NL8001599A - MERCAPTOACYL DERIVATIVES OF KETO SUBSTITUTED PROLINE AND PIPECOLIC ACID. - Google Patents

Description

Η

Mercaptoacyl derivatives of keto-substituted proline and pipecolic acid.

The invention relates to keto derivatives of mercaptoacylproline and pipecolic acid of the formula 1 and the salts thereof, wherein R and R 1 are independently selected from hydrogen and lower alkyl, where R 2 is only lower alkyl if R 1 is also lower alkyl , R 1 and R 1 are independently selected from hydrogen, lower alkyl, lower alkyl thio, - (CH 2) -SH and halogen-substituted lower alkyl, R 1 represents hydrogen, a hydrolyzable removable protecting group, a chemically removable protecting group or, when R 1 and R ^ 10 have a meaning other than - (G ^) -SH, a sulfide of the formula la, m represents 0, 1 or 2, n represents 1, 2 or 3 and p and q each represent 1 or 2, wherein these cannot be 2 at the same time.

The asterisk in the above formulas indicates an asymmetry center in the ring. In the case of proline, i.e. when p and q are both 1, this center has the L configuration. In the case of pipecolic acid, i.e. 1 when one of the symbols p and q is 2, this center has the D.L or L configuration.

Asymmetric centers may also be present in the mercaptoacyl side chain depending on the definition of R 1, R 2 and R 1. The products can therefore exist in stereoisomeric forms or in the form of racemic mixtures thereof.

These all fall within the scope of the invention. The synthesis described below may use the race measure or one of the enantiomers as starting materials. When the racemic starting material is used in the synthesis, the resulting stereoisomers in the final product can be separated using conventional chromatographic or fractional crystallization methods. If an asymmetry center is present in the mercaptoacyl side chain, it preferably has the D configuration.

The invention broadly relates to the mercaptoacyl derivatives of proline and pipecolic acid of the formula 1 and their salts, to compositions containing such compounds, and to a method of using these compounds as anti-hypertensive agents.

By the term "lower alkyl" as used in the definition of the symbols R, R 1, R 2, and R 2 is meant straight or branched chain hydrocarbon radicals having up to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, etc. The preferred lower alkyl groups are those having up to 4 carbon atoms, with methyl and ethyl being particularly preferred. Similarly, the terms "lower alkoxy" and "lower alkylthio" are understood to mean such lower alkyl groups attached to oxygen or sulfur.

The term "halogen-substituted lower alkyl" refers to lower alkyl groups as mentioned above, wherein one or more hydrogen atoms are replaced by chlorine, bromine or fluorine, such as trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.

The term "hydrolyzable removable protective group" as used in the definition of R 1 refers to a group which can be removed by conventional hydrolysis or ammonolysis. Acyl groups of the formula O.

II

R ^ -C- are suitable for this purpose, where R ^ can represent lower alkyl of 1-7 carbon atoms, lower alkyl substituted by one or more chlorine, bromine or fluorine atoms, - (CH ^) r ~ cyclo- alkyl, where the term "cycloalkyl" refers to saturated rings of 3-7 carbon atoms, preferably cyclohexyl, an aryl group such as 35 - (CVr-, a hetero group such as ^ yy

X

8001599

V

3 • J ί or “(CH) —j” 0 J, where r represents 0, 1, 2 or 3, r Sr

Rg represents hydrogen, lower alkyl of 1-4 carbon atoms, especially methyl, lower alkoxy of 1-4 carbon atoms, especially methoxy, lower alkylthio of 1-4 carbon atoms, especially methylthio, chlorine, bromine, fluorine, trifluoromethyl or hydroxy, and X represents oxygen or sulfur. Preferred groups are the lower alkanoyl groups with up to 4 carbon atoms, especially acetyl and benzoyl.

The term "chemically removable protecting group" as used in the definition of R 1 refers to groups such as p-methoxy, p-methoxybenzylcarbonyl, trityl, t-butoxycarbonyl, etc. These groups can be removed after the completion of the acylation reaction - removed using various agents, such as by treatment with trifluoroacetic acid and anisole.

Preferred compounds of the formula 1 are the L-proline-containing derivatives, i.e. where p and q are both 1 and R represents hydrogen.

With regard to the mercaptoacyl side chain, it is noted that as end products, preferred are the compounds wherein R 1 represents hydrogen, m represents 0 or 1, R 1 represents hydrogen and R 1 and R 1 both represent lower alkyl of 1-4 carbon atoms. , especially both methyl, or R 2 represents hydrogen and R 1 represents hydrogen, lower alkyl of 1-4 carbon atoms, especially methyl, trifluoromethyl, methylthio or mercaptomethyl. As intermediates as well as final products, the above-mentioned side chains are also preferred, wherein R 1 represents lower alkanoyl having 1 to 4 carbon atoms, in particular acetyl, or benzoyl.

Particularly preferred as end products are compounds of the formula I having a mercaptoacyl side chain, wherein R 1 represents hydrogen, m 1, R 1 and R 1 represent hydrogen, R 2 represents methyl or hydrogen, and, 8001599 4 when R methyl represents, the asymmetric carbon atom to which R1 is attached is in the D-configuration.

The compounds of the formula I are obtained by coupling a keto-substituted proline or pipe-5-colinic acid of the formula 2 with an acid or a chemical equivalent thereof of the formula 3, wherein R 1 'represents hydrogen, a hydrolyzable or chemically removable protecting group to form the product of the formula IV.

This reaction can be conducted in the presence of a coupling agent, such as dicyclohexylcarbodiimide or the like, or the acid can be activated by formation of its mixed anhydride, symmetrical anhydride, acid halide, active ester or using Woodward reagent K, N -ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline or the like. For an overview of the methods of acylation, reference is made to Methods of Organic Chemistry (Houben-Weyl), Vol. XV, Part II, p. 1 et seq. (1974). Preferably, the acid halide, in particular the acid chloride, of the formula 3 is reacted with the acid of the formula 2.

When the proline or pipecolic acid of the formula II is reacted in the ester form, the resulting ester product can be converted into the free acid, ie R represents hydrogen, using conventional means. For example, if R represents ethyl, this ester protecting group can be removed by saponification.

The product of formula IV is preferably isolated and purified by crystallization, for example by formation of the dicyclohexylamine salt and subsequent conversion of the salt to the free acid by treatment with an aqueous solution of an acid, such as potassium acid sulfate.

The product of formula IV, which bears the acyl group R 2 -CO-, can be converted into the products of formula 1, wherein R 2 represents hydrogen, by conventional hydrolysis or by ammonolysis.

The products of formula I, in which R 1 and R 1 have a meaning other than - (CH 2) -SH and R, represent a

Zn 4 8001599 5 of the formula Ib are obtained by direct oxidation with iodine of a product of the formula 1 wherein hydrogen represents.

The esters of formula I, wherein R represents lower alkyl, may be obtained from the carboxylic acid compounds, i.e., wherein R represents hydrogen, using conventional esterification procedures, for example, by esterification with a diazoalkane, such as diazomethane, a 1-alkyl- 3-p-tolyltriazene, such as 1-butyl-3-p-tolyltriazene, or the like.

The compounds of the formula I can also be prepared by removing the protecting group, by conventional methods, of a keto-substituted proline or pipecolic acid product of the formula 1, the keto-15 group of which is protected by conventional protecting groups, for example a ketal protecting group, for example a dialkoxy ketal, such as the compound of formula 5, the protecting group of which can be removed by hydrolysis, such as with an aqueous solution of hydrochloric acid at room temperature.

The compounds of formula 5 can be prepared from an N-carbobenzyloxyketo-substituted proline or pipecolic acid of formula 2, which is then treated with methanol in the presence of trimethyl orthoformate in concentrated sulfuric acid, after which the N-protecting group is removed by hydrogenolysis in the presence of a palladium-carbon catalyst to form the dimethoxy intermediate of the formula 6. The intermediate of the formula 6 is then coupled with an acid or a chemical equivalent thereof of the formula 3 to form the dimethoxy compounds of formula 5.

Reference is also made to the following publications which describe further illustrative methods for the preparation of the starting materials and intermediates, namely, U.S. Pat. Nos. 4,046,889, 4,105,776, 4,154,935 and 4,116,962, Can. J. Biochem. & Physiol. 37, 583-587 (1959), JACS

79, 185-192 (1957), JACS 79, 192-397 (1957). Bump. Soc. Chem.

800 1 5 99 6 1965 (8), 2253-2259, and Aus. J. Chem. 20, 1493-1509 (1967).

The procedures illustrated in these publications can be used as general methods for the synthesis of the compounds and the separation of the isomers which can be used in the present invention. Further illustrative details can be found in the examples, which serve as models for the preparation of other members of the group.

The compounds of the invention form basic salts with a variety of inorganic or organic bases. The salt-forming ions derived from such bases can be metal ions, for example aluminum, alkali metal ions, such as sodium or potassium, alkaline earth metal ions, such as calcium or magnesium, or amine salt ions, some of which are known for this purpose, for example aralkylamines, such as dibenzyl -15 amine, NN-dibenzylethylenediamine, lower alkylamines, such as methylamine, t-butylamine, procaine, lower alkylpiperidines, such as N-ethylpiperidine, cycloalkylamines, such as cyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathine, or salts derived from arginine lysine or the like.

The physiologically acceptable salts, such as the sodium or potassium salts, can be used medicinally, as described below, and are preferred. These and other salts, which are not necessarily physiologically acceptable, are useful in the isolation or purification of a product acceptable for the purposes described below, as illustrated with the die-cyclohexylamine salt in the examples. The salts are prepared by reacting the acid form of the compound with an equivalent of the base to provide the desired basic ion, in a medium in which the salt precipitates, or in an aqueous medium and subsequent lyophilization. The free acid form can be obtained from the salt using conventional neutralization techniques, for example, with potassium hydrogen sulfate, hydrochloric acid, etc.

The compounds of formula 1, wherein 35 represents hydrogen, R 1 -C 4 -C- or a substituent of the disulfide-800 1 5 99 7 type, especially wherein hydrogen represents, are useful as hypotensive agents. They inhibit the conversion of the deca-peptide angiotensin I to angiotensin II and are therefore useful for reducing angiotensin-related hypertension.

Angiotensin I is formed by the action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma. Angiotensin I is converted into angiotensin II by angiotensin converting enzyme (ACE). The latter is an active blood pressure enhancer, which is believed to be the cause of varying forms of hypertension in varying mammalian species, for example, rats and dogs. The compounds of the invention break the angiotensinogen - * (renin) * * angiotensin I - »· (ACE) -> · angiotensin II chain by inhibiting the angiotensin converting enzyme and reducing or eliminating the formation of the blood-boosting blood substance angiotensin II. Thus, by administration of a product containing one or more compounds of the formula 1, angiotensin-dependent hypertension in the mammalian species suffering therefrom is reduced. A single dose or preferably 2-4 partial doses daily based on about 0.1-100 mg per kg body weight per day, preferably about 1-15 mg per kg body weight per day, is suitable for reducing the blood pressure. The substance is preferably administered orally, but parenteral routes of administration, such as subcutaneous, intramuscular, intravenous or intraperitoneal administration, can also be used.

The compounds of the invention can also be formulated in combination with a diuretic for the treatment of hypertension. A combination product containing a compound of the invention and a diuretic can be administered in an effective amount comprising (for a 70 kg mammal) a total daily dose of about 30 to 600 mg, preferably about 30-300 mg of a compound of the invention and about 15-300 mg, preferably about 15-200 mg of the diuretic, to a mammalian species, for which such treatment is necessary. Examples of diuretics, which can be used in combination with a compound 800 1 5 99 * »

V

In accordance with the invention, the thiazide diuretics, for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroglume thiazide, benzdroflumethiazide, methchlothiazide, trichloromethiazide, polythiazide or benzthiazide, as well as ethacrynin-5-acid, ticryridaphthonamide tanide, triamterene, amiloride and spironolactone, and the salts of such compounds.

The compounds of formula 1 can be formulated for use in the reduction of blood pressure to formulations, such as tablets, capsules or elixirs, for oral administration or sterile solutions or suspensions for parenteral administration. About 10-500 mg of a compound or mixture of compounds of the formula 1 is mixed with a physiologically acceptable vehicle, carrier material, excipient, binder, preservative, stabilizer, flavoring, etc., to form a unit dosage form as required in the accepted pharmaceutical practice. The amount of active substance in these preparations or products is such that an appropriate dosage in the indicated range is obtained.

The invention is further illustrated but not limited by the following examples.

Example I

1- / 3- (acetylthio-1-oxopropyl / 1-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) potassium hydrogen carbonate and 69.2 g (0.50 mol) potassium carbonate and worked up with 90 ml concentrated hydrochloric acid as described in Can. J. Biochem. & Physiol. 37, 584 (1959) to provide N-carbobenzyloxy-4-hydroxy-L-proline. This product is reacted with cyclohexylamine to form the cyclohexylamine salt in a yield of 69 g; mp -193-195 ° C. The salt (34 g) is neutralized with N. chloro-35 hydrochloric acid to yield 27 g of the free acid as a colorless glass; / ct_7p ° ““ 70 (c 1% in chloroform).

800 1 5 99 9 (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 79, 189 (1957).

To facilitate the subsequent filtration of the chromium salts, 30 g of Celite (diatomaceous earth) is added to the acetone solution before the oxidizing agent is added. An air stirrer is used. The reaction mixture is filtered and the acetone filtrate is concentrated to about 300 ml before diluting with 1 liter of chloroform. The solution is washed with 300 ml of saturated sodium chloride (4x), dried (MgSO4), filtered and the solvent is evaporated, yielding N-carbobenzyloxy-4-keto-L-proline (22.8 g), which is crystallized from ether (50 ml) -hexane 15 (150 ml), whereby 17.2 g (81%) of product are obtained; melting point = 99-101 ° C, / o 7 ^ 6 = + 17 ° (c = 1% in chloroform).

(c) 4-keto-L-proline hydrobromide

20 ml of hydrogen bromide in acetic acid (30-32%) are added to 4.0 g (0.015 mol) of N-carbobenzyloxy-4-keto-L-proline, and the mixture is shaken (rotated) frequently over a period of 8 minutes. At the end of this period (when effervescence no longer occurs), the yellow-orange solution is covered with a 250 ml layer of ether, rubbing the gummy product. The ether is discarded and the resulting sticky solid triturated with fresh ether and finally with 50 ml of acetonitrile to give 4-keto-L-proline hydrobromide as a crystalline solid weighing 2.7 g (85%); melting point = 153-155 ° C (dec.); / a_7 ^ = -49 ° (c * 1% in water).

30 (d) 1- / 3- (acetylthio) -1-oxopropyl / -4-oxo-L-proline

A stirred solution of 4.1 g (0.0195 mol) of 4-keto-L-proline hydrobromide in 50 ml of water is cooled to 5 ° C and treated in portions with solid sodium carbonate (the foam is controlled by adding a few drops of ether) 35 to a pH of 8.0 (about 2 g are needed). Then, with continued stirring and cooling, a solution of 3.5 g of 8001599 10 (0.012 mol) of 3-acetylthiopropionyl chloride in 5 ml of ethyl acetate is added portionwise using a pipette while maintaining the pH at 7.0-8.0 by dropwise addition addition of 25% (w / v) sodium carbonate solution (about 10 ml). After about 5 minutes, the pH stabilizes at 8.0-8.4. After continued stirring and cooling for a total of 1 hour, the solution is washed with ethyl acetate (2 x 50 ml), covered with a 50 ml layer of ethyl acetate, stirred, cooled, carefully acidified with concentrated hydrochloric acid to a pH of 2.0 , Saturated with sodium chloride and then the layers are separated. The aqueous phase is extracted with a further amount of ethyl acetate (3 x 50 ml), the combined organic layers dried (MgSO 2) and the solvent evaporated, finally at 0.2 mm, to give 4.8 g of a yellow-orange glassy residue 15 is obtained. The 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 seeding and rubbing, 1 / 3- (acetylthio-1-oxopropyl) / - 4-oxo-L-proline, dicyclohexylamine salt crystallizes; weight after cooling overnight 2.7 g (almost 20 colorless); melting point = 191-193 ° C (dec.); +/- 24 ° (c = 1% in CHCl3).

This cyclohexylamine salt is converted to the free acid by slurrying it in ethyl acetate and treating it with 45 ml of 10% potassium hydrogen sulfate and stirring until two layers are obtained. After separating the layers, the aqueous phase is extracted with ethyl acetate (4 x 75 ml), the organic layers are combined, dried (MgSO 2) and the solvent is evaporated, yielding 3.7 g of a light yellow glassy material .

30 Anal. Calculated for CjoH13N05S:

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 II

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

Argon is passed through a cold solution of 9 ml concentrated ammonium hydroxide in 22 ml water for 800 1 99% 11 30 minutes. This material is then added to 3.65 g (0.014 mol) 1- (3- (acetylthio) -1-oxopropyl / -4-oxo-L-proline) under cooling and in an argon atmosphere. Approximately 30 minutes are required to dissolve of the proline starting material using a magnetic stirrer. Stirring in an argon atmosphere is continued at room temperature for an additional 2 hours, after which the solution is extracted with 30 ml of ethyl acetate (this operation and the operations described below are performed as much as possible in an argon atmosphere). The aqueous layer is cooled, stirred, covered with a 30 ml layer of ethyl acetate and acidified in portions with 1: 1 HCl. Sodium chloride is added, the layers are separated and the aqueous phase is extracted with a further amount of ethyl acetate (3 x 30 ml).

A brown gummy fraction remains insoluble in any of the 15 phases. After drying over MgSO 2, the combined ethyl acetate layers are evaporated to give a substantially solid residue which changes to an amorphous solid when triturated with ether and the evaporation is repeated, 1.4 g of light being repeated. yellow material.

1.3 g of this material are rubbed under 50 ml of ether, cooled for 1 hour in an argon atmosphere, filtered, washed with ether and dried in vacuo to give 1.0 g of 1- (3-mercapto-1-oxopropyl) - 4-oxo-L-proline are obtained; & 0.67 (methanol on silica gel, visualized in iodine-25 vapor).

Anal. Calculated for CgHjjNO ^ S. 0.5 ^ 0 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 III

(S) -1 - / (3-ace ty1thio) -2-methyl-1-oxopropyl) -4-oxo-L-proline.

Following the procedure of Example 1 but using D-3-acetylthio-2-methylpropionyl chloride instead of 3-acetylthiopropionyl chloride, (S) -1 - ((3-acetylthio) -2-methyl-1-oxopropyl) is obtained. -4-oxo-L-proline.

35 800 1 5 99 k.

12

Example IV

(S) ύ1- (3-mercapto-2-methyl-1-oxopropy1) -4-oxo-L-proline.

The product of example III is treated with ammonium hydroxide according to the procedure of example II, whereby (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline is obtained.

Example V

1 - / (3-ace ty1thio) -2-tr iflufme thy1-1-oxopropy1 / T4-oxo-L-proline.

(a) D.L-3- (acetylthio) -2-trifluoromethylpropionic acid.

10 α-Trifluoromethyl-acrylic acid (10 g, 0.071 mol) / prepared according to the procedure described in J. Chem. Soc. 1954, 37.1 / is cooled in a salt-ice-water bath, stirred and treated in portions with 5.7 ml (0.075 mol) of 97% thiol acetic acid. After the addition, the yellow liquid is stirred in the cold for 1 hour and after the temperature is allowed to rise to room temperature, distillation takes place with 14 g (91%) DL-3- (a <Btylthio) -2-trifluoromethylpropionic acid as light yellow oil is obtained; boiling point 149-153 ° C / 13 mm. The material solidifies when stored in the cold.

(B) D.L-3- (acetylthio) -2-trifluoromethylpropionyl chloride.

The D.L-3- (acetylthio) -2-trifluoromethylpropionylic 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 excess thionyl chloride on a rotary evaporator, the residue is distilled to give 6.8 g of DL-3- (acetylthio) -2-trifluoromethyl-propionyl chloride as a pale yellow oil: boiling point = 80-82 ° C / 16 mm.

(c) 1- (3-acetylthio) -2-trifluoromethyl-1-oxopiopyl / -4-oxo-30 L-proline.

The DL-3- (acetylthio) -2-trifluoromethylpropionyl chloride is reacted with 4-keto-L-proline hydrobromide according to the procedure of Example 1 (d) to form 1 - / (3-acety1thio) -2 -trifluoromethyl-1-oxopropy1 / 4-oxo-1-proline.

This mixture of diastereoisomers can then be separated using conventional procedures.

8001599 13

Example VI

1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline.

The product of Example V (in the form of the diastereoisomer mixture or as the separated isomers) is hydrolyzed with concentrated ammonia according to the procedure of Example II to form 1- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline.

Example VII

(S) -1- (3-mercapto-2-mercapomethyl-1-oxopropyl) -4-oxo-L-proline.

10 (a) (S) -1- / 3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl / -4-oxo-L-proline,

Following the procedure of Example 1 but using D-3-acetylthiomethyl-1-3-acetylthiopropionyl chloride instead of 3-acetylthiopropionyl chloride in part (d), (S) -1- / 3- (acetylthio) -2- (acetylthiomethyl) -1-oxopropyl / -4-oxo-L-proline.

(b) (S) -1- (3-Mercapto-2-mercaptomethyl-1-oxopropyl) -4-oxo-L-proline.

The product from part (a) is hydrolysed with concentrated ammonia according to the procedure of Example II to obtain (S) -1- (3-mercapto-2-mercaptomethyl-1-oxopropyl) -4-oxo-L-proline gt.

Example VIII

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 of Gundesmann et al. Chemische Berichte _94 , 3254 (1916) / are stirred with 1N aqueous sodium hydroxide (94 ml) under cooling with ice. The temperature of the mixture is allowed to rise to room temperature and then stirred for 5 hours. The resulting solution is washed with ether and then acidified to a pH of 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; 8001599 ft 14 melting point = 70-75 ° C, is used directly in the next reaction.

Equimolar amounts of 2- (methylthio) acrylic acid and thiol acetic acid are mixed in an argon atmosphere and stirred at 80 ° C for several hours to form 3- (acetyl-5 thio) -2- (methylthio) propionic acid.

(b) 3- (acetylthio) -2- (methylthio) propionic acid chloride.

The 3- (acetylthio) -2- (methylthio) propionic acid is heated to reflux 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- (acetyithio) -2- (methylthio) propionic acid chloride.

(c) 1- / 3- (acetylthio) -2-methylthio-1-oxopropyl / -4-oxo-L-proline.

The 3- (acetylthio) -2- (methylthio) propionic acid chloride is reacted with 4-keto-L-proline hydrobromide according to the procedure of Example 1 (d) to form 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 portion (c) is hydrolyzed with concentrated ammonia according to the procedure of Example II to form 1- (3-mercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline.

Example IX

1- (4-mercapto-1-oxobuty 1) -4-oxo-L-proline 25 (a) 1- / 4- (acetylthio) -1-oxobuty1 / -4-oxo-L-proline.

Following the procedure of Example 1, but using 4-acetylthiobutyroyl chloride instead of 3-acetylthiopropionyl chloride in part (d), 1- / 4- (acetylthio) -1-oxobutyl / -4-oxo-L- is obtained. proline.

(B) 1- (4-mercapto-1-oxobutyl) -4-oxo-L-proline.

The product from part (a) is hydrolysed with concentrated ammonia according to the procedure of Example II, whereby 1- (4-mercapto-1-oxobutyl) -4-oxo-L-proline is obtained. Example X.

35 [(2-mercapto-1-oxoethyl) -4-oxo-L-proline.

(a) 1- / 2- (acetylthio) -1-oxoethyl / -4-oxo-L-proline.

8001599 +> 15

Following the procedure of Example 1, but using acetylthioacetyl chloride instead of 3-acetyl-thiopropionyl chloride in section (d), 1- / 2- (acetyl-thio) -1-oxoethyl / -4-oxo-L-proline are obtained, 5 (b) 1- (2-mercapto-1-oxoethyl) -4-oxo-L-proline.

The product from part (a) is hydrolysed with concentrated ammonia according to the procedure of Example II to obtain 1- (2-mercapto-1-oxo thy1) -4-oxo-L-proline.

Example XI

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

Following the procedure of Example 1 but using 3-acetylthio-2,2-dimethylpropionyl chloride instead of 3-acetylthiopropionyl chloride in part (d), 1- / 3- (acetylthio) -2,2-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 hydrolysed with concentrated ammonia according to the procedure of Example II, 20 to obtain 1- (3-mercapto-2,2-dimethyl-1-oxopropyl) -4-oxo-L-proline.

Example XII

(S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-oxo-L-proline (a) (S) —1— / 3— (acetylthio) -2-ethyl-1-oxopropyl / -4-oxo-L-proline.

According to the procedure of Example I but using D-3-acetylthio-2-ethylpropionyl chloride instead of D-3-acetylthio-2-methylpropionyl chloride in part (d), (S) -1- / 3- ( acetylthio) -2-ethyl-1-oxopropyl / -4-oxo-L-proline.

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

The product from part (a) is hydrolysed with concentrated ammonia according to the procedure of Example II, whereby (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-oxo-L-proline is obtained.

Example XIII

1- (3-Mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid 8001599 16 (a) 1- / 3- (acetylthio) -1-oxopropyl / -4-oxo-L-pipecolic acid

Following the procedure of Example 1 but using 4-keto-L-pipecolic acid instead of 4-keto-L-proline in part (d), 1 / 3- (acetylthio) -1-oxo-5 propyl is obtained. -4-oxo-L-pipecolic acid.

(b) 1- (3-Meircapto-l-oxopropyl) -4-oxo-L-pipecolic acid

The product from part (a) is hydrolyzed with concentrated ammonia to give 1- (3-mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid.

Example XIV

(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -5-oxo-L-pipecolic acid (a) (S) -1- / 3- (acetylthio) -2-methyl-1-oxopropyl / -5-oxo-1-pipecolinic acid

Following the procedure of Example I but under you use 5-keto-Lp ip eco line acid instead of 4-keto-L-proline in part (d) and D-3-acetylthio-2-methylpropionyl chloride instead of acetylthiopropionyl chloride in section (d) gives (S) -1- / 3- (acetylthio-2-methyl-1-oxopropyl / -5-keto-L-pipeclinic acid.

20 (b) (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -5-keto-L-pipecolinic acid

The product from part (a) is hydrolysed with concentrated ammonia according to the procedure of Example II, whereby (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -5-keto-L-25 pipecolic acid.

Example XV

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

(a) 3 - // (4-methoxy) phenylmethyl / thio / -2-trifluoromethylpropionyl chloride, A pure mixture of 1-trifluoromethyl acrylic acid (3.9 g) and 4-methoxybenzylthiol (4.3 g) is added Stirred at 100-110 ° for 1 hour. The mixture is allowed to cool to room temperature and the solid is recrystallized from cyclohexane to give 3 - ((4-methoxy) phenylmethyl / thio / -2-trifluoro-35-methopionic acid; melting point »72-74 ° G.

Treatment of this acid with thionyl chloride 800 1 5 99 17 gives 3 - // (4-methoxy) phenylmethyl / thio / -2-trifluoromethylpropionyl chloride.

(b) 1- / 3 - // (4-methoxy) phenylmethyl / thio / -2-trifluoromethyl-1-oxo-propyl / -4-oxo-L-proline 5 The 3 - // (4-methoxy) phenylmethyl / thio / -2-trifluoromethyl-propionyl 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 anisole in a nitrogen atmosphere. The solvents are removed in vacuo to give 1- (3-mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline as a residue.

Example XVI

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

(a) (S) -1- / 3- (acetylthio) -3-methyl-1-oxopropy1 / -4-oxo-L-proline.

Following the procedure of Example I but using D-3-acetylthio-3-methylpropionyl chloride instead of 3-acetylthiopropionyl chloride in part (d), (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-3-25 methyl-1-oxopropyl) -4-oxo-L-proline.

Examples XVII-XXV

Following the procedure of Example I but replacing the 3-acetylthiopropionyl chloride with the acid chloride in column I of the table below, the acylmercapto product in column II of the table below is obtained.

8001599 18

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Example XXVI

(S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline-1-adaman-tanamine salt

The product of Example IV can also be prepared according to the procedure described below.

(a) N-Carbobenzyloxy-4,4-dimethoxy-L-proline methyl ester,

A stirred solution of 7.8 g (0.03 mol) of N-carbobenzyloxy-4-keto-L-proline from Example I in 60 ml of methanol is treated with 96 ml of trimethyl orthoformate, followed by 0.6 ml of concentrated sulfuric acid, after which the mixture is left 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 most of the solvent is removed on a rotary evaporator to give a syrupy residue, which is shaken with 30 ml water and 30 ml of chloroform. After separating the layers, the aqueous phase is extracted with a further amount of chloroform (3 x 30 ml) and the combined organic layers are washed with 45 ml of saturated sodium 20 chloride solution and dried (MgSO 2). 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) 25 is dissolved in 80 ml of methanol, treated dropwise at -1 to 4 ° C with 18 ml (0.036 mol) 2N. sodium hydroxide, kept at 0 ° C for 1 hour and at room temperature overnight.

After removing about 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 with cooling with 63 ml of 1: 1 hydrochloric acid to a pH of 2 and extracted with ethyl acetate (4 x 750 ml).

The combined extracts are washed with 50 ml of saturated sodium chloride solution, dried (MgSO4) and the solvent is evaporated, yielding 8.0 g of a pale yellow viscous oil. The oil is dissolved in 35 ml of ethanol, treated with 800 1 of 5 99 20 3.0 g of cyclohexylamine in 10 ml of ethanol and diluted to 500 ml with ether. Upon grafting and rubbing, the crystalline N-carbobenzyl-oxy-4,4-dimethoxy-L-proline cyclohexylamine salt is separated; weight after cooling overnight 7.0 g; melting point = 5 157-159 ° C (s, 151) / a 7-7 = -34 ° (c = 1% in EtOH). This material is recrystallized from 100 ml of acetonitrile, whereby the salt is obtained as a colorless solid; melting point = 158-160 ° C (s, 154 °); faj * 6 = -33 ° (c = 1% in EtOH).

The N-carbob enzymloxy-4,4-dimethoxy-L-proline-10 cyclohexylamine salt is suspended in 40 ml ethyl acetate, stirred and treated with 25 ml IN. hydrochloric acid. After two clear layers are obtained, they are separated and the aqueous phase is extracted with a further amount of ethyl acetate (3 x 40 ml), the combined organic layers are dried (MgSO 2) and the solvent is evaporated, finally at 0, 2 mm and 40 ° C, whereby 7.2 g (70%) of N-carbobenzyloxy-4,4-dimethoxy-L-proline are obtained as a pale yellow viscous syrup.

(c) 4.4-άίιηΒίίκ ^ -Ι-ρή) 1ίη6.

A solution of N-carbobenzyloxy-4,4-dimethoxy-L-proline (72 g, 0.022 mol) in 210 ml of methanol-water (2: 1) is treated with 2.3 g%% palladium carbon and shaken on a Parr hydrogenator for 6 hours. The catalyst is filtered off in a nitrogen atmosphere, washed with methanol and the combined filtrates are evaporated, finally at 0.1-0.2 mm, yielding a partially crystalline residue.

This residue is taken up in 200 ml of methanol and the evaporation is repeated. When the solid is triturated under ether (evaporation is repeated again) 3.6 g (95%) of nearly colorless 4.4-dimethoxy-L-proline are obtained; melting point * 192-194 ° C (dec.); / "a_7p6 = -47 ° (c - 1% in MeOH).

A sample, crystallized from methanol-ether, is colorless and melts at 197-198 ° C (dec.); / a_7 ^ = -49 ° (c - 1% in MeOH).

(D) (S) -1- / 3- (acetylthio) -2-methyl-1-oxopropyl / -4,4-dimethoxy-L-proline.

800 1 5 99 21

A stirred solution of 3.3 g (0.019 mol) o 4.4-dimethoxy-L-proline with 50 ml of water is cooled to 5 C and brought to a pH of 8.5 by adding 25% sodium carbonate solution (g / v). Then, with continued stirring and cooling, a solution of 3.8 g (0.021 mol) of D-3-acetyl-thio-2-methylpropanoyl chloride in 5 ml of ether is added portionwise while maintaining the pH at 7.5-8 .5 by dropwise addition of 25% sodium carbonate solution. After the pH has stabilized at 8.2-8m4 (after about 15 minutes), stirring and cooling are continued for a total of 1 hour. The solution is then washed with 50 ml of ethyl acetate (the washing liquid is discarded), covered with a 50 ml layer of ethyl acetate, cooled, stirred, carefully acidified with 1: 1 hydrochloric acid to a pH of 2.0, saturated with sodium chloride and the layers are separated. The aqueous phase is extracted with a further amount of ethyl acetate (3 x 50 ml), the combined organic layers are dried (MgSO 2) and the solvent is evaporated, finally at 0.2 mm, yielding 6.7 g of a viscous product obtained. This syrup is treated in 70 ml of ethyl acetate with 3.9 g of dicyclohexylamine, 6.5 g of colorless (S) -1- / 3- (acetylthio) -2-methyl-1-oxopropyl / - 4,4-dimethoxy-L- proline dicyclohexylamine salt are obtained in two yields (3.1 g and 3.4 g); melting point = 158-160 ° C (s, 145 °) /) ct_7 ^ 6 = -71 ° (c = 1% in EtOH).

After recrystallization from 20 ml of hot ethyl acetate - 60 ml of hexane, the colorless solid salt weighs 6.0 g; melting point = 158-166 ° C (s, 155 °); / ~ a_7 ^ 5 = -69 ° (c = 1% in EtOH).

The dicyclohexylamine salt is converted to the free acid by suspending 5.0 g in 50 ml of ethyl acetate, cooling and treatment with 60 ml of 10% fs potassium hydrogen sulfate solution to form two clear layers. After the separation, the aqueous phase is extracted with ethyl acetate (3 x 50 ml), the combined organic layers are dried (MgSO 2) and the solvent is evaporated, finally at 0.1-0.2 mm and 45 ° C, 35 4.1 g (69%) (S) -1- / 3- (acetylthio -) - 2-methyl-1-oxopropyl / ~ 4.4-dimethoxy-L-proline as a viscous, almost glassy material 800 1 5 99 22 are obtained; / α_7 ^ * -112 ° (c = 1% in EtOH).

(d) (S) -1- (3-mer captó-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline

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 latter is then added to 4.1 g (0.013 mol) (S) -1- / 3- (acetyl-thio) -2-methyl-1-oxopropyl / -4,4-dimethoxy-L- under cooling and in an argon atmosphere. proline and the mixture is swirled in an ice bath until a pale yellow solution 10 is obtained (about 15 minutes). Stirring in an argon atmosphere is continued at room temperature for an additional 2 hours and then the solution is extracted with 30 ml of ethyl acetate (this operation and the subsequent operations are carried out as much as possible in an argon atmosphere). The aqueous layer is cooled, stirred, covered with a 30 ml layer of ethyl acetate and acidified in portions with about 16 ml of 1: 1 hydrochloric acid. The layers are separated, the aqueous phase is extracted with a further amount of ethyl acetate (3 x 30 ml), the combined ethyl acetate layers are dried (MgSO4) and the solvent is evaporated, 3.5 g (100%) ( S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline are obtained as a colorless viscous syrup; / a _ / ^ = -72 ° (c = 1% in EtOH).

The latter (3.4 g) is triturated with 20 ml of ethyl acetate, triturated (scratched), diluted with 30 ml of hexane and cooled to give a colorless solid weighing 2.6 g; melting point = 108-110 ° C; Γ <x _! ^ S -77 ° (c = 1% in EtOH).

(f) (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline, 30 1-adamantanamine salt

The (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline (0.4 g, 0.0014 mol) is added to 8 ml of stirred N.HCl, whereby Argon has been fed in advance for 10 minutes. After a solution is obtained, the flask is sealed under argon and kept at room temperature overnight. The following steps are also carried out in an 8001599 23 argon atmosphere to the extent possible. 20 ml of methylene chloride are added to the stirred solution and after saturation with sodium chloride the layers are separated. The aqueous phase is extracted with a further amount of methylene chloride (3 x 15 ml), the organic layers are combined, dried (MgSO 2) and the solvents are evaporated, yielding a foamy residue. After the trituration with ether (evaporation repeated), 0.26 g of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline are obtained as an amorphous solid (hygroscopic ).

0.245 g of this product are dissolved in 7 ml of acetonitrile and treated with 0.17 g of 1-adamantanamine, precipitating the salt as a bulky solid. After cooling overnight, the colorless material is filtered off, 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 = 188-190 ° C (dec.); s. 184 °; / 7 7 ^ = -13 ° (c = 1% in methanol).

Anal. Calculated for CnH, N0, S. C, H,., N. 0.25 H „0: - 9 13 4 10 17 2 20 C 58.96, H 8.02, N 7.24, S 8.29

Found: C 58.60, H 8.37, N 7.36, S 8.29

Example XXVII

1.1 * - / dithiobis (1-oxo-3,1-propanediyl) / bis / 4-oxo-L-proline /

The product of Example II is dissolved in water and the pH is adjusted to 6.5 by adding IN.

sodium hydroxide. To this stirred solution, a 0.5 M iodine solution in 95% ethanol (6.34 g iodine / 50 ml solution) is added dropwise while maintaining the pH at 5.5-6.5 with 1N. sodium hydroxide. The excess iodine is removed with dilute sodium thiosulfate and the solution is concentrated, cooled and acidified with 1: 1 hydrochloric acid. Solvent is added and the layers are separated. The organic layer is dried (MgSO4) and the solvent is evaporated, yielding 1.1 '/ dithiobis (1-oxo-3,1-propanediyl) / bis / 4-oxo-L-proline / as a residue.

8001599 24

Example XXVIII

1/3 "(acetylthio) -1-oxopropyl / -4-oxo-L-proline methyl ester,

A solution of the product of Example I in ether is treated with a small excess of diazomethane.

After standing at room temperature for 2 hours, the solvent is evaporated to yield 1 / 3- (acetylthio) -1-oxopropyl / -4-oxo-L-proline methyl ester.

Example XXIX

1- (3-Mercapto-1-Oxopropyl) -4-oxo-L-proline-methyl ester The product of Example XXVIII is hydrolysed with concentrated ammonia according to the procedure of Example II, wherein 1- (3-Mercapto-1 -oxopropyl) -4-oxo-L-proline methyl ester is obtained.

Example XXX

1- (3-mercapto-1-oxopropyl) -1-oxo-L-proline sodium salt.

A solution of 1.0 g of the product of Example II is dissolved in 10 ml of water and treated with an equivalent sodium hydrogen carbonate. The solution is lyophilized to yield 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline-20 sodium salt.

Analogously, the corresponding potassium salt is obtained using potassium hydrogen carbonate.

Example XXXI

25 (S) -1- (3-mercapto-2-methyl-1-oxopropyl) ^ - oxo-L-proline sodium salt

A solution of 1.0 g of the product of Example IV is dissolved in 10 ml of water and treated with one equivalent of sodium hydrogen carbonate. The solution is lyophilized to yield 1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline sodium salt.

Analogously, the corresponding potassium salt is obtained using potassium hydrogen carbonate.

Example XXXII

1000 tablets, each containing the following ingredients 8001599 25: 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 100 mg

Corn starch 50 mg 5 Gelatin 7.5 mg

Avicel (microcrystalline cellulose) 25 mg

Magnesium stearate 2.5 mg 185 mg are prepared (from sufficient amounts by mass) 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 into a fine powder. The Avicel and then the magnesium stearate are mixed under granulation. This mixture is then compressed in a tablet press to form 1000 tablets, each containing 100 mg of the active ingredient. Example XXXIII

Tablets each containing 100 mg (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline are prepared as described in Example XXXII.

Example XXXIV

1000 tablets, each containing 50 mg of 1- (3-mer-capto-1-oxopropyl) -4-oxo-L-proline, are prepared from the following ingredients: 1- (3-mercapto-1-oxopropyl) - 25 4 -oxo-L-proline 50 g

Lactose 100 g

Avicel 150 g

Corn starch 50 g

Magnesium stearate 5 g. The 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline, lactose and Avicel are mixed and the mixture is then mixed with corn starch. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 tablets of 355 mg each, each containing 50 mg of the active ingredient. The tablets are coated with a solution of Methocel E 15 (methyl cellulose), containing as dye a 800 1 5 99 R * 26 lacquer, containing yellow No. 6.

Example XXXV

Tablets each containing 50 mg of (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline are prepared as described in Example XXXIV.

Example XXXVI

Two-piece No. 1 gelatin capsules, each containing 100 mg of 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline sodium salt, are filled with a mixture of the 10 following ingredients: 1- 3-mercapto-1-oxopropyl) -4-oxo-L-proline 100 mg

Magnesium stearate 7 mg

Lactose 193 mg

Example XXXVII

Gelatin capsules containing 100 mg (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline sodium salt are prepared in the manner described in Example XXXVI.

Example XXXVIII

An injectable solution is prepared from the following ingredients: 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 500 g

Methylparaben 5 g

Propylparaben 1 g

Sodium chloride 25 g 25 Water for injections qs. 5 liters

The active substance, preservatives and sodium chloride are dissolved in 3 liters of water and then the volume is brought to 5 liters. The solution is filtered through a sterile filter and aseptically filled into pre-sterilized vials, which are then sealed with pre-sterilized rubber seals. Each vial contains 5 ml of solution at a concentration of 100 mg of active ingredient per ml of solution for injection.

Example XXXIX

An injection solution containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline is prepared in 8001599 27 as described in Example XXXVIII.

Example XL

6000 tablets, each containing the following ingredients: 5 l- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 100 mg

Avicel (microcrystalline cellulose) 100 mg

Hydrochlorothiazide 12.5 mg

Lactose U.S.P. 113 mg

Corn starch U.S.P. 17.5 mg 10 Stearic Acid U.S.P. 7 mg 350 mg are prepared in sufficient amounts to form slag from 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline, Avicel and part of the stearic acid. The snails are ground and passed through a No. 2 screen, then mixed with the hydrochlorothiazide, lactose, corn starch and the rest of the stearic acid. The mixture is compressed into 350 mg capsule-shaped tablets in a tablet press. The tablets are scored to allow them to break in two.

Example XLI

Tablets containing (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline and hydrochlorothiazide are prepared as described in Example XL.

The product of Examples I, III, V-XXV and XXVII-XXIX can also be formulated according to the procedures of Examples XXXII-XLI.

300 1 5 99

Claims (43)

1. Compounds of the general formula 1 or physiologically acceptable salts thereof, wherein R represents hydrogen or lower alkyl, R 1 and R 4 are independently selected from hydrogen, lower alkyl, lower alkyl thio, - (C 2 -S-SH and substituted by halogen) lower alkyl, R2 represents hydrogen or lower alkyl, where R2 is only lower alkyl when Rj represents lower alkyl, m represents 0, 1 or 2, n represents 1, 2 or 3, p and q each represent 1 or 2, both not at the same time are 10 2, and R 1 represents hydrogen, a hydrolyzable removable protective group, a chemically removable protective group or, when R 1 and R 2 have a meaning other than - (®2) n-SH, a group of the formula 1a . 2. Compounds according to claim 1, characterized in that p 2 and q is 1. Compounds according to claim 1, characterized in that p is 1 and q 2. Compounds according to claim 1, characterized in that p and q are both 1. 2Q 5. Compounds of the general formula 7 or physiologically acceptable salts thereof, wherein R 1 and R 2 both represent lower alkyl of 1-4 carbon atoms or R 2 represents hydrogen and R 2 represents hydrogen, lower alkyl of 1-4 carbon atoms, trifluoromethyl, methylthio , or mercaptomethyl, m-22 represents 0 or 1 and R 2 represents hydrogen, lower alkanoyl of 1-4 carbon atoms or benzoyl. Compounds according to claim 5, characterized in that R 1 and R 2 both represent methyl and η 1. Compounds according to claim 5, characterized in that R 2 represent hydrogen, R 1 trifluoromethyl and m 1. Compounds according to claim 5, characterized in that R 2 represents hydrogen, R 1 methylthio and m 1. Compounds according to claim 5, characterized in that R 2 represents hydrogen, R 1 mercaptomethyl and m 1. Compounds according to claim 5, characterized in that R 1 and R 2 both represent hydrogen. 8001599 Compounds according to claim 10, characterized in that m is 1. Compounds according to claim 11, characterized in that acetyl is, Compounds according to claim II, characterized in that R 1 is hydrogen. Compounds according to claim 10, characterized in that m is 0. 15. Compounds according to claim 5, characterized in that R 1 represents hydrogen, R 1 methyl and m 1. Compounds according to claim 15, characterized in that R 1 is acetyl. Compounds according to claim 15, characterized in that R 1 is hydrogen. The compound according to claim 17, namely (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline. Pharmaceutical preparation for the treatment of hyper tension, characterized in that it comprises a pharmaceutically acceptable carrier and one or more hypotensive agents or physiologically acceptable salts thereof of the general formula 1, wherein R represents hydrogen or lower alkyl , R 1 and R 1 are independently selected from hydrogen, lower alkyl, lower alkylthio, - (CHp 2 -SH and halogen-substituted lower alkyl, R 2 represents hydrogen or lower alkyl, where R 2 represents only lower alkyl when R 1 is lower alkyl, m represents 0, 1 or 2, n represents 1, 2 or 3, p and q each represent 1 or 2, both being not 2 at the same time, R ^ represents hydrogen, a hydrolysable removable protective group or, when Rj and R2 have a meaning other than - (C0 ^ - - SH, a group 30 of the formula la. Pharmaceutical composition according to claim 19, characterized in that the hypotensive agent is a compound of formula 17, wherein R 1 and R 2 both represent lower alkyl of 1-4 carbon atoms or R 2 represents hydrogen and R 1 represents hydrogen, lower alkyl of 1 -4 carbon atoms, trifluoromethyl, methylthio or mercaptomethyl, m represents 0 or 1 and R 1 represents 8001599 hydrogen, lower alkanoyl of 1-4 carbon atoms or benzoyl. 21. A composition according to claim 20, characterized in that R 1, R 2 and R 1 represent hydrogen and m 1. 22. A composition according to claim 20, characterized in that R 1 represents methyl, R 2 and R 1 represent hydrogen and m 1. Preparation according to claim 19, characterized in that it also contains a diuretic. 24. A method of reducing hypertension, characterized in that an effective amount of a composition according to claim 19 is administered. 25. Process for preparing a keto-substituted poline or pipecolic acid of the general formula 1 or a physiologically acceptable salt thereof, wherein R represents hydrogen or lower alkyl, R 1 and R 4 are independently selected from hydrogen, lower alkyl, lower alkylthio, - (G 1) -SH and halogen-substituted lower alkyl, R 2 represents hydrogen or lower alkyl, where R 2 represents only lower alkyl when R 1 represents lower alkyl, m represents 0, 1 or 2, n represents 1, 2 or 3 , p and q each represent 1 or 2, both of which are not 2 at the same time, and R 1 represents hydrogen, a hydrolyzable removable protective group, a chemically removable protective group, or, when R 1 has a meaning other than - (CE ^^ - SH, a group of the formula la, characterized in that (a) a keto-substituted proline or pipecolin-acid of the formula 2 is coupled with an acid or a chemical equivalent thereof of the formula 3 , where R ^ 'represents what a substance or a hydrolyzable or chemically removable protective group, to form a product wherein R 1 represents hydrogen or a hydrolyzable or chemically removable protective group, and this protective group is optionally removed and, when R 1 and R 1 have a meaning other than - (C 2 -SH, the product in which R 1 represents hydrogen, oxidizes with iodine to form a product, in which R 1 represents a group of the formula la, or (b) from the desired product, wherein the keto group is protected, the protecting group removes. The method of claim 25, characterized in that 8001599 is characterized in that p is 2 and q is 1. A method according to claim 25, characterized in that p is 1 and q is 2. 28. A method according to claim 25, characterized in that p and q are both 1. 29. Process according to claim 25, characterized in that the product is a product of the formula 7 or a physiologically acceptable salt thereof, wherein R 1 and R 2 both represent lower alkyl of 1-4 carbon atoms or R 8 represents hydrogen and R 1 represents hydrogen, lower alkyl of 1-4 carbon atoms, trifluoromethyl, methylthio or mercaptomethyl, m represents 0 or 1 and R 1 represents hydrogen, lower alkanoyl of 1-4 carbon atoms or benzoyl. 30. A process according to claim 29, characterized in that R 1 and R 2 both represent methyl and η 1. 31. Process according to claim 29, characterized in that R 2 represents hydrogen, R 1 trifluoromethyl and m 1. 32. Process according to claim 29, characterized in that R 2 represents hydrogen, R 1 methyl-thio and m 1. 20 The process according to claim 29, characterized in that R 2 represents hydrogen, R 1 mercaptomethyl and m 1. A method according to claim 29, characterized in that R 1 and R 2 both represent hydrogen. 35. A method according to claim 34, characterized in that m is 1. 36. Process according to claim 35, characterized in that R 1 is acetyl. 37. A process according to claim 35, characterized in that R 1 is hydrogen. A method according to claim 35, characterized in that m is 0. 39. Process according to claim 29, characterized in that R 2 represents hydrogen, R 1 methyl and m 1. 40. A method according to claim 39, characterized in that R 1 is acetyl. A method according to claim 39, characterized in 8001599, which is hydrogen. 42. Process according to claim 41, characterized in that the product is (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline. 43. Compounds, preparations and methods as described in the description and / or examples. I .. 8001599