HK1013283B - Nitrato amino acid disulphides for use in the therapy of disorders of the cardiovasculary system - Google Patents

Description

The invention relates to new nitrates containing a disulfide group and to methods for their production.

Organic nitrates (esters of nitric acid) are well-established drugs for the treatment of heart disease, acting both by reducing the load on the heart by reducing the load on the heart and by improving the oxygen supply to the heart by enlarging the coronary arteries.

In recent years, however, it has been observed that the classical organic nitrates used in therapy, such as glycerol trinitrate, isosorbide dinitrate or isosorbide-5 mononitrate, show a significant reduction in nitrate tolerance within a short period of time when given at high doses.

According to EP 0 362 575 and EP 0 451 760, the action of nitrate compounds is mediated by the NO radicals formed from them. The reaction of the nitrate with the thiol group of cysteine initially results in the formation of a reactive and short-lived, hitherto hypothetical intermediate product, which is probably the thiolester of nitric acid or a thionitrate, which is deposited intramolecularly and then decomposes into a pharmacologically active NO radical and an unstable thionitrate radical, which is converted with further thionitrate radicals to the corresponding disulfide. The formation and release of the NO radical requires a reduced nitrile group which is released from the cysteine, which is disulfide-containing in such a way that the continued intake of this nitrile compound is tolerated at a high dose in the case of EP 0 575 or EP 0 452 or in the case of the nitrile groups already contained in the sample.

Surprisingly, it has now been found that nitrate compounds containing a disulfide group instead of a free thiol group are also effective and do not have a nitrate tolerance when continuously fed. in the R and R' groups of the general formulae The following are the main R11 Hydrogen, alkyl with 1 to 6 carbon atoms, substituted C1-C6-low alkyl, wherein the substituent halogen, hydroxy, C1-C6-low alkyl, aryloxy, amino, C1-C6-low alkyl, acylamino, acyloxy, arylamino, mercapto, C1-C6-low alkyl, aryl is R12 as R11hydrogen or C1-C6-low alkyl means R13Nitrato alkyl with 1 to 6 carbon atoms R1, R1'Hydrogen or C1-C6 low-alkyl meansR2, R2'Hydrogen, C1-C6 low-alkyl, phenyl, methoxyphenyl, phenyl-C1-C6 low-alkyl, methoxyphenyl-C1-C6 low-alkyl, hydroxyphenyl-C1-C6 low-alkyl,Alcoxy-C1-C6-niedrigalkyl, alkoxy-C1-C6-niedrigalkyl, amino-C1-C6-niedrigalkyl, acylamino-C1-C6-niedrigalkyl, mercapto-C1-C6-niedrigalkyl or C1-C6-niedrigalkyl is a low-alkylthio-C1-C6-niedrigalkyl or C1-C6-niedrigalkyl is a C3, R3'Hydroxy, C1-C6-niedrigalkyl, C1-C6-niedrigalkyl, C1-C6-niedrigalkyl, C1-C6-niedrigalkyl, C1-C6-niedrigalkyl, C1-C1-C1-C1-C1-C1-C2-C2-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C-C4-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-C-Cwhich has a double bond or an alkyl bridge as above, substituted with hydroxy, C1-C6-low-alkyl, C1-C6-low-alkyl or Di-C1-C6-low-alkyl, m, n, o, p, q, m', n', o', p' and q' having values from 0 to 10, and their physiologically compatible salts.

The present invention also covers compounds bearing the following names: The following substances are to be classified in the same category as the active substance:

These are asymmetric disulfides, which generally contain sulphur-containing amino acids, in particular glutathione or penicillamine.

The compounds of the invention may also be present in the form of their acid-addition salts.

Following a further development of the invention, the aliphatic part (s) of nitroalkyllarylactic acid and nitroalkanes have a chain length of 2-6 carbon atoms and may be straight chain, branched chain, racemic or optical isomeric.

The nitroalkanes and nitroalkylarylalkanes of the general formula (I) according to the invention preferably contain disulfides of sulphur-containing amino acids, in particular cysteine, homocysteine or penicillamine disulfide.

Following further development of the invention, the amino acid disulfides are in the stereochemical L or DL form.

After a particularly advantageous development of the invention, the compounds claimed have the following chemical formulae: The following shall be indicated in the column for the product: 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether' (Diphenyl ether), 'Diphenyl ether'), 'Diphenyl ether' (Diphenyl ether), 'Diphen' (Diphen) and Diphen)), 'Diphen' (Diphen) and 'Diphen' (Diphen) and Diphen'), 'Diphen' (Diphen' and 'Diphen'), 'Diphen' and 'Diphen' and 'Diphen' (Diphen'), 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' (Diphen'), 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and 'Diphen' and '

According to EP 0 362 575, the compounds of the invention of general formula I can be prepared in a known manner by condensation of the corresponding nitric acid or its reactive derivatives with the amino group of a free, esterified or amidized amino acid disulfide.

Compounds of general formula I, in which R3 and R3' together with the neighboring carbonyl group form an acid amide function, have a delayed and long-lasting effect compared to the previously known nitrates. This results in a reduced activation of the physiological counter-regulations caused by vasodilation and allows an extension of the application interval. In particular, the attenuation of compensatory mechanisms is advantageous as it can be expected to reduce side effects such as reflective tachycardia that occur under nitrate therapy.

Therefore, it is particularly preferable to use compounds of general formula I in which R3 and R3' denote a substituted or unsubstituted amino group.

Alternatively, the nitroalkyl or nitroalkylarylalkyl carbon acids concerned or their reactive derivatives may be condensed first with the amino group of an amino acid containing a thiol group to the corresponding acid amide, which is then oxidised by means of an oxidizing agent such as potassium iodate under dimerization to the corresponding disulfide of general formula I.

However, the production of these compounds using these methods results in mixtures of products which are not uniform and which contain only a small amount of the desired compounds and require extensive purification.

These disadvantages can be avoided by condensing the corresponding nitrocarbons or their reactive derivatives with the amino groups of amino acids bound freely by disulfide bridges, converting the resulting compounds at their carboxylic acid functions into activated esters and then translating them into the desired compounds with ammonia, a primary or secondary amine. in the R and R' groups of the general formulae means: In which R11 Hydrogen, an alkyl with 1 to 6 carbon atoms, substituted with C1-C6-lower alkyl, in which the substituent halogen, hydroxy, C1-C6-lower alkyl, aryloxy, amino, C1-C6-lower alkyl, acylamino, acyloxy, arylamino, mercapto, C1-C6-lower alkyl,Arylthio isR12 as R11hydrogen or C1-C6 low-alkyl meansR13nitroalkyl with 1 to 6 carbon atoms isr having numerical values 0 to 10 and is used in the R1, R1',Hydrogen or C1-C6-nickel means R2, R2'Hydrogen, C1-C6-nickel, phenyl, methoxyphenyl, phenyl-C1-C6-nickel, methoxyphenyl-C1-C6-nickel, hydroxyphenyl-C1-C6-nickel, hydroxy-C1-C6-nickel, alkoxy-C1-C6-nickel, amino-C1-C6-nickel, acylamino-C1-C6-nickel, mercapto-C1-C6-nickel or C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C1-C6-nickel, hydroxy-C1-C1-C1-C4-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C1-C1-C1-C1-C1-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C4-C-C4-C4-C4-C-C-C-C-C-C-C-Substituted with hydroxy, C1-C6-lower-alkyl-coxy, C1-C6-lower-alkyl or Di-C1-C6-lower-alkyl, may be bound,m, n, o, p, qand m', n', o', p' and q' have numerical values from 0 to 10, which is characterised by the fact that compounds of general formula III where R is a group of the general formula means where R11 is hydrogen, an alkyl with 1 to 6 carbon atoms, substituted with C1-C6-low alkyl, where the substituent is halogen, hydroxy, C1-C6-low alkyl, aryloxy, amino, C1-C6-low alkyl, acylamino, acyloxy, arylamino, mercapto, C1-C6-low alkyl, arylthioR12 as hydrogen or C1-C6-low alkyl means R13 is nitroalkyl with 1 to 6 carbon atoms and rthe numerical values 0 to 10 are in the form of their free acids, reactive acid alkyl acids, acid acids, esters and acid anhydrides in a general way known as formula IV In which R1,'Hydrogen' or 'C1-C6-nickel' meansR2, R2'Hydrogen, C1-C6-nickel, phenyl, methoxyphenyl, phenyl-C1-C6-nickel, methoxyphenyl-C1-C6-nickel, hydroxyphenyl-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, amino-C1-C6-nickel, acylamino-C1-C6-nickel, mercapto-C1-C6-nickel or C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C6-nickel, hydroxy-C1-C1-C6-nickel, hydroxy-C1-C1-C6-nickel, hydroxy-C1-C1-C6-nickel, hydroxy-C1-C1-C1-C6-nickel, hydroxy-C1-C1-C1-C6-nickel, hydroxy-C1-C1-C1-C1-C6-C6-C6-C1-C6-C1-C6-C1-C6-nickel, hydroxy-C1-C1-C1-C1-C1-C1-C1-C1-C6-C6-C6-C6-nickel, hydroxy-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C6-C1-C1-C6-C6-C1-C1-C6-C1-C1-C6-C1-C1-C1-C1-C1-C1-C6-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-This product is intended to be used in the manufacture of a product containing a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of a mixture of hydrocarbons obtained from the distillation of the distillation of the mixture of hydrocarbons obtained from the distillation of the mixture of the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons obtained from the mixture of hydrocarbons. be transferred, In which R32 and R32' other than the above means and then converted by ammonia, a primary or secondary amine, in particular C1-C6-niggalkylamine, Di-C1-C6-niggalkylamine, aryl-C1-C6-niggalkylamine, hydroxy-C1-C6-niggalkylamine, pyrrolidine, piperidine, morpholine, piperazine or amino acids, into compounds of general formula II.

Err1:Expecting ',' delimiter: line 1 column 84 (char 83)

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

The halogen atoms are fluorine, chlorine, bromine and iodine atoms, with chlorine and bromine atoms being preferred.

Err1:Expecting ',' delimiter: line 1 column 43 (char 42)

The substituted benzyl or phenyl residues shall preferably contain the substituent in the 4 position.

The hydroxy-substituted lower alkyl residues have a hydroxyl group attached to an alkyl residue of the type described above, preferably at the end carbon atoms.

The novel compounds of the invention of general formulae I and II and their salts may be administered orally, enteral or parenterally, in liquid or solid form.

The preferred medium for injection is water, which contains the additives commonly used in solutions for injection, such as stabilizers, solvents or buffers. Such additives include tartrate and citrate buffers, ethanol, complexes (such as ethylene diamine tetracyclic acid and its non-toxic salts), high molecular polymers (such as liquid polyethylene oxide) to regulate viscosity. Solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, talcum, high dispersion polyethylene acids, higher molecular fatty acids (such as malic acid), gelatine, agar-agar, calcium, magnesium, animal starch, plant and vegetable fats and polymers (such as orange oil) and may be suitable for high molecular weight preparations.

After further study of the invention, medicinal products shall contain a content of one and/or a mixture of the compounds of the invention.

These medicines may be used to treat diseases of the cardiovascular system, for example, to treat coronary heart disease, high blood pressure and heart failure, and to dilate peripheral vessels, including the brain and kidney.

Pharmaceutical preparations containing a pre-calculated amount of one or more of the compounds of the invention may be administered once daily in the form of delayed preparations or several times daily at regular intervals (2-3 times daily). The excess amounts of active substance applied per day are 20 to 300 mg per day, based on 75 kg body weight. In the form of injections, the compounds of the invention may be administered 1-8 times per day or by continuous infusion.

A typical tablet may be composed of: Other

1)	N,N'-Di-(3-Nitratopivaloyl)-L-cystindiamid	30 mg
2)	Stärke, U.S.P.	57 mg
3)	Lactose, U.S.P.	73 mg
4)	Talkum, U.S.P.	9 mg
5)	Stearinsäure	6 mg

Substances 1, 2 and 3 are sifted, granulated, mixed with homogeneous substances 4 and 5 and then tabletized.

The examples of execution shall explain the invention without being limited to that.

Example 1 The following table shows the results of the analysis of the data:

149.1 g (3.727 mol) of sodium hydroxide were dissolved in 2.5 1 water, cooled to 0°C and added 448.0 g (1,864 mol) of L-cysteine per serving, not exceeding 5°C, stirred and ice-bath cooled. 2.0 1 dichloromethane was added.After three extractions of this mixture with 2.0 1 ethyl acetate each, the extracts were combined and pressed on to Rotavapor®, leaving a brown, oily residue, which was dissolved in 2.0 l of distilled ethyl acetate and pressed to weight consistency (product foaming) at a very low pressure (oil pump vacuum) and bath temperature of about 55°C. The resulting residue was dissolved in 1.0 1 distilled ethyl acetate, cooled at room temperature, diluted with 1.0 1 distilled methanol and added to a crystal of ethanol at ca. -30°C. The product was sub-cristallised to 200 ml of 200 ml of a solution of ethyl chloride and 250 ml of a crystal of ethanol.Washed at -30°C and dried in a vacuum dryer at about 40°C to weight consistency.

The yield was 318.03 g (32.16% d.e.). Fp: 47.2°C

Example 2 The following table shows the results of the analysis of the data:

The presentation and processing were carried out in analogy to example 1. Acidification with 37% hydrochloric acid produced a solid product which was extracted and compressed with ethyl acetate as described, leaving 51.3 g of white solid product (73.5% d.th).

This was heated, dissolved in 400 ml of methanol, filtered and cooled to room temperature, to which 400 ml of water were added by stirring and stirred for 3 hours at room temperature, slowly crystallizing a product.

The yield was 31.3 g (44.8% d.h.). Fp: about 42°C

Example 3 The following table shows the results of the analysis of the product:

24.4 g (82.9 mmol) 3-nitratopivaloyl-L-cysteine ethyl ester was dissolved in 150 ml of ice vinegar at room temperature and a solution of 2.9 g (13.9 mmol) potassium iodate was slowly dripped into 300 ml of water by stirring, with the solution turning brown and producing a crystalline substance after 15 minutes of stirring. The substance was suctioned, dissolved in 150 ml of dichloromethane and successively washed with 100 ml of 1% sodium thiosulphate solution, 100 ml of hydrochloric acid and 100 ml of water. The dichloromethane phase was completed by drying the remaining amount (25.4 g) in approximately 150 ml of methanol and dissolving it in 45 ml of water. The substance was dissolved in a crystalline solution of methanol in a vacuum at a temperature of 30°C. The substance was mixed with methanol at approximately 30 ml of water and drunk at room temperature (approximately 30°C). The substance was then completely cooled and dissolved in water at a temperature of 30°C.

The yield was 16.9 g (69.5% d.e.). Fp: 84.9°C. Other

Example 4 The following table shows the results of the analysis of the product:

11.4 g (35 mmol) homocystine diethyl ester and 12.0 g (73.5 mmol) 3-nitratopival acid were dissolved in 200 ml dichloromethane, cooled to approximately 10 °C and stirred to add a solution of 15.2 g (73.5 mmol) DCC to 100 ml dichloromethane for approximately 15 minutes, with DCC urine being released by the end of the drip. The combined dichloromethane solutions were then stirred at room temperature over the weekend, the urine was sucked and washed twice with 50 ml dichloromethane each. The combined dichloromethane solutions were washed twice with 100 1 n of hydrochloric acid, twice with 100 ml of hydrochloric acid solution and once with water. Each solution was washed once with 100 ml of ethanol, which was stored in a vacuum and filtered at a temperature of approximately 20 °C. The solution was then filtered and dried at a temperature of approximately 250 °C. The mixed solutions were then placed in a room with a temperature of approximately 25 °C and filtered with ethanol.

The yield was 12.4 g (corresponding to 57.6% of the total). The temperature of the water is:

Example 5 The following table shows the total number of products for which the product is intended to be used:

17.76 g (0.03 mol) L-cysteine di-tert-butyl ester and 10.36 g (0.126 mol) sodium acetate were dissolved in 80 ml of water and 120 ml of dichloromethane and dripped at 10°C to 15°C into a solution of 12.0 g (0.066 mol) 3-nitratopivaloyl chloride and 50 ml of dichloromethane. This solution was stirred overnight at room temperature, the organic phase was separated and washed with 50 ml of 1 n of hydrochloric acid and 1 n of sodium hydrogen carbonate solution.

The remaining residue was crystallized from ethanol, which was completed overnight at -25°C and washed once with 10 ml of ethanol (-25°C).

The yield was 12.73 g (corresponding to 66.02 % d.e.). Fp: 93.7°C. Other

Example 6 The following table shows the total number of samples of the product:

After stirring, 1,48 g (0.055 mol) L-cystindimethylester base was dissolved in 10 ml of methyl chloride, 0,56 g (0.055 mol) triethylamine was added, and then a solution of 2,16 g (0.01 mol) 4-nitratomethyl benzoyl chloride was slowly dripped into 10 ml of methyl chloride. After stirring for 2 h, the product was extracted, washed with 2 x 15 ml of 1 n of hydrochloric acid and 2 x 15 ml of water, dried and crystallized from ethyl acetate to obtain colourless crystals.

The yield was 1.89 g (corresponding to 60.4% of the Community average). Fp: 155°C

Example 7 The following table shows the total number of samples of the product:

The presentation was carried out in analogy with the 4-nitratomethylbenzoyl derivative, and since the raw product remained dissolved in the methyl chloride of the reaction method, after 2 h of stirring, it was washed with 15 ml of hydrochloric acid and 2 x 15 ml of water, dried, vaporized and then decrystallized from diisopropyl ether, resulting in colourless needles.

The yield was 2.68 g (85.6% d.e.). Fp: 91°C

Example 8 The following table shows the total number of samples of the product:

After 2 hours of stirring, wash with 20 ml of 1 n salt acid and 2 x 15 ml of water, dry with sodium sulphate, compress i. v. to dry and crystallize from un-methylened chloride to obtain a colourless powder.

The yield was 0.93 g (26.3% d.v.th). Fp: 183°C

Example 9 The following table shows the total number of active substances in the active substance:

The use of the product in the manufacture of the product concerned was based on the same method as that used for the 4-nitratomethylbenzoyl derivative. Appearance: Colourless powder

The yield was 0.4 g (11.3% d.v.h.). Fp: 174-175°C

Example 10 The following table shows the total number of units of the product:

After stirring overnight, washed with 20 ml of 1 n of hydrochloric acid and 2 x 20 ml of water, dried with sodium sulphate, crushed and incrystallised the methyl chloride residue to obtain a colourless powder.

The yield was 0.32 g (15.3% d.e.). Fp: 143°C

Example 11 The following table shows the total number of active substances in the active substance:

The product obtained was treated in the same way as the 4-nitratomethylbenzoyl derivative, resulting in a colourless powder.

The yield was 0.25 g (12.2 % d.e.). Fp: 136°C

Example 12 The following table shows the total number of units of the active substance: The Commission has not received any comments from the interested parties.

Approximately 100 ml of liquid ammonia were placed in 7.95 g (0.02 mol) L-penicillamine disulfide dimethyl ester x 2 HCl at -40 to -55 °C, stirred overnight at -40 to -30 °C and the cooling bath was removed, whereupon the ammonia evaporated. The solution was then compressed at 50 °C in the Rotavapor® bath, the entire residue was absorbed and filtered into 40 ml of warm isopropanol. HCl gas was introduced into the filter, leaving the product to evaporate and be sucked out.

The yield was 4.6 g (62.61 % d.e.).

The product obtained from the extraction of N,N'-Di- ((3-Nitratopivaloyl) L-penicillamine disulfide diamide.

4.41 g (12 mmol) L-penicillamine disulfide bisamide x 2 HCl and 4.03 g (48 mmol) sodium hydrocarbonate were dissolved in 100 ml of water, 60 ml dichloromethane was added and stirred until both phases were clearly dissolved.

The yield was 3.45 g (49.17% d.e.).

Example 13 The following table shows the total number of active substances in the active substance: The following table shows the results of the analysis of the product characteristics:

477.5 g (0.9 mol) N,N'-Di-(3-nitratopivaloyl) -L-cystine (Example 1) and 213.4 g (1.854 mol) N-hydroxysuccinimide were dissolved in 1400 ml of tetrahydrofuran, cooled to 5°C and stirred and chilled in an ice bath to a solution of 382.5 g (1.854 mol) DCC in 600 ml of tetrahydrofuran in 30 min. The solution was then heated to 30°C and crystallized so that it was maintained in the stirring state by first filling it with 0.5 g tetrahydrofuran, then heated to about 0.2 °C and then diluted with 0.5 g aceton at approximately 1 °C. This was done for about 30 min. At about 50 °C, the solution was dissolved in water under vacuum.

The yield was 373.9 g (corresponding to 57.3% of the total)

The following table shows the results of the analysis of the test chemical in the test chemical:

72,4 g (0.1 mol) N,N'-Di-(3-nitratopivaloyl) -L-cystin-di-(N-hydroxysuccinimidester) were dissolved in 300 ml of ethyl acetate, a solution of 16.5 ml (25%) ammonia solution and 60 ml water was added by stirring, dripped, stirred for 15 minutes, a solution of 1.65 ml (25%) ammonia solution and 6 ml water was added again and stirred for 30 minutes.

After separation of the organic phase, the solvent was washed with 100 ml of water, dried with sodium sulphate, clarified with activated carbon and completely removed, leaving 56.72 g of residue.

The product was vacuumed and washed twice with 25 ml of methanol/water 1:1.

The yield was 37.4 g (70·75% d.e.). Fp: 82,3°C. The temperature of the water is

Example 14 The following table is provided for the determination of the active substance:

72,4 g (0.1 mol) N,N'-Di-(3-nitratopivaloyl) -L-cystine-di-(N-hydroxysuccinimidester) (Stage 13, example 1) were dissolved in 300 ml of ethyl acetate, a solution consisting of 19 ml (40%) N-methylamine solution and 60 ml of water was added at room temperature, dripped and stirred for 15 minutes, then added 1.7 ml again and stirred for 30 minutes.

The organic phase was separated, washed with 100 ml of water, dried with sodium sulphate and clarified with activated carbon. The solvent was completely removed, leaving 59.44 g of residue. This was dissolved in 90 ml of methanol, added to 40 ml of water and decrystallized.

The product was vacuumed and washed twice with 25 ml of methanol/water 1:1.

The yield was 38.51 g (69.18% d.t.). The temperature of the water is:

Example 15 The following table is provided for the determination of N,N'-Di- ((3-Nitratopivaloyl) -L-cystine-di- ((N-butylamide)

7,3 g (0.01 mol) N,N'-Di(3-nitratopivaloyl) -L-cystin-di-(N-hydroxysuccinimidester) (Stage 13, Step 1) were dissolved in 80 ml of dichloromethane at room temperature, a solution of 1,61 g (0.022 mol) n-butylamine was added to 20 ml of dichloromethane while stirring and stirred for one hour. The organic phase was then washed successively with 10 ml of 1 n of hydrochloric acid, 10 ml of 9 per cent sodium hydrocarbonate solution and 10 ml of water and distilled on the Roaportav®, yielding a 5.7 g (= 89.0 d.Th.) % residue which was crystallized at 20 ml of methanol and 2 ml of H2O2 at 0 °C.

The yield was 4.3 g (67.1% d.e.). Fp: 78,4°C. Other

Example 16 The following table is provided for the determination of N,N'-Di- ((3-Nitratopivaloyl) -L-cystine-di- ((N-tert-butylamide))

7.3 g (0.01 mol) N,N'-(3-nitratopivaloyl) -L-cystin-di-(N-hydroxysuccinimidester) (Stage 13, Example 1) were dissolved in 80 ml dichloromethane, a solution of 1.61 g (0.022 mol) tert-butylamine was added to 20 ml dichloromethane by stirring and stirred for one hour, then the organic phase was successively washed with 10 ml of 1 n of hydrochloric acid, 10 ml of 9 per cent sodium hydrocarbonate solution and 10 ml of water and destilled with Rotavapor®, yielding a residue of 6.1 g (= 95.2 per cent d.Th.) which was decrystallized from 25 ml of methanol and 2 ml of H2O at 0°C.

The yield was 2.4 g (37.5% d.v.th). Fp: 81 to 82°C

Example 17 The following table shows the results of the analysis of the product characteristics:

7.3 g (0.01 mol) N,N-Di(3-nitratopivaloyl) -L-cystin-di-(N-hydroxysuccinimidester) (Stage 13, Example 1) was dissolved in 80 ml dichloromethane, a solution of 1.92 g (0.022 mol) morpholine was dripped into 20 ml dichloromethane by stirring and stirred at room temperature overnight. The organic phase was then successively washed with 10 ml of 1 n of hydrochloric acid, concentrated sodium hydrocarbonate solution and water, dried, filtered and completely de-distilled with sodium sulphate, leaving 6.06 (corresponding to 91.2 d.Th.) % of the residual residue to be gestrified, and the column was cleaned on chromatography.

The yield was 4.71 g (70·9% of the total). Fp: 33,6 °C

Example 18 The following table shows the total number of products for which the product is intended to be used:

7,3 g (10 mMol) N,N'-Di-(3-Nitratopivaloyl) -L-cystin-di-(N-hydroxysuccinimidester) (Stage 13, Example 1) was dissolved in 150 ml of propanol-2, stirred overnight at room temperature and then largely removed from the propanol-2 on the Rotavapor®. The remaining residue was absorbed into 50 ml of dichloromethane, washed twice with 25 ml of water, dried on sodium sulphate and completely roasted on the rotary evaporator, leaving a residue of 5,86 g (95.28 % d.Th.) of oil.

The product was dissolved in 35 ml of methanol and crystallized at -25°C, the resultant product was vacuumed, washed twice with 5 ml of deep-chill methanol and dried in a vacuum dryer at room temperature.

The yield was 4.01 g (or 65.31% d.e.). Fp: 88,2°C. The temperature of the water is

Example 19 The following table shows the results of the analysis of the test chemical:

The 3,1 g (10 mmol) glutathione was dissolved in 10 ml H2O and chromatographed by a RP-18 column using a solution consisting of 5,3 g (10 mmol) N,N'-Di-(3-nitratopivaloyl) -L-cysteindiamide (Example 13) in 50 ml of methanol under nitrogen gas, left at room temperature for three days and then agglomerated to dry on the Rotavapor®. The 8,7 g residue was dissolved in 30 ml of Met and 20 ml of water and chromatographed by a book chromatography system using an RP-18 column. The second reaction was obtained on the Rotavapor® to dry on the rotavapor®, agglomerated to dry, with a residue of 1,5 g, heated in 1 ml of water and 25 ml of ethanol. The ethanol was dissolved overnight in a vacuum at 0°C and submerged in water at a temperature of 2°C, and then submerged in a vacuum with ethanol at a temperature of 5°C.

The yield was 0.87 g (15.3% d.v.th). Fp: 87,7°C. Other

Example 20 The following table shows the results of the analysis of the test chemical in the feed additive:

17.7 g (60 mmol) 3-nitratopivaloyl-L-cysteine ethyl ester was dissolved in 100 ml of acetic acid and mixed with a solution of 18.50 g (60 mmol) glutathione in 85 ml H2O and 50 ml of acetic acid. This mixture was mixed with a water solution of 4.28 g (20 mmol) potassium iodate in 65 ml of water, stirred and cooled at 10°C, and dripped for about 30 minutes until the solution was exothermic. After a few minutes of stirring, a substance crystallized at room temperature and was identified by thin-film chromatography as N,N'-di-nitratopivaloyl-L-cysteine. The solution was mixed with 100 ml of water and cooled to 0°C. The substance was then crystallized, and the substrate was removed.The mother liquor was reduced to dry by Rotavapor® and the remaining residue was stirred with 100 ml of water and 250 ml of ethyl acetate, resulting in a jelly-like product which could not be extracted and was therefore dissolved by adding 100 ml of 1 n HCl. The combined aqueous solutions were reduced to dry by Rotavapor®, resulting in an oily residue (15.5 g). This was dissolved in 50 ml of water and set to a pH of 4.5 with a 25% ammonia solution. The set solution was cooled to 0 °C,The solution was then compressed and the resulting residue (10.9 g) was separated in 15 column runs by the Abimed chromatography system. The combined second fractions were compressed at the Rotavapor® until dry, the remaining residue (1.2 g) was dissolved in 25 ml ethanol and 1.5 ml water under heating and refrigerated overnight at 0 °C. The resulting product was vacuumed twice with 5 ml ethanol of 0 °C and washed in a room and at room temperature and vacuum.2 Dried by phosphorus dioxide to weight consistency.

The yield was 0.77 g (or 6.4% of the total). The temperature of the water is:

Example 21 The following table shows the results of the analysis of the test chemical in the feed additive:

5.9 g (20 mmol) 3-nitratopivaloyl-L-cysteine ethyl ester was dissolved in 50 ml of acetic acid and added to 25 ml of water with a solution of 3.3 g (20 mmol) N-acetyl-L-cysteine. This mixture was mixed with a water solution of 1.43 g (0.866 mmol) potassium iodate in 25 ml of water, stirred and cooled at 10°C, until the solution was exothermic. After a few minutes, a substance crystallized at room temperature and was identified by thin film diathesis as N,N'-N-nitratopivaloyl-L-cysteine. The solution was added to 100 ml of water and cooled to 0 °C. The substance was then removed from the substrate and sub-cristallised to 7°C.The remaining residue was stirred with 50 ml of water and 200 ml of ethyl acetate. The org phase was separated, washed successively with 50 ml of 1 n HCl and 50 ml of H2O, dried with sodium sulphate and dried with rotavapor®. This left 4.1 g of oily product, which was cleaned column chromatographically by RP column via the Büchi system. The residue, which was stirred with the second fraction (3.9 g) at rotavapor®, was dissolved in 10 ml of methanol and cooled with 15 ml of water and cauterized to 0 °C. The R was cooled. The substance was then crystallized and vacuumed to a vacuum drying tank.

The yield was 2.4 g (79.0% d.e.). FP: Crystals, after a few weeks hard oil.

Example 22 The following table shows the results of the analysis of the product:

8.82 g (30 mmol) 3-nitratopivaloyl-L-cysteine ethyl ester was dissolved in 120 ml of methanol and a solution of 4.50 g (30 mmol) D,L-penicillamine was added at 5°C - 10°C to 40 ml of water and 20 ml of 1 n hydrochloric acid. After adding 2.14 g (10 mmol) potassium iodate, stirring for approximately 1.5 h at 10°C - 15°C, discoloring with sodium thiosulfate and suctioning the crystallized residue at approximately 5°C. After air drying, 5.8 g of residue was obtained, which was thinly diochromatographically identified as N,N'-L-nitratopivaloyl-ethyl-ethyl-ethyl-steroid.

The filtrate was completely evaporated in the rotary evaporator, the residue was incorporated into 100 ml of concentrated sodium acetate solution, clarified at about 80°C with 1 g of activated carbon and replaced with 20 g of sodium chloride (clear solution).

The yield was 1.83 g (corresponding to 13.8% of the total) The temperature of the water is:

Example 23 The following table is added to the table of the active substance:

1.91 g (10 mmol) N-acetyl-D,L-penicillamine and 2.94 g (10 mmol) 3-nitratopivaloyl-L-cysteine ethyl ester were dissolved in 40 ml of methanol and 15 ml of water. 710 mg (3.3 mmol) potassium iodate were added at 15°C - 20°C in portions. (After adding an additional spatula tip of potassium iodate, a permanent yellowing was maintained due to free iodine.) The solution was discoloured and neutralized by adding a small amount of sodium thiosulfate. The residue was absorbed in concentrated sodium carbonate solution (CO2 development) and the N,N'-di-di-nitratopivaloyl-L-cysteine ethyl ester was removed by DC-methanol extraction under controlled conditions with a resistance of 1.1 g.

The aqueous phase was acidified with concentrated hydrochloric acid and extracted with 50 ml of ethyl acetate, with the ethyl acetate removed completely, leaving a residue of 1.48 g.

The total residue was column chromatographically purified in 150 mg servings (Abimed Chromatography System, RP-18 column).

The residue from fraction 2 was decrystallized from 30 ml ethyl acetate/n-hexane 1/1

The yield was 350 mg (7.24% d.i.). The temperature of the water is:

Pharmaceutical data Vessel relaxation in vitro

The vasodilatory effects of the compounds of generic formula I were studied in vitro in isolated rat ovary rings, where the aorta was removed from the aorta after anaesthesia, stripped of fat and adventive tissue and divided into ring segments approximately 5 mm wide. The aortic rings were transferred to a tempered, carbogen-coated bath with a 2 g pre-load of tyrodel solution. Continuous force development was recorded after 90 minutes of equilibrium with 2 x 10-7 mol/l phenylephrine. After reaching a stable contraction level, the relative concentrations of the ovary were added according to the ECF, with the concentration of the ovary being determined at the next stable concentration of the active substance (ECF) being approximately 50 to 50% (see Table 1). Tabelle 1

Substanz		Anzahl der Einzelversuche [n]
N,N'-Di-(3-Nitratopivaloyl)-L-cystindiethylester		6
N,N'-Di-(3-Nitratopivaloyl)-L-cystin		6
N,N'-Di-(3-Nitratopivaloyl)-L-cystindiamid		6
N,N'-Di-(3-Nitratopivaloyl)-L-cystin-di-tert.-butylester		3
N,N'-Di-(3-Nitratopivaloyl)-L-cystindipiperidid		6
N,N'-Di-(3-Nitratopivaloyl)-L-cystin-di-(N,N'-methylamid)		4

Blood pressure effects on the watch dog

To demonstrate the effect of nitrate in vivo, the effects of the compounds of the invention on systolic arterial (SAP), central venous (CVP) and pulmonary arterial (PAP) blood pressure in the waking dog were investigated by measuring the SAP by a tip catheter transducer injected into the aorta via the femoral artery, the CVP and PAP by a swan catheter injected through the V.jugularis sin. whose catheter tips were extended to the A. pulmonalis court or right heart, respectively, over whose lumens the pressure on the statham pressure was measured. To quantify the blood pressure produced by the invention, the FISN was measured by a transducer below the blood pressure of the IV (A 5-5 μg/kg/m2 of isofloxacin) after the intravenous administration of the AUC of the compound, measured at a pressure of 26.8 μg/kg/m3 of GABA. Other Tabelle 2

	AUC (SAP) (mg)	AUC (CVP) (mg)	AUC (PAP) (mg)
N,N'-Di-(3-Nitratopivaloyl)-L-cystindiethylester	94,1	85,7	12,0
N,N'-Di-(3-Nitratopivaloyl)-L-cystin	17,3	67,9	2,7
N,N'-Di-(3-Nitratopivaloyl)-L-cystindiamid	55,3	46,9	28,1
N,N'-Di-(3-Nitratopivaloyl)-L-cystindipiperidid	10,4	36,9	18,5
N,N'-Di-(3-Nitratopivaloyl)-L-cystin-di-(N,N'-methylamid)	41,9	33,7	3,5
5-ISMN	22,2	25,4	8,9

The significantly increased AUC values for reducing blood pressure after administration of the compounds of the invention compared to the classical nitrate 5-ISMN demonstrate their high efficacy.

Claims (11)

1. Compounds of the general formula I in which R and R' denote groups of the general formulae in which

   R¹¹   denotes hydrogen, alkyl having 1 to 6 carbon atoms, substituted lower alkyl in which the substituent is halogen, hydroxyl, lower alkoxy having 1 to 6 carbon atoms, aryloxy, amino, lower alkylamino having 1 to 6 carbon atoms, acylamino, acyloxy, arylamino, mercapto, lower alkylthio having 1 to 6 carbon atoms, arylthio,

   R¹²   denotes hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R¹³   is nitratoalkyl having 1 to 6 carbon atoms,

   r   has the numerical values 0 to 10,

   and in which

   R¹, R^1'   denote hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R², R^2'   are hydrogen, lower alkyl having 1 to 6 carbon atoms, phenyl, methoxyphenyl, phenyl-lower-alkyl having 1 to 6 carbon atoms, methoxyphenyllower-alkyl having 1 to 6 carbon atoms, hydroxy-phenyl-lower-alkyl having 1 to 6 carbon atoms, hydroxylower-alkyl having 1 to 6 carbon atoms, alkoxy-lower-alkyl having 1 to 6 carbon atoms, amino-lower-alkyl having 1 to 6 carbon atoms, acylamino-lower-alkyl having 1 to 6 carbon atoms, mercapto-lower-alkyl having 1 to 6 carbon atoms or lower alkyl-thio-lower-alkyl having 1 to 6 carbon atoms,

   R³, R^3'   are hydroxyl, lower alkoxy having 1 to 6 carbon atoms, lower alkenoxy having 1 to 6 carbon atoms, di-loweralkylamino-lower-alkoxy having 1 to 6 carbon atoms, acylamino-lower-alkoxy having 1 to 6 carbon atoms, acyloxylower-alkoxy having 1 to 6 carbon atoms, aryloxy, aryl-lower-alkoxy having 1 to 6 carbon atoms, substituted aryloxy or substituted aryl-lower-alkoxy having 1 to 6 carbon atoms in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino having 1 to 6 carbon atoms, di-loweralkylamino having 1 to 6 carbon atoms, aryl-lower-alkylamino having 1 to 6 carbon atoms, hydroxy-loweralkyl-amino having 1 to 6 carbon atoms, pyrrolidine, piperidine, morpholine, piperazine or amino-acid residues via peptide linkage,

   R⁴, R^4'   are hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R⁵, R^5'   denote like R⁴, R^4' hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R² and R³,   and R^2' and R^3', can be linked together and R and R , can be linked together to form an ester or amide,

   R¹ and R²,   and R^1' and R^2', can be linked together to form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge having 3 to 4 carbon atoms which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy having 1 to 6 carbon atoms, lower alkyl having 1 to 6 carbon atoms or di-lower-alkyl having 1 to 6 carbon atoms,

   m, n, o, p, q   and m', n', o', p' and q' have the numerical values 0 to 10,

   and the physiologically tolerated salts thereof.
2. Compounds according to Claim 1, characterized in that their nitratoalkane- or nitratoalkylarylalkanecarboxylic acid components have a chain length of 2 to 6 carbon atoms which are straight-chain, branched, racemic or optically isomeric.
3. Compounds according to Claims 1 and 2, characterized in that the amino-acid disulphides contained in them are cystine, homocystine or penicillamine disulphide.
4. Compounds according to Claims 1 to 3, characterized in that the amino-acid disulphides are in the stereochemical L-form.
5. Compounds according to Claims 1 to 4, characterized in that the amino-acid disulphides are in the stereochemical D,L-form.
6. Compounds according to Claims 1 to 5, characterized in that they have the following chemical formulae

   N,N'-di(3-nitratopivaloyl)-L-cystine

   N,N'-di(3-nitratopivaloyl)-D,L-homocystine

   N,N'-di(3-nitratopivaloyl)-L-cystine diethyl ester

   N,N'-di(3-nitratopivaloyl)-D,L-homocystine diethyl ester

   N,N'-di(3-nitratopivaloyl)-L-cystine-di-(2-methyl-2-propylester)

   N,N'-di(4-nitratomethylbenzoyl)-L-cystine dimethyl ester

   N,N'-di(3-nitratomethylbenzoyl)-L-cystine dimethyl ester

   N,N'-di(4-nitratomethylbenzoyl)-L-cystine-di(N,N'-butyl-amide)

   N,N'-di(3-nitratomethylbenzoyl)-L-cystine-di(N,N'-butyl-amide)

   N,N'-di(4-nitratomethylbenzoyl)-L-cystinediamide

   N,N'-di(3-nitratomethylbenzoyl)-L-cystinediamide

   N,N'-di(3-nitratopivaloyl)-L-penicillamine disulphide-diamide

   N,N'-di(3-nitratopivaloyl)-L-cystinediamide

   N,N'-di(3-nitratopivaloyl)-L-cystine-di(N,N-methylamide)

   N,N'-di(3-nitratopivaloyl)-L-cystine-di((N,N-butylamide)

   N,N'-di(3-nitratopivaloyl)-L-cystine-di(N,N-tert.-butylamide)

   N,N'-di(3-nitratopivaloyl)-L-cystine-dimorpholide

   N,N'-di(3-nitratopivaloyl)-L-cystinediisopropyl ester.
7. Process for the preparation of compounds according to Claims 1 to 6, characterized in that the compounds are obtained in a manner known per se by condensation of the appropriate nitratoalkyl- or nitratoalkylarylalkylcarboxlic acid or its reactive derivatives with the amino groups of an amino-acid sulphide.
8. Process for the preparation of compounds according to Claims 1 to 6, characterized in that the appropriate nitratoalkyl- or nitraoalkylarylalkylcarboxylic acids or their reactive derivatives are condensed with the amino group of amino acids containing thiol groups, and the resulting compounds are subsequently oxidized with dimerization to the corresponding disulphides.
9. Process for the preparation of compounds of the general formula II in which R and R' denote groups of the general formulae in which

   R¹¹   denotes hydrogen, alkyl having 1 to 6 carbon atoms, substituted lower alkyl having 1 to 6 carbon atoms in which the substituent is halogen, hydroxyl, lower alkoxy having 1 to 6 carbon atoms, aryloxy, amino, lower alkylamino having 1 to 6 carbon atoms, acylamino, acyloxy, arylamino, mercapto, lower alkylthio having 1 to 6 carbon atoms, arylthio,

   R¹²   denotes hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R¹³   is nitratoalkyl having 1 to 6 carbon atoms,

   r   has the numerical values 0 to 10,

   and in which

   R¹, R^1'   denote hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R², R^2'   are hydrogen, lower alkyl having 1 to 6 carbon atoms, phenyl, methoxyphenyl, phenyl-lower-alkyl having 1 to 6 carbon atoms, methoxyphenyllower-alkyl having 1 to 6 carbon atoms, hydroxy-phenyl-lower-alkyl having 1 to 6 carbon atoms, hydroxylower-alkyl having 1 to 6 carbon atoms, alkoxy-lower-alkyl having 1 to 6 carbon atoms, amino-lower-alkyl having 1 to 6 carbon atoms, acylamino-lower-alkyl having 1 to 6 carbon atoms, mercapto-lower-alkyl having 1 to 6 carbon atoms or lower alkyl-thio-lower-alkyl having 1 to 6 carbon atoms,

   R³, R^3'   are amino, lower-alkylamino having 1 to 6 carbon atoms, di-loweralkylamino having 1 to 6 carbon atoms, aryl-lower-alkylamino having 1 to 6 carbon atoms, hydroxy-loweralkylamino having 1 to 6 carbon atoms, pyrrolidine, piperidine, morpholine, piperazine or amino-acid residues via peptide linkage,

   R⁴ , R^4'   are hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R⁵, R^5'   denote like R⁴, R^4' hydrogen or lower alkyl,

   R¹ and R²,   and R^1' and R^2', can be linked together to form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge having 3 to 4 carbon atoms which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy having 1 to 6 carbon atoms, lower alkyl having 1 to 6 carbon atoms or di-lower-alkyl having 1 to 6 carbon atoms,

   m, n, o, p, q   and m', n', o', p' and q' have the numerical values 0 to 10,

   which is characterized in that compounds of the general formula III in which R denotes a group of the general formulae in which

   R¹¹   denotes hydrogen, alkyl having 1 to 6 carbon atoms, substituted lower alkyl having 1 to 6 carbon atoms in which the substituent is halogen, hydroxyl, lower alkoxy having 1 to 6 carbon atoms, aryloxy, amino, lower alkylamino having 1 to 6 carbon atoms, acylamino, acyloxy, arylamino, mercapto, lower alkylthio having 1 to 6 carbon atoms, arylthio,

   R¹²   denotes hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R¹³   is nitratoalkyl having 1 to 6 carbon atoms,

   m and r   have the numerical values 0 to 10,

   in the form of their free acids, reactive halides, azides, esters and anhydrides are condensed in a manner known per se with compounds of the general formula IV in which

   R¹, R^1'   denote hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R², R^2'   are hydrogen, lower alkyl having 1 to 6 carbon atoms, phenyl, methoxyphenyl, phenyl-lower-alkyl having 1 to 6 carbon atoms, methoxyphenyllower-alkyl having 1 to 6 carbon atoms, hydroxy-phenyl-lower-alkyl having 1 to 6 carbon atoms, hydroxylower-alkyl having 1 to 6 carbon atoms, alkoxy-lower-alkyl having 1 to 6 carbon atoms, amino-lower-alkyl having 1 to 6 carbon atoms, acylamino-lower-alkyl having 1 to 6 carbon atoms, mercapto-lower-alkyl having 1 to 6 carbon atoms or lower alkyl-thio-lower-alkyl having 1 to 6 carbon atoms,

   R³¹, R^31'   denote hydroxyl or halogen,

   R⁴ , R^4'   are hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R⁵, R^5'   denote like R⁴, R^4' hydrogen or lower alkyl having 1 to 6 carbon atoms,

   R¹ and R²,   and R^1' and R^2', can be linked together to form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge having 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy having 1 to 6 carbon atoms, lower alkyl having 1 to 6 carbon atoms or di-lower-alkyl having 1 to 6 carbon atoms,

   m, n, o, p, q   and m', n', o', p' and q' have the numerical values 0 to 10,

   to give compounds of the general formula V the latter are converted at their free or halogenated carboxyl functionalities with N-hydroxysuccinimide into activated carboxylic acid N-hydroxysuccinimide esters of the general formula VI in which R³² and R^32' denote, deviating from the abovementioned meaning, and the latter are subsequently reacted with ammonia, a primary or a secondary amine, in particular with lower alkylamine having 1 to 6 carbon atoms, di-lower-alkylamine having 1 to 6 carbon atoms, aryllower-alkylamine having 1 to 6 carbon atoms, hydroxylower-alkylamine having 1 to 6 carbon atoms, pyrrolidine, piperidine, morpholine, piperazine or amino acids to give the compounds of the general formula II.
10. Compounds which have the following names

    - N-3-nitratopivaloyl-L-cysteinamide-glutathione mixed disulphide,

    - N'-3-nitratopivaloyl-L-cysteine ethyl ester-glutathione mixed disulphide,

    - N-3-nitratopivaloyl-L-cysteine ethyl ester-N'-acetyl-L-cysteine mixed disulphide,

    - N-(3-nitratopivaloyl)-L-cysteine ethyl ester-D,L-penicillamine mixed disulphide,

    - 2-acetylamino-3-[2-(2,2-dimethyl-3-nitrooxy-propionyl-amino)-2-ethoxycarbonylethyldisulphanyl]-3-methylbutyric acid.
11. Pharmaceutical containing one or more compound(s) according to Claims 1 to 16 and 10 as well as conventional excipients and ancillaries.