NO810941L - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ALKYLTIOACYLAMINOS ACIDS - Google Patents

Abstract

Therapeutically active alkylthioacylamino acids of the general formula. where. RX represents a nitro, cyano or pyridyl group or one of the groups -COR ', -COOR', -PO (OR ') or. R represents hydrogen, a lower alkyl group having 1 or 2 carbon atoms, one of the groups -COOR 'or -COR' or the residue -SOCH 2. R represents hydrogen, an alkoxy group having 1 to 3 carbon atoms, a phenyl group or a thienyl radical. R represents hydrogen or a methyl group ,. X represents one of the groups -CH-C- or -CH-S-CH- and. R 'represents an alkyl group having 1 or 2 carbon atoms and salts thereof. The new compounds have a particularly antihypertensive effect. Preparation of the compounds is described.

Description

This invention relates to the preparation of new substituted alkylthioacylamino acids with the general formula

and their basic salts.

In this formula means:

R^ is a nitro, cyano or pyridyl group or one of the groups

1*2 hydrogen, a lower alkyl group with 1 or 2 carbon atoms, one of the groups -COOR' or -COR' or the remainder -SO2CH3,

R^ hydrogen, an alkoxy group with 1-3 carbon atoms, a phenyl group or a thienyl residue,

R^ hydrogen or a methyl group,

X one of the groups -CH2-CH2-CH2- or -CH2-S-CH2~, and

R' an alkyl group with 1 or 2 carbon atoms.

The pyridyl group mentioned as meaning for the residue R can be attached to the other molecule in the 2-, 3- or 4-position, preferably the 4-position.

The new compounds generally exhibit several centers of asymmetry and therefore exist as diastereoisomers or in the form of the racemates or the racemic mixtures. The invention includes the preparation of both the racemic mixtures and the individual pairs of diastereomers. The preferred compounds are the enantiomers where the asymmetric C atom in the amino acid is in the L configuration.

The new compounds form salts with inorganic and organic bases. Examples of inorganic bases are ammonia, alkali metal hydroxides such as sodium or potassium hydroxide, or alkaline earth metal hydroxides such as calcium or magnesium hydroxide; and as organic bases, mention may be made of dicyclohexylamine, N,N'-dibenzylethylenediamine, N,N'-bis-(dehydro-abiethyl)-ethylenediamine, N-methyl-D-glycamine, arginine or lysine.

The new compounds can be produced according to different methods:

a) By addition of the free mercapto group in a compound with the general formula

where the residues R. and X have the meanings indicated above, and R,- means hydrogen or a lower alkyl group with 1 to 3 carbon atoms, to the double bond in an olefin which is activated with at least one electron-withdrawing group, and which has the general formula

where the residues R^, R ? and R^ have the meanings given above, • and when R^ is different from hydrogen, subsequent acidic or alkaline cleavage of the ester group.

The addition reaction can be carried out in the presence or absence of solvents. Suitable solvents are water, alcohol, ether, tetrahydrofuran, dioxane, halogenated hydrocarbons such as dichloromethane, benzene, toluene, ethyl acetate, acetone, dimethyl sulfoxide, dimethylformamide and pyridine. The activated olefin used can also, if it is liquid, be used as a solvent.

Preferred solvents are water and ethanol.

The addition can take place as a radical reaction or ion reaction. The preferred ionic addition is carried out in a pH range from 6 to 14, preferably between pH 7 and 10. It has then proven beneficial to add one or more basic substances such as ammonia, triethylamine, trimethylamine, dicyclohexylamine, N-methylmorpholine, piperidine , pyridine, trimethylbenzylammonium hydroxide, alkali hydroxide, alkali carbonate or alkali alcoholate. Preferred bases are ammonia, triethylamine, dicyclohexylamine and N-methylmorpholine.

The reaction temperature for the ionic addition can, depending on the starting materials used, vary within wide limits and lies between -80 and +150°C. A temperature range between 0 and 50°C is preferred.

The reaction is usually carried out under normal pressure and a nitrogen atmosphere, but the use of elevated pressure can in many cases be advantageous.

When carrying out the addition by radical reaction, a radical generator must be introduced, e.g. benzoyl peroxide, di-tert.butyl peroxide,, ascaridol, . azobis-(isobutyronitrile) or potassium persulfate. The reaction takes place under the conditions mentioned for ionic addition. b) A further method for the preparation of the new compounds consists in reacting a substituted alkylthio-carboxylic acid with the general formula

where the residues R^, R2, R^ and R^ have the meanings indicated above, with an amino acid of the general formula where R,, has the meaning given above.

The coupling of the compounds with the general formulas IV and V takes place by means of coupling reactions which are common in peptide chemistry, using an activated alkylthiocarboxylic acid of formula IV. As carboxyl-activating groups, one can use acid chlorides, azides, anhydrides, p-nitrophenyl esters, trichlorophenyl esters, thiophenyl esters, o-cyanomethyl esters, etc. As coupling agents, carbonyldiimidazole, dicyclohexylcarbodiimide or chloroformic acid esters are preferably used (see Houben-Weyl, Methoden der organischen Chemie, vol. XV, Part II, 1974).

A possibly present ester group (R^ = O-alkyl) is removed in connection with the coupling reaction by hydrolytic or acidolytic cleavage.

c) Dimeric compounds of the general formula I where R^ means the group .. ■ are obtained by reacting a compound of the general formula II with divinylsulfone in the molar ratio 2:1 under the reaction conditions specified in a) and b).

In the methods described above, the starting compounds can be present in the form of their racemic mixtures or their diastereisomers. If the racemic mixtures are used, the reaction products obtained can be cleaved by usual methods, e.g. by fractional crystallization or by ordinary chromatography.

Preference is given to such compounds of the general formula I where R 1 means hydrogen, acetyl or methoxycarbonyl, R 2 means nitro, acetyl or methoxycarbonyl, R 2 means phenyl, thienyl or methoxy, and R 2 means methyl, and X has the above meaning.

Particularly preferred are 1-[3-(1-phenyl-2-nitroethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-thienyl(2)-2-nitroethylthio)-2-D- methylpropanoyl]-L-proline, 1-[3-(1-methoxy-2,2-bis-methoxycarbonyl-ethylthio)-2-D-methylpropanoyl]-L-proline, l-[3-(l-phenyl-2 -nitroethylthio)-2-D,L-methylpropanoyl]-L-proline and 1-[3-(1-phenyl-2,2-diacetyl-ethylthio)-2-D-methylpropanoyl]-L-proline and their salts.

Furthermore, compounds are preferred in which the 3-mercapto-2-methyl-propionic acid is present in D-form, and the amino acid which forms the basis of formula I is present in L-form.

According to the methods described above, e.g. the following compounds are prepared: 1-[3-(1-phenyl-2-nitroethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-thienyl(2)-2-nitroethylthio)-2 -D-methylpropanoyl]-L-proline, 1-[3-(1-phenyl-2-nitroethylthio)-2-D,L-methylpropanoyl]-L-thiazolidine-4-carboxylic acid, 1-[3-(1-thienyl(3)-2-nitroethylthio)-propanoyl]-L-proline, 1-[3-(1-phenyl-2,2-diacetyl-ethylthio)-2-D-methylpropanoyl] -L-proline, 1-[3-(2-methyl-2-nitrilo-ethylthio)-2-D-methylpropanoyl]-L-proline, 1- [ 3-(2-pyridyl (4 )-ethylthio) - 2-D-methylpropanoyl ] -L-proline ,- 1-[3-(1-phenyl-2,2-bis-(ethoxycarbonyl)-ethylthio)-propanoyl]-L-proline, 1-t 3-(3-oxo-n-butylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-p-cyanophenyl-2-nitro-ethylthio)-2-D-methylpropanoyl ]-L-proline, 1- [ 3-(1-p-tolyl-2-nitro-ethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-thienyl(3)-2-nitro-ethylthio)-propanoyl]-L-proline, 1-[3-(1-phenyl-2,2-diacetyl-ethylthio)-2-D- methylpropanoyl]-L-proline, 1-[3-(1-phenyl-2,2-bis-(ethoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-methoxy-2,2-bis-(methoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(2-(0,0-diethylphosphonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(1-phenyl-2-methylsulfonyl-ethylthio)-2-D-methylpropanoyl]-L-proline, I-[3-(1-Methoxy-2,2-bis-(methoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, 1-[3-(2-ethoxycarbonyl-ethylthio)-2-D-methylpropanoyl]-L-proline, sulfonyl-bis-[(ethylthio-2-D-methylpropanoyl)-L-proline] of the formula

sulfony1-bis-[(ethylthio-propanoyl)-L-proline], 1-[3-(1-phenyl-2-methylsulfonylethylthio)-2-D-methylpropanoyl]-L-proline.

The starting compounds with the general formulas II, III and V are known from the literature. Compounds of the general formula IV are new, and they can be prepared by addition of the free SH group in a mercaptoalkylcarboxylic acid to the double bond in an olefin substituted with one or more electronegative groups.

The substituted alkylthioacylamino acids of the general formula I possess a strong, long-lasting blood pressure-lowering effect. This is due to an inhibition of the angiotensin I-converting enzyme and thereby 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 and which can be considered identical with the above-mentioned converting enzyme. As bradykinin has a vasodilating effect, the blood pressure-lowering effect is enhanced due to this additional effect. The blood pressure lowering achieved by bradykinin in normal rats is enhanced by the new compounds. The observed blood pressure-lowering effect on non-pretreated genetic hypertensive rats may also be an expression of this effect.

Thus, the end product according to example 1 on a genetically hypertensive rat causes a blood pressure reduction of 19% at a dosage of 30 mg/kg p.o.

The blood pressure lowering caused in rats by i.v. injection of 3.0 µg/kg bradykinin is enhanced by 142% by administration of 1.38 µmol/kg i.v.

The final products obtained according to examples 1 and 3 show angiotensin-I-converting enzyme in vitro inhibition activities (IC5q) of 1-10<-8> and 1.8-10~<9> M/l, respectively. The inhibitory concentration which results in the angiotensin-I-converting enzyme being inhibited by up to 50% is denoted here as ICj-q (see H.S. Cheung, D.W. Cushman, Biochem. Biophys. Acta 293, 451 (1973)).

The new compounds lack the SH group, as for substances with a similar structure, e.g. captopril, to a large extent is made responsible for the side effects. It can thus be expected that the new connections will be more conciliatory.

For use in therapy, the new compounds are mixed with common pharmaceutical fillers or carriers, diluting, disintegrating, binding, sliding, thickening or diluting agents. As. pharmaceutical preparation forms can e.g. tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders are used, possibly further known active substances, e.g. saluretics, diuretics and/or antihypertensives can be added.

Suitably, tablets can e.g. is produced by mixing the active substance or substances with known excipients, e.g. 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 consist of several layers.

Similarly, dragees can be produced by coating cores produced analogously to the tablets with agents that are usually used in dragee coatings, e.g. collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depository effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the dragee coating can also consist of several layers to achieve a depot effect, as the excipients mentioned above for tablets can be used.

Juices of the new active ingredients or active ingredient combinations. may also contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste enhancing agent such as e.g. flavoring agents such as vanillin or orange extract. In addition, they may contain suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions are prepared in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid, with the addition of suitable dissolution-improving agents, and filled into injection bottles or ampoules. Capsules containing one or more active substances or combinations of active substances can e.g. is produced by mixing the active ingredient with inert carriers such as milk sugar or sorbitol and encapsulating in gelatin capsules.

The daily dose for use of the new compounds of the general formula I and salts thereof is 50 - 1000, preferably 100 - 600 mg and can be administered in 1 - 4 single doses.

The following examples shall serve to further illustrate the invention.

Example 1

1-[ 3- ( 1- phenyl- 2- nitro- ethylthio)- 2- D- methylpropanoyl]- L- proline

2.7 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline-tert.butyl ester and 1.5 g of w-nitrostyrene are dissolved in 20 ml of anhydrous ethanol and 1 ml of N-methylmorpholine is added under nitrogen at room temperature . After approx. After standing for 2 hours at room temperature, the solvent is driven off under reduced pressure, and the residue is taken up in ethyl acetate. The ethyl acetate phase is decanted twice with KHSO^ solution and once with NaCl solution, dried with MgSO^ and evaporated in vacuo. The obtained oil is treated at room temperature over 1 hour with approx. 30 ml. IN HC1 in glacial acetic acid, the solvent is stripped off on a rotary evaporator, and the residue is added to ether several times and evaporated. You get 2 g (= 56% of the theoretical) of the title compound as a colorless oil. Analysis: C-^ H^ ^O^ S Calculated: C 55.72, H 6.05, N 7.64, S 8.75% Found: C 56.09, H 6.31, N 7.43, S 8.09%.

Example 2

1-[ 3-( 2- ethoxycarbori1- ethylthio)- 2- D- methylpropanoyl]- L- proline

8.5 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline-tert.butyl ester are dissolved in 30 g of acrylic acid ethyl ester, 2.6 g of piperidine and 10 drops of "Triton B" are added and boiled for 5 hours under reflux cooling. After distilling off the excess of the acrylic acid ester on the rotary evaporator, the residue is purified by chromatography on a silica gel column with the eluent CH^C^/methanol (19:1). Pour approx. over the oil thus obtained. 100 ml IN HC1 in glacial acetic acid, and the whole is stirred for 1 hour at 20°C. After evaporation and addition of ether to the residue, 3.2 g of the title compound is obtained as an oil which is dissolved in a little ether, the equivalent amount of dicyclohexylamine is added and allowed to stand for several days in a refrigerator. By suctioning off the separated crystals, washing with ether and drying in a desiccator, 3.5 g (= 23% of the theoretical) of the dicyclohexylammonium salt of the title compound, which has a paste-like consistency, can be isolated. An al <yse:> ' <C> 26 <H> 46 <N> 2°5 <S> Calculated: C 62.62, H 9.30, N 5.62, S 6.43% Found: C 61.89, H 8.81, N 5.39, S 6.48%.

Example 3

1- [ 3-( 1- thienyl( 2)- 2- nitro- ethylthio)- 2- D- methylpropanoyl)-L-proline

0.35 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline and 0.25 g of w-nitro-2-vinyl-thiophene are dissolved in anhydrous ethanol, 0.16 ml of N-methylmorpholine are added under nitrogen , and the mixture is stirred overnight. at room temperature. After evaporation and acidification of the reaction mixture with 2N HC1, extraction is carried out with ethyl acetate, the ethyl acetate extract is decanted with NaHCO3 solution, and after acidification with 2N HC1 this solution is extracted again with ethyl acetate. The organic phase thus obtained is dried over MgSO4 and evaporated. The remaining oil is added to the equivalent amount of dicyclohexylamine and triturated with petroleum ether. In this way, 0.3 g (= 34% of the theoretical) of the dicyclohexylammonium salt of 1-[ 3-(1-thienyl(2)-2-nitroethylthio)-2-D-methylpropanoyl]-L-proline is obtained in crystalline form with sm.p. 61°C. Analysis: C27 H43 N3 °5 S2 Calculated: C 58.56, H 7.83, N 7.59, S 11.58% Found: C 58.56, H 7.95, N 7.33, S 11.85%.

Example 4

1-[ 3-( 1- thienyl( 2)- 2- nitro- ethylthio)- 2- D- methylpropanoyl]-L-proline

2 g of w-nitro-2-vinyl-thiophene and 1.55 g of 3-mercapto-2-D-. methylpropionic acid is dissolved in anhydrous ethanol and 1.3 ml of N-methylmorpholine is added under nitrogen, and the mixture is stirred overnight at room temperature. After evaporation, the residue is taken up in dilute hydrochloric acid, the aqueous phase is extracted with ethyl acetate, the ethyl acetate extract is decanted with NaHCO3 solution, and after acidification with 2N HCl, this solution is extracted again with ethyl acetate. After drying the solution over MgSO4 and evaporation, 2.5 g of 3-(1-thienyl(2)-2-nitro-ethylthio)-2-D-methylpropionic acid is obtained as an oil. The oil is dissolved in anhydrous methylene chloride, 0.9 ml of N-methylmorpholine is added, cooled to -15°C while excluding moisture and 1.2 g of chloroformate isobutyl ester is added. After 8 minutes, a solution of 1.4 g of L-proline tert-butyl ester in anhydrous methylene chloride is added. The mixture is allowed to come to room temperature and stirred overnight. The solution is then shaken three times with NaHCO^ solution, with saturated KHSO^ solution and once with distilled water, dried and evaporated, whereby the becomes an oil again. The oil is treated for 1 hour with IN HC1 in glacial acetic acid at room temperature. Evaporation is then carried out, ether is poured over the residue several times, and the solvent is evaporated. The remaining oil is added to the equivalent amount of dicyclohexylamine and triturated with ether, thereby obtaining 2.8 g (= 42% total yield) 1-[ 3-(1-thienyl(2)-2-nitro-ethylthio)-2- D -methylpropanoyl]-L-proline-dicyclohexylammonium salt in the form of white crystals with .m.p. 61°C.

Example 5

3- [ 3-( 1- ferriyl- 2- nitro- ethylthio)- 2- D, L- methylpropanoyl]-L- 1 i a zolidi ri- 4- carboxylic acid

0.85 g of 3-(3-mercapto-2-methylpropanoyl)-L-thiazolidine-4-carboxylic acid is reacted with 0.5 g of co-nitrostyrene as described in Example 3. 300 mg of 3-[3-(1 -phenyl-2-nitroethylthio)-2-D,L-methylpropanoyl]-L-thiazolidine-4-carboxylic acid dicyclohexylammonium salt with m.p. 190°C (split.) Analysis.: C^H^O^ Calculated: C 59.44, H 7.66, N 7.43% Found: C 59 , 49 , H 7.73., N 7.05%

E xample' 6

1- [. 3-(2-cyano-propylthio)-2-D-methylpropanoyl]-L-proline

0.35 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline is dissolved in water, the solution is adjusted to pH 8.1 with ammonia and 0.2 g of methacrylonitrile is added under nitrogen. The reaction mixture is stirred overnight, the water is distilled off under reduced pressure, and an equivalent amount of dicyclohexylamine is added to the oily residue and triturated with ether. 0.4 g (-53% of the theoretical) of white crystals of the dicyclohexylammonium salt of the title compound with m.p. are obtained; 125°C. Analysis: C25H'4 3N3°3S Calculated: C 64.48, H 9.31, N 9.02, S 6.89% Found: C 64.10, H 9.51, N 8.79, S 7.05%.

Example 7

1-[3-(2-pyridyl('4)-ethylthio)-2-D-methylpropanoyl]-L-proline

0.35 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline is dissolved in water, adjusted to pH 7 with triethylamine and 0.2 g of 4-vinylpyridine is added under nitrogen. The mixture is stirred overnight and then extracted with ethyl acetate three times to remove excess vinylpyridine. The aqueous phase is evaporated, an equivalent amount of dicyclohexylamine is added to the residue and triturated with petroleum ether (b.p. 40-60°C). 0.4 g (= 50% of the theoretical) 1-[3-(2-pyridyl(4)-ethylthio)-2-D-methylpropanoyl]-L-proline-dicyclohexylammonium salt with m.p. 121°C. .Yield: C28 H45<N> 3°3 <S> Calculated: C 66.76, H 9.00, N 8.34, ■ S 6.37% Found: C 66.64, H 8.61, N 8.06, S 6.74%

Example. 8

1- [ 3- ( 1- p- cy' ano' phenyl- 2- nitroethylthio) - 2- D- methylpropanoyl ] - L- proline

3 g of 1-(3-mercapto-2-D-methylpropanoyl)-L-proline and 1.3 g of p-cyano-o-nitrosterene are dissolved in ethanol and 0.75 g of N-methylmorpholine are added under nitrogen. The mixture is stirred overnight at room temperature, the ethanol is distilled off and the residue is taken up in saturated KHSO^ solution. The emulsion thus formed is extracted three times with ethyl acetate, and the combined ethyl acetate phases are decanted three times with a 10% KHCO 3 solution. The combined KHCO-j phases are cooled, acidified with concentrated hydrochloric acid and extracted again three times with ethyl acetate. The combined ethyl acetate phases are washed with saturated sodium chloride solution, dried with MgSO 4 . and evaporated. The residue is taken up in isopropanol and ether is added. The precipitated crystals are taken up in methanol, boiled and evaporated. By dissolving in ethyl acetate and adding dropwise to ether/petroleum ether (40-60°C, 1:1) the title compound is obtained in crystalline form. Yield: 2.1 g = 72% of the theoretical, m.p. '78-80°C. Analysis: ci8<H> 21 <N> 3°5 <S> Calculated: C 55.23, H 5.41, N 10.73, S 8.19% Found: C 55.37,. H 5.52, N 9.60, S 8.78%.

Analogous to example 6, the following end products were also produced: 1-[3-(1-thienyl(3)-2-nitro-ethylthio)-propanoyl]-L-proline, dicyclohexylammonium salt (hygroscopic) Analysis: C^H^O^ Calculated: C 57.86, H 7.66, N 7.78, S 11.88% Found: C 58.68, H 7.86, N 7.01, S 10.79%. 1-[3-(1-phenyl-2,2-diacetyl-ethylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 144-145°C. Analysis: C3 3 <H> 5 <Q> N2<0>5 S Calculated: C 67.54, H 8.59, N 4.77, S 5.46% Found: C 66.84, H 8.65, N 4.99, S 5.53%. 1-[3-(1-phenyl-2,2-bis-(ethoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 76°C Analysis: C3 5 <H5> 4 <N> 2 <0> 7 <S> Calculated: C 6 4.99, H 8.41, N 4.33, S 4.96% Found: C 66.30, H 8.95, N 4.24, S 4.20%. 1-[3-(1-Methoxy-2,2-bis-(methoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 103°C. Analysis: C2 gH^ gN2<0gS> Calculated: C 58.72, H 8.45., N. 4.89, S 5.59% Found: C.62.02, H 8.47, N 5.15,. S 4.96%. 1-[3-(2-(0,0-diethylphosphonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 117°C. Analysis: C2 7 <H> 51 <N> 2°6 <P> S Calculated: C 5.7.63, H 9.15, N 4.98, S-5.70% Found: C 58.15, H 9.46, N 5.25, S 5.10%. Sulfonyl-bis-[(ethylthio-2-D-methylpropanoyl)-L-proline], bis-dicyclohexylammonium salt. Sm.p. 127°C. Analysis: <C> 46 <H> 82 <N> 4 <0> 8 <S> 3 Calculated: C 60.36, H 9.03, N 6.12, S 10.51% Found: C 58.30, H 7.35, N 6.08, S 10.07%. 1-[3-(1-phenyl-2-methylsulfonyl-ethylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 168°C (dec.) Analysis: C3o <H> 4 <8> N2 °5 S2 Calculated: C 62.04, H 8.33, N 4.82, S 11.04% Found: C 62.49, H 8.41, N 5.17, S 10.48%. 1-[3-(3-oxo-n-butylthio)-2-D-methylpropanoyl]-L-proline, dicyclohexylammonium salt. Melting point: 125°C. Analysis: C^H^I^O^S Calculated: C 64.06, H 9.46, N 5.98, S 6.84% Found: C 63, 78, H 9.53, N .5.64,. S 7.58%. 1-[3-(1-p-tolyl-2-nitroethylthio)-2-D-methylpropanoyl]-L-proline. Melting point: 58°C. Analysis: C18 H24 H2 05 S Calculated: C 56.83, H 6.36, N 7.36, S 8.43% Found: C 56.33, H 6.34, N 7.03, S 8.67%.

Claims (6)

1. Analogy method for the preparation of therapeutically active compounds of the general formula where R^ means a nitro, cyano or pyridyl group or one of the groups -COR', -COOR', -PO(OR1) - or R2 means hydrogen, a lower alkyl group with 1 or 2 carbon atoms, one of the groups -COOR' or -COR' or the remainder -SO2 CH3 , R^ means hydrogen, an alkoxy group with 1-3 carbon atoms, a phenyl group or a thienyl residue, R^ means hydrogen or a methyl group, X means one of the groups -CH2 -CH2 -CH2 - or -CH2"S-CH2- and -R <1> means an alkyl group with 1 or 2 carbon atoms, and salts thereof, characterized by a) the free mercapto group in a compound with the general formula where the residues R^ and X have the meanings indicated above, and R,- means hydrogen or a lower alkyl group with 1-3 carbon atoms, is added to the double bond in an olefin with at least one electron-withdrawing group activated with the general formula where the residues R 1 , R 2 and R 2 have the meanings given above, and if R 1 is different from hydrogen, the ester group is split off ■in an acidic or alkaline environment, or b) a substituted alkylthiocarboxylic acid of the general formula where the residues , R2 , R^ °9 R4 have the meanings given above, are reacted with an amino acid of the general formula where R,- has the meaning given above, and any ester group present is removed by hydrolytic or acidolytic cleavage, or c) for the preparation of dimeric compounds of the general formula I where R^ denotes the group is transacted a connection with. the general formula II with divinyl sulfone in the molar ratio 2:1, and optionally a product thus prepared is transferred with the general formula I to a salt. 2. Method as stated in claim 1 for the production of 1-[3-(1-phenyl-2-nitro-ethylthio)-2-D-methylpropanoyl]-L-proline, characterized in that starting materials are used where R^ means nitro , R2 means hydrogen, R-j means phenyl, R^ means methyl and X. means the group (CI-^)^- 3. Process as stated in claim 1 for the production of 1-[3-(1-thienyl(2)-2-nitro-ethylthio)-2-D-methylpropanoyl]-L-proline, characterized in that starting materials are used where R -^ means nitro, R2 means hydrogen, R^ means thienyl-2, R^ means methyl and X. means the group (CH,,)^. 4. Process as stated in claim 1 for the production of 1-[3-(l-phenyl-2-nitro-ethylthio)-2-D,L-methylpropanoyl]-L-thiazolidine-4-carboxylic acid, characterized in that it is used starting materials where R-^ means nitro, R2 means hydrogen, R-. means phenyl, R 1 means methyl and X means CH 2 -S-CH 2 . 5. Process as stated in claim 1 for the production of 1-[3-(1-methoxy-2,2-bis-(methoxycarbonyl)-ethylthio)-2-D-methylpropanoyl]-L-proline, characterized in that it is used starting materials where R 1 and R 2 are each methoxycarbonyl, R 2 is methoxy, R 2 is methyl and X is the group (CH-j ) 2 . 6. Process as stated in claim 1 for the production of 1-[3-(2-pyridyl(4)-ethylthio)-2-D-methylpropanoyl]-L-proline, characterized in that starting materials are used where R^ means pyridyl- 4, R 2 and R 3 are each hydrogen, R 3 is methyl and X is the group (CH-^-j-