CS9100984A2 - Derivatives of nitratoalkanecarboxylic acid, method of its production, their application and these substances containing pharmaceutical - 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

The nitroalkanecarboxylic acid derivatives, the process for their preparation, their use and the drug containing them. Technical field

The present invention relates to carboxylic acid nitrate derivatives, to processes for their preparation, to their use and to medicaments containing them. ř> ·. '

BACKGROUND OF THE INVENTION 8

Organic nitrates / nitric esters / have proven useful in the treatment of heart disease.

They exert their effect by relieving the heart by reducing systolic and diastolic pressure, as well as improving oxygen supply to the heart by expanding the coronary vessels. However, in recent years, it has been found that inorganic nitrates, so far used in therapy, such as glycerol trinitrate (Gin), isosorbide-5-mononitrate or isosorbide - dinitrate. exhibit substantial weakening of the effect of nitrate tolerance during a relatively short period of time in high and continuous feed into organisms. Numerous experiments show that the presence of sulfhydryl groups suppresses the loss of tolerance and can weaken the already existing tolerance. tp ’Ígíá feš?

The mechanism of tolerance development is currently explained as follows:

effect of cysteine.

According to the current level of knowledge, the pharmacologically-organic nitro compounds are dependent on presence.

jýP

(IV

In the decomposition, 110-radicals are released which activate the target enzyme, the soluble guanylate cyclase of smooth muscle cells. Subsequent reactions triggered by cGMP then lead to relaxation or dilatation of the reactive and short-lived, yet hypothetical intermediate product may be a nitric acid thioester or a thionitrate. Finally, the formation of nitrosothiol, from which the nitric oxide or nitrite ions is released, is believed to be produced by the use of a tramolecular rearrangement and other subsequent reactions which have not yet been elucidated, whereas, on the other hand, the enzymatic degradation by GSH reductase could be used for pharmacological Heenzymatic degradation requires tedycysteine, as described, and is thus dependent on the swelling to be depleted / depleted of SH-group supplies, so that no longer enough NO can be formed as a separate guanyl cyclase activator for a certain period of time. so clinically attenuating ú incubation.. EP 89 116 700.9 are shown specifically synthesized by the compounds which are composed of nitrátomastnýchkyselin / nitrátoalkankarboxyloyých acids and / or sulfur contained exceeding-amino acids or peptides. The presence of sulfhydryl groups has the ability to suppress or weaken the nitrate tolerance or already tolerated tolerance.

Amongst others, there are mentioned compounds which contain a sulfur-containing amino acid such as cysteine or methionine in the form of their methyl esters, ethyl esters or propyl esters. Finally, the sulfhydryl groups may be cysteine esterified with lower alkanecarboxylic acids having from 2 to 8 carbon atoms.

K -? TO·:. <:? Ai / £: ·

i A.

AND

Although said compounds already possess valuable pharmacological properties with respect to the removal of nitrate tolerance, or to the removal of thinning or weakening of pre-existing tolerance, they are disadvantaged. They have low melting points, have low solubility in water and cause difficulties with respect to purity.

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide novel organic compounds which do not exhibit the aforementioned disadvantages.

According to the present invention, this object is achieved by the preparation of the novel nitroalkanecarboxylic acid derivatives of the formula I

1 3 A 'R-. · · -. R &lt; R &gt; - R &lt; 1 &gt; ... ol &lt; tb &gt; lkkk-O-CH2-C- (CH2) r-CH- (CH2) nC- (CH2) oCR (l), R is hydroxy, lower alkoxy, lower alkenoxy, di- (lower al-quinolino) lower alkoxy, acylamino- lower alkoxy, acyloxy- lower alkoxy, aryloxy, aryl- lower alkyl / oxy, substituted aryloxy or substituted aryl / lower alkoxy,

iSiiSSSieiSliiSI ’; · ϊ

Wherein the substituent is a methyl group, a halogen atom or a methoxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an aryl-lower alkylamino group, a hydroxy- lower alkylamino group, or amino acid residues selin via peptide bond, r! a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a substituted lower alkyl group, the substituent being a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, an amino group, a lower alkyl amino group, an acylamino group, an acyloxy group, an arylamino group, a mercapto group lower alkylthio, or arylthio; . R @ 2 is a hydrogen atom or a hydrogen atom or a lower alkyl group, R @ 4 is a hydrogen atom, a lower alkyl group, a phenyl group, a methoxyphenyl group, a phenyl- lower alkyl group, a me, a hydrogen atom or a lower alkyl group. -thoxy-phenyl-lower alkyl / group, hydroxyphenyl / lower alkyl / lower lower alkyl group, alkoxy / lower alkyl / lower alkylamino, acylamino- lower alkyl / group lower alkylthio or lower alkylthio lower alkyl group R &lt; 5 &gt; S-acyl compounds lower alkylthiol, ob

//.-. ·: · · · · · ·

Especially their thioesters of amino acids, thioesters of N-acylamino acids, thio-. peptide esters or thioesters of l-acyl peptides with 2 to 5 peptide linkages of amino acid residues, wherein R a may be linked to each other to form an α-cyano-naphtha-xstHS ± kH ester or amide and R- 'and they may be linked to each other to form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge having 3 to 4 carbon atoms containing a double bond, or the alkylene bridge mentioned above n is substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower alkyl and m, n, o is from 0 to 10, as well as their physiologically acceptable salts.

According to another embodiment of the invention, the nitrate fatty acid moieties have a chain length of CL to Cb, they may be straight chain, branched chain, racemic or optically isomeric. Preferably, the nitroalkanecarboxylic acid derivatives of the formula I contain cysteine, methionine or homocysteine from a series of sulfur-containing amino acids. '- 6 í .. ·. * · / ··; .‘Ί.ν ^. ^ Μ - '. Ί'-λιζν> £ \ t

According to another preferred embodiment of the invention, the amino acids have the stereochemical form L. Sulfur-containing amino acids can be esterified at the C-terminus.

According to a particularly preferred embodiment of the invention, the amino acids cysteine and / or methionine are present in the form of a methyl ester, an ethyl ester or a propyl ester.

Particularly preferred within the meaning of the present invention are h-nitrate-pivaloyl-S- (R-acetylglycyl) -L-cysteine methyl ester, k-nitrate-pivaloyl-S- (H-acetylalanyl) -L-cysteine ethyl ester and R-nitrate-pivaloyl-S- (R-acetylleucyl) - L-cysteine ethyl ester.

The compounds of the general formula (I) according to the invention can be prepared in a manner known per se in such a way that the compound of the formula (II) R 10 R 3 R 4 O 10 R 10 -O-CH 2 -C- (CH 2) mC-1 - (CH 2) nC - / CHo // 0-CR '/ 11 /,' 2 * 6

7Γ. R

F wherein R is hydroxy, lower alkoxy, lower alkenoxy, di- (lower alkyl) -ino- (lower alkoxy), 'acylamino- (lower alkoxy), acyl-oxy- (lower alkoxy) , aryloxy, aryl- (lower alkoxy), b '- 7 - substituted aryloxy or substituted aryl- (lower alkoxy), wherein the substituent is methyl, halogen or methoxy; lower alkylamino, di- (lower alkyl) amino, aryl- (lower alkylamino), hydroxy- (lower alkylanino) or amino acid residues through the peptide bond; a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a substituted lower alkyl group wherein the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio , R as R is a hydrogen atom or a lower alkyl group, R 4 is a hydrogen atom or a lower alkyl group, R 4 is a hydrogen atom, a lower alkyl group, a phenyl group, a methoxyphenyl group, a phenyl- lower alkyl group, - methoxyphenyl lower alkyl group, hydroxyphenyl lower alkyl group, hydroxy / lower alkyl group, alkoxy lower alkyl group, lower alkylamino group, lower acylaminoalkyl group, lower mercaptoalkyl group or lower alkyl group alkylthio- lower alkyl / group, wherein R 3 and R 4 may be linked together to form an ester or amide and may be linked together to form an al- of 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulfur atom, a alkylene bridge having 3 to 4 carbon atoms containing a double bond, or an alkylene bridge substituted with a hydroxyl group lower, lower alkoxy or di-lower alkoxy, lower alkylthio, n, o are as defined above. subject to a known thioester coupling reaction with amino acids, R-acylamino acids, peptides or J-acyl peptides with 2 to 5 peptide bonds of amino acid residues. Compounds of formula 11 may be prepared as described in EP 89 116 700.9 ·

Accordingly, nitrate fatty acids of formula (A), (1) may be used

O-CH, 5- C- (CHp) rf-O-OH (A),

In which: i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i, i. ! · »; ..... '· ..' ·, 'h'ý * Ϊ' l

in the form of their free acids, reactive halides of acids, azides, esters and acid anhydrides, and reacting them with a compound of formula BII in HB-OCH2 (nC- / CH / oCR / B) in which they have R, O ®, R 0, as defined above, comprising amino acids and / or peptides, to form compounds of formula II.

To convert the compounds of formula (I) to their pharmacologically acceptable salts, they are reacted, preferably in an organic or aqueous organic solvent, with an equivalent amount of inorganic or organic acid. Among these 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, acid. salicylic acid, O-acetoxybenzoic acid, cinnamic acid, naphthoic acid, acid-alkanic acid, citric acid, malic acid, acidic acid, aspartic acid, glutamic acid, ethanesulfonic acid or p-toluenesulfonic acid. the novel compounds of the general formula (I) of the present invention and their salts can be administered enterally or parenterally in liquid or solid form.

- 10 - rk.kr / .XX '

MiléimSíSlmeO. The injectable medium is preferably a conduit which contains conventional additives for injection media, such as stabilizing agents, dissolving agents, or buffers. Such additives include, for example, tartrate and citrate, ethyl alcohol, plexifiers (such as ethylenediaminetetraacetic acid and non-toxic salts thereof), high molecular weight polymers (such as liquid polyethylene oxide) for controlling viscosity and the like. Solid carriers are, for example, starches, lactose, mannitol, methylcellulose, talc, high-dispersion silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Formulations suitable for oral administration may contain flavorings and sweeteners as desired.

In another embodiment of the invention, the medicaments comprise one compound of the present invention and / or a mixture thereof. . .

Said medicaments may be applied to circulatory diseases such as coronary dilators, such as high pressure agents, cardiac insufficiency and for the expansion of peripheral blood vessels as well as brain 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 daily in the formulated formulation or the formulation; several times a day at controlled intervals (twice to three times a day), the amount of active compound administered daily is usually 20 to 300 mg / day based on 75 kg body weight. In the form of injection, the compounds of the present invention can be administered 1 to 8 times a day, possibly in the form of a continuous infusion. 5 to 200 mg per day.

Typical tablets have the following composition:. 1. N-nitrate opi valoyl 1-3- (17-acetylglyctyl) -L-cysteine ethyl ester 25 mg 2. starch U.S.P. 57 mg 3rd lactose U.S.P. 73 mg '4 · talc U.S.P. 9 mg 5. Stearic acid 6 mg. Compounds 1, 2 and 3 are sieved, granulated, mixed homogeneously with substances 4 and 5, and then the mixture is tabletted. The following examples illustrate the invention without limiting it. EXAMPLES Example Preparation of U-nitrate-pivaloyl-S- (N-acetylglycyl) -L-cysteine-ethyl ester 48 g (0.41 mol) of U-acetylglycine was stirred in 300 ml of methylene chloride / CH2Cl2 with stirring at room temperature. and cooled to 10 ° C. While stirring, a solution of 109.8 g (0.373 mol) of N-nitrate-pivaloyl-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 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 ml of methylene chloride were slowly added dropwise with stirring, the temperature being maintained at 5-10 ° C. After warming to room temperature, the reaction mixture was stirred at this temperature for four days. The cyclohexylcarbodiimide urea was filtered off with suction 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 bicarbonate solution, 300 ml of 1N hydrochloric acid and 300 billion distilled water. finally, the methylene chloride phases are dried over anhydrous sodium sulfate and concentrated to a constant weight on a rotary evaporator (Ro-tavapor, Bttchi). 1,

• M: 'V-

The yield was 162.9 g (theoretically 146.74 g) of R-nitrate-pivaloyl-S- (h-acetylglycyl) -L-cysteine ethyl ester as a pale yellow oily liquid.

/ ?; 162.9 g of N-nitrate-pivaloyl-3- (K-acetylglycyl) -L-cysteine ethyl ester are dissolved in 470 ml of ethyl acetate at room temperature. After stirring for 15 minutes at room temperature, the undissolved white precipitate was filtered off. The light yellow filtrate was slowly mixed with 390 mL of n-hexane at room temperature with stirring. Inoculum crystals were added to the 3 g of the solution obtained and the mixture was stirred at room temperature overnight. The crystals formed are aspirated and washed twice with 100 ml of a mixture of 20 ml of ethyl acetate and 0 ml of n-hexane at room temperature. The crystals obtained were taken to room temperature and vacuum weight. The yield was 85.4 dried in a vacuum drying oven 2 to a constant / theoretically 146.74 S / - 13 - f -1 of &lt; &gt; &quot; SSlSilaSiSSei

N-nitrate-pivaloyl-S- (1-acetylglycyl) -L-cysteine ethyl ester. Melting point: 71.8 ° C. [0098] 53.8 g (0.41 mol) of k-acetylalanine are stirred in 300 ml of methylene chloride (CHCl3) with stirring at room temperature and cooled to 10 [deg.] C. After stirring, a solution of 109.8 g (0.373 mol) of E-nitrate diployl-L-cysteine ethyl ester in 300 ml of methylene chloride was added by exotherm. The reaction mixture was cooled with stirring at 5 ° C and a solution of 84.6 g (0.41 mol) of dicyclohexylcarbodiimide (DCC) in 200 ml of methylene chloride was slowly added dropwise while the temperature of the reaction mixture stabilized at 5 to 10 ° C. After warming to room temperature, the reaction mixture was stirred for four days. The dicyclohexylcarbodiimide-urea is filtered off with suction and 100 ml of methylene chloride are passed through twice.

The combined methylene chloride phases are successively screened once with 200 ml of 9% sodium bicarbonate solution, 300 ml of 1N hydrochloric acid and 300 ml of distilled water. Finally, the methylene chloride phase is dried over sodium sulphate and rotary evaporation. [Rotavapor, Bttchi] is concentrated to constant weight. The yield was 160.5 g / theoretically 151.84. g) E-nitro-o-pivaloyl-S- (11-acetyllalanine) -1-cysteine thylester in the form of a pale yellow oil. 160.5 g E-ni trátopivaloy1-S- / E-ac ethylalany1 / - - 14 - ··; ·. v? and

.ilŽňnXiliůUCViť.L «7 J t ^ 1>

The L-cysteine ethyl ester was 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 is then slowly mixed with 345 ml of n-hexane at room temperature and with stirring.

Seed crystals were added 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 at room temperature. The crystals obtained are dried in a vacuum oven at room temperature and a vacuum of 2 Torr to constant weight. The yield was 78.2 g (theoretically 151.84 g) of N-nitrate-pivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester.

i'i i. '' '

EXAMPLE 3 Preparation of N-nitrate-pivaloyl-S-N-acetyl-cyanomethyl-ester of 0.02 mol (6 g) cysteine ethyl nitrate ester was dissolved in 100 ml of dichloromethane. At 0 ° C, 0.03mol (5.19g) of N-acetyl-leucine and 0.1g of dimethylaminopyridine (DMAP) are added slowly under nitrogen. Then, 0.03 mol (6.15 g) of dicyclohexylcarbodiimide (DGO) dissolved in 80 ml of dichloromethane was added dropwise to the reaction mixture, whereupon the reaction mixture was stirred at room temperature overnight.

Processing:

The pellet is filtered off with suction and the solution obtained is washed with an equivalent amount of 0.1 n hydrochloric acid, saturated sodium bicarbonate solution and distilled water in the process. Then the solvent is removed on a rotavapor evaporator (Rotavapor, Buchi). 10 g of oily residue are obtained.

Crystallization: 10 g of the oily substance are dissolved in a mixture of 45 ml of ethyl alcohol and 40 ml of distilled water with light heating. The solution was allowed to crystallize overnight in the refrigerator. The crystals are then aspirated and dried in a vacuum oven. The mass spectra were confirmed.

Melting point: 91.4 ° C HPLC chromatography: 98.7% Yield: 5 g = 0.012 mol = 57.4% of theory.

Claims (7)

Claims 1. Nitrátoalkanecarboxylic acid derivatives of the general formula I - 2 - 0 - CI - L - - IM c - / cn 2 / m - c Rk - R - IR - / CEL · / - C - / CHO / - C - R (1) in which R is hydroxy, lower alkoxy, lower alkenoxy, di- / lower alkyl (amino) - lower alkoxy, acylamino - lower alkoxy, acyloxy- / lower an alkoxy group, an aryloxy group, an aryl-lower alkoxy group, a substituted aryloxy group, or a substituted aryl-lower alkoxy group, wherein the substituent is methyl, halo, or methoxy; amino, / lower alkyl / amino, di- / lower alkyl / amino, aryl- / lower alkyl / amino, hydroxy / lower alkyl / amino or amino acid residue via peptide bond, R 1 hydrogen atom, alkyl group with 1 C 1-6 carbon atoms, substituted lower alkyl group in which it is - II - halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, 2 R as R is hydrogen or lower alkyl - a group, RJ is a hydrogen atom or a lower alkyl group, a hydrogen atom, a lower alkyl group, a phenyl group, a methoxyphenyl group, a phenyl / lower alkyl group, a methoxyphenyl- lower alkyl group, a hydroxyphenyl group nyl / lower alkyl / hydroxy / lower alkyl / alkoxy / lower alkyl / amino / lower alkyl / acylimino / lower alkyl / mercapto / lower alkyl / or lower alkyl / thio / lower alkyl /, S-acyl compounds of lower alkylthiols, especially thioesters thereof with amino acids, thioesters with R q, cylamino alkyls, peptidyl thioesters or R-acyl peptidyl thioesters having 2 to 5 peptide bonding es the amino acids, wherein R a may be linked together to form an ester or amide and R 4 and R 4 may be attached to each other to form an alkylene bridge of 2 to 4 carbon atoms. The atoms of an alkylene bridge having 2 to 3 carbon atoms and a sulfur atom, an alkylene bridge having 3 to 4 carbon atoms containing a double bond, or the above-mentioned alkylene bridge, substituted with hydroxy, lower alkoxy, lower alkyl or lower alkyl and M, n, o denotes 0-10,? as well as their physiologically acceptable salts Compounds according to claim 1, characterized in that their n-s-fatty acid component has a chain length of 2 to 6 carbon atoms, the chain being straight or branched, and the acid being racemic or optically isomeric. 3. The compounds of items 1 and 2 are characterized by. s e. that contains sulfur. The amino acids are preferably cysteine, methionine or homocysteine. Compounds according to claims 1 to 3, characterized in that the amino acids are present in stoichiometric L-form »- Compounds according to claims 1 to 4, characterized in that the sulfur-containing amino acids are esterified at the G-terminus. Compounds according to claims 1 to 6. 3, characterized in that the cysteine and / or methionine amino acids are present as methyl ester, ethyl ester or propyl ester. Compounds according to Claims 1 to 6, characterized in that they are: (a) N-nitrate-pivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester, (b) N-nitretopivaloyl-S ethyl ester - (N-acetylalanyl) -L-cysteine, c) N-nitrate-pivaloyl-3- (N-acetylleucyl) -L-cysteine ethyl ester. 8. A process for the preparation of nitroalkanecarboxylic acid derivatives of the general formula (IO) R (R) t R9N-O-CHO-C (CHO) -CN- (CH9) -C (CH-) -C-RZ2. (I, R 4 R "in which R is hydroxy, lower alkoxy, lower alkenoxy, di- (lower alkyl) -amino- (lower alkoxy), acylai, i-lower alkexr / group, acyl-oxy a lower alkoxy group, ayloxy group, an aryl- lower alkyloxy group, a substituted aryloxy group or a substituted aryl- lower alkoxy group, the substituent being a methyl group, a halogen atom or a methoxy group; lower alkyl / amino, di- / lower alkyl / amino, aryl- / lower alkyl / amino- a hydroxy-lower alkyl / amino group or an amino acid residue via a peptide bond, a β "hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a substituted lower alkyl group, wherein the substituent is halo, a hydroxy group, a lower alkoxy group , aryloxy, amino, lower alkyl amino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio or arylthio, R is hydrogen or lower alkyl, R 1 is hydrogen or lower alkyl, R 4 is hydrogen, lower alkyl- a phenyl group, a phenyl group, a methoxyphenyl group, a phenyl / lower alkyl group, a methoxyphenyl lower alkyl group, a hydroxyphenyl lower alkyl group, a hydroxy lower alkyl group , alkoxy- / lower alkyl / group, amino-lowered alkyl / group, allylamino- / lower alkyl / group, mer-capto- / lower alkyl / and aixixE- or lower alkyl / thio- / lower alkyl / group the lower alkylthio compounds, in particular their amino acid thioesters, thioesters N-acylamino acids, thioesters of peptides or N-acylpeptide thioesters with 2 to 2-peptide bonds and amino acid derivatives, wherein R and R 1 may be linked together to form an ester or amide, or R 1 and R 4 can be linked together to form al-. of a 2 to 4 carbon-VI - VI - alkylene. the bridge with 2 to 3 * carbon-_ ml? sulfur atom, rH «´ 'η' * · 1 - ί &amp; ί% ί &amp; $ ΐ £ &amp; &amp;amp;amp; Ά alkylene,. carbon atoms, comprising a double bond or the above-mentioned alkylene bridge, substituted by a 4-hydroxy group, a lower alkoxy group, a lower alkyl group or a di-lower alkyl group, and a - group. 4 to 10, as well as physiologically acceptable salts thereof, characterized in that the compound of formula (II) is present in a manner known per se; R 2 in which R represents a hydroxy group, a lower alkoxy group, a lower alkenoxy group, a di- (lower alkyl) amino-lower alkoxy, acyl-1-amino-lower alkoxy, acyloxy lower alkoxy, aryloxy, aryl- lower alkoxy, substituent aryloxy (or substituted aryl / lower / alkoxy) upine, wherein the substituent is methyl, halogen, or methoxy, amino, lower alkylamino, - VII - R and R may be linked together to form an ester or amide and may be linked together to form an amp; S- &amp; Gr &quot; di- (lower) alkylamino, - (1- (lower) alkylamino), (hydroxy) groups. lower alkylamino / group or amino acid residue * &quot; and &quot; 33 &quot; A hydrogen atom is an alkyl group having from 1 to 6 carbon atoms or a substituted lower alkyl group, the substituent being a halogen atom, a hydroxy group, a lower alkyl group or a lower alkyl group; an alkoxy group, an aryloxy group, an amino group, an acylamino group, an acyloxy group, an arylamino group, a mercapto group, a lower alkylthio group or an arylthio group such as a R 6 hydrogen or lower alkyl group, a hydrogen atom or a lower alkyl group, a hydrogen atom a lower alkyl group, a phenyl group, a methoxyphenyl group, a phenyl- lower alkyl group, a methoxyphenyl lower alkyl group, a hydroxyphenyl lower alkyl group, a hydroxy group - (lower alkyl), alkoxy (lower), (alkyl), alkoxy (lower alkyl), lower alkylamino, lower acylamino (lower), lower mercaptoalkyl or lower alkylthio (lower alkyl) group, taking '...... - R3 and R4 5? Wr rk * »? *!, <£ _? 1 S * v - rai - alkylene bridge to 2 to 4 carbon-carbonated alkylene bridges having a double bond or higher alkylene bridge, which is substituted by hydroxy lower-alkoxy or di-lower alkoxy and denotes a lower alkylthio which is a thioester coupling reaction with amino acids (or M-acylamino acids, peptides and / or JS-acyipep-M &amp; These are 2, 5, 5, 5, 5, 5, 6, 6, 6, 7 by the peptide bonds of the amino acid residues, and then the compound obtained in the case of need is converted. To its pharmacologically harmless salts. A medicament comprising one or more compounds according to claims -1 "to 8" as well as conventional carrier and adjuvants. The use of the compounds according to the formulas 1 to 8 for the manufacture of medicaments for the prophylaxis of circulatory diseases of the heart 7 ' ' *** * - -. Compounds according to claims 1 to 7 for the manufacture of medicaments for the prophylaxis of heart and circulatory diseases. . c-ft. .z? 4 ',' 4-; Wik-ffiRS