DE3009684A1 - 1-MERCAPTOACYL DERIVATIVES OF KETO-SUBSTITUTED PROLIN OR KETO-SUBSTITUTED PIPERIDINE-2-CARBONIC ACID - Google Patents

Description

The invention relates to the subject matter identified in the claims.

The asterisk (*) in general formula I indicates a Center of asymmetry in the heterocyclic ring. In the case of proline, i.e. when ρ and q both have the value 1, lies this asymmetry center in the L-configuration. In the case of piperidine-2-carboxylic acid, i.e. if one of the symbols ρ or q has the value 2, the center of asymmetry is in the D, L or in the L configuration.

Centers of asymmetry can also be present in the meicaptoacyl side chain, depending on the nature of the radicals R _{1, R 1 and R-.} Accordingly, the compounds occur in stereoisomeric forms or as racemic mixtures, all of which are the subject of the invention. In the production process described below, the racemate or one of the enantiomers can be used as starting compounds. When using the racemic mixture as the starting compound, the stereoisomers obtained in the end product can be separated by customary chromatographic or fractional crystallization processes. A center of asymmetry in the mercaptoacyl side chain is preferably in the D configuration.

The term "lower alkyl" in the definition of the radicals R, R., R_ and R means branched or unbranched Hydrocarbon radicals with a maximum of 7 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl and isopentyl groups. The lower alkyl radicals preferably contain a maximum of four carbon atoms. The methyl and ethyl groups are special preferred· . . Similarly, the designations mean

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"lower Alko; _k yrest" and "lower alkylthio group" such lower alkyl groups attached to an oxygen or sulfur atom.

The term "halogen-substituted lower alkyl" refers to the lower alkyl groups described above, in which at least one hydrogen atom through one Chlorine, bromine or fluorine atom is replaced. Specific examples are the. Trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl, Chloromethyl and bromomethyl groups.

The term “protective group removable by hydrolysis” in the definition of the radical R. means a radical which can be split off by customary hydrolysis or ammonolysis. Acyl radicals of the general formula

Il

R ₅ -C-

are suitable for this purpose, where R _{5 is} a lower alkyl radical with 1 to 7 carbon atoms, one with at least

a chlorine, bromine or fluorine atom substituted lower alkyl radical, a radical of the general formula - (CH ₂ ) -cycloalkyl, in which the term "cycloalkyl" denotes saturated hydrocarbon rings with 3 to 7 carbon atoms, preferably a cyclohexyl group, an aryl radical, like the ■ · "

Remainder of the general formula

or a heterocyclic radical, such as the radicals of the general formulas

2> rr I

^x x '

or - (CH ,.)

2'r

represents. In the above general formulas, r has the value 0, 1, 2 or 3, R _g denotes a hydrogen atom, a lower alkyl radical with 1 to 4 carbon

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atoms, especially a methyl group, a lower alkoxy radical with 1 to 4 carbon atoms, in particular a methoxy group, a lower alkylthio radical with 1 to 4 carbon atoms, in particular a methylthio group, a chlorine, bromine or fluorine atom, or a trifluoromethyl or Hydroxyl group and X is an oxygen or sulfur atom. The lower alkanoyl radicals are preferred at most 4 carbon atoms, especially the acetyl group, and the benzoyl group.

The designation “chemically removable protective group” in the definition of the radical R ₄ means radicals such as the p-methoxy, p-methoxybenzylcarbonyl, trityl and tert-butoxycarbonyl groups. After the acylation has ended, these residues can be split off in various ways, for example by treatment with trifluoroacetic acid and anisole.

Preferred compounds of the general formula I are the L-proline-containing derivatives, i.e. the compounds in where ρ and q both have the value 1 and R represents a hydrogen atom.

as end products

With regard to the mercaptoacyl side chain, preference is given to the compounds of the general formula I in which R. is a hydrogen atom, m is O or 1, R_ is a hydrogen atom and R ₁ and R "are each lower alkyl radicals with 1 to 4 carbon atoms, in particular both represent a methyl group, or R »represents a hydrogen atom and R _{1 represents} a hydrogen atom, a lower alkyl radical having 1 to 4 carbon atoms, in particular a methyl group, a trifluoromethyl, methylthio or mercaptomethyl group. The abovementioned side chains in which R. denotes a lower alkanoyl radical having 1 to 4 carbon atoms, in particular an acetyl group, or a benzoyl group, are also preferred both in intermediate and in end products.

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Particularly preferred end products are the compounds of general formula I with a mercaptoacyl side chain in which R- is a hydrogen atom, m is 1, R_ and R _{1 are} hydrogen atoms and R _{2 is} a methyl group or a hydrogen atom and, if R _{2 is} a Methyl group means that the asymmetric carbon atom to which the radical R _{2 is} bonded is in the D configuration.

To prepare the compounds of general formula I, a keto-substituted proline or piperidine-2-carboxylic acid derivative is used of the general formula II

HN q

H
20th

with a carboxylic acid or its chemical equivalent of the general formula III

RR I ³ I ¹

R1-S- (CH) -C-COOH

4 m. .

2Q in the R 'is a hydrogen atom or one by hydrolysis or is a protective group which can be split off chemically, converted to a compound of the general formula IV

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ο
ι Il

^ - C

R ₃ R ₁ < ^H ₂ ^C) _P

I ³ III. < ^IV)

Rj-S- (CH) _n J- C CO-N -Cf-COOR

• ^R 2

This reaction can be carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide / or the Acid can be converted into its mixed anhydride, symmetrical anhydride, acid halide, active ester or by using the Woodward reagent K (N-ethoxycarbonyl-

J ₅ 2-ethoxy-1,2-dihydroquinoline) are activated. Such acylation processes are explained in Houben-Weyl, Methods of Organic Chemistry, Vol. 15, Part II ^ 1974), pp. 1 ff. - Preferably the acid halide, in particular the acid chloride, of the compound of the general formula III with the

2Q compound of general formula II implemented.

If the proline or the piperidine-2-carboxylic acid of the general formula II is used in the form of an ester, can the ester obtained as product can be converted into the free acid, i.e. into a compound, by conventional methods of the general formula I, in which R is a hydrogen atom. For example, if R represents an ethyl group, this ester protective group can be split off by saponification.

The obtained compound of the general formula IV is preferred separated off and purified by crystallization, for example by conversion into the Dxcyclohexylaminalz and then converting the salt to the free acid by treatment with an aqueous acid solution such as

acidic potassium sulfate. ·.

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The compounds of the general formula IV in which R _{4 represents} the acyl radical R ₅ -CO- can be converted into the compounds of the general formula I in which R ₄ denotes a hydrogen atom by customary hydrolysis or ammonolysis.

The compounds of the general formula I in which R ₁ and R ~ do not denote the radical - (CH ₂ J-SH and R _{4 denote} the radical of the general formula

O jj

R- R ₁ (HC), 3 | 1 2, ρ

-S- (CH) -— C CO N Cr COOH

I 1

ό Η

represents, can be obtained by direct oxidation of a compound of the general formula I in which R _{4 is} a hydrogen atom.

The esters of the compounds of the general formula I in which R represents a lower alkyl radical can be selected from the corresponding Carboxylic acids in which R represents a hydrogen atom, by customary esterification processes, for example by esterification with a diazoalkane, such as diazomethane, or with a 1-alkyl-3-p-tolyltriazene, such as i-n-butyl-3-p-tolyltriazene, getting produced.

The compounds of general formula I can also by customary removal of the protecting groups from a keto-substituted proline or piperidine-2-carboxylic acid derivative of general formula I are prepared, the keto function of which has a customary protective group, for example a ketal Protecting group, such as a dialkoxy ketal. For example, can from a compound of the general formula V

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HC

CH

R ₄ -S-

(H ₂ C) _p

(CH ₂ ) _q

-Cr- COOR
I *.
H

(V)

the protective group can be split off by hydrolysis, for example with aqueous hydrochloric acid at room temperature.

The compounds of the general formula V can proceed from an N-carboxybenzyloxy-keto-substituted proline or

be prepared, piperidine-2-carboxylic acid derxvate of the general formula II / which is treated with methanol in the presence of trimethyl orthoformate and concentrated sulfuric acid. The protecting group the nitrogen atom is then split off by hydrogenolysis in the presence of palladium on carbon as a catalyst, whereby the dimethoxy intermediate of the general formula VI is obtained.

H-C

CH-

(VI)

HN-

-C COOR

The intermediate of the general formula VI is then treated with a carboxylic acid or its chemical equivalent general formula III to the dimethoxy compound of the general Formula V implemented.

Further explanations on the preparation of the starting compounds and intermediates are disclosed, for example, in U.S. Patents 4,046,889, 4,105,776, 4,154,935, and 4,116,962 as well

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in Can. J. Biochem. & Physiol. 37 (1959), pp. 583-587, JACS 79 (1957), pp. 185 to 192, JACS 79 (1957), pp. 192 197, Bull. Soc. Chem., 1965 (8), pp. 2253-2259 and in The end. J. Chem. 20, pp. 1493-1509 (1967).

The processes described there can be used as general processes for preparing the compounds and separating the Isomers are used in the context of the present invention. Further details can be found in the examples below.

The compounds of the general formula I according to the invention form basic salts with a large number of inorganic and organic bases. The salt-forming ones derived from such bases Ions Can be metal ions, for example aluminum, alkali metal, such as sodium or potassium, or alkaline earth metal ions, such as calcium or magnesium ions, or Be ions of amine salts. A number of the latter are known for this purpose, for example aralkylamines, such as dibenzylamine, Ν, Ν-dibenzylethylenediamine, lower alkylamines, such as methylamine, tert-butylamine, procaine, lower alkylpiperidines, such as N-ethylpiperidine, cycloalkylamines, such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathine, or salts derived from amino acids such as arginine or lysine. The physiologically acceptable salts, like that Sodium or potassium salts, which can be used in drugs, are preferred. This and other Salze that need not necessarily be physiologically acceptable, are also suitable for isolating or purifying a product suitable for the purpose described below, as in the examples using the dicyclohexylamine salt explained. The salts are obtained by reacting an acid of the general formula I with an equivalent of the desired basic ion-supplying base in a medium in which the Salt precipitates, or prepared in an aqueous medium and subsequent lyophilization. The free acid can from the

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Salt can be obtained by conventional neutralization, for example with potassium bisulfate or hydrochloric acid.

The compounds of the general formula I in which R. denotes a hydrogen atom, the remainder of the general formula Rc-c- or the substituents of the disulfide type, in particular the compounds in which R. denotes a hydrogen atom, are valuable antihypertensive agents. She. inhibit the conversion of the decapeptide angiotensin I into angiotensin II and are therefore suitable for eliminating the hypertension caused by angiotensin. The action of the enzyme renin on angiotensinogen, a pseudoglobulin in the blood plasma, produces angiotensin I. Angiotensin I is converted into

jg angiotensin II converted. The latter connection is an active antihypertensive agent that causes various forms of hypertension in mammals such as rats and dogs, was recognized. The compounds according to the invention act by inhibiting angiotensin converting

enzymes in the conversion sequence angiotensinogen ^ (renin)

> Angiotensin I > (ACE) ^ Angiotensin II and reduce or prevent the formation of the hypertensive compound angiotensin II. By administering a drug containing one or more compounds of the general formula I, the hypertension caused by angiotensin in mammals is accordingly eliminated. A single dose, or preferably one to two to two, is suitable for reducing blood pressure. four divided daily doses based on from about 0.1 to 100, preferably from about 1 to 15 mg / kg body weight / day. The compounds are preferably administered orally, but can also be administered parenterally, such as subcutaneously, intramuscularly, intravenously or intraperitoneally.

The compounds according to the invention can also be used together with a diuretic agent for the treatment of hypertension

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A combination preparation that contains an inventive Compound and a diuretic compound can be used in a total daily dose of about 30 to 600, preferably about 30 to 300 mg of the compound according to the invention and about 15 to 300, preferably about 15 to 200 mg for a body weight of 70 kg. Examples of suitable diuretic substances, which together with the invention Compounds that can be used are the thiazide diuretics, such as chlorothiazide, hydrochlorothiazide, Flumethiazide, hydroglumethiazide, benzdroflumethiazide, Methchlothiazide, trichloromethiazide, polythiazide and benzothiazide, as well as ethacrynic acid, ticrynafen, chlorothaiidone, Furodemide, Musolimin, Bumetanid, Triamteren, Amilorid and Spironolactone and its salts.

For use in the treatment of hypertension, the compounds according to the invention can be given in tablets, capsules or Elixirs for oral administration or formulated into sterile solutions or suspensions for parenteral administration.

About 10 to 500 mg of one or a mixture of compounds of the general formula I with customary carrier, Processed auxiliaries and / or additives. The amount of the active ingredient in these formulations is dimensioned such that they are a suitable dosage in the range given above represents.

The examples illustrate the invention.

example 1
1 ~ [3- (Acetylthio) -1 -oxopropyl] -4-

a) N-carbobenzyloxy-4-hydroxy-L-proline

26.5 g (0.02 mol) 4-hydroxy-L-proline and 32.8 ml (0.23 mol) Benzyl chloroformate is dissolved in 200 ml of water and 100 ml of acetone in the presence of 20 g (0.02 mol) of potassium bicarbonate and 69.2 g (0.50 mol) of potassium carbonate reacted and

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^Γ ·. - ie - - "'·. 3Ü09684

according to Can. J. Biochem. & Physiol. 37 (1959), p. 584 worked up with 90 ml of concentrated hydrochloric acid. The N-carbobenzyloxy-4-hydroxy-L-proline is obtained, which is reacted with cyclohexylamine. Yield: 69 g of the cyclohexylamine salt with a melting point of 193 to 195.degree. Then 34 g of the salt are neutralized with 1 η hydrochloric acid. 27 g of free acid are obtained as a colorless, glass-like solid [ct] p ⁶ : -70 ° (c, 1% in chloroform).

b) N-carbobenzyloxy-4-keto-L-proline

21.5 g (0.81 moles) of N-carbobenzyloxy-4-hydroxy-L-proline will be used according to J.A.C.S. 79 (1957), p. 189 in 1.2 liters of acetone with 83 ml of 8 η chromic acid oxidized in sulfuric acid. To make things easier the subsequent filtration of the chromium salts, the acetone solution before the addition of the oxidizing agent 30 g Celite (diatomaceous earth) added. An air stirrer is used. Then the reaction mixture filtered, the acetone solution obtained as a filtrate concentrated to a volume of about 300 ml and then with 1 liter Diluted chloroform. The solution is then washed four times with 300 ml of saturated sodium chloride solution, over magnesium sulfate dried, filtered and evaporated. There are 22.8 g of N-carbobenzyloxy-4-keto-L-proline obtained from a mixture of 50 ml of diethyl ether and 150 ml of hexane

be crystallized. Yield:. 17.2 g (81%) of the title compound, melting at 99 to 101 of ⁰ C, ta] ^ ^6: + 17 ° (c, 1% in chloroform).

c) 4-keto-L-proline hydrobromide

4.0 g (0.015 moles) of N-carbobenzyloxy-4-keto-L-proline mixed with 20 ml of a 30 to 32 percent solution of hydrogen bromide in acetic acid. The mixture obtained is im Frequently shaken over the course of 8 minutes. After this time, the foaming has stopped and the yellow-orange Solution is covered with 250 ml of diethyl ether and that

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^Γ - ι? - "3U09684 ¹

gummy product is digested. Then the diethyl ether discarded and the sticky solid obtained with fresh diethyl ether and finally with 50 ml of acetonitrile digested. The 4-keto ~ L-proline hydrobromide is called

crystalline solid obtained. Yield: 2.7 g (85%), melting point 153 to 155 ° C (decomp.) [Α] £ ⁶ : -49 ° (c, 1% in water).

d) 1- [3- (Acetylthio) -1-oxopropyl] -4-oxo-L-proline

A solution of 4.1 g (0.0195 mol) of 4-keto-L-proline hydrobromide in 50 ml of water is cooled to 5 ° C. with stirring and treated batchwise with solid sodium carbonate up to pH 8.0 , with the foaming is controlled by adding a few drops of diethyl ether. About 2 g of sodium carbonate are required. The mixture is then mixed, with constant stirring and cooling, with the aid of a pipette in batches with a solution of 3.5 g (0.012 mol) of 3-acetylthiopropionyl chloride in 5 ml of ethyl acetate, the pH value being reduced by the dropwise addition of about 10 ml of a 25 percent ( W / V) sodium carbonate solution is kept at 7.0 to 8.0. After about 10 minutes the pH stabilizes at 8.0 to 8.4. The reaction mixture is stirred and cooled for a total of 1 hour, then washed twice with 50 ml of ethyl acetate, then covered with 50 ml of ethyl acetate and carefully acidified to pH 2.0 with concentrated hydrochloric acid while stirring and cooling. The solution is then saturated with common salt and the layers are separated. The aqueous phase is extracted three times with 50 ml of ethyl acetate. The organic layers are then combined, dried over magnesium sulphate and evaporated, finally at a pressure of 0.2 mm. 4.8 g of a yellow-orange glass-like residue are obtained, which are dissolved in 35 ml of ethyl acetate and treated with a solution of 3.5 g of dicyclohexylamine in 5 ml of ethyl acetate. After adding seed crystals and rubbing, crystalline dicyclohexylamine salt separates from

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1- [3- (Acetylthio-1-oxopropyl)] - 4-oxo-L-proline. After about 15 hours of cooling, the yield is 2.7 g of almost colorless crystals of F. 1!
(c, 1% in chloroform).

loose crystals with a temperature of 191 to 193 ° C (decomp.), [a] J * ⁶ : -24 °

To convert the dicyclohexylamine salt into the free acid, it is suspended in ethyl acetate and treated with 45 ml of 10 percent potassium bisulfate solution with stirring until two layers are obtained. After separation, the aqueous phase is extracted with 4-75 ml of ethyl acetate. The organic layers obtained are combined, dried over magnesium sulfate and evaporated. Yield: 3.7 g of a light yellow glass-like solid. Analysis for C ₁₀ H ₁₃ NO ₅ S: CH NS

calc .: 46.32, 5.05, 5.40, 12.37.

Found: 47.05, 5.50 5.18, 12.07

Example -2
1- (3-mercapto-i-oxopropyl) -4-oxo-L-proline

xid With a cold solution of 9 ml of concentrated ammonium hydro- / a stream of argon is passed in 22 ml of water for 30 minutes. 3.65 g (0.014 mol) of 1- [3- (acetylthio) -I-oxopropyl] -4-oxo-L-proline are then added with this solution, while cooling and under an argon shower offset. It takes about 30 minutes to dissolve the proline, with the help of a Magnetic stirrer is started. The mixture obtained is then for a further 2 hours at room temperature under argon as Protective gas stirred. The solution is then extracted with 30 ml of ethyl acetate. This and the following procedural steps are carried out as much as possible under argon as a protective gas. The aqueous layer is cooled and covered with 30 ml of ethyl acetate while stirring and acidified batchwise with 1: 1 hydrochloric acid. Which he-

^ ⁵ held solution is then mixed with common salt, the layers are separated and the aqueous phase three times with 30 ml

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Ethyl acetate extracted. An insoluble brown gummy fraction remains in both phases. After drying The combined ethyl acetate layers are poured over magnesium sulfate evaporated. A largely solid residue is obtained, which on digestion with diethyl ether becomes an amorphous solid. After repeated evaporation, 1.4 g of pale yellow product are obtained.

1.3 g of this product are introduced into 50 ml of diethyl ether and rubbed. The mixture is cooled for 1 hour under argon as a protective gas, then filtered off, washed with diethyl ether and dried under reduced pressure. Yield: 1.0 g of 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline, R _f : 0.67 (methanol on silica gel, made visible in iodine vapor). Analysis for CgH ₁₁ NO ₄ S ₁ CSH ₂ O: CHN S

calc .: 42.46, 5.35, 6.19, 13.71 Found: 42.66, 5.39, 6-, 3O, 13.30.

Example3
(S) -1 - [(3-Acetylthio) -2-methyl-1-oxopropy 17-4-OXO-L-PrOlJn

Example 1 is repeated with the change that instead of D-3-Acetylthio-2-Raethylpropionylchlorid the 3-Acetylthiopropionylchlorid. Used will. The title compound is obtained.

Example 4
(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline

The compound obtained in Example 3 is treated according to Example 2 with ammonium hydroxide. It becomes the title compound obtain.

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Example 5 1 - [(3-Acetylthio) -2-trifluoromethyl-1-oxopropyl] -4-oxo-L-proline

a) D _f L-3- (Acetylthio) -2-trifluoromethyl! propionic acid 5

10 g (0/071 mol) of a-trifluoromethyl acrylic acid (prepared according to J. Chem. Soc, 1954, p. 371) are cooled in a salt-ice-water bath and, with stirring, batchwise with 5.7 ml (0.075 mole) 97 percent thiolacetic acid. After the addition is complete, the yellow liquid becomes 1 hour stirred in the cold, then warmed to room temperature and distilled. Yield: 14 g (91% of the title compound as light yellow oil with a boiling point of 149 to 153 ° C / 13 mm. The product solidifies when standing in the cold.

b) D, L-3- (acetylthio) -2-trifluoromethyl propionyl chloride

7 grams (0.032 moles) of D, L-3- (acetylthio) -2-trifluoromethylpropionic acid are treated with 18 ml (0.25 mol) of double-distilled thionyl chloride. Then the resulting mixture Boiled under reflux for 3 hours. After removing excess thionyl chloride on a rotary evaporator the residue is distilled. Yield: 6.8 g of the title compound as a pale yellow oil with a boiling point of 80 to 82 ° C./16 mm.

C-) 1- [(3-acetylthio) -2-trifluoromethyl-1-oxopropyl] -4-oxo-L-proline

The D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride will according to Example 1 d) reacted with 4-keto-L-proline hydrobromide. The title compound is obtained in the form of a mixture of diastereomers, which is then separated in the customary manner can be.

130039/0351

■ ■ - ²¹ - "'■'""""3Ü09684

E e i s ρ ie 1 6

1 - (3-mercapto-2-tri £ luoromethyl-1-oxopropyl) -4-oxo-L-proline

The product obtained in Example 5 is in the form of the mixture of diastereomers or hydrolyzed the separated isomers according to Example 2 with concentrated ammonia. It becomes the title compound obtain.

Example 7

(S) -1- p-Mercapto - ^ - mercaptomethyl-i-oxopropyl) -4-oxo-L-proline

a) (S) -1- [3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl] -4-oxo-L-proline

Example 1 is repeated with the change that D-3-acetylthiomethyl-3-acetylthiopropionyl chloride is used instead of 3-acetylthiopropionyl chloride in stage d). It will be the Title compound obtained.

b) (S) -1- (3-mercapto-2-mercaptomethyl-1-oxo-propyl) -4-oxo-L-proline

The compound obtained according to a) is hydrolyzed according to Example 2 with concentrated ammonia. It becomes the title compound obtain.

Example 8

1-P-Mercapto - ^ - methylthio-i-oxopropyl) -4-oxo-L-proline a) 3- (Acetylthio) -2- (methylthio) -propionic acid 30

12.5 g (0.094 mol) of 2- (methylthio) acrylic acid methyl ester (made from methyl 2-chloroacrylate according to Gundesmann and Mitarb., Chemischeberichte 94 (1916), p. 3254) are stirred with 94 ml of 1N sodium hydroxide solution while cooling with ice. The mixture is then warmed to room temperature and stirred for a further 5 hours. The resulting solution is then

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^Γ · - 22 - - .. '. '■. ; 3Ü09684 ¹

washed with diethyl ether and then acidified to pH 2 with concentrated hydrochloric acid. The solid precipitation is then extracted into methylene chloride. The solution is washed with saturated saline, and the solvent is evaporated. The 2- (methylthio) acrylic acid obtained as a solid residue with a melting point of 70 to 75 ° C is immediately used for the following implementation is used.

Equimolar amounts of 2- (methylthio) acrylic acid and thiolacetic acid are mixed under argon as a protective gas and stirred at 80 ° C for several hours. The title compound is obtained.

b) 3- (Acetylthio) -2- (methylthio) propionyl chloride 15

The 3- (acetylthio) -2- (methylthio) propionic acid obtained according to (a) is in thionyl chloride for 2 hours Refluxed. Thereafter, the conversion mixture is used for ■ distilled removal of excess thionyl chloride. The residue obtained is distilled under reduced pressure. The title compound is obtained.

c) 1- [3- (Acetylthio) -2-methylthio-1-oxopropyl] -4-oxo-L-proline

The 3- (acetylthio) -2- (methylthio) propionic acid chloride obtained under b) above is treated with 4-keto-L-proline hydrobromide implemented according to Example 1 d). The ■ title compound is obtained.

d) 1- (3-Mercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline

The compound obtained above under c) is hydrolyzed according to Example 2 with concentrated ammonia. The title compound is obtained.
35

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- 23 - ■■ """■■·"'3Ü09684 ¹

Example 9

1 - (4-mercapto-1-oxobutyl)> - 4-oxo-1-proline

^a ) 1- [4- (Acetylthi.o) -1-oxobutyl] -4-oxo-L-proline

Example 1 is repeated with the change that 4-acetylthiobutyroyl chloride is used instead of 3-acetylthiopropionyl chloride in part d). It becomes the title compound obtain.

b) 1- (4-mercapto-1-oxobutyl) -4-oxo-L-proline

The compound obtained above under a) is hydrolyzed according to Example 2 with concentrated ammonia. The title compound is obtained.
15th

Example 10

1- (2-Mercapto-1-oxoethyl) -4-OXO-L-PrOLIN a) 1- [2- (Acetylthio) -1-oxoethyl] -4-OXO-L-PrOLIN

Example 1 is repeated with the change / that acetylthioacetyl chloride instead of S-acetylthiopropionyl chloride in Part d) is used. The title compound is obtained.

b) 1- (2 ~ mercapto-1-oxoethyl) -4-oxo-L-proline

The compound obtained above according to a) is concentrated with Ammonia hydrolyzed according to Example 2. It will

obtained the title compound.
30th

Example 11

1- (3-Mercapto-2 _/ 2-dimethyl-1-oxopropyl) -4-oxo-L-proline a) 1- [3- (Acetylthio) -2,2-dimethyl-1-oxopropyl] -4-oxo -L-proline

Example 1 is repeated with the change that 3-acetylthio-2,2-dimethylpropionyl chloride instead of 3-acetylthiopropio-

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^Γ - 24 - ■■ "■ · 3Ü09684 ¹

nyl chloride is used in part d). The title connection will be retained.

b) 1- (3-Mercapto-2 _/ 2-dimethyl-1-oxopropyl) -4-oxo-L-proline 5

The compound obtained above under a) is hydrolyzed according to Example 2 with concentrated ammonia. It will obtained the title compound.

Example 12 (S) -1- (3-Mercapto-2-ethyl-1-oxopropyl) -4-OXO-L-PrOlJn a) (S) -1- [3- (Acetylthio) -2-ethyl-i- oxopropyl] -4-

Example 1 is repeated with the change that D-3-acetylthio-2-ethylpropionyl chloride instead of 3-acetylthio-

propionyl chloride is used in part d). The title compound is obtained.

b) (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-L-proline 20

The compound obtained above according to (a) is hydrolyzed according to Example 2 with concentrated ammonia. It will be the Title compound obtained. ■

Example13

1- (3-Mercapto-1-oxopropyl) -4-oxo-L-piperidine-2-carboxylic acid a) 1- [3- (Acetylthio) -1-oxopropyl] ^ -oxo-L-piperidine ^ -carboxylic acid

Example 1 is repeated with the change that 4-keto-L-piperidine-2-carboxylic acid is used instead of 4-keto-L-proline in part d). The title compound is obtained.

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k) iO-Mercapto-io.xopropyD ^ -oxo-L-piperidine - ^ - carboxylic acid

The compound obtained above according to a) is concentrated with Hydrolyzed ammonia. The title compound is obtained.

Example 14

(S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -5-oxo-L-piperidine- 2-carboxylic acid

^a ) (S) -1- [3- (Acetylthio) - ^ - methyl-i-oxopropyl] -5-oxo-L-piperidine-2-carboxylic acid

Example 1 is repeated with the change that 5-keto-L-piperidine-2-carboxylic acid instead of 4-keto-L-proline and D-3 ~ acetylthio-2-methylpropionyl chloride instead of acetylthiopropionyl chloride in part d). The title compound is obtained.

^b ' (S) -T- (3-mercapto-2-methyl-1-oxopropyl) -5-keto-L-piperidine-2-carboxylic acid or the like

The compound obtained above according to a) is hydrolyzed according to Example 2 with concentrated ammonia. It will be the Title compound obtained.

Example 15

1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L ^ proline a) 3- -f [(4-methoxy) -pheny-methyl] -thioJ-2-trifluoromethylpropionyl chloride

A neat mixture of 9.3 g of 1-trifluoromethylacrylic acid and 4.3 g of 4-methoxybenzylthiol is stirred for 1 hour at a temperature of 100 to 11O ⁰ C. The mixture is then cooled to room temperature and the solid precipitate obtained is recrystallized from cyclohexane. It becomes the 3 - {[(4-methoxy) -

13-039 / 03-1

"..":. ^: Λ -> ⁶ - ^;; '"'" ■ '· ■ ■ ' 3Ü0968A ¹

\ pheny! methyl] -thioj-2-trifluoromethylpropionic acid from 72

Maintained up to 74 ° C.

Treatment of this acid with thionyl chloride gives the title compound.

b) 1- [3- £ [ (4-methoxy) pheny! methyl3-thio $ -2-trifluoromethyl-1-oxopropyl] -4-oxo-L-proline

The propionyl chloride obtained above according to a) is with 4-keto-L-proline converted to the title compound.

c) 1- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline

The product obtained above according to b) is trifluoroacetic acid and anisole mixed under nitrogen as a protective gas. The solvents are then reduced under reduced pressure Distilled pressure. The title compound is obtained as a residue.

Example 16

(S) -1-p-Mercapto-S-methyl-i-oxopropyl) -4-oxo-L-proline a) (S) -1- [3- (Acetylthio) -3-methyl-1-oxopropyl] - 4-oxo-L-proline

Example 1 is repeated with the change, D-3-acetylthio-3-methylpropionyl chloride is used instead of 3-acetylthiopropionyl chloride in part d). It becomes the title compound obtain.

b) (S) -1- (3 ~ mercapto-3-methyl-1-oxopropyl) -4-oxo-L-proline ,

The product obtained in accordance with a) above is hydrolyzed with concentrated ammonia. The title compound is obtained.
35

^L 130039 / 03S1

Examples 17 to 25

Example 1 is repeated with the change that instead of 3-Acetylthiopropionylchlorld one of the following Column I listed acid chlorides is used. The compounds listed in column II below are used obtain.

Column I.

3-benzoylthiopropionyl chloride

Column II

1- [3- (Benzoylthio) -1-oxopropyl] 4-oxo-L-proline

D-3-Benzoylthio-2-raethylpropionyl chloride (S) -1- [3- (Benzoylthio) -2-methyl-1xoxo-propyl] -4-oxo-L-proline

D-3 - {[(2-thienyl) carbonyl] -thiq} -2-methylpropionyl chloride

(S) -1 - [3-jfT (2-ihienyl) carbonyl7-thio? -2-methyl-1-oxopropyl] -4-oxo-L-proline

3 -. [[(2,2,2-Trichloroethyl) carbonyl] thioj-propionyl chloride

1- [3- { [(2,2,2-trichloroethyl) carbonyl] thioj-1-oxopropyl] -4-oxo-L-proline

D-3 - ^ [(2-furyl) carbonyl] thioj -2-methylpropionyl chloride

(S) -1- [3 - {[ (2-FuryI) carbonyl] thio} -2-methyl-1-oxopropyl] -4-oxo-L-proline

3 - <"[(4-pyridyl) carbonyl] thioj propionyl chloride 1-13-f [(4-pyridyl) carbonyl] thiof-1-oxopropyl] -4-oxo-L-proline

D-3 - {[ (4-Methy! Phenyl) - (S) -1- [3- [[ (4-Methylphenyl) -carcarbonyl] -thio} · -2-methylpro- bonyl] -thio} -2- methyl-1-oxopropionyl chloride pyl] -4-oxo-L-proline

2 - {[ (Pheny! Methyl) carbonyl] thioj-acetyl chloride 1-12- {[ (Phenyl methyl) carbonyl] thio} -1-oxoethyl] -4-oxo-L-proline

4 - ft (cyclohexyl) carbonyl] thio} • butyroy! Chlorine id 1 - Γ4 - il (cyclohexyl) carbonyl] - thioj-1-oxobutyl] -4-oxo-L-proline

130039 / 03S1

^Γ . . - 28 - 300968V

Example- 26

1-adamantanamine salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline

g The compound according to Example 4 can also be used according to the following Process are produced:

a) N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester

A solution of 7.8 g (0.03 mol) of N-carbobenzyloxy-4-keto-L-proline according to Example 1 in 60 ml of methanol is stirred with 96 ml of trimethyl orthoformate and then treated with 0.6 ml of concentrated sulfuric acid and then left to stand at room temperature for about 15 hours. On that the pale yellow solution is treated with stirring with 1.5 g of potassium carbonate and then with 30 ml of water. Then the majority of the solvent is removed on a rotary evaporator. The syrupy residue obtained is 30 ml Water and 30 ml of chloroform shaken. After separating the layers, the aqueous phase is washed three times with 30 ml of chloroform extracted, the combined organic layers are washed with 45 ml of saturated sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent 8.4 g (88%) of the title compound are obtained.

b) N-carbobenzyloxy-4,4-dimethoxy-L-proline

8.4 g (0.026 mol) of the ester obtained above according to a) are dissolved in 80 ml of methanol and treated dropwise at a temperature of -1 to + 4 ° C. with 18 ml (0.036 mol) of 2 η sodium hydroxide solution. The solution is then left to stand for 1 hour at ⁰ ° C. and then for about 15 hours at room temperature. After about half of the solvent has been removed on a rotary evaporator, the solution is diluted with 150 ml of water and washed with 100 ml of diethyl ether (washing liquid

^L 130039/0351 ^J.

is discarded), acidified to pH 2 with 63 ml of 1: 1 hydrochloric acid while cooling and extracted four times with 750 ml of ethyl acetate. The combined extracts are washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated. 8.0 g of a pale yellow, viscous oil are obtained, which is dissolved in 35 ml of ethanol, treated with 3.0 g of cyclohexylamine in 10 ml of ethanol and diluted with diethyl ether to a volume of 500 ml. After adding seed crystals and rubbing, the crystalline cyclohexylamine salt of N-carbobenzyloxy-4,4-dimethoxy-L-proline separates. After about 15 hours cooling, 7.0 g of the compound from P. 157-159 ° C (sintering at 151 ⁰ C) was obtained; [a] _Q : -34 ° (c, 1% in ethanol). This product is recrystallized from 100 ml of acetonitrile. The salt is obtained as a colorless solid with a melting point of 158 ° to 160 ° C. (sintering at 154 ° C.); [a] p ⁶ - 33 ° (c, 1% in ethanol).

The cyclohexylamine salt of N-carbobenzyloxy-4,4, -dimethoxy-L-proline is suspended in 40 ml of ethyl acetate and treated with 25 ml of 1 η hydrochloric acid while stirring. It will get two clear layers that are separated. The aqueous phase is extracted three times with 40 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and evaporated, finally with one Pressure of 0.2 mm and a temperature of 40 ° C. Yield:

7.2 g (70%) of the title compound as a pale yellow viscous syrup.

c) 4,4-dimethoxy-L-proline

A solution of 72 g (0.022 moles) of N-carbobenzyloxy-4,4-dimethoxy-L-proline in 210 ml of a mixture of methanol and water in a ratio of 2: 1, 2.3 g of 5 percent Treated palladium on carbon and shaken on a Parr hydrogenator for 6 hours. After that, the The catalyst is filtered off under nitrogen as a protective gas, washed with methanol, and the combined filtrates are

^L 130039/0351

steamed, last at a pressure of 0.1 to 0.2 mm. A partially crystalline residue is obtained, which is taken up in 200 ml of methanol and evaporated again. When the solid obtained is rubbed under dietary ether (the evaporation is repeated again), 3.6 g (95%) of the title compound with a melting point of 192 ° to 194 ° C. (decomposition) are obtained as a virtually colorless solid; [a] ^ ⁶ - 47 ° (c, 1% in methanol).

A sample recrystallized from a mixture of methanol and diethyl ether is colorless and melts at 197 ° to 198 ° C. (decomp.); [a] ^ ⁶ : -49 ° (c, 1% in methanol).

d) (S) -T- [3- (acetylthio) -2-methyl-i-oxopropyl] -4,4-dimethoxy-L-proline

A solution of 3.3 g (0.019 mol) of 4,4-dimethoxy-L-proline in 50 ml of water is cooled to 5 ° C. and, by adding, of 25 percent sodium carbonate solution (w / v) adjusted to pH 8.5. Then, with constant stirring, and Cool a solution of 3.3 g (0.021 mol) D-3-acetylthio-2-methylpropar.oyl chloride in 5 ml of diethyl ether added intermittently, the pH value by dropwise addition of 25 percent Sodium carbonate solution is maintained at 7.5 to 8.5.

After the pH stabilizes at 8.2 to 8.4 (after about 15 minutes), the mixture is left to stand for a total of Stirred and cooled for 1 hour. The solution is then washed with 50 ml of ethyl acetate (washing liquid is discarded), covered with 50 ml of ethyl acetate, and carefully with 1: 1 hydrochloric acid while cooling and stirring acidified to pH 2.0. The mixture is then saturated with sodium chloride and the resulting / layers become separated. The aqueous phase is extracted three times with 50 ml of ethyl acetate, the combined organic phases are dried over magnesium sulfate and evaporated, to-; last at a pressure of 0.2 mm. There are 6.7 g of a syrupy Product obtained in 70 ml of ethyl acetate

L ^ V ■ "J

/ I 130039/0351

is treated with 3.9 g of dicyclohexylamine. Yield: 6.5 g of the dicyclohexylamine salt of (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-L-proline as a colorless solid in two batches (3.1 or 3.4 g) from a melting point of 158 to 160 ° C. (sintering at 145 ° C.); ία] ^ ⁶ : -71 ° (c, 1% in ethanol).

After recrystallization from 20 ml of a mixture of hot ethyl acetate and 60 ml of hexane 6.0 g of a colorless solid salt C obtained from F. 158-166 ° (sintering at 155 ⁰ C)); [a] ^ ⁵ : -69 ° (c, 1% in ethanol).

To convert it into the free acid, 5.0 g of the dicyclohexylamine salt are suspended in 50 ml of ethyl acetate and treated with 60 ml of a 10 percent potassium bisulfate solution while cooling. Two clear layers are obtained which are separated, the never aqueous phase is extracted three times with 50 ml of ethyl acetate. The organic layers are combined, dried over magnesium sulphate and evaporated, finally at a pressure of 0.1 to 0.2 mm and a temperature of 45 ° C. Yield: 4.1 g (69%) of the title compound as a tough, almost glassy product; [a] ^ ⁵ - 112 ° (c, 1% in ethanol).

e) (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline

By a cold solution of 8.5 ml of concentrated ammonium hydroxide argon is passed into 20 ml of water for 0.25 hours. This solution is then cooled and under an argon shower to 4.1 g (0.013 mol) of (S) -1- [3- (acecylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-L-prolln added. The resulting mixture is agitated in an ice bath until a pale yellow solution

T - 1, - · .- ,,, _ «r-. ■ . ",. ^{,, / 3} ^ will keep room temperature (about 15 minutes). The solution is then stirred for a further 2 hours under argon as a protective gas and then extracted with 30 ml of ethyl acetate. This and the following process steps are carried out under argon as far as possible

^L 13Ö039 / 03S1 ^J

alp protective gas carried out. The aqueous layer is cools and covered with a layer of 30 ml of ethyl acetate while stirring and then acidified intermittently with about 16 ml of 1: 1 hydrochloric acid. Then the layers are separated that aqueous phase is extracted three times with 30 ml of ethyl acetate, the ethyl acetate layers are combined, dried over magnesium sulfate and evaporated. Yield: 3.5 g (100%) of the title compound as a colorless one

'2

chewy syrupy substance; [a] _n - 72 ° (c, 1% in ethanol).

3.4 g of the compound obtained are treated with 20 ml of ethyl acetate, rubbed and diluted with 30 ml of hexane. On cooling, 2.6 g of a colorless solid with a melting point of 108 ° to 110 ° C. are obtained; [a] ^ ⁵ - 77 ° (c, 1% in ethanol). 15th

f) 1-Adamantanamine salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline

8 ml of 1 η hydrochloric acid, through which argon for 10 minutes was passed, while stirring with 0.4 g (0.0014 mol) of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline offset. After a solution has been obtained, the vessel is sealed under argon and at room temperature for about 15 hours ditched. The following stages are also carried out under argon as a protective gas as far as possible. The solution is mixed with 20 ml of methylene chloride with stirring, saturated with sodium chloride and the layers obtained are separated. The aqueous phase is then extracted three times with 15 ml of methylene chloride and the organic layers are combined, dried over magnesium sulfate and evaporated. A foam-like residue is obtained which is digested with diethyl ether. After renewed evaporation, 0.26 g of (S) -1- (3-mercapto-2-methy1-1-oxopropyl) -4-oxo-L-proline are obtained obtained in the form of an amorphous hygroscopic solid.

130039/0351 ^J.

^Γ - ³ * ^: - ''' ■ "300968Α ¹

0.245 g of the compound obtained above are dissolved in 7 ml of acetonitrile and reacted with 0.17 g of 1-adamantanamine. The salt precipitates out as a voluminous solid. After about 15 hours of cooling, the colorless precipitate is filtered off, washed with cold acetonitrile and diethyl ether and dried under reduced pressure. Yield: 0.36 g the title compound (1: 1 salt) with a melting point of 188 to 190 ° C (dec.);

Sintering at 1 84 O 3 ^N0 ta] 25th
D ^: - 13 ° (c, 1 % in Me thar analysis for C. 9 ^H. 1 C. 4 ^pp . C. 10 ^H 17 ^N . O, 25th H ₂ O: 58 H N S. ber. •
• 58 96, 8.02, 7th , 24 8th , 29 found •
• 60, 8.37, 7th , 16 8th , 29.

Example 27 1,1 '- [Dithiobis-d-oxo-Syl-propanediyl)] -bis- [4-oxo-L-proline 3

The compound obtained according to Example 2 is dissolved in water and the solution obtained is η by adding 1 Sodium hydroxide solution adjusted to pH 6.5. The solution is then mixed dropwise with 0.5 molar iodine solution while stirring in 95 percent ethanol (6.34 g of iodine in 50 ml of solution) added, the pH value with 1 η sodium hydroxide solution to 5.5 to 6.5 is held. Excess iodine is then removed with dilute sodium thiosulfate solution. Then the Concentrated solution and acidified with 1: 1 hydrochloric acid while cooling. Then a solvent is added and the er. holding layers are separated. The organic layer is dried over magnesium sulphate and evaporated. as The title compound is obtained residue.

Example 28 1- [3- (Acetylthio) -1-oxopropyl] -4-oxo-L-proline methyl ester

A solution of the compound obtained in Example 1 in Diethyl ether is treated with a slight excess of diazomethane and then for 2 hours at room temperature

^L 130039/0361

ditched. The solvent is then evaporated. The title compound is obtained.

Example 29 1- (3-Mercapto-1-oxopropyl) -4-oxo-L-proline methyl ester

The compound obtained according to Example 28 is hydrolyzed according to Example 2 with concentrated ammonia. The title compound is obtained.
10

Example 30 Sodium Salt of 1- (3-Mercapto-1-oxopropyl) -4-

A solution of 1.0 g of the compound obtained according to Example 2 is dissolved in 10 ml of water and treated with 1 equivalent of sodium bicarbonate. The solution is then freeze-dried. The title compound is obtained. Similarly, if potassium bicarbonate is used, the corresponding potassium salt is obtained.
20th

Example '31

Sodium salt of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline

A solution of 1.0 g of the compound obtained according to Example 4 is dissolved in 10 ml of water and treated with 1 equivalent of sodium bicarbonate. Freeze-drying makes the Title compound obtained. Similarly, when using potassium bicarbonate, the corresponding potassium salt becomes obtain.

Example 32

1000 tablets of the following composition: 35

^L 130039 / 03S1

1 1- (3-mercapto-1-oxopropyl) -

4-oxo-L-proline 100 mg

Corn starch 50 mg

Gelatin 7.5 mg

Microcrystalline Cellulose ⁵ (Avicel) Magnesium Stearate

are prepared by mixing 1- (3-mercapto-1-oxopropyl) -A- oxo-L-proline and corn starch with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. The microcrystalline cellulose and the magnesium stearate are then mixed with the granules. The mixture obtained is then in

a tablet press of 1000 tablets with an active ingredient content of 100 mg each pressed.

Example -33

According to example 32 tablets with a content of each

because 100 mg (S) -1- (S-Mercapto ^ -methyl-i-oxopropyl) -4-oxo-L-proline manufactured.

Example 34

1000 tablets containing 50 mg of 1- (3-Me.rcapto-1-oxopropyl) -4-oxo-L-proline are made from the following components:.

1- (3-mercapto-T-oxopropyl) -

4-oxo-L-proline 50 G Lactose 100 G microcrystalline cellulose 150 G Cornstarch 50 G "Magnesium stearate 5 G

The i-O-mercapto-i-oxo-propyl) -4-oxo-L-proline is with the Lactose and the microcrystalline cellulose and then with

^L 130039/0351

the cornstarch mixed together. Then the magnesium stearate admitted. The dry mixture is in a tablet press to 1000 tablets with a mass of 355 mg and a content of 50 mg of the active ingredient in each case. The tablets are made with a methyl cellulose solution (Methocel E 15), which has a pigment containing yellow no. 6 as the dye.

Example 35 10

According to example 34 tablets with a content of 50 mg (S) -I- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline are made manufactured.

Example 36

Two pieces of No. 1 gelatin capsules are made with a mixture filled with the following components:

Na salt of 1- (3-mercapto-i-oxo-.

propyl) -4-oxo-L-proline 100 mg

Magnesium stearate 7 mg

Lactose 139 mg

Example 37

'According to example 36 will be. Gelatin capsules containing 100 mg Na salt of (S) -1- (3-mercapto-2-methyl-T-oxopropyl) -4-oxo-L-proline manufactured.

Example 38 30

An injectable solution is prepared with the following composition:

. ' 1- (3-mercapto-1-oxopropyl) -4-

oxo-L-proline 500 g

Methyl paraben 5 g

Propyl paraben 1g

Sodium chloride 25 g

Water for injection qs. 5 1

^L 130039/0351 ^J.

The active ingredient, the preservative and the sodium chloride are dissolved in 3 liters of water and then on a Brought volume of 5 liters. The solution is then filtered through a sterile filter and aseptically in advance sterilized ampoules are filled, which are then closed with previously sterilized rubber stoppers. Each ampoule contains 5 ml solution at a concentration of 100 mg active ingredient per ml of the injection solution.

10 Example 39

According to Example 38, an injection solution containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline is prepared.
15th

Example 40

6000 tablets from the following ingredients:

1- (3-mercapto-1-oxopropyl) - ₂₀ 4-oxo-L-proline

microcrystalline cellulose hydrochlorothiazide lactose USP corn starch O.SP 2 ₅ stearic acid O.SP

350 mg

are made from sufficient quantities by slurrying 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline, the micro-

₃ q crystalline cellulose and part of the stearic acid produced. The mixture obtained is ground, passed through a No. 2 sieve and then mixed with the hydrochlorothiazide, lactose, corn starch and the remaining stearic acid. The mixture is then compressed in a tablet press to give capsule-shaped tablets with a mass of 350 mg. The tablets are grooved so that they can be cut in half.

^L 130039/0351

100 5 mg 100 mg 12, 5 mg 113 mg 17, mg 7th mg

1 example 41

According to Example 40 tablets containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline and 5 Hydrochlorothiazide produced.

130039 / Q3S1 ^J.

Claims (22)

u.z .: P 566 (Ra / kä) 13. MSfZ 1980 Case: M-112, OO3-S E.R. SQUIBB & SONS, INC. Princeton, New Jersey, V.St.A. 10 "1-mercaptoacyl derivatives of keto-substituted proline or keto-substituted piperidine-2-carboxylic acid" claims 1. 1-Mercapto acy Ideriva te of keto-substituted proline or keto-substituted piperidine-2-carboxylic acid of the general formula I. * 3 | * 1 ° ^(H 2 ^ p ^ Vq (D R ..- S- (CH ^ C C-N C-COOR ^m ι '* »2
' in which R denotes a hydrogen atom or a lower alkyl radical, R ^ and R ₃ independently represent hydrogen atoms, lower alkyl or lower alkylthio radicals, or radicals of the general formula - (CH ₂ J _n -SH ₇ or halogen-substituted lower alkyl radicals represent R ₃ Hydrogen atom or one ^L 130039/0361 - ^J. means lower alkyl group, with the proviso that R ~ only denotes a lower alkyl group when R. "also represents a lower alkyl group, m is 0, 1 or 2 and η is 1, 2 or 3, ρ and q each have the value 1 or 2, with the proviso that not both have the value 2 at the same time and R. is a hydrogen atom, a protective group which can be split off by hydrolysis or by chemical means, or if neither R ₁ nor '. R_ represent a radical of the general formula - (CH ₀ ) -SH, j Ct Il '■ a sulfide radical of the general formula 0
P. J ³ I ¹ Il ² I ^P I ^{2 q} -S- (CH) - C - C N: C-COOR ^m ι ■ ■ ι * ' R H means and their salts with bases. 2. Compounds according to claim 1 of the general formula I, where ρ is 2 and q is 1. 3. Compounds according to claim 1 of the general formula I, where ρ is 1 and q is 2. 4. Compounds according to claim 1 of the general formula I, in which ρ and q are 1. 30th 5. Compounds na.ch claim 1 of the general formula Ia ^R l ° 35 R.-S- (CH Ϊ— C - C M _H (D 4th I.
^R 2 130039/0351
ORIGINAL BATH COOH L 130036/0361 J. in which R ₁ and R_ represent lower ACyl radicals with 1 to 4 carbon atoms or R ₂ a hydrogen atom and R ₁ a hydrogen atom, a lower alkyl radical with 1 to 4 carbon atoms, or a trifluoromethyl, methylthio or mercaptomethyl group, m the value O or 1 and R. is a hydrogen atom, a lower alkanoyl radical having 1 to 4 carbon atoms or a benzoyl group, and their salts with bases. 6. Compounds according to claim 5 of the general formula Ia, in which R ₁ and R,
has the value 1. in which R ₁ and R ₂ each represent a methyl group and m 7. Compounds according to claim 5 of the general formula Ia, in which R _{9 is} a hydrogen atom and R _{1 is} a trifluoromethyl group pe and m has the value 1. 8. Compounds according to claim 5 of the general formula Ia, in which R _{9 is} a hydrogen atom and R _{1 is} a methylthio group mean and m has the value 1.
20th 9. Compounds according to claim 5 of the general formula Ia, in which R _{9 is} a hydrogen atom and R _{1 is} a mercaptomethyl group and m is 1. 10. Compounds according to claim 5 of the general formula Ia, in which R ₁ and R ₉ each represent a hydrogen atom. 11. Compounds according to claim 10 of the general formula Ia, in which m has the value 1. 12. Compounds according to claim M of the general formula Ia, in which R. is an acetyl group. 13. Compounds according to claim 11 of the general formula Ia, in which R _{4 is} a hydrogen atom. L 130039/0351 J. 14. Compounds according to claim 10 of the general formula Ia, in which m is O. . 15. Compounds according to claim 5 of the general formula Ia, in which R "is a hydrogen atom and R _{1 is} a methyl group and m is 1. 16. Compounds according to claim 15 of the general formula Ia, in which R. means an acetyl group. 17. Compounds according to claim 15 of the general formula Ia ₁ in which R _{4 is} a hydrogen atom. 18. (S) -1-p-mercapto-Z-methyl-i-oxopropyl) -4-oxo-L-proline. . 19. Process for the preparation of the compounds according to claim 1, characterized in that one (a) for the preparation of the compounds of the general formula I in which R ₄ denotes a hydrogen atom or a protective group which can be split off by hydrolysis or chemically, a keto-substituted proline or piperidine-2-carboxylic acid derivative of the general formula II (II) COOR in which R, ρ and q have the meaning given above, with a carboxylic acid or its chemical equivalent of the general formula III R ^ —S— (CH) _m —C — C00H (H ₁ ) I. ^R 2 130039 / 03S1 in which R., R ", R and m have the meaning given above and R 'is a hydrogen atom or one by hydrolysis or represents a protective group which can be split off chemically, and optionally splits off the protective group, for the preparation of the compounds of the general formula I in R. a radical of the general formula fs -NS) -COOR means the compounds of the general formula I obtained in which R .. and R- are not radicals of the general formula - (CH ₂ ) -SH and R _{4 is} a hydrogen atom, oxidized with iodine, or
(b) splitting off the protecting group from the compounds of the general formula I in which the keto group is provided with a protective group, and optionally the compounds obtained from the general Formula I converted into a salt with a base. 20. Use of the compounds according to claim 1 to 18 in the treatment of hypertension. 21. Medicaments for the treatment of hypertension, characterized by a content of a compound according to An 3Q claim 1 to 18 and the usual additional and / or carrier and / or auxiliary materials. 22. * Means according to claim 21, characterized in that it also contains a diuretic compound. L 130039/0351 J.