.0 g (0.15 mol) of dimethylcyanoimidodithiocarbonate in 150 ml of tetrahydrofuran. The solution is stirred for 24 hours at ambient temperature and then mixed with 100 ml of 4N hydrochloric acid. After phase separation, the aqueous phase is extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed with saline solution and dried with sodium sulphate.

The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using first petroleum 46 ether and then mixtures of petroleum ether/ethyl acetate (19:1, 9:1 and Similar fractions are combined and evaporated down.

Yield: 4.65 g (22% of theory), Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate 9:1) b) 4 '-L[2-n-Propyl-4-methyl-6-(N-(2-methyl-l-cyaniminopropyl) -amino) -1H-benzimidazol-1-yl]-methyl] (lH- -biphenyl Prepared analogously to Example lc from 4'-[(2-n-propyl- 4-methyl-6-amino-lH-benzimidazol-l-yl) -methyl] (lH- -biphenyl and (1-methyl-ethyl) (methylmercapto) -methylene-imino-nitrile in isopropanol.

Yield: 20.3% of theory, *64*CMelting point: 208-210*C (sintering from 162*C),

C

30

H

31 N (517.65) Mass spectrum: M+ =517 Example 22 ~a 'gsa4 [2-n-Propyl-4-methyl-6-[2-cyano-3-(2-hydroxy-ethyl) 3-methyl-guanidino] -1H-benzimidazol-l-yl] -methyl] biphenyl-2-carboxylic acid 41 Prepared analogously to Example ld from methyl 41-[[2-nsa. S propyl-4-methyl-6-[2-cyano-3- (2-hydroxy-ethyl) -3-methyl- 4: guanidino] -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 9.5% of theory, Melting point: 212*C (sintering from 190'C),

C

30

H

32

N

6 0 3 (524.64) Mass spectrum: 523 47 Example 23 [[2-n-Propyl-4-methyl-6- [2-cyano-3 Ibis (2diethylaminoethyl)] -guanidino] -1H-benzimidazol-1-yl] methyl] -biphenyl-2-carboxylic acid Prepared analogously to Example id from methyl 41-[[2-npropyl-4-methyl-6- [2-cyano-3,3-[Ibis(2-diethylaminoethyl) I-guanidino] -lH-benzimidazol---ylI -methyl] biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 28.89s of theory, Melting point: 168 0 C (sintering from 112 0

C),

C

39 H5 1

N

8

O

2 (663.89) Mass spectrum: 663 Example 24 4' I[2-Ethyl-4-methyl-6- [3-cyano-2- (4-methylpiperazino) -amidino] -1H-benzimidazol-1-yl] -methyl] biphenyl-2-carboxylic acid Prepared analogously to Example id from methyl 41-[[2- V. thy-4-methylr-6-[13-cvano-2- (4-methvl-piperazino) amidinol -1H-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: of theory, Melting point: 218 0 C (sintering from 173 0

C),

C

3 1 H1 3 3

N

7 0 2 (535.66) Mass spectrum: 536 .4.

48 Example [2-Ethyl-4-methyl-6- (2-cyano-3 ,3-dimnethylguanidino) -lH-benzimidazol-1-yl]-methylj-2-(lH-tetrazol- -biphenyl Prepared analogously to Example 6d from 4'-[[2-ethyl-4methyl-6- (2-phenoxy-3-cyano-isoureido) -lH-benzimidazoll-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl and dimethylamine in isopropanol.

Yield: 17.8% of theory, Melting point: sintering from 202*C 0.

C

28

H

28

N

10 (504.61) Mass spectrum: M+ 504 0 Example 26 [2-Ethyl-4-methyl-6-(2-cyano-3, 3-dimethylguanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2- 0 0, carboxylic acid Prepared analogously to Example id from methyl ethyl-4-methyl-6- (2-cyano-3 ,3-dimethyl-guanidino) -lH- 0000 benzimidazol-l-yl] -methyl] -biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 25.0% of theory, 0* 000 Melting point: 208-210'C (sintering from l76*C)

C

28

H

28

N

6 0 2 (480.58) Mass spectrum: M4+ 480 49 Ex ample-27 4' -[[2-Propyl-4-met'hyl-6- (2-dimethylamino-ethyl) methylamino) -2-nitro-ethenylaminol -lH--benzimidazol-lyll -methyl] -biphenyl-2-c-arboxylic acid Prepared analogously to Example id from methyl 41-[[2-npropyl-4-methyl-6-[Il- (2-dimethylamino-ethyl) methylamino) -2-nitro-ethyleneamino] -lH-benzimidazol-1yl]-methyll-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 25.0*1 of theory, Melting point: 218 0 C (sintering from 202 0

C)

C

32

H

3 BN6O 4 (570.70) Mass spectrum: (M-I1) =569 Example 28 II[2-n-Propyl-4-methyl-6- l-dimethylamino-2-nitroethenylamino) -lH-benzimidazol-l-yll -methyl] (21- -biphenyl SPrepared analogously to Example 14b from propyl-4-methyl-6- (l-methylmercapto-2-nitroethyleneamino) -lH-benzimidazol-l-yl) -methyl] (lH- -biphenyl and dimethylamine.

Yield: of theory, Melting point: sintering from 172'C

C

29

H

31

N

9 0 2 (537.64) *Mass spectrum: 538 50 Example 29 ethenylamino) -lH-benzimidazol-1-yl] -methyl] (lH- -biphenyl Prepared analogously to Example 14b from 41-[(2-ethyl-4methyl-6- (l-methylmercapto-2-nitro-ethyleneamino) benzimidazol-1-yl) -methyl] (lH-tetrazol-5-yl) -biphenyl and dimethylamine.

Yield: 23.10- of theory, Melting point: sintering from 196'C

C

28

H

29

N

9 0 2 (523.61) Mass spectrum: 524 ExaLmple 4' I[2-n-Propyl-4-methyl-6- (1-rorpholino-2-nitroethenylamino) -1H-benzimidazol-1-yl] -methyl] (lH- -biphenyl Prepared analogously to Example 14b from propyl-4-methyl-6- (l-methylmercapto-2-nitroethyleneamino) -lI-benzimidazol-l-yl] yl)-biphenyl and morpholine.

Yield: of theory, Melting point: 178 0 C (sinterinig from 118 0

C)

C

31

H

33

N

9 0 3 (579.67) :Mass spectrum: 580 0 0 0 4 4.* 51 Examiple 31 4' -[[2-n-Propyl-4-methyl-6-[li- (2-dimethylaminoethyl) -metl-ylamino) -2-nitro-ethenylamino] -11benzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 14b from 4'-H12-npropyl-4-methyl-6- (l-methylmercapto-2-nitroethyleneamino) -lH-benzimidazol-l-yl] -methyl] -biphenyl and 2-dimethylamino-methylamine.

Yield: 9.20- of theory, Melting point: 182 0 C (sintering from 145 0

C)

C

32 H~s 8

N

10

O

2 (594.73) Mass spectrum: 595 Examiple 32 II[2-Ethyl-4-methyl-6- [(2-dimethylamino-3,4-dioxo-lcyclobuten-l-yl) -amino] -li-benzimidazol-l-yl] -methyl] biphenyl carboxylic acid a) Methyl [[2-ethyl-4-methyl-6- [(2-dimethylamino-3,4dioxo-l-cyclcbDuten-l-yl) -amino] -lH-benzimidazol-l-yl] methyll -bipohenyl-2-carboxylate Prepared analogously to Example ic from methyl 41-[112ethyl-4-methyl-6-amino-lH--benzimidazollyl] -methyl] biphenyl-2-carboxylate, 3, 4-diethoxy-3-cyclobuten-l, 2dione and dimethylamine in isopropanol.

Yield: 74%- of theory, Resin, Rf value: 0.40 (silica gel, methylene chloride/methanol 9:1) b) [[2-Ethyl-4-methyl-6-[I(2dimethylamino-3,4-dioxol-cyclobuten-l-yl) -amino] -lH-benzimidazol-l-yl] -methy-.

1 bip~henyl-2 -carboxylic acid Prepared analogously to Example id from methyl 41-[[2ethyl-4-methyl-6-[I(2-dimethylamino-3,4-dioxo-l- T0L 52 cyclobuten-l-yl) -amino] -lH-benzimidazol-l-yl] -methyl] biphenyl-2-carboxylate and 1N sodium hydroxide solution in ethanol.

Yield: 26.5% of theory, Melting point: 312-315*C C 30

H

28

N

4 0 4 (508.60) Mass spectrum: M+ 508 Example 33 ease* I2-Ethyl-4-methyl-6-[~(2-dimethylamino-3,4-dioxo-l- .9,*cyclobuten-l-yl) -amino] -lH-benzimidazol-l-yl] -methyl] -2- -biphenyl Prepared analogously to Example 14b from 4'-[[2-ethyl-4methyl-6-[ (2-ethoxy-3 ,4-dioxo-l-cyclobuten-l-yl) -amino]lH-benzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) biphenyl and dimethylamine.

Yield: 38.8% of theory, Melting point: 286-290*C

:C

30

H

28

N

8 0 2 (532.61) Mass spectrum: 533 Example 34 4 [2-Ethyl-4-methyl-6-(3 ,3-dimethyl-2-methylsulphonylguanidino) -1H-benzimidazol-l-yl] -methyl] -biphenyl-2rarboxylic acid Prepared analogously to Example id from methyl ethyl-4-methyl-6- 3-dimethyl-2-methylsulphonylguanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 47.9% of theory, Melting point: 204-206'C C 8

H

31

N

5 0 4 S (533.60) 53 Mass spectrum: 532 Example 4 [[2-Ethyl-4-methyl-6- (3 ,3-dimethyl-2-methylsulphonylguanidino) -11-benz imidazol-l-yl] -methyl] (11-tetrazol- -biphenyl Prepared analogously to Example 14b from 4'-[[2-ethyl-4methyl-6--(2-phenoxy-3-methylsulphonyl-isoureido) -11benzimidaizol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl and dimethylamine.

Yield: 58.0% of theory, '~**Melting point: 197-199*C (sintering from 172*C) a...C 28

H

31

N

9 0 2 S (557.69) Mass spectrum: 558 Example 36 99 6* ee: 4' -[[2-Ethyl-4-methyl-6- 3-dimethyl-2-phenylsulphonylto guanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid 0 Prepared analogously to Example ld from methyl 41-[[2- .00.ethyl-4-methyl-6- 3-dimethyl-2-phenylsulphonyl- 000.guanidino) -lH-benzimidazol-l-yl]-methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 30.8% of theory, Melting point: 218-220'C

C

33

H

33

N

5 0 4 S (595.70) Mass spectrum: 596 54 Example 37 4'-[[2-n-Propyl-4-methyl-6-[N-(3-nitro-pyrrol-2-yl)amino]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylic acid a) Methyl 4'-[[2-n-propyl-4-methyl-6-[l-(2-diethoxyethylamino)-2-nitro-ethyleneamino]-1H-benzimidazol-lyll-methyll-biphenyl-2-carboxvlate Prepared analogously to Example 14b from methyl n-propyl-4-methyl-6-(l-methylmercapto-2-nitroethyleneamino)-1H-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate and aminoacetaldehyde-diethylacetal.

Yield: 32% of theory, Oil, Rf value: 0.50 (silica gel; methylene chloride/ethanol 19:1) b) Methyl 4'-[[2-n-propyl-4-methyl-6-[N-(3-nitro-pyrrol- 2-yl)-amino]-lH-benzimidazol-l-yl]-methyl]-biphenyl-2carboxylate 190 mg (0.3 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6- [1-(2-diethoxy)-ethylamino-2-nitro-ethyleneamino]-lHbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate are heated in 50 ml of 0.05N hydrochloric acid over a steam bath for 30 minutes. After cooling, the pH is adjusted Sto pH 8 using sodium carbonate solution and the mixture is extracted 3 times with ethyl acetate. The combined organic phases are washed with saline solution and dried over sodium sulphate. After evaporation the residue obtained is chromatographed on silica gel, using methylene chloride to start with, followed by methylene chloride/ethanol 25:1 and 19:1. Similar fractions are combined and evaporated down.

Yield: 105 mg (65% of theory), Oil, Rf value: 0.50 (silica gel; methylene chloride/ethanol 19:1) 55 c) I[2-n-Propyl-4-methyl-G- (3-nitro-pyrrol-2-yl) amino] -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid.

Prepared analogously to Example id from methyl 41-[[2-npropyl-4-methyl-G- (3-nitro-pyrrol-2-yl) -amino] -11benzimidazol-1-yl] -methyl] -biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.

Yield: 1G.9*% of theory, Melting point: sintering from 1G5 0

C

C

29

H

27

N

5 0 4 (509.60O) Mass spectrum: 508 Example 38 [[2-Ethyl-4-methyl-G- (3,3-dimethyl-2-cyano-l-methylguanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl-2carboxylic acid Prepared analogously to Example ld from methyl 41-[[2ethyl-4-methyl-G- (3,3-dimethyl-2-cyano-1-methylguanidino) -JA-benzimidazol-1-yl] -methyl] -biphenyl-2carboxylate and 2N sodium hydroxide solution in ethanol.

:Yield: 12.9%- of theory, Melting point: 182-184 0 C (sintering from 135 0

C)

C

2 9H 3 ON6O 2 (494.61) 4..4 Mass spectrum: M+ 494 Poo: 4 4 Example 39 [[2-n-Propyl-4-chloro-6- (l-dimethylamino-2-nitroethenylamino) -lH-benzimidazol-l-yll -methyl] (1Htetrazol-5-yl) biphenyl-potassium salt Prepared analogously to Example 14b from 41-[[2-npropyl-4-chloro-6- (1-methylmercapto-2-nitro- -6 RI q~v ethenyleneamino) -11-benzimidazol-1-yll -methyl] (lH- 56 and dimethylamine. The solution thus obtained is then converted into the corresponding potassium salt with potassium hydroxide solution in alcoholic solution.

Yield: 47.2% of theory, Melting point: sintering from 118 0

C

C

28

H

27 C1KN 9 0g (596.16) Mass spectrum: (M+H) 596/598 (Cl) Example 4'-[[2-n-Propyl-4-chloro-6-(2,2-dicyano-l-dimethylaminoethenylamino)-1H-benzimidazol-l-yl]-methyl]-2-(1Hsalt Prepared analogously to Example 10d from propyl-4-chloro-6-(2,2-dicyano-l-methylmercaptoethyleneamino)-iH-benzimidazol-l-yl]-methyl]-2-(1Hand dimethylamine in the presence of 3-chloroperoxybenzoic acid. The compound thus obtained is then converted into the corresponding S' potassium salt in an alcoholic solution using potassium hydroxide solution.

Yield: 52.5% of theory, Y Melting point: 210-212 0 C (sintering from 177 0

C)

C

3 0

H

27 C1KN 1 0 (563.09) Mass spectrum: (M+H) 563/565 (Cl) oo* 0 g 57 In the pharmaceutical examples which follow, any suitable compound of formula I may be used as active substance, but particularly those wherein Rd represents a carboxy or 1H-tetrazolyl group: Example I Tablets containing 50 mg of active substance

S

S@

*o S *5

S

S*S

S

S.

S S. 55 Composition: Active substance Calcium phosphate Lactose Corn starch Polyvinylpyrrolidone Magnesium stearate 50.0 mg 70.0 mg 40.0 mg 35.0 mg 3.5 mg 1.5 mc 200.0 mg 5 Preparation: The active substance, CaHP04, lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50*C in a circulating air dryer and screened again.

After the lubricant has been added, the granules are compressed in a tablet making machine.

Example II Coated tablets containing 50 mg of active substance f *a 0* Composition: Active substance Lysine Lactose 50.0 mg 25.0 mg 60.0 mg 58 Corn starch Gelatin Magnesium stearate 34.0 mg 10.0 mg 1.0 mq 180.0 mg 0* 0O 0 *0 4 4* @0@ Preparation: The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying the granules are mixed with magnesium stearate and compressed to form cores.

The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.

Example III Coated tablets containing 100 mg of active substance o 00 .0 0 Composition: Active substance Lysine Lactose Corn starch Polyvinylpyrrolidone Microcrystalline cellulose Magnesium stearate 100.0 mg 50.0 mg 86.0 mg 50.0 mg 2.8 mg 60.0 mg 1.2 mq 350.0 mg .0 0* 0 f QbD Preparation: The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at After drying, it is screened again and the magnesium stearate is added. This mixture is compressed into 59 cores.

The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.

Example IV Capsules containing 250 mg of active substance 9.

90 9 .9 *9* 94

S

*9 9k *9 904 Composition: Active substance Corn starch Magnesium stearate 250.0 mg 68.5 mg 1.5 mq 320.0 mg 1 .9 9 9 9 S S Preparation: The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size 1 hard gelatin capsules.

Example V Oral suspension containing 50 mg of active substance per ml Composition: Active substance Hydroxyethylcellulose Sorbic acid sorbitol Glycerol Flavouring 50.0 mg 50.0 mg 5.0 mg 600.0 mg 200.0 mg 15.0 mg 60 Water ad 5.0 ml Preparation: Distilled water is heated to 70"C. Hydroxyethylcellulose is dissolved therein with stirring. With the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature, sorbic acid, flavouring and active substance are added. The suspension is degassed with stirring. One dose of 50 mg is contained in 5.0 ml.

0. Example VI 4 4S Suppositories containing 100 mg of active substance *4 Sr *4 Composition: Active substance 100.0 mg Solid fat 1600.0 mq 1700.0 mg 4 Preparation: The hard fat is melted. At 40°C the ground active substance is dispersed homogeneously in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.

Claims (9)

1. Compounds of formula I C C C (wherein: R a denotes a methyl group or a hydrogen, fluorine, chlorine or bromine atom; Rb denotes an RINR e group in which Re denotes an R-CX- group or a 3,4-dioxo-l-cyclobuten-l-yl group substituted in the 2-position by a CI.3-alkoxy group or by an (RINR3) group, or Re denotes a 3-nitro-pyrrol-2-yl group optionally substituted in the 1-position by a methyl group; R denotes a C 1 _3-alkyl or (R 2 NR 3 group; X denotes an N0 2 (NC) 2 C= or R 6 group; R, denotes a hydrogen atom or a C 1 3 -alkyl group; Ir 62 R 2 denotes a C 1 .3-alkyl group optionally substituted in the 2- or 3-position by a hydroxy, C_. 3 -alkoxy, amino, C 1 _3-alkylamino, di 3 -alkyl) amino or Cs.,-cycloalkyl group, and R 3 denotes a hydrogen atom or a C 1 _--alkyl, 2- methoxyethyl, 2-dimethylaminoethyl or 2- diethylaminoethyl group, or R 2 and R 3 together with the intervening nitrogen atom denote a cyclic C4_ 5 -alkyleneimino group optionally substituted by one or two methyl groups, a morpholino group or a piperazino group optionally substituted in the 4-position by a C 1 3 -alkyl group; R 6 denotes an CI_3-alkylsulphonyl, cyano, aminosulphonyl or phenylsulphonyl group; o. R denotes a C2_4-alkyl group; and R d denotes a carboxy, 1 l-triphenylmethyl-tetrazolyl or 2-triphenylmethyl- tetrazolyl group) S* and the 3-isomer mixtures and salts thereof.

2. Compounds of formula I as claimed in claim 1 we P wherein: I I I 63 Ra in the 4-position denotes a methyl group or a chlorine atom; Rb in the 6-position denotes an RiNR e group in which Re denotes an R-CX- group, a 3,4-dioxo-l-cyclobuten-l-yl group substituted in the 2-position by an (RiNR 3 group, or a 3-nitro-pyrrol-2-yl group optionally substituted in the 1-position by a methyl group; R denotes an (R 2 NR3)- or C1. 3 -alkyl group; X denotes an NO2-CH=, (NC) 2 C= or R 6 group; RI denotes a hydrogen atom or a methyl group; S. R 2 denotes a Ci_ 3 -alkyl, 2-hydroxyethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl or C5-7- cycloalkyl group, and R 3 denotes a hydrogen atom or a C 1 3 -alkyl, 2- Smethoxyethyl, 2-dimethylaminoethyl or 2- diethylaminoethyl group, or R 2 and R 3 together with the intervening nitrogen atom denote a pyrrolidino, piperidino, morpholino or 4- methyl-piperazino group; SAc/ L j 64 R 6 denotes a cyano, aminosulphonyl, methylsuiphonyl or phenylsulphonyl group; Rc denotes a C 2 4 -alkyl group; and Rd denotes a carboxy or IH-ietrazol-5-yl group; and the 3-isomer mixtures and salts thereof.

3. A compound as claimed in claim 1 being: 4 [[2-n-propyl-4--methyl-6- (2-cyano-3-methyl- guanidino) -lH-benzimidazol-l-yl] -methyl] -biphenyl- 2-carboxylic acid, f12-n-propyl-4-methyl-6- (2-cyano-3,3-dimethyl- guanidino) -l-benzimidazol-l-yll -methyl] (1K- -biphenyl, [[2-n-propyl-4-methyl-6- (?,2-dicyano-l- dimethylamino-ethenylamino) -lH-benzimidazol-l-yll methyl] -biphenyl-2-carboxylic acid, [[2-n-propyl-4-methyl-6- (1,-dimethylamino-2- nitro-ethenylamino) -lH-benzimidazol-l-yll -methyl] 0 biphenyl-2-carboxylic acid, [[2-n-propyl-4-methyl-6- (3-methyl-2- 65 amidosulphonyl-guanidino)-1H-benzimidazol-l-yl]- methyl]-biphenyl-2-carboxylic acid, 4'-[[2-n-propyl-4-methyl-6-(l-dimethylamino-2- nitro-ethenylamino)-lH-benzimidazol-l-yl]-methyl]- 2-(1H-tetrazol-5-yl)-biphenyl, 4'-[[2-ethyl-4-methyl-6-[(2-dimethylamino-3,4- dioxo-1-cyclobuten-l-yl)-amino]-1H-benzimidazol-l- yl]-methyl]-biphenyl-2-carboxylic acid and 4'-[[2-ethyl-4-methyl-6-(3,3-dimethyl-2- methylsulphonyl-guanidino)-1H-benzimidazol-l-yl]- or a 3-isomer mixture or salt thereof.

4. A compound as claimed in any one of claims 1 to 3 being a physiologically acceptable salt of a compound of formula I as defined in any one of claims 1 to 3 with an inorganic or organic acid or base. *0 *o

5. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof together with one or more physiologically acceptable carriers or excipients. I 66

6. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R denotes a C 1 -3-alkoxy, C_. 3 -alkylthio, pheny.oxy or phenylthio group) reacting a compound of formula II H'N NRc R/ (wherein Ra, Re, Rd and RI are as defined in any one of claims 1 to 3) with a compound of formula III (III) *o* (wherein X is as defined in any one of claims 1 to 3, and 9* the groups which may be identical or different, each "represent a C 1 3 -alkoxy, C 1 3 -alkylthio, phenoxy or phenylthio group); 67 b) (to prepare compounds of formula I wherein R denotes an (R 2 NR 3 group) reacting a compound of formula IV X R R d (wherein Rat Rcr Rd, R, and X are as defined in any one of claims 1 to 3 and Y" denotes a C 1 3 -alkoxy, C 3 -alkylthio, C,- 3 alkylsuiphinyl, C 1 3 -alkylsuiphonyl, phenyloxy, phenylthio, phenylsulphlnyl or phenylsulphonyl group) with an amine of formula V 6 0 00 0 a a 0:. 00.. R 2 R 3 NH wherein R 2 and R 3 are as def ined in any one of claims 1 to 3; c) (to prepare compounds of formula I wherein R denotes a Cl. 5 '-alkyl group) iaa reacting a compound of formula II 68 R N Rd (wherein Ra, Rc, Rd and Ri are as defined in any one of claims 1 to 3) with a compound of formula VI X R' C (VI) (wherein X is as defined in any one of claims 1 to 3, R' denotes a Ci-_-alkyl group and denotes a C 3 -alkylthio group; a ee d) (to prepare compounds of formula I wherein Ra denotes a carboxy group, converting a compound of formula VII R N R N (VII) ""ex 69 (wherein Ra to R c are as defined in any one of claims 1 to 3 and Rd' denotes a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound by hydrolysis, thermolysis or hydrogenolysis; e) (to prepare compounds of formula I wherein Rd denotes a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula VIII R Rb -Rc y N Rd o0 q. (wherein R a to R c are as defined in any one of claims 1 to 3 and Rd" denotes a 1H-tetrazolyl or 2H-tetrazolyl group protected in the 1- or 2-position by a protecting group); f) (to prepare compounds of formula I wherein R b denotes R; an RNR e group in which R e denotes a 3-nitro-pyrrol-2-yl group optionally substituted in the 1-position by a I 70 CI- 3 -alkyl group) cyclising a compound of formula IX OS @6 6* 0*O 6* 6 @6ee 6* 6 6* (wherein R 1 R 3 Rc and Rd are as defined in any one of claims 1 to 3, and the groups which may be identical or different, each represent a C 1 3 -alkoxy group); g) (to prepare compounds of formula I wherein Rb denotes an RINRe- group wherein Re denotes a 3,4-dioxo-1- cyclobuten-l-yl group substituted in the 2-position by a C 1 3 -alkoxy or RjNR 3 group) reacting a compounC~ of formula II R H N D N R R -IN- I- 6 71 (wherein Ra, R c Rd and R, are as defined in any one of claims 1 to 3, with a 3,4-dioxo-1,2-di(CI. 3 -alkoxy)-1-cyclobutene and, if desired (to prepare a corresponding 2-amino compound), subsequently reacting a 2-alkoxy compound thus obtained with an amine of formula V R 2 R 3 NH wherein R 2 and R 3 are as defined in any one of claims 1 to 3; h) (to prepare compounds of formula I wherein R d denotes a 1H-tetrazolyl group) reacting a compound of formula X R -N I (x) S S S *5 S S...r S S 5555 S S (wherein Ra to R c are as defined in any one of claims 1 to 3) with hydrazoic acid or a salt thereof; -72 C i) performing a process as defined in any one of steps to above as a corresponding protected compound and subsequently removing the protecting group used; j) resolving a compound of formula I by isomer separation from a 3-isomer mixture into the individual isomers; and k) converting a compound of formula I into a salt thereof.

7. A method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia, diabetic nephropathy, glaucoma, gastrointestinal disease, bladder disease, pulmonary disease, vascular wall thickening, arteriosclerosis, diabetic angiopathy, central nervous e system disorders and cognitive fuction disorders, said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 3 or a physiologically acceptable salt thereof. 00* i"

8. A compound of formula I as claimed in claim 1 or a pharmaceutical composition thereof substantially as 0*0 herein disclosed in any one of the Examples. DATED this 16th day of April, 1996 DR KARL THOMAE GmbH RAA By their Patent Attorneys: CALLINAN LAWRIE I A.- 7/3 Abstract Benz imidazoles The invention relates to benzimidazoles of formula I R Rb (I) 9 9* .9 S.. v9 .5

9.. *955 (wherein Rato Rd are as defined in claim 1) and the 3-isomer mixtures and salts thereof. Such compounds have valuable properties, particularly angiotensin- antagonistic activity. 9 9 S 9~99 SS 0% fee