CS254345B2 - Method of amino acids' derivatives production - Google Patents

Description

The invention relates to novel amino acid derivatives of the formula I

S'R2 СНз

I I

R1-CH-CO-NH-CH-CO-A (I) and their salts. The present invention relates to a process for the preparation of these substances. The invention further provides pharmaceutical compositions comprising the above compounds as active ingredients, and their use as medicaments.

In the formula

R 1 represents a hydrogen atom, a phenyl group, a benzyl group or a phenethyl group,

R2 is hydrogen, acetyl, benzoyl, 3-sulfamoyl-4-chlorobenzoyl, 3-sulfamoyl-4-chloro-6-hydroxybenzoyl, 3-sulfamoyl-4-chloro-5- [furyl jamino] benzoyl 2,3-dichloro-4- [β-phenylacryloyl] phenoxyacetyl, pivaloyl or pivaloyloxymethyl,

A represents the α-amino acid residue of the general formula

.....

hn-c (h) -cor _with f2ebo

H. ^N - (m

R3 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms to which a phenyl ring, a phenyl group, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a heterocyclylalkyl (C 1 -C 4) alkyl group in which the heterocycle is a five or six membered ring having 1 or 2 heteroatoms selected from oxygen, sulfur and carbon;

R 1 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a phenyl group, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a heterocyclylalkyl group having 1 to 4 carbon atoms in the alkyl moiety wherein the heterocycle is five- or a six membered ring having 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen; or

R 3 and R 4 together with the nitrogen atom and the carbon atom form a five-, six- or seven-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 four-, five- or six-membered ring containing optionally 1 or 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen,

R 5 is hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -phenylalkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 -alkylamino; 1-4 carbon atoms, the remainder of the formula

C ^H ₃ -0-CH ₂ s = R 0 0 · T or phenylalanine residue, or vali.nu proline bound peptide bond to the carbonyl group of the molecule,

Re represents a straight or branched (C1-C4) alkyl, (C1-C3) alkenyl or (C3-C3) alkynyl, hydroxyl, nitro, amino, (C1-C4) alkoxy, mercapto, (C1-C4) alkylthio group 1-4 carbon atoms, hydroxyalkyl of 1-4 carbon atoms, mercaptoalkyl of 1-4 carbon atoms, fluorine, chlorine or bromine, aminoalkyl of 1-4 carbon atoms, sulfonamido, methylenedioxy, fluoroalkyl of 1-4 carbon atoms, C 1 -C 4 chloroalkyl, 254345 k, C 1 -C 4 bromoalkyl, cyano or trifluoromethyl,

R 7 represents a hydrogen atom or a methyl group,

R 5 represents a straight or branched (C 1 -C 4) alkyl group optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, phenyl or pyridyl,

X, Y and Z independently of one another are oxygen, sulfur, CR 10, CH 10,

Rio Rio - CH — CH— or

Rto Rio —C = C - with lim that only one of X, Y and Z is oxygen, sulfur,

Rio Rio

I I —CH — CH— or

Rio Rio —C = C— and one or two of X, Y, and Z may be NR9,

R 9 represents a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group,

R 10 represents a hydrogen atom or, together with the vicinally bonded R 10 radical, a phenyl ring or, if man has a value of i, its dihydroderivative with a double bond in conjugation to the C-terminal carboxyl group and ama 11 are each 0, 1 or 2; 1 or 2.

When R3 and / or R4 represent a 5- or 6-membered heterocyclylalkyl radical, examples of the heterocyclic radicals in this group are thiophene, furan, pyrrole, thiazole, oxazole, isoxazole, pyrazole, imidazole, pyran, thiopyran, pyridine, morphine, morphine , pyrimidine, pyridazine and oxathiin, as well as their di- and tetrahydroderivatives.

When R3 and R4 together with the nitrogen and carbon atom form a five-membered ring, an example of an unsubstituted ring is pyrrolidinediyl and, for example, a substituted ring is a radical of formula

in which

R x and R x buď are either the same or different and are each a hydrogen atom, a hydroxyl group or a methoxy group, or

Rx and Rx ‘together form an oxo or dimercaptoethylene group.

Optionally substituted R 5 alkyl groups may be straight or branched.

The 5- or 6-membered heterocyclic rings fused to the pyrrolidine- or piperidinecarboxylic acid in the meaning of the symbol A may be saturated or unsaturated. Preferred heterocycles are fural, pyrrole, thiophene, benzofuran, indole, benzothiophene, oxazole, imidazole, thiazole, isoxarol, pyrazole, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, pyridazine, quinoline, isoquinoline or piperidine.

The new compounds generally contain several centers of asymmetry and therefore occur as diastereomers or in the form of racemates or racemic mixtures. The invention includes both racemic mixtures and individual diastereomers. Preferred are those enantiomers having the S configuration on asymmetric carbon atoms.

The above racemates can be enriched in spherically uniform forms or can be obtained in pure form, for example, by fractional crystallization or by chemical or biochemical resolution.

The acids of 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 hydrox ^; d calcium or magnesium. Examples of organic bases include dicyclopentyl ohexylamin, N, ^{N-dibenzylethylenediamine,} N, N'-bi s (1 dehydroabiety} ethylenediamine, N-methyl-1-D-glycamine, argiírn or lysine.

The novel compounds of the formula I and their salts are prepared in accordance with the invention by producing a compound of the formula II

Br СНз

R 1 -CH-CO-NH-CH-CO-A (II) wherein

R1 and A, as defined above, are reacted with a mercapto compound of formula III

4.

HS-R2 (III) wherein

R @ 1 is as defined above, the optionally present protecting groups are cleaved, then the optionally obtained product of the formula I is converted into a salt or the product of the formula I in which R5 is hydroxyl is optionally converted to the corresponding ester of formula I, wherein R 5 represents an ehor defined ester residue.

The reaction of the intermediate bromo derivative of the formula II with the mercapto compound of the formula III is preferably carried out in ether as solvent. Reaction with thiol acids (e.g., thiol acetic acid) yields the corresponding acyl mercapto compounds from which the acyl group can be cleaved by strong ibases.

The starting materials of formula (II) are prepared by conventional condensations which are carried out using generally known methods as described for peptide synthesis in Houben-Weyl, Vol. XV /, 4th edition, 1974.

In general, conventional coupling reactions using the activated form of the appropriate acids are employed in peptide chemistry, optionally in the presence of a suitable coupling agent. Suitable carboxylic acid activating groups are acid chlorides, azides, anhydrides, p-nitrophenyl esters, trichlorophenyl esters, thiophenyl esters, o-cyanomethyl esters and the like. The condensation agent used is preferably carbonyldiimidazole, dicyclohexylcarbodiimide, ethoxyacetylene, diphenylphosphoryl azide or diphenylphosphoryl azide. The reaction is carried out at a temperature between 0 ° C and + 10 ° C.

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

The preparation of the starting materials is described in detail in the examples.

Preferred are those compounds of formula I wherein R 1 is hydrogen, phenyl, benzyl, or phenethyl, R 2 is hydrogen, acetyl or 3-sulfamoyl-4-chlorobenzoyl and A is proline.

For example, the following resulting products, optionally in the form of salts, can be obtained as described above.

N- [N- (2-mercaptoacetyl) jalanyl] proline

2. N - [(2-Phenyl-2-mercaptoacetyl) alanyl] proline

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

N- [N- (4-phenyl-2-mercapto-butyryl) alanyl] proline

5. N- [N- (2-acetylmercaptoacetyl) jalanyl] proline

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

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

8. N- [N- (3-phenyl-2-S-mercapto-propanoyl) -S-alanyl] -S-, proline pivaloyloxymethyl ester

9. N - [(3-Phenyl-2-S- [4-chloro-3-sulfamoylbenzoyl] mercaptopropanoyl) -S-alanyl] -S-proline

10. N- [N- (3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-phenylalanine

11. N - [(3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-valine

12. N- [N- (3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-prolm

13. N- (N- (3-Phenyl-2-S-mercaptopropan-1-yl) -S-alanyl) -S-thiazolidine-4-carboxylic acid

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

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

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

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

18. N- [N- (3-Phenyl-2-S-acetylmercaptopropanoyl) -Salanyl] -S-proline pivaloyl methyl ester

19. N- (N- (3-phenyl-2-S-benzoylmercaptopropanoyl) -S-alanyl) -S-proline pivaloyloxymethyl ester

20. N- [N- (3-phenyl-2-S-pivaloylmercaptopropanoyl) -S-alanyl] -S-porlinine pivaloyloxymethyl ester

21. N- [N- (3-phenyl-2-S-acetylmercapropropanoyl) -S-alanyl] -N-cyclopentylglycine.

The amino acid derivatives of formula I exhibit a strong long-lasting blood pressure lowering effect. This activity consists in inhibiting angiotensin I converting enzyme and thereby blocking the formation of vasoconstricting angiotensin II from angiotensin I. In addition, the novel compounds inhibit the kininase II enzyme, which is considered identical to the aforementioned converting enzyme and is responsible for the degradation of bradykinin. Since bradykinin widens the blood vessels, this additional effect enhances the hypotensive action of the compounds of the invention. These novel compounds enhance the blood pressure reduction induced by bradykinin in normal rats. Expression of this activity could also be the observed blood pressure lowering effect in untreated, genetically hypertensive rats.

Thus, N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-proline in anesthetized rat in which blood pressure was increased by intravenous administration of angiotensin I at 0.1 mg / kg when administered intravenously at a dose of 0.3 mg / kg, a prolonged blood pressure reduction of 67%.

In a waking rat stimulated by intravenous administration of 0.2 mg / kg angiotensin I, a sustained 100% suppression of blood pressure increase was observed following oral administration of the above compound at 1 mg / kg.

In rabbits (blood pressure measured in the arteria carotis), a blood pressure reduction of 1.9 kPx was observed following intravenous administration of 1 mg / kg of this compound.

N- [N- (3-phenyl-2-S-merkaptopropa.noyi) -S-alanyl] -S-proline has in vitro inhibitory activity for angiotensin converting enzyme I, IC50 = 5,0.10 ~ ⁹ (mol). The S-acetylated analog of this compound shows an IC50 -7.4 inhibitory activity. ^10.9 (mol).

IC 50 refers to an inhibitory concentration at which 50% of the inhibition of zngiotensin I converting enzyme occurs [see H. S. Cheu.ng and D. W. Cushmam Biochern. Biophys. Acta 293, 451 (1973)].

For therapeutic application, the novel compounds are mixed with conventional pharmaceutical fillers or carriers, binders, tablet disintegrants, glidants, thickeners or diluents. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders, which preparations may optionally contain other known active substances, for example saluretics, diuretics and / or antihypertensive agents.

Suitable tablets may be prepared, for example, by mixing the active ingredient with known excipients such as inert diluents, such as calcium carbonate, calcium phosphate or milk sugar, tablet disintegrating agents such as corn starch or alginic acid, binders such as starches or gelatin, glidants substances such as magnesium stearate or talc, and / or a depot effecting agent such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tables may also consist of several layers.

Similarly, dragees can be prepared by coating dragee cores, prepared analogously to tablets, with compositions commonly used in dragee coating such as collidone or shellac, acacia, talcum titanium dioxide or sugar. To achieve a depot effect or to prevent compatibility, the core may also consist of several layers. In order to obtain a depot effect, the dragee coatings may also consist of several layers, the preparation of which may be carried out using the adjuvants mentioned above for the preparation of tablets.

The syrups containing the active ingredient according to the invention or the active ingredient combination may further comprise sweetening agents, such as saccharin, cyclamate, glycerin or sugar, as well as a flavoring agent, for example a flavoring agent, such as vanillin or orange extract. These syrups may additionally contain suspending aids or thickeners, such as sodium carboxymethylcellulose, a wetting agent, for example a condensation product of a fatty alcohol with ethylene oxide, or a preservative, such as p-hydroxybenzoate.

Injectable solutions are prepared in conventional manner, for example, using preservatives such as p-hydroxybenzoates or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid and with the addition of suitable dissolution aids, and filled into vials or ampoules.

Capsules containing one or more active compounds or combinations of active compounds can be obtained, for example, by mixing the active compounds with inert carriers, such as inert sugar or sorbitol, and filling the gelatin capsules.

The daily dose of the compounds of formula (I) or salts thereof is between 5 and 500 milligrams, preferably between 10 and 100 mg, and can be administered in one to four divided doses.

The following Examples illustrate the invention. however, the scope of the invention is not limited in any way. The structures of all synthesized compounds were confirmed by NMR spectroscopy.

Example 1

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

To a solution of 5.33 g (70 mmol) of thiol acetic acid in 150 ml of anhydrous ether, 7.1 g (70 mmol) of triethylamine are added under nitrogen, while cooling with ice, and the solution is added dropwise to a solution of 15.9 g (35 mmol). N- [N- (3-phenyl-2-R-bromopropanol) -S-alanyl] -S-proline tert-butyl ester in 75 ml of anhydrous ether. The reaction mixture was refluxed for a further 90 minutes, cooled and filtered, and the filtrate was washed with dilute potassium hydrogen sulfate solution, dilute potassium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off and the oily residue (16.4 g) was chromatographed on silica gel using ethyl acetate / n-hexane (2: 1) as eluent to give 13.1 g (83.4% of theory). Rf 0.41 (silica gel; ethyl acetate - n-hexane 2: 1).

To saponify the tert-butyl ester with a solution

13.1 g (29.2 mmol) of this ester in 65 ml of anisole and 130 ml of trifluoroacetic acid are stirred at room temperature for 2 hours and then evaporated in vacuo. The residue is dissolved three times in approximately 100 ml of acetone and then in chloroform, after which each solution is evaporated under vacuum on a rotary evaporator. The resulting residue was dissolved in dichloromethane and extracted twice with saturated sodium bicarbonate solution. The combined sodium bicarbonate solutions are washed with dichloromethane, the aqueous phase is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. 10.6 g (92.5% of theory) of a solidified foamed material consisting of N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -E-proline as the free acid is obtained.

R _f = 0.6 (silica gel, chloroform - methanol - glacial acetic acid 90 ': 10: 5).

To saponify the thiol acetic acid ester, 250 ml of water are added to 10.6 g (27 mmol) of N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -S-proline under stirring under nitrogen. 22 ml of 5N sodium hydroxide are added and the mixture is left to react at room temperature for 1.5 hours, a further 10 ml of sodium hydroxide are added thereto, and the resulting mixture is stirred at the same temperature for another hour.

1.5 hours.

The resulting aqueous solution was washed twice with dichloromethane, acidified with dilute hydrochloric acid, and extracted three times with dichloromethane. The organic phase is washed with saturated sodium chloride solution and, after drying over magnesium sulphate, evaporated.

9.2 g (97.2% of theory) of the title compound is isolated as a solidified foam which is confirmed by IC and NMR spectra.

R _f = 0.6 (silica gel; chloroform - Methane 1 - glacial acetic acid 90:10: 5).

¹ H-NMR (CD 3 OD, δ values):

1.31 (d, I = 7Hz, 3H,

СНз-СН),

1.80 to 2.41 (m, 4H, Pro-CH2CH2),

3.16 (m, 2 H,

Ph — OH2 —CH—),

3.43. 3.89 (m, 3H, Pro-NCH 2,

AND

Ph — CH2 —CH—),

4.41 (m, 1H, Pro-α-CH),

4.61 (m, 1 H,

AND

СНзСН—),

7.24 (m, 5H, aryl-H).

SH, NH and COOH signals were not observed in the spectrum.

In this and the following spectra, signal shapes are referred to by the following common abbreviations:

• s - singlet d = doublet t = triplet q = quartet m = multiplet

Ph denotes a phenyl radical. The starting materials are prepared as follows:

3-phenyl-2-R-bromopropionic acid.

References: Chemistry of the Amino

Acids, Vol. I, N.Y. (1961), 165; Ann. 357,1 (1907).

Modified procedure known from literature:

To 51.2 g (0.31 mole) of R-phenylalanine, 620 ml of 2.5 N sulfuric acid and 125 g (1.05 mole) of potassium bromide are added successively. After cooling the solution to 0 ° C, the solution was added portionwise over 80 minutes

Sodium nitrite (32.75 g, 0.475 mol) was added and the mixture was stirred at room temperature for 1 hour. The resulting emulsion is extracted three times with about 200 ml of ether each time, the organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and the ether is distilled off. The oily residue (63 g) was purified by chromatography on silica gel using ethyl acetate / n-hexane (2: 1) as eluent.

45.1 g of the title compound is obtained in the form of a reddish oil, the structure and optical purity of which are confirmed by NMR spectroscopy. The preparation of the S- and R-, S-analogs is carried out according to the same recipe.

N- (3-phenyl-2-R-bromo, propanoyl) -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, 20.6 g (0.1 mol) of N, N'-dicyclohexylcarbodiimide was added with stirring at 0 ° C. The reaction mixture was stirred for 15 minutes at 0 ° C and then allowed to stand overnight at room temperature, filtered off with suction, the solvent was distilled off, the residue was dissolved in ethyl acetate and the solution was filtered after cooling. The ethyl acetate solution was washed successively with dilute potassium bisulfate solution, saturated sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, and ethyl acetate was distilled off. The oily residue (29.9 g) was chromatographed on silica gel using a 2: 1 mixture of N-hexane and ethyl acetate as eluent. 23.9 g (76% of theory, corresponding to 76 mmol) of the title compound are obtained as the methyl ester.

К saponification compound thus obtained was dissolved in 150 ml of methanol, cooled to 0 ^{0 C} and stirring к thereto 80 mL of 1N sodium hydroxide solution (80 mmol). The solution was stirred at room temperature for 3 hours, then evaporated in vacuo, diluted with water and extracted three times with dichloromethane. After evaporation in the aqueous phase of dissolved dichloromethane in vacuo, the aqueous portion is acidified with concentrated hydrochloric acid and the precipitated crystals are filtered off. 17.8 g (78% of theory) of the title compound of melting point 156 DEG-157 ^DEG C. are obtained.

_Rf = 0.7 (silica gel, chloroform - methanol - glacial acetic acid 50: 10: 5).

The S S- and (R, S) S-diastereomers are obtained in an analogous manner.

Comparison of the S- and R, S-d'astereomers by NMR spectroscopy indicates a 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 dichloromethane а к solution with stirring and cooling to 0 ^DEG C. was added 12.2 g (59.3 mmol) of N, N'-dicyclohexylurea. After suctioning off the dicyclohexylurea, the solvent was distilled off in vacuo, the oily residue was dissolved in diethyl acetate and the solution was allowed to stand in the cold for some time. After aspiration, the organic phase is washed successively with dilute sodium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo. The oily residue (24.2 g) was chromatographed on silica gel using ethyl acetate / n-hexane (2: 1) as eluent.

15.9 g (59.1% of theory) of the title compound are isolated in the form of a viscous oil which is uniform by NMR spectroscopy and chromatography.

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

The corresponding S S S and R, S S S S diastereomers are obtained in an analogous manner.

b) 2.29 g (10 mmol) of 3-phenyl-2-S-bromopropionic acid, 2.78 g (10 mmol) of S-alanyl-S-tert-butyl ester hydrochloride and 1 g (10 mmol) of triethylamine are dissolved. in 100 ml of anhydrous dichloromethane а к solution under stirring and cooling at 0 ^C ° C was added 2.06 g (10 mmol) of N, N'-dicyclohexylcarbodiimide-ethylcarbodiimide. The reaction mixture was stirred at room temperature overnight, then cooled and the precipitated dicyclohexylurea was filtered off with suction. The solvent was distilled off under vacuum, the oily residue was dissolved in ethyl acetate, the solution was cooled, filtered to remove insoluble matter and washed successively with dilute potassium hydrogen sulfate solution, saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off to give 4.3 g (94.8% of theory) of a colorless viscous oil.

In a similar manner, analogous R S S- and R S S S diastereomers are obtained.

Example 2

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

Analogously to Example 1, using the tert-butyl N- [N- (3-phenyl-2-S-bromopropanoyl) -S-alanyl] -S-proline ester affords the title diastereomeric compound, i.e. N- [N- (3-phenyl-2-R-mercaptopropanoyl) -S-alanyl] -S-proline.

R f = 0.54 (silica gel; chloroform-methanol-glacial acetic acid 90: 10: 5).

¹ H-NMR (CDCl 3, δ values):

1.15 (d, J = 7Hz, 3H,

CHsCH—),

1.77 to 2.39 (m, 4H, Pro-CH2CH2-),

2.05 (d, J = 10Hz, SH)

3.13 (m, 2H). AND 1 Ph — CH2 —CH—), 3.43 (m, 1H, Ph - CH2 --CH--), 3.63 (m, 2H, Pro — N — CH2—), 4.55 (m, 1 H, Pro-a-H), 4.77 (m, 1H, N, N - CH -), 7.25 (m, 5H, aryl-H), 8.93 (s, broad, COOH). Example 3 N- [N- (3-Phenyl-2-R-mercaptopropanoyl) -S-alanyl] -S-proline

In analogy to Example 1, N- [N- (3-phenyl-2-R, S-bromopropanoyl-S-alanyl) -S-proline tert-butyl ester yields N- [Ν- (3-phenyl) -2-R, S-mercaptopropanoyl) -S-alanyl] -S-proline in the title.

Example 4

Ν- [N- (mercaptyl) -S-alanyl] -S-proline

In analogy to Example 1, using the N- [N-bromoacetyl] -S-alanyl] -S-proline tert-butyl ester yields the title N- [N- (mercaptoacetyl) -S-alanyl] -S-proline.

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

1 H-NMR (CD 3 OD, δ values):

1.35 (d, 3H, J = 7Hz,

СНзСН—),

1.81 to 2.52 (m, 4H, Pro-OH2CH2-),

3.17 (s, 2 H,

SCH2-C),

II o

3.69 (m, 2H, Pro-N-CH2),

4.47 (m, 1 H,

AND

For-a-CH—),

4.64 (q, 1H, J = 7Hz)

СNзСН—), signals SH, NH and COOH were not observed in the spectrum.

Example 5

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

Analogous to Example 1, using N- [N- (2-phenyl-2-R, S-bromoacetyl) -S-alanine] -S-proline tert-butyl ester yields Ν- [N- (2-phenyl) -2-R, S-mercapto (ptoacetyl) -S-alanine] -S-proline in the title.

Rf ~ 0.48 (silica gel; chloroform-methanol-glacial acetic acid 90: 10: 5).

1 H-NMR (CD 3 OD, values <5):

1.32 (d, J = 7Hz, 3H,

СНз— CH—),

1.77 to 2.45 (m, 4H, Pro-CH2CH2-),

3.65 (m, 2H, Pro-N-CH2),

4.48 (m, 1 H,

Pro-a-CH]

4.66 (m, 1 H,

СНз — CH—),

4.82 (s, 1H, Ph - CH -),

7.24 to 7.59 (m, 5H, aryl-H), signals SH, NH, COOH were not observed in the spectrum.

Example 6

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

Analogously to Example 1, N- [N- (4-phenyl-2-R, S-bromobutanoyl) -S-alanine] -S-proline yields N- [N- (4-phenyl-2-R) , S-mercaptobutanoyl) -S-alanin-S-proline in the title.

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

1 H-NMR (CDCl 3, values <5):

1.35 (d, 3H,

СNз — CH—, J = 7 Hz),

2.08 (m, 2H, Ph - CH2 --CH2),

1.80 to 2.44 (m, 4H, Pro-CH2-CH2-),

2.72 (m, 2H, Ph - CH 2),

3.65 (m, 2H, Pro - NCH 2 -),

3.26 (m, 1 H,

Ph — CH2 — CH2 —CH—),

4.50 (m, 1 H,

AND

For-a-CH—),

4.77 (m, 1 H,

AND

СНз— CH—),

7.23 (m, 5H, aryl-H),

7.50 (m, 1 H, NH),

8.96 (s, 2H, SH and COOH).

Example 7

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

To a solution of 815 mg (10.7 mmol) of thiol acetic acid in 35 ml of anhydrous ether, 1.08 g (10.7 mmol) of triethylamine is slowly added dropwise to the resulting solution dropwise under nitrogen, while cooling with ice and stirring. 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 and heated to reflux for 90 min. reflux condenser. After cooling, the reaction mixture is filtered off with suction and the residue on the filter is dissolved in dichloromethane. Wash the solution with saturated sodium bicarbonate solution, dilute potassium hydrogen sulfate solution, water and saturated sodium chloride solution. _% After drying over magnesium sulfate, the solvent was distilled off and the solid residue weighing 3.3 g was recrystallized from ethyl acetate. 2.03 g (68% of theory) of the desired methyl ester of melting point 157 DEG-158 DEG C. are obtained.

R _f = 0.13 (silica gel; ethyl acetate - n-hexane 2: 1).

For saponification, 2 g (3.6 mmol) of the above-prepared mercaptoacyl methyl ester was suspended in 50 ml of methanol and 20 ml of water were added and 6 ml of 5 N sodium hydroxide was added under stirring under a nitrogen atmosphere. The mixture was stirred at room temperature for 1.5 hours, then an additional 2 ml of 5 N sodium hydroxide was added and stirring was continued for 1.5 hours. The methanol was evaporated in vacuo on a rotary evaporator, the residue was diluted with water and washed twice with dichloromethane. The aqueous phase is acidified with dilute hydrochloric acid solution and extracted three times with dichloromethane. The organic phase is washed with a saturated sodium chloride solution and, after drying over magnesium sulphate, is distilled off under vacuum.

1.7 g (94.9 percent of theory) of the title compound are obtained in the form of a solidified foam, the structure of which is confirmed by NMR spectroscopy.

R ^f = 0.48 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

NMR-NMR (CDCl 3, δ values):

1.05 (d, J = 7Hz, 3H,

AND

СНз— CH—),

2.08 (d, J = 10Hz, 1H, SH).

1.59 to 2.25 (m, 4H, Pro-CH2CH2),

2.84 to 3.93 (m, 7H, Pro-NCH 2,

Ph — CH2 — CH—,

Ph — CH.2-CH '

AND

COOH),

4.46 to 4.99 (m, 3H, Pro-a-CH,

CH.:—CH ,.

Ph — CH? —CH — COOH) ’

7.24 (m, 12H, aryl-H, NH, COOH),

7.75 _(d? J - 8 _H.; Nile). '

By the same procedure, analogous R, S S S and R S S diastereomers are obtained.

The starting material was prepared as follows.

N- [N- (3-phenyl-2-R-bromopropanol) -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 [deg.] C., 1.44 g (7 mmol) of N, N &apos; -dicyclohexylcarbodiimide. The reaction mixture was stirred for 15 minutes at 0 ° C, then overnight at room temperature, filtered, the solvent was distilled off in vacuo and the residue was dissolved in ethyl acetate. The solution was cooled, filtered again and the filtrate was washed successively with dilute potassium bisulfate solution, saturated sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue (4 g) was recrystallized from a small amount of ethyl acetate. Yield: 3 g (76.7% of theory).

R _f = 0.37 (silica gel; ethyl acetate - n-hexa n 2: 1).

Example 8

N- [N- (3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-prolyl-S-valine

The title compound is obtained in an analogous manner to Example 7 using N- [N- (3-phenyl-2-R-bromopropanoyl) -S-prolyl-S-valine as starting material.

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

ГО ^с з $ ^H 3

J in C-NH-CH-COOH 1 H-NMR (CDCl 3, δ values):

0.86 (d, J = 7Hz, 6H, isobutyl-NH2),

1.32 (d, J = 7Hz, 3H,

AND

СНз — CH—),

2.09 (d, J = 10Hz, 1H, SH)

1.71 to 2.70 (m, 5H, Pro-CH2CH2, isobutyl-CH- (R)),

3.14 (m, 2H, '

Ph — CH2 —CH—),

3.41 to 4.00 (m, 3H, Pro-N-CH2,

Ph — CH2 —CH—),

4.34-4.99 (m, 3H, Pro-α-CH,

(N-CH-isobutyl-CH),

6.58 (s, 1H, COOH);

7.22 (m, 5H, aryl-H),

7.53 (d, J = 10Hz, 1 H,

СНз

NH — CH),

7.75 (d, J = 8 Hz, 1H, NH-1-butyl).

Example 9

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

The title compound was obtained in an analogous manner to Example 7, starting with N- [N- (3-phenyl-2-R-ibromopropanoyl) -S-alanyl] -S-prolyl-S-proline.

R f = 0.26 (silica gel; ethyl acetate).

1 H-NMR (CDCl 3, δ values):

1.34 (d, J = 7Hz, 3H)

СНз — CH—),

1.97 (d, J = 10Hz, 1H, SH).

1.71 to 2.43 (m, 8H, Pro-CH2CH2),

2.84 to 4.00 (m, 7H, Pro-NCH2,

AND

Ph — CH2 —CH—),

4.26 to 4.96 (m-3H, Pro-α-CH,

II

СНз — CH—),

6.20 (s, 2Η²ΝΗ, COOH),

7.26 (m, 5H, aryl-H).

Example 10

N- [N- (3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-thiazolidine-4-carboxylic acid

The title compound is obtained in an analogous manner to that in Example 1, starting from S-thiazolidine-4-carboxylic acid. The yield of product melting at 144-146 ^C. C is 85.4 ° / o of theory.

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

Elementary analysis:

Calcd for C15H20N2O4S2:

H, 5.47; N, 7.60; S, 17.40. Found:

% C, 51.96;% H, 5.41;% N, 7.46.

The structure of the product was confirmed by NMR spectroscopy.

¹ H-NMR (CDCl 3, δ values):

1.35 (d, J = 7, 3H,

СНз — CH—),

2.03 (d, J = 10Hz, 1H, SH)

3.20 (m, 2H)

Ph — CH2 —CH—),

3.27 (d. 2H,

AND

S — CH2 —CH—, J = 7 Hz),

3.50 (m, IH,

AND

Ph — CH2 —CH—),

4.72 (m, 2H, N - CH2 --S),

4.77 (m, 1 H,

I СНз— CH—),

5.10 (t, J = 7Hz)

AND

S — CH2 —CH—),

6.52 (s, 1H, COOH);

7.27 (m, 5H, aryl-H);

7.78 (d, J = 8Hz, NH).

Example 11

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

Using the analogous procedure of Example 1, 4,5,6,7-tetrahydrothieno [2,3-c] pyridine-7-carboxylic acid in the R, S-, R- and S- configuration yields the corresponding dlastereomers of the title compound. .

R ₍ for mixture of SSR, S-diastereomers: 0.18 (silica gel; chloroform-methanol-glacial acetic acid 90:10: 5)).

Example 12

N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -4,5,6-tetrahydrothieno [3,2-c] pyridine-4-carboxylic acid

Using the analogous procedure of Example 1, 4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-4-carboxylic acid was obtained to give the title diastereomers.

Rf for a mixture of SSR ₇ S-diastereomers: 0.53 (silica gel; chloroform-methanol-glacial acetic acid 90: 10: 5).

Ш-NMR (CDCl 3, δ values):

1.34 (d, J = 7Hz, 3H,

CH5 — CH-),

2.02 (d, J = 9Hz, SH)

2.72 to 4.43 (m, 7%)

Ph — CH2 —CH—, —CH2 — CH2-),

5.00 (m, 1H '—СНз — CH—),

5.91 (s, 1H, CH - COOH),

7.23 (m, 9H, aryl-H, thiophene-H, NH, COOH).

Example 13

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 was slowly added under stirring at 0 ^° C under nitrogen. A solution of 3.5 g (7.7 mmol) of N- [N- (3-phenyl-2-R-bromopropanol-1) -S-alanyl] -S-proline tert-butyl ester is then added dropwise in the mixture. 30 ml of anhydrous ether, the reaction mixture is heated to reflux for 90 minutes and then filtered off with suction. The ethereal solution was washed with dilute potassium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The residue (3.7 g) was chromatographed on silica gel, eluting with ethyl acetate / n-hexane. It is obtained

3.4 g (86.5% of theory) of the tert-butyl ester of the title compound as a solidified foam.

R _t = 0.27 (silica gel; ethyl acetate - n-hexane 1: 1).

For saponification, 3.4 g (6.6 mmol) of the tert-butyl ester prepared above were dissolved in 34 ml of trifluoroacetic acid and 17 ml of anisole, the reaction mixture was stirred at room temperature for 2 hours, then evaporated in vacuo, the residue was dissolved three times. in acetone and chloroform, and after each dissolution was re-evaporated in vacuo on a rotary evaporator. The residue was dissolved in dichloromethane and the solution was washed with water and saturated sodium chloride solution. After drying over magnesium sulfate, the solution was evaporated and the residue (3.1 g) was chromatographed on silica gel, eluting with 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, pan-like mass.

R _f = 0.25 (silica gel; methylene chloride - methyl-ethanol · - glacial acetic acid 120: 5: 2).

Ш-NMR (CDCl 3, δ values):

1.21 (d, 3H, J = 7.0Hz,

I — СНз — CH—),

1.77 - 2.39 (m, 4H, Pro — NONС—),

3.24 (P), 2H,

AND

Ph — CH2 —CH—),

3.58 (m, 2H, Pro-N-N);

AND

4.47 (m, 1H, Ph - NH - CH -), <

4.53 (m, 1 H,

For — and —CH—),

4.75 (m, 1 H,

СНз — CH—),

7.02 - 8.00 (m, 10 H, two aromatic residues),

8.50 (s, 1H, COOH).

Example

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

The same procedure as in the previous example was followed except that thiolpivalic acid was used instead of thiolbenzoic acid. Reaction of 3.17 g (7 mmol) of N- [N- (3-phenyl-2-R-bromoproppanoyl) -S-alanyl) -S-proline tert-butyl ester and 1.65 g [14 mmol) of thiolpivalic acid 3.3 g (06% of theory) of the tert-butyl ester of the title compound are obtained.

R _f = 0.34 (sili.kagel; ethyl acetate - n-hexane 1: 1).

The saponification of this ester with trifluoroacetic acid afforded the title compound (2.4 g, 82.4%).

R _f = 0.3 (silica; dichloromethane - methanol - glacial acetic acid of 120: 6: 2).

U-1-NMR (CDCl 3, δ values):

1.17 ps, 9H, С (СНз) з),

1.26 (d, 3H, J = 7Hz)

I — СНз — CH—),

1.82 - 2.27 (m, 4H,

For —CH2CH2—),

3.14 (m, 2 H,

Ph — СНг — CH—),

3.57 (m, 2H, Pro - N - N -) -

4.19 (m, IH,

AND

Ph — СНг — CH—),

4.50 (m, 1H, Pro — and —CH—),

4.73 (m, 1 H,

I — СНз— CH -),

AND

6.98 (d, 1H, J = 8Hz, -NH),

7.21 (m, 5H, aryl-H),

8.30 (s, 1H, COOH).

The compounds of the following examples 15 to 37 are also obtained in an analogous manner to the preceding examples.

Example 15

Pivaloyloxymethyl ester N- [N- (3-phenyl-2-S-mercaptopropanoate 1) -S-alanyl] -S-proline ^J H-NMR (CDC13, 5 values):

1.20 [s, 9H, С (СНз) з],

1.34 (d, J = 7Hz, 3H, -N-CH),

1.96 (d, J = 10Hz, 1H, SH);

1.82-2.42 (m, 4H, Pro-CH2CH2-),

2.91 - 3.81 (m, 5H,

For N-CH ₂ -Ph-CH 2 -CH-)

4.49 (m, 1H, Pro-a-CH),

4.66 (m, 1 H,

СНз — CH—),

5.75 (m, 2H, --OOH2 - O),

7.23 (m, 6H, 5-aryl-1, NH).

Example 16

N- [N- (3-phenyl-2-S- [4-chloro-3-sulfamoylbenzoyl] mercaptopropanoyl) -S-alanyl] -S-proline

R _f = 0.3 (butanol - acetone - water 60: 6 ': 10; silica gel).

O

-CH-C-NH-CH-C-N-I

O ( ^S ^C COH (s) ¹¹ ortho ²¹ ortho / meta ³¹ meta

1 H-NMR (CD'OD, δ values):

Г '

1.30 (d, J = 7Hz, 3H,

AND

CHs — CH—),

1.78-2.40 (m, 4Ή, Pro — CH2CH2),

2.90 - 3.42 (m, 2H,

Ph — CH2 —CH—),

3.56 (m, 2H, Pro-N-CH2),

4.27-4.84 (m, 3H, Pro-a-CH, Ph-CH 2 -CH-, CH 3 -CH-),

7.27 (m, 5H, aryl-H);

7.73 (d, J = 8Hz, 1H, ortho-aryl-H),

8.08 (dd, J = 8Hz, 3Hz, 1H, ortho-metaaryl-H), 8.57 (d, J = 3Hz,

1H, meta-aryl-H, signals NH2, NH, COOH were not observed in the spectrum.

Example 17

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

Rf = 0.42 (silica gel; ethyl acetate-n-hexane 2: 1).

⁴ H-NMR (CDCl 3, δ values):

1.21 [s, 9.H, С (СNз) з),

1.23 (d, 3H, J = 7Hz)

AND

СНз — CH-),

1.77-2.27 (m, 4H, Pro-CH2CH2-),

2.30 (s, 3H, 2H-C = 0),

3.15 (m. 2H,

Ph — CH.2 — CH—),

3.58 (m, 2H, Pro - NCH 2 -),

4.15 (m. 1H,

Ph-CH 2 -CH-),

4.48 (m, ΙΗ,

For — re — CH—),

4.67 (m, 1 H,

AND

СШ-СН-)

5.75 (m, 2H "- O - CH 2 - O"),

6.92 (d, 1H, J = 8Hz, NH),

7.23 (m, 5H, aryl-H). ”

Example 18

N- [N- (3-Phenyl-2-S-benzoyl-mercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester

_Rf = 0.43 [silica gel; ethyl acetate - n-hexane 1: 1).

¹ H-NMR (CDCl 3, δ values):

Ph — CHž — CH—),

3.57 (m, 2H, Pro-N-CH2),

4.16 (m, 1 H,

Ph — СНз — CH—),

4.48 (m, IH,

For — re — CH—),

4.71 (m, IH,

СНз — CH—),

5.76 (m, 2H, O-CH2-O),

6.82 (d, 1H, J = 8Hz, NH),

7.22 (m, 5H, aryl-H).

Example 20

N- [N- [3-phenyl-2-S-acetylmercaptopropanoyl] -S-alanyl] -N-cyclopentylglycine

1.19 [s, 9H. С (СНз) з),,

1.31 (d, 3H,

AND

СНз — CH— (J-7 Hz),

1.80-2.34 (m, 4H, Pro-CH2CH2-),

3.26 (m, 2 H,

Ph-CH 2 (CH 2),

3.58 (m, 2H, Pro - NCH 2 -),

4.48 (m, IH,

Ph — CH2 —CH—),

4.50 (m, 1H, Pro-re-CH-),

4.73 (m, 1 H,

AND

СНз — CH—),

7.00 (d, 1H, J = 7Hz, NH--),

5.76 (m, 2H, O-CH2-O),

7.27 (m, 5H, aryl-H),

7.34 - 8.08 (m, 5H, Ph - H - H).

ΊΙ o

Example 19

R _f = 0.55 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

NMR-NMR (CDCl 3, δ values):

1.31 (d, 3H, J = 7Hz, J1)

СНз — CH—),

1.16-2.11 (m, 8H, cyclopentyl-CH2),

2.28 (s, 3H, 2H = C = O), ^_

3.15 (m, 2 H,

Ph - CH 2 - CH 2),

2.92 (m, 2H, N - CH2 - C = 0), ’

4.22 (m, 1H, cyclopentyl-OH),

4.26 (m, 1 H,

Ph — CH2 —CH—),

4.92 (m, 1 H,

AND

CH:, - CH—),

5.61 (s, 1H? 0Ό0Η), ’

7.18 (d, 1H, J = 8Hz, NH).

7.24 (m, 5H, aryl-H).

Example 21

N- [N- (3-phenyl-2-S-pi-valoylmercaptopropanoyl) -S-alanyl] -S-proline pivaloyloxymethyl ester

N- (N- (3-phenyl-2-S-mercaptopropanoyl))

-R-alanyl] -S-proline

R f = 0.45 (silica gel; ethyl acetate - n-hexane 2: 1).

NMR-NMR (CDCl 3, δ values):

1.16 [s, · 9H, С]

1.20 [s, 9H, C (S)],

1.27 (d, 3H, J = 7Hz)

AND

СНз — CH—),

1.82-2.32 (m, 4H, Pro-CH2CH2),

3.16 (m. 2H,

The title SRS-diastereomer was prepared analogously to Example 1 from N- [N- (3-phenyl-2-R-bromopropanoyl) -R-alanyl] -S-proline tert-butyl ester.

_Rf = 0.45 (chloroform - methanol - glacial acetic acid A 90: 10: 5).

Example 22

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

The title SSR-diastereomer was prepared analogously to Example 1 from N- [N- (3-phenyl-2-R-bromopropanoyl) -S-alanyl] -R-proline tert-butyl ester.

Example 23

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

The title RRR-diastereomer was prepared analogously to Example 1 from N- [N- (3-phenyl-2-S-bromopropanoyl) -R-alanyl] -R-proline tert-butyl ester.

Example 24 N- [N- (3-Phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -S-proline (5-methyl-2-oxo-1,3-dioxolein-4-yl) methyl ester

The title compound was prepared in a manner analogous to Example 1. The product was obtained as an oil with Rf = 0.17 (silica gel; ethyl acetate - n-hexane 2: 1).

@ 1 H-NMR (CDCl3, .delta.):

1.29 (d, 3H, J = 7Hz)

СНз — CH—),

1.7-6.31 (m, 4H, Pro-CH2-CH2),

2.16 (s, 3H,

AND

СНз — C =)

2.31 [s, 3H, N-C —], '

O

3.13 (m, 2H, Ph - CH2),

3.58 (m, 2H, Pro-N-CH2),

4.24 (m, 1 H,

AND

Ph — CH2 —CH—),

4.48 (m, 1H, _[ delta] -CH-), 4.58 (m, 1H,

For — and —CH—),

4.78 (m, 2H, O-OH-),

6.87 (d, 1H, J = 7.5Hz, NH),

7.23 (m, 5H, aryl-H).

Example 25

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

The title compound is prepared analogously to Example 1. The product was obtained as a solidified foam R _f = 0.63 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

1 H-NMR (CDCl 3, values <5):

1.34 (d, 3H, J = 7Hz,

AND

СНз — CH—),

1.34-1.99 (m, 8H, cyclopentyl-CH 2 -), 2.00 (d, J = 10 Hz, SH),

3.16 (m, 2 H,

Ph — СНз — CH—),

3.53 (m, 1 H, 1 ')

Ph — CH2 —CH—),

3.92 (m, 2H, N - CH 2 - C = O),

4.28 (m, 1H, cyclopentyl-CH),

4.99 (m, IH,

СНз — CH—),

5.91 (s, 1H, COOH);

7.24 (m, 5H, aryl-H),

7.46 (d, 1H, J = 8Hz, NH).

Example 26

N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -S-thiazolidine-4-carboxylic acid

The title compound was prepared in a yield of 80% of theory in analogy to Example 1 from N- [N- [3-phenyl-2-S-acetylmercaptopropanoyl] -S-alanyl] -S-proline tert-butyl ester.

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

Example 27

N- [N- (3-phenyl-2-S-acetylmercaptopropanoyl) -S-alanyl] -S-thiazoline-4-carboxylic acid pivaloyloxymethyl ester

The title compound was prepared analogously to example 1 as an oil, R _f = 0.35 (silica gel; ethyl acetate - n-hexane 1: 1).

1 H-NMR (CDCl 3, δ values):

1.19 [s, 9H, С (СИз) з],

1.32 (d, J = 7Hz, 3H,

СНз — CH—),

2.30 Ts, 3H, N (C = O),

3.11 (m, 2H);

Ph - CH2 --CH--)

22 (m, 2H)

S — CH2 —CH—),

AND

4.12 (m, 1 H,

AND

Ph — CH2 —CH—),

4.59 (m, 2H, N - CH2 --S--),

4.64 (m, 1 H,

СНз — CH—),

5.07 (m, 1 H,

N - CH - C = O),

5.74 (m, 2H, O - CH2 --O),

6.86 (d, J = 8Hz, 1H, NH);

7.18 (m, 5H, aryl-H).

Example 28

N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -S-thiazolidine-4-carboxylic acid pivaloyloxymethyl ester

The title compound was prepared in an analogous manner to Example 1. The product melted after crystallization from a mixture of ethyl acetate and hexane at 103-104 ° C.

1 H-NMR (CDCl 3, δ values):

1.18 [s, 9H, С (СNз) з],

1.34 (d, J = 7Hz, 3H,

СНз — CH—),

1.99 (d, J = 10 Hz, 1H, S-H),

2.93 - 3.77 (ni, 5H,

AND

Ph — CH2 —CH—),

SCHz — CH—),

4.41-4.94 (m, 3H, N-CH2-S,

AND

СНз — CH—),

5.07 (m, 1 H,

S — CH2 —CH—),

5.77 (m, 2H, O - N - O),

7.07 (d, J = 9Hz, 1H, NH).

7.23 (m, 5H, aryl-H).

Example 29

N- [N- (3-Phenyl-2-S-pivaloyloxymethylmercaptopropanoyl) -S-alanyl] -S-thiazolidine-4-carboxylic acid pivaloyloxyinethole ester

The title compound was prepared analogously to Example 1. The product was obtained as an oil, R _f = 0.33 (silica gels; ethyl acetate - hexane 1: 1).

o C (CH ₃ ) ₃ c ^z

II o

1 H-NMR (CDCl 3, δ values) 1.15 [s, 9H, С (СНз) з], (s, 9H, С (СНз) з), 1,22 1.36 (d, J = 7Hz, 3H) СНз — CH—), 2.83 - 3.43 (m, 4H, Ph — CH2 —CH—, 1 1 S — CHg — CH—), 3.74 (m, 1 H,

Ph — CHž — CH—,

4.39-4.84 (m, 3H, N - CH2 --S, 1H)

СНз — CH—),

5.07 (m, 1 H,

SCHz — CH—),

5.76 (m, 2H, O-CH2-O),

7.23 (m, 6H, aryl-H, NH).

The title compound was prepared in an analogous manner to Example 1, starting from R, S-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-6-carboxylic acid methyl ester.

_Rf (diastereomer mixture SSR, S) = 0.68 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

Example 31

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

The title compound was prepared in a manner analogous to Example 1.

R _f = 0.37 (silica gel; ethyl acetate - n -hexane 1: 1).

Example 1 a d 32

Example 30

N- [N- (3-Phenyl-2-S-mercaptopropanoyl) -S-alanyl] -R, S-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-6-carboxylic acid acid

N- [N- (3-phenyl-2-S-pivaloyloxymethylmercaptopropanoyl) -5-alanyl] -R, S-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-6-carboxylic acid pivaloyloxymethyl ester

The title compound is prepared analogously to Example 1. The product was obtained as an amorphous solid R _f = 0.49 (silica gel; ethyl acetate - n-hexane 1: 1).

Example 33

The title compound is obtained by the sequence of reactions described in Example 1, starting with 4-R-hydroxy-2-S-proline methyl ester. The product was obtained as a solidified foam R _f = 0.23 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] -4-R-hydroxy-2-S-proline

1 H-NMR (CDCl 3, i values):

7.46 (d, J = 8 Hz 1H, 1H).

1.33 (d, J = 7Hz, 3H,

СНз — CH—),

2.02 (d, J = 10Hz, 1H, SH)

2.00 - 2.50 (m, 2H, Pro - β - CH 2 -),

2.84 - 3.66 (m, 3H,

AND

Ph — CH? —CH—),

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, min-1),

Example 34

N- [N- (3-phenyl) -2-S-mercaptopropanoyl) -S-alanyl] -4-oxo-2-S-proline

The title compound was prepared by the sequence of reactions described in Example 1, starting from 4-oxo-2-S-proline methyl ester. The product was obtained as an oil, R _f = 0.34 (silica gel; chloroform - - methanol - glacial acetic acid 90: 10: 5).

(WITH)

CH ₃ (S) o

¹ H-NMR (CDCl 3, δ values):

1.30 (d, J = 7Hz, 3H,

AND

СНз — CH—),

2.09 (d, J = 10Hz, lH, SHJ,

2.48 - 3.81 (m, 5H,

AND

Ph - CH 2 - CH -, CH 2 - C = O),

4.13 (m, 2H, N-CH 2),

4.64 (m, 1H, ...)

СНз— CH—),

4.99 (m, 1H, H)

CH — COOH), /

7.24 (m, 5H, aryl-H),

7.57 (cl, J = 8Hz, 1H, NH),

9.69 (s, 1H, COOH).

Example 35

N- [N- (3-phenyl-2-S-mercaptopropanoyl) -S-alanyl] 4,4-etban-1,2-diyl-dithio-S-proline

The title compound was prepared as described in Example 1 using 4,4-ethane-1,2-diyl-dithio-S-proline methyl ester hydrobromide and N- (3-phenyl-2-R-). bromopropanoyl) -S-alanine. The product was obtained as a solid, R _f = 0.5 (silica gel, chloroform - methanol - glacial acetic acid 90: 10: 5).

(s) —CH 2 CH-C-N and II

I - ~ 1 p. S ί ^ Д _{N s} (s) COOH

@ 1 H-NMR (CDCl3, .delta.):

1.30 (d, J = 7Hz, 3H,

CHs — CH—),

2.02 (d, J = 10Hz, 1H, SH)

2.67 (m, 2 H,

For —CH2 —CH—),

3.15 (m, 2 H,

Ph (CH2-CH-),

3.36 (s, 4H; -SCH2CH2-S-),

3.55 (m, 1 H,

Ph — CH2 —CH—),

4.00 (m, 2H, Pro-N-CH ₂ -),

4.64 (m, 2 H,

CHs — CH—.

For — and —CH—),

7.23 (m, 5H, aryl-H),

7.41 (d, J = 8Hz, 1H, NH).

7.56 (s, 1H, COOH).

Example 1 a d 36

N- [N- (3-phenyl-2-S-mercap topropanoyl) -S-alanyl] -4,4-dimethoxy-S-proline

The title compound was prepared according to the procedure described in Example 1, starting from N- (3-phenyl-2-R-bromopropanoyl) -S-alanine and 4,4-dimethoxy-S-proline methyl ester. Product Amorphous .pevného material of R _f = 0.49 [silica gel; chloroform-methanol-ethyl acetate 90: 10: 5].

¹ H-NMR (CDCl 3, values <5):

1.31 (d, 3H, J = 7Hz,

AND

CHs — CH-),

2.05 (d, 1H, J = 10 Hz, SH),

2.35 (d, 2H, J = 7Hz)

Pro-CH ₂ -CH-)

3.19 (m, 2 H,

AND

Ph — C'H2 — CH—)

3.27 (s, 6H, 20'CHs),

3.50 (m, IH,

Ph — CH2 —CH—),

3.68 (m, 2H, Pro-N-CH2),

4.59 (m, 1 H,

For · —and —CH—),

4.70 (m, IH,

AND

CHs — CH—),

5.95 (s, broad, 2H, NH and COOH),

7.23 (m, 5H, aryl-H).

Example 37

N- [N- (3-phenyl-2-S-acylmercaptopropanoyl) -S-alanyl] -S-thazolidine-4-carboxylic acid

The title compound was prepared in a manner analogous to Example 1.

соон

1 H-NMR (CDCl 3, δ values):

1.32 (d, 3H, J = 7Hz)

AND

СНз — CH—),

2.30 (s, 3Ή,

AND

СНз — С-O),

3.14 (m, 2 H,

Ph — CH2 —CH—),

3.25 (d, 2H, I = 6Hz)

SCH2 —CH—),

4.25 (m, 1 H,

Ph — CH2 —CH—),

4.65 (m, 2H, N-CH 2 -S), 4.78 (m, 1H,

CH.; - CH-),

5.07 (t, 1H, J = 6Hz)

AND

N — CH — COO)

7.16 (1H, J = 8 Hz, NH),

7.20 (m, 5H, aryl-H),

8.48 (s, 1 H, COOH).

Rf = 0.48 (chloroform-methanol-glacial acetic acid 90: 10: 5).

The following is an example of the composition and preparation of pharmaceutical compositions.

(a) Dragees

Ingredients: 1 dragee core contains

active ingredient according to the invention 10.0 mg milk sugar 60.0 mg cornstarch 35.0 mg gelatine 3.0 mg magnesium stearate 2.0 mg

110.0 mg

Preparation:

The mixture of the active ingredient with milk sugar and corn starch is granulated through a 1 mm mesh screen using a 10% aqueous gelatin solution, the granulate is dried at 40 ^° C and passed through a sieve again. The granules thus obtained are mixed with magnesium stearate and dragee cores are pressed from the mixture, which are then coated in a conventional manner with an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished dragee is polished with beeswax.

(b) Tablets

Ingredients:

the active ingredient according to the invention milk sugar corn starch soluble starch magnesium stearate 10.0 mg 70 · fl fl 50.0 mg 7.0 mg 3.0 mg 140.0 mg

Preparation:

The active ingredient together with the magnesium stearate is granulated using an aqueous solution of soluble starch, the granulate is dried and mixed thoroughly with milk sugar and corn starch. The mixture is then compressed into tablets weighing 230 mg each containing 100 mg of active ingredient.

c) Solution for injection

Ingredients:

active compound of this invention 5.0 mg sodium chloride, ethanolamine 60,0mg 20,0mg ^one alkoxylated rain water to 2 ml

Preparation:

The active ingredient together with the excipients are dissolved in a sufficient amount of distilled water and the concentration is adjusted to the desired value with additional water. The solution is from the filter and is filled with a 2 ml ampoule under aseptic conditions. The ampoules are then sterilized and sealed. Each ampoule contains 5 mg of active substance.

(d) Capsules

Ingredients:

active ingredient according to the invention 10.0mg milk sugar 250.0mg corn starch 40.0mg talc 10.0mg

(e) Suppositories

Ingredients:

active ingredient according to the invention 0.1 g cocoa butter melting point 38-37 ° C) 1.6 g Kirnauba wax 0.1 g

310.0 mg

Preparation:

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

1.8 g

Preparation:

Cocoa butter and Kanauba wax will melt. It is mixed thoroughly and the melt is cooled to 45 DEG C. The finely divided active substance is then mixed into the mass. The mixture is poured into slightly pre-cooled rosehip molds of appropriate size and allowed to cool.

Claims (2)

A process for the preparation of amino acid derivatives of the general formula I SR2 СНзI I R 1 = CH-CO-NH-CH-CO-A (I) in which R 1 represents a hydrogen atom, a phenyl group, a benzyl group or a phenothyl group, R 5 represents a hydrogen atom, an acetyl group, a benzoyl group, a 3-sulfamoyl-4-chlorobenzoyl group, a 3-sulfamoyl-4-chloro-6-hydroxybenzoyl group. 3-sulfamyl-d-chloro-5 - [(furyl 1 -amino) benzoyl, 2,3-bis-4-methyl-4 - ([methyl] benzoyl) acetyl, pivaloyl or pivaloyloxymethyl, A is a N-amino acid residue of the general formula R 3 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms to which a phenyl ring, a phenyl group, a phenyl group having 1 to 4 carbon atoms in the alkyl moiety can be fused; hunter heterocyclylalkyl means a group having 1 to 4 carbon atoms in the alkyl moiety in which the heterocycle is a five- or six-membered ring having 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, Rd represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a phenyl group, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a heterocyclylalkyl group having 1 to 4 carbon atoms in the alkyl moiety wherein the heterocycle is five - or a six-membered ring having 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or R 5 and R d, taken together with the nitrogen atom and the carbon atom, form a five-, six- or seven-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 form a four, five or six membered ring containing optionally 1 or 2 additional heteroatoms selected from oxygen, sulfur and nitrogen; R 5 represents hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-alkoxy, C 1 -C 4 -alkylamino, dialkyl- an amino group containing from 1 to 4 carbon atoms in each alkyl moiety; -?and -о-сн- -c-Rq or or a phenylalanine, valine or proline residue linked by a peptide bond to the carbonyl group of the molecule, R6 is straight or branched and ^one alkyl group of 1-4 carbon atoms, alkenyl having up to 3 carbon atoms or alki.nylovou having up to 3 carbon atoms, hydroxyl, nitro, amino, alkoxy having 1 to 4 carbon atoms, dipstick C1-C4alkylthio, C1-C4 hydroxyalkyl, C1-C4 mercaptoalkyl, fluorine, chlorine or bromine, C1-C4 aminoalkyl, sulfonamido, methylenedioxy, fluoroalkyl (C 1 -C 4) group, (C 1 -C 4) chloroalkyl, (C 1 -C 4) bromoalkyl, cyano or trifluoromethyl group, R 7 represents a hydrogen atom or a methyl group, Re represents a straight or branched (C 1 -C 4) alkyl group optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, phenyl or pyridyl, X, Y and Z are each independently O, S, CR 10, CH 10, Rio Rio I I —CH — CH— or Rio Rio I - c = c - with only one of X, Y and Z being oxygen, sulfur, a group Rio Rio I I —CH — CH— R10 Rio I - c = c - and one or two of X, Y and Z may be NR9, R 9 represents a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group, R10 represents a hydrogen atom or, together with a vicinally bonded R10 radical, a phenyl ring or, if man has a value of 1, its double bond dihydroderivative in conjugation to the C-terminal carboxyl group, and man each have a value of 0, 1 or 2, is equal to 1 or 2, and salts thereof, characterized in that the compound of formula (II) Br СНз I I R1-CH-CO-NH-CH-CO-A [П] in which R1 and A, as defined above, are reacted with a mercapto compound of formula III HS-R2 (III) wherein R2 is as defined above, or any protecting groups present are cleaved, whereupon the optionally obtained product of formula (I) is converted into a salt or the product of formula (I) in which R5 is hydroxyl is optionally converted to the corresponding ester of formula (I). wherein R 5 is an ester residue as defined above. 2. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula (I) wherein R1 and R2 are as defined in (1). A represents the residue of the--amino acid of the general formula neibo? 3 (ΜΗΝ ”C (hK ^0R 5 or / ^0R S - N - \ (H _? C) and (CH 2) nx In xR / * X ' X _Y / R3 represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms to which the phenyl ring, a phenyl group, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl part may be unfused; a (C 1 -C 4) heterocyclylalkyl group in which the heterocycle is a five or six membered ring having 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, R 4 represents a hydrogen atom, a direct or a. a branched alkyl group having 1 to 4 carbon atoms, a phenyl group, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a heterocyclylalkyl group having 1 to 4 carbon atoms in the alkyl moiety wherein the heterocycle is a 5- or 6-membered ring with 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; or R 3 and R 1 together with the nitrogen atom and the carbon atom form a five-, six- or seven-membered ring which may be saturated or contain a double bond and which is optionally substituted by oxo, dimethoxyethylene or one or two hydroxy or methoxy groups, or form a four-, five- or six-membered ring containing optionally 1 or 2 additional heteroatoms selected from oxygen, sulfur and nitrogen, R 5 is hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 alkoxy, C 1 -C 4 phenylalkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each case 1 to 4 carbon atoms, a radical of formula or a radical of phenylalanine, valine or proline, linked by a peptide bond to the carbonyl group of the molecule, R 8 is a straight or branched (C 1 -C 4) alkyl, (C 3 -C 3) alkenyl or (C 3 -C 3) alkynyl, hydroxyl, mtro, amino, (C 1 -C 4) alkoxy, mercapto, (C 1 -C 4) alkylthio group C 1 -C 4 hydroxyalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 mercaptoalkyl, fluorine, chlorine or bromine, C 1 -C 4 aminoalkyl, sulfonamido, methylenedioxy, C 1 -C 4 fluoroalkyl carbon, C 1 -C 4 chloroalkyl, C 1 -C 4 bromoalkyl, cyano or trifluoromethyl, R 7 represents a hydrogen atom or a methyl group, R 5 represents a straight or branched (C 1 -C 4) alkyl group optionally substituted by fluorine, chlorine, bromine, trifluoromethyl, phenyl or pyridyl, X, Y and Z are each independently O, S, CR 10, CH 10, Rio Rw I I —CH — CH— or Rio Rio I - c = c - with only one of X, Y and Z being oxygen, sulfur, a group Rio Rio I I —CH — CH— or Rio Rio I I —c = c— Rd represents a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group, R 10 represents a hydrogen atom · or, together with the vicinally linked R 10 radical, a phenyl ring or · if man has a value of 1, its double bond dihydroderivative in conjugation with a C-terminal carboxyl group, and man each have a value of 0, 1 or 2, wherein the sum of m and n is equal to 1 or, 2, and their salts. and one or two of X, Y and Z may be NR9,