IE911023A1 - Nitratoalkanecarboxylic acid derivatives, a process for their preparation, use thereof and medicaments containing them - Google Patents

Abstract

Nitratoalkanoic acid derivatives of the general formula (I), in particular containing N-acylamino acids or N-acylpeptides, of the general formula (I) <IMAGE> in which the symbols have the meanings mentioned in the claims. They are distinguished by advantageous physicochemical properties and good physiological tolerability for active substances already preventing known nitrate tolerance or weakening a tolerance which has already set in. The compounds are used in medicaments for the treatment of circulatory disorders, high blood pressure, cardiac insufficiency and for dilating the peripheral vessels.

Description

Description Nitratoalkanecarboxylic acid derivatives, a process for their preparation, use thereof and medicaments containing them The invention relates to nitratoalkanecarboxylic acid derivatives, to a process for their preparation, to the use thereof and to medicaments containing them.

Organic nitrates (nitric acid esters) have proved reliable in the therapy of cardiac disorders.

They exhibit their action both through a relief of the strain on the heart via a lowering of preload and afterload and by an improvement in the oxygen supply to the heart by a dilatation of the coronary vasculature.

However, in past years it has been established that the organic nitrates hitherto employed in therapy, such as glycerol trinitrate (GTN), isosorbide 5-mononitrate or isosorbide dinitrate show a clear decrease in the action - nitrate tolerance - within a relatively short time with high and continuous supply to the organism. Numerous experiments indicate that the presence of sulphydryl groups can prevent the formation of a nitrate tolerance and reduce a tolerance which has already set in.

The mechanism of the production of tolerance is nowadays interpreted as follows: According to the present state of knowledge, the pharmacological action of the organic nitro compounds is - 2 dependent on the presence of cysteine. The organic nitrate forms a common precursor with this, from the decomposition of which, inter alia, NO radicals are released, which activate the target enzyme, the soluble guanylate cyclase of the smooth muscle cell. Other subsequent reactions caused by the formation of cGMP then lead to relaxation or vascular dilatation.

The reactive and short-lived, hitherto still hypothetical intermediate product could be the thioester of nitric acid or a thionitrate. By means of intramolecular rearrangement and other subsequent reactions which have still not been elucidated, the formation, finally, of a nitrosothiol is postulated, from which nitric oxide or nitrite ions are released. The enzyme15 dependent degradation with the aid of GSH reductase could on the other hand, since it leads exclusively to the formation of nitrite ions, be insignificant for the pharmacological action. The non-enzymatic degradation thus requires, as described, cysteine and is thus exhaustible in a dose-dependent manner (exhaustion of the SH group pool) so that in the long term sufficient NO can no longer be formed as an intrinsic activator of the guanyl cyclase and, clinically, a decrease in action occurs.

In EP 89 116 700.9, specifically synthesized compounds which are composed of nitrato fatty acids (nitratoalkanecarboxylic acids) and sulphur-containing amino acids or peptides are mentioned. The presence of sulphydryl groups should prevent a nitrate tolerance or - 3 reduce a tolerance which has already set in.

Inter alia, compounds are mentioned which contain sulphur-containing amino acids such as cysteine or methionine in the form of their methyl, ethyl or propyl esters. Finally, the SH group of cysteine can be esterified with lower alkanecarboxylic acid having 2 to 8 carbon atoms.

Although these compounds already have useful pharmacological properties with respect to avoidance of a nitrate tolerance or abolishment or reduction of tolerance which has already set in, they are afflicted with disadvantages. They possess low melting points, have a low water solubility and are difficult to prepare in pure form.

The object of the present invention is therefore to prepare new organic compounds which avoid the abovementioned disadvantages and to make them available to the person skilled in the art.

This object has been achieved in that the com20 pounds according to the invention are nitratoalkanecarboxylic acid derivatives of the general formula (I) —N—(CH2)n—C—(CH2)O—C—R (I) in which R is hydroxyl, lower alkoxy, lower alkenoxy, di-lower 25 alkylamino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl-lower alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, hydroxy-lower alkylamino or amino acid radicals are via peptide linkage, R1 is hydrogen, alkyl having 1 to 6 carbon atoms, or substituted lower alkyl, in which the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R2, like R1, denotes hydrogen or lower alkyl, R3 is hydrogen or lower alkyl, R* is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl-lower alkyl, methoxyphenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, amino-lower alkyl, acylaminolower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R5 denotes S-acyl compounds of lower alkylthiol, in particular its amino acid thioesters, N-acylamino acid thioesters, peptide thioesters or N-acylpeptide thioesters containing 2-5 peptide-linked amino acid radicals, R and R* can be connected with one another with the formation of an ester or amide, R3 and R* can be connected with one another with the formation of an alkylene bridge containing 2 to 4 ,E 911023 carbon atoms, an alkylene bridge containing 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge containing 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, sub5 stituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o denote the numbers 0-10 and their physiologically tolerable salts.

According to a development of the invention, the nitrato fatty acid constituents have a chain length of C2-C8; they can be straight-chain, branched, racemic or optically isomeric.

The nitratoalkanecarboxylic acid derivatives of the general formula (I) according to the invention preferably contain the amino acids cysteine, methionine or homocysteine from the series comprising sulphurcontaining amino acids.

According to a further embodiment of the invention, the amino acids are present in the stereochemical L-form.

The sulphur-containing eunino acids can be esterified at the C-terminal end.

According to an advantageous development according to the invention, the amino acids cysteine and/or methionine are present as methyl, ethyl or propyl esters.

N-nitratopivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester, N-nitratopivaloyl-S-(N-acetylalanyl)-Lcysteine ethyl ester and N-nitratopivaloyl-S-(N-acetylleucyl)-L-cysteine ethyl ester - 6 are in particular preferred in the sense of the invention.

The compounds of the general formula (I) according to the invention can be prepared in a manner known per se if a compound of the general formula (II) —2)m-H2>nR* 0 I I (II) -C—(CH2 )o—C—R in which R is hydroxyl, lower alkoxy, lower alkenoxy, di-lower alkylamino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl-lower alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, hydroxy-lower alkylamino or amino acid radicals are via peptide linkage, R1 is hydrogen, alkyl having 1 to 6 carbon atoms, or substituted lower alkyl, in which the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R2, like R1, denotes hydrogen or lower alkyl, R3 is hydrogen or lower alkyl, R* is hydrogen, lower alkyl, phenyl, methoxyphenyl, 25 phenyl-lower alkyl, methoxyphenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, - 7 alkoxy-lower alkyl, amino-lower alkyl, acylaminolower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R and R* can be connected with one another with the 5 formation of an ester or amide, R3 and R* can be connected with one another with the formation of an alkylene bridge containing 2 to 4 carbon atoms, an alkylene bridge containing 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge containing 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl, Re denotes lower alkylthiol is subjected to a thioester formation reaction known per se using amino acids, N-acylamino acids, peptides or Nacylpeptides having 2-5 peptide-linked amino acid radicals . The preparation of a compound of the general formula (II) can be carried out in the manner described in EP 89 116 700.9.

Nitrato fatty acids of the general formula (A) R1 0 1 1 02N—0—CH2—C—(CH2)m—c—OH (A) RJ in which R1, R2 and m have the abovementioned meanings, can then be employed in the form of their free acids, reactive acid halides, acid azides, esters and acid - 8 anhydrides and reacted with a compound of the general formula (B) R3 R4 0 I I I HN— (CH2 ) n—C—(CH) o—C—R (B) A« in the meaning of R, R3, R*, R6, n and o as mentioned 5 above, containing amino acids and/or peptides with the formation of compounds of the general formula (II).

To convert the compounds of the general formula (I) into their pharmacologically acceptable salts, the former are preferably reacted with the equivalent amount of an optionally inorganic or organic acid in an organic or aqueous organic solvent. Possible acids are hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulphuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, adipic acid, benzoic acid, salicylic acid, 0acetoxybenzoic acid, cinnamic acid, naphthoic acid, mandelic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, methanesulphonic acid or ptoluenesulphonic acid.

The new compounds of the general formula (I) according to the invention and their salts can be administered enterally or parenterally in liquid or solid form.

The injection medium used is preferably water, which contains the additives customary in injection solutions such as stabilisers, solubilisers or buffers. Additives of this type are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid excipients are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acids, higher molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as, for example, polyethylene glycols); preparations suitable for oral administration may, if desired, contain flavourings and sweeteners.

According to a further embodiment of the invention, medicaments contain one compound and/or a mixture of the compounds according to the invention.

These medicaments can be employed for the treat20 ment of circulatory disorders, for example as coronary dilators, as agents for the treatment of high blood pressure, cardiac insufficiency and for dilating the peripheral vasculature, including the cerebral and renal vasculature.

Pharmaceutical preparations containing a previously calculated amount of one or more of the compounds according to the invention can be administered once daily in the form of sustained release preparations or several times daily at regular intervals (2-3 times daily). The - 10 amounts of active compound customarily administered per day are 20 - 300 mg per day, relative to a body weight of 75 kg. The compounds according to the invention can be given in the form of injections 1-8 times per day or by continuous infusion. Amounts of 5 - 200 mg/day are normally sufficient.

A typical tablet may have the following composition: 1) N-nitratopivaloyl-S-(N-acetylglycyl)- L-cysteine ethyl ester 25 mg 2) Starch, U.S.P. 57 mg 3) Lactose, U.S.P. 73 mg 4) Talc, U.S.P. 9 mg 5) Stearic acid 6 mg The substances 1, 2 and 3 are sieved, granulated, mixed homogeneously with 4 and 5 and then tabletted.

The exemplary embodiments illustrate the invention without being restricted thereto.

Example 1 Preparation of N-nitratopivaloyl-S-(N-acetylglycyl)-Lcysteine ethyl ester g (0.41 mol) of N-acetylglycine were suspended in 300 ml of methylene chloride (CH2C12) with stirring at room temperature and the suspension was cooled to 10"C.

A solution of 109.8 g (0.373 mol) of N-nitratopivaloylL-cysteine ethyl ester in 300 ml of CH2C12 was added in a weakly exothermic reaction with stirring. The reaction mixture was cooled to 5’C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in - 11 200 ml of CH2C12 was slowly added dropwise with stirring such that the temperature was in the range between 5°C and 10eC. After warming to room temperature, the mixture was stirred at RT for four days. Dicyclohexylurea was filtered off with suction ana washed twice using 100 ml of CH2C12 each time.

The combined CH2C12 phases were successively washed once each with 200 ml of 9% strength NaHCO3 solution, 300 ml of IN HCI and 300 ml of distilled water.

The methylene chloride phase was finally dried over anhydrous sodium sulphate and concentrated on a rotary evaporator (Rotavapor*, Buchi) to constant weight.

The yield was 162.9 g (theoretical 146.74 g) of N-nitratopivaloyl-S-(N-acetylglycyl)-L-cysteine ethyl ester as a pale yellow oil. 162.9 g of N-nitratopivaloyl-S-(N-acetylglycyl)L-cysteine ethyl ester were dissolved in 470 ml of ethyl acetate at room temperature. After stirring at RT for 15 minutes, the undissolved white precipitate was filtered off. The clear pale yellow filtrate was slowly treated with 390 ml of n-hexane at RT with stirring.

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

The crystals were dried to constant weight in a vacuum drying oven at room temperature and a vacuum of 2 Torr.

The yield was 85.4 g (theoretical 146.74 g) of Nnitratopivaloyl-S-(N-acetylglycyl) -L-cysteine ethyl ester.

M.p.: 71.8eC 5 Example 2 Preparation of N-nitratopivaloyl-S-(N-acetylalanyl)-Lcysteine ethyl ester 53.8 g (0.41 mol) of N-acetylalanine were suspended in 300 ml of methylene chloride (CH2C12) with stirring at room temperature and the suspension was cooled to 10°C. A solution of 109.8 g (0.373 mol) of N-nitratopivaloyl-L-cysteine ethyl ester in 300 ml of CH2C12 was added in a weakly exothermic reaction with stirring. The reaction mixture was cooled to 5*C with stirring and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 ml of CH2C12 was slowly added dropwise with stirring such that the temperature was in the range between 5*C and 10’C. After warming to room temperature, the mixture was stirred at RT for four days. Dicyclo20 hexylurea was filtered off with suction and washed twice with 100 ml of CH2C12 each time.

The combined methylene chloride phases were successively washed once each with 200 ml of 9% strength NaHCO3 solution, 300 ml of 1 N HC1 and 300 ml of distilled water. The methylene chloride phase was finally dried over anhydrous sodium sulphate and concentrated to constant weight on a rotary evaporator (Rotavapor*, Biichi).

The yield was 160.5 g (theoretical 151.84 g) of N-nitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester as a pale yellow oil. 160.5 g of N-nitratopivaloyl-S-(N-acetylalanyl)L-cysteine ethyl ester were dissolved in 345 ml of ethyl acetate at room temperature. After stirring at RT for 15 minutes, the undissolved white precipitate was filtered off. The clear pale yellow filtrate was slowly treated with 345 ml of n-hexane at RT with stirring.

Seed crystals were added to this solution and it 10 was stirred overnight at room temperature. The deposited crystals were filtered off with suction and washed twice at room temperature with 100 ml of a mixture of 20 ml of ethyl acetate and 80 ml of n-hexane each time.

The crystals were dried to constant weight in a 15 vacuum drying oven at room temperature and a vacuum of Torr.

The yield was 78.2 g (theoretical 151.84 g) of Nnitratopivaloyl-S-(N-acetylalanyl)-L-cysteine ethyl ester.

M.p.: 76.6’C Example 3 Preparation of N-nitratopivaloyl-S-(N-acetylleucyl)-Lcysteine ethyl ester 0.02 mol = 6 g of nitratopivaloylcysteine ethyl 25 ester are dissolved in 100 ml of dichloromethane. 0.03 mol » 5.19 g of N-acetylleucine and 0.1 g of dimethylaminopyridine (DMAP) are slowly added at 10 C and with introduction of nitrogen. 0.03 mol = 6.15 g of dicyclohexylcarbodiimide (DCC), dissolved in 80 ml of - 14 dichloromethane, are then added dropwise. The mixture is stirred overnight at RT.

Working up: The mixture is filtered with suction. The solu5 tion is successively extracted with equivalent amounts of 0.1 N HCI solution, saturated NaHC03 solution and distd. H20. The solvent is then stripped off in a rotary evaporator (Rotavapor*, Biichi). 10 g of oily residue remain. Recrystallisation: g of oily substance are dissolved in 45 ml of ethanol and 40 ml of distd. H20 with slight warming. The substance is allowed to crystallise out overnight in a refrigerator. The crystals are filtered off with suction and dried in a vacuum drying oven.

The mass spectrum confirms the structure.

Melting point: 91.4eC HPLC analysis: 98.7% g = 0.012 mol = 57.4% of theory.

Yield:

Claims (13)

1. Patent Claims

1. Compounds of the general formula (I) R a 0 R J R* 0 I II I I 0 2 N—0—CH 2 —C—(CH 2 ) m —C—N— (CH 2 ) n—C— (CH 2 ) o —C—R (χ} in which R is hydroxyl, lower alkoxy, lower alkenoxy, di-lower alkylamino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl-lower alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, hydroxy-lower alkylamino or amino acid radicals are via peptide linkage, R 1 is hydrogen, alkyl having 1 to 6 carbon atoms, or substituted lower alkyl, in which the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R 2 , like R l , denotes hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl, R* is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl-lower alkyl, methoxyphenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, amino-lower alkyl, acylaminolower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R 5 denotes S-acyl compounds of lower alkylthiol, in particular its amino acid thioesters, N-acylamino acid thioesters, peptide thioesters or N-acylpeptide 5 thioesters containing 2-5 peptide-linked amino acid radicals, R and R* can be connected with one another with the formation of an ester or amide, R 3 and R* can be connected with one another with the 10 formation of an alkylene bridge containing 2 to 4 carbon atoms, an alkylene bridge containing 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge containing 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, sub15 stituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o denote the numbers 0-10 and their physiologically tolerable salts.

2. Compounds according to Claim 1, characterised in 20 that their nitrato fatty acid constituents have a chain length of C 2 -C e , and are straight-chain, branched, racemic or optically isomeric.

3. Compounds according to Claims 1 and 2, characterised in that the sulphur-containing amino acids are 25 preferably cysteine, methionine or homocysteine.

4. Compounds according to Claims 1-3, characterised in that the amino acids are present in the stereochemical L-form.

5. Compounds according to Claims 1 - 4, characterised in that the sulphur-containing amino acids are esterified at the C-terminal end.

6. Compounds according to Claims 1-5, characterised In that the amino acids cysteine and/or methio5 nine are present as methyl, ethyl or propyl esters.

7. Compounds according to Claims 1 - 6, characterised in that they are a) N-nitratopivaloyl-S-(N-acetylglycyl) -L-cysteine 10 b) ethyl ester N-nitratopivaloyl-S-(N-acetylalany 1) -L-cysteine c) ethyl ester N-nitratopivaloyl-S- (N-acetylleucyl) -L-cysteine 8. ethyl ester. Process for the preparation of nitratoalkane- 15 carboxylic acid derivatives of the general formula (I) R 1 0 R J I I I 0 2 N_o__CHj—C— (CHj ) m —C—N— (CHj ) n I R* 0 1 1 ill -C—(CHj) o —C—R' 1 ) In which R is hydroxyl, lower alkoxy, lower alkenoxy, di-lower alkylamino-lower alkoxy, acylamino-lower alkoxy, 20 acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl-lower alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, hydroxy-lower alkylamino or amino acid radicals are via peptide linkage, R 1 is hydrogen, alkyl having 1 to 6 carbon atoms, or substituted lower alkyl. In which the substituent Is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R 2 , like R 1 , denotes hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl, R* is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl-lower alkyl, methoxyphenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, alkoxy-lower alkyl, amino-lower alkyl, acylaminolower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R 5 denotes S-acyl compounds of lower alkylthiol, in particular its amino acid thioesters, N-acylamino acid thioesters, peptide thioesters or N-acylpeptide thioesters containing 2-5 peptide-linked amino acid radicals, R and R* can be connected with one another with the formation of an ester or amide, R 3 and R* can be connected with one another with the formation of an alkylene bridge containing 2 to 4 carbon atoms, an alkylene bridge containing 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge containing 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o denote the numbers 0-10 and their physiologically tolerable salts, characterised in that, in a manner known per se, a compound of the general formula (II) R 1 0 R 3 R 4 0 1 o 2 n—0——ch 2 ——C—( ch 2 ) ra — 1 1 1 -C—N—(CH 2 ) n -C- (CH 2 ) O —C—Ri 11 ) l 2 R 2 R 6 in which R is hydroxyl, lower alkoxy, lower alkenoxy, di-lower alkylamino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy,

8. 10 substituted aryloxy or substituted aryl-lower alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, hydroxy-lower alkylamino or amino acid radicals are via peptide 15 linkage, R 1 is hydrogen, alkyl having 1 to 6 carbon atoms, or substituted lower alkyl, in which the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, 20 mercapto, lower alkylthio or arylthio, R 2 , like R 1 , denotes hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl, R 4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl-lower alkyl, methoxyphenyl-lower alkyl, 25 hydroxyphenyl-lower alkyl, hydroxy-lower alkyl, IE 9110 23 alkoxy-lower alkyl, amino-lower alkyl, acylaminolower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl, R and R* can be connected with one another with the 5 formation of an ester or amide, R 3 and R* can be connected with one another with the formation of an alkylene bridge containing 2 to 4 carbon atoms, an alkylene bridge containing 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge 10 containing 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl, R 8 denotes lower alkylthiol 15 is subjected to a thioester formation reaction with amino acids and/or N-acylamino acids, peptides and/or N-acylpeptides containing 2-5 peptide-linked amino acid radicals and then, if desired, the compounds obtained are converted into their pharmacologically acceptable salts. 20 9. Medicaments containing one or more compound(s) according to Claims 1-8 and customary excipients and auxiliaries. 10. Use of compounds according to Claims 1-8 for the production of medicaments for the prophylaxis of 25 cardiac and circulatory disorders.

9. 11. Compounds according to Claims 1-7 for the production of medicaments for the prophylaxis of cardiac and circulatory disorders. -2112. A compound of the general formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, substantially as hereinbefore described and exemplified.

10. 13. A process for the preparation of a compound of the general formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, substantially as hereinbefore described and exemplified.

11. 14. A compound of the general formula (I) given and defined in claim 1, or a physiologically tolerable salt thereof, whenever prepared by a process claimed in a preceding claim.

12. 15. A medicament according to claim 9, substantially as hereinbefore described.

13. 16. Use according to claim 10, substantially as hereinbefore described.