SE431331B - NEW THERAPEUTICALLY ACTIVE SULFUR CONTAINING N-ACYLATED DERIVATIVES OF 4-OXO-L-PROLINE - Google Patents

Description

R represents hydrogen, a hydrolysis-removing protecting group, a chemically removable protecting group or when R 1 and R 3 together have other meanings than - (CH 2) n -SH a sulfide of the formula 0 ll CO (nc) p ( cH2) q RR 3 11 n II -s- (ca) mc-cc_ N q-coøn i I Rz H m denotes 0, 1 or 2, n denotes l, 2 or 3, - p and q denotes each l or 2 provided that both p and q are not 2.

The asterisk in the above formula shows an asymmetry center in the ring. In the case of proline, i.e. p and q both denote l, this is the center of L configuration. Ask about pipecolic acid, i.e. one of p and q is 2 is this center in D, L or L configuration.

Asymmetric centers may also be present in the mercaptoacyl side chain depending on the definition of R1, R2 and R3. The products can consequently exist in stereoisomeric forms or as racemic mixtures thereof. All of these are within the scope of the invention. The synthesis described below can use the racemate or one of the enantiomers as starting material. When the racemic starting material is used in the synthesis process, the stereoisomers obtained in the final product can be separated according to conventional chromatography or fractional crystallization methods. If there is an asymmetric center in the mercaptoacyl side chain, this is preferably in the D-configuration. The present invention relates in its entirety to mercaptoacyl derivatives of proline and pipecolic acid of the above formula I and the salts thereof, compositions containing such compounds and the method of using such compounds as antihypertensive agents.

The term lower alkyl used to define the symbols R1, R1, R2 and R3 are straight or branched chain hydrocarbon having up to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl etc. The preferred lower alkyl groups have up to 4 carbon atoms with methyl and ethyl being preferred. Likewise, the terms lower alkoxy and lower alkylthio refer to such lower alkyl groups attached to oxygen or sulfur; The term halogen-substituted lower alkyl refers to such lower alkyl groups as described above wherein one or more hydrogen atoms are replaced by chlorine, bromine or fluorine groups such as trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl etc.

When the term hydrolysis removable protecting group is used to define R 4, it means a group which can be removed by conventional hydrolysis or ammonolysis. Acyl groups of the formula R 5 -a-, wherein R 5 may represent lower alkyl having 1 to 7 carbon atoms, lower alkyl substituted with one or more chlorine, bromine or fluorine groups, - (CH 2) r -cycloalkyl, wherein the term cycloalkyl refers to saturated rings with 3 to 7 carbon atoms, preferably cyclohexyl, an aryl group such as' (CH 2); '<: š: ï;> R, a heterogroup such as' (C 52); Wherein X represents O, 1, 2 or 3, N R6 represents hydrogen, lower alkyl having 1 to 4 carbon atoms, especially methyl, lower alkoxy having 1 to 4 carbon atoms, especially methoxy, lower alkylthio having 1 to 4 carbon atoms, especially methylthio, chlorine, bromine, fluorine, trifluoromethyl or hydroxy and X represents oxygen or sulfur. Preferred groups are lower alkanoyl having up to 4 carbon atoms, especially acetyl and benzoyl. The term chemically removable protecting group as used in the definition of R 4 refers to groups such as p-methoxy, p-methoxybenzylcarbonyl, trityl, t-butoxycarbonyl etc. These groups can be removed when the acylation reaction is complete in various ways such as by treatment with trifluoroacetic acid and anisole.

Preferred compounds of formula I are the L-proline-containing derivatives, i.e. wherein p and q both denote l and R denote hydrogen.

With respect to the mercaptoacyl side chain, such end products are preferred wherein R 4 is hydrogen, m is 0 or 1, R 3 is hydrogen and R 1 and R 2 both represent lower alkyl of 1 to 4 carbon atoms, especially wherein both are methyl or wherein R 2 is hydrogen and R 1 is hydrogen. hydrogen, lower alkyl having 1 to 4 carbon atoms, especially methyl, trifluoromethyl, methylthio or mercaptomethyl. Also preferred as both intermediates and final products are the above-mentioned side chains in which R4 represents lower alkanoyl having 1-4 carbon atoms, especially acetyl or benzoyl. Particularly preferred as end products are those compounds of formula I having a mercaptoacyl side chain wherein R 4 represents hydrogen, m represents O, R 3 and R 1 represent hydrogen, R 2 represents methyl or hydrogen and when R 2 represents methyl is the asymmetric carbon atom to which R 2 is attached in D-configuration.

The compounds of formula I can be obtained by coupling keto-substituted proline or pipecolic acid of the formula 8001620-7 OH / C 2 (H 2 O 2 (<| 2H 2) qn; HN --- g-coon 1 H with an acid or its chemical equivalent wherein Ra represents hydrogen, a hydrolysis or chemically removable protecting group for the preparation of the product of the formula o II '' c 123 nl (Hzmp (Hzmp (cmn-f C-COOH III 112))) wherein Ra This reaction may be effected in the presence of a coupling agent such as dicyclohexylcarbodiimide or the like or the acid may be activated by formation of its mixed anhydride, symmetrical anhydride, acid halide, active ester or using Woodward reagent K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like.As for the acylation methods, compare Methoden der Organischen Chemie ( Houben-Weyl), Volume XV, Part II, Page 1 et seq. (1974) Preferably, the acid halide, especially acid the chloride of formula III react with l = eoo1s2o-7 with the acid of formula II.

If proline or pipecolic acid of formula II is allowed to react in ester form, the resulting ester product can be transferred to the free acid, i.e. R represents hydrogen, in a conventional manner.

For example, when R represents ethyl, this ester protecting group can be removed by saponification.

The product of formula IV is preferably isolated and purified by crystallization, e.g. by formation of the dicyclohexylamine salt and then transferring the salt to the free acid form by treatment with an aqueous solution of the acid such as potassium hydrogen sulphate.

The product of formula IV bearing the acyl group R5-CO- can be transferred to the products of formula I wherein R4 represents hydrogen by conventional hydrolysis or by ammonolysis.

The products of formula I wherein R 1 and R 3 have other meanings than - (CH 2) n -SH and R 4 represent o c 1: 3 TI (HZÃUP (äíznzjq -s- (cznxï- c-_ co _gu f; coon r L _ H 2) is obtained by direct oxidation with iodine of a product of formula I in which R4 represents hydrogen.

The esters of formula I wherein R represents lower alkyl can be obtained from the carboxylic acid compounds, i.e. wherein R represents hydrogen according to conventional etherification procedures, e.g. by etherification with a diazoalkane such as diazomethane, an oxo-7-alkyl-3-p-tolyltriazen such as 1n-butyl-3-p-tolyltriazen or the like. The compounds of formula I may also be prepared by removing the the protecting group from a keto-substituted proline or pipecolic acid product of formula I wherein the keto function is protected with conventional protecting groups such as, for example, a protecting ketal group, e.g. a dialkoxy number such as, for example, H3:: H3. \ / c '(HC (CH)' VRR 2) P 2 q PP li 114-9- (cm m-ï-co-N 'gt-coon a Rz from which the protecting group can be removed by hydrolysis as with a aqueous solution of hydrochloric acid at room temperature.

The compounds of formula V can be prepared from an N-carbobenzyloxy-keto-substituted proline or pipecolic acid of formula II which is then treated with methanol in the presence of trimethyl orthoformate and concentrated sulfuric acid and from which the N-protecting group is subsequently removed by hydrogenolysis optionally a palladium-on-carbon catalyst for the dimethoxy intermediate of the formula H3C CH3 O \\ C // O mzmp ulznpq VI HN CrCOOR H 8001620-7 The intermediate of formula VI is then coupled with an acid or a chemical equivalent of the formula III and gives the dimethoxy compounds of formula V.

Reference is also made to the following publications for further illustrative methodologies for the preparation of starting materials and intermediates: U.S. Pat. patents 4,046,889, 4,105,776, 4,154,935 and 4,116,962; Can. J. Biochem. & PhysioL volume.37, pp. 583 - 587 (1959): JACS, volume 79, pp. 185 - 192 (l957); JACS, Volume 79, pp. 192 - 197 (1957): Bull. Soc. Chem., 1965 (8), pp. 2253 - 2259; and Äus. J. Chem., Vol. 20, pp. 1493-1509 (1967).

The methods illustrated therein can be used as a general method for the synthesis of the compounds and separation of the isomers which can be used according to the present invention. Further illustrative details can be found in the examples that serve as a model for the presentation of other members of the group.

The compounds of the present invention form base salts with a variety of inorganic or organic bases. The salt-forming ion derived from such bases may be metal ions, e.g. aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium or an amine salt ion, a number of which are known for this purpose such as, for example, aralkylamines such as dibenzylamine, N, N-dibenzylethylenediamine, lower alkylamines such as methylamine, t -butylamine, procaine, lower alkylpiperidines such as N-ethylpiperidine, cycloalkylamines such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzatin or salts derived from amino acids such as arginine, lysine or the like.

The physiologically acceptable salts such as the sodium or potassium salts may be used in medicine in the manner described below and are preferred. These and other salts, which may not necessarily be physiologically acceptable, may be used for the isolation and purification of a product acceptable for the purposes described below, as illustrated by the dicycloamine salt in the examples. The salts are prepared by reacting the acid form of the compound with one equivalent of the base to give the desired base ion in a medium in which the salt precipitates or in aqueous medium and subsequent lyophilization. The free acid form can be obtained from the salt according to conventional neutralization techniques, e.g. with potassium bisulfate, hydrochloric acid etc.

The compound of formula I wherein R 4 represents hydrogen, R 5 -g- or a disulfide-type substituent, especially when R 4 represents hydrogen can be used as hypotensive agents. They inhibit the transfer of decapeptide angiotensin I to angiotensin II and can therefore be used to relieve angiotensin-related hypertension. Effect of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is transferred by angiotensin-transferring enzyme (ACE) to angiotensin II. The latter is an active compressor substance which is stated as a causative agent in various forms of hypertension in various mammalian species, e.g. rats and dogs. The compounds of the present invention intervene in the angiotensinogen -9 (renin) -9 angiotensin I-w> (ACE) ~ +> angiotensin II sequence by inhibiting the angiotensin-transferring enzyme and reducing or eliminating the formation of the pressor substance angiotensin II. Thus, by administering a compound containing one or a combination of compounds of formula I, angiotensin-dependent hypertension in mammalian species suffering therefrom is alleviated. A single dose or preferably two to four divided daily doses, provided on a basis of about 0.1 - 100 mg per kg of body weight per day, preferably about 1 - 15 mg per kg of body weight per day is suitable for reducing blood pressure. The substance is preferably administered orally, but parenteral routes such as subcutaneous, intramuscular, intravenous or intraperitoneal routes may be used.

The compounds of the present invention may also be formulated in combination with a diuretic for the treatment of hypertension. A combination product comprising a compound of the present invention and a diuretic may be administered as an effective amount comprising (for a 70 kg mammal) a total daily dose of about 30 - 600 mg, preferably about 30 F 300 mg of a compound of the present invention. and about 15 to 300 mg, preferably about 15 to 200 mg of the diuretic to mammalian species in need thereof. Examples of diuretics suitable for use in combination with a compound of the present invention are thiazide diuretics, e.g. chlorothiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, benzdroflumethiazide, methclothiazide, trichloromethiazide, polythiazide or benstiazide as well as ethacrynic acid, ticrynaphene, chlorthalidone, furodemide, musolimine, bumethanilide, triamidene and the pyramids

The compounds of formula I may be formulated for use in reducing blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.

Approximately 10 to 500 mg of a compound or mixture of compounds of formula I is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavoring, etc. in a unit dosage form according to accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dose within the stated range is obtained.

The invention is further illustrated by the following examples in which the temperatures refer to degrees Celsius.

Example 1- 1- [3- (Acetylthio) -1-oxopropyl] -4-oxo-L-proline a) N-carbobenzyloxy-4-hydroxy-L-proline 26.5 g (0.02 mol) of 4-hydroxy- L-proline and 32.8 ml (0.23 mol) of benzyl chloroformate are reacted 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 and work up with 90 ml of soo162o-7 ll concentrated hydrochloric acid as described in Can. J. Biochem. & Physiol, Volume 37, Page 584 (1959) to give N-carbobenzyloxy-4-hydroxy-L-proline. This product is reacted with cyclohexylamine to form the cyclohexylamine salt in one (exchange if possible 69 g, melting point 193 - 195 °. The salt (34 g) is neutralized with N-hydrochloric acid to give 27 g of free acid as colorless glass [u] š6 - 700, (c, 1% in chloroform) b) N-carbobenzyloxy-4-keto-L-proline 21.5 g (0.81 mol) of N-carbobenzyloxy-4-hydroxy-L-proline are oxidized in 1.2 liters of acetone with 83 ml of 8N chromic acid in sulfuric acid as described in JACS, volume 79, page 189 (1957). To facilitate the subsequent filtration of chromium salts, 30 g of Celite (diatomaceous earth) are added to the acetone solution before the introduction of the oxidizing agent. An air stirrer was used. The reaction mixture is filtered and the acetone filtrate is concentrated to about 300 ml before dilution with 1 liter of chloroform. The solution is washed with 300 ml of saturated sodium chloride (four times), dried (MQSO 4), filtered and the solvent is evaporated to give N-carbobenzyloxy-4-keto-L-proline (22.8 g) which is crystallized from ether (50 g). ml) -hexane (150 ml) to give 17.2 g (81%) of the product, melting point 99 - lol °, [e1š6 + 17 ° (e, 1% l chloroform). c) 4-Keto-L-proline hydrobromide To 4.0 g (0.065 mol) of N-carbobenzyloxy-4-keto-L-proline is added 20 ml of hydrogen bromide in acetic acid (30 - 32%). The mixture is stirred occasionally for a period of 8 minutes. At the end of this period (foaming has ceased), the yellow-orange-colored solution is layered with 250 ml of ether and the gum-like product is decomposed. The ether is discarded and the resulting sticky solid is decomposed with freshly prepared ether and finally with 50 ml of acetonitrile to give 4-keto-L-proline hydrobromide as a crystalline solid weighing 2.7 g (85%), m.p. 153-1550 (decomposition), [d] š6 -490 (c, 1% in water). 8001620-7 12 d) 1- [3- (acetylthio) -1-oxopropyl] -4-oxo-L-proline A stirred solution of 4.1 g (0.095 mol) of 4-keto-L-proline hydro bromide in 50 ml of water is cooled to 50 and treated portionwise with solid sodium carbonate (foaming is controlled by adding a few drops of ether) to pH 8.0 (approximately 2 g required. With continued stirring and cooling, a portion is added using a pipette a. solution of 3.5 g (0,0l2 mol) of 3-acetylthiopropionyl chloride in 5 ml of ethyl acetate while maintaining the pH at 7.0 - 8.0 by dropwise addition of 25% (w / v) sodium carbonate solution (approx. After about 10 minutes, the pH stabilizes at 8.0 - 8.4 After further stirring and cooling for a total of 1 hour, the solution is washed with ethyl acetate (2 x 50 ml), layered with 50 ml of ethyl acetate, stirred , cooled, thoroughly acidified with concentrated hydrochloric acid to pH 2.0, saturated with sodium chloride and the layers separated The aqueous phase is extracted with additional ethyl acetate (3 x 50 ml), the combined organic s the layers are dried (MgSO 4) and the solvent is evaporated, finally at 2.0 mm to give 4.8 g of a yellow-orange-colored glass-like residue. This residue is 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 inoculation and shredding, crystalline 1- [3- (acetylthio-1-oxopropyl)] [4] oxo-L-proline-dicyclohexylamine salt is separated, which after cooling overnight weighs 2.7 g (almost colorless), m.p. 191 - 1930 (dec. aelningy), [a1š6 -24 ° (c, 1% in cHc13).

This dicyclohexylamine salt is transferred to the free acid by suspending in ethyl acetate and treating with 45 ml of 10% potassium bisulfate and stirring until two layers are obtained. After separation, the aqueous phase is extracted with ethyl acetate (4 x 75 ml), the organic layers are combined, dried (MgSO 4) and the solvent is evaporated to give 3.7 g of a light yellow glass-like material. 8001620--7 13 Analysis. Calculated for ClOH 13 NO 5 S: C, 46.32; H, 5.05; N, 5.40; S, 12.37; Found: C, 47.05; H, 5.50; N, 5.18; S, 12.07.

Example 2 - 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline Argon is passed through a cold solution of 9 ml of concentrated ammonium hydroxide in 22 ml of water for 30 minutes. This material is then added under cooling and under an argon atmosphere to 3.65 g (0.014 mol) of 1- [3- (acetylthio) -1-oxopropyl] -4-oxo-L-proline. Approximately 30 minutes are required to dissolve the proline starting material using a magnetic stirrer. Stirring under an argon atmosphere is continued at room temperature for a further 2 hours, after which the solution is extracted with 30 ml of ethyl acetate (this and subsequent procedures are carried out as much as possible under an argon atmosphere). The aqueous layer is cooled, stirred, layered with 30 ml of ethyl acetate and acidified portionwise with 1: 1 HCl. Sodium chloride is added, the layers are separated and the aqueous phase is extracted with additional ethyl acetate (3 x 30 ml). A brown rubber-like fraction remains insoluble in any of the phases. After drying over MgSO 4, the combined ethyl acetate layers are evaporated to give a substantially solid residue which becomes an amorphous solid on decomposition with ether and the evaporation proceeds to give 1.4 g of a light yellow material. 1.3 g of this material are triturated with 50 ml of ether, cooled under an argon atmosphere for 1 hour, filtered, washed with ether and dried in vacuo to give 1.0 g of 1- (3-mercapto-1-oxopropyl) -4-oxo- L-proline, Rf 0.67 (methanol on silica gel, visualized in iodine vapors). 1850041620-7 14 Analysis. Calculated for C8H11NO4S. 0.5 H 2 O; C, 42.46; H, 5.35; N, 6.19; S, 13.71 Found: C, 42.66; H, 5.39; N, 6.30; S, 13.30.

Example 1-3 (S) -1 - [(3-acetylthio) -2-methyl-1-oxopropyl) -4-oxo-L-proline According to the procedure of Example 1 but replacing the 3-acetylthiopropionyl chloride with D-3 Acetylthio-2-methylpropionyl chloride gives (S) -1 - [(3-acetylthio) -2-methyl-1-oxopropyl] -4-oxo-L-proline.

Example 4 (S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -4-oxo * L-proline The product of Example 3 was treated with ammonium hydroxide according to the procedure of Example 2 to give (S) -1 - (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline.

Example 5 1 - [(3-acetylthio) -2-trifluoromethyl-1-oxopropyl] -4-oxo-L-proline a) D, L-3- (acetylthio) -2-trifluoromethylpropionic acid d-trifluoromethylacrylic acid (10 g, 0.071 mol) [prepared according to the procedure of J. Chem. Soc., 1954, page 371] is cooled in a salt-ice-water bath, stirred and treated portionwise with 5.7 ml (0.075 mol) of 97% thiolactic acid. After the addition, the yellow liquid is stirred under cooling for 1 hour, allowed to warm to room temperature and distilled to give 14 g (91%) of D, L-3- (acetylthio) -2-trifluoromethylpropionic acid as a light yellow solid, boiling point 149 - 1530/13 mm. The material solidifies when stored under cold conditions. B) D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride D, L-3- (acetylthio) -2-trifluoromethylpropionyl acid (7 g, 0.032 mol) is treated with 18 ml (0.25) redistilled thionyl chloride and the mixture is refluxed for 3 hours. After removing the excess thionyl chloride on a rotary evaporator, the residue is distilled to give 6.8 g of D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride as a pale yellow oil, b.p. 80 - 0 82/16 mm. c) 1 - [(3-acetylthio) -2-trifluoromethyl-1-oxopropyl] -4-oxo-L-Erolin D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride is reacted with 4-keto-L-proline hydrobromide according to the procedure of Example 1 (d) to give 1 - [(3-acetylthio) -2-trifluoromethyl-1-oxopropyl] + 4-oxo-1-proline. This mixture of diastereoisomers can then be separated according to conventional techniques.

Example Gel 6 1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline The product from Example 5 (in the form of the diastereoisomeric mixture or as the separated isomers) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give 1- (3-mercapto-2-trifluoromethyl-leoxopropyl) -4-oxo-L-proline.

Example 7 (S) -1- (3-mercapto-2-mercaptomethyl-1-oxopropyl) -4-oxo-L-proline a) (S) -1- [3- (acetylthio) -2- (acetylthiomethyl) - 1-Oxopropyl-4-oxo-L-Eroline According to the procedure of Example 1, but by using D-3-acetylthiomethyl-3-acetylthiopropionyl chloride instead of the 3-acetylthiopropionyl chloride in part (d), (S) -le [3- (acetylthio) -2 "aceto-7-2- (acetylthiomethyl) -1-oxopropyl] -4-oxo-L-proline. B) (S) -1- (3-mercapto-2-mercaptomethyl-1- oxopropyl) -4-oxo-L-Qrolin The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give (S) -1- (3-mercapto-2-mercaptomethyl-1-oxopropyl) -4-oxo -L-proline.

Example gel 8 - 1- (3-mercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline a) 3- (acetylthio) -2- (methylthio) propionic acid 12.5 g (0.094 mol) methyl- 2- (methylthio) acrylate [prepared from methyl 2-chloroacrylate according to the procedure in Gundesmann et al., Chemische Berichte, volume 94, page 3254 (1916)] - is stirred with 1N aqueous sodium hydroxide (94 ml) under ice-cooling. The mixture is warmed to room temperature and then stirred for 5 hours. The bone solution obtained is washed with ether, then acidified to pH 2 with concentrated hydrochloric acid. The solid precipitate is extracted into methylene chloride and the solution is washed with saturated sodium chloride and the solvent is evaporated. The solid residue 2- (methylthio) acrylic acid, m.p. 70-750, was used immediately in the following reaction.

Equal amounts of 2- (methylthio) acrylic acid and thiolacetic acid are mixed under an argon atmosphere and stirred at 800 for several hours to give 3- (acetylthio) -2- (methylthio) propionic acid. b) 3- (acetylthio) -2- (methylthio) propionic acid chloride 3- (acetylthio) -2- (methylthio) propionic acid is refluxed in thionyl chloride for 2 hours. The reaction mixture is distilled to remove excess thionyl chloride and the product is distilled in vacuo to give 3- (acetylthio) -2- (methylthio) propionic acid chloride. 8001620-7 17 c) 1- [3- (acetylthio) -2-methylthio-1-oxopropyl] -4-oxo-L-proline 3- (acetylthio) -2- (methylthio) propionic acid chloride is reacted with 4-keto- L-proline hydrobromide according to the procedure of Example 1 (d) to prepare 1- [3- (acetylthio) -2-methylthio-1-oxopropyl] -4-oxo-L-proline. d) 1- (3-Mercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline The product from part (c) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give 1- (3-mercapto-2 -methyl-thio-1-oxopropyl) -4-keto-L-proline.

Example 9 1- (4-mercapto-1-oxobutyl) -4-oxo-L-proline a) 1- [4- (acetylthio) -1-oxobutyl] -4-oxo-L-proline According to the procedure of Example 1 but by using 4-acetylthiobutyroyl chloride instead of the 3-acetylthiopropionyl chloride in part (d), 1- [4- (acetylthio) -1-oxobutyl] -4-oxo-L-proline is obtained. b) 1- (4-Mercapto-1-oxobutyl) -4-oxo-L-proline The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give 1- (4-mercapto-1-oxo-butyl ) -4-oxo-L-proline.

Example 10 1- (2-Mercapto-1-oxoethyl) -4-oxo-L-proline a) 1- [2- (acetylthio) -1-oxoethyl] -4-oxo-L-proline According to the procedure of Example 1 but by using acetylthioacetyl chloride instead of the 3-acetylthiopropionyl chloride in part (d), 1- [2- (acetylthio) -1-oxoethyl] -4-oxo-L-proline is obtained. B) 1- (2-Morcapto-1-oxoethyl) -4-oxo-L-proline The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give 1- (2-mercapto-1-oxoethyl). -oxoethyl% - 4-oxo-L-proline.

Example 11 1- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -4-oxo-L-prolin-u) 1- [3- (N-cutylthio) -2,2-Gimethyl-1-oxopropyl] -4- oxo-Lvproline According to the procedure of Example 1, but by using 3-acetyl-β-thio-Z, Zwdimethylpropionyl chloride instead of the S-acetylthiopropionyl chloride in part (d), 1- [3- (acetylthio) -2,2-S is obtained. dimethyl-1-oxopropyl] -4-oxo-L-proline. b) 1- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -4-oxo-L-proline The product from part (a) is hydrolyzed by concentrated ammonia according to the procedure of Example 2 to give 1- (3-mercapto -2,2-dimethyl-1-oxopropyl) -4-oxo-L-proline. Example Gel 1-2 7 1 (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-oxo-L-proline a) (S) -1- [3- (acetylthio) -2- ethyl 1-oxopropylphyl-4-oxo-L-proline J-sulgL ILS: lunuulul. I, L: xu |||| _: u. |. L: nun grmum uLt dixylilxlla U-Iiuethylthio-2-otylpropionylchlorld instead of D-3-acetylthio-2-methylpropionyl chloride in part (d) is obtained (S) -1- [3- (acetylthio) -2- ethyl-1-oxopropyl] -4-oxo-L-proline. B) (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-L-proline product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give (S) - 1- (3-mercapto-2-ethyl-1-oxopropyl) -4-oxo-L-proline. ; soo162o-7 Example gel 13 1- (3-mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid a) 1- {3- (acetylthio) -1-oxopropyl] -4-oxo-L-pipecolic acid According to the procedure in Example 1 but by using 4-keto-L-pipucolic acid instead of the 4-keto-L-proline in part (d), 1- [3- (acetylthio) -1-oxopropyl] -4-oxo- L-pipecolic acid. b) 1- (3-mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid = The product from part (a) is hydrolyzed with concentrated ammonia to give 1- (3-methylpert-J-oxopropyl) -4-oxo-propyl L-pipolinic acid. Example Gel 14 (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -5-oxo-L-pipecolic acid a) (S) -1- [3- (acetylthio) -2-methyl-1 -oxopropyl] -5-oxo-L-pipecolius acid According to the procedure of Example 1 but using S-keto-L-pipecolic acid instead of the 4-keto-L-proline in part (d) and D-3 acetylthio-2-methylpropionyl chloride instead of the acetylthiopropionyl chloride in part (d) there is obtained (S) -1- [3- (acetylthio-2- * muLyl-1-oxopropyl] -5-chloro-L-pipucolic acid. b) (S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -5-keto-L-pipecoline-Syphae The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to give (S) - 1- (3-mercapto-2-methyl-1-oxopropyl) -5-keto-L-pipecolic acid. Sooeezo-7 Exemgel 15 1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline - [_>;; _ '* _ ~ _I1lllflfwsal vari)) .f's: = .. w_ln11a1y.) htffalrl2-ll lfif.).

The mixture is allowed to cool to room temperature and the solid is recrystallized from cyclohexane to give 34E [(4-methoxy) phenylmethyl] thio] -2-trifluoromethylpropionic acid, m.p. 72-74 °. Treatment of this acid with thionyl chloride gives 3- [i (4-methoxy) -phenylmethyl] thio] 42-trifluoromethylpropionyl chloride. b) 1- [3 - [[(4-methoxy) phenylmethyl] thio) -2-trifluoromethyl-phoxopropyl] -4-oxo-L-proline 1 3 - [[(4-methoxy) phenylmethyl] thio] -2- the trifluoromethylpropionyl chloride from part (a) is reacted with 4-keto-L-proline to give 1- [3 - [[(4-methoxy) phenylmethyl] thio] -2-trifluoromethyl-1-oxopropyl] -4-oxo-L- proline. c) 1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline The product from part (b) is mixed with trifluoroacetic acid and anisol under a nitrogen atmosphere. The solvents are removed in vacuo to give the remaining 1- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline. Example 16 (S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4-oxo-Lifproline a) (S) -1- [3- (acetylthio) -3-methyl- 1-oxopropyl] -4-oxo-L-proline According to the procedure of Example 1, but using D-3-acetylthio-3-methylpropionyl chloride instead of the 3-acetylthio-propionyl chloride in part (d), the (S) -1- [3- (acetylthio) -3-methyl-1-oxopropyl] -4-oxo-L-proline. b) (S) -1- (3-mercapto-3-methyl-1-oxopropyl) -4-oxo-L-proline The product from part (a) is hydrolyzed with concentrated ammonia to give (S) -1- (3- mercapto-3-methyl-1-oxopropyl) -4-oxo-L-proline.Exemgel 17 - 25 _; According to the procedure of Example 1, but by replacing the 3-acetyl-g-Liuproplonyl chloride with the acid chlorides listed in column I below, the acyl mercapto product of column II is obtained. ____. .., _.__ .. _ soßmezß-7 22 n fl H0Hm | fl | ox01 «| HHæn5Qox0 | H | H0 fl» HH> @ onHmM ^ Hmxw @ oHx> uvH_ | «H | H 1 G flfi oHm | fl | 0 x0 | w | H fi huwoxol fl | ~ o fi ß fi H> aonnmx ^ Hm »meH> n @ wvH ~ | ~ H1 ~ flfifl onm n fl nøxolw ~ Hmm0nm0x0 | H | HævmE | N | fi o fl u | HHm = 0nHmx ^ H> = w | _ | ~ | ^ wV flflfl onml fl noxonwuH fi æmonmoxo | fi «Ho fi» H fi> = onHmx ^ fl h @ fi n »m |«, ~ H | m_- ~ Q fi HoHm1A | 0N0 | w | H fi hmonmoxox fl u fl Hevo fl m ». > huw- ~ V_H | m_ | fi »^ wV n flfl onmr fl aoxowwl fifl zmohmoxon fi l fi o fi v 1H fl> noQHmx ^ Hh» wno fi x fl M@|~_~.Nv~H|m_|H G flfi onmn fl rxOHH | ^ H>: m fl p | NV__ | mH | H | ^ wv n fi H0nm1Q | 0xo | w | fi H% moHm | oxo- fl «H>» wa »N-ßo fl p fl wownmßv | m_ | fi | ^ wv ¶ c flfl onmlq noxonwn vlm alw Hfim. .w fi no fi x | Hw0H> ßsn1_o fl @ ñH »= onHmx ^ H> xmn0 fi x> uH ~ |« u fl no fi x fi mpwumr fi o fl pH fl wnonnmxñ fi ævwa fi wnwmv ~ _ | ~> U mHH »Wa |« .H_ | m1n 1 ø fi uo fi x fl h fl o fl monm | HoH »fi H>: øn ~ mx ^ H> w fi H> m |« v_H | m ø fi no fl x fl æao fl monm »H» pmE | ~ | _ø fi »fi H> aonHmx ^ vH. | m | n w fi n0Hx fi> G0 fl mOHm | ~ oHuH fi mnonnmx ^ fi w »m» o fi x fl Hp | ~ _N.NV__ | m ø fi uoax fl ænø fl moum | H> »ws | N | HoH» 1HH> aonH. n ø fl uo fi x fi mcø fl monm fl æuw ünmlb fl u fi àomnwnlmnn ø fi noax fl æno fl monmo fi u exempel æomnwnxm H u fl mmm 8Û0l620-7 23 Example 26 (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline example procedure. a) N-Carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester A stirred solution of 7.8 Q (0.03 mol) of N-carbobenzyloxy-4-keto-L-proline from Example 1 in 60 ml of methanol is treated with 96 ml of trimethyl orthoformate followed by 0.6 ml of concentrated sulfuric acid and the mixture is then allowed to stand overnight at room temperature.

The light yellow solution is stirred, treated with 1.5 g of potassium! carbonate followed by 30 ml of water and the bulk of the solvent is removed on a rotary solution to give a syrup-like residue which is shaken with 30 ml of water and 30 ml of chloroform.

After separation of the layers, the aqueous phase is extruded with additional chloroform (3 x 30 ml) and the combined organic layers are washed with 45 ml of saturated sodium chloride solution and dry matter (MgSO 4). Evaporation of the solvent gives 8.4 g (88%) of N-carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester. b) N-Carbobenzyloxy-4,4-dimethoxy-L-proline The ester (8.4 g, 0.026 mol) from part (a) is dissolved in 80 ml of methanol, treated dropwise at -1 to 40 with 18 ml (0.036 mol) ZN sodium hydroxide, kept at 00 overnight and at room temperature overnight. After removing approximately half of the solvent on a rotary evaporator, the solution is diluted with 150 ml of water, washed with 100 ml of ether (the washing liquid is discarded), acidified under cooling with 63 ml of 1: 1 hydrochloric acid to pH 2 and extracted with ethyl acetate (4 x 750 ml). The combined extracts are washed with 50 ml of saturated sodium chloride solution, dried in vacuo (MgSO 4) and the solvent is evaporated to give 8.0 g of a pale yellow. carbobenzyloxy-4,4-dimethoxy-L-proline; (72 g, partition); [alšö -47 yiskös olja. The oil is dissolved in 35 ml of ethanol, treated with 3.0 g of cyclohexylamine in 10 ml of ethanol and diluted with 500 ml of ether. Upon grafting and guiding, the crystalline N-carbobenzyloxy-4,4-dimethoxy-L-proline cyclohexylamine salt is separated; weight after cooling overnight, 7.0 g, mp 157 - 159 ° (5, 151) § [a] š6 -340 (c, 1% in EtOH). This material is recrystallized from 100 ml of octonitrile to give the salt as a colorless solid, the N-carbobenzyloxy-4,4-dimethoxy-L-proline cyclohexylamine salt is suspended in 40 ml of ethyl acetate, stirred and treated with 25 ml of 1N hydrochloric acid. . When two clear layers are obtained, these are separated, § the aqueous phase is extracted with additional ethyl acetate (3 x 40 ml), š the combined organic layers are dried (MgSO 4) and the solvent is evaporated, finally at 0.2 mm and 4Ö to give 7.2 g (70%) N-carbobenzyloxy-4,4-dimethoxy-L-proline as a light yellow viscous syrup. c) 4,4-Dimethoxy-L-proline - 1 in 0.022 mol) in 210 ml of methanol-water (2: 1) is treated with 2.3 g of 5% pulludlum-on-carbon and shaken on a Part-hydrogen nut for 6 hours. The catalyst is filtered off under a nitrogen atmosphere, washed with methanol and the combined filtrates are evaporated, finally at 0.1 - 0.2 mm to give a partially crystalline residue. This residue is taken up in 200 ml of methanol and evaporation is repeated. When the solid is triturated under ether (evaporation is repeated) 3.6 g (95%) of an almost colorless 4,4-dimethoxy-L-proline are obtained, m.p. 192 DEG-194 DEG. (Dec. (C, 1% in MeoH) ).

A sample crystallized from methanol-ether is colorless and narrows at 197 DEG-1980 (decomposition); [α] D 6 -490 (c, 1% in MeOH). ; d) (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-L-Praline An unstirred solution of β, β (0.019 mol ) 4,4-DLmotoxy-L-proline in 50 ml of water is cooled to SU and transferred to pH 8.5 by the addition of a 25% sodium carbonate solution (w / v).

With continued stirring and cooling, a solution of 3.8 g (0.02 l mol) of D-3-acetylthio-2-methyl-propanoyl chloride in 5 ml, etc. is added portionwise while maintaining the pH at 7.5 - 8.5. by dropwise addition of 25% sodium carbonate solution. When the pH has stabilized at 8.2 - 8.4 (after about 15 minutes), stirring and cooling continue for a total of 1 hour. The solution is then washed with 50 ml of ethyl acetate (the washing liquid is discarded), layered with 50 ml of ethyl acetate, cooled, stirred, thoroughly acidified; with 1: 1 hydrochloric acid to pH 2.0, saturated with sodium chloride and the layers are filtered. The aqueous phase is filtered with additional ethyl acetate (3 x 50 ml), the combined layers are dried (MgSO 4) I and the solvent is evaporated, finally at 0.2 mm to give 0.7 g of a syrupy product. This syrup is treated in 70 ml of ethyl acetate with 3.9 g of dicyclohexylanxine to give 6.5 g of colorless I (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy -L- proline dicyclohexylamine salt in two harvests (3, g and 3.4 g), melting point isa - 1so ° <5, 14s °>, [a1š6 -71 ° (C, 1% 1 mare).

After recrystallization from 20 ml of hot ethyl acetate-60 ml of hexane, the colorless solid salt weighs 6.0 g, m.p.

The dicyclohexylamine salt is transferred to the free acid by suspending 5.0 g thereof in 50 ml of ethyl acetate, after which the mixture is cooled and treated with 60 ml of 10% potassium bisulfate solution to give two clear layers. After separation, the aqueous phase is extracted with ethyl acetate (3 x 50 ml), the combined organic layers are dried (MgSO 4) and the solvent is finally evaporated at 0.1 - 0.2 mm and 45 ° to give 4.1 Q (59%) ( s) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-Lwproline as a viscous, almost glass-like material [a] å5 -1120 (c, 1% i_E fl1 D. 'J ua s (o1e2o-7 26 e) (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy> L-Prulin Argon is passed through a cold solution of 8.5 ml of concentrated ammonium hydroxide in 20 ml of water for 0.25 hours. The mixture is then added under cooling and under an argon atmosphere to 4.1 g (0.013 mol) of (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-L-proline and the mixture is stirred in an ice bath until a pale yellow solution is obtained (about 15 minutes). Stirring for a while is continued at room temperature for a further 2 hours, then the solution is extracted with 30 ml of ethyl acetate (this and subsequent procedures are carried out as much as possible under an argon atmosphere). The aqueous layer is cooled, stirred, layered with 30 ml of ethyl acetate and acidified portionwise with about 16 ml of 1: 1 hydrochloric acid. The layers are separated, the aqueous phase is extracted with additional ethyl acetate (3 x 30 ml), the combined ethyl acetate layers are dried (MgSO 4) and the solvent is evaporated to give 3.5 g (100%) of (S) -1- (3-mercapto-). 2-Methyl-1-ommmwyU-Lß w hwumkllflfi u fi nswx fl mm fl mm [q1â5 -72 ° (C, 1% 1 Ecom) Ice cream syrup 3.4 g of the obtained compound are decomposed with 20 ml of ethyl acetate, grated, diluted with 30 ml of hexane to give a colorless solid, weighing 2.6 g, m.p. 108 DEG-110 DEG, [.alpha.] D @ -5 -77 DEG (C, 1% 1 Eton), in -F) (S) - [- (3-murine -2-methyl-1-oxopropyl) -4-oxo-L-proline-1-adamantanamine salt (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline L (0.4 g, 0.0014 mol) is added to 8 ml of stirred N HCl through which; argon previously passed for 10 minutes. When a solution is obtained, the flask is sealed under an argon atmosphere and kept overnight at room temperature. The following steps are also performed under * argon atmosphere as much as possible. To the stirred solution is added 20 ml of methylene chloride and after saturation with sodium chloride the layers are separated. The aqueous phase is extracted with additional methylene chloride (3 x 15 ml), the organic layers are combined, dried (MgSO 4) and the solvents are evaporated to give a foaming residue. After decomposition with ether (evaporation is repeated), 0.26 g of (S) -1- (3-near-capto-2-methyl-1-oxopropyl) -4-oxo-L-proline is obtained as an amorphous solid 0.245 g of this product is dissolved in 7 ml of acetonitrile and treated with 0.17 g of 1-adamantanamine to precipitate the salt in as a bulky solid. After cooling overnight, the colorless material is filtered, washed with cold acetonitrile and ether and dried in vacuo to give 0.36 g of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo -L-proline-1-adamantanamine salt (1: 1); melting point 188 - 1900 (decomposition); s, 1840; {α1š5 -13 ° (C, 1% 1 methanol). - 1 Analysis. Calculated for C 9 H 13 NO 4 S _ ClOH 17 N. 0.25 H 2 O: C, 58.96; H, 8.02; N, 7.24; S, 8.29 Found: C, 58.60; H, 8.37; N, 7.16; S, 8.29.

Example 27 1,1 '- [dithiobis (1-oxo-3,1-propanediyl)] bis [4-oxo-L-proline] The product from Example 2 is dissolved in water and the pH is adjusted to 6.5 by adding 1N sodium hydroxide. To this stirred solution is added dropwise 0.5 M iodine solution in 95% ethanol (6.34 g iodine / 50 ml solution) while maintaining the pH at 5.5 - 6.5 with 1N sodium hydroxide. The excess iodine is removed with dilute sodium thiosulphate and the solution is concentrated, cooled and acidified with 1: 1 hydrochloric acid. The solvent is added and the layers are separated. The inorganic layer is dried (MgSO 4) and the solvent is evaporated to give the remaining 1,1 '- [dithiobis (1-oxo-3,1-propanediyl)] bis [4-oxo-L-proline]. Example 28 28 1- [3- (Acetylthio) fl-oxopropyl] -4-oxo-L-proline methyl ester A solution of the product of Example 1 in ether is treated with a slight excess of diazomethane. After standing at room temperature for 2 hours, the solvent is evaporated to give 1- [3- (acetylthio) -1-oxopropyl] -4-oxo-L-proline methyl ester. (3-mercapto-1-oxopropyl) -4-oxo-L-proline methyl ester The product from Example 28 is hydrolyzed with concentrated ammonia according to the procedure of Example 1. 2 to give 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline methyl ester Example 30 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline sodium salt A solution of 1.0 g of the product from Example 2 is dissolved in 10 μl of water and treated with one equivalent of sodium bicarbonate. The solution is lyophilized to give 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline sodium salt. In the same way, the use of potassium bicarbonate corresponding to potassium salt is obtained.

Example 31 AS) -1- (3-Mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline sodium salt A solution of 1.0 g of the product of Example 4 is dissolved in 10 ml of water and treated with one equivalent of sodium bicarbonate.

The solution is lyophilized to give 1- (3-mercapto-2-methyl-1-oxo-propyl) -4-oxo-L-proline sodium salt.

In the same way, the corresponding potassium salt is obtained using potassium bicarbonate.

Example gel 32 I 1000 tablets each containing the following ingredients: 1- (3-mercapto-1-oxopropyl) - fl-oxo-L-proline 100 - mg maize starch 50 mg gelatin 7.5 mg Avicel (microcrystalline cellulose) 25 mg magnesium stearate A 2 1.5 mg 185 mg 1 x is prepared (from sufficient bulk quantities) by mixing 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline and corn starch with an aqueous solution of the gelatin. The mixture is dried and ground to a fine powder. Avicel and then magnesium stearate are mixed while granulating. This mixture is then compressed in a tablet press to form 1000 tablets: each containing 100 mg of active ingredient.

Example Gel 33 Tablets each containing 100 mg of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline were prepared as described in Example 32.

Example 34 34 71 tablets each containing 50 mg of 1- (3-mercapto-1-oxo-propyl) -4-oxo-L-proline were prepared from the following ingredients: - š & --_-_-_-_-- í7 - ____ v. 8000016205? 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 50 g lactose 100 g Avicel - 150 g maize starch 50 g magnesium stearate 5 g 1- (3-mercapto-1-oxopropyl) -4 -oxo-L-proline, lactose and Avicel are mixed and then mixed with corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 355 mg tablets each containing 50 mg of active ingredient. The tablets are coated with a solution of Methocel E (methylcellulose) comprising as color a pigment containing yellow No. 6.

Example 35 Tablets each containing 50 mg of (S) -1- (3-mercapto-2-mutyl-1-oxuprupyl) -4-oxo-L-proline LrnmsLällus as described in Example 34.

Example Gel 36 Two gelatin capsules No. 1 each containing 100 mg of 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline sodium salt are filled with a mixture of the following ingredients: 1- (3-mercapto-1-oxopropyl ) - 4-oxo-L-proline 100 mg magnesium stearate 7 mg lactose 193 mg Exemgel 37 Gelatin capsules containing 100 mg (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline sodium salt is prepared as described in Example 36. Example 16 A sample injectable is prepared as follows: 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 500 g methyl paraben 5 g propyl paraben gi nnlrium chloride 25 ql water sat LnjekLion gu. 5 l 3 The active substance, preservative and sodium chloride are dissolved in 3 liters of water and then the volume is transferred to 5 liters. The solution is filtered through a sterile filter and filled; read aseptically in pre-sterilized bottles which are then sealed with pre-sterilized rubber closures. Each vial contains 5 ml of solution in a concentration of 100 mg of active ingredient per ml of solution for injection.

Example 39 L An injection solution containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline is prepared as described in Example 38.

Exemgel 40 C000 tablets each containing the following ingredients: 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 100 mg, Avicel (microcrystalline cellulose) 100 mg hydrochlorothiazide 1.2 mg lactose U.S.P. ll3 mg corn starch U.S.P. , 7.5 mg stearic acid U.S.P. 7 .mg in 350 mg - is prepared from sufficient bulk amounts by processing 8- (3-mercapto-1-oxopropyl) -4-oxo-L-proline, Avicel and a portion of the stearic acid. The processed product is ground and passed through a No. 2 sieve, then mixed with the hydrochlorothiazide, lactose, corn starch and the remainder of the stearic acid. The mixture is compressed into 350 mg capsule-shaped tablets in a tablet press. the tablets are cut to be able to be divided into halves.

Example Gel 41 Tablets each containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline and hydrochlorothiazide can be prepared as described in Example 40.

The product of Examples 1, 3, 5 to 25 and 27 - 29 can be prepared according to the procedures of Examples 32 - 41. ¿

Claims (2)

A compound of the formula ïlñ R 1 S- (CH 2) ï ~ C * -__ C N 'COOH (L)' H or a physiologically acceptable acid addition salt thereof, wherein R 1 represents hydrogen or lower alkyl having 4 carbon atoms, m represents 0 or 1 and R 4 represents hydrogen, lower alkanoyl having 1-4 carbon atoms or benzoyl. A compound according to claim 1, characterized in that it is (S) -1- (3-mercapto-2-methyl-1-oxo-propyl) -4-oxo-L-proline. 09 V3 CD ... x O \ ßå (S | * J Abstract Compound of the formula OHCRRO HC) 13 | ln (WP (f fl zq l R4-s- (cm- c - c N c; cooR | 1 I 'H Rz or a physiologically acceptable salt thereof wherein 3 represents hydrogen or lower alkyl, R 1 and R 3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, - (CH 2) n -SH or halogen-substituted lower alkyl, R 2 buLecknur hydrogen e] 1s lower nylkyl provided that R 2 represents lower alkyl only when R 1 is lower alkyl, 'm represents 0, 1 or 2, n represents 1, 2 or 3, p and q each represents 1 or 2, provided that both groups is not 2 and R4 represents hydrogen, a protecting group which can be removed by hydrolysis, a chemically removable protecting group or tubular provided that neither R1 nor R3 is - (CH2) n-SH O II / °. \ l I (H2C) p ( CH2) q. 'TB Flíï II. -S- (Cßnm-CC- N i ... g-cooa _ 1 III _ I _ R2 H - with hypotensive properties, composition for the treatment of 8001620-7 hypertension comprising a pharmaceutical acceptance table carrier 'in and one or more hypotensive agents or physiologically acceptable salts thereof lut-dl above formula szuut process' for the preparation of keto-substituted prolic or pipecolic acids of the above formula. in