WO2003066627A1

WO2003066627A1 - Deuterated spirocyclopentanimidazolinones and the use thereof in the treatment of cardiovascular diseases

Info

Publication number: WO2003066627A1
Application number: PCT/DE2003/000366
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: DE10205432A1; AU2003208289A1

Abstract

The invention relates to deuterated biphenyl-substituted spirocyclopentanimidazolinones of formula (I) and to the use thereof in the treatment of cardiovascular diseases such as high blood pressure and heart failure, disturbances of the central nervous system, glaucoma, diabetic nephropathy and retinopathy.

Description

DEUTERED SPIROCYCLOPENTANIMIDAZOLINONE AND THEIR USE FOR TREATMENT

CARDIOVASCULAR DISEASES

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

10 A well-known representative of the biphenyl-substituted spirocyclopentanimidazolinones is irbesartan (US 5270317, EP 454511), which is used for the treatment of cardiovascular diseases such as high blood pressure and heart failure, the treatment of disorders of the central nervous system and for the treatment

15 of glaucoma as well as diabetic nephropathy and retinopathy.

The object of the present invention is to provide biphenyl-substituted spirocyclopentanimidazolinones 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 spirocyclopentanimidazolinones according to the invention have significantly better pharmacokinetic and / or pharmacodynamic properties than the undeuterated compounds.

30 According to the invention, the object is therefore achieved by

Provision of deuterated biphenyl-substituted spirocyclopentanimidazolinones of the general formula I,

Formula I.

wherein

R ^{1 is} independently D or H,

R ² Ci-e-alkyl or partially or completely deuterated

C ₆ alkyl or substituted C ₆ alkyl means

R ³ independently represents D or H,

R ^{4 is} independently D or H and

R ^{5 is} D or H and at least one of the radicals R ¹ to R ^{5 is} deuterium or contains deuterium.

Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I, where R ^{1 is} D, R ^{2 is} C ₆ alkyl or partially or fully deuterated C ₆ alkyl or substituted C 6 alkyl, R ^{3 is} independently D or H R ^{4 is} independently D or H and R ^{5 is} D or H. Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I are particularly preferred, where

R ^{1 is} independently D or H, R ^{2 is} fully deuterated C ₆ alkyl,

R ^{3 is} independently D or H, R ^{4 is} independently D or H and R ^{5 is} D or H.

Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I are particularly preferred, where

R ^{1 is} independently D or H, R ^{2 is} C ₆ alkyl or partially or fully deuterated C ₆ alkyl or substituted C 6 alkyl, R ^{3 is} D,

R ^{4 is} independently D or H and R ^{5 is} D or H and at least one of the radicals R ¹ to R ^{5 is} deuterium or contains deuterium.

Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I are advantageous, where R ^{1 is} independently D or H,

R ^{2 is} C ₆ alkyl or partially or completely deuterated C ₆ alkyl or substituted C 6 alkyl, R ^{3 is} independently H or D, R ^{4 is} D, R ^{5 is} H or D and at least one the radicals R ¹ to R ^{5 are} deuterium or contain deuterium.

Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the general formula I are particularly advantageous, where R ^{1 is} independently D or H,

R ² denotes alkyl, deuteroalkyl or perdeuteroalkyl,

R ^{3 is} independently H or D,

R ⁴ independently of one another denotes H or D,

R ^{5 is} D and at least one of the radicals R ¹ to R ^{5 is} deuterium or contains deuterium.

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

2-Nonadeuterobutyl-β, 6, 9, 9-tetradeutero-3- {[2, 3, 5, 6, 3 ', 4', 5 ',' -octadeutero-2 '- (1H-tetrazol-5-yl ) biphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [4.4] non-l-en-4-one,

2-butyl-β, 6,7,7,8,8,9,9-octadeutero-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3rd -diazaspiro [4.4] non-l-en-4- one,

2-nonadeuterobutyl-3- {[2 '- (lH-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4.4] non-l-en-4-one,

2-Nonadeuterobutyl-β, 6,7,7,8,8,9,9-octadeutero-3- {[2'- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3 - diazaspiro [4.4] non-l-en-4-one,

2-butyl-6, 6,7,7,8,8,9, 9-octadeutero-3- {[2,3,5,6,3 ', 4', 5 ', 6' -octadeutero-2 ' - (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [. ] non-l-en-4-one,

2-Nonadeuterobutyl-3- {[2,3,5, 6, 3 ', 4', 5 ',' -octadeutero- 2 '- (lH-tetrazöl-5-yl) biphenyl-4-yl] dideuteromethyl} - l, 3-diazaspiro [4.4] non-l-en-4-one, 2-Butyl-6, 6, 9, 9-tetradeutero-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4. 4] on-l-en-4- on,

2-butyl-6, 6, 9, 9-tetradeutero-3- {[2, 3, 5, 6, 3 ', 4', 5 ', 6' - octadeutero-2 '- (1H-tetrazole-5- yl) biphenyl-4-yl] methyl} - 1,3-diazaspiro [4.4] non-l-en-4-one,

2-Nonadeuterobutyl-6, 6, 9, 9-tetradeutero-3- {[2, 3, 5, 6- tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -l , 3-diazaspiro [4.4] non-l-en-4-one,

2-Nonadeuterobutyl-β, 6, 9, 9-tetradeutero-3- {[3 ', 4', 5 ', 6' - tetradeutero-2 '- (lH-tetrazol-5-yl) iphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [4.4] non-l-en-4-one and

2-butyl-6, 6, 9, 9-tetradeutero-3- {[2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4.4] non-l -en-4- one.

Preference is given to using the interpreted biphenyl-substituted spirocyclopentanimidazolinones according to the invention and their physiologically tolerable salts, for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma and diabetic nephropathy and retinopathy.

The use of the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention and their physiologically tolerable salts is particularly preferred for the production of medicaments for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and Treatment of glaucoma, diabetic nephropathy and retinopathy.

Particularly preferred are pharmaceutical compositions which contain the deuterated biphenyl-substituted spirocyclopentane imidazolinones according to the invention and their physiologically tolerable salts for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma as well as diabetic nephropathy and auxiliary and retinopathy / or additives.

The preparation of the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention is carried out on the basis of the production processes of analogous non-deuterated compounds using deuterated starting materials with a degree of deuteration above 98%.

For the synthesis of the deuterated 2-butyl-l, 3-diazaspiro [4.4] non-l-en-4-one, starting with an optionally deuterated cyclopentanone, a spirohydantoin is produced analogously to EP 206605, from which the corresponding 1-aminocyclopentane carboxylic acid is prepared. Of the various possibilities of hydrolysis of hydantoin to 1-aminocyclopentane carboxylic acid (see, inter alia, WO 01/60862, EP 206605, WO 99/32488), the acidic hydrolysis according to US Pat. No. 3,419,655 is carried out when a deuterated starting material is present.

The ethyl ester of 1-aminocyclopentane carboxylic acid is produced via the acid chloride in aqueous ethanol. This optionally deuterated ester is then reacted with an optionally deuterated ethyl pentanimide as in US 532788, at least one of the starting materials containing deuterium. The optionally deuterated ethyl pentanimide is prepared according to Suydam et al. [J. Org. Chem., Vol. 34, No. 2, 292-296 (1969)] by reacting the carboxamide with ethyl chloroformate. The resulting pentanimidic acid ethyl ester hydrochloride is converted analogously to US 5411980 by treatment with a base into the free acid, which is then immediately reacted with the 1-aminocyclopentanecarboxylic acid ethyl ester.

An embodiment of the invention describes the use of 2, 2, 3, 3, 4, 4, 5, 5, 5-nonadeuteropentane carboxamide, which is derived from 2,2,3,3,4,4,5,5,5 - Nonadeuteropentanecarboxylic acid was obtained via the corresponding acid chloride and its reaction with ammonium hydroxide [Tsuzuki et al., J. Chem. Research (S), 144-145 (1993)].

The N-alkylation of the deuterated 2-butyl-l, 3-diaza-spiro [4.4] non-l-en-4-one is carried out using 2'-substituted and optionally deuterated (bromomethyl) biphenyl derivatives.

Here it is possible, analogously to US 5559233, to use a cyano-substituted (bromomethyl) biphenyl as the biphenyl derivative and the desired tetrazole in the target compound after the reaction with 2-butyl-1,3-diazaspiro [4.4] non-l-ene Build up 4-ons.

The 4, 2'-disubstituted biphenyl derivatives are synthesized by known processes.

The Ullmann reaction can be used to produce symmetrically and asymmetrically substituted biphenyls. Halogenaryl compounds are preferred for this Iodine compounds reacted with each other in the presence of copper at high temperatures. The review article "Modern Methods Of Aryl-Aryl Bond Formation" by M. Sainsbury [Tetrahedron, 36, 3327-3359 (1980)] provides an overview of methods for forming aryl-aryl bonds.

For the preparation of deuterated biphenyl derivatives, the method of A.I. Meyers and E.D. Mihelich [J. At the. Chem. Soc, 97, 7383 (1975)], which also in

EP 733366 is described, adapted to the production of 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-di ethyloxazoline. 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 converted to deuterated 4'-methyl-2-biphenylnitrile via the acid amide which is obtained from the acid chloride with ammonium hydroxide solution. 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 with

Deuterium chloride is converted into the deuterated 5- (4 '-methylbiphenyl-2-yl) tetrazole.

The tetrazole group is subsequently protected by reaction with trityl chloride and the deuterated obtained

N-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) tetrazole with N-bromosuccinimide converted into the deuterated (bromomethyl) biphenyl derivative.

The latter is used in one embodiment of the invention for the synthesis of a spirocyclopentanimidazolinone, which is also deuterated in the biphenyl radical.

Deprotection of the deuterated 2-butyl-3- {[2 '- (1-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl} - 1, 3-diazaspiro [4.4] non-1-ene -4-ones takes place in acid and the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to the invention are obtained.

Conventional physiologically acceptable inorganic and organic acids can be used to prepare physiologically acceptable salts of the spirocyclopentanimidazolinones according to the invention. These are, 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, pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977).

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 its solutions in an organic solvent, for example a lower alcohol such as methanol, ethanol, n-propanol or 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 in a manner known per se, for. B. 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 medicaments for oral, sublingual, buccal, rectal, subcutaneous, intravenous, intramuscular, topical, intratracheal, intranasal, transdermal or rectal application, which in addition to conventional carriers and diluents agents contain a compound of general formula I or its acid addition salt as active ingredient.

The medicaments of the invention are produced in a known manner with the customary solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries in accordance with the desired type of application with a suitable dosage. 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 found, 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 to achieve a depot effect such as carboxyl polymethylene, carboxylmethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. 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. It can the coated tablet also consists of several layers, it being possible to use the auxiliaries mentioned above for the tablets.

Solutions or suspensions with the active ingredient used according to the invention can additionally taste-improving agents such as saccharin, cyclamate or sugar and e.g. Contain flavorings 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 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, 622-1045; List et al. , Drug form theory, Stuttgart: Wiss. Publishing company , 1985; Sucker et al. , Pharmaceutical Technology, Stuttgart: Thie e 1991; Ullmann's Encyclopedia (5th) A 19, 241-271; Voigt, Pharmaceutical Technology, Berlin: Ullstein Mosby 1995. The compounds according to the invention, specifically substituted with deuterium, have a number of advantages over the compounds known in the prior art which contain deuterium only in the natural distribution. 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 is 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 production takes place in a manner known per se. 17 g of 2-amino-2-methyl-l-propanol are dissolved in dichloromethane and the ice-cooled solution is treated dropwise with a solution of 14.75 g of 2-methoxy-3, 4, 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%

¹ H 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-di ethyloxazoline

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, 4-dimethyloxazoline 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% ^α 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 of 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 obtained in a manner known per se with 10 equivalents Implemented 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-biphenylnitrile are reacted with 24.6 g of triethyltin 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%

¹ H-NMR (200 MHz, d6-DMSO): δ 0.39 (9H) Example 8

Preparation of 5- (dll-4 '-methylbiphenyl-2-yl) -1D-tetrazole. In variation of the literature specification, the product is prepared by 33 g of N-trimethylstannyl-5- (dll-4' - methylbiphenyl-2-yl) tetrazole can be dissolved in a mixture of toluene and tetrahydrofuran and so long dry

Deuterium chloride is blown through the solution at room temperature until a clear solution is formed. The product crystallizes out of the solution and is obtained

U crystallization 16.8 g of 5- (dll-4 '-methylbiphenyl-2-yl) -

ID-tetrazole.

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-4' -

Methylbiphenyl-2-yl) -ID-tetrazole in dichloroethane reacted with 25 g of trityl chloride with the addition of triethylamine 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 removed in a vacuum. 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- [dlO-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 the educt is dissolved in carbon tetrachloride and 11.5 g of N-bromosuccinimide and 1.1 g of dibenzoyl peroxide are added at room temperature. The reaction mixture becomes for 3 hours

Boiling heated, 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% ^X H-NMR (200 MHz, CDC1 ₃ ): δ 6.4-7.9 (15 H, m) Example 11

Preparation of l-amino-2, 2, 5, 5-tetradeuterocyclopentane carboxylic acid

Analogously to the preparation of the non-deuterated compound, 17.6 g of 2, 2, 5, 5-tetradeuterocyclopentanone are dissolved in 800 ml of 50% aqueous ethanol, and 19.3 g of ammonium carbonate and 13.1 g of potassium cyanide are added. The reaction mixture is heated in a reactor provided with a cooler to 60 ° C. for two hours and then cooled. The volume is reduced to approx. 250 ml and the crystallization is completed by ice cooling. The crystals are filtered off, washed with water and dried. This gives 26.3 g of 2, 2, 5, 5-tetradeutero-cyclopentane-5, 5 '- spirohydantoin, which is immediately processed further. Yield: 83%

Melting point: 213-215 ° C

26 g of the hydantoin obtained are mixed with 60 ml of 60% sulfuric acid and heated to reflux under nitrogen for 72 hours. The reaction mixture is cooled and brought to pH 5 by adding sodium hydroxide. The mixture is cooled to 0 ° C., filtered and the solid is washed with water. The solid is dissolved in 300 ml of warm water at pH 2, mixed with activated carbon and then brought to pH 5. The reaction product is filtered off from the mixture cooled to 0 ° C., washed several times with cold water and then dried. 11.6 g of l-amino-2, 2, 5, 5-tetradeuterocyclopentane carboxylic acid are obtained as white crystals. Yield 53% Melting point: 325-333 ° C calculated: C: 54.11%; H: 11.35%; N: 10.52% found:

C: 54.87%; H: 11.24%; N: 10.41% ¹³ C NMR (200 MHz, CDC1 ₃ ): δ 17, 20 (s), 33, 90 (quint); 63, 90 (s), 180, 20 (s).

Example 12:

Preparation of l-amino-2,2,5,5-tetradeuterocyclopentanecarboxylic acid ethyl ester

9 g of l-amino-2, 2, 5, 5-tetradeuterocyclopentanecarboxylic acid are suspended in 750 ml of 96% ethanol. 5.5 ml of thionyl chloride are added dropwise to the suspension with stirring and cooling at such a rate that the temperature of the reaction mixture is kept below -5 ° C. After the addition has ended, the reaction mixture is used for

Heated to 50 ° C for 10 hours and then the remaining ethanol was distilled off under reduced pressure. The

The residue is taken up in chloroform and shaken with ammonium hydroxide solution. After drying it will

Chloroform is distilled off and there are 8.61 g of ethyl ester as a light yellow oil. Yield: 79% calculated:

C: 59.59%; H: 11.87%; N: 8.69% found:

C: 60.01%; H: 11.79%; N: 8.73% ¹³ C NMR (200 MHz, CDC1 ₃ ): δ 12.90 (s); 17.20 (s), 34.50

(Quint); 58.30 (s); 62.40 (s), 177.50 (s)

Example 13 Preparation of 2,2,3,3,4,4,5,5,5-

Nonadeuteropentanimidic acid ethyl ester hydrochloride In a 250 ml three-necked flask equipped with a cooler, 11 ml of 2, 2, 3, 3, 4, 4, 5, 5, 5, 5-nonadeuteropentanecarboxamide are added with stirring with 0.1 ml of ethyl chloroformate from a dropping funnel. The reaction mixture is achieved with a 40-45 ° C water bath. warms. The beginning of the reaction is visible through the development of C0 ₂ which is discharged via the cooler into a barium hydroxide solution. After stirring for 2.5 hours while maintaining the water bath temperature, the CO ₂ evolution is complete. The reaction product is washed several times with anhydrous ether and then dried. 12.4 g of imidate hydrochloride are obtained in the form of a syrup. Yield: 71% calculated:

C: 48.12%; H: 14.41%; N: 8.02% found:

C: 48.23%; H: 15.01%; N: 8.11%

Example 14

Production of 2,2,3,3,4,4,5,5,5-

Nonadeuteropentanimidsäureethylester

12 g of 2,2,3,3,4,4,5,5,5-nonadeuteropentanimidic acid ethyl ester hydrochloride are dissolved in a potassium carbonate solution from 15 g of potassium carbonate in 30 ml of water. The reaction solution is immediately shaken out three times with 40 ml each. The organic phase is dried, the solvent is removed in vacuo and 6.65 g of imidate are obtained as a colorless oil which is immediately processed further. Yield: 70% calculated: C: 60.81%; H: 17.48%; N: 10.13% found:

C: 60.70%; H: 17.33%; N: 10.21%

¹³ C NMR (200 MHz, CDC1 ₃ ): δ 13.20 (sept); 14.3 (s); 22,90-

23.20 (m); 33.50 (quint); 56.20 (s); 165.20 (s). Example 15

Preparation of 2-nonadeuterobutyl-6, 6, 9, 9, -tetradeutero-1, 3-diazaspiro [4.4] on-l-en-4-one

1.62 g of ethyl l-amino-2,2,5,5-tetradeuterocyclopentane and 1.67 g of ethyl 2, 2, 3, 3, 4, 4, 5, 5, 5, 5-nonadeuteropentanimide are dissolved in 12 ml of xylene , to which 6 drops of acetic acid were added. The reaction mixture is heated to reflux for 7 hours and then concentrated in vacuo. The residue is separated by column chromatography on silica gel, using a mixture of chloroform, methanol and acetic acid in a volume ratio of 94/4/2. To remove the acetic acid, xylene and benzene are added to the concentrated product fraction several times and the solvents are distilled off in vacuo. 1.97 g of 2-nonadeutero-butyl-6, 6.9, 9-tetradeutero-l, 3-diazaspiro [4.4] non-l-en-4- one are obtained in the form of an oil. Yield: 95% calculated: C: 63.72%; H: 15.06%; N: 13.51% found:

C: 64.20%; H: 15.19%; N: 13.60%

¹³ C NMR (200 MHz, CDC1 ₃ ): δ 13.20 (sept); 17.60 (s); 22.50-22.80 (m); 33.00 (quint); 36.80 (quint); 67.30 (s); 165.20 (s); 181.30 (s).

Example 16

Preparation of 2-nonadeuterobutyl-6, 6, 9, 9-tetradeutero- 3- {[2, 3, 5, 6, 3 ', 4', 5 ', 6' -octadeutero-2 '- (1-triphenyl- methyl-lH-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -

1, 3-diazaspiro [4.4] non-l-en-4-one

1.04 g of 2-nonadeuterobutyl-6, 6, 9, 9-tetradeutero-l, 3-diazaspiro [4.4] are added dropwise to 250 mg of sodium hydride (80% dispersion in mineral oil) in 50 ml of diethylfor amide under nitrogen. non-l-en-4-one dissolved in 10 ml dimethylfor mamid, added. The reaction mixture is stirred for 30 minutes at room temperature and then a solution of 3.13 g of N-triphenylmethyl-5- [dl0-4 '- (bromomethyl) biphenyl-2-yl] tetrazole in 15 ml of dimethylformamide is added. The reaction mixture is stirred for 3 hours at room temperature and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and water is carefully added. The organic phase is washed with water and dried and the solvent is distilled off in vacuo.

The product is isolated by column chromatography on aluminum oxide with hexane / ethyl acetate in a ratio of 17/3. After removing the solvent, 2.90 g of product are obtained as a white solid. Yield: 83%

Melting point: 146-149 ° C calculated:

C: 76.17%; H: 9.43%; N: 12.11% found: C: 76.60%; H: 9.54%; N: 12.21%

¹³ C NMR (200 MHz, CDC1 ₃ ): δ 13.20 (sept); 17.60 (s); 23.20 (quint); 23.70 (quint); 33.10 (quint); 35.50 (quint); 48.00 (quint); 62.10 (s); 66.80 (s); 126.30 (s); 127.50-129.00 (m); 134.20 (, s); 135.10 (s); 135.60 (s); 141.50 (s); 143.40 (s); 163.70 (s); 178.70 (s).

Example 17

Preparation of 2-nonadeuterobutyl-6, 6, 9, 9-tetradeutero- 3- {[2,3,5,6,3 ', 4', 5 ', 6' -octadeutero-2 '- (1H-tetrazole- 5- yl) biphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [4.4] non-l-en-4-one

2.1 g 2-nonadeuterobutyl-6, 6, 9, 9 ~ tetradeutero-3-

{[2, 3, 5, 6, 3 ',', 5 ', 6' -octadeutero-2 '- (1-triphenylmethyl-1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -1, 3- diazaspiro [4.4] non-l-en-4-one are made up in a mixture 10 ml of methanol and 10 ml of THF were added and the mixture was cooled to 5 ° C. 2 ml of semi-concentrated hydrochloric acid are added and the mixture is stirred at room temperature for three hours and at 30 ° C. for one hour. The solvent is removed, the residue is taken up in water and brought to pH 12 by adding sodium hydroxide solution. The aqueous phase is extracted with ether, toluene and ether and then brought to pH 2 by adding hydrochloric acid. The aqueous phase is shaken out with ethyl acetate and the organic phase is separated off and dried. The solvent is removed in vacuo and the residue is dried. 0.87 g of product is obtained as a white solid. Yield 64% melting point: 179-181 ° C calculated:

C: 66.48%; H: 11.37%; N: 18.61% found: C: 66.53%; H: 11.10%; N: 18.52% ¹³ C-NMR (200 MHz, CDC1 ₃ ): δ 13.20 (sept); 17.60 (s); 23.30

(Quint); 23.70 (quint); 33.10 (quint); 35.50 (quint); 48.00 (quint); 66.80 (s); 127.50-128.30 (m); 129.20 (t); 135.10 (s); 135.60 (s); 141.50 (s); 163.70 (s); 178.70 (s).

Claims

claims

Deuterated biphenyl-substituted spirocyclopentanimidazolinones of the general formula I, where

Formula I.

R ^{1 is} independently D or H, R ^{2 is} C ₆ alkyl or partially or completely deuterated C ₆ alkyl or substituted C ₆ alkyl,

R ^{3 is} independently D or H, R ^{4 is} independently D or H and R ^{5 is} D or H and at least one of the radicals R ¹ to R ^{5 is} deuterium or contains deuterium.

Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to claim 1, wherein R ^{1 is} D,

R ² Ci-g-alkyl or partially or completely deuterated C ₆ alkyl or substituted C ₆ alkyl- indicated

3. Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to claim 1, wherein

R ^{1 is} independently D or H, R ^{2 is} fully deuterated C 6 alkyl, R ^{3 is} independently D or H, R ^{4 is} independently D or H and R ^{5 is} D or H.

4. Deuterated biphenyl-substituted spirocyclopentane imidazolinones according to claim 1, wherein

R ^{1 is} independently D or H, R ^{2 is} C ₆ alkyl or partially or completely deuterated C ₆ alkyl or substituted C ₆ alkyl, R ^{3 is} D,

R ⁴ independently of one another D or H and

5. Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to claim 1, wherein

R ^{1 is} independently D or H,

R ^{2 is} C ₆ alkyl or partially or completely deuterated C ₆ alkyl or substituted C ₆ alkyl,

R ^{3 is} independently H or D, R ^{4 is} D, R ^{5 is} H or D and at least one of the radicals R ¹ to R ^{5 is} deuterium is or contains deuterium.

6. Deuterated biphenyl-substituted spirocyclopentanimidazolinones according to claim 1, wherein R ^{1 is} independently D or H,

R ^{2 is} C 6 alkyl or partially or completely deuterated C ₆ alkyl or substituted C ₆ alkyl,

R ^{3 is} independently H or D, R ^{4 is} independently H or D, R ^{5 is} D and at least one of the radicals R ¹ to R ^{5 is} deuterium or contains deuterium.

7. 2-Nonadeuterobutyl-6, 6, 9, 9-tetradeutero-3-

{[2,3,5,6,3 ', 4', 5 ', 6' -octadeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} - !, 3-diazaspiro [4.4] non-l-en-4-one.

8. 2-Nonadeuterobutyl-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-

4-yl] methyl} -l, 3-diazaspiro [4.4] non-l-en-4-one.

9. 2-Butyl-6, 6, 1, 1, 8, 8, 9, 9-octadeutero-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] naethyl} -l , 3-diazaspiro [4.4] non-l-en-4-one.

10. 2-Nonadeuterobutyl-6, 6, 1, 1, 8, 8, 9, 9-octadeutero-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-4 ~ yl] methyl} -l , 3-diazaspiro [4.4] non-l-en-4-one.

11. 2-butyl-6, 6,7,7,8,8,9, 9-octadeutero-3-

{[2, 3, 5, 6, 3 ', 4', 5 ', 6' -octadeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [4.4] non-l-en-4-one.

12. 2-Nonadeuterobutyl-3- {[2,3,5,6,3 ', 4', 5 ', 6'-octadeutero-2' - (1H-tetrazol-5-yl) iphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [. ] Non-l-en-4-one.

13. 2-Butyl-6,6,9,9-tetradeutero-3- {[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4.4] non -l-en- 4-one.

14. 2-Butyl-6,6,9,9-tetradeutero-3- {[2, 3, 5, 6, 3 ', 4', 5 ', 6'-octadeutero-2' - (1H-tetrazole- 5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4.4] non-l-en-4-one.

15. 2-Nonadeuterobutyl-6,9,9-tetradeutero-3- {[2,3,5,6-tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} - l, 3-diazaspiro [4.4] non-l-en-4-one.

16. 2-Nonadeuterobutyl-6, 6,, 9-tetradeutero-3-

{[3 ', 4', 5 ', 6' -tetradeutero-2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] dideuteromethyl} -l, 3-diazaspiro [. ] Non-l-en-4-one.

17. 2-Butyl-6, 6, 9, 9-tetradeutero-3- {[2 '- (ID-tetrazol-5-yl) biphenyl-4-yl] methyl} -l, 3-diazaspiro [4.4] non -l-en- 4-one.

18. Use of the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to any one of claims 1 to 17 and their physiologically tolerable salts, for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma and diabetic nephropathy and retinopathy.

19. Use of the deuterated biphenyl-substituted spirocyclopentanimidazolinones according to any one of claims 1 to 17 and their physiologically tolerated Salts, for the manufacture of medicaments for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma as well as diabetic nephropathy and retinopathy.

20. Pharmaceutical composition containing deuterated biphenyl-substituted spirocyclopentanimidazolinones according to one of claims 1 to 17 and their physiologically tolerable salts for the treatment of cardiovascular diseases such as high blood pressure and heart failure, disorders of the central nervous system and for the treatment of glaucoma and diabetic nephropathy and phytopathic and retinopathy, in addition to phytopathology and retinopathy Auxiliaries and / or additives.