SI9110630A - Nitratoalkanecarboxylic acid derivatives, process for their preparation and pharmaceuticals 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

NITRATOALCANKARBONIC ACIDS DERIVATIVES, PROCEDURE WITH ?. THEIR OBTAINING AND THE MEDICINAL PRODUCTS CONTAINING THEM

1. TECHNICAL FIELD

The present invention is in the field of organic and pharmaceutical chemistry. According to the International Patent Classification, it belongs to groups C 07 C 327/34, A 61 K 31/21, A 61 K 31/195, A 61 K.37 / 02 and C 07 K 5/06.

2. TECHNICAL PROBLEM

Specific compounds known to date, consisting of nitrate fatty acids (nitratoalkanecarboxylic acids) and sulfur-containing amino acids, e.g. peptides have these problems, which are difficult to obtain in pure form and have a relatively low pharmacological activity.

3. BACKGROUND OF THE INVENTION

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

Do they develop their effect by cutting the heart, lowering it before and afterwards? burdens, as well as improved supply of oxygen to the heart, widening of the coronal vessels.

Certainly in previous years it has been established that organic nitrates, such as trinitroglycerin, have been used so far in therapy.

2.

(TNG), isosorbide-5-mononitrate or isosorhiddinitrate at high and conti- nuous intake, show, over a relatively short period of time, a significant decrease in nitrate tolerance. Numerous experiments have suggested that the presence of sulfhydryl groups prevents the formation of a single nitrate tolerance and the resulting mono tolerance to weaken.

The mechanism of tolerance generation today is not interpreted as follows:

To the present state of knowledge, the pharmacological action of organic nitro compounds is dependent on the presence of cysteine. With this organic nitrate forms a common previous step, the decomposition of which also releases NO radicals, which then activate the target enzyme, soluble guanylate cyclase, a class of smooth muscle cells. Furthermore, the formation of cGMP-induced alternating reactions then leads to relaxation or dilation of blood vessels.

In the case of reactive CT and short-lived, still hypothetical intermediate, it can be a nitric acid thioester or a thionitrate. freed. nitrogen monoxide or nitrite ions. Enzyme-dependent degradation with the help of GSHreductase should, however, have no effect on the pharmacological action, since it only leads to the formation of nitrite ions. Non-enzymatic degradation, as described above, is cysteine, and thus is exhaustible (depletion of SH-groups), so that it is no longer permanently formed 'enough NO' as an intrinsic activator of guanyl cyclase and clinically attenuates its action

3.

EP 89 116 700.9 describes specifically constructed compounds consisting of nitro atomic acids (nitratoalkanoic acid) and amino acids containing sulfur or. peptides. The presence of sulfhydryl groups is required. to prevent or reduce nitrate tolerance or one already occurring tolerance.

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

Although these compounds have significant pharmacological properties with respect to the avoidance of nitrate tolerance or preventing or weakening the already tolerance, they also have disadvantages. They have low melting points, have low solubilities in water and cause difficulty in obtaining them in pure form.

It is therefore an object of the present invention to provide new organic compounds and to make them available to a person skilled in the art, which avoids the above disadvantages. DESCRIPTION OF THE SOLUTION

This problem is solved in such a way that the compounds of the invention are nitrate derivatives of alkanoic acids of general formula (I)

4.

in which it is

R is hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower dialkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, where halogen or substituted methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues via a peptide bond,

R is hydrogen, alkyl of 1 to 6 carbon atoms, substituted lower alkyl, wherein the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylaryano, mercapto, lower alkyl .. thio, arylthio,

1

R represents as R hydrogen or lower alkyl,

R is hydrogen or lower alkyl,

R is hydrogen. lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl lower alkyl, hydroxy-lower alkyl, alkoxy lower alkyl, amino-lower alkyl, acylamino lower alkyl, mercapto-loweralkyl or lower alkylthio-lower alkyl,

R denotes S-acyl compounds of lower alkyl thiols, in particular their thioesters of amino acids, thioesters of N-acylamino acids, thioesters of peptides or thioesters of N-acyl peptides of 2-5 peptide-linked amino acid residues.

R and R may be linked together to form one ester of tli amide,

5.

and ich may be bonded together to form one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms, and one sulfur atom of one alkylene bridge of 3 to 4 carbon atoms containing one double bond or alkylene bridge as above substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, m, nio represent the numbers 0-10, as well as their physiologically tolerable salts.

According to a further embodiment of the invention, the nitrate fatty acid moieties have a chain length of C 2 - C _g ; they can be normal, branched, racemic or optical isomers.

Preferably, the derivatives of 'nitratoalkanecarboxylic acids according to the invention of general formula (I) contain from a series of amino acids containing sulfur, amino acids cysteine, methionine or homo cysteine.

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

Sulfur-containing amino acids can be esterified at the C-terminal end.

According to one preferred embodiment of the invention the amino acids cysteine and / or methionine are / are methyl, ethyl or propyl esstar, in particular

N-Nitratopivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester, N-Nitratopivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester as

6.

The N-Nitratopivaloyl-S- (N-acetylethyl) -L-cysteine ethyl ester of the invention is preferred.

The compounds of the invention of the general formula (I) can be prepared in a known manner, which is the compound of the general formula (II)

R ¹ OR ³ R ⁴ Ο Ι II II o ₂ n - o - ch _{2 -} c - (CH ₂ ) _m - - c - n - (CH ₂ ) _{n - C -} (CH ₂ ) _o - G - R ( II) in which

R is hydroxy, 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, where the substituent is methyloxy, wherein the halogen is methoxy; amino, lower alkylamino, di-loweralkylamino, aryl-lower alkylamino, hydroxy lower alkylamino or amino acid residues bound via a peptide bond.

-j

R is hydrogen, alkyl of 1 to 6 carbon atoms, substituted lower alkyl, wherein the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkyl thio, arylthio.

1

R represents as R hydrogen or lower alkyl

R is hydrogen or lower alkyl,

R is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl lower alkyl, hydroxyphenyl7.

lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alkylthio-lower alkyl,

R and R may be linked together to form one ester or amide,

4 '·

R and R may be bonded together · along the face of one alkylene bridge of 2 to 4 carbon atoms, one alkylene bridge of 2 to 3 carbon atoms and one sulfur atom, one alkylene bridge of 3 to 4 carbon atoms, which it contains one double link or one link. alkylene bridge as above, substituted with hydroxy, t

lower alkoxy, lower alkyl or di-lower alkyl,

R4 represents lower alkylthiol according to one known reaction for the preparation of thioethers by subjecting the amino acids, the K-acylamino acids, the peptides or the N-: acyl peptides to the reaction with 2-5 peptide-linked amino acid esters. The preparation of the compound of general formula (II) can be carried out as described in EP 89 116 700.9.

The nitrate fatty acids of the general formula (A) may then be

R ¹ O

I s'

0 ₂ N - 0 - CH ₂ - - C - - (CH2) jjj - C - OH (A)

2 in which R, R have the meanings given above, in the form of their free acids, reactive acid chlorides, acid azides, esters and anhydrides of acids to be used and

8.

with the compound of general formula (B)

R ³ R ₄ O

I I »

HN— (CH ₂ ) _n —C— (CH) _O —C — R (B) ίβ ..... '' ·

4 6 in which the meanings for R, R, R r R, n and o as given and * above, are converted amino acids and / or peptides to form compounds of general formula (II) *

For the conversion of compounds of general formula (I) into their pharmacologically harmless salts, these are treated in an organic or aqueous organic solvent, with an equivalent amount of one in the case of inorganic or organic acid. Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, amber acid, adipic acid, benzoic acid, salicylic acid acetoxybenzoic acid, cinnamic acid, naphthoic acid, almond acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, methanesulfonic acid or p-toluenesulfonic acid.

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

r

9.

As an injection medium, it is primarily suitable for the use of water, which contains conventional additives for injection solutions, such as stabilizing agents, solubility enhancers or buffers. Such additives are pry tartrate and citrate buffer, ethanol, complexing agent (ethylenediaminotetrasuric acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for regulating viscosity. Solid fillers are e.g. Starch, lactose, mannitol, methylcellulose, talc, high dispersible silica gel, 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 polyol-ethers; for oral administration, suitable preparations may optionally contain substances to impart taste and sweet substances.

According to a further embodiment of the invention, the medicaments have the content of one and / or mixture of compounds of the invention.

These drugs can be used to treat bloodstream diseases, for example as coronary dilators, as a means of treating high blood pressure, heart failure and enlargement.peripheral blood vessels including brain and kidney blood vessels.

Pharmaceutical preparations containing a previously calculated amount of one or more compounds of the invention may be administered once daily in the form of retarded preparations or several times daily at regular intervals (2-3 times daily). The usual amounts of active substances per day are 20 - 300 mg per day, relative to a body weight of 75 kg. In the form of injections, the compounds of the invention may be administered 1-8 times daily in the form of sustained infusions. In normal cases, 5 - 200 mg / day are sufficient.

10.

A typical tablet can 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) Talk, U.S.P. 9 mg 5) Stearic acid 6 mg

Substances 1, 2 and 3 are sieved, granulated, mixed with 4 and 5 and finally tableted.

Exemplary embodiments, without limitation thereof, illuminate the invention.

EXAMPLE 1

Preparation of N-chitratopivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester g (0.41 mol) of N-acetylglycine was stirred at room temperature with 300 ml of methylene chloride (CH ₂ C1 ₂ ), and cooled. at 10 ° C. A solution of 109.8 g (0.373 mol) of N-nitratopivaloyl-L-cysteine ethyl ester in 300 ml of CH ₂ Cl ₂ was added with stirring under a slightly exothermic reaction. 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 CH ₂ Cl _{2 was} added dropwise with stirring, so that the temperature was between 5 ° C and 10 ° C. After warming to room temperature, stir for 4 days at room temperature. DCC-urea is sucked in and washed twice with 100 ml CH ₂ C1 _{2 each} ·

The combined CH ₂ C1 ₂ phases were washed one after the other each time with 200 ml of 9% NaHCO 3 solution, 300 ml of 1 n HCl and.

300 ml of distilled water. Finally, the methylene chloride phase is dried over anhydrous sodium sulfate and evaporated to dryness on a rotary vacuum evaporator. (Rotavapor, Btichi)

The yield was 162.9 g (theoretical 146.74 g) of N-nitratopivaloylS- (N-acetylglycyl) -L-cysteine ethyl ester as a light yellow oil.

162.9 g of N-nitratopivaloyl-S- (N-acetylglycyl) -L-cysteine ethyl ester was dissolved in 470 ml of ethyl. of acetate at room temperature. After stirring at room temperature for 15 minutes, the undissolved white precipitate was filtered off. The clear light yellow filtrate was lightly treated at room temperature with stirring with 390 ml n-hex.

The grafting crystals were added to this solution and stirred at room temperature overnight. The precipitated crystals were filtered off and washed twice with 100 ml of a mixture of 20 ml ethyl acetate and 80 ml n-hexane at room temperature.

The crystals were dried in a vacuum oven at room temperature, vacuum 2 torus to constant weight.

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

T.t. 71.8 ° C.

EXAMPLE 2

Preparation of N-nitratopivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester

53.8 g (0.41 mol) of N-acetylalanine was suspended with stirring at room temperature in 300 ml of methylene chloride (Cl 2) and cooled to 10 ° C. A solution of 109.8 g was added with stirring

12.

(0.373 mol) of N-initratopivaloyl-L-cysteine ethyl ester in 300 ml in a slightly exothermic reaction. 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 CH 2 Cl 2 was added dropwise with stirring at 5 ° C so that the temperature was between 5 ° C and 10 ° C. After warming to room temperature, it was stirred at room temperature for four days. The DCC-carbamide is sucked in and washed twice with 100 ml of Ci ^ C ^ each.

The combined methylene chloride phases are washed one after the other with 200 ml of 9% NaHCO3 solution, 300 ml of 1 n HCl and 300 ml of distilled water. Finally, the rnethylene chloride phase * is dried over anhydrous sodium sulfate and evaporated under a rotary vacuum p

evaporator (Rotavapor, Btichi) to constant weight.

The yield was 160.5 g (theoretical 151.84 g) of N-nitratopivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester as a light 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 room temperature for 15 minutes, the insoluble precipitate was filtered off. The clear light yellow filtrate was treated lightly with stirring at room temperature with 345 ml of n-hexane.

The grafting crystals were added to this solution and stirred at room temperature overnight. The precipitated crystals were sucked off 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 were dried in a vacuum oven at room temperature, vacuum 2 torus, to constant weight.

The yield was 78.2 g (theoretical 151.84 g) of N-nitratopivaloyl-S- (N-acetylalanyl) -L-cysteine ethyl ester. T.t. 76.6 ° C.

13.

EXAMPLE 3

N-nitratopivaloyl-S- (N-acetylethyl) -L-cysteine ethyl ester is obtained

Λ

0.02 Mole = 6 g of nitratopivalin acid cysteine ethyl ester is dissolved in 100 ml of dichloromethane. At 10 ° C and under nitrogen supply, 0.03 Mole = 5.19 g of N-acetyl leucine and 0.1 g (DMAP) of dimethylaminopyridine are added gently. Finally, 0.03 Mole = 6.15 g of dichloxyhexylcarbodiimide (DCC) dissolved in 80 ml of dichloromethane is added dropwise. It is stirred overnight at room temperature.

PROCESSING

The mixture is dried. The solution was washed one after the other with equivalent amounts of 0.1 n HCl solution, saturated NaHCO 3 solution and extracted with distilled water. Finally, the solvent was evaporated on a rotary vacuum evaporator (Rotavapor, Btichi). 10 g of oily residue are left.

RECYCLING g of the oily substance is dissolved with gentle heating in 45 ml of ethanol and 40 ml of 1 ^ 0 dest. The substance was left overnight in the refrigerator to crystallize. The crystals were dried and dried in a vacuum oven.

The mass spectrum confirmed the structure.

Melting point. 91.4 ° C

HPLC-analytics: 98.7%

Yield: 5 g = 0.012 Mole = 57.4% of theory

Claims (9)

PATENT APPLICATIONS 1. Compounds of general formula (I) O R ' O ₂ N — o — ch ₂ —C— (CH ₂ ) _ra —C — n— (CH ₂ ) _n —C— (CH ₂ ) _o —c — R (i) R ^J R 'marked by these »that they are R hydroxy, lower alkoxy, lower alkenoxy, di-lower alkali 1-am and rio-n and zia 1 coke, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted aryl lower alkoxy, wherein the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues via a peptide bond, and R is hydrogen, alkyl of 1 to 6 carbon atoms, substituted lower alkyl, wherein the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyl oxi, aryl 1 amine, mercapto, lower alkylthio , ar and 11 io ,? 1 R * denotes as R ¹ hydrogen or lower alkyl R ^J is hydrogen or lower alkyl, r4 is hydrogen, lower alkyl, phenyl, methoxyphenyl 1, phenyl lower alkyl, methoxy-phenyl 1-lower-alky, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, aminonyl alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alky 1 thio-lower alkyl, • r · * C R denotes lower alkyl thiol S-acyl compounds, in particular their amino acid thioesters, N-acyl amino acid thioesters, peptide thioesters, or 2-5 N-acyl peptide thioesters with peptidyl-linked amino acid residues, R and R ^ may be linked together to form an ester or amide, R ³ and R 4 may be bonded to each other to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing erio double bond or alkylene bridge as above substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, m, n and o are numbers from 0 to 10 as well as their salts which are physiologically acceptable. Compounds according to claim 1, characterized in that their fatty acid nitrate components have a chain length of C2 to Cg and are normal, branched, racemic or optically isomeric. Compounds according to claims 1 and 2, characterized in that the amino acids containing sulfur are preferably cysteine, methionine or homocysteine. Compounds according to claims 1-3, characterized in that the amino acids are in stereochemical L form. Compounds according to claims 1-4, characterized in that the sulfur-containing amino acids are esterified at the C terminal end. Compounds according to claims 1-5, characterized in that the amino acids cysteine / or methionine are present in the form of methyl, ethyl or propyl ester. Compounds according to claims 1-6, characterized in that they are a) N-Nitratopival o1-S- (N-Aeti1 glycyl) -L-cysteine ethyl ester b) N-Nitratopival o1-S- (N-acetylalanine) -L-cysteine ethyl ester c) N-Nitratopivaloyl-S- (N-acetylethyl) -L-cysteine ethyl ester 8. Process for the preparation of nitratoalkanecarboxylic acid derivatives of general formula (I) R ^J O R ' O 2 N — O — CH 2 —C— (CH 2) _m —C — N— (CH ₂ ) _n —C— (CH ₂ ) _o —C — R (I) R R 'in which it is R is hydroxy, lower alkoxy, lower alkenoxy, di-lower alkyl-amino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl-lower alkyloxy, substituted aryloxy or substituted! aryl-lower alkoxy, wherein the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower alkylamino, aryl lower alkylamino, hydroxy lower alkylamino or amino acid residues linked by a peptide bond, r1 hydrogen, alkyl of 1-6 carbon atoms, substituted lower alkyl wherein the substituent is halogen, hydroxy, lower alkoxy , aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio, R ² means, like R ^1, hydrogen or lower alkyl, R ³ is hydrogen or lower alkyl, r ⁴ is hydrogen, lower alkyl, phenyl, methoxyphenyl 1, phenyl lower alkyl, methoxy-phenyl-lower alkyl, hydroxyphenyl-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, aminonyl alkyl, acylamino lower alkyl , mercapto-lower alkyl or lower alkylthio-lower alkyl, r5 denotes S-acyl compounds of lower alkylthiol, in particular their thioesters of amino acids, thioesters of N-acylamino acids, thioesters of peptides or thioesters of N-acyl peptides with 2-5 peptide-linked acid residues, R and R ^ may be linked to form an ester or amide, R ³ and R 4 may be linked together to form an alkylene bridge of 2 to 4 carbon atoms, an alkyl bridge of 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing one double bond or an alkylene bridge as above substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, mn and o are Numbers 0-10 as well as their physiologically acceptable salts, characterized in that in a known manner a compound of general formula (II ), R ^J o κΙ O ₂ N - O - CH ₂ - C - (CH ₂ ) _{m -} C - N - (CH ₂ ) _{n -} c - (CH ₂ ) _{o -} C - R (II) R 'in which it is ΜR hydroxy, lower alkoxy, lower alkoxy, di-lower alkylamino-lower alkoxy, acylamino-lower alkoxy, acyloxy-lower alkoxy, aryloxy, aryl lower alkyloxy, substituted aryloxy, or substituted aryl lower alkoxy, wherein the substituent is methyloxy, wherein the substituent is methyloxy; amino, lower alkyamino, di-lower alkyamino, aryl-lower alkyamino, hydroxy lower alkyamino, or amino acid residues bound via a peptide bond. R is hydrogen, alkyl of 1 to 6 carbon atoms, substituted lower alkyl wherein the substituent is halogen, hydroxy, lower alkoxy, aryloxy, amino, lower alkyamino, acylamino, acyloxy, arylamirio, mercapto, lower alkylthio, arylthio. R1 is as r1 hydrogen or lower alkyl Oh R is hydrogen or lower alkyl, R4 is hydrogen, lower alkyl, phenyl, methoxyphenyl, phenyl lower alkyl, methoxy-phenyl lower alkyl, hydroxyphenyl 1-lower alkyl, hydroxy lower alkyl, alkoxy lower alkyl, amino lower alkyl, acylamino lower alkyl, mercapto-lower alkyl or lower alky 11 and o-zy and alkyl, R and R ^ may be linked together to form an ester or amide, R ³ and R 4 may be linked together to form an alkylene bridge of 2 to 4 carbon atoms, an alkylene bridge of 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of 3 to 4 carbon atoms containing one double bond or one alkylene bridge as above substituted with hydroxy, lower alkoxy, lower alkyl or di-lower alkyl, R 'represents lower alkylthiol - * 9 undergoes the reaction of forming a thioester with amino acids, N-acyl amino acids, peptides or N-acyl peptides with 2-5 peptide-linked amino acid esters and then, if desired, converts the resulting compounds into their harmless salts. A composition comprising one or more compounds according to claims 1-8, as well as conventional fillers and excipients.