SK278385B6 - Nitratoalkane carboxylic acid derivatives, method of their preparation, their use and medicine containing these matters - Google Patents

Abstract

This patent describes derivatives of nitrato alkane carboxyl acids with a general formula (I), N-acylaminoacids or N-acylpeptides especially. The procedure closed to the production of the mentioned acids is based on the reaction of a compound with a general formula (II) which is undertaken to the thioester reaction and this compound is combined with aminoacids and/or N-acylaminoacids, with peptides and or N-acylpeptides containing 2 up to 5 peptide bonds related to aminoacid rests, in this reaction, and after that, the gained compound is converted to its salts being not harmful from pharmaceutical point of view, if necessary. The above mentioned compounds are applied as the medication used for curing of the diseases related to the blood circulation or heart failures and also in the case of the blood high pressure, to expand peripheral catheters.

Description

The invention relates to nitratoalkanecarboxylic acid derivatives, processes for their preparation, their use and medicaments containing them.

BACKGROUND OF THE INVENTION

Organic nitrates (nitric acid esters) have proven successful in the treatment of heart disease.

They exert their effect by relieving the heart by reducing systolic and diastolic pressure, and by improving the supply of oxygen to the heart by widening the coronary vessels.

In recent years, however, it has been found that the organic nitrates currently used in therapy, such as glycerol nitrates (GIN), isosorbit-5-mononitrate or isosorbitdiniral, exhibit a substantial attenuation of nitrate-based activity over a relatively short period of time tolerance. Initial experiments show that the presence of sulfhydryl groups suppresses nitrate tolerance and tolerance that has already occurred may weaken.

The mechanism of tolerance development is currently explained as follows:

To date, the pharmacological effect of organic nitro compounds is dependent on the presence of cysteine. With it, the nitrate forms a common precursor, which breaks down, among other things, releasing the RO-radicals that activate the target enzyme, soluble guanylate cyclase of smooth muscle cells. Further downstream reactions triggered by cGMP formation then lead to relaxation or vascular dilatation.

As for the reactive and short-term, yet hypothetical intermediate product, it may be nitric acid thioester or thionitrate, by intramolecular rearrangement with further subsequent reactions not yet elucidated, the formation of nitrosothiol is finally assumed, from which nitric oxide is then released, optionally nitrite ions. On the other hand, enzymatic degradation by GSH-reductase could be of no significance for pharmacological action, since it leads exclusively to the formation of nitrite ions. Thus, non-enzymatic degradation requires cysteine as described and is thus dose-dependent (depletion of the SH-group pool), so that after a certain period of time, sufficient NO can no longer form as a guanylcyclase activator and clinically attenuate the effect.

EP 89 116 700.9 discloses specifically synthesized compounds which consist of nitro fatty acids (nitratoalkanecarboxylic acids) and sulfur-containing amino acids or peptides. The presence of sulfhydryl groups has nitrate tolerance or suppressed or weakened tolerance already established.

Among others, compounds having sulfur-containing amino acids such as cysteine or methionine in the form of their methyl, ethyl or propyl esters are disclosed. Finally, the sulfhydryl groups of cysteine can be esterified with lower alkanecarboxylic acids having 2 to 8 carbon atoms.

Although these compounds already possess valuable pharmacological properties with respect to the removal of nitrate tolerance, or to the removal or weakening of already unstable tolerance, they are disadvantaged. They have low melting points, have minimal solubility in water and cause difficulties with respect to purity. Furthermore, their pharmacological activity is relatively low.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide novel organic compounds which are to be available to the skilled person and which do not exhibit the aforementioned drawbacks and exhibit enhanced pharmacological activity, in particular potency.

This object was achieved according to the present invention by the preparation of novel nitratoalkanecarboxylic acid derivatives of the general formula (I)

R ¹ OR ³ R ⁴ O

II

O _! XO-CH ₂ -C- (CH ₂ ) n -, CN- (CH ₂ ) _i -C- (CH ₂ ) ₀ -CR (I),

II

R ² R ⁵ in which is

R hydroxy, Ci-6-alkoxy, C ₂ .6_alkénoxyskupinu, di-C1-5-alkylamino-alkoxy C4.e, acylanúno-C-e-alkoxy, acyloxy Ci.e-alkoxy, aryloxy, aryl-C 6-alkoxy, substituted aryloxy or substituted aryl-C 1-6 -alkoxy, wherein the substituent is methyl, halogen or methoxy, amino, C 1-4 -alkylamino. di-C 1-6 -alkylamino, aryl-C 1-6 -alkylamino, hydroxy-C 1-6 -alkylamino or amino acid residues via a peptide bond,

R 1 is hydrogen, C 1 -C 6 alkyl, substituted C 1-6 alkyl, wherein the substituent is halogen, hydroxy, C 1-6 -alkoxy, aryloxy, amino, C 1-6 -alkylamino, acylamino, acyloxy, arylamino, mercapto, C 1-6 -alkylthio or arylthio,

R ² as R ^{1 is a} hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R ^{3 is a} hydrogen atom or C 1-6 alkyl; _s -alkyl,

R ^{4 is a} hydrogen atom, a C 1-6 alkyl group, a phenyl group, a methoxyphenyl group, a phenyl-C 1-6 alkyl group, a C 1-6 alkyl group, a phenyl group, a methoxyphenyl group or a phenyl-C 1-6 alkyl group; _6- alkyl, methoxyphenyl-C 1-6 -alkyl, hydroxyphenyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, alkoxy-C 1-6 -alkyl, C 1-6 -alkylamino, acylamino-C 1-6 -alkyl; .e-alkyl, mercapto-Cie-alkyl group or a C ₆ alkylthio-C. _6- alkyl,

R ⁵ S-acyl compounds of C 1-6 -alkylthiol, in particular their glycine thioesters, alanine thioesters or leucine thioesters, N-acylglycine thioesters, N-acylalanine thioesters or N-acylleucine thioesters, peptide thioesters Tyr-Pro-Phe-Pro-Gly or N-acr-Ac-Gly Pro-Phe-Pro-Gly-thioesters, wherein

R @ ⁴ and R @ ⁴ may be linked to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing a double bond, or the aforementioned alkylene bridge; substituted with hydroxyl, C 1-6 -alkoxy, C 1-6 -alkyl or di-C 1-6 alkyl. _fl -alkyl m, n, o = 0-10,

And their physiologically acceptable salts.

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

According to another embodiment of the invention, the nitrate fatty acid components have a chain length of C ₂ to C ₆ . They may be straight chain or branched chain, may be racemic or optically isomeric.

Preferably, the nitratoalkanecarboxylic acid derivatives of formula (I) comprise a series of amino acids containing sulfur amino acids such as cysteine, methionine, homocysteine or -dimethylcysteine.

According to another preferred embodiment of the invention, the amino acids have the stereochemical form I.

Amino acids containing sulfur may be esterified at the C-terminus.

According to another preferred embodiment of the invention, the amino acids such as cysteine, homocysteine, methionine and / or -dimethylcysteine are present in the form of methyl ester, ethyl ester or propyl ester.

Particularly preferred within the meaning of the present invention are:

N-nitratopivaloyl-S- [N-acetylglycyl] -1-cysteine ethyl ester, N-nitratopivaloyl-S- [N-acetylalanyl] -1-cysteine ethyl as well as N-nitratopivaloyl-S- [N-acetylleucyl] -1-cysteine ethyl ester.

The compounds of formula (I) of the present invention can be prepared according to known methods by treating a compound of formula (H)

R ¹ OR 'R ⁴ O

II

O ₂ NO-CH ₂ -C- (CH ₂ ) _m -CN- (CH ₂ ) n -C (CH ₂ ) ₀ -CR (II),

II

R ² R in which they are

R is hydroxyl, Ci-s-alkoxy, C _2, 6-alkenoxy, di-Ci_6-alkylamino-Ci.6-alkoxy, acylamino-C 'alkoxy, aryloxy, aryl-C' alkoxy, substituted aryloxy or substituted aryl-Ci-6-alkoxy, wherein the substituent is methyl, halo or methoxy, amino, C _b5 -alkvlaminoskupinu, di-Ci-6-alkylamino, aryl-C '-alkylamino, hydroxy-C' -alkylamino or amino acid residues via a peptide bond,

R ^{1 is} hydrogen, C 1 -C 6 alkyl, or substituted C 1-6 alkyl, wherein the substituent is halogen, aryloxy, amino, acylamino, acyloxy, arylamino, mercapto, C 1-6 -alkylthio, or arylthio

R ² as R ^{1 is a} hydrogen atom or a C 1-6 -alkyl group,

R ^{3 is a} hydrogen atom or a C 1-6 alkyl group,

R ⁴ hydrogen, C «alkyl, phenyl, methoxyphenyl, phenyl-C ₁ .ŕ. alkyl, methoxyphenyl-C 6 alkyl group, a hydroxyphenyl-C '-alkyl, hydroxy-C-6 -alkyl, alkoxy-C 1 -alkyl, C 1-6 -alkyl; _6- alkylamino, C1-acylaminoalkyl, mercapto-C1-alkyl or C1-alkylthio-C1-alkyl,

R ⁴ and R ⁴ may be linked to each other to form an ester or amide and

R ³ and R ⁴ may be linked to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing a double bond, or said alkylene bridge, substituted with hydroxy, C '-alkoxy or di-C' _e alkoxy group,

R ⁶ C ⁶ -alkylthioam, n, o are as defined above, undergo the known thioester coupling reaction with amino acids, 2-acylamino acids, peptides or 2-acyl peptides with 2-5 peptide bonds of amino acid residues. Compounds of the general formula (Π) can be prepared as described in EP 89 116 700.9.

Accordingly, it is possible to use nitro-fatty acids of the general formula (A)

RiO

III

O ₂ NC-CH ₂ -C- (CH ₂ ) _m -C-OH (A),

I

R ² in which R ^1, R ² pm as defined above, in the form of their free acids, reactive halides, azides, esters and anhydrides, and let them react with a compound of formula (B)

R ³ R ⁴ O II II H _{N -} (CH ₂ ) _n -C- (CH ₂ ) ₀ -CR (B),

IR ⁶ wherein R ³ , R ⁴ , R ⁶ , as defined above, comprising amino acids and / or peptides, to form compounds of formula (Π).

Reactive nitratoalkanecarboxylic acid derivatives which can be used according to the method, such as: acid halides, acid anhydrides, activated amides and activated esters. Acid chlorides, acid azides, symmetrical acid anhydrides, activated esters and mixed anhydrides with organic and inorganic acids are preferred.

The condensation reactions of a nitratoalkanecarboxylic acid with an amino group of an amino acid may also be carried out in an inert solvent and in the presence of a condensation promoting agent which promotes the formation of an acid amide such as carbodiimide, N, N'-dicyclohexylcarbodiimide or similar carbodiimides; or pentamethylene ketene-N-cyclohexylimine, or phosphate, or fossil such as triethyl phosphite, ethyl polyphosphate or isopropyl polyphosphate, for 1 to 48 hours at temperatures of -10 ° C to the reflux temperature of the solvent.

Amino acids which may be used in the process as glycine, N-acetylglycine, alanine, N-acetylalanine, arginine, N-acetylarginine, N -? - benzoylargine, cysteine, N-acetylcysteine, N, S-dipivaloylcysteine, cysteine, N, N -diacetylcysteine, leucine, N-acetylleucine, lysine, N - & - and cetyllysine, N-acetyllysine, N - < - > diacetyllysine, proline, N-acetylproline, serine, N-acetylserine, O-acetylserine, N, O-diacetylserine, methionine, N-benzyolmethionine, phenylalanine, N-benzyolfenylalanine, N-acetylphenylalanine, asparagine, N-acetylasparagine, N-acetylasparagine monoethyl ester, N-acetylasparagine, N-acetylglutamic acid monomethyl ester.

In order to convert the compounds of formula (I) to their pharmacologically acceptable salts, these compounds are reacted, preferably in an organic or aqueous organic solvent, with an equivalent amount of inorganic or organic acid. Possible are hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, adipic acid, benzoic acid, salicylic acid, O -acetoxybenzoic acid, cinnamic acid, naphthoic acid, manilic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, methanesulfonic acid or p-toluenesulfonic acid.

The novel compounds of the present invention of formula (I) and their salts can be administered in liquid or solid form enterally or parenterally.

Water for injection is preferably water containing conventional additives for injectable media, such as stabilizing agents, solubilizers or buffers. Such additives include tartrate or citrate buffer, ethyl alcohol, complexing agents (such as ethylenediaminetetraacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity, and the like. Solid carriers include, for example, starches, lactose, mannitol, methylcellulose, talc, high disperse silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solids high molecular weight polymers (such as polyethylene glycols). Formulations suitable for oral administration may contain flavorings and sweeteners as appropriate.

According to another embodiment of the invention, the medicaments have a content of one compound of the present invention and / or a mixture thereof.

Said medicaments may be used in circulatory diseases, for example as coronary dilators, as agents for high pressure, cardiac insufficiency and for the expansion of peripheral vessels as well as of cerebral and cardioid vessels.

Pharmaceutical compositions containing a pre-calculated amount of one or more of the compounds of the present invention may be administered once a day in retarded formulations or several times a day at controlled intervals (two to three times a day). The amount of active ingredient administered daily is usually 20 to 300 mg based on a body weight of 75 kg. In the form of injections, the compounds of the present invention may be administered 1 to 8 times daily, optionally by continuous infusion. Normally an amount of 5 to 200 mg per day is sufficient.

A typical tablet may have the following composition:

1. N-Nitratopivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl-ster25 mg

2. starch U. S. P.57 mg

Lactose U. S. P.73 mg

4. talc U. S. P.9 mg

5. Stearic acid6 mg

The substances 1, 2 and 3 are sieved, granulated, mixed homogeneously with the substances 4 and 5 and then the mixture is tabletted.

The following examples illustrate the invention without limiting it.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of N-acetylglycine g (0.41 mol) of N-nitratopivaloyl-S- [N-acetylglycyl] -L-cysteine ethyl ester g is stirred in 300 ml of methylene chloride (CH 2 Cl 2) with stirring at room temperature and cooled to 10 ° C. While stirring, a solution of 109.8 g (0.373 mol) of N-nitratopivaloyl-L-cysteine ethyl ester in 300 ml of methylene chloride is added, with a slight exothermic reaction. The reaction mixture was cooled to 5 ° C with stirring, and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DDC) in 200 ml of methylene chloride was slowly added dropwise with stirring, maintaining the temperature between 5 and 10 ° C. After warming to room temperature, the reaction mixture was stirred at this temperature for four days. The dicyclohexylcarbodiimide is sucked off and washed twice with 100 ml of methylene chloride each time.

The combined methylene chloride phases are successively washed once with 200 ml of 9% sodium hydrogen carbonate solution, 300 ml of 1 N hydrochloric acid and 300 ml of distilled water. Finally, the methylene chloride phases are dried over anhydrous sodium sulphate and concentrated to constant weight on a rotavap (Rotavapor ^R , Buchi).

Yield: 162.9 g (146.74 g of theory) of N-nitratopivaloyl-S- [N-acetylglycyl] -L-cysteine ethyl ester as a pale yellow oil.

169.2 g of N-nitratopivaloyl-3- [N-acetylglycyl] -L-cysteine ethyl ester are dissolved in 470 ml of ethyl acetate at room temperature. After stirring at room temperature for 15 minutes, the undissolved white precipitate was filtered off. The clear pale yellow filtrate was slowly mixed with 390 ml of n-hexane at room temperature with stirring.

Seed crystals were added to the obtained solution and the mixture was stirred at room temperature overnight. The crystals formed are filtered off with suction and washed twice with 100 ml of a mixture of 20 ml of ethyl acetate and 80 ml of n-hexane each at room temperature.

The crystals are dried at room temperature in a vacuum oven, at a vacuum of 267 Pa, to constant weight.

Yield: 85.4 g (146.74 g of theory) of N-nitratopivaloyl-S- [N-acetylglycyl] -L-cysteine ethyl ester. Melting point: 71.6 ° C.

Example 2

Preparation of N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteine ethyl ester

53.8 g (0.41 mol) of N-acetylglycine are stirred in 300 ml of methylene chloride (CH 2 Cl 2) with stirring at room temperature and this mixture is cooled to 10 ° C. While stirring, a solution of 109.8 g (0.373 mol) of N-nitratopivaloyl-N-cysteine ethyl ester in 300 ml of methylene chloride is added, with a slight exothermic reaction. The reaction mixture is cooled to 5 ° C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DDC) in 200 ml of methylene chloride is slowly added dropwise while maintaining the temperature of the reaction mixture at 5-10 ° C. After warming to room temperature, the reaction mixture was stirred for four days. The dicyclohexylcarbodiurea is suctioned off and washed twice with 100 ml of methylene chloride each time.

The combined methylene chloride phases are successively washed once with 200 ml of 9% sodium hydrogen carbonate solution, 300 ml of 1 N hydrochloric acid and 300 ml of distilled water. Finally, the methylene chloride phases are dried over anhydrous sodium sulphate and concentrated to constant weight in a rotavapor evaporator (Rotavapor * Bilchi).

Yield: 160.5 g (151.84 g of theory) of N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteinethyl ester in the form of a pale yellow oil.

160.5 g of N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteine ethyl ester are dissolved in 345 ml of ethyl acetate at room temperature. After stirring at room temperature for 15 minutes, the undissolved white precipitate was filtered off. The clear pale yellow filtrate was slowly stirred with 345 ml of n-hexane at room temperature with stirring.

Seed crystals were added to the solution and the mixture was stirred at room temperature overnight. The precipitated crystals are filtered off with suction and washed twice with 100 ml of a mixture of 20 ml of ethyl acetate and 80 ml of n-hexane each at room temperature.

The crystals are dried at room temperature in a vacuum oven, at a vacuum of 267 Pa, to constant weight.

Yield: 78.2 g (151.84 g of theory) of N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysttin ethyl ester. M.p .: 76.6 ° C

Example 3

Preparation of N-nitratopivaloyl-S- [N-acetylleucyl] -L-cysteine ethyl ester

0.02 mol (= 6 g) of nitratopivalic acid cysteine ethyl ester is dissolved in 100 ml of dichloromethane. 0.03 mol (= 6.15 g) of N-acetylleucine and 0.1 g of dimethylaminopyridine (DMAP) are slowly added at 10 ° C and nitrogen. 0.03 mol (= 6.15 g) of dicyclohexylcarbodiimide (DCC) dissolved in 80 ml of dichloromethane is then added dropwise to the reaction mixture, and the reaction mixture is then stirred overnight at room temperature. treatment:

The pellet is suctioned off. The solution is extracted successively with an equivalent amount of 0.1 N hydrochloric acid solution, saturated bicarbonate solution and distilled water. The solvent was then removed by rotary evaporation (Rotavapor ^R , Buchi). 10 g of an oily residue are added. recrystallization:

g of the oily substance is dissolved in a mixture of 45 ml of ethanol and 40 ml of distilled water with slight heating. The solution was allowed to crystallize in a refrigerator overnight. The crystals are aspirated and dried in a vacuum oven.

The structure was confirmed by mass spectra. Melting point: 91.4 ° C HPLC chromatography: 98.7% Yield: 5 g = 0.012 mol = 57.4% of theory. Pharmacological data:

Hemodynamic profile of N-nitratopivaloyl-S- [N-α cetylalanyl] -L-cysteine ethyl ester and N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteine ethyl ester, m. j. The compounds of the invention, selected as an example, were examined by direct comparison with classical nitrates on Beagle dogs. Both oral and intravenous administration of both compounds (dose range: 0.01 to 1 mol / kg i.v. or 1 to 10 mol / kg po) results in a dose-dependent decrease in mean arterial and venous pressure with a predominant effect on the vessels. Enlargement of arterial blood vessels increased while cardiac output remained unchanged. The observed duration of action characterized both compounds as nitrates with a longer duration of action.

The observed dose-effect curves of the compounds, GTN (glyceryl trinitrate and IS-5-N isosorbide-5-mononitrate) showed convincingly that both new compounds are more effective in vivo than the most potent classical nitrate in reducing arterial and central venous blood pressure.

The following data show the effect of i. in. applications

1.7 mol / kg of two selected compounds of the invention in terms of systolic arterial and central venous blood pressure of awake Beagle dogs (n = 15).

compound SAP _m ax CVPmax N-nitratopivaloyl-S- [N-acetylglycyl] -L-cysteine ethyl ester -23 3 -46 4 N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteine ethyl ester -21 2 -46 4 GTN -25 3 -35 4 IS-5-N -6 1 -16 6

SAF = systolic arterial pressure CVP = central venous pressure

The effect of a relaxing vessel, for example selected compounds of the invention, N-nitratopivaloyl-S [N-acetylglycyl] -L-cysteine ethyl ester and N-nitratopivaloyl-S-N-acetylalanyl] -L-cysteine ethyl ester over conventional nitrates can also be confirmed in vitro on isolated rat aortic rings.

In addition, the nitrates in question were recorded by isometric registration of the strength of the effect curve at 4-5 mm wide and 2 g pre-loaded and 2 x W 'M phenylferin pre-contracted aortic rings in the Krebs-Henseleit solution at 37 ° C under an oxygen atmosphere. The following data show the mean values of these concentration-derived concentration-response curves (EC 50), which simultaneously induce semi-maximal relaxation of the pre-contracted aortic rings (n = 5).

compound EC50 (mol / l) N-nitratopivaloyl-S- [N-acetylglycyl] -L-cysteine ethyl ester N-nitratopivaloyl-S- [N-acetylalanyl] -L-cysteine ethyl ester GTN IS-5-N 8.3 x 10 ' ⁷ 8.3 x 10' ⁷ 2.8 x 10 ' ⁸ 2.1 x 10' ⁴

Claims (11)

1. Nitratoalkanecarboxylic acid derivatives of general formula (I) R ¹ OR ³ R ⁴ O I III I II O ₂ NO-CH ₂ -C- (CH ₂ ) _m -CN- (CH ₂ ) _n -C- (CH ₂ ) ₀ -CR (1), II R ² R in which is R is hydroxy; _n -alkoxy, C _; 6-alkenoxy, di-C 1-6 -alkylamino-C 1-6 -alkoxy, methoxyphenyl, phenyl-C 1-6 -alkoxy, substituted phenyl or substituted phenyl-C 1-6. _6- alkoxy, wherein the substituent is methyl, halogen, for example chlorine, bromine, fluorine or methoxy, amino, C1-6alkoxy; _6- alkylamino, di-C 1-6 -alkylamino, phenyl-C 1-6 -alkylamino, hydroxy-C 1-6 -alkylamino; _6- alkylamino or residues of glycine, leucine, alanine, cysteine via a peptide bond, R ^{1 is} hydrogen, C 1 -C 6 alkyl, substituted C 1-6 alkyl, wherein the substituent is halogen such as chlorine, bromine or fluorine, hydroxy, C 1-6 -alkoxy, phenyloxy, NH ₂ , C 1-6 -alkylamino , mercapto, C 1-6 -alkylthio, R ² as R ^{1 is} hydrogen or C _1-6 -alkyl, R ^{3 is} hydrogen or C 1-6 -alkyl, R ⁴ hydrogen, C 6 alkyl, phenyl, methoxyphenyl, phenyl-Ci-e-alkyl, methoxyphenyl-C 6 -alkyl, hydroxy-C _w -alkyl, hydroxy-C | _6 alkyl , alkoxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, mercapto-C 1-6 -alkyl, or C 1-6 -alkylthio-C 1-6 -alkyl, R ⁵ S-acyl compounds of mercaptomethyl, mercaptoethyl or mercaptopropyl, in particular their glycine thioesters, alanine thioesters or leucine thioesters, such as N-acetylglycine thioesters, N-acetylalanine thioesters or N-acetylleucine thioesters-thi-esters Pro-thiere pentapters Pro-Phe-Pro-Gly-thioesters. R @ ⁴ and R @ ⁴ may be linked to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing a double bond, or said alkylene bridge substituted hydroxy, C 1-6 -alkoxy, C 1-6 -alkyl or di-C 1-6 -alkyl and m, n, o are from 0 to 10, as well as their physiologically acceptable salts. Nitratoalkanecarboxylic acid derivatives according to claim 1, characterized in that they are in the form of their acid addition salts. Nitratoalkanecarboxylic acid derivatives according to claim 1 and 2, characterized in that their nitrous fatty acid components have a chain length of 2 to 6 carbon atoms, the chains being linear, branched and the acid is racemic or optically isomeric. Nitratoalkanecarboxylic acid derivatives according to claim 1 and 3, characterized in that the sulfur-containing amino acids are preferably cysteine, methionine, homocysteine or -dimethylcysteine. 5. Nitratoalkanecarboxylic acid derivatives according to claims 1 and 4, characterized in that the amino acids are present in the stereochemical L-form. Nitratoalkanecarboxylic acid derivatives according to claims 1 and 5, characterized in that the sulfur-containing amino acids are esterified at the O-terminus. Nitratoalkanecarboxylic acid derivatives according to claims 1 and 6, characterized in that the amino acids cysteine, homocysteine, dimethylcysteine and / or methionine are present as methyl ester, ethyl ester or propyl ester. 8. Nitratoalkanecarboxylic acid derivatives according to claim 7, characterized in that they are (a) N-nitratopivaloyl-S- [N-acetylglycyl] -1-cysteine ethyl ester b) N-nitratopivaloyl-S- [N-acetylalanyl] -1-cysteine ethyl ester c) N-nitratopivaloyl-S- [N-acetylleucyl] -1-cysteine ethyl ester. A process for the preparation of nitratoalkanecarboxylic acid derivatives of general formula (I) R ¹ OR ³ R ⁴ O I III I II O ₂ NO-CH ₂ -C- (CH ₂ ) n -CN- (CH ₂ ) n -C- (CH ₂ ) 0 -CR (I), II R ² R in which is R is hydroxy; _É -alkoxvskupinu, C _2, 6-alkenoxy, di-C I-a-amino-C-ι-6 alkoxy group, methoxyphenyl, phenyl-Ci-6-alkoxy, substituted phenyl or a substituted phenyl-Ci-s-alkoxy, wherein the substituent is methyl, halogen, for example chlorine, bromine, fluorine or methoxy, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino, phenyl-C 1-6 -alkylamino, hydroxy-C 1-6 -alkylamino or glycine residues, leucine, alanine, cysteine via a peptide bond, ^R1 hydrogen, alkyl having 1 to 6 carbon atoms, a substituted C "alkyl group, wherein the substituent is halo, for example chloro, bromo or fluoro, hydroxy, C-6-alkoxy, phenyloxy, NH _2, C-6 alkylamino, mercapto, C 1-6 -alkylthio R ² as R ^{1 is a} hydrogen atom or a C 1-6 alkyl group, R ^{3 is a} hydrogen atom or C 1-6 alkyl; _6- alkyl, R ^{4 is} hydrogen, C 1-6 -alkyl, phenyl, methoxyphenyl, phenyl-C 1-6 -alkyl, methoxyphenyl-C 1-6 -alkyl, hydroxyphenyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, mercapto-C 1-6 -alkyl or C 1-6 -alkylthio-C 1-6 alkyl. _6- alkyl, R ⁵ S-acyl compounds of mercaptomethyl, mercaptoethyl or mercaptopropyl, in particular their glycine thioesters, alanine thioesters or leucine thioesters, such as N-acetylglycine thioesters, N-acetylalanine thioesters or N-acetylleucine thioesters or thioesteres Pro-thesters-Proapters T yr-Pro-Phe-Pro-Gly-thioesters, R @ ⁴ and R @ ⁴ may be linked to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing a double bond, or said alkylene bridge substituted hydroxy, C 1-6 -alkoxy, C 1-6 -alkyl or di-C 1-6 -alkyl and m, n, o are numbers from 0 to 10, as well as their physiologically acceptable salts, characterized in that the compound of the general formula (Π) R ¹ OR ³ R ⁴ O I III I II O ₂ NO-CH ₂ -C- (CH ₂ ) _m -CN- (CH ₂ ) n -C (CH ₂ ) ₀ -CR (II), II R ² R in which is R hydroxy, Ci-6-alkoxy, C ₂ -6-alkenoxy, di-Ci-s-alkylamino-Ci-ealkoxyskupinu, methoxyphenyl, phenyl-C ealkoxyskupinu, substituted phenyl or a substituted phenyl-Ci-6-alkoxy, wherein the substituent is methyl, halogen, for example chlorine, bromine, fluorine or methoxy, amino, C 1-6 -alkylamino, di-C 1-6. _6- alkylamino, phenyl-C 1-6 -alkylamino, hydroxy-C 1-6 -alkylamino or amino acid residues via a peptide bond, R ^{1 is} hydrogen, C 1 -C 6 alkyl, substituted C 1-6 alkyl, wherein the substituent is halogen such as chlorine, bromine or fluorine, hydroxy, C 1-6 -alkoxy, phenyloxy, NH ₂ , C 1-6 -alkylamino, mercapto, C 1-6 -alkylthio R ² as R ^{1 is} hydrogen or C 1-6 -alkyl, R ^{3 is} hydrogen or C 1-6 -alkyl, R ^{4 is} hydrogen, C 1-6 alkyl, phenyl, methoxyphenyl, phenyl-C 1-6 -alkyl, methoxyphenyl-C 1-6 -alkyl, hydroxyphenyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, alkoxy-C 1-6 -alkyl, amino-C 1-6 -alkyl, mercapto-C 1-6 -alkyl or C 1-6 -alkyl; _6- alkylthio-C 1-6 -alkyl, R @ ⁴ and R @ ⁴ may be linked to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing a double bond, or said alkylene bridge substituted hydroxy, C 1-6 -alkoxy, C 1-6 -alkyl or di-C 1-6 -alkyl, R ⁶ represents a C _1-4 alkylthiol, undergoes a thioester coupling reaction with amino acids and / or N-acylamino acids, peptides and / or N-acylpeptides with 2 to 5 peptide bonds of amino acid residues, and then, if necessary, converts the compound to its pharmacologically acceptable salts . Nitratoalkanecarboxylic acid derivatives according to claims 1 to 8 for use as a medicament Use of nitratoalkanecarboxylic acid derivatives for the manufacture of a medicament for the prophylaxis of cardiac diseases of the circulatory system.