WO2003066626A1

WO2003066626A1 - Deuterated biphenyl-substituted benzimidazoles and medicament containing said compounds for the treatment of hypertonia

Info

Publication number: WO2003066626A1
Application number: PCT/DE2003/000365
Authority: WO
Inventors: Rudolf-Giesbert Alken
Original assignee: Turicum Drug Development Ag
Priority date: 2002-02-07
Filing date: 2003-02-06
Publication date: 2003-08-14
Also published as: DE10205335A1; AU2003208288A1

Abstract

The invention relates to deuterated biphenyl-substituted benzimidazoles and to medicaments containing said compounds. The invention further relates to the use of said deuterated biphenyl-substituted benzimidazoles for vasodilatation, especially for the treatment of hypertonia, and to the production of corresponding medicaments. The invention also relates to pharmaceutical compounds containing deuterated biphenyl-substituted benzimidazoles and the physiologically acceptable salts thereof, in addition to pharmaceutically acceptable adjuvants and/or additives for vasodilatation, especially for the treatment of hypertonia.

Description

DEUTERED BIPHENYL-SUBSTITUTED BENZIMIDAZOLES AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS FOR THE TREATMENT OF HYPERTONIA

The invention relates to deuterated biphenyl-substituted benzimidazoles and medicaments containing these compounds.

A well-known representative of the biphenyl-substituted benzimidazoles is candesartan cilexetil (EP 459136 and

US 5705517). This compound is used for vasodilation, especially for the treatment of hypertension.

The object of the present invention is to provide biphenyl-substituted benzimidazoles which have improved pharmacokinetic and / or pharmacodynamic properties compared to the already known compounds.

Surprisingly, it has now been found that the deuterated biphenyl-substituted benzimidazoles according to the invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the undereverted compounds.

According to the invention, the object is therefore achieved by providing deuterated biphenyl-substituted benzimidazoles of the general formula I:

formula 1

in which R ^{1 is} H, D or partially or completely deuterated alkyl or substituted alkyl having 1-5 carbon atoms,

R ² independently represents H or D, R ^{3 is} partially or completely deuterated alkoxy with 1-5 carbon atoms, R ^{4 represents} H or D and

R ^{5 is} independently H or D and at least one of the radicals R ² to R ^{5 is} deuterium or contains deuterium.

Deuterated biphenyl-substituted benzimidazoles of the general formula I in which R ^{1 is} ethyl or partially or completely deuterated ethyl are preferred,

R ^{2 is} independently H or D, R ^{3 is} ethoxy or partially or completely deuterated ethoxy,

RH or D means and R ^{5 is} independently H or D and at least one of the radicals R ² to R ^{5 is} deuterium or contains deuterium.

Also preferred are deuterated biphenyl-substituted benzimidazoles of the general formula I, in which R ^{1 is} ethyl or partially or completely deuterated ethyl, R ² independently of one another represents H or D, R ^{3 is} H or D,

R ^{4 is} H or D and

Deuterated biphenyl-substituted benzimidazoles of the general formula I in which R ^{1 is} 1- (cyclohexyloxycarbonyloxy) ethyl or partially or completely deuterated 1- (cyclohexyloxycarbonyloxy) ethyl are particularly preferred,

R ² independently of one another represents H or D,

R ³ denotes H or D,

R ^{4 is} H or D and

The following deuterated, biphenyl-substituted benzimidazoles are particularly advantageous according to the invention:

Ethyl 2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylate, 2-ethoxy-l- {[2, 3, 5, β-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester,

2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester,

2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-dl-carboxylic acid,

2-ethoxy-l- {[2,3,5,6-tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-dl-carboxylic acid,

2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazol-7-dl-carboxylic acid,

2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[2,3,5, β-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[3 ", 4 ', 5", 6' -tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid, 2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[2,3,5,6-tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[2 '- (N-triphenylmethyltetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[2, 3, 5, 6-tetradeutero-2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid,

[1- (cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 '- (1D-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester,

[1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2,3,5,6-tetradeutero-2 '^' - (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole- 7-carbonsäureester, [1- (cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l-

{[3 ', 4', 5 ', 6' -tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-

4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester,

[1- (cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 ^r - (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester,

[1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2, 3, 5, 6- tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7 -carboxylic acid esters and

[1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[3 ', 4', 5 ', 6' tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl } benzimidazole-7-carbonsäureester.

Preference is given to using the interpreted biphenyl-substituted benzimidazoles and their physiologically tolerable salts for vasodilation, in particular for the treatment of hypertension.

Also preferred is the use of the deuterated biphenyl-substituted benzimidazoles according to the invention and their physiologically tolerable salts for the manufacture of medicaments for vasodilation, in particular for the treatment of hypertension.

Pharmaceutical compositions are particularly preferred which contain the deuterated biphenyl-substituted benzimidazoles according to the invention and their physiologically tolerable salts for vasodilation, in particular for Treatment of hypertension, in addition to pharmaceutically acceptable auxiliaries and / or additives.

Analogously to a production process in US 5705517, a suitably substituted benzimidazole derivative is alkylated with a (bromomethyl) biphenyl building block or a deuterated (bromomethyl) biphenyl building block.

To prepare the biphenyl derivatives according to the invention, the method of A.I. Meyers and E.D. Mihelich [J. At the. Chem. Soc, 97, 7383 (1975)], which is also described in EP 733366, adapted to the preparation of the deuterated compounds using deuterated starting materials with a degree of deuteration above 98%.

Starting from deuterated methoxybenzoic acid, the deuterated acid chloride is generated and this is reacted with 2-amino-2-methyl-l-propanol to give the deuterated 4,4-dimethyl-2- (2-methoxyphenyl) oxazoline.

This oxazoline is further processed with deuterated 4-methylphenyl-Grignard reagent, obtained from deuterated 4-bromotoluene, to give deuterated 2- (4 '-methylbiphenyl-2-yl) -4, 4-dimethyl-oxazoline. The deuterated 4'-methyl-2-biphenylcarboxylic acid is obtained from this by heating in deuterium chloride solution.

The deuterated 4 '-methyl-2-biphenylcarboxylic acid is over the acid amide, which with ammonium hydroxide solution from the

Acid chloride is obtained, converted to deuterated 4'-methyl-2-biphenylnitrile. Analogously to EP 291969, the deuterated 4'-methyl-2-biphenylnitrile with trimethyltin azide is now used to obtain the deuterated N-trimethylstannyl-5- (4'-methylbiphenyl-2-yl) tetrazole.

In a modification of the known regulation, this is converted into the deuterated 5- (4 '-methylbiphenyl-2-yl) tetrazole using deuterium chloride.

The tetrazole group is subsequently protected by reaction with trityl chloride and the deuterated N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole obtained is converted into the deuterated (bromomethyl) biphenyl derivative with N-bromosuccinimide.

The benzimidazole derivatives suitable as starting material can be prepared analogously to known production processes, such as by P.N. Preston [The Chemistry of Heterocyclic Compounds, Vol. 40, 1-286 (1981)] or N.J. Leonhard, D.Y. Curtin and K.M. Beck [J. At the. Che. Soc. 69, 2459 (1947)].

The two regioisomers formed in this alkylation are separated from one another by known separation and purification processes.

In this way, according to the invention, in the alkylation of 2-ethoxy-7-carbethoxy-1H-benzimidazole, the deuterated 2-ethoxy-1- [[2- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] benzimidazole -7-carboxylic acid ethyl ester prepared, which is hydrolyzed with deuterium chloride solution to give the deuterated carboxylic acid.

The tetrazole residue of the deuterated carboxylic acid according to the invention thus obtained is protected by a trityl group and deuterated with (1-iodoethyl) cyclohexyl carbonate in the inventive, deuterated

[1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 '- (1D-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} - benzimidazole-7-carboxylic acid ester.

The deuterated starting materials used in the syntheses have a degree of deuteration above 98%.

For the preparation of physiologically compatible salts of the deuterated biphenyl-substituted benzimidazoles according to the invention, customary physiologically compatible inorganic and organic acids can be, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid,

Tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that can be used are, for example, in Progress in Pharmaceutical Research, Vol. 10, pp. 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol. 66, pp. 1-5 (1977) described.

The acid addition salts are generally in a manner known per se by mixing the free base or its solutions with the corresponding acid or their solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, or n-propanol Isopropanol or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, physiologically compatible aqueous solutions of acid addition salts of the compounds used according to the invention can be prepared in an aqueous acid solution.

The acid addition salts of the compounds according to the invention can be carried out in a manner known per se, e.g. with alkalis or ion exchangers, are converted into the free base. Additional salts can be obtained from the free base by reaction with inorganic or organic acids, in particular those which are suitable for forming therapeutically usable salts. These or other salts of the new compound, e.g. the picrate can also be used to purify the free base by converting the free base into a salt, separating it and releasing the base from the salt.

The present invention also relates to pharmaceuticals for oral, sublingual, buccal, rectal, subcutaneous, intravenous, intramuscular, topical, intratracheal, intranasal, transdermal or rectal application, which, in addition to conventional carriers and diluents, contain a compound of the general formula I o which contain their acid addition salt as an active ingredient.

The medicaments of the invention are mixed with the usual solid or liquid carriers or diluents. teln and the commonly used pharmaceutical technical auxiliaries according to the desired type of application with a suitable dosage in a known manner. The preferred preparations are in a dosage form which is suitable for oral administration. Such dosage forms are, for example, tablets, film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.

Of course, parenteral preparations such as injection solutions are also suitable. Suppositories may also be mentioned as preparations. Corresponding tablets can be prepared, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or agents Achieving a depot effect such as carboxyl polymethylene, carboxyl ethyl cellulose, cellulose acetate phthalate or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used. Solutions or suspensions with the active ingredient used according to the invention can additionally contain taste-improving agents such as saccharin, cyclaat or sugar and, for example, flavoring agents such as vanillin or orange extract. They can also contain suspending agents such as sodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.

Suitable suppositories can be produced, for example, by mixing them with suitable carriers such as neutral fats or polyethylene glycol or their derivatives.

Topical application can take place, for example, in the form of ointments, creams, gels, solutions or by plasters.

The preparation of the pharmaceutical preparations according to the invention is known per se and is described in the manuals known to the person skilled in the art, for example Hager's Handbuch (5.) 2, pp. 622-1045; List et al., Pharmaceutical Forms, Stuttgart: Wiss. Publishing company , 1985; Sucker et al. , Pharmaceutical Technology, Stuttgart: Thieme 1991; Ullann's Encyclopedia (5th) A 19, pp. 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995.

The compounds according to the invention, specifically substituted with deuterium, have a comparison with those in the prior art. Known compounds, which contain deuterium only in the natural distribution, have a number of advantages. On the one hand, deuteration slows down metabolism in the organism. This makes it possible to create preparations with a longer effect and thus to reduce the dose.

In addition, the pharmacodynamics have also changed, since the deuterated compounds according to the invention form other hydration shells, so that their distribution in the organism differs from that of the undeuterated compounds.

This makes it possible to develop new types of preparation.

The following examples illustrate the invention:

example 1

Preparation of 2-methoxy-3, 4, 5, 6-d4-benzoyl chloride 15.7 g of 2-methoxy-d5-benzoic acid are reacted with thionyl chloride in a manner known per se. To this end, the deuterated 2-methoxybenzoic acid is added dropwise with 25 ml of thionyl chloride, the reaction mixture is stirred for 20 hours at room temperature and then the excess thionyl chloride is distilled off. The reaction product is isolated by vacuum distillation. 14.85 g of 2-methoxy-3, 4, 5, 6-d4-benzoyl chloride are obtained as a colorless liquid. Bp .: 127-128 ° C (8 torr) yield: 85% calculated:

C: 55.03%; H: 6.35% found:

C: 55.00%; H: 6.37%

Example 2

Preparation of 4, 4-dimethyl-2- (2-methoxy-d4-phenyl) oxazoline The preparation is carried out in a manner known per se.

17 g of 2-amino-2-methyl-l-propanol are dissolved in dichloroethane and the ice-cooled solution is treated dropwise with a solution of 14.75 g of 2-methoxy-3, 5, 6-d4-benzoyl chloride in dichloromethane. After the addition has ended, the ice cooling is removed and the reaction mixture is stirred at room temperature for a further 3 hours. The solvent is removed and the resulting solid is mixed with water and filtered off. After drying, the isolated solid is again mixed with thionyl chloride, and 13.9 g of 4,4-dimethyl-2- (2-methoxy-d4-phenyl) oxazoline are obtained after working up. Yield: 79% Melting point: 71-74 ° C calculated: C: 68.87%; H: 9.15%; N: 6.69% found:

C: 68.91%; H: 9.13%; N: 6.67%

^ Η NMR (200 MHz, CDC1 ₃ ): δ 3.68 (3H, s); 3.92 (2H, s); 1.26 (6H, s). Example 3

Preparation of 2- (dll-4 '-methylbiphenyl-2-yl) -4, 4-dimethyloxazoline

The d7-4-methylphenyl Grignard reagent is prepared from 10 g of d7-4-bromotoluene in a manner known per se by reaction with magnesium in anhydrous tetrahydrofuran. This is added to 5.3 g of 4,4-dimethyl-2- (2-methoxy-d4-phenyl) oxazoline in anhydrous tetrahydrofuran and the reaction mixture is stirred at room temperature for 2 hours. After working up, 5.7 g of 2- (dll-4 '-methylbiphenyl-2-yl) -4, -dimethyloxazoline are obtained as a colorless liquid. Yield: 81% calculated: C: 78.21%; H: 10.93%; N: 5.07% found:

C: 78.23%; H: 10.90%; N: 5.06% ¹ H NMR (200 MHz, CDC1 ₃ ): δ 3.93 (2H, s); 1.25 (3H, s).

Example 4:

Preparation of dl2-4 'methyl-2-biphenylcarboxylic acid

In a modification of the literature regulation, 6 g

2- (dll-4 '-methylbiphenyl-2-yl) -4, 4-dimethyloxazoline in deuterium chloride solution heated to reflux for 15 hours. The reaction product is oily on the surface and solidifies after the reaction solution has cooled. After working up, 3.7 g of dl2-4'-methyl-2-biphenylcarboxylic acid are obtained as a colorless solid.

Yield: 76% melting point: 139-141 ° C calculated:

C: 74.96%; H: 10.77% found:

C: 74.98%; H: 10.74%

¹³ C NMR (75 MHz, CDC1 ₃ ): δ 173.5; 142.9; 138; 136.5; 133.2

(t); 130.3 (t); 129.8 (t); 129.2; 127.6 (t); 127 (t);

127.6 (t); 19.4 (sept).

Example 5

Preparation of 4'-trideuteromethyl-d8-biphenyl-2-carboxamide

In a manner known per se, 8 g of dl2-4 'methyl-2-biphenylcarboxylic acid are mixed with 10 equivalents of thionyl chloride, heated to reflux for 2 hours and then the thionyl chloride is removed from the reaction mixture. The acid chloride formed is added to an ammonium hydroxide solution and the solid formed is worked up. 5.9 g of 4'-trideuteromethyl-d8-biphenyl-2-carboxamide are obtained in the form of a white solid. Yield: 74% Melting point: 125-128 ° C calculated: C: 75.63%; H: 10.87%; N: 6.30% found: C: 75.64%; H: 10.86%; N: 6.27%

Example 6

Preparation of dll-4 'methyl-2-biphenylnitrile 6.5 g of 4'-trideuteromethyl-d8-biphenyl-2-carboxamide are reacted in a manner known per se with 10 equivalents of thionyl chloride. After the thionylchloride has been removed, hexane is added to the batch, and 4.7 g of dll-4'-methyl-2-biphenylnitrile are obtained as a white solid.

Yield: 78% melting point: 43-46 ° C. calculated: C: 82.30%; H: 10.84%; N: 6.86% found:

C: 82.35%; H: 10.82%; N: 6.83%

¹³ C NMR (75 MHz, CDC1 ₃ ): δ: 144.7; 138.1; 137.2; 133 (t); 132.1 (t); 129.9 (t); 128.5 (t); 127.8 (t), 127.1 (t), 115.9; 19.5 (sept).

Example 7

Preparation of N-trimethylstannyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole

In a manner known per se, 20.4 g of dll-4'-methyl-2-bipenyl nitrile are reacted with 24.6 g of trimethyltin azide in toluene at room temperature. The reaction mixture is then heated to reflux for 24 hours and then cooled to room temperature. 32 g of product are isolated as a white solid. Yield: 75%

Melting point: 263 ° C (decomposition) calculated: C: 50.73%; H: 8.27%; N: 13.15% found: C: 50.71%; H: 8.24%; N: 13.18% ^X H-NMR (200 MHz, d6-DMSO): δ 0.39 (9H)

Example 8 Preparation of 5- (dll-4 '-methylbiphenyl-2-yl) -1D-tetrazole

Modifying the literature specification, the product is prepared by dissolving 33 g of N-trimethylstannyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole in a mixture of toluene and tetrahydrofuran and so long dry deuterium chloride at room temperature through the solution is blown until a clear solution is obtained. The product crystallizes out of the solution and, after recrystallization, 16.8 g of 5- (dll-4 '-methylbiphenyl-2-yl) - ID-tetrazole are obtained. Yield: 82% Melting point: 148-151 ° C calculated: C: 68.14%; H: 10.67%; N: 21.19% found:

C: 68, 18%; H: 10.65%; N: 21, 17%

Example 9 Preparation of N-triphenylmethyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole

In a manner known per se, 19.8 g of 5- (dll- '- methylbiphenyl-2-yl) -ID-tetrazole in dichloromethane are reacted with 25 g of trityl chloride with the addition of triethyl in at room temperature. The reaction mixture is heated to reflux for 2 hours and then cooled to room temperature. It is washed with water the organic phase is dried and the solvent is removed in vacuo. After recrystallization, 28.8 g of product are obtained. Yield: 75% melting point: 162-166 ° C

^X H-NMR (200 MHz, CDC1 ₃ ): δ 6.8-8.1 (15 H, m) calculated:

C: 80.75%; H: 8.17%; N: 11.08% found: C: 80.78%; H: 8.15%; N: 11.07%

Example 10

Preparation of N-triphenylmethyl-5- [dl0-4 '- (bromomethyl) biphenyl-2-yl] tetrazole

The reaction of 31.8 g of N-triphenylmethyl-5- (dll-4 '- methylbiphenyl-2-yl) tetrazole with N-bromosuccinimide is carried out in a manner known per se by dissolving the starting material in carbon tetrachloride and at room temperature with 11. 5 g of N-bromosuccinimide and 1.1 g of dibenzoyl peroxide are added. The reaction mixture is heated to boiling for 3 hours, then cooled to 40 ° C. and filtered. The filtrate is evaporated to dryness, mixed with isopropyl ether and 27 g of product are obtained. Yield: 74%

Melting point: 134-137 ° C calculated:

C: 69.97%; H: 6.73%; N: 9.60% found: C: 69.93%; H: 6.75%; N: 9.58%

¹ HN R (200 MHz, CDC1 ₃ ): δ 6.4-7.9 (15 H, m) Example 11

Preparation of 2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester

The preparation is carried out in a manner known per se by reacting 0.93 g of 2-ethoxy-7-carbethoxy-1H-benzimidazole in DMF with ice cooling with sodium hydride and 2.5 g of l-triphenylmethyl-5- [dlO- 4 '- (Bromomethyl) biphenyl-2-yl] 1H tetrazole can be added. The reaction mixture is stirred for 5 hours at room temperature and then mixed with ice water and ethyl acetate. The organic phase is washed with water and then the solvent is removed. The residue is dissolved in methanol and, in a variation of the literature specification, deuterium chloride solution is added and the mixture is stirred at 60 ° C. for 2 hours. Water and ethyl acetate are added to the reaction mixture and it is made basic by adding sodium hydroxide solution. The mixture is shaken, the aqueous phase is acidified by adding deuterium chloride solution and then extracted with chloroform. The reaction product is isolated by column chromatography and 0.45 g of 2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester is obtained. Yield: 24% Melting point: 158-160 ° C calculated: C: 65.25%; H: 7.16%; N: 17.56% found: C: 65.27%; H: 7.13%; N: 17.58% ^X H NMR (200 MHz, CDC1 ₃ ): δ 1.07 (3H, t); 1.40 (3H, t); 4.05 (2H, q), 4.3 (2H, q); 7.25-7.33 (1H, m); 7.43 (1H, dd); 8.02-8.09 (1H, m).

Example 12

Preparation of 2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazol-7-dl-carboxylic acid The carboxylic acid is prepared by acidic hydrolysis of the carboxylic acid ester by dissolving 0.5 g of 2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester in ethanol and adding deuterium chloride solution , The reaction mixture is stirred for

Heated to 60 ° C for 4 hours and then concentrated. Ethyl acetate is added to the residue and a sodium hydrogen carbonate solution is added. It is washed with D ₂ 0 and the organic phase is dried. After recrystallization, 0.23 g of 2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-dl-carboxylic acid is obtained. Yield: 47% Melting point: 183-186 ° C calculated:

C: 63.70%; H: 7.12%; N: 18.57% found:

C: 63.73%; H: 7.10%; N: 18.60%

^X H NMR (200 MHz, CDC1 ₃ ): δ 1.42 (3H, t); 4.61 (2H, q); 7.21 (1H, t); 7.52-7.63 (2H, m) Example 13

Preparation of 2-ethoxy-l- {[2 '- (N-triphenylmethyltetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid

The reaction of 2.5 g of 2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) d8-biphenyl-4-yl] dideuteromethyl} benzimidazol-7-dl-carboxylic acid with trityl chloride takes place in itself known manner in dichloromethane and with the addition of triethyamin. After working up, 2.1 g of 2-ethoxy-l- {[2 '- (N-triphenylmethyl-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid are obtained as colorless crystals , Yield: 54% Melting point: 167-170 ° C calculated:

C: 74.54%; H: 6.40%; N: 12.13% found: C: 74.57%; H: 6.43%; N: 12.10% ^X H NMR (200 MHz, d6-DMSO): δ 1.37 (3H, t); 4.58 (2H, q); 6.8-7.9 (18H, m)

Example 14 Preparation of [1- (cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester Reaction of 0.55 g of 2-ethoxy-l- {[2 '- (N-triphenylmethyl-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid with

(1-Iodethyl) cyclohexyl carbonate is carried out in a manner known per se in dimethylformamide in the presence of potassium carbonate. After stirring for one hour at room temperature, the reaction mixture is mixed with water and ethyl acetate and the organic phase is washed with water and dried. In a modification of the procedure known from the literature, deuterium chloride solution is added and the reaction mixture is stirred for a further hour at room temperature. After working up, 0.22 g of [1- (cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benz is obtained - imidazole-7-carboxylic acid ester as a colorless powder. Yield: 44% Melting point: 102-106 ° C calculated: C: 63.75%; H: 7.29%; N: 15.44% found:

C: 63.78%; H: 7.25%; N: 15.46%

^ H NMR (200 MHz, CDC1 ₃ ): δ 1.10-1.79 (16 H, m); 4.33-4.51 (3H, m); 7.1 (1H, t); 7.35-7.39 (1H, m); 7.99-8.07 (1H, m)

Claims

claims

1. Deuterated biphenyl-substituted benzimidazoles of the general formula 1

Formula I.

in which R ^{1 is} H, D or alkyl or partially or completely deuterated alkyl or substituted alkyl having 1-5 carbon atoms,

R ² independently represents H or D, R ^{3 is} alkoxy or partially or completely deuterated alkoxy or perdeuteroalkoxy with 1-5 carbon atoms,

R ^{4 is} H or D and

2. Deuterated biphenyl-substituted benzimidazoles of the general formula I according to claim 1, wherein R ^{1 is} ethyl or partially or completely deuterated ethyl,

R ² independently represents H or D, R ^{3 is} ethoxy or partially or fully deuterated ethoxy,

R ^{4 is} H or D and

3. Deuterated biphenyl-substituted benzimidazoles of the general formula I according to claim 1, in which R ^{1 is} ethyl or partially or fully deuterated ethyl, R ^{2 is} independently H or D, R ^{3 is} H or D, R ^{4 is} H or D and

4. Deuterated biphenyl-substituted benzimidazoles of the general formula I according to claim 1, in which R ^{1 is} (cyclohexyloxycarbonyloxy) ethyl or partially or completely deuterated cyclohexyloxycarbonyloxyethyl,

R ² independently of one another represents H or D,

R ^{3 is} H or D,

R ^{4 is} H or D and R ^{5 is} independently H or D and at least one of the radicals R ² to R ^{5 is} deuterium or

Deuterium contains.

5. 2-Ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester.

6. 2-Ethoxy-l- {[2,3,5,6-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ethyl ester.

7. 2-Ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl jbenz-imidazole-7-carboxylic acid ethyl ester ,

8. 2-Ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-dl-carboxylic acid.

9. 2-Ethoxy-l- {[2, 3, 5, 6-tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazol-7-dl-carboxylic acid.

10. 2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1D-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazol-7- dl-carboxylic acid.

11. 2-Ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

12. 2-Ethoxy-l - {[2,3,5,6-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

13. 2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazol-7- carboxylic acid.

14. 2-Ethoxy-l- {[2 '- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

15. 2-Ethoxy-l- {[2, 3, 5, 6-tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

16. 2-ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1D-tetrazol ~ 5-yl) biphenyl-4-yl] ideuteromethyl} benzimidazol-7- carboxylic acid.

17. 2-Ethoxy-l- {[2 '- (N-triphenylmethyltetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

18. 2-Ethoxy-l- {[2,3,5, 6-tetradeutero-2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

19. 2-Ethoxy-l- {[3 ', 4', 5 ', 6' -tetradeutero-2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid.

20. [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2'- (ID-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester.

21. [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l-

{[2,3,5, 6-tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester.

22. [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[3 ', 4', 5 ', 6' tetradeutero-2 '- (ID-tetrazol-5-yl) biphenyl-4-yl ] dideuteromethyl} benzimidazole-7-carboxylic acid ester.

23. [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2 '- (1H-tetrazol-5-yl) -d8-biphenyl-4-yl] dideuteromethyl} benzimidazole-7-carboxylic acid ester.

24. [1- (Cyclohexyloxycarbonyloxy) ethyl] -2-ethoxy-l- {[2,3,5,6-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} benzimidazole -7-carbonsäureester.

25. [1- (Cyclohexyloxycarbonyloxy) thyl] -2-ethoxy-l- {[3 ', 4', 5 ', 6' tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl ] dideuteromethyl} benzimidazole-7-carboxylic acid ester. ^■

26. Use of the deuterated biphenyl-substituted benzimidazoles according to one of claims 1 to 25 and their physiologically compatible salts for vasodilation, in particular for the treatment of hypertension.

27. Use of the deuterated biphenyl-substituted benzimidazoles according to one of Claims 1 to 25 and their physiologically tolerable salts for the production of medicaments for vasodilation, in particular special for the treatment of hypertension.

28. Pharmaceutical composition containing deuterated biphenyl-substituted benzimidazoles according to one of claims 1 to 25 and their physiologically tolerable salts, in addition to pharmaceutically acceptable auxiliaries and / or additives, for vasodilation, in particular for the treatment of hypertension.