DD240547A5 - PROCESS FOR THE PREPARATION OF AMINOSAEUREDERIVATES - Google Patents

Abstract

The invention relates to a process for the preparation of amino acid derivatives for use as medicaments. The aim of the invention is the provision of new compounds with a strong hypotensive effect. According to the invention, novel amino acid derivatives of the general formula I are prepared in which, for example, R 1 is H, phenyl, benzyl, phenethyl, R 2 is H, acetyl, benzoyl, 3-sulfonamido-4-chlorobenzoyl, 3-sulfonamido-4-chloro-6 hydroxybenzoyl, pivaloyl, C1-C2-alkylaminocarbonyl and the like; a. Aden the remainder of an a-amino acid u. a., Formula II, wherein, for example: R3 is hydrogen, C1-C4-alkyl, C5-C7-cycloalkyl, phenyl and. R4 is hydrogen, C1-C4-alkyl, phenyl, phenyl-C1-C4-alkyl or a hetero-C1-C4-alkyl radical u. a; R5OH, an α-amino acid, and the like; a. Formula I and II

Description

Characteristic of the known technical solutions

No information is available on what compounds have been used as a hypotensive.

Object of the invention

The aim of the invention is the provision of new compounds with a strong hypotensive effect.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new amino acid derivatives of the general formula

SR ₉ CH,

ι ι ³

R ₁ -CH-CO-NH-CH-CO-A (I)

and their salts and optionally pharmaceutical compositions containing these compounds.

In formula I mean:

R _{1 is} H, phenyl, benzyl, phenethyl; R _{2 is} H, acetyl, benzoyl-sulfonamido-chloro-benzoyl, S-sulfonamido-chloro-e-hydroxy-benzoyl, 3-sulfonamido-4-chloro-5 ((furyl) -amino) -benzyl, 2, 3-dichloro-4- (β-phenyl-acryloyl) -phenoxy-acetyl, pivaloyl, C ₁ -C ₂ -alkylaminocarbonyl, C ₁ -C ₂ -alkylaminothiocarbonyl, pivaloylmethoxy or the radical

CH-

- S - CH - CO - NH - CH - CO - A; ^R l

A is the remainder of one of the a-amino acids

R _{3 is} hydrogen, C ₁ -C ₄ -alkyl, straight or branched, Cs-Cy-cycloalkyl, where a phenyl ring may be fused, phenyl,

-4- £. * * \ Ι St /

Phenyl-C 1 -C ₄ -alkyl, a hetero-C 1 -C ₄ -alkyl radical, where the heterocycle consists of a 5-or 6-membered ring with 1 to 2 of the heteroatoms O, S or N,

R _{4 is} hydrogen, C ₁ -C ₄ -alkyl, straight or branched, phenyl, phenyl-C ₁ -C ₄ -alkyl or a hetero-C ₁ -C ₄ -alkyl radical, where the heterocycle consists of a 5 or 6 ring with 1-2 of the heteroatoms 0, S or N,

R ₃ and R _{4 taken} together with the N and C atoms form a 5-, 6- or 7-membered ring which may be saturated or contain a double bond and which is optionally substituted by oxo, dimercaptoethylene or one or two hydroxy or methoxy groups , or a 4-, 5- or 6-membered ring containing one or two further of the heteroatoms O, S or N:

R _s OH Ci-Gromega-hydroxyalkyl, Ci-C ₄ -alkoxy, phenyl-C- | -C ₄ -alkoxy, C ^ Ct-alkylamino, Ci-C ₄ -dialkylamino one of the groups

? 7

Γ Il

-O-CH-N-> -0-0H-OCR ₈

-CH odsr - 0 - CH,

, 0

or an α-amino acid peptide-like linked to the CO group of the molecule; R _{6 is} C ₁ -C ₄ -alkyl, C ₁ -C ₃ -alkenyl, C ₁ -C ₃ -alkyl, straight or branched, hydroxy, nitro, amino, C ₁ -C ₄ -alkoxy, mercapto, C ₁ -C ₄ Alkylthio, hydroxy-C 1 -C 4 -alkyl, mercapto-C 1 -C -alkyl, F, Cl, Br, amino-C 1 -C 4 -alkyl, sulfonamido, methylenedioxy, fluoro

C ₁ -C ₄ -alkyl, chloro-C ₁ -C ₄ -alkyl, bromo-C ₁ -C ₄ -alkyl, cyano or trifluoromethyl; R _{7 is} hydrogen or methyl;

R _{8 is} C ₁ -C ₄ -alkyl, straight or branched, where the alkyl radical may be substituted by F, Cl, Br, CF ₃ , phenyl or pyridyl; X, Y and ZO, S, CR ₁₀ , CHR ₁₀ ,

j or

- CH - CH ^; - -C »C -

with the proviso that only one of the radicals X, Y and Z 0, S

^R 10

or I and

-CH-CH- -C = C-

one or two of X, Y and Z may be NR ₉ ; Rg is hydrogen or C ₁ -C ₄ alkyl, straight or branched; R _{10 is} hydrogen, or together with a vicinal radical Ri ₀ a phenyl ring or, for mouth η = 1, whose dihydro-

form with the double bond in conjugation to the C-terminal carboxy group and m and η are each 0.1 or 2, wherein the sum of m and η is 1 or 2.

If the radicals R ₃ and / or R ₄ signify a 5- or 6-membered heteroalkyl radical, examples of the heterocycle may be thiophene, furan, pyrrole, thiazole, oxazole, isoxazole, pyrazole, imidazole, pyran, thiopyran, pyridine, morpholine , Pyrazine, pyrimidine, pyridazine, oxathiine and their di- and tetrahydroforms.

If the radicals R ₃ and R ₄ form a 5-membered ring together with the N and C atoms, pyrrolidinediyl is used as an example for the unsubstituted ring and the group for the substituted ring

"N 1

wherein Rx and Rx 'may be the same or different and denote hydrogen, hydroxy or methoxy, or Rx and Rx' together are oxo or dimercaptoethylene.

The optionally substituted alkyl groups mentioned as being important for the radical R ₅ can be straight or branched; as α-amino acids, which may be peptide-like linked to the CO group of the molecule, there are particularly considered proline, valine, leucine, isoleucine and phenylalanine.

In one of the meanings for A, the 5- or 6-membered ring heterocycles fused to the pyrrolidine or piperidinecarboxylic acid can be saturated or unsaturated. Preferred heterocycles are furan, pyrrole, thiophene, benzofuran, indole, benzothiophene, oxazole, imidazole, thiazole, isoxazole, pyrazole, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, pyridazine, quinoline, isoquinoline or piperidine.

The novel compounds generally have several asymmetric centers and are therefore present as diastereomers or in the form of their racemates or their racemic mixtures. The invention includes both the racemic mixtures and the individual diastereomers. Preferred are those enantiomers in which the asymmetric C atoms are in the S configuration.

The racemates mentioned may be conveniently prepared, e.g. by fractional crystallization, by chemical or by biochemical cleavage, enriched in their sterically uniform forms or pure.

The acids according to the invention form salts with inorganic and organic bases. Examples of inorganic bases are ammonia, alkali metal hydroxides such as sodium or potassium hydroxide or alkaline earth metal hydroxides such as calcium or magnesium hydroxide; of organic bases may be mentioned dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine, N, N'-bis (dehydroabietyl) ethylenediamine, N-methyl-D-glycamin, arginine or lysine.

The new substances of general formula I can be obtained by various methods:

a) By condensation of an acid of the general formula

H. - CH - COOH (II)

Ri and R _{2 have} the abovementioned meaning, with a dipeptide of the general formula

fs

H ₂ N - CH - CO - A (III)

A has the meaning given above.

b) a compound of the general formula

SR ₀ CH-

I ² I ³

R ₁ -CH-CO-NH "CH - COOH (Ha)

Ri and R _{2 have} the abovementioned meaning, with an amino acid A, wherein A has the meaning given above, is condensed.

A compound of general formula Ma can be obtained by peptidic linkage of a compound of general formula II with alanine.

c) a compound of the general formula

R ₁ -CH-CO-NH-CH-CO-A (V)

R ₁ and A have the abovementioned meaning, with a mercapto compound of the general formula

HS-R ₂ (VI)

wherein R _{2 has} the meaning given above is implemented.

Compounds according to formula V can be prepared by condensation of a bromocarboxylic acid of the general formula

Br "" ~

R ₁ -CH- COOH - (IV)

R _{1 has} the meaning given above, with a dipeptide of the general formula II d) condensation of a compound of the general formula

Br CH,

I i

R ₁ -CH-CO-NH-CH-COOH (IVa)

Ri has the abovementioned meaning, with an amino acid A, wherein A has the meaning indicated above, and subsequent reaction of the resulting condensation product of general formula V with a mercapto

compound of the general formula Vl.

A compound of general formula IVa can be obtained by peptide-like linkage of a compound of general formula IV with alanine.

e) conversion of a compound according to formula I in which R _{2 is} acetyl or benzoyl into a compound of formula I in which R _{2 is} hydrogen, by saponification with basic agents.

f) conversion of a compound of formula I in which R _{2 is} hydrogen by reaction with a compound BR ₂ in which R _{2 has} a meaning other than hydrogen and B is an easily cleavable group, for. As chlorine, bromine, means in

a compound of formula I in which R _{2 has} the above meaning except hydrogen, the reaction conveniently in the presence of an acid-binding agent, for. As a base or an alkali carbonate is carried out. In the above processes a) to f), each protecting group is cleaved off at a suitable stage of the process. If appropriate, a final product of the general formula thus obtained is converted into a salt or, if R ₅ -OH, is an ester according to formula I. ,

The condensations described above are carried out by generally conventional methods, as described in Houben-Weyl, Volume XV / 1,4.Auflage, 1974 for the synthesis of peptides.

In general, one uses the usual coupling reactions in peptide chemistry using an activated form of acids II, Ha, IV and IVa; Suitable carboxyl-activating groups are acid chlorides, azides, anhydrides, p-nitrophenyl esters, trichlorophenyl esters, thiophenyl esters, o-cyanomethyl esters, etc. Preferred coupling agents are carbonyldiimidazole, dicyclohexylcarbodiimide, ethoxyacetylene, diphenylphosphoryl azide or chloroformic acid esters; the reaction takes place at temperatures between 0 ° C and +10 ⁰ C.

In the present case, the use of methylene chloride as a solvent together with dicyclohexylcarbodiimide and triethylamine has proved to be advantageous.

The reaction of the bromine intermediates with a mercapto compound of the general formula VI advantageously takes place in ether as solvent. Reaction with thiol acids (eg thiolacetic acid) gives the corresponding acylmercapto compounds; the acyl group can be cleaved off with strong bases. Dimers of the general formula I (R ₂ =

CH ₃

- S - CH - CO - NH-CH-CO-A)

For example, you get

α) by oxidation of a compound of general formula I in which R _{2 is} hydrogen, with an oxidizing agent such as oxygen or iodine;

β) by reacting a compound of general formula IVa with thiolacetic acid to give a compound II a and then saponifying to a compound having free mercapto group. The oxidation to the corresponding dimer is carried out as described under α); the resulting intermediate product is condensed with an amino acid A as described under process b) on page 7.

Preference is given to those compounds of the general formula I in which R 1 is hydrogen, phenyl, benzyl or phenethyl; R _{2 is} hydrogen, acetyl or 3-sulfonamido-4-chloro-benzoyl and A is proline.

The following end products, optionally in the form of their salts, can be obtained by the processes described above:

1. N- [N- (2-mercaptoacetyl) -alanyl] -proline,

2. N- [N- (2-phenyl-2-mercaptoacetyl) -alanyl] -proline,

3. N- [N- (3-phenyl-2-mercaptopropanoyl) -alanyl] -proline,

4. N- [N- (4-phenyl-2-mercaptobutyryl) -alanyl] -proline,

5. N- [N- (2-acetylmercaptoacetyl) -alanyl] -proline,

6. N- [N- (2-phenyl-2-acetylmercaptoacetyl) -alanyl] -proline,

7. N- [N- (3-phenyl-2-acetylmercaptopropanoyl) -alanyl] -proline,

8. N, N '- [N, N' - {2,2'-dithiobis- (3-phenylpropanoyl)} - bis-S-alanyl] -bis-S-proline,

9. N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester,

10. N- [N- (3-phenyl-2-S- {4-chloro-3-sulfone-aminobenzoyl} -mercaptopropanoyl) -S-alanyl] -S-proline,

11. N-tN-O-phenyl-S-mercaptopropanoyO-S-alanyl-S-prolyl-S-phenylalanine,

12. N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-valine,

13. N-IN-O-phenyl-S-mercaptopropanoyD-S-alanyl-S-prolyl-S-proline,

14. N-IN-O-phenyl-S-mercaptopropanoyl-S-alanyl-S-thiazolidine-carboxylic acid,

15. N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-7-carboxylic acid,

16. N-IN-fS-phenyl-S-mercaptopropanoyl J-S-alanyne-JB ^^ - tetrahydro-thieno-S-c-pyridinecarboxylic acid,

17. N- [N- (3-phenyl-2-S-benzoylmercaptopropanoyl) -S-alanyl] -S-proline,

18. N- [N- (3-phenyl-2-S-pivaloylmercaptopropanoyl) -S-alanyl] -S-proline,

19. N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester,

20. N- [N- (3-phenyl-2-S-benzoylmercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester,

21. N- [N- (3-phenyl-2-S-pivaloylmercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester,

22. N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -N-cyclopentylglycine,

23. N -t-N-is-phenyl-S-methylaminothiocarbonyl-mercaptopropanoyl-S-alanyl-S-proline,

24. N-tN-O-phenyl-S-ethylaminocarbonyl-mercaptopropanoyD-S-alanyn-S-proline.

The starting materials are usually known compounds, and any new starting materials are prepared by processes known per se; Compounds of the general formula III are obtained, for. B. by peptide-like linkage of alanine with an amino acid A.

The amino acid derivatives of general formula I have a strong, long-lasting hypotensive effect. This is due to an inhibition of the angiotensin I converting enzyme and thus a blockage of the formation of the vasoconstrictor angiotensin II from angiotensin I. In addition, the new compounds act inhibiting the responsible for bradykinin degradation enzyme kininase II, which is identical to the above-mentioned converting enzyme applies. Because bradykinin has a vasodilatory effect, the hypotensive effect is enhanced by this additional effect. Bradykinin-induced blood pressure reduction in normal rats is enhanced by the new compounds. An expression of this effect could also be the blood pressure lowering effect observed on untreated high pressure genetic rats.

Thus, N- (N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl) -S-proline in the anesthetized rat is produced at a dosage of 0.3 mg / kg i.v. a long-term blood pressure reduction of 67%, if you increase the blood pressure beforehand by an i.v. dose of 0.1 mg / kg angiotensin I.

In the awake rat, following angiotensin! Stimulation (0.2 mg / kg, i.v.) when administered at 1 mg / kg p.o. said compound observed a long-lasting 100% cancellation of blood pressure elevation.

In the rabbit (blood pressure test from the carotid), after the administration of 1 mg / kg of the substance, i.v., a blood pressure reduction of 37 mm was observed.

The N- (N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl) -S-proline shows the angiotensin I Convertin enzyme in vitro inhibitory activity IC ₅₀ = 5.0 x 10 ^"9 (M). the S-Acetylanaloge the compound has an inhibition value IC ₅₀ = 7.4 x 10 ^-9 (M).

IC ₅₀ is the inhibitor concentration at which the angiotensin I converting enzyme is inhibited to 50% (see HSCheung, DWCushman, Biochem Biophys Acta 293, 451 [1973]).

For use in therapy, the new compounds are mixed with customary pharmaceutical fillers or excipients, extenders, disintegrants, binders, lubricants, thickeners or diluents.

As pharmaceutical preparation forms, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders in question, wherein, if desired, further known active compounds, for. For example, Saluretica, Diuretica and / or Antihypertonica can be added.

Corresponding tablets may be prepared, for example, by mixing the active ingredient (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or Achieving the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar and a taste-improving agent, for. B. flavorings such as vanillin or _; Orange extract, included. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

Injection solutions are in the usual manner, for. B. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid and with the addition of suitable solubilizers prepared and filled into injection bottles or ampoules.

The capsules containing one or more active ingredients or combinations of active ingredients can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.

The daily dose for the application of the compounds of the general formula I or their salts according to the invention should be 5-500, preferably 10-100 mg and can be administered in 1-4 single doses.

embodiment

The following examples serve to illustrate the invention. The structure of all synthesized examples was confirmed by NMR spectra.

-8- £ MM Dt /

Example 1 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-proline

A solution of 5.33 g (70 mmol) of thiolacetic acid in 15OmI of anhydrous ether is slowly added under nitrogen and ice cooling with 7.1 g (70 mmol) of triethylamine and then added dropwise to a solution of 15.9 g (35 mmol) of N- [ Add N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-proline tert -butyl ester in 75 mL of anhydrous ether with stirring. The mixture is then refluxed for a further 90 minutes, the previously cooled solution is filtered and washed with dilute KHSO4 and NaHCOa solution, water and saturated NaCl solution. After drying over MgSO ₄ , the solvent is distilled off and the oily residue (16.4 g) on silica gel chromatography (eluent: ethyl acetate, n-hexane [2: 1]). 13.1 g (= 83.4% of theory) of the acetylmercapto-tert.

Butyl esters are obtained as a colorless, viscous oil;

Rf = 0.41 (ethyl acetate, n-hexane = 2: 1, silica gel).

To saponify the tert-butyl ester, a solution of 13.1 g (29.2 mmol) of the above ester in 65 ml of anisole and 130 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. It is then concentrated in vacuo and the residue in each case three times in about 100 ml of acetone, then dissolved in chloroform, and then evaporated in vacuo. The residue is dissolved in dichloromethane and extracted twice with saturated NaHCO ₃ solution. The combined NaHCO3 solutions are washed with dichloromethane, the aqueous phase with conc. HCI acidified and extracted with dichloromethane. The dichloromethane solution is washed with water, saturated NaCl solution, dried over MgSO ₄ and evaporated in vacuo. 10.6 g (= 92.5% of theory) of the free acid, N-IN-O-phenyl-S-acetylmercaptopropanoyl-S-alanyl-S-proline, are isolated as a solidified foam;

Rf = 0.6 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

To saponify the thiolacetic acid ester, 10.6 g (27 mmol) of N-IN-β-phenyl-S-acetylmercaptopropanoyo-S-alanyl-S-proline under an N ₂ atmosphere and with stirring, 250 ml of H ₂ O and 22 ml of 5 N NaOH and leave the solution for 1.5 hours at room temperature.

Thereafter, another 10 ml of 5N NaOH are added and stirring is continued for 1.5 hours at the same temperature. The aqueous solution is washed twice with dichloromethane, acidified with half-concentrated HCl and extracted three times with dichloromethane. The organic phase is washed with saturated NaCl solution, dried over MgSO ₄ and evaporated.

9.2 g (= 97.2% of theory) of the title compound are isolated as a solidified foam, the structure of which was confirmed on the basis of the IR and NMR data.

Rf = 0.6 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

The starting compounds are prepared as follows:

3-phenyl-2-R-bromopropionic acid

Lit.iChemistryoftheAminoAcids.VoiaN.Y. (1961), p. 165; Ann. 357.1 (1907).

Modified literature regulation:

51.2 g (0.31 mol) of R-phenylalanine are added successively with stirring 620 ml of 2.5N H ₂ SO ₄ and 125 g KBr (1.05 mol).

After cooling the solution to 0 ⁰ C in portions over 80 minutes 32,75g (0.475 mol) of NaNO ₂ are added and stirring is continued for 1 hour at room temperature. The resulting emulsion is extracted three times with about 200 ml of ether, the organic phase washed with water and saturated NaCl solution, dried over MgSO ₄ and the ether was distilled off. The oily residue (63 g) is purified by chromatography on silica gel with ethyl acetate, n-hexane (= 2: 1) as eluent.

45.1 g of the title compound are obtained as a reddish oil, the structure and the optical purity confirmed by NMR spectroscopy. The preparation of the S and R, S analogues is carried out according to the same procedure.

N- (3-phenyl-2-R-brompropanoyI) -S-alanine

To a solution of 22.9 g (0.1 mol) of 3-phenyl-2-R-bromopropionic acid, 13.9 g (0.1 mol) of S-alanine methyl ester hydrochloride and 10 g (0.1 mol) of triethylamine in 500 ml of anhydrous dichloromethane are added optionally stirring at 0 ⁰ C 20.6 g (0.1 mol) of N, N'-dicyclohexylcarbodiimide for 15 minutes at ⁰ ° C, then overnight at room temperature, further stirred. After aspirating and distilling off the solvent, the residue is dissolved in ethyl acetate and filtered off after cooling. The ethyl acetate solution is washed successively with dilute KHSO ₄ , saturated NaHCO ₃ solution, water, saturated NaCl solution and dried over MgSO ₄ . After distilling off the ethyl acetate, the oily residue (29.9 g) is chromatographed on silica gel (n-hexane, ethyl acetate = 2: 1) while 23.9 g (= 76% of theory, corresponding to 76 mmol) of the title compound as the methyl ester receive.

To saponify it is dissolved in 150 ml of methanol, cooled to 0 ° C and added with stirring 80 ml of 1 η NaOH (80 mmol). After three hours of stirring at room temperature, it is evaporated in vacuo, the residue is diluted with water and extracted three times with dichloromethane. After removal of the dissolved in the aqueous phase dichloromethane in vacuo is acidified with concentrated HCl and the precipitated crystals are filtered off. Yield: 17.8 g (= 78% of theory) of the title compound of mp.

156-157 ⁰ C are obtained.

Rf = 0.7 (chloroform, methanol, glacial acetic acid 90: 10: 5, silica gel).

Analogously, the S S and (R, S) S diastereomers are obtained.

An NMR spectroscopic comparison of the S S and R, S diastereomers shows the stereoselective course of the synthesis.

N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-proline tert.-butyl ester

a) 17.8 g (59.3 mmol) of N- (3-phenyl-2-R-bromopropanoyl) -S-alanine and 10.1 g (59.3 mmol) of S-proline-tert-butyl ester are dissolved in 250 ml of anhydrous Dissolved dichloromethane and with stirring and cooling (0 ° C) with 12.2 g (59.3 mmol) of N, N'-dicyclohexylurea. After aspirating the Dicyclohexylhamstoffs the solvent is distilled off in vacuo, the oily residue dissolved in ethyl acetate and set aside for some time. After renewed suction, it is washed successively with dilute KHSO ₄ solution, saturated NaHCO ₃ solution, water and saturated NaCl solution and, after drying over MgSO _4, the solvent is distilled off in vacuo. The oily residue (24.2 g) is chromatographed on silica gel (mobile phase: ethyl acetate, n-hexane [2: 1]).

15.9 g (= 59.1% of theory) of the title compound can be isolated as a colorless, viscous oil which appears to be uniform by NMR spectroscopy and chromatographically.

Rf = 0.45 (ethyl acetate, hexane (2: 1), silica gel).

Analogously, the SSS and R, S S S-analogous diastereomers are obtained.

b) A solution of 2.29 g (10 mmol) of 3-phenyl-2-S-bromopropionic acid, 2.78 g (10 mmol) of S-alanyl-S-proline tert-butyl ester hydrochloride and 1 g (10 mmol) of triethylamine dissolved in 100 ml of anhydrous dichloromethane and treated with stirring and cooling (O ⁰ C) with 2.06g (10 mmol) of I ^ N'-dicyclohexylcarbodiimide. The mixture is stirred overnight at room temperature, cooled and filtered from the precipitated dicyclohexylurea from. The solvent is distilled off in vacuo, the oily residue dissolved in ethyl acetate, cooled, filtered off from the undissolved and washed successively with dilute KHS0 ₄ solution, saturated NaHCO3 solution, water and saturated NaCl solution. After drying over MgSO ₄ , the solvent is distilled off and 4.3 g (= 94.8% of theory) of a colorless, viscous oil are obtained.

Analogously, the RSS and R, S S S-analogue diastereomers are obtained.

Example 2 N- [N- (3-phenyl-2-R-mercaptopropanoyl) -S-alanyl] -S-proline

Using N- [N- (3-phenyl-2-S-bromopropanoyl) -S-alanyl] -S-proline ter-t-butyl ester, the diastereomeric title compound N- [N- (3-phenyl-2 -R-mercaptopropanoyl) -S-alanyl] -S-proline. Rf = 0.54 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 3

N- [ISL (3-phenyl-2-R, S-mercaptopropanoyl) -S-alanyl] -S-proline

Using N- [N- (3-phenyl-2-R, S-bromopropanoyl) -S-alanyl] -S-proline tert.butyl ester, the title compound N-IN-P-phenyl-R is obtained analogously to Example 1 ^ -mercaptopropanoyO S alanyU-S-proline.

Example 4

N- [1,1-mercaptoacetyl) -S-alanyl] -S-proline ,%

When using N- [N-bromoacetyl) -S-alanyl] -S-proline tert-butyl ester, the title compound N- [N- (mercaptoacetyl) -S-alanyl-S-proline is obtained analogously to Example 1.

Rf = 0.35 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 5 N- [N- (2-phenyl-2-R, S-mercaptoacetyl) -S-alanine] -S-proline

Using N- [N- (2-phenyl-2-R, S-bromoacetyl) -S-alanine] -S-proline tert-butyl ester, the title compound N- [N- (2-phenyl-) is obtained analogously to Example 1. 2-R, S-mercaptoacetyl) -S-alanine] -S-proline

 Rf = 0.48 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 6 N- [N- (4-phenyl-2-R, S-mercaptobutanoyl) -S-alanine] -S-proline

When using N- [N- (4-phenyl-2-R, S-bromobutanoyl) -S-alanine] -S-proline, the title compound N- [N- (4-phenyl-2-R , S-mercaptobutanoyl) -S-alanine] -S-proline.

Rf = 0.59 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 7 N, N '- [N, IM' - {2,2'-dithiobis- (3-phenylpropanoyl)} - bis-S-alanyl] -bis-S-proline

2.5 g (4.95 mmol) of N, N '- [2,2'-S-didthiobis- (3-phenyl-propanoyl)] - bis-S-alanine and 1.69 g (9.9 mmol) of S-proline tert-butyl ester are dissolved in 50 ml of anhydrous dichloromethane and admixed with stirring and ice-water cooling with 2.0 g (9,9OmMoI) N, N'-dicyclohexylcarbodiimide. It is stirred for 15 minutes, then overnight at room temperature, filtered off with suction and distilled off from the solvent. The residue is dissolved in ethyl acetate, cold-pressed, filtered off again and washed with dilute KHSO ₄ solution, saturated NaHCO ₃ solution, water and saturated NaCl solution. After drying over MgSO ₄ , the ethyl acetate is distilled off in vacuo, thereby obtaining 3.4 g of a solidified foam.

The residue is chromatographed on silica gel (eluent: dichloromethane, methanol [95: 5]).

2.6 g of the title compound in bis-tert-butyl ester form are obtained chromatographically and uniformly by NMR spectroscopy.

To saponify the diester, a mixture of 2.6 g (3.2 mmol) of the above dimerentert.Butylesters, 13 ml of anisole and 26 ml of trifluoroacetic acid for 2 hours at room temperature and then evaporated in vacuo to dryness. The residue (2.7 g) is treated three times with acetone and chloroform and distilled off again in vacuo. The crude product is taken up in dichloromethane, washed with saturated NaHCO ₃ solution, the aqueous phase is acidified with concentrated HCl and the crystalline precipitate is filtered off with suction, washed with water and dried.

1.1 g (= 49% of theory) of the title compound are purified by chromatography and purified by NMR spectroscopy;

Rf = 0.62 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

The preparation of the R, S S S-analog dimers is carried out according to the same procedure.

R f = 0.57 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

The starting compounds are prepared as follows:

N-IS-phenyl-Z-S-acetylmercaptopropanoylJ-S-alanine methylester

To a solution of 1.98 g (26 mmol) of thiolacetic acid in 70 ml of anhydrous ether with stirring, cooling to 0 ° C and N ₂ atmosphere 2.6 g (26 mmol) of triethylamine, dissolved in 20 ml of anhydrous ether, added dropwise slowly. Subsequently, 4.1 g (13 mmol) of N- (3-phenyl-2-R-bromopropanoyl) -S-alanine methyl ester (preparation see Example 1) in 50 ml of anhydrous ether are added dropwise and boiled for 90 minutes at reflux. After cooling to room temperature, the mixture is filtered and the solvent is distilled off. The oily residue (6.2 g) is chromatographed on silica gel with η-hexane, glacial acetic ester (2: 1) and 3.9 g (96.9% of theory) of a crystalline product which is identical in NMR spectroscopy as the title compound.

N, N '- [2,2'-S-dithiobis (3-phenylpropanoyl)] - bis-S-alanine

3.9 g (12.6 mmol) of N-P-phenyl-S-acetylamercaptopropanoyD-S-alanine methyl ester are dissolved in 40 ml of methanol, and 37.8 ml (37.8 mmol) of 1 N NaOH are added with stirring and ice cooling. The solution is stirred for 3 hours at room temperature, then treated with a 2% strength methanolic iodine solution until a permanent yellow color.

It is then destained with dilute Na ₂ S ₂ Os-LoSUnQ, distilled off from the solvent in vacuo, the residue dissolved in water and washed with dichloromethane. The aqueous phase is concentrated in vacuo to remove the dichloromethane and acidified with concentrated HCl. The precipitated reaction product is extracted with dichloromethane, washed with saturated NaCl solution, dried over MgSO ₄ and distilled off from the solvent.

2.5 g (= 78.6% of theory) of the title compound can be isolated as a solidified foam.

Rf = 0.5 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

The preparation of the RSS and R, S S S-analogue diastereomers is carried out by the same process.

Example 8 N-tN-fS-phenyl-S-mercaptopropanoyl J-S-alanyl-S-proline pivaloyloxymethyl ester 1.75 g (5 mmol) of N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S- alanyl] -S-proline are dissolved in 30 ml of acetone and 500 mg (5 mmol) of KHCO ₃ , 140 mg (0.84 mmol) of KI and 0.81 ml (5 mmol) of chloromethyl pivalate are added successively with stirring under nitrogen. The mixture is refluxed for 3 hours and filtered with suction after cooling. The filtrate is concentrated in vacuo, the residue taken up in ethyl acetate and washed successively with water, saturated NaHCO3 solution, water and saturated NaCl solution. It is dried over MgSO4 and the solvent is distilled off in vacuo. The oily residue (1.5 g = 69% of theory) is chromatographed on silica gel (mobile phase: ethyl acetate, n-hexane [2: 1]) and thereby 2 fractions are obtained: 0.7 g (= 32% of theory). ) correspond to the title compound; Rf = 0.28.

0.3 g (13.7% of theory) corresponds to the S-alkylation product N-tN-fS-phenyl ^ -S-pivaloyloxymethylmercaptopropanoylJ-S-alanyl] -S-proline pivaloyloxymethyl ester.

The preparation of the RSS and R, S S S-analogue diastereomers and the corresponding S-acyl compounds is carried out in the manner described in Example 11.

Example 9

N- [N- (3-phenyl-2-S- {4-chloro-3-sulfonamidobenzoyl} -mercaptopropanoyl-S-alanyl] -S-proline To a solution of 2.1 g (6 mmol) N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-proline in 100 ml of water and 1.008 g (12 mmol) of NaHCO ₃ are added with 1.524 g (6 mmol) of 4-chloro-3-sulfamoylbenzoic acid chloride and After standing for 2 hours, the mixture is washed with dichloromethane, the aqueous phase is acidified with dilute HCl and the precipitated crystals are filtered off with suction.

1.4 g (= 82.1% of theory) of the title compound can be isolated as a solid substance.

Rf = 0.3 (butanone, acetone, water = 60: 6: 10, silica gel). The NMR spectroscopic data confirm the structure and purity of the substance.

Example 10 N-tIM-O-phenyl-a-S-mercaptopropanoyD-S-alanyl J-S-prolyl-S-phenylalanine

1.08 g (10.7 mmol) of triethylamine are slowly added dropwise to a solution of 815 mg (10.7 mmol) of thiolacetic acid in 35 ml of anhydrous ether under N ₂ atmosphere, ice cooling and stirring. Then, a solution of 3 g (5.37 mmol) of N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-prolyl-S-phenylalanine methyl ester in 20 ml of anhydrous dichloromethane is added dropwise to the above solution, and Boiled for 90 minutes at reflux. After cooling, the product is filtered off with suction and the filter residue is dissolved in dichloromethane. It is washed with saturated NaHCO ₃ solution, dilute KHSO 4 solution, water and saturated NaCl solution. After drying over MgSO ₄ the solvent is distilled off to obtain 3.3 g of a solid residue, which gave a yield of 2.03 g (= 68% of theory) after recrystallization from Essigester.

The methyl ester has a mp of 157-158 ° C and an Rf value of 0.13 (ethyl acetate, η-hexane = 2: 1, silica gel).

For saponification, 6 ml of 5 N NaOH are added to a suspension of 2 g (3.6 mmol) of the above mercaptoacylmethyl ester in 50 ml of methanol and 20 ml of water with stirring under an N ₂ atmosphere and stirred for 1.5 hours at room temperature. Another 2 ml of 5 N NaOH are added and stirring is continued for a further 1.5 hours. The methanol is evaporated in vacuo, the residue is diluted with water and washed twice with dichloromethane.

The aqueous phase is acidified with dilute HCl solution and extracted three times with dichloromethane. The organic phase is then washed with saturated NaCl solution, dried over MgSO ₄ and distilled off in vacuo.

1.7 g (= 94.9% of theory) of the title compound are obtained as a solidified foam whose structure has been confirmed by NMR spectroscopy.

Rf = 0.48 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Following the same procedure, the R, S S S and R S S analogue diastereomers are obtained.

The starting compound is prepared as follows: IM- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-prolyl-S-phenylalanine

To a solution of 2.8 g (7 mmol) of N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-proline, 1.5 g (7 mmol) of S-phenylalanine methyl ester hydrochloride and 708 mg ( 7 mmol) of triethylamine in 50 ml of anhydrous dichloromethane are added with stirring at 0 ° C 1.44 g (7 mmol) of N, N'-dicyclohexylcarbodiimide, 15 minutes at 0 ⁰ C, then stirred at room temperature overnight. The mixture is filtered, the solvent is distilled off in vacuo and the residue is dissolved in ethyl acetate.

Then the solution is cooled, filtered again and washed successively with dilute KHSO ₄ solution, saturated NaHCO ₃ solution, water, saturated NaCl solution.

It is dried over MgSC> 4 and the solvent is distilled off in vacuo. The residue (4g) is recrystallized from a little ethyl acetate;

Yield: 3 g (76.7% of theory)

Rf = 0.37 (ethyl acetate, n-hexane = 2: 1, silica gel).

Example 11 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-valine

Using N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-prolyl-S-valine, the title compound is obtained analogously to Example 10.

Rf = 0.48 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 12 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-proline

When using N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-prolyi-S-proline, the title compound is obtained analogously to Example 10.

Rf = 0.26 (ethyl acetate, silica gel).

Example 13 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-thiazolidine-4-carboxylic acid Analogously to Example 1, the title compound is obtained in yields when using S-thiazolidine-4-carboxylic acid of 85.4% of theory

Mp 144-146 ⁰ C

Rf = 0.46 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Elemental analysis: C ₁₆ H ₂ ON ₂ O ₄ S ₂

CHASE

Calculated: 52.15 5.47 7.60 17.40

Found: 51.96 5.41 7.46 17.41

The structure is confirmed by NMR spectroscopy.

Example 14 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-7-carboxylic acid Analogously to Example 1 When using 4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-7-carboxylic acid in the R, S, R and S configuration, the corresponding diastereomers of the title compound are obtained.

Rf-We'rtfürsS S R, S-diastereomer mixture: 0.18 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 15 N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-4-carboxylic acid Analogously to Example 1 When 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-4-carboxylic acids are used, the corresponding diastereomers of the title compound are obtained. Rf value for the S S RjS diastereomeric mixture: 0.53 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 16 N- [N- (3-phenyl-2-S-benzoylmercaptopropanoyl) -S-alanyl] -S-proline

To a solution of 2.1 g (15.4 mmol) of thiolbenzoic acid in 50 ml of anhydrous ether, 1.56 g (15.4 mmol) of triethylamine are slowly added at ⁰ ° C., under nitrogen atmosphere and with stirring. Then, a solution of 3.5 g (7.7 mmol) of N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-proline tert-butyl ester in 30 ml of anhydrous ether is added dropwise and boils for 90 minutes under reflux. After aspirating, the ethereal solution is washed with dilute KHSO ₄ solution, saturated NHCO 3 solution, water and saturated NaCl solution, dried over MgSO ₄ and evaporated to dryness. The residue (3.7 g) is chromatographed on silica gel (eluent: ethyl acetate, n-hexane = 1: 1) and 3.4 g (= 86.5% of theory) of tert.butyl ester of the title compound as a solidified foam.

Rf = 0.27 (ethyl acetate, n-hexane = 1: 1, silica gel).

For saponification, 3.4 g (6.6 mmol) of the above tert-butyl ester are dissolved in 34 ml of trifluoroacetic acid and 17 ml of anisole and stirred for 2 hours at room temperature. In vacuo, the reaction solution is evaporated and dissolved three times each with acetone and chloroform and concentrated again in vacuo. The residue is dissolved in dichloromethane and washed with water and saturated NaCl solution. After drying over MgSO ₄ , the mixture is evaporated and the residue (3.1 g) is chromatographed on silica gel (eluent: dichloromethane, methanol, glacial acetic acid = 120: 5: 2).

2.2 g (= 73.3% of theory) of the title compound are obtained as a colorless, solidified foam.

R f = 0.25 (dichloromethane, methanol, glacial acetic acid = 120: 5: 2, silica gel).

Example 17 N- [N- (3-phenyl-2-S-pivaloylmercaptopropanoyl) -S-alanyl-S-proline

The procedure is as described in the previous example. Instead of thiolbenzoic acid is thiolpivalic acid. Reaction of 3.17 g (7 mmol) of N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -S-proline tert -butyl ester and 1.65 g (14 mmol) of thiolpivalic acid gave 3.3 g (= 96% of theory) of the tert-butyl ester of the title compound. Rf = 0.34 (ethyl acetate, n-hexane = 1: 1, silica gel).

Its saponification with trifluoroacetic acid led to the title compound in a yield of 2.4 g (= 82.4% of theory).

Rf = 0.3 (dichloromethane, methanol, glacial acetic acid = 120: 6: 2, silica gel).

Example 18 N-tN-IS-phenyl-S-acetylmercaptopropanoy O-S-alanyl-S-proline pivaloyloxymethyl ester 2.3g (5.8 mmol) N-IN-O-phenyl-S-acetylmercaptopropanoyU-S-alanyl J-S -proline (intermediate of Example 1) are dissolved in 40 ml of anhydrous acetone and successively 580 mg (5.8 mmol) KHCO 3.161 mg (0.97 mmol) of potassium iodide and 873 mg (5.8 mmol) of chloromethyl pivalate are added with stirring under a nitrogen atmosphere. The mixture is refluxed for 3 hours and filtered with suction after cooling. The filtrate is concentrated in vacuo, the residue taken up in ethyl acetate and washed sequentially with water, saturated NaHCO3 solution, water and saturated NaCl solution. It is dried over MgSO ₄ and the solvent is distilled off in vacuo. The oily residue (2.7 g) is chromatographed on silica gel (eluent: ethyl acetate, n-hexane = 2: 1) while 2.2 g (= 75% of theory) of the title compound as an oil. Rf = 0.42 (ethyl acetate, n-hexane = 2: 1, silica gel).

Example 19 N- [N- (3-phenyl-2-S-benzoylmercaptopropanoyl) -S-alanyl] -S-proline-pivaloyloxymethyl ester Analogously to Example 18, the use of N- [N- (3-phenyl-2-S benzoylmercaptopropanoyl) -S-alanyl-S-proline the.

Title compound.

Rf = 0.43 (ethyl acetate, n-hexane = 1: 1, silica gel).

Example 20 N-CN-tS-phenyl-S-pivaloylmercaptopropanoyl-S-alanyl-S-proline pivaloyloxymethyl ester Analogously to Example 18, the use of N- [N- (3-phenyl-2-S-pivaloylmercaptopropanoyl) -S -alanyl] -S-prolidine the title compound.

Rf = 0.45 (ethyl acetate, n-hexane = 2: 1, silica gel).

Example 21 N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -1,1-cyclopentylglycine 6g (2OmMoI) N- (3-phenyl-2-R-bromopropanoyl) -S-alanine and 4 g (2OmMoI) N-cyclopentylglycine tert-butyl ester are dissolved in 100 ml of dichloromethane and with stirring and cooling (O ⁰ C) with 4.1 g (2OmMoI) N, N'-dicyclohexylcarbodiimide and 15 minutes at this temperature, then Stirred at room temperature overnight. After aspirating the Dicyclohexylharnstoffs the solvent is distilled off in vacuo, the oily residue dissolved in ethyl acetate and allowed to stand for some time in the cold. After renewed suction, the filtrate is washed with dilute KHSO ₄ solution, saturated NaHCO 3 solution, water and saturated NaCl solution and distilled off after drying over MgSO ₄ in vacuo. The oily residue (6.7 g) is chromatographed on silica gel (mobile phase: ethyl acetate, n-hexane = 1: 2). Yield 4.3 g (= 44.6% of theory) Bromoteit.Butylester as a colorless oil are obtained. Rf = 0.28 (ethyl acetate, n-hexane = 1: 2, silica gel).

The exchange of the bromine for thiolacetic acid and the subsequent saponification of the t-butyl ester to the title compound is carried out in the manner described in Example 1

 Rf = 0.55 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

Example 22

N- [I \ I- (3-phenyl-2-S-methylaminothiocarbonyl-mercaptopropanoyl) -S-alanyl] ^-S-proline. "

A solution of 1.73 g (4.96 mmol) of N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-proline in 10 ml of 0.5 N NaOH and 25 ml of pyridine is added under nitrogen atmosphere with 0, 4 g (5.47 mmol) of methyl isothiocyanate and heated to 40 ° C for 2 hours.

It is then evaporated to dryness in vacuo, the residue slurried with water and acidified with concentrated HCl. The aqueous phase is extracted with ethyl acetate, washed with NaCl solution and dried over MgSO ₄ . The ethyl acetate extract is evaporated to dryness to give 1.5 g (71.4% of theory) of the title compound as a solidified foam, which is purified by chromatography on silica gel.

(Eluent: toluene, acetic acid = 75:25).

Rf = 0.47 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

Example 23 N- [N- (3-phenyl-2-S-ethylammocarbonyl-mercaptopropanoyl) -S-alanyl] -S-proline A solution of 1.72 g (4.92 mmol) of N- [N- (3-phenyl -2-S-mercaptopropanoyl) -S-alanyl] -S-proline in 5 ml of 1 η NaOH and 5 ml of pyridine with 0.45 ml (5.7 mmol) of ethyl isocyanate was added and 4 hours at 40 ^c C under N ₂ - Atmosphere stirred. Thereafter, it is evaporated to dryness in vacuo. The residue is slurried in water, acidified with 0.1 .mu. HCI and, as described in the preceding example, further processed.

1.7 g (82.1% of theory) of the title compound are obtained as a solidified foam.

Rf = 0.45 (chloroform, methanol, glacial acetic acid = 90: 10: 5, silica gel).

NMR data for several compounds of the invention as follows:

- IO - LTU

Example 1 1 H-NMR data (CD ₃ OD) d, J = 7Hz, 3H, CH ₃ -CH- m, 4 H, Pm-CH ₂ CH ₂ 8 = 1.31, 1.80-2.41, m, 2 H, 0-CH ₂ -CH- 3:16, m, 3 H, Pm-NCH ₂ , 0-CH ₂ -CH- m, 1 H, Pro ciCH 3.43-3.89, 4.41, m, 1 H CH ₃ -CH- m, 5H, H-Arg, 4,61, 7,24,

SH, NH, COOH in solvent blank peak Example 2

^ -NMR data (CDCI ₃ )

5 = 1.15, 1.77-2.39, 2.05, d, J = 7 Hz, 3 H, CH ₃ -CH- m, 4 H, CH ₂ CH ₂ Pro - d, J = 10Hz, SH 3.13, 3.43, 3.63, 4.55, m, 2 H, 0-CH ₂ -CH- m, 1 H, 0-CH ₂ -CH ₂ -m, 2 H, PrO-N-CH ₂ -m, 1H, ProaH 4.77, 7.25, 3.93, m, 1 H, CH ₃ -CH- m, 5H, aryl-H s, broad, COOH Example 4 ¹ H-NMR Data (CD ₃ OD) δ = 1.35, 1.81-2.52, 3.17, d, 3 H, J = 7 Hz, CH ₃ -CH- m, 4 H, Pm-CH ₂ CH ₂ -s, 2H, PrO-CH ₂ CH ₂ - 3.69, 4.47, m, 2H, ProN-CH ₂ m, 1H, Pro a-CH-

4.64 qu, 1H, J = 7Hz, CH ₃ -CH-

SH, NH u. (coH in solvent blank bacon.

Example 5 ¹ H NMR (CD ₃ OD) d, J = 7Hz, 3H _; CH ₃ -CH- m, 4 H, PrO-CH ₂ CH ₂ -m, 2 H, PrO-N-CH ₂ δ = 1.32, 1.77-2.45, 3.65, m, 1 H, Pro α CH- 4:48, m, 1 H, CH ₃ -CH- 4.66, s, 1H, 0-CH-m, 5H, aryl-H 4.82, 7.24-7.59,

SH, NH, COOH in the solvent blank Peck

Example 6

δ = 1.35 d, 3 H ₁ CH ₃ -CH-J = 7 Hz

2.08, 1.80-2.44, 2.72, m, 2 H, 0-CH ₂ -m, 4 H, PrO-CH ₂ -CH ₂ -m, 2 H, 0-CH ₂ - 3.26, 3.65, m, 1H, 0-CHz-m, 2H, PrO-N-CH ₂ - 4:56, m, 1H, ProaCH-

4.77, 7.23, 7.50, 8.96, m, 1 H, CH ₃ -CH- m, 5H, aryl-H m, 1 H, NH, s, 2 H, SH u. COOH Example 7 ¹ H = NMR data (CDCI ₃ ) δ = 1.28 1.66-2.51, 3.06, d, J = 7Hz, 6 HCH ₃ -CH m, 8 H, Pm-CH ₂ CH ₂ - m, 4 H, _0-CH2 -CH- 3:33 to 4:01, m, 6H, PrO-NCH ₂ O-CH 4:42, m, 2 H, Pro α CH 4.75, 6.75, 7.21, 7.50, m, 2H, CH ₃ -CH- s, 2H, COOH m, 10H, aryl-H d, J = 8Hz, 2H, NH

Example 8 - Title compound H-NMR data (CDCl ₃ ) δ = 1.20,

s, 9 H, C (CH ₃ I ₃

1.34, 1.96, 1.82-2.42, d, J = 7Hz, 3H, CH ₃ -CH- d, J = 10HB, 1H, SH m, 4H, Pm-CH ₂ CH ₂ - d, J = 7 Hz, 3 H, CH ₃ -CH- m, 4 H, Pm-CH ₂ CH ₂ 2.91-3.81, 4.49, m, 5 H, N-CH ₂ Pro, 0-CH ₂ CH- m, 1H, CH α Pro m, 2 H, 0-CH ₂ -CH- 4.66, 5.75, 7.23, m, 1 H, CH ₃ -CH- m, 2H, oCH ₂ om, 6H, 5Aryl-H, l \ IH m, 3H, O-CH ₂ -CH-, PrO-NCH ₂ Example 8 -N-fN-S-phenyl-S-pivaloyloxymethylmercaptoproi 1 H-NMR data (CDCl ₃ ) δ = 1.16, s, 9 H, C (CH ₃ ) ₃ 1.21, s, 9 H, C (CH ₃ ) ₃ m, 2 H, Pro α CH, CH ₃ -CH- m, 2 H, OCH ₂ -O d, J = 8Hz, 1H, NH m, 5H, aryl-H 1.33, 1.78-2.43, 3:14, d, J = 7 Hz, 3 H, CH ₃ -CH- d, J = 10Hz, 1H, SH m, 8 H, CH ₂ CH ₂ Pro 3.34-3.89, m, 7H, Pro NCI ₂ , 0-CH ₂ -CH- 4.36-4.89, 5.75, 7.14, 7.23, m, 3 H, Pro α CH, CH ₃ -CH- s, 2 H, NH, COOH m, 5H, aryl-H Example 12 ¹ H NMR Data (CDCI ₃ ) δ = 1.34, 1.97, 1.71-2.43, 2.84-4.00, 4.26-4.96, 6.20, 7.26,

Example 13 Ή-NMR Data (CDCl ₃ ) δ = 1.35, 2.03, d, J = 7Hz, 3H, CH ₃ -CH- d, J = 10Hz, 1H, SH 3:20, m, 2 H, 0-CH ₂ -CH- 3.27, 3.50, d, 2 H, S-CH ₂ -CH-, J = 7 Hz m, 1 H, 0-CH ₂ -CH- 4.72 m, 2H, N-CH ₂ -S 4.77, m, 1 H, CH ₃ -CH- 5.10, 6.52, 7.27, 7.78, t, J = 7 Hz, SCH ₂ -CH- s, 1 H, COOH m, SH, aryl-H d, J = 8Hz, 1H, 1 \ IH

Example 14

Ή = NMR data (CD ₃ OD)

5 = 1.33, d, J = 7 Hz, 3 H, CH ₃ -CH- 2.50-3.91, m, 7H, O-CH ₂ -CH-, CH ₂ -CH ₂ - 4.99, m, 1 H, CH ₃ -CH- 5.85, 6.84, 7.34, 7.18, SH, NH, COOH in S, 1H, N-CH-C-d, 1H, thiophene 4H d, 14, thiophene 5H m, 5H, aryl-H solvent blank Example 15 'H NMR Data (CDCI ₃ ) δ = 1.34, 2.02, d, J = 7Hz, 3H, CH3-CH-d, J = 9Hz, 1H, SH 2.72 ^ .43, m, 7H, O-CH ₂ -CH-, -CH ₂ -CH ₂ - 5.00, 5.91, 7.23, m, 1 H CH ₃ -CH- s, 1 H, CH-COOH, - m, 9H, aryl-H, thiophene-H, NH, COOH Example 16 Ή-NMR Data (CDCI ₃ ) δ = 1.28, 1.77-2.39, d, 3 H, J = 7.0 Hz, CH ₃ -CH- m, 4 H, PrO-CH ₂ CH ₂ - 3.24, 3.58, m, 2H, 0-CH ₂ -CH- m, 2 H, PrO-NCH ₂ 4:47, m, 1 H, 0-CH ₂ -CH- 4:53, m, 1H, Proa-CH- 4.75, 7.02-8.00, 8.50, m, 1 H, CH ₃ -CH- m, 10H, 2-aromatics s, 1 H, COOH

Example 17 Ή-NMR data (CDCl ₃ ) δ = 1.17, s, 9 H, C (CH ₃ J ₃ 1.26, 1.82-2.37, d, 3 H, J = 7 Hz, CH ₃ -CH m, 4 H, PrO-CH ₂ CH ₂ - 3.14, 3.57, 4.19, m, 2 H, _0-CH2 -CH- m, 2 H, N-CH ₂ Pro - m, 1 H, _0-CH2 -CH- 4:50, m, 1H, Proa-CH- 4.73, 6.98, m, 1 H, CH ₃ -CH- d, 1H, J = 8Hz, -NH 7.21, 8.30, m, 5H, arylH s, 1H, COOH Example 18 Ή-NMR data (CDCl ₃ ) δ = 1.21, s, 9H, C (CHg) ₃ 1.23, 1.77-2.27, 2.30, d, 3 H, J = 7 Hz, CH ₃ -CH m, 4 H, CH ₂ CH ₂ Pro - s, 3H, CH ₃ -C = O 3.15, 3.58, m, 2 H, O-CH ₂ -CH- m, 2 H, Pm-NCH ₂ - 4:15, m, 1 H, 0-CH ₂ -CH- 4:48, m, 1 H, Pro α CH- 4.67, 5.75, 6.92, 7.23, m, 1 H, CH ₃ -CH- m, 2 H, -O-CH ₂ -O-d, 1H, J = 8Hz, NH m, 5H, aryl-H Example 19 Ή-NMR data (CDCl ₃ ) 5 = 1.19, s, 9 H, C (CH ₃ ) ₃ 1.31, 1.80-2.34, d, 3 H, CH ₃ -CH-J = 7 Hz m 4 H, PrO-CH ₂ CH ₂ - 3.26, 3.58, m, 2H, O-CH ₂ -CH- 171.2 ^ PrO-NCH ₂ - 4:48, m, IH, O-CH ₂ -CH- 4:50, m, IH, Pro α CH- 4.73, 7.00, 5.76, 7.27, 7.34-8.02, m, 1 H, CH ₃ -CH- d, 14, J = 7Hz, NH-m, 2 H, OCH ₂ o m, 5H, aryl-H m, 5 H, .0-C ₅ -H

Example 20 Ή-NMR Data (CDCI ₃ ) δ = 1.16, 1.20, s, 9 H, C (CH ₃ ) ₃ s, 9H, C (CH ₃ ) ₃ 1.27, 1.82-2.32, d, 3H, J = 7Hz, CH ₃ -CH- m, 4H, Pro CH2 _CH2 3.16, 3.57, m, 2H, Phe-CH ₂ -CH- m, 2 H, Pro N CH ₂ - 4:16, m, 1 H, 0-CH ₂ -CH- 4:48, m, 1 H, Pro αCH- 4.71, 5.76, 6.82, 7.22, m, 1 H, CH ₃ -CH- m, 2 H, OCH ₂ -O d, 1H, J = 8Hz, NH m, 5H, aryl-H Example 21 Ή-NMR Data (CDCI ₃ ) 5 = 1.31, 1.16-2.11, 2.28, d, 3 H, J = 7 Hz, CH ₃ -CH- m, 8 H, cyclopentyl CHz s, 3 H, CH ₃ -C = ο 3.15, 2.92, 4.22, m, 2 H, 0-CH ₂ -CH- m, 2 H, N-CH ₂ -C = o m, 1 H, cyclopentyl-CH 4:26, m, 1 H, 0-CH ₂ -CH- 4.92, 5.61, 7.18, 7.24, m, 1 H, CH ₃ -CH- s, 1 H, COOH d, 1H, J = 8Hz, NH m, 5H, aryl-H Example 22 'H NMR Data (CDCI ₃ ) 5 = 1.27, 1.73-2.41, 3.18, d, J = 7 Hz, 3 H, CH ₃ -CH- m, 4 H, PrO-CH ₂ -CH ₂ - d, J = 4Hz, 3H, _NH-CH3 3.21, 3.57, 4.48, m, 2H, O-CH ₂ -CH- m, 2H, ProN-CH ₂ m, 1H, Proa-CH 4.65, m, 1 H, CH ₃ -CH- 4.48, 7.24, m, 1H, O-CH ₂ -CH- m, 5H, aryl-H 7.47, 8.48, 8.77, d, J = 7Hz, NH-CH-qu, J = 4Hz, Nh-CH _3s , 1H, COOH

Example 23

Ή-NMR data (CDCl ₃ ) δ = 1.11, 1.28, 1.77-2.41,

3.15, 3.23, 3.56,

4.19, 4.52,

4.73, 5.65, 7.23,

t, J = 7Hz, 3H, CH ₃ -CH ₂ d, J = 7Hz, 3H, CH ₃ -CH m, 4 H, CH ₂ CH ₂ Pro

m, 2 H, 0-CH ₂ CH-m, 2 H, N-CH ₂ -CH ₃ m, 2 H, Pm-N-CH ₂

m, O-CH ₂ -CH-m, Pro α CH

(Ti ₁ CH ₃ -CH-

s, broad, 2 χ NH u. COOH

m, 5H, aryl-H

CM ₂ -CH

C-NH-CH - C-CS)

CS) 5 "

H O Ή NMR data (CDCI ₃ ) δ = 1.15, 1.22, s, 9 H, C (CH ₃ ) ₃ s, 9 H, C (CH ₃ J ₃ 1:36, d, J = 7 Hz, 3 H, CH ₃ -CH- 2.83-3.49, m, 4H, O-CH ₂ -CH-, S-CH ₂ -CH 3.74, m, 1 H, 0-CH ₂ -CH- 4.39-4.84, ITi ₇ SH ₁ N-CH ₂ -SH ₃ -CH- 5.07, 5.76, 7.23, m, 1 H, SCH ₂ -CH- m, 2 H, OCH ₂ -O m, 6H, aryl-H, NH

= 0.48 (ethyl acetate, 1-hexane = 1: 1)

5 = 1.05, 2.08,

1:59 to 2:25,

2.84-3.93,

4.46-4.99, 7.24, 7.75,

U O

COOH

d, J = 7Hz, 3H, CH ₃ -CH-d, J = 10Hz, 1H, SH m, 4 H, Pm-CH ₂ CH ₂

m, 7H, PrO-NCH ₂ , 0-CH ₂ -CH-, 0-CH ₂ -CH

m, 3 H, Pro α CH, CH ₃ -CH-, 0-CH ₂ -CH-COOH

m, 12H, aryl H, NH, C00h

d, J = 8Hz, NH

SH

¹ H NMR data (CDCl ₃ ) δ = 0.86, d, J = 7 Hz, 6 H, CH ₃ isobutyl 1.32, 2.09, 1.71-2.70, d, J = 7Hz, 3H, CH ₃ -CH- d, J = 10Hz, 1H, SH m, SH, Pm-CH ₂ CH _2, iso-CH- (CH _{3) 2} 3:14, m, 2 H, 0-CH ₂ -CH- 3:41 to 4:00, m, 3 H, Pm -NCH ₂ , 0-CH ₂ -CH- 4.34-4.99, 6.58, 7.22, m, 3 H, Pro α CH, CH ₃ -CH-, isobutyl-CH s, IH, COOH m, 5 H, aryl-H 7.53, 7.75, d, J = 10Hz, 1H, NH-CH d, J = 8Hz, 1H, NH-isobutyl

-MH-CH- C-

CS)

Ή NMR data (CD ₃ OD)

δ = 1.30, 1.78-2.40,

2.90 - 3.42 3.56,

4.27-4.84, 7.27, 7.73, 8.08, 8.57,

d, J = 7Hz, 3H, CH ₃ -CH-m, 4 H, CH ₂ CH ₂ Pro

m, 2 H, O-CH ₂ -CH-m, 2 H, Pro N-CH ₂

m, 3 H, Pro α CH, O-CH ₂ -CH-, CH ₃ -CH-

m, 5H, aryl-H

d, J = 8Hz, 1H, ortho-aryl-H

dd, J = 8Hz, 3Hz, 1H, ortho / meta aryl-H

d, J = 3Hz, 1H, metacryph-H

NH ₂ , NH, COOH, in the solvent blank

CS) OV ^ -C "- C-NH-CH - C -

SH

CS)

Ή NMR data (CDCI ₃ )

= 1.33, 2.02,

2:00 to 2:50,

2.84-3.66, 3.48-3.89 ,. 4.50, 5.40, 7.24, 7.46,

d, J = 7 Hz, 3 H, CH ₃ -CH-d, J = 10Hz, 1H, SH m, 2H, Proß-CH ₂ -

m, 3 H, 0-CH ₂ -CH-

m, 2 H, PrO-N-CH ₂ m, 2H, Proa-CH, CH-OH s, broad, OH, COOH m, 5 H, aryl-H d, J = 8Hz, 1H, NH

= 0.23 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

Cs)

Ή NMR data (CDCI ₃ )

= 1.34,

1.34 to 1.99,

2.00

3:16,

3.53, 3.92, 4.28, 4.99,

d, 3 H, J = 7 Hz, CH ₃ -CH-m, 8H, cyclopentyl -CH ₂ d, J = 10Hz, SH

m, 2H, 0 -CH ₂ -CH-

m, 1H, O-CH ₂ -CH-m, 2H, N-CH ₂ -C = V m, 1H, cyclopentyl-CH m, 1 H, CH ₃ -CH-

5.91, s, 1H ₁ COOH

7.24 m, 5H, aryl H

7.46, d, 1H, J = 8Hz, NH

Rf = 0.63 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

i H NMR data (CDCI ₃ ) 5 = 1.29, d, (3H), J = 7 HzCH ₃ -CH 1.76 to 2.31, m, 4H, PrO-CH ₂ -CH ₂ 2,16, 2,31, s, 3H, .CH ₃ -C = s, 3H, CH ₃ -C- 3,13, 3,58, m, 2HO-CH ₂ m, 2H, Pro N-CH ₂ - 4.24, m, 1 H, 0-CH ₂ -CH- 4.48, m, 1H, CH ₃ -CH- 4.58, 4.78, 6.87, 7.23, m, 1H, Pro α CH- m, 2H, 0-CH ₂ -d, 1H, J = 7.5 Hz, CH m, 5H, aryl-H

Rf = 0.17 (ethyl acetate, hexane = 2: 1)

H NMR data (CDCl ₃ ) 5 = 1.19 s, 9H, C (CH ₃ J ₃ 1.32, 2.30, d, J = 7Hz, 3H, CH ₃ -CH- s, 3H ₁ CH ₃ -C = O 3:11, m, 2H, 0-CH ₂ -CH- 3,22, 4,12, m, 2H, S-CH ₂ -CH- m, 1H, O-CH ₂ -CH- 4.59; m, 2H, N-CH ₂ -S- 4.64, m, 1H, CH ₃ -CH- 5.07, 5.74 / 6.86, 7.18, m, 1H, N-CH-C = ν m, 2H ₁ OCH ₂ -O d, J = 8Hz, 1H, NH m, 3H, aryl-H

Rf = 0.35 (ethyl acetate, n-hexane = 1: 1)

• I C-O H NMR data (CDCi ₃ ) 5 = 1.32, d, 3H, J = 7 Hz, CH ₃ -CH- 2.30, s, 3H, CH ₃ -C = O 3:14, m, 2H, 0-CH ₂ -CH- 3,25, 4,25, 4,65, d, 2H J = 6Hz, SCH ₂ -CH- m, 1H, 0 -CH ₂ -CH- m, 2H, N-CH ₂ -S 4.78, m, 1H, CH ₃ -CH- 5.07, 7.16, 7.20, 8.48, t, 1H, J = 6Hz, N-CH-COO d, 1H, J = 8Hz, NH m, 5H, aryl-H s, 1H, COOH

it)

R _f = 0.47 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

¹ H NMR data (CDCI ₃ )

5 = 1.30, 2.09,

2.48-3.81, 4.13,

4.64, 4.99,

d, J = 7Hz, 3H, CH ₃ -CH-d, J = 10Hz, 1H, SH

m, 5H, O-CH ₂ -CH-, CH ₂ -C = O m, 2H ₁ N-CH ₂

m, 1H ₁ CH ₃ -CH-m, 1HD CH-COOH

7.24, m, 5H, aryl-H

7.57, d, J = 8Hz, 1H, NH

9.69, s, 1H, COOH

Rf = 0.34 (chloroform, methanol, glacial acetic acid = 120: 5: 2)

KIH-c-cH-c-ts}

O QS)

it)

ffttNJ

¹ H NMR data (CDCI ₃ )

= 1.31, 2.05,

2.35

3,19, 3,27, 3,50,

3.68, 4.59,

4,70, 5,95, 7,23,

d, 3H, J = 7Hz, CH ₃ -CH-d, 1H, J = 10Hz, SH

d, 2H, J = 7Hz, Pro-CH2-CH-

m, 2H, 0-CH ₂ -CH-

s, 6H, 20 CH ₃

m, 1H, 0-CH ₂ -CH-

m, 2H, Pm-N-CH ₂ m, 1H, Proa-CH-

m, 1H ₁ CH ₃ -CH-

s, broad, 2H, NH u. COOH

m, 5H, aryl-H

Rf = 0.49 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

-C-M-C ^ -C-

¹ H NMR data (CDCl ₃ )

δ = 130, 2.02,

2.67,

3,15, 3,36,

3,55, 4,00,

4.64, 7.23, 7.41, 7.56,

d, J = 7Hz, 3H, CH ₃ -CH-d, J = 10Hz, 1H, SH

m, 2H, PrO-CH ₂ -CH-

m, 2H, 0 -CH ₂ -CH-s, 4H, -S CH ₂ CH ₂ -S-

m, 1H, O-CH ₂ -CH-m, 2H ₇ PrO-H-CH ₂ -

m, 2H, CH ₃ -CH-, α-CH-Pro m, 5H, aryl-H d, J = 8Hz, 1H, NH s, 1H, COOH

Rf = 0.5 (chloroform, methanol, glacial acetic acid = 90: 10: 5)

Cs.)

sw

Ή NMR data (CDCl ₃ ) δ = 1.18, s, 9H, C (CH ₃ ) ₃ 1.34, 1.99, d, J = 7 Hz, 3H, CH ₃ -CH- d, J = 10Hz, 1H, SH 2.93 to 3.77, m, 5H, 0 -CH ₂ -CH- S CH ₂ -CH- 4.41 to 4.94, m, 3H, N-CH ₂ -S, CH ₃ -CH-

5.07, m, 1 H, S-CH ₂ -CH-

5.77, m, 2H, OCH ₂ -O

7.07, d, J = SHz, 1H, NH

7.23, m, 5H, aryl-H

= 0.33 (ethyl acetate, n-hexane = 1: 1)

Pharmaceutical application examples 10.0 mg a) dragees 60.0 mg 1 drag core contains: 35.0 mg Active ingredient according to claim 1 3.0 mg lactose 2.0 mg corn starch gelatin magnesium stearate

110.0 mg Production:

The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with 1 mm mesh size, dried at 4O ⁰ C and rubbed through a sieve again. The granules thus obtained are mixed with magnesium stearate and pressed. The cores thus obtained are coated in a conventional manner with a shell which is applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragees are polished with beeswax.

b) tablets

Active ingredient according to claim 1 10.0 mg

Lactose 70.0 mg

Cornstarch 50.0 mg

soluble starch 7.0 mg

Magnesium stearate 3.0 mg '

140.0 mg Production:

Active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules dried and intimately mixed with lactose and corn starch. The mixture is then compressed into tablets of 230 mg in weight, each containing 100 mg of active ingredient.

c) Injection solutions

Active ingredient according to claim 1 5.0 mg

Ethanolamine 60.0 mg

Sodium chloride 20.0 mg

distilled water ad 2.0 ml

production:

The active ingredient and the excipients are dissolved in a sufficient amount of distilled water and brought to the desired concentration with the required amount of water. The solution is filtered and bottled under aseptic conditions in 2 ml ampoules. The ampoules are sterilized and sealed. Each vial contains 5 mg of active ingredient.

d) capsules

Active ingredient according to claim 1 10.0 mg

"Milk sugar 250.0 mg

Corn starch 40.0 mg

Talc 10.0 mg

310.0 mg

Active ingredient, milk sugar and corn starch are first mixed in a mixer and then in a crusher. The mixture is again added to the mixer, mixed thoroughly with the talc and machine-filled into hard gelatin capsules.

e) Suppositories

Active ingredient according to claim 1 0.1 g

Cocoa butter (mp 36-37 ⁰ C 1.6 g

Carnauba wax 0.1 g

1.8g

Cocoa butter and carnauba wax are melted, mixed thoroughly and cooled to 45 ° C. In this mass of finely pulverized active ingredient is stirred. The mixture is then poured into slightly pre-cooled suppository molds of appropriate size and allowed to cool.

Claims (3)

-1- Z4UÖ4 / claim for invention: 1. A process for the preparation of amino acid derivatives of the general formula SR- CH, I ² I R _- - CH - CO - NH - CH - CO - A (I) R _{1 is} H, phenyl, benzyl, phenethyl; R _{2 is} H, acetyl, benzoyl, 3-sulfonamido-4-chloro-benzoyl, S-sulfonamido-chloro-e-hydroxybenzoyl, S-sulfonamido-chloro-BKfuryo-aminolbenzoyl, 2,3-dichloro 4- (β-phenyl-acryloyl) -phenoxy-acetyl, pivaloyl, C ₁ -C ₂ -alkylaminocarbonyl, C ₁ -C ₂ -alkylaminothiocarbonyl, pivaloylmethoxy or the radical CH, - S - CH - CO - NH - CH - CO - A; ^R l A is the remainder of one of the α-amino acids I: ii HN-C (HJc COR ₅ R, Cj-C alkyl group ₃ is hydrogen, C ₁ -C ₄ -alkyl, straight or branched ₇ cycloalkyl, wherein a phenyl ring may be fused, phenyl, _{phenyl-Ci-C4-alkyl,} a _{hetero-Ci-C4-} in which the heterocycle consists of a 5 or 6 ring with 1-2 of the heteroatoms O, S or N, R _{4 is} hydrogen, C ₁ -C ₄ -A ^ yI, straight or branched, phenyl, phenyl-Cr-C ^ alkyl or a hetero-C ^ d-alkyl radical, wherein 'the heterocycle of a 5- or 6-ring with There are 1-2 heteroatoms O, S or N, R ₃ and R _{4 taken} together with the N and C atoms form a 5-, 6- or 7-membered ring which may be saturated or contain a double bond and which is optionally substituted by oxo, dimercaptoethylene or one or two hydroxy or methoxy groups or a 4-, 5- or 6-membered ring containing one or two more of the heteroatoms O, S or N; R ₅ OH is C ₁ -C ₄ -hydroxyalkyl, C ₁ -C 4 -alkoxy, phenyl-C ₁ -C 4 -alkoxy, C ₁ -C 4 -alkylamino, C ₁ -C 4 -dialkylamino, one of the groups CH. \ _t -O-CH-N R ₇ O It -O-CH-O-C-R or - O- CH, or an α-amino acid peptide-like linked to the CO group of the molecule; R _{6 is} C ₁ -C ₄ -alkyl, C ₁ -C -alkenyl, C ₁ -C ₃ -alkyl-straight or branched, hydroxy, nitro, amino, C ₁ -C ₄ -alkoxy, mercapto, C ₁ -C ₄ - AIkYHhio, hydroxy-C 1 -C 4 -alkyl, mercapto-C 1 -C 4 -alkyl, F, Cl, Br, aminoC 1 -C 4 -alkyl, sulfonamido, methylenedioxy, Fluoro-C ₁ -C ₄ -alkyl, chloro-C ₁ -C ₄ -alkyl, BrOm-C ₁ -C ₄ -alkyl, cyano or trifluoromethyl; R _{7 is} hydrogen or methyl; R _{8 is} C ₁ -C ₄ alkyl, straight or branched, where the alkyl radical may be substituted by F, Cl, Br, CF ₃ , phenyl or pyridyl; X, Y and ZO, S, CR ₁₀ , CHR ₁₀ , or I - ÖH - CH - -C = with the proviso that only one of the radicals X, Y and Z O, S or and - CHGH - -C = C- one or two of X, Y, and Z may be NR ₉ ; R _{9 is} hydrogen or C ₁ -C ₄ -alkyl, straight or branched; R is hydrogen, or together with a vicinal radical R _{10 is} a phenyl ring or, for m and η = 1, its dihydroform having the double bond in conjugation to the C-terminal carboxy group and m η in each case 0.1 or 2, the sum of m and η is 1 or 2, and their salts and optionally their pharmaceutical administration forms, characterized in that a compound of the general formula br - GH'-CO -ITH-CH-CO - A wherein R ₁ and A have the abovementioned meaning, with a mercapto compound of the general formula HS-R ₂ (VI) wherein R _{2 has} the abovementioned meaning, and if appropriate, the compounds or salts prepared in this way with customary pharmaceutical auxiliaries and / or excipients to conventional pharmaceutical applications. Process according to item 1, characterized in that amino acid derivatives of the formula I are prepared in which R _{1 is} H, phenyl, benzyl or phenethyl, R _{2 is} H, acetyl or 3-sulfonamido-4-chloro-benzoyl and A is proline and their salts. 3. The method according to item 1, characterized in that N-dSI-O-phenyl ^ -S-mercaptopropanoyD-S-alanyD-S-proline and its salts are prepared. 4. The method according to item!, Characterized in that amino acid derivatives are prepared according to points 1 to 3, wherein the asymmetric carbon atoms in S-configuration. Field of application of the invention The invention relates to a process for the preparation of amino acid derivatives with valuable pharmacological properties. The compounds according to the invention are used as medicaments, in particular as hypotensives.