NO853444L - ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES - Google Patents

Description

The present invention relates to an analogue method for the production of new therapeutically active amino acid derivatives with the general formula and their salts.

In formula I means:

H, phenyl, benzyl, phenethyl; R2H, acetyl, benzoyl, 3-sulfonamido-4-chloro-benzoyl, 3-sulfonamido-4-chloro-6-hydroxy-benzoyl, 3-sulfonamido-4-chloro-5-[(furyl)-amino]-benzoyl, 2,3-dichloro-4-(o-phenyl-acryloyl)-phenoxy-acetyl, pivaloyl, C1-C2-alkylaminocarbonyl, C^-C^' alkylaminothiocarbonyl, pivaloylmethoxy or the residue A the residue of one of the α-amino acids or

R 3 hydrogen, C 1 -C 4 -alkyl, straight chain or branched, C 3 -C 4 -cycloalkyl, under which a phenyl ring may be fused to, phenyl, phenyl-C 3 -C 4 -alkyl, a hetero-C 3 -C 4 -alkyl radical , where the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0, S or N,

R4hydrogen, -C4-alkyl, straight-chain or branched, phenyl, phenyl-Cj-C^-alkyl or a hetero-C^-C4-alkyl radical, wherein the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0 , S or N,

R^ and R^ 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 optionally substituted with 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 0, S or N;

R5OH, C1-C4-uj-hydroxyalkyl, C1-C4-alkoxy, phenyl-Cj-C^-alkoxy, C1-C4-alkylamino, -C4-dialkylamino, one of the groups

or

or an α-amino acid which is peptide-like linked to the CO group of the molecule;

R6C1-C4-alkyl, C1-C3-alkenyl, C1-C3-alkynyl, straight or branched hydroxy, nitro, amino, C1-C4-alkyl, mercapto, C1-C4-alkylthio, hydroxy-C1-C4-alkyl , mercapto-Cj-C4~alkyl, F, Cl, Br, amino-C1-C4-alkyl, sulfonamido, methylenedioxy, fluoro-Cj-C4~alkyl, chloro-C^-C4-alkyl, bromo-C1-C4~ alkyl, cyano

or trifluoromethyl;

R 3 is hydrogen or methyl;

Rg C1-C3-alkyl, straight-chain or branched, in which the alkyl residue may be substituted with F, Cl, Br, CF3, phenyl or

pyridyl;

X, Y and Z 0, S, CR1Q,<CH>R1Q,

with the proviso that only one of the residues X, Y and Z can mean 0, S

one or two of the residues X, Y and Z NRg;

R 9 hydrogen or C 1 -C 4 alkyl, straight chain or branched;

R^q hydrogen, or together with a vicinally standing residue R^q a phenyl ring, or, for m and n = 1, its dihydroform with a double bond in conjugation to the C-terminal carboxy group and

m and n 0,1 or 2, where the sum of m and n is 1 or 2.

If the residues R^ and/or R^ are a 5- or 6-membered heteroalkyl residue, examples of the heterocyclic ring include thiophene, furan, pyrrole, thiazole, oxazole, isoxazole, pyrazole, imidazole, pyran, thiopyran, pyridine, morpholine , pyrazine, pyrimidine, pyridazine, oxathiine and their di- and tetrahydro forms.

If the residues R^ and R^ together with N and C atoms form a 5-ring, for example the unsubstituted ring becomes pyrrolidinediyl and the substituted ring group

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

The optionally substituted alkyl residues which are mentioned as meaning the residue Rc can be straight-chain or branched; as α-amino acids, which can be peptide-like bound to the CO group in the molecule, particularly proline, valine, leucine, isoleucine and phenylalanine come into consideration.

In one of the meanings for A, the 5- or 6-ring heterocycle which is condensed on the pyrrolidine or piperidine carboxylic 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 new compounds generally have several centers of asymmetry and therefore exist as diastereomers or in the form of their racemates or their racemic mixtures. The invention includes both the preparation of the racemic mixtures and the individual diastereomers. Preferred are the enantiomers in which the asymmetric C atoms are present in the S configuration.

The mentioned racemates can be obtained in the usual way, for example by fractional crystallisation, by chemical or by biochemical cleavage enriched•or one in their sterically uniform forms.

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

The new substances with the general formula I can be prepared by different methods:

a) By condensation of an acid with the general formula in which

R 1 and R 2 have the previously indicated meaning, with a dipeptide of the general formula

in which

A has the aforementioned meaning,

b) a compound with the general formula

in which

R^ and Rj have the meaning indicated above. is condensed with an amino acid A, where A has the meaning indicated above, and a compound of the general formula IIa can be obtained by peptidic attachment of a compound of the general formula II to alanine,

c) a compound with the general formula

in which

R 1 and A have the above meaning are reacted with a mercapto compound of the general formula

in which

R2 has the meaning indicated above, and

compounds of formula V can be obtained by condensation of a bromocarboxylic acid of the general formula

in which

R^ has the meaning given above with dipeptide of the general formula II,

d) condensation of a compound with the general formula

in which

R^ has the meaning given above, with an amino acid A, where A has the meaning given above and subsequent reaction of the thus produced condensation product of the general formula V with a mercapto compound of the formula VI, and a compound of the general formula IVa can be prepared by peptide-like attachment of a compound of the general formula IV with alanine,

e) conversion of a compound of formula I in which R2 is acetyl or benzoyl into a compound of formula I in which R2 is hydrogen by saponification with basic reagents,

f) conversion of a compound of formula I in which R2 is hydrogen by reaction with a compound B-R2, in which R2 has a

meaning other than hydrogen, and B means an easily cleavable group, for example chlorine, bromine, in a compound of formula I, in which R 2 has the meaning given above except hydrogen. About-

deposition is suitably carried out in the presence of an acid-binding agent (for example a base or an alkali carbonate).

In the above methods a) to f) any protecting group is removed at a suitable step in the process. An end product thus obtained with the general formula is optionally transferred into a salt, or when R o,, is -OH, into an ester of formula I.

The condensations described above take place by generally common methods as described in Houben-Weyl, volume XV/1, 4th edition, 1974 for the synthesis of peptides.

In general, the coupling reactions that are common in peptide chemistry are used using an activated form of the acids II, Ila, IV and IVa; carboxyl-activating groups include acid chloride, azide, anhydride, p-nitrophenyl ester, trichlorophenyl ester, thiophenyl ester, o-cyanomethyl ester, etc. Preferred coupling agents are carbonyldiimidazole, dicyclohexylcarbodiimide, ethoxyacetylene, diphenylphosphoryl azide or chloromauric acid esters; the turnover takes place at temperatures between 0°C and +10°C.

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

The reaction of the bromine intermediate with a mercapto compound of the general formula VI takes place advantageously in ether as solvent. By reaction with thiol acid (for example thiolacetic acid) the corresponding acyl mercapto compounds are obtained; the acyl group can be cleaved off with strong bases.

Dimers with the general formula I ( R^ = are obtained, for example

a) by oxidizing a compound of the general formula I in which R 2 is hydrogen with an oxidizing agent such as

oxygen or iodine;

0) by reaction of a compound of the general formula IVa with thiolacetic acid to a compound Ila and subsequent saponification to a compound with a free mercapto group. The oxidation to the corresponding dimer occurs as described

under a); the intermediate product obtained is condensed as under method b) described above with an amino acid A.

Preferred are the compounds of the general formula I in which R 1 is hydrogen, phenyl, benzyl or phenethyl; R2hydrogen, acetyl or 3-sulfonamido-4-chloro-benzoyl and A proline.

With the method described above, the following end products can be produced, possibly in the form of their salts: 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)-alanyl3-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}-mercapto-propanoyl)-S-alanyl]-S-proline, 11. N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-prolyl-S-phenylalanine, 12. N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-prolyl-S-valine, 13. N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-prolyl-S-proline, 14. N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-thiazolidine-4-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-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-4-carboxylic 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-CN-(3-phenyl-2-S-methylaminothiocarbonyl-mercaptopropanoyl)-S-alanyl]-S-proline, 24. N-[N-(3-phenyl-2-S-ethylaminocarbonyl-mercaptopropanoyl)-S-alanyl]-S-proline.

The starting materials were mostly known compounds, and possibly new starting materials are also prepared according to known methods; the compound with the general formula III is obtained, for example, by peptide-like attachment of alanine to an amino acid A.

The amino acid derivatives of the general formula I have a strong, long-lasting blood pressure-lowering effect. This is due to an inhibition of the angiotensin I converting enzyme and thus a blocking of the formation of the vasoconstrictor angiotensin II from angiotensin I. In addition, the new compounds inhibit the enzyme kininase II which is responsible for the breakdown of bradykinin, which applies identically to the above said conversion enzyme. As bradykinin has a vasodilating effect, the blood pressure-lowering effect is enhanced by this additional effect. The blood pressure reduction achieved with bradykinin in normal rats is enhanced with the new compounds. Also the observed blood pressure-lowering effect on non-pretreated genetic hypertensive rats was only an expression of this effect.

Thus N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-proline in anesthetized rats in a dosage of 0.3 mg per kg i.v. a long-term drop in blood pressure of 67% when, through an i.v. injection, the blood pressure is increased by 0.1 mg per kg of angiotensin

IN.

In the awake rats, after an angiotensin I stimulation (0.2 mg/kg, i.v.) by administration of a 1 mg per kg p.o. of the said compound a long-lasting 100% ig abrogation of the increase in blood pressure.

In rabbits (blood pressure test from the carotid), observed after administration of 1 mg per kg of substance, i.v., a blood pressure drop of 37 mm.

N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-proline shows on the angiotensin I converting enzyme in vitro a heme-nxng activity ICC_ =5.0• 10 [M]. The S-acetyl analogue of the bO _g compound has an inhibition value ICC„ =7.4 ■ 10 [M]. YOU

As ICD,-U_ is denoted here the inhibitor of the concentration which inhibits the angiotensin I converting enzyme by 50% (pp. H.S. Cheung, D.W. Cushman, Biochem. Biophys. Acta 293, 451 (1973)).

For therapeutic use, the new compounds are mixed with common pharmaceutical fillers or carriers, stretching, disintegrating, binding, sliding, thickening or diluting agents. Pharmaceutical preparation forms include, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders, to which, if desired, additional known active substances can be added, for example saluretics, diuretics and/or antihypertensives.

Corresponding tablets can, for example, be prepared by mixing the active substance or substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents to achieve a depot effect such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Similarly, dragees can be produced by coating a core prepared analogously to the tablets with agents normally used in dragee coatings, for example collidon 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, to achieve a depot effect, the dragée sleeve can also consist of several layers, under which the same excipients as with tablets mentioned above can be used.

Juices of the active ingredients produced according to the invention, respectively active ingredient combinations, can also contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar, as well as a flavor enhancer, for example flavoring agents such as vanillin or orange extract. They may also contain suspension aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions are prepared in the usual way, for example with the addition of preservatives such as p-hydroxybenzoates or stabilizers such as alkali salts or ethylenediaminetetraacetic acid and with the addition of a suitable solvent and filled in injection bottles or ampoules.

The capsules containing one or more active ingredients or combinations of active ingredients can likewise be prepared by mixing the active ingredients with inert carriers such as milk sugar or sorbitol and encapsulating in gelatin capsules.

The daily dose for the use of the compound produced according to the invention with the general formula I or their salts should be 5 to 500, preferably 10 to 100 mg and can be given in 1 to 4 single doses.

The following examples serve to further elucidate the invention. The structure of all synthesized examples has been confirmed with the NMR spectrum.

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 150 ml of anhydrous ether is mixed under nitrogen and ice-cooling slowly with 7.1 g (70 mmol) of triethylamine and then added dropwise to a solution of 15.9 g (35 mmol) of N -[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl]-S-proline tert-butyl ester in 75 ml of anhydrous ether with stirring. It is then boiled for a further 90 minutes at reflux, the previously cooled solution is filtered and washed with dilute KHSO 4 and NaHCO 3 solution, water and saturated NaCl solution. After drying over MgSO4, the solvent is distilled off and the oily residue (16.4 g) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane (2:1)). 13.1 g (= 83.4% of the theoretical) acetyl mercapto-tert-butyl esters are obtained as colorless, viscous oil;

Rf = 0.41 (acetic ester, n-hexane = 2:1, silica gel).

To saponify the tertiary butyl ester, a solution of 13.1 g (29.2 mmol) of the above-mentioned ester in 65 ml of anisole and 130 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. Then evaporate under vacuum and the residue is dissolved three times in approx. 100 ml of acetone, then in chloroform and then rotary evaporated in vacuo. The residue is dissolved in dichloromethane and extracted twice with saturated NaHCO 3 solution. The combined NaHCO^ solutions are washed with dichloromethane, the aqueous phase is acidified with conc. HCl 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 theoretical) of the free acid, N-[N-(3-phenyl-2-S-acetylmercaptopropanoyl)-S-alanyl]-S-proline, is isolated as a solidified foam;

R^ = 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-[N-(3-phenyl-2-S-acetyImercaptopropanoyl)-S-alanyl]-S-alanyl]-S-proline are added under an N2 atmosphere and stirring 250 ml H20 and 22 ml 5 n NaOH and the solution to stand for 1.5 hours at room temperature. A further 10 ml of 5 n NaOH is then added, and the mixture is stirred for a further 1.5 hours at the same temperature. The aqueous solution is washed twice with dichloromethane, acidified with semi-concentrated HCl and extracted three times with dichloromethane. The organic phase is washed with saturated NaCl solution, dried over MgSO4 and evaporated. 9.2 g (= 97.2% of theory) of the title compound is isolated as a solidified foam, and the structure was confirmed by IR and NMR data.

Rf = 0.6 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel). The output connections are made as follows:

3-phenyl-2-R-bromopropionic acid

Litt.: Chemistry of the Amino Acids, Vol. I, N.Y. (1961),

p. 165; Ann. 357, 1 (1907).

Modified literature Thursday:

51.2 g (0.31 mol) of R-phenylalanine are mixed in sequence with 620 ml of 2.5 n H 2 SO 4 and 125 g of KBr (1.05 mol). After cooling the solution to 0°C, 32.75 g (0.475 mol) NaN02 are added in portions over 80 minutes and the mixture is stirred for 1 hour at room temperature. The emulsion formed is extracted three times with approx. 200 ml of ether each time, the organic phase is washed with water and saturated NaCl solution, dried over MgSO4 and the ether is distilled away. The oily residue (63 g) is purified chromatographically over silica gel with ethyl acetate, n-hexane (= 2:1) as eluent.

45.1 g of the title compound is obtained as a reddish oil, and the structure and optical purity are confirmed NMR spectroscopically. The production of the S and R,S analogues takes place according to the same regulations.

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

To a solution of 22.9 g (0.1 mol) 3-phenyl-2-R-bromopropionic acid, 13.9 g (0.1 mol) S-alanine methyl ester hydrochloride and 10 g (0.1 mol) triethylamine in 500 ml anhydrous dichloromethane is added with stirring at 0°C 20.6 g (0.1 mol) N,N'-dicyclohexylcarbodiimide, and it is stirred further for 15 minutes at 0°C and then overnight at room temperature. After filtering and distilling off the solvent, the residue is dissolved in vinegar and filtered off after cooling. The ester solution is washed successively with dilute KHSO4~, saturated NaHCO-^ solution, water, saturated NaCl solution and dried over MgSO4 , ethyl acetate = 2:1) and thereby obtain 23.9 g (= 76% of the theoretical; corresponding to 76 mmol) of the title compound as methyl ester.

To saponify it, dissolve it in 150 ml of methanol, cool to 0°C and add, while stirring, 80 ml of 1 n NaOH

(80 mmol). After stirring for three hours at room temperature, the mixture is evaporated in vacuo, the residue is diluted with water and extracted three times with dichloromethane. After evaporation of the dichloromethane which dissolves in the water phase under vacuum, acidify with concentrated HC1 and the precipitated crystals are filtered off.

Yield: 17.8 g (= 78% of the theoretical) of the title compound with melting point 156-157°C.

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 collection of the S S and R,S diastereomers shows a stereoselective model of the synthesis.

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

a) 17.8 g (59.3 mmol) N-(3-phenyl-2-R-bromopropanoyl)-S-alanine and 10.1 g (59.3 mmol) S-proline tert-butyl ester are dissolved in

250 ml of anhydrous dichloromethane and mixed with stirring and cooling (0°C) with 12.2 g (59.3 mmol) of N,N'-dicyclohexylurea. After filtering off the dicyclohexylurea, the solvent is distilled away in a vacuum, the oily residue is dissolved in vinegar and allowed to cool for a while. After filtering off again, wash in sequence with dilute KHSO 3 solution, saturated NaHCO 3 solution, water and saturated NaCl solution and after drying over MgSO 3 , the solvent is distilled away in vacuum. The oily residue (24.2 g) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane (2:1)).

15.9 g (=59.1% of theoretical) of the title compound can be isolated as a colorless, viscous oil, which shows uniformity NMR spectroscopically and chromatographically.

Rf = 0.45 (acetic ester, hexane (2:1), silica gel).

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

b) A solution of 2.29 g (10 mmol) 3-phenyl-2-S-bromopropionic acid, 2.78 g (19 mmol) S-alanyl-S-proline-triethylamine is dissolved in

100 ml of anhydrous dichloromethane and mixed with stirring and cooling (0°C) with 2.06 g (10 mmol) of N,N'-dicyclohexylcarbodiimide. The mixture is stirred overnight at room temperature, cooled and filtered from the precipitated dicyclohexylurea. The solvent is distilled away in vacuo, the oily residue is dissolved in vinegar, cooled, filtered from undissolved material and washed in sequence with dilute KHSO 3 solution, saturated NaHCO 3 solution, water and saturated NaCl solution. After drying over MgSO^, the solvent is distilled away and

you get 4.3 g (= 94.8% of the theoretical) of a colourless, viscous oil.

Analogously, the R S S and R,S S S analog diastereomers are prepared.

Example 2

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

Analogous to example 1, by using N-[N-(3-phenyl-2-S-bromopropanoyl)-S-alanyl]-S-proline tert-butyl ester, the diastereomeric title compound N-[N-(3-phenyl- 2-R-mercapto-propanoyl)-S-alanyl]-S-proline.

Rf = 0.54 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel).

Example 3

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

Analogously to example 1, the title compound N-[N-(3-phenyl- 2-R,S-mercaptopropanoyl)-S-alanyl]-S-proline.

Example 4

N-[N-(mercaptoacetyl)-S-alanyl]-S-proline

Analogously to example 1, the title compound N-[N-(mercaptoacetyl)-S-alanyl-S-proline is obtained by using N-[N-bromo-acetyl)-S-alanyl]-S-proline tert-butyl ester.

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

Example 5

N-[ N-( 2- phenvl- 2- R. S- mercaptoacetvl)- S- alanine]- S- proline

Analogously to example 1, the title compound N-[N-(2-phenyl- 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

Analogously to example 1, 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'- CN. N'-{2.2'-dithiobis-(3-phenylpropanoyl)>-bis-S-alanyl]-bis-S-proline

2.5 g (4.95 mmol) N,N'-[2,2'-S-dithiobis-(3-phenylpropanoyl)]-bis-S-alanine and 1.69 g (9.9 mmol) S- proline tert-butyl ester was dissolved in 50 ml of anhydrous dichloromethane and mixed with 2.0 g (9.90 mmol) of N,N'-dicyclohexylcarbodiimide under stirring and ice water cooling. It is stirred for a further 15 minutes, then overnight at room temperature, filtered off and the solvent is distilled off. The residue is dissolved in acetic acid, allowed to cool, filtered again and washed with dilute KHSO 4~10 solution, saturated NaHCO 3 solution, water and saturated NaCl solution. After drying over MgSO 4 , the acetic ester is distilled off in vacuum and 3.4 g of a solidified foam is thereby obtained. The residue is chromatographed over silica gel (eluent: dichloromethane, methanol (95:5)). 2.6 g of the title compound in bis-tert-butyl ester form is obtained uniformly chromatographically and NMR spectroscopically.

To saponify the diester, a mixture of 2.6 g (3.2 mmol) of the above-mentioned dimeric tert-butyl ester, 13 ml of anisole and 26 ml of trifluoroacetic acid is stirred for 2 hours at room temperature and then evaporated in vacuo to dryness. The residue (2.7 g) is mixed three times with acetone and chloroform and evaporated again in vacuo. The crude product is taken up in dichloromethane, washed with saturated NaHCO3 solution, the aqueous phase is acidified with concentrated HCl and the crystalline precipitate is filtered off, washed with water and dried. 1.1 g (= 49% of the theoretical) of the title compound is obtained chromatographically and NMR spectroscopically pure; m.p. 178°C. R^ = 0.62 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel).

The production of R,S S S-analog dimer proceeds according to the same regulations. Temp. 174°C.

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

The output connections are made as follows:

N-(3- phenyl- 2- S- acetylmercaptopropanoyl)- S- alanine- roetl ester

To a solution of 1.98 g (26 mmol) thiolacetic acid in 70 ml of anhydrous ether, 2.6 g (26 mmol) of triethylamine dissolved in 20 ml of anhydrous ether are slowly added dropwise while stirring, cooling at 0°C and N2 atmosphere. 4.1 g (13 mmol) N-(3-phenyl-2-R-bromopropanoyl)-S-alanine methyl ester (preparation see example 1) in 50 ml of anhydrous ether is then added dropwise to this solution and boiled for 90 minutes at reflux. After cooling to room temperature, filter and the solvent is distilled off. The oily residue (6.2 g) is chromatographed over silica gel with n-hexane, acetate (2-.1) and 3.9 g (96.9% of theory) of an NMR spectroscopically uniform crystalline product is obtained as the title compound.

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

3.9 g (12.6 mmol) of N-(3-phenyl-2-S-acetylmercaptopropanoyl)-S-alanine methyl ester are dissolved in 40 ml of methanol and mixed with stirring and ice-cooling with 37.8 ml (37.8 mmol ) 1 n NaOH. The solution is stirred for 3 hours at room temperature and then mixed with a 2% methanolic iodine solution until it becomes yellow. Then decolorize with dilute Na2S20.j solution, the solvent is distilled away in vacuum, the residue is dissolved in water and washed with dichloromethane. The aqueous phase is evaporated 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 the solvent is distilled away.

2.5 g (= 78.6% of theoretical) 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 R S S and R,S S S analogue diastereomers takes place according to the same procedure.

Example 8

N- TN-( 3- phenyl- 2- S- mercaptopropanoyl)- S- alanyl]- S- proline- pivaloyl- oxmet<y>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 added under stirring and nitrogen atmosphere in sequence 500 mg (5 mMol) KHCO3,

140 mg (0.84 mmol) KJ and 0.81 ml (5 mmol) chloromethyl pivalate. The mixture is boiled for 3 hours at reflux and filtered after cooling. The filtrate is evaporated in vacuo, the residue is taken up in vinegar and washed successively with water, saturated NaHCO 3 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 the theoretical) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane (2:1)) and thereby 2 fractions are obtained: 0.7 g (= 32% of the theoretical) corresponding to the title compound; R f = 0.28.

0.3 g (13.7% of the theoretical) corresponds to the S-alkylation product N-[N-(3-phenyl-2-S-pivaloyloxymethylmercaptopropanoyl)-S-alanyl]-S-proline pivaloyloxymethyl ester.

The production of R S S and R,S S S analogue diastereomers as well as the corresponding S-acyl compounds takes place in the manner described in example 11.

Example 9

N-[ N-(3-phenyl-2-S-{4-chloro-3-sulfone-amidobenzoyl}-mercaptopropan-oyl-S-alanyl]-S-proline

To a solution of 2.1 g (6 mmol) N-[N-(3-phenyl^-S-mercapto-propanoyl)-S-alanyl]-S-proline in 100 ml of water and 1.008 g (12 mmol) 1.524 g (6 mmol) of 4-chloro-3-sulfamoylbenzoic acid chloride are added to NaHCO3 and the mixture is stirred for a further 2 hours at room temperature. After standing for 2 days, wash with dichloromethane, the aqueous phase is acidified with dilute HCl and the precipitated crystals are filtered off.

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

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

Example 10

N-[ N-(3- phenyl- 2- S- mercaptopropanoyl)- S- alanyl]- S- prolyl- S- phenylalanine

To a solution of 815 mg (10.7 mmol) of thiolacetic acid in 35 ml of anhydrous ether, 1.08 g (10.7 mmol) of triethylamine are slowly added dropwise under an N2 atmosphere, ice cooling and stirring. A solution of 3 g (5.37 mmol) N-[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl]-S-prolyl-S-phenylalanine methyl ester in 20 ml anhydrous dichloromethane is then added dropwise to the above said solution and boil for 90 minutes at reflux. After cooling, filter off and dissolve the filter cake in dichloromethane. Wash with saturated NaHCO 3 solution, dilute KHSO 4 solution, water and saturated NaCl solution. After drying over MgSO4, the solvent is distilled off and 3.3 g of a solid residue is obtained which, after recrystallization from acetic acid, gave a yield of 2.03 g (= 68% of the theoretical).

The methyl ester and its melting point of 157-158°C and an R^ value of 0.13 (acetic ester, n-hexane = 2:1, silica gel).

To saponify, add to a suspension of 2 g (3.6 mmol) of the above-mentioned mercaptoacyl methyl ester in 50 ml of methanol and 20 ml of water while stirring and in an N2 atmosphere 6 ml of 5 n NaOH and stir for 1.5 hours at room temperature. 2 ml of 5 n NaOH are then added and stirred again for a further 1.5 hours. The methanol is rotated away 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 evaporated in vacuo. 1.7 g (= 94.9% of the theoretical) of the title compound is obtained as a solidified foam whose structure was confirmed NMR spectroscopically. R^ = 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 - analog diastereomers were prepared.

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

To a solution of 2.8 g (7 mmol) N-[N-(3-phenyl^-R-brora-propanoyl)-S-alanyl]-S-proline, 1.5 g (7 mmol) S- Phenylalanine methyl ester hydrochloride and 708 mg (7 mmol) of triethylamine in 50 ml of anhydrous dichloromethane are added, while stirring at 0°C, to 1.44 g (7 mmol) of N,N'-dicyclohexylcarbodiimide, which is stirred for 15 minutes at 0°C and then overnight at room temperature. One filters, distills off the solvent in a vacuum and dissolves the remainder in vinegar. Then the solution is cooled, filtered again and washed successively with dilute KHSO 4 solution, saturated NaHCO 4 solution, water, saturated NaCl solution. It is dried over MgSO4 and the solvent is distilled off in vacuo. The residue (4 g) is recrystallized from a little acetic acid;

Yield: 3 g (76.7% of theoretical)

Rf = 0.37 (acetic ester, n-hexane = 2:1, silica gel).

Example 11

N-CN-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-prolvyl-S-valine

Analogous to example 10, the title compound is obtained by using N-[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl]-S-prolyl-S-valine. Rf = 0.48 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel).

Example 12

N- EN-( 3- phenyl- 2- S- mercaptopropanovl)- S- alanvl3- S- prolvl- S- proline

Analogous to example 10, the title compound is obtained by using N-[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl3-S-prolyl-S-proline.

Rf = 0.26 (ethyl acetate, silica gel).

Example 13

N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl3-S-thiazolidine-4-carboxylic acid

Analogous to example 1, by using S-thiazolidine-4-carboxylic acid, the title compound is obtained in yields of 85.4% of the theoretical. Temp. 144-146°C

Rf = 0.46 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel). Elemental analysis: ,Ho„N-0.S„

16 20242

The structure has been NMR spectroscopically confirmed.

Example 14

N- CN-( 3- phenyl- 2- S- mercaptopropanovl)- S- alanyl1- 4. 5. 6. 7- tetra-hydro- thieno[ 2. 3- c 3 pyridine- 7- carboxylic acid

Analogous to example 1, by using 4,5,6,7-tetrahydro-thienoC2,3-c3pyridine-7-carboxylic acid in R,S, R and S configuration, the corresponding diastereomers of the title compound are obtained. The Rf value of the S S R, S diastereomer mixture: 0.18 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel).

Example 15

N-[ N-( 3- phenvl- 2- S- mercaptopropanovl)- S- alanyl3- 4. 5. 6. 7- tetra-hydro- thieno[ 3. 2- c3pyridine- 4- carboxylic acid

Analogous to example 1, by using 4,5,6,7-tetrahydro-thieno[3,2-c3pyridine-4-carboxylic acid, the corresponding diastereomers of the title compound are obtained.

The Rf value of the S S R, S diastereomer mixture: 0.53 (chloroform, methanol, glacial acetic acid = 90:10:5, silica gel).

Example 16

N-[ N-(3- phenyl- 2- S- benzoyl mercaptopropanoyl)- S- alanyl3- S- proline

To a solution of 2.1 g (15.4 mmol) of thiolbenzoic acid in 50 ml of anhydrous ether is added at 0°C, nitrogen atmosphere and stirring slowly 1.56 g (15.4 mmol) of triethylamine. It is then added dropwise to a solution of 3.5 g (7.7 mmol) N-[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl3-S-proline-tert-butyl ester in 30 ml of anhydrous ether and boil for 90 minutes under reflux. After filtering off, the ether solution is washed with dilute KHSO 4 solution, saturated NHCO solution, water and saturated NaCl solution, dried over MgSO 4 and evaporated to dryness. The residue (3.7 g) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane = 1:1) and 3.4 g (= 86.5% of the theoretical) of the tertiary butyl ester of the title compound is obtained as a solidified foam.

Rf = 0.27 (acetic ester, n-hexane = 1:1, silica gel).

To saponify, 3.4 g (6.6 mmol) of the above-mentioned tert-butyl ester are dissolved in 34 ml of trifluoroacetic acid and 17 ml of anisole and stirred for 2 hours at room temperature. The reaction solution is evaporated in vacuo and dissolved three times with acetone and chloroform and rotated again into vacuum. 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 over silica gel (eluent: dichloromethane, methanol, glacial acetic acid = 120:5:2).

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

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

Example 17

N-[N-(3-phenyl-2-S-pivalolmercaptopropanoyl)-S-alanyl-S-proline

You proceed as described in the previous example. IN

instead of thiolbenzoic acid, thiolpivalic acid is used. The reaction of 3.17 g (7 mmol) N-[N-(3-phenyl-2-R-bromopropanoyl)-S-alanyl]-S-proline tert-butyl ester and 1.65 g (14 mmol) thiolpivalic acid 3 .3 g (= 96% of the theoretical) of the tert-butyl esters of the title compound.

Rf = 0.34 (acetic ester, n-hexane = 1:1, silica gel).

The saponification of this 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- CN-(3- phenyl- 2- S- acetvlmercaptopropanoyl)- S- alanyl3- S- proline pivalovloxymethyl ester

2.3 g (5.8 mmol) of N-[N-(3-phenyl-2-S-acetylmercaptopropanoyl)-S-alanyl]-S-proline (intermediate from example 1) are dissolved in 40 ml of anhydrous acetone and added under stirring and nitrogen atmosphere sequentially 580 mg (5.8 mmol) KHCO 3 , 161 mg (0.97 mmol) potassium iodide and 873 mg (5.8 mmol) chloromethylpivalate. The mixture is boiled for 3 hours at reflux and filtered after cooling. The filtrate is evaporated in vacuo, the residue is taken up in vinegar 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 a vacuum. The oily residue (2.7 g) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane = 2:1), thereby obtaining 2.2 g (= 75% of the theoretical) of the title compound as an oil. Rf = 0.42 (acetic ester, n-hexane = 2:1, silica gel).

Example 19

N- CN-( 3- phenyl- 2- S- benzoylmercaptopropanoyl)- S- alanyl]- S- proline pivaloyl oxmethyl ester

Analogous example 18 is obtained by using the title compound N-[N-(3-phenyl-2-S-benzoylmercaptopropanoyl)-S-alanyl-S-proline. Rf = 0.43 (acetic ester, n-hexane = 1:1, silica gel).

Example 20

N- CN-( 3- phenyl- 2- S- pivaloylmercaptopropanoyl)- S- alanyl3- S- proline pivaloyloxymethyl ester

Analogous to example 18, the title compound is obtained by using N-[N-(3-phenyl-2-S-pivaloylmercaptopropanoyl)-S-alanyl3-S-proline.

Rf = 0.45 (acetic ester, n-hexane = 2:1, silica gel).

Example 21

N-CN-(3-phenyl-2-S-acetvlmercaptopropanoyl)-S-alanyl3-N-cyclo-pentvlalycine 6 g (20 mmol) N-(3-phenyl-2-R-bromopropanoyl)-S-alanine and 4 g (20 mmol) of N-cyclopentylglycine tert-butyl ester is dissolved in 100 ml of dichloromethane and mixed with stirring while cooling (0°C) with 4.1 g (20 mmol) of N.N'-dicyclohexylcarbodiimide and stirred for 15 minutes at this temperature and then overnight at room temperature. After filtering off the dicyclohexylurea, the solvent is distilled off in a vacuum, the oily residue is dissolved in acetic acid and allowed to stand cold for a while. After new filtration, the filtrate is washed with dilute KHSO 4 solution, saturated NaHCO 3~10 solution, water and saturated NaCl solution and evaporated in vacuo after drying over MgSO 4 . The oily residue (6.7 g) is chromatographed over silica gel (eluent: ethyl acetate, n-hexane = 1:2).

Yield: 4.3 g (= 44.6% of the theoretical) bromo-tert-butyl ester is obtained as a colorless oil.

Rj = 0.28 (acetic ester, n-hexane = 1:2, silica gel).

The replacement of the bromine with thiolacetic acid and the subsequent saponification of the tertiary butyl ester to the title compound takes place in the manner described in example 1.

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

Example 22

N-[ N-(3- phenyl- 2- S- methylaminothiocarbonyl- mercaptopropanoyl)- S-alanvl3- S- proline

A solution of 1.73 g (4.96 mmol) N-[N-(3-phenyl^-S-mercapto-propanoy 1 )-S-alanyl3-S-proline in 10 ml of 0.5 N NaOH and 25 ml pyridine is mixed under a nitrogen atmosphere with 0.4 g (5.47 mmol) methyl isothiocyanate and heated for 2 hours at 40°C. It is then evaporated to dryness in vacuo, the residue is 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 acetic ester extract is evaporated to dryness, thereby obtaining 1.5 g (71.4% of the theoretical) of the title compound as a solidified foam which is purified chromatographically over silica gel. (Eluent: toluene, acetic acid = 75 : 25).

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

Example 23

N-CN-(3-phenyl-2-S-ethylaminocarbonyl-mercaPtopropanoyl)-S-alanyl]-S-proline

A solution of 1.72 g (4.92 mmol) N-[N-(3-phenyl^-S-mercapto-propanoyl)-S-alanyl]-S-proline in 5 ml of 1 N NaOH and 5 ml of pyridine is mixed with 0.45 ml (5.7 mmol) ethyl isocyanate and stirred for 4 hours at 40°C under a N2 atmosphere. It is then evaporated to dryness in a vacuum. The residue is slurried in water, acidified with 0.1 n HCl and processed further as described in the previous example.

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

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

NMR data for several compounds prepared according to the invention:

Example 1

<1>H-NMR data (CD30D)

6 = 1.31, d, J=7Hz, 3H, CH_3-CH-, 1.80-2.41, m, 4H, Pro - CH2CH2, 3.16, m, 2H, 0 - CH2- CH -, 3.43-3.89, m, 3H, Pro - NCH2,

ø - CH2- CH -, 4.41, m, 1H, Pro a CH, 4.61, m, 1H, CH3- CH -, 7.24, m, 5H, aryl - H, SH, NH, CO0H, in solvent blank.

Example 2

<1>H-NMR data (CDC1-)

5 = 1.15, d, J=7Hz, 3H, CH3- CH -, 1.77-2.39, m, 4H, Pro CH2CH2-, 2.05, d, J=10Hz, SH, 3.13 , m, 2H, 0 - CH2- CH -, 3.43, m, 1H, 0 - CH2- CH -, 3.63, m, 2H, Pro-N-CH2". 4.55, m, 1H, Pro a H, 4.77, m, 1H, CH3- CH -, 7.25, m, 5H, aryl-H, 8.93, s, broad,

COOH.

Example 4

<1>H-NMR data (CD3OD)

6 = 1.35, d, 3H, J=7Hz, £H3- CH -, 1.81-2.52, m, 4H, Pro-CH2CH2-, 3.17, s, 2H, S CH2- C, 3.69, m, 2H, Pro N - CH2, 0 , 4.47, m, 1H, Pro a - CH-, 4.64, qu, 1H, J=7Hz, CJ£3- CH -, Sfl, NH and COOH in solvent blank peak.

Example 5

<1>H-NMR-(CD3OD)

5 = 1.32, d, J=7Hz, 3H, CH3- CH -, 1.77-2.45,m, 4H, Pro - CH2CH2, 3.65, m, 2H, Pro - N - CH2, 4 .48, m, 1H, Pro a CH-, 4.66, m, 1H, CH3-£H-, 4.82, s, 1H, 0 - QE~, 7.24-7.59, m, 5H , aryl-H, SH, NH, COOH in solvent blank peak.

Example 6

5 = 1.35, d, 3H, CH3-CH-, J=7Hz, 2.08, m, 2H, 0 - CH2- £H2-, 1.80-2.44, m, 4H, Pro - CH2 - CH2-. 2.72, m, 2H, 0 - CJi2-, 3.26, m, 1H, 0 - CH2CH2- CH -, 3.65, m, 2H, Pro - NCH2-, 4.50, m, 1H, Pro a CH -, 4.77, m, 1H, CH3- £H~, 7.23, m, 5H, aryl-H, 7.50, m, 1H, NH, 8.96, S, 2H, SH p COOH.

Example 7

<1>H-NMR data (CDC1_)

5 = 1.28, d, J=7Hz, 6H, CH3- CH -, 1.66-2.51, m, 8H, Pro - CH2CH2-, 3.06, m, 4H, 0 - CH_2- CH - , 3.33-4.01, m, 6H, Pro - NCH2, 0 - CH2- CH -, 4.42, m, 2H, Pro a CH, 4.75, m, 2H, CH3- CH -, 6 .75, s, 2H, COOH, 7.21, m, 10H, aryl-H, 7.50, d, J=8Hz, 2H, NH.

Example 8 - Title connection

<1>H-NMR data (CDC13)

5 = 1.20, s, 9H, C(CH3)3, 1.34, d, J=7Hz, 3H, CH3- CH -, 1.96, d, J=10Hz, 1H, SH, 1.82 -2.42, m, 4H, Pro - CH2CH2-, 2.91-3.81, m, 5H, Pro N-CH2, 0 - CH2- CH -, 4.49, m, 1H, Pro a CH, 4.66, m, 1H, CH3- Qi -, 5.75, m, 2H, - 0 CH2- O, J23, m, 6H, 5 aryl-H,

NH.

Example 8 - N-[N-3-phenyl-2-S-pivaloyloxymethylmercaptopropanoyl)-S-alanyl]-S-thiazolidine-4-carboxylic acid <1>H-NMR data (CDCl3) 6 = 1.16, s, 9H, C(CH3)3, 1.21, s, 9H, C(CH3)3, 1.33, d, J=7Hz, 3H, CH3- CH -, 1.78-2.43, m , 4H, Pro - CH2CH2, 3.14, m, 2H,

0 - CH2- CH -, 3.34-3.89, m, 3H, 0 - CH2- CH - , Pro - N CH2, 4.36-4.89, m, 2H, Pro a CH, CH3- £ H_ -, 5.75, m, 2H, 0 CH2- 0, 7.14, d, J=8Hz, 1H, NH, J23, m, 5H, aryl-H.

Example 12

<1>H-NMR data (CDC13)

5 = 1.34, d, J=7Hz, 3H, CH3- CH -, 1.97, d, J=10Hz, 1H, SH, 1.71-2.43, m, 8H, Pro CH2CH2, 2, 84-4.00, m, 7H, Pro N CH2,

0 - CH2- £H -, 4.26-4.96, m, 3H, Pro a CH, CH3- £H -, 6.20, s, 2H, NH, COOH, 7.26, m, 5H, aryl-H.

Example 13

<1>H-NMR data (CDC13)

6 = 1.35, d, J=7Hz, 3H, CH3- CH -, 2.03, d, J=10Hz, 1H, SH, 3.20, m, 2H, 0 - CH2- CH -, 3, 27, d, 2H, S - C_E2- CH -, J=7Hz, 3.50, m, 1H, 0 - CH2- £H -, 4.72, m, 2H, N - CH2- S, 4.77 , m, 1H, CH3- CH -, 5.10, t, J=7Hz, S CH2- CH - , 6.52, s, 1H, COOH, 7.27, m, 5H, aryl-H, 7, 78, d, J=8Hz, 1H, NH.

Example 14

<1>H-NMR data (CD30D)

6 = 1.33, d, J=7Hz, 3H, CH3- CH -, 2.50-3.91, m, 7H,

0 -CH2- CH -, - £H2- CH2-, 4.99, m, 1H, CH3- CH -, 5.85, S, 1H, N - CH - C=0, 6.84, d, 1H , thiophene 4H, 7.34, d, 1H, thiophene 5H, 7.18, m, 5H, aryl-H, SH, NH, COOH in solvent blank.

Example 15

1H-NMR data (CDC13 > 6 = 1.34, d, J=7Hz, 3H, CH3- CH -, 2.02, d, J=9Hz, 1H, SH, 2.72-4.43, m , 7H, 0 -<C>H2<-><£>H -, - CH2"CH2-, 5.00, m, 1H,

CH3- CH -, 5.91, s, 1H, CH - COOH, 7.23, m, 9H, aryl-H, thiophene-H, NH, COOH.

Example 16

<1>H-NMR data (CDCl )

6 = 1.61, d, 3H, J=7.0Hz, CH-, - CH -, 1.77-2.39, m, 4H, Pro - CH2CH2-, 3.24, m, 2H, 0 - C_H2 - CH -, 3.58, m, 2H, Pro - N CH2, 4.47, m, 1H, 0 - CH2CH -, 4.53, m, 1H, Pro a - CH -, 4.75, m , 1H, CH3- £H -, 7.02-8.00, m, 10H, 2-aromatics, 8.50, s, 1H, COOH.

Example 17

<1>H-NMR data (CDCl.)

5 = 1.17, s, 9H, C(CH3)3, 1.26, d, 3H, J=7Hz, £H3- CH -, 1.82-2.27, m, 4H, Pro - CH2CH2- , 3.14, m, 2H, 0 - CH2- CH -, 3.57, m, 2H, Pro N - CH2-, 4.19, m, 1H, 0 - CH2-£H -, 4.50, m, 1H, Pro a - CH -, 4.73, m, 1H, CH3- CH - , 6.98, d, 1H, J=8Hz, -NH, 7.21, m, 5H, aryl-H, 8, 30, p, 1H, COOH.

Example 18

<1>H-NMR data (CDCl.)

6 = 1.21, s, 9H, C(CH3)3, 1.23, d, 3H, J=7Hz, CH3- CH -, 1.77-2.27, m, 4H, Pro CH2CH2-, 2 .30, s, 3H, CH3- C=0, 3.15, m, 2H, 0 - £H2- CH -, 3.58, m, 2H, Pro - N CH2-, 4.15, m, 1H , 0 - CH2- CH -, 4.48, m, 1H, Pro a CH -, 4.67, m, 1H, CH3- CH -, 5.75, m, 2H, - O - CH2- 0 -, 6.92, d, 1H, J=8Hz, NH, 7.23, m, 5H, aryl-H.

Example 19

<1>H-NMR data (CDC13)

6 = 1.19, s, 9H, C(CH3)3, 1.31, d, 3H, Cfi3 - CH -, J=7Hz, 1.80-2.34, m, 4H, Pro - CH2CH2-, 3.26, m, 2H, 0 - CH2- CH -, 3.58, m, 2H, Pro - N CH2-, 4.48, m, 1H, 0 - CH2- CH -, 4.50, m, 1H, Pro a CH -, 4.73, m, 1H, CH3- CH -, 7.00, d, 1H, J=7Hz, NH-, 5.76, m, 2H, 0 CH2- 0, 7.27, m, 5H, aryl-H, 7.34-8.02, m, 5H, 0 - C - H. 0

Example 20

<1>H-NMR data (CDC13)

5 = 1.16, s, 9H, C(CH3)3, 1.20, s, 9H, C(CH3)3, 1.27, d, 3H, J=7Hz, CJi3- CH -, 1.82 -2.32, m, 4H, Pro CH2CH2, 3.16, m, 2H, Phc - CH2CH -, 3.57, m, 2H, Pro N CH2-, 4.16, m, 1H,

0 - CH2- CH"r 4.48, m, 1H, Pro a CH -, 4.71, m, 1H, CH3- CH -. 5.76, m, 2H, 0 CH2- 0, 6.82, d, 1H, J=8Hz, NH, 7.22, m, 5H, aryl-H.

Example 21

<1>H-NMR data (CDC13)

6 = 1.31, d, 3H, J=7Hz, CH - CH -, 1.16-2.11, m, 8H, cyclopentyl-CH2, 2.28, s, 3H, CH3- C=0, 3 .15, m, 2H, 0 - CH2- CH -, 2.92, m, 2H, N - CH2- C=0, 4.22, m, 1H, cyclopentyl-C_H, 4.26, m, 1H, 0 - CH2- CH -, 4.92, m, 1H, CH3- CH -, 5.61, s, 1H, COOH, 7.18, d, 1H, J=8Hz, NH, 7.24, m, 5H, aryl-H.

Example 22

<1>H-NMR data (CDC13)

5 = 1.27, d, J=7Hz, 3H, CH3- CH -, 1.73-2.41, m, 4H, Pro - CH2-CH2-, 3.18, d, J=4Hz, 3H, NH - CH_3, 3.21, m, 2H, 0 - CH2- CH -, 3.57, m, 2H, Pro N - CH2, 4.48, m, 1H, Pro a - CH, 4.65, m , 1H, CH3- CH -, 4.48, m, 1H, 0 - CH2- CH -, 7.24, m, 5H, aryl-H, 7.47, d, J=7Hz, NH - CH -, 8.48, qu, J=4Hz, NH - CH3, 8.77, s, 1H, COOH-

Example 23

<1>H-NMR data (CDC13)

5= 1.11, t, J=7Hz, 3H, CH3- CH2, 1.28, d, J=7Hz, 3H, CH3- CH, 1.77-2.41, m, 4H, Pro CH2CH2, 3 .15, m, 2H, 0 - CH2- CH -, 3.23, m, 2H, N - CH2- CH3, 3.56, m, 2H, Pro - N - CH2, 4.18, m, 0 - CH3- CH -, 4.52, m, Pro a CH, 4.73, m, CH3- CH -, 5.65, s, broad, 2 x NH p COOH, 7.23, m, 5H, aryl- H.

<1>H-NMR data (CDC13)

6 = 1.15, s, 9H, C(CH3)3, 1.22, s, 9H, C(CH3)3, 1.36, d, J=7Hz, 3H, CH_ - CH -, 2.83 -3.49, m, 4H, 0 - CH„ - CH -, 3.74, m, 1H, 0 - CH2- CH -, 4.39-4.84, m, 3H, N-CH2"S, CH3- CE - , 5.07, m, 1H, S CH2- CH -, 5.76, m, 2H, O CH2- 0, 7.23, m, 6H, aryl-H,

NH.

Rf = 0.48 (acetic ester, n-hexane = 1:1).

<1>H-NMR data (CDC13)

5 = 1.05, d, J=7Hz, 3H, CH_3- CH -, 2.08, d, J=10Hz, 1H, SH, 1.59-2.25, m, 4H, Pro - CH„CH „, 2.84-3.93, m, 7H, Pro - N CH,, COOH i 0 - CH2 - CH -, 0 - CH2- CH , 4.46-4.99, m, 3H, Pro a CH , CH3- CH -, 0 - CH2- CH - COOH, 7.24, m, 12H, aryl-H, NH, COOH, 7.75, d, J=8Hz, NH.

<1>H-NMR data (CDC13)

6 = 0.86, d, J=7Hz, 6H, isobutyl-CH3, 1.32, d, J=7Hz, 3H, CH3- CH -, 2.09, d,J=10Hz, 1H, SH, 1 ,71-2.70, m, 5H, Pro - CH2CH2, isobutyl - CH(CH3)2, 3.14, m, 2H, 0 -C]J2- CH -, 3.41-4.00, m, 3H, Pro - N CH2, 0 - CH2- £H - , 4.34-4.99, m, 3H, Pro a CH, CH- - £H_ -, isobutyl - CH, 6.58, s, 1H, COOH, 7.22, m,

CH-

5H, aryl-H, 7.53, d, J=10Hz, 1H, HH - CH , 7.75, d, J=8Hz, 1H, NH - isobutyl.

<1>H-NMR data (CD30D)

5 = 1.30, d, J=7Hz, 3H, CH3- CH -, 1.78-2.40, m, 4H, Pro CH2CH2, 2.90-3.42, m, 2H, 0 - CH„ - CH -, 3.56, m, 2H, Pro N-CH,, 4.27-4.84, m, 3H, Pro a CH, 0 - CH2- £H -, CH3- £H -, 7, 27, m, 5H, aryl-H, 7.73, d, J=8Hz, 1H, ortho-aryl-H, 8.08, dd, J=8Hz, 3Hz, 1H, ortho/meta-aryl-H, 8.57, d, J=3Hz, 1H, meta-aryl-H, NH_2, NH, COOH in solvent blank peak.

<1>H-NMR data (CDC13)

6 = 1.33, d, J=7Hz, 3H, CH_3- CH -, 2.02, d, J=10Hz, 1H, SH, 2.00-2.50, m, 2H, Pro p - CH2- , 2.84-3.66, m, 3H,

0 - CH2- £H -,3.48-3.89, m, 2H, Pro - N- CH2, 4.50, m, 2H, Pro a - CH, CH - OH, 5.40, s, broad , OH, COOH, 7.24, m, 5H, aryl-H, 7.46, d, J=8Hz, 1H, NH.

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

<1>H-NMR data (CDC13)

6 = 1.34, d, 3H, J=7Hz, £H-. - CH -, 1.34-1.99, m, 8H, cyclopentyl - CH2-, 2.00, d, J=10Hz, SH, 3.16, m, 2H, 0 - Cfi2- CH -, 3, 53,

m, 1H, 0 - CH2- CH -, 3.92, m, 2H, N - CH2- C=0, 4.28, m, 1H, cyclopentyl-CH, 4.99, m, 1H, CH3-CJ3 -, 5.91, s, 1H, COOH, 7.24, m, 5H, aryl-H, 7.46, d, 1H, J=8Hz, NH.

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

<1>H-NMR data (CDClg)

6 = 1.23, d, (3H), J=7Hz, CH_3- CH -, 1.76-2.31, m, 4H, Pro

- CH2-CH2, 2.16, s, 3H, CH3- C =, 2.31, s, 3H, CH3- C - „

3.13, m, 2H, 0 - CH2, 3.58, m, 2H, Pro N - CH2-, 4.24, m, 1H,

0 - CH2- CH -, 4.48, m, 1H, CH3- CH -, 4.58, m, 1H, Pro a CH -, 4.78, m, 2H, 0 - CH2-, 6.87, d, 1H, J=7.5Hz, NH, 7.23, m, 5H, aryl-H.

Rf = 0.17 (acetic ester, hexane = 2:1).

<1>H-NMR data (CDCl )

5 = 1.19, s, 9H, C(CH3)3, 1.32, d, J=7Hz, 3H, CH3 - CH -, 2.30, s, 3H, CH3 - C=0, 3.11 , m, 2H, 0 - CR2- CH -, 3.22, m, 2H, S - £H2- CH -, 4.12, m, 1H, 0 - CH2- £H -, 4.59, m, 2H, N - CH2- S -, 4.64, m, 1H, CH3- CH - , 5.07, m, 1H, N - £h - C=0, 5.74, m, 2H, 0 CH2- 0, 6.86, d, J=8Hz, 1H, NH, 7.18, m, 5H, aryl-H.

R, = 0.35 (acetic ester, n-hexane = 1:1)

<1>H-NMR data (CDCl_)

5 = 1.32, d, 3H, J=7Hz, CH3- CH -, 2.30, s, 3H, CH3 - C=0, 3.14, m, 2H, 0 - CH2- CH -, 3, 25, d, 2H, J=6Hz, S CJ32 - CH -, 4.25, m, 1H, 0 - CH2- SB -, 4.65, m, 2H, N - £H2- S, 4.78, m, 1H, CH3- CH -, 5.07, t, 1H, J=6Hz, N - CH - CO0, 7.16, d, 1H, J=8Hz, NH, 7.20, m, 5H, aryl -H, 8.48, p, 1H, COOH.

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

<1>H-NMR data (CDC13)

6 = 1.30, d, J=7Hz, 3H, CH3- CH -, 2.09, d, J=10Hz, 1H, SH, 2.48-3.81, m, 5H, 0 - CH2- CH -, CH2- C=0, 4.13, m, 2H, N - CH2, 4.64, m, 1H, CH3- CH -, 4.99, m, 1H, 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).

<1>H-NMR data (CDC13) I

5 = 1.31, d, 3H, J=7Hz, £H^ - CH -, 2.05, d, 1H, J=10Hz, SH, 2.35, d, 2H, J=7Hz, Pro - CH_2 - CH -, 3.19, m, 2H, 0 -

CH2- CH -, 3.27, s, 6H, 2 0 CH3, 3.50, m, 1H, 0 - CH2- CH -, 3.68, m, 2H, Pro - N - CH2, 4.59, m, 1H, Pro a - CH -, 4.70, m, 1H, CH3- £H -, 5.95, s, broad, 2H, NH m COOH, 7.23, m, 5H, aryl-H.

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

<1>H-NMR data (CDC13)

6 = 1.30, d, J=7Hz, 3H, CH3- CH -, 2.02, d, J=10Hz, 1H, SH, 2.67, m, 2H, Pro - CH2- CH -, 3, 15, m, 2H, 0 CH2 - CH -, 3.36, S, 4H, - S CH2CH2-S-, 3.55, m, 1H, 0 - CH2- CH 4.00, m, 2H, Pro - N - CH2-, 4.14, m, 2H, CH3- CH -, Pro a - CH -, 7.23, m, 5H, aryl-H, 7.41, d,J=8Hz, 1H, NH, 7.56, p, 1H, COOH.

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

<1>H-NMR data (CDCl )

5 = 1.18 (s, 9H, C(CH3)3, 1.34, d, J=7Hz, 3H, CH^ - CH -, 1.99, d, J=10Hz, 1H, S H, 2, 93-3.77, m, 5H, 0-CH2-CH

S CH2- CH -, 4.41-4.84, m, 3H, N - CH2- S, CH3- CH -, 5.07, m, 1H, S - CH2- CH -, 5.77, m, 2H, 0 CH2- 0, 7.07, d, J=9Hz, 1H, NH, 7.23, m, 5H, aryl-H.

Rf = 0.33 (acetic ester, n-hexane = 1:1).

Pharmaceutical application examples

a) Dragees

Manufacturing:

The mixture of the active substance with milk sugar and corn starch is granulated with a 10% iq aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40°C and torn again through a sieve. The granules thus obtained are mixed with magnesium stearate and pressed. The cores thus obtained are covered in the usual way with a coating which is applied using an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragées are polished with beeswax.

b) Tablets

Manufacturing:

Active ingredient and magnesium stearate are granulated with an aqueous solution or soluble starch, the granulate is dried and thoroughly mixed with milk sugar and corn starch. The mixture is then pressed into tablets with a weight of 230 mg, each containing 100 mg of active ingredient.

c) Injection solutions

Manufacturing

Active substances and auxiliary substances 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 filled under aseptic conditions into 2 ml ampoules. The ampoules are sterilized and closed. Each ampoule contains 5 mg of active ingredient.

d) Capsules

Active ingredient, milk sugar and cornstarch are first mixed in

mixer and then in a crusher. The mixture is brought back into the mixer, thoroughly mixed with talc and mechanically filled into hair gelatin capsules.

e) Suppositories

Cocoa butter made from carnauba wax is melted, mixed thoroughly and cooled to 45°C. This mass stirs in the finely powdered active ingredient. The mixture is then poured into slightly pre-cooled suppository forms of one size and allowed to cool.

Claims (4)

1. Process for the preparation of therapeutically active new amino acid derivatives with the general formula in which R 1 means H, phenyl, benzyl, phenethyl; R2 means H, acetyl, benzoyl, 3-sulfonamido-4-chloro-benzoyl, 3-sulfonamido-4-chloro-6-hydroxy-benzoyl, 3-sulfonamido-4-chloro-5-[(furyl)-amino]- benzoyl, 2,3-dichloro-4-(p-phenyl-acryloyl)-phenoxy-acetyl, pivaloyl, C 1 -C 2 -alkylaminocarbonyl, C 1 -C 2 -alkylaminocarbonyl, C 1 -C 2 -alkylaminothiocarbonyl, pivaloylmethoxy or the residue A residue of one of the a-amino acids or R3 hydrogen, Cj -C^ -alkyl, straight-chain or branched, C5~ C7 -cycloalkyl, under which a phenyl ring may be fused to, phenyl, phenyl-Cj -C4~alkyl, a hetero-C^-C4 -alkyl residue, under which the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0, S or N, R 4 hydrogen, C 1 -C 4 -alkyl, straight chain or branched, phenyl, phenyl-C 1 -C 4 ~ alkyl or a hetero-C 1 -C 4 -alkyl radical, wherein the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0, S or N, R3 and R^ 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 optionally substituted with 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, C 1 -C 4 -uj-hydroxyalkyl, C 1 -C 4 -alkoxy, phenyl-C 1 -C 4 -alkyl, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, one of the groups or an α-amino acid which is peptide-like linked to the CO group of the molecule; R6 C1 -C4~ alkyl, C1 -C^ -alkenyl, Cj -C3 -alkynyl, straight chain or branched hydroxy, nitro, amino, C1 -C4 -alkoxy, mercapto, C.|-C4 -alkylthio, hydroxy-Cj -C4 ~ alkyl, mercapto-Cj-C4~alkyl, F, Cl, Br, amino-C1 -C4 -alkyl, sulfonamido, methylenedioxy, fluoro-Cj -C^ alkyl, chlorine-Cj -C4~ alkyl, bromo-C1 - C 4 - alkyl, cyano or trifluoromethyl; R 1 is hydrogen or methyl; Rg C1 -C4~ alkyl, straight-chained or branched, under which the alkyl residue may be substituted with F, Cl, Br, CF3 , phenyl or pyridyl; X, Y and Z 0, S, CR1Q , CHR1Q , with the proviso that only one of the residues X, Y and Z can mean 0, S one or two of the residues X, Y and Z NRg; R 8 is hydrogen or C 1 -C 4 -alkyl, straight chain or branched; R1Q hydrogen, or together with a vicinally standing residue R1Q one phenyl ring, or, for m and n = 1, its dihydro form with a double bond in conjugation to the C-terminal carboxy group and m and n 0,1 or 2, where the sum of m and n is 1 or 2, and their salts and dimeric compounds, characterized in that mana) condenses an acid with the general formula wherein R 1 and R 2 have the above-mentioned meaning, with a dipeptide of the general formula in which A has the meaning stated above, or that one b) condenses a compound with the general formula in which R.j and R2 have the meaning given above, with an amino acid A, where A has the meaning given above, or that one c) reacts a compound of the general formula wherein and A has the above meaning, with a mercapto compound of the general formula in which R2 has the above meaning, d) condenses a compound with the general formula in which R1 has the meaning given above, with an amino acid A, where A has the meaning given above, and reacts the thus obtained condensation product of the general formula V with a mercapto compound of the general formula VI, e) converts a compound of formula I in which R2 is acetyl or benzoyl into a compound of formula I in which R^ means hydrogen by saponification with basic agents, f) converts a compound of formula I in which R 2 is hydrogen by reaction with a compound B-R 2 , in which R 2 is a meaning other than hydrogen, and B is an easily leaving group, for example chlorine, bromine, into a compound of formula I , in which R2 has the above-mentioned meaning except for hydrogen, the reaction being suitably carried out in the presence of an acid-binding agent (for example a base or an alkali carbonate), and that any protective groups present are removed at a suitable step in the methods a), b), c ), d), e) or f), and one optionally transfers a thus obtained end product with the general formula I in a salt, or transfers a thus obtained final product of the general formula I in which R^ is -OH in an ester of formula I, or for the preparation of dimeric compounds of the general formula I, in which R 2 means the group and the other residues have the above-mentioned meanings, treating a compound of the general formula I, in which R^ means hydrogen, with an oxidizing agent, and that one optionally transfers a dimer compound thus prepared in a salt. 2. Process according to claim 1 for the preparation of compounds of formula I in which R1 means H, phenyl, benzyl or phenethyl, R2 means H, acetyl or 3-sulfonamido-4-chloro-benzoyl and A means proline, and their salts, characterized by using correspondingly substituted starting materials. 3. Process according to claim 1 for the production of N-[N-(3-phenyl-2-S-mercaptopropanoyl)-S-alanyl]-S-proline and its salts, characterized in that correspondingly substituted starting materials are used. 4. Method according to claim 1 for the preparation of compounds according to claims 1 to 3, in which the asymmetric carbon atoms are in S-configuration, characterized by using correspondingly substituted starting materials. Summary New amino acid derivatives of the general formula in which R 1 means H, phenyl, benzyl, phenethyl; R 2 means H, acetyl, benzoyl, 3-sulfonamido-4-chloro-benzoyl, 3-sulfonamido-4-chloro-6-hydroxy-benzoyl, 3-sulfonamido-4-chloro-5-t(furyl)amino]-- benzoyl, 2,3-dichloro-4-(p-phenyl-acryloyl)-phenoxy-acetyl, pivaloyl, C1 -C2 -alkylaminocarbonyl, C1 -C2 -alkylaminocarbonyl, C1 -C2 -alkylaminothiocarbonyl, pivaloylmethoxy or the residue A residue of one of the a-amino acids R 3 hydrogen, C 1 -C 4 -alkyl, straight chain or branched, C 8 -C 4 -cycloalkyl, under which a phenyl ring may be fused to, phenyl, phenyl-C 1 -C 4 -alkyl, a hetero-C 1 -C 4 -alkyl radical, wherein the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0, S or N, R 4 hydrogen, C 1 -C 4 -alkyl, straight chain or branched, phenyl, phenyl-C 1 -C 4 -alkyl or a hetero-C 1 -C 4 -alkyl radical, wherein the heterocycle consists of a 5- or 6-ring with 1 to 2 of the heteroatoms 0, S or N, R3 and R4 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 optionally substituted with oxo, dimercaptoethylene or a 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, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -alkoxy, phenyl-C 1 -C 4 -alkyl, C 3 -C 4 -alkylamino, C 1 -C 4 -dialkylamino, one of the groups or an α-amino acid which is peptide-like linked to the C0 group of the molecule; Rc C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 1 -C 6 -alkynyl, straight chain or branched b 1 4 1 J 1 J hydroxy, nitro, amino, C₁ -C₂ ₂ ₂ -alkyl, mercapto, C₁ -C₄ -alkylthio, hydroxy-C₂ -C₂ -alkyl, mercapto-C₁ -C₄ -alkyl, F, Cl, Br, amino-C₂ - 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 hydrogen or methyl; Ro C.-C.-alkyl, straight chain or branched, below which the alkyl residue 0 14 may be substituted with F, Cl, Br, CF₂, phenyl or pyridyl; X, Y and Z 0, S, CR1Q , CER^, with the proviso that only one of the residues X, Y and Z can mean 0, S one or two of the residues X, Y and Z NR^ ; R 9 hydrogen or C 1 -C 6 alkyl, straight chain or branched; R10 hydrogen, or together with a vicinally standing residue R1Q a phenyl ring, or, for m and n = 1, its dihydroform with a double bond in conjugation to the C-terminal carboxy group and m and n 0,1 or 2, where the sum of m and n is 1 or 2, and their salts and dimeric compounds. Preparation of the compounds is described. The compounds have a strong angiotensin-I converting enzyme inhibition and can be used as hypotensive agents.