NL8000206A - CARBAMATE DERIVATIVES OF MERCAPTOACYL HYDROXYPROLINS, AND METHODS FOR PREPARING AND USING THESE PROLINS. - Google Patents

Description

s ',' -t * "Carbamate derivatives of marcaptoacylhydroxyprolines, as well as processes for the preparation and use of these prolines”.

The invention relates to novel carbamate derivatives of mercaptoacylhydroxyprolines of formula 1, wherein R, R 1 and R 2 independently of each other / a hydrogen atom / a lower alkyl group or a trifluoromethyl group and R and S, independently of one another, a hydrogen atom / a lower alkyl group, a cyclo-lower alkyl group, an allyl, propargyl, phenyl, or substituted phenyl group, or wherein R q and R 2 together with the nitrogen atom form a 5- or 6-ring heterocycle, R 1 a hydrogen atom or a hydrolyzable, organic, protecting group of formula R 1 -CO- or of formula 1a and R 1. a lower alkyl group, a phenyl, substituted phenyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, cycloalkyl, thienyl or furyl group and n »0, 1 or 2, as well as the salts thereof, as well as new intermediates -ducts therefor, as well as to methods of preparing and using these derivatives.

The asterisks in the formulas indicate centers of asymmetry. The carbon atom in the non-cyclic side chain is asymmetric if R2 and / or has a meaning other than hydrogen. Each of the centers of asymmetry give D and L shapes which can be separated by conventional methods described below. The carbamate group of formula

> R

/ 0

-0C0N

\ R

R1 25 also gives rise to cis tranaisomeria.

The invention is directed to new compounds of formula 1 and their salts, to methods of preparing 8000206 2 drugs containing such compounds and / or their salts, and to a method of using these compounds as anti-hypertensive agents. The substituents and symbols have the meanings indicated above.

The lower alkyl groups represented by the substituents or symbols include straight or branched chain hydrocarbon groups having up to 7 carbon atoms, such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl - or isopentyl group, etc. The lower alkyl groups with up to 10 4 carbon atoms and in particular those with 1 or 2 carbon atoms are recommended.

The cyclo-lower alkyl groups are the alicyclic groups with up to 7 carbon atoms, i.e. the cycloproyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group. Of these, the cyclopentyl and cyclohexyl groups are recommended.

Examples of substituted phenyl groups are mono-substituted phenyl rings in which the phenyl substituent is halogen, lower alkyl, lower alkoxy, lower alkylthio or trifluoromethyl. The lower alkoxy and lower alkyl capo groups include empty alkyl groups of the type described above. Examples of this are the

V

methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, methyl thio, ethylthio, propylthio and isopropylthio group, etc. The preferences expressed above for groups 1 to 4 and 1 or 2 carbon atoms also apply here. Halogen atoms are the four common halogens, preferably chlorine or bromine, which provide groups such as o-, m- and p-chlorophenyl, o-, m- and p-chlorophenyl, etc.

The phenyl group and substituted phenyl group can also be described as 30 wherein Rg represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkylthio or trifluoromethyl group.

Examples of phenyl-lower alkyl groups are lower alkyl groups of the type described above which are attached to the phenyl ring 35. Phenylmethyl and phenylethyl are the recommended phenyl-8000206 Α Ά 3 lower alkyl groups, especially the phenylmethyl group.

Preferred groups of form Rg-CO- are those in which Rj. represents a lower alkyl, phenyl, or phenyl-lower alkyl group.

The lower alkanoyl groups, represented by Rg-CO-, are those which are just the acyl groups of the lower (C2-C7) fatty acids, such as, for example, acetyl, propionyl, fautyryl, isobutyryl, etc. The lower alkanoyl groups, with at most 4 carbon atoms, in the especially the acetyl group, deserve recommendation. The same recommendations apply to the phenyl-lower alkanoyl groups, wherein Rj. in the R 1 -CO group is the phenyl-lower alkyl group. The benzoyl group is particularly recommended.

The carbamate group on the pyrrolidine ring may be non-cyclic, including, for example, the carbamoyl group, lower alkyl-15 carbamoyl group, such as the methyl carbamoyl group, ethyl carbamoyl group, propyl carbamoyl group, and isopropyl carbamoyl group, propylcaroyl carbyl group, dimethyl diethyl group allylcarbamoyl group. Also included are cycloalkylcarbamoyl groups such as the cyclopentylcarba-20 maoyl, dicyclopentylcarbamoyl, cyclohexylcarbamoyl and dicyclohexylcarbamoyl group, etc. In addition, the phenyl and substituted phenylcarbamoyl soaps, such as the phenylcarbamoyl, 4-chloro-phenylcarbamoyl, 3-ethylphenylcarbamoyl, 4-methoxyphenylcarbamoyl and 4- (trifluoromethyl) phenylcarbamoyl group, etc. Preferably, only 25 substituents are used. ^ ea R ^ a cycloalkyl, phenyl or substituted phenyl group. _

The -N group can also be a heterocyclic

Sr 5- or 6-ring forms of the 1 pyrrolidine, piperidine or morpholine series.

Preferably, only one of the substitents R and R has a meaning other than water, unless both o 1

Rq and R 'substituents represent a lower alkyl group.

Preferred compounds of formula 1 are those wherein R is a hydrogen atom or a lower alkyl group, Rq and 35, independently, an alkyl group having up to 4 carbon atoms, and, independently, a hydrogen atom or an alkyl group with also at most 4 carbon atoms, R 1 a hydrogen atom, a lower alkanoyl or benzoyl group and n represent 0 or 1. The carbamate group is in the 3- or 4-position of the pyrrolidine ring, preferably in the 4-position.

Especially recommended are compounds of formula 1, wherein R is a hydrogen atom, R and R ,, independently of each other, an alkyl group with at most 4 carbon atoms, in particular an alkyl group with at most 3 carbon atoms, a methyl group, 10 R. a hydrogen atom , R. represent a hydrogen atom and η 1, 3 4 where the carbamate group is in the 4 position.

The recommended method for synthesizing compounds of formula 1 is based on a hydroxyproline of formula 2.

Herein, the nitrogen atom is first protected with, for example, a nitrogen protecting group of the type commonly used in the peptide synthesis, such as the carbomethoxy, t-toluenesulfonyl or acetyl group, etc., thereby providing a protected compound, such as the compound having formula 3, wherein CB represents the z20 carbobenzyloxy protecting group.

The protective compound of formula 3 is then esterified, for example, by reaction with a diazoalkane, such as diazomethane, to give an ester of formula 4, wherein R represents a lower alkyl group, such as the methyl or isobutyl group, preferably the methyl group .

/ ¾

Then the carbamate group of formula -OCO-N

where R represents a hydrogen atom and R has a meaning other than 1 o 1 than hydrogen are introduced by reacting a compound of formula 4 with an isocyanate (R 1 -NCO) in an inert organic solvent, such as benzene, etc. to obtain the following intermediate of formula 5.

To prepare the cis isomer, the above-described reaction is carried out in the presence of a catalytic amount of a base, such as pyridine or triethylamine.

It is also possible to prepare a compound of formula 5 8000206 t 5 by reacting the protective compound of formula 4 with phosgene to form an intermediate of formula 6 (which does not necessarily need to be isolated), which is then treated with a suitable amine yRq or NH ^ (in which both substituents

SN

\ R1

Rq and R ^ represent a hydrogen atom) to a compound of the formula 5, react.

If R and R (in formula 5) both have a different meaning than hydrogen or complete a heterocyclic ring together, the protective compound of formula 4 is reacted with the carbamoyl halide of formula 7, wherein hal a halo no atom, preferably chlorine.

Alkaline hydrolysis of a compound of formula 15 with a base such as sodium hydroxide, barium hydroxide or potassium hydroxide, etc., results in an acid of formula 8.

This compound of formula 8 in acid or ester form can then be released, for example, by the usual hydrogenation in the presence of palladium on carbon, whereby a compound of formula 9 is obtained.

The next step of the synthesis involves the coupling of a proline derivative of the formula 9 with an acid of the formula 10, most suitably in the form of acid chloride, whereby a product of the formula 11 is obtained.

The formed proline derivative of formula 11 is preferably separated by crystallization and purified, for example, by formation of a salt, such as dicyclohexylamine salt, and then conversion of this salt to the free acid form by treatment with an acid solution, such as potassium hydrogen sulfate, in water.

The product of formula 11 containing the acyl group R 1 -C 0 may optionally be converted into the product of formula 1 wherein R 1 represents a water phosphate by hydrolysis with ammonia, sodium hydroxide, etc.

Esters of formula 1, in which R represents a lower alkyl group 8000206 6, can be used according to conventional esterification methods, for example by esterification with a diazoalkane, such as diazomethane, 1-alkyl-3-t-tolyltriazene, such as 1-butyl-3-p-tolyltriazene , etc., preferably after completing the series of reactions described above, are converted. However, it is also possible to esterify earlier and to omit the alkaline hydrolysis.

The compounds of formula 1 in which the symmetrical bis compound forms are obtained by direct oxidation of a compound of formula 1, in which R 4 is a hydrogen atom, with iodine 10.

For further information regarding the preparation of the starting materials and intermediates, reference is made to the following publications: U.S. Pat. Nos. 4,046,889 and 4,105,776, J. Chem. Soc. (1945), 429-432, J. Amer. Chem. Soc., 79, 15 185-192 (1957) and J. Amer. Soc., 85, 3863-3865 (1963). The methods described therein can be used as general methods for the synthesis and stereo conversion of compounds useful in the invention.

Additional experimental data can be found in the examples, which show recommended embodiments and also serve as guidelines for preparing other members of the group.

As mentioned above, the compounds of the invention have a number of centers of asymmetry. These compounds can thus exist in stereoisomeric forms or in racemic mixtures thereof. These various stereoisomeric forms and mixtures thereof are within the scope of the invention. In the synthesis methods described above, both the racemate and one of the enantiomers can be used as starting material. If a product is obtained as a mixture of stereoisomers, these stereoisomers can, if desired, be used by conventional chromatographic or fractional crystallization methods or by conversion to a salt with an optically active base followed by fractional crystallization, or by corresponding known methods. , 35 are separated. Generally, those compounds are recommended in 8000206 «4 7 wherein the proline portion is in the L configuration, the carbate group is cis, and the acyl side chain is in the D configuration.

The compounds according to the invention form basic salts with a large number of inorganic and inorganic bases.

The salt-forming ion derived from such bases may be a metal ion, for example aluminum, an alkali metal ion such as sodium or potassium, an alkaline earth metal ion such as calcium or magnesium or an amine salt ion, some of which are known for this purpose, e.g. ar ^ alkylamine, such as dibenzylamine, N, N-dibenzylethylenediamine, a low alkylamine, such as methylamine, triethyl amine, t-butylamine and procaine, a low alkylpiperidine, such as N-ethylpiperidine, a hydroalkylamine, cyclohexylamine, di-cyclohexylamine 1-adamantanamine, and benzathine, or a salt derived from an amino acid, such as arginine, lysine, etc. The physiologically acceptable salts, such as the sodium or potassium salt, can be used in medicine as described below. and are recommended for this. These and other salts which are not necessarily physiologically acceptable are useful for separating and purifying a product for the purposes described below as well as purifying or separating intermediates as illustrated in the examples. These salts are obtained by reacting the acid of a compound with an equivalent of a base which provides the desired basic ion in the environment in which the salt is deposited or in an aqueous medium and then freeze drying. The free acid form can be liberated from the salt by conventional neutralization methods, for example with potassium bisulfate, hydrochloric acid, etc.

The compounds of the invention inhibit the conversion of the decapeptide angiotensins I to angiotensins II by the enzyme that converts angiotensin and can therefore be used to reduce or alleviate hypertension in various mammals, eg cats, dogs, mice, rats, etc. with elevated blood pressure. Thus, by administration of an effective amount of a drug containing one or more of the 800020e 8 compounds of formula 1 and / or their physiologically acceptable salts, hypertension in a mammal suffering therefrom will be , are diminished or illuminated.

A single dose, or preferably two to four partial daily doses, provided on a basis of about 0.1 to 100 mg / kg / day, preferably about 1 to 15 mg / kg / day, is suitable for lowering of blood pressure, as shown in animal experiments described by SL Engel, T.R, Schaeffer, M.H. Waugh and B. Rubin, Proc. Soc. Exp. Biol. Med. 143, 483 (1973). The compound 10 (s) of the invention are preferably administered orally, but parenteral routes, such as subcutaneous, intramuscular, intravenous or intraperitoneal, may also be employed.

The compounds of the invention may also be incorporated into a medicament together with a diuretic to treat hypertension. Such a medicament containing a compound of the invention and a diuretic can be used in an effective amount, (for a 70 kg mammal) a total daily dose of between about 30 and 600 mg, preferably about 30 to 300 mg, of a compound of the invention and containing about 15 to 300 mg, preferably about 15 to 200 mg, of a diuretic to a mammal in need thereof. Examples of diuretics, which can be used in conjunction with a compound of the invention, are the thiazide diuretics, for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethyl, trichlorothiazide, ethylthiazide, furthiazamide, furthiazide , bumetanide, triamterene, amiloride and spironolactone, as well as the salts of such compounds.

The compounds of the invention can be used to lower blood pressure by incorporating them into medicaments such as tablets, capsules and elixirs for oral administration or in sterile solutions or suspensions for parenteral administration and administration of these preparations. For this purpose, about 10 to 500 mg of a compound or mixture of compounds 8000206 9 according to the invention according to formula 1, and / or the physiologically acceptable salts thereof, together with a physiologically acceptable carrier, excipient, binder, preservative agent, stabilizer, can be used. incorporate flavors and fragrances, etc., in unit dosage form as is common in pharmaceutical practice. The amount of the active ingredient (s) in these drugs is such that an appropriate dosage in the indicated range is obtained.

Examples of additives that can be included in the tablets, 10 capsules and similar drugs are the following, a binder such as gum tragacanth, acacia, corn starch or gelatin, an excipient such as dicalcium phosphate or microcrystalline cellulose, a disintegrant such as corn starch, potato starch, alginic acid, etc., promotes a lubricant, such as magnesium stearate, a sweetener, such as sucrose, lactose or saccharin, a flavoring agent, such as peppermint oil, etc. the materials of the aforementioned type contain a liquid carrier, such as a bogem oil. Also, various other materials, coatings or agents that otherwise modify the physical form and the dosage unit may be present. For example, tablets may be coated with shellac, sugar or a mixture thereof. For example, a syrup or elixir may contain an active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, a colorant and a flavoring agent, such as an orange or cherry flavor.

Injectable sterile drugs by conventional pharmaceutical methods can be obtained by an active ingredient in a carrier, such as water for injection purposes, a naturally occurring vegetable oil, such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic dissolve or suspend oil, such as ethyl oleate.

8000206 10

Example X.

trans-1- / D- (3-acetylthlo) -2-methyl-1-oxopropyl7-4 - / "7 ~ (methylamlno) -carbonyl? -οχγ7-L-proline" 5 a) N-Carbobenyloxy-trans-4 -hydroxy-L-prollne.

26.5 g (0.20 mol) of trams-4-hydroxy-L-proline and 32.8 ml (0.23 mol) of benzyl chloroformate were left in the presence of 20 g (0.20 mol) of potassium bicarbonate and 69.2 g (0.50 mol) potassium carbonate react in 200 ml water and 100 ml acetone, after which the resulting reaction mixture is worked up with 90 ml concentrated hydrochloric acid as described in Can. J. Biochem. and Physiol. 32, 584 (1959).

To form the cyclohexylamine salt. the resulting product was reacted with cyclohexylamine, yield: 69 g, melting point: 193-195 ° C. Neutralizing 34 g of this salt with 1N hydrochloric acid gave 27 g of the free acid as a colorless glass.

/ <* _ 7q - 70 ° (c, 1% in chloroform).

b) The methyl ester of N-carbobenzyloxy-trans-4-hydroxy-L-proline.

12.4 g (0.047 mol) of N-carbobenzyloxy-20 trans-4-hydroxy-L-proline were esterified in the manner described in J.A.C.S. 79, 191 (1957) in dioxane ether with diazomethane. To avoid dioxane solidification, the addition of diazomethane was started at 10 ° C and the addition completed at 0-2 ° C. The yield of the methyl ester of N-carbobenzyloxy-trans-4-hydroxy-L-25 proline, which is an almost colorless, viscous oil, was 14.6 g (100%).

/ Α? D * -62 (c, 1% in chloroform).

c) The methyl ester of trans-N-carbdbenzyloxy-4- / / (methylamino) -30 carbonyl7-oxy7-L-prollne.

To a stirred solution of 6.0 g (0.021 mol) of the methyl ester of N-carbobenzyloxy-trans-4-hydroxy-L-proline (JACS 79 supra) in 120 ml of benzene was added 6 ml (0.10 mol) with ethyl isocyanate and allowed this reaction mixture to stand overnight at room temperature. After refluxing it for 1 hour 800020? Boiled, the solvent was removed using a rotary evaporator, finally at 0.2 mm and 50 ° C. The obtained viscous residue was then taken up in 150 ml diethyl ether, washed three times with 50 ml water and dried over magnesium 5 sulfate. Distillation of the ether yielded 6.5 g (90%) of a syrupy product, the ethyl ester of trans-N-carboben-zyloxy-4- (methylamino) carbonyl / ox-L-proline.

d) Trans-N-carbobenzyloxy-4 - // (methylamino) carbonyl7-oxy7-L-prollne.

10 Hen dissolved 7.6 g (0.023 mol) of the crude ester of part c in 60 ml of methanol, added dropwise to this solution at a temperature between -1 and 4 ° C, 14 ml (0.028 mol) of 2N sodium hydroxide and kept this reaction mixture first at 0 ° C for 1 hour and then at room temperature overnight. After removing about half of the solvent using a rotary evaporator, the resulting solution was diluted with 160 ml of water, washed with diethyl ether (discarded washings), acidified with 5.5 ml of 1: 1 with cooling hydrochloric acid to pH 2 and extracted four times with 75 ml of ethyl acetate. The combined extracts were washed with 50 ml of a saturated aqueous sodium chloride solution and dried over magnesium sulfate to obtain 7.2 g of a highly viscous syrup by distilling off the solvent. This syrup was dissolved in 30 ml of ethanol, treated with 2.3 g of cyclohexylamine in 5 ml of ethanol and diluted with 600 ml of diethyl ether. The crystalline cyclohexylamine salt separated off by grafting and rubbing. The yield after cooling overnight was 8.5 g, melting point: 172-174 ° C. / * -20 ° (c, 1% in ethanol).

After crystallization from 25 ml of isopropanol, the colorless solid trans-N-carbobenzyloxy-4- / 7 ** (methylamino) carbonyl-7oxy-7-L-proline weighed.

Cyclohexylamine salt 7.8 g, melting point: 174-176 ° C.

~ a 725 - -18 ° (c, 1% in ethanol).

- - D

The resulting cyclohexylamine salt was suspended in 60 ml of ethyl acetate, this suspension was stirred and treated with 40 ml of 1N hydrochloric acid. Once two clear layers were obtained, they were separated, the resulting water layer was extracted three times 8000206 12 with 60 ml of additional ethyl acetate and the combined organic layers were dried over magnesium sulfate. By distilling off the solvent, 5.5 g (81%) of the glassy free acid were obtained.

E) trans-4 - // (methylamino) carbonyl / -oxy / -L-prollne.

They treated a solution of 2.7 g (0.0084 mol) of trans-N-carbobenzyloxy7-4 - // ~ (methylamino) carbonyl7oxy7-L-proline in 100 ml of a mixture of methanol and water (2: 1) with 1 g 5% palladium on charcoal and 45 lb. hydrogen and shake this mixture in a hydrogenator according to Parr. The catalyst was then filtered in a nitrogen atmosphere, washed with methanol and the combined filtrates were evaporated, finally at a pressure between 0.1-0.2 nm, to obtain 1.5 g (96%) of a residue. which gradually crystallized to yield trans-4/7 (methyl-thylamino) carbonyl-7oxy-7-L-proline as a grayish solid product. Melting point: 213-215 ° C (dec.), Preceded by gradual darkening and sintering. / "Α 7β *" 12 ° (c, 0.25% in 1: 3 ethanol-methanol).

F) Trans-1- (D- (3-acetylthio) -2-methyl-1-oxopropyl-7-4 - // (methyl-1-amino) carbonyl-7oxy7-L-proline.

A stirred solution of 2.9 g (0.0154 mol) of trans-4- (methylamino) carbonyl-7oxy-7-L-proline in 45 ml of water was cooled to 5 ° C and solid sodium carbonate 25 to pB 8 was added thereto. 5 (about 0.4 g needed). While stirring and cooling were continued, a solution of 3.1 g (0.017 mol) of D-3-acetylthio-2-methylpropanoyl chloride in 4 ml of diethyl ether was added in portions using a pipette, adding 25% dropwise (w / v) sodium carbonate kept the pH between 7.0 and 8.0. After about 10 minutes, the pH stabilizes between 8.1 and 8.3 (with about 14 ml of the sodium carbonate solution added). After continuing stirring and cooling for a total of 1.25 hours, the solution was washed with 50 ml of ethyl acetate, a layer of 50 ml of ethyl acetate was added, stirred, cooled and acidified carefully with 35 1: 1 hydrochloric acid to pH: 2 , 0. After saturation with sodium chloride 8000206 13, the layers were separated, the aqueous phase was extracted three times with 50 ml of additional ethyl acetate, the combined organic layers were dried over magnesium sulfate and the solvent was distilled off, finally at a pressure of 0.2 mm, yielding 5. 3 g of a glassy residue were obtained. This was dissolved in 40 ml of ethyl acetate and this solution was treated with a solution of 2.8 g of dicyclohexylamine in 15 ml of ethyl acetate. Grafting and rubbing separated the crystalline trans-1- (D-3-acetylthio) -2-methyl -1-oxypropyl / -4 / // (methylamino) -carbonyl-7axy7-1 / -proline. dicyclohexylamine, which, after overnight cooling, weighed 5.8 g. The colorless product melted between 187 and 189 ° C (s. 183 ° C), α7p6- -64 ° (c, 1% in MeOH). After recrystallization from a mixture of 15 ml of methanol and 100 ml of diethyl ether, weighed the colorless solid product 4.5 g. melting point: 190-192 ° C, / α / 55 - -67 ° (c, 1 L in MeOH).

The acid was liberated from the dicyciohexylamine salt by suspending the salt in 50 ml of ethyl acetate, cooling the suspension and treating with 50 ml of a 10% potassium bisulfate solution and honing until two clear layers were formed. After separation, the aqueous layer was extracted three times with 50 ml of ethyl acetate, the combined organic layers were dried over magnesium sulfate and the solvent was distilled off, yielding 2.8 g (55%) of trans-1 - / - b- (3- acetylthio) -2-methyl-1-oxypropyl7-4- / 7 "(methyl-amino) carbonyl7oxy7-L-proline as a foamy hygroscopic residue.

23

Example IX

trans-1- (D-3-Mercapto-2-methyl-1-oxopropyl) -4- / 7 "(methylamino) carbonyl 7oxy / -L-proline.

Argon was passed through a cold solution of 6 ml of concentrated ammonium hydroxide in 4 ml of water for 10 min. This solution was then added to the product of Example 1 under cooling and an atmosphere of argon and the resulting mixture was shaken in an ice bath (about 3 min.) Until a pale yellow solution was obtained. Stirring was continued in an argon atmosphere and at room temperature for a total of 2 hours / after which the 8000206 14 solution was extracted with 20 ml of ethyl acetate (this and subsequent treatments were carried out as much as possible in an argon atmosphere). The water layer was then cooled, stirred, covered with 20 ml of ethyl acetate, and aliquoted with approximately 13 ml of 5 1: 1 hydrochloric acid. The layers were then separated, extracted water phase three times with 20 ml of additional ethyl acetate, the combined ethyl acetate layers were dried over magnesium sulfate and the solvent was distilled off, yielding trans-1- (D-3-mercapto-2-methyl-1-oxopropyl) ) -4 - // (methylamino) carbonyl / ox 2 ZL-proline as a tacky foamy residue. Give them this with diethyl ether and repeat the evaporation treatment, finally at a pressure between 0.1 and 0.2 mm, giving 2.2 g (90% of the product as a colorless, slightly hygroscopic, amorphous product, melting point: 54- 57 ° C, (S, 45 °) Ob./a · -53 ° (c, 1% in ethanol).

The racemic forms of the final products obtained in any of the previous examples were obtained using the DL form of the amino starting material instead of the L form.

Similarly, the D-forms of the final products in each of the previous examples were obtained by starting from the D-form of the amino starting material instead of the L-form.

Example III

A) The methyl ester of N-carbobenzyloxy-cls-4-hydroxy-L-proline.

Hen dissolved 6.5 g (0.024 mol) of N-carbobenzyloxy-cis-4-hydroxy-L-proline / JACS, TSj 189 (1957) / in 65 ml of methanol, stirring this solution and adding 0.65 ml of concentrated sulfuric acid After stirring at room temperature for 30 min, the solution was allowed to stand overnight, after which most of the solvent was removed by rotary evaporator, the resulting oily residue (13 g) in 70 ml of diethyl ether and washing with 35 ml of a 10% sodium bicarbonate solution The washing liquid was again extracted with 35 ml of diethyl-35 ether, combined organic layers were dried over magnesium dphate and the diethylather was distilled off to give 6.5 g (96%) of the product as a pale yellow viscous oil - 25 o / ct_ / D * "24 (c, 1% in chloroform), 5 b) The methyl ester of cis-N-carbobenzyloxy-4- (7- (methylamino) carbonyl-7-oxy7-L-prollne.

To a solution of 5.4 g (0.019 mol) of the methyl ester of N-carbobenzyloxy-cis-4-hydroxy-L-proline in 120 ml of acetonitrile was added first 5.4 ml of triethylamine and then 5.4 ml of methyl isocyanate. After the reaction mixture was held overnight at room temperature and refluxed for 2 hours, the reaction mixture was worked up as described in Example 1c to obtain 5.6 g (86%) of a pale yellow viscous oil.

C) cis -N- (Carbobenzyloxy-4- / 7 (methylamino) carbonyl7-oxy7-L-prollne.

5.6 g (0.017 mol) of the crude ester of part b were saponified with 11 ml (0.022 mol) of 2N sodium hydroxide in 45 ml of methanol as described in example 1d to obtain 5.1 g of a foamy residue . The colorless cyclohexylamine salt, prepared in 25 ml of ethanol and 400 ml of methyl ether using 1.7 g of cyclohexylamine, weighed 4.8 g; melting point: 171-173 ° C.

-25 o / q / D -16 (c, 1% in ethanol). A sample recrystallized from a mixture of ethanol and diethyl ether showed no change in melting point or optical rotation.

The cyclohexylamine salt gave 3.5 g (65%) of the free acid as a colorless, foamy residue.

d) cis-4- / 7- (methylamlno) carbonyl7oxy7-L-proline, 3.5 g (0.011 mol) of cis-N-carbobenzyloxy-4 - // (methylamlno) carbonyl / oxy7-L- were hydrogenated proline in 130 ml of a mixture of methanol and water (2: 1) using 1.3 g of a mixture of methanol and water (2: 1) and 1.3 g of 5 t palladium on charcoal, as described in example Ie to obtain 1.9 g (95%) of the product as a grayish solid product. Melt-8000206 16 point: 232-234 ° C (dec.), Preceded by gradual darkening ** -25 o and sintering. / α / -42 (c, 0.5% in 1: 1 methanol-water).

e) cis-1- / D- (3-acetylthlo) -2-methyl-1-oxopropyl7-4-1 / 7 (methylamino) mm mm 5 carbonyl / oxy / -L-proline.

The reaction of 1.85 g (0.0098 mol) cis-4 - // (methylamino) carbonyl 7oxy 7 "L-proline and 2.0 g (0.011 mol) D-3-acetylthio-2-methylpropanoyl chloride in 30 ml water in presence of sodium carbonate, as in Example If, gave 3.35 g of a gummy pro-10 duet. The dicyclohexylamino salt, prepared in 35 ml of ethyl acetate using 1.8 g of dicyclohexylamine, weighed 4.0 g; melting point: 177-179 ° C. / e * -54 ° (c, 1 * in methanol).

After treatment with 20 ml of acetonitrile and cooling, the colorless solid product weighed 3.6 g, melting point: 179-181 ° C.

15 / α / 5 * -54 ° (c, 1% in methanol).

Treatment with a 10% solution of potassium bisulfate and extraction in ethyl acetate gave 2.5 g (76%) of the free acid as a colorless, foamy residue.

Example IV

cis-1- (D-3-Mercapto-2-methyl-1-oxopropyl) -4- / 7 (methylamino) carbonyl 7oxy 7-L-proline.

Treatment of the material of Example III with 5.5 ml of concentrated ammonium hydroxide in 12.5 ml of water according to the procedure described in Example II gave 1.8 g (82%) of the product as a colorless, hygroscopic, sticky foam .

/ a_7 ^ ~ 59 ° (c, 1 * in ethanol).

Example V

Cis-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7- (athylamino) carbonyl7oxy7-L-prollne.

Using the procedure of example III, but using ethyl isocyanate for the methyl isocyanate of part b, cis-1- / -D- (3-acetylthio) -3-methyl-1-35-oxopropyl7-4- // ~ (ethyl amino) carbonyl 7oxy 7-11 proline.

800020e »17

Example VI

cis-1- (D-3-Mercapto-2-ethyl-1-oxopropyl) -4 - // (ethylamino) carbonyl / -oxy / -L-proll.ne,

Treatment of the material of Example V 5 with ammonia according to the method described in Example IV gave cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (ethylamino) -carbonyl / oxy7-L-proline.

Example VII

10 cis-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl7-4- / 7 (propylamino) -carbonyl7oxy7-L-prollne.

Using the procedure described in Example III using n-propyl isocyanate instead of the methyl socyanate of part b, cis-1 / D-15 (3-acetylthio) -2-methyl-1-oxopropyl7 was obtained -4 - // (propylamino) carbonyl7-oxy7-L-proline.

Example VIII

cis -1- (P-3-Mercapto-2-methyl-1-oxopropyl) -4- / 7 (propylamino) carbonyl / -20 oxy7-L-prollne.

Treatment of the material of Example VII with ammonia according to the procedure described in Example IV gave cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (propylamino) -carbonyl7oxy7-L -proline.

25

Example IX

cis-1- / D- (3-Acetylthlo) -2-methyl-1-CTopropyl7-4 - // (phenylamino) carbonyl7oxy7-L-proline.

Using the procedure of Example III, 30, however, replacing the methyl isocyanate in part b with phenyl isocyanate gave cis-1 - / "D- (3-acetylthio) -2-methyl-1-oxopropyl7-4 - //" (phenylamino) -carbonyl7oxy7-L-proline.

8000206 18

Example X.

cis-1- (D-3-Mercapto-2-methyl-1-oxopropyl) -4 - // (phenylamino) carbonyl-7-oxy7-L-proline.

Treatment of the material of Example IX 5 with ammonia according to the method described in Example IV gives cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- // ”(phenylamino) -carbonyl / ox ^ / - L-proline obtained.

Example XI

10 cis-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7 (4-chlorophenyl) -carbonyl7oxy7-11-proline,

Using the procedure described in Example III, but replacing the methyl isocyanate of part b with 4-chlorophenyl isocyanate, one has cis-1- / -d- (3-acetyl-1S thio) -2-methyl-1-oxopropyl ) -4- / 7 "(4-chlorophenyl) carbony 17oxy7-1 * proline.

Example XII

cis-1- (D-3-Mercapto-2-methyl-1-oxopropyl) -4- / 7 (4-chlorophenyl) carbonyl 7oxy7-L-prollne.

By treating the material of Example XI with ammonia according to the method described in Example IV, cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (4-chlorophenyl) - carbonyl7 oxy7-L-proline.

25

Example XIII

cls-1- / D- (3-Acetylthlo) -2-methyl-1-oxopropyl7-4 - // '~ (3-trifluoro-methylphenyl) carbonyl7oxy7-L-proline ♦

However, using the procedure of Example III, replacing the methyl isocyanate in part b with 3-trifluoromethylphenyl isocyanate, cis-1 - / - d- (3-acetylthio) -2-methyl-1-oxopropyl-7-4- / 7 ~ (3-Trifluoromethylphenyl) carbonyl7oxy7-L-proline.

8000206 S.; # 19

Example XIV

cis-1- / D- (Acetylthlo) -2-ethyl-1-oxopropyl-7- / 7- (2-methoxyphenyl) carbonyl / oxy7-L-proline.

Using the procedure of Example III, 5 but replacing the methyl isocyanate of part b with 2-methoxyphenyl isocyanate, one has cis -1- / "* D- (acetylthio) -2-methyl-1-oxopropy1 / -4- // (2-ethoxyphenyl) carbonyl7ox2 / -L-proline.

Example XV

10 trans-1- / ~ D- (Benzoylthio) -2-methyl-1-oxopropyl7-4- / 7 ~ (2-ethylphenyl) -carbonyl7oxy7-L-prollna,

Using the procedure of Example I, but replacing the methyl isocyanate in part c with 2-ethylphenyl isocyanate and the D-3-acetylthio-2-ethylpropanoyl chloride in part f with D-3-benzoylthio-2-methylpropanoyl chlorida Trans-1- (D- (benzoylthio) -2-methyl-1-oxopropyl-7-4- / 7 (2-ethyl-phenyl) carbonyl-7oxy-7-L-proline was prepared.

Example XVI

Trans-1- (D- (phenacetylthlo) -2-methyl-1-oxopropyl-7-4- / 7- (4-methyl-thlophenyl) carbonyl / oxy7-L-proline.

Using the procedure of Example 1, but replacing the methyl isocyanate in part c with 4-methylthiophenyl isocyanate and the D- (3-acetylthio) -2-methylpropanoyl chloride in part f with D-phenylacetylthio-2-methylpropanoyl- chloride, trans-1- (d- {phenacetylthlo) -2-ethyl-1-oxopropy-7-4-4 // (4-methylthiophenyl) carbonyl-7oxy-7-pAine is obtained.

Example XVII

30 trans-1- / D- (3-Phenylpropionylthlo) -2-methyl-1-oxopropyl7-4- / 7 ~ (3-bromophenyl) carbony ΐ7οχγ7-Ι »-ρ: το11ηο,

Using the procedure of Example I, but replacing the methyl isocyanate in part c with 3-bromophenylsocyanate and the D- (3-acetylthio) -2-methylpropanoyl-35 chloride in part f with D- (3-phenylpropionylthio) - 2-Methylpropanoyl-8000206 chloride, trans-1- / D- (3-phenylpropionylthio) -2-methyl-1-oxopropyl-7-4 - //- (3-bromophenyl) carbonyl7oxy7-L-proline was prepared.

Example XVIII

5 trans-1- / -D- (3-Acetylthlo) -2-methyl-1-oxopropyl7-4- / 7- (cyclopentylamino) carbonyl7oxy7-L-prollne.

Using the procedure of Example I, but replacing the methyl isocyanate in part c with cyclopentyl isocyanate, trans-1 - / - D - (3-acetylthio) -2-methyl-

1-oxopropyl7-4 - // (cyclopentylamino) carbonyl7oxy / -L-proline. Example XIX

trans-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7- (cyclohexyl-amino) carbonyl7oxy7-L-proline.

Using the procedure described in Example I, but replacing the methyl isocyanate in part c with cyclohexyl isocyanate, trans-1- / -D- (3-acetylthio) -2-methyl-1-oxopropyl7-4- / / (cyclohexylamino) -carbonyl7oxy7-L-proline.

20

Example XX

cis-1 - (-) - (3-Acetylthio) -2-methyl-1-oxopropy3,7-4- / 7-allylamlno) -carbonyl-7oxy-7-L-proline.

Using the procedure of Example 11, but replacing the methyl isocyanate in part b with allyl isocyanate, one has cis-1- / D- (3-acetylthio) -2-methyl-1-oxopropy 17-4- / 7 (Allylamino) carbonyl7oxy7-L-proline.

Example XXI

30 cis-1- Tb- (3-Mercapto-2-methyl-1-oxopropyl) -4- / 7 ** (allylamino) carbonyl 7oxy7-L-proline,

Treatment of the material of Example XX with ammonia according to the method described in Example IV gives cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4 - // (allylamino) -35 carbonyl / oxy7-L-proline.

8000206 i * 21

Example XXII

trans-1- (b-β-Acetylthlo) -2-methyl-1-oxopropyl / -4- / 7- (diethylamino) -earbonyl / oxy7-I-prollne, 4.

5 a) The ethyl ester of trana-N-carbobenzyloxy - // (dimethylamino) -carbonyl7oxy7-L-proline «

An equivalent amount of dimethyl carbamyl chloride was added dropwise to a solution of the ethyl ester of N-carbobenzyloxy-trans-4-hydroxy-L-proline (Example 1, part b) in chloroform. The resulting mixture was then stirred for an additional 2 hours, washed with water and the organic phase was dried over magnesium sulfate.

Filtration of the solution and distillation of the solvent gave the methyl ester of trans-N-carbobenzyloxy-4 - (- - - {- {dimethylamino) carbonyl-oxoxy / -L-proline.

B) trans-N-Carbobenzyloxy-4- / 7- (dimethylamino) carbonyl7oxy7-L-proline,

By hydrolysis of the methyl ester of part a with a sodium hydroxide solution as described in Example I, part d, trans-N-carbobenzyloxy-4 - ((dimethylamino) -20 carbonyl-7ox-7-L-proline is obtained.

c) trans-4- / 7 ~ (Dimethylamino) -carbony1 / χχγ7-L-proline.

Hydrogenation of the material of part b according to the method described in example I, part e gave trans-4- (dimethylamino) carbony1 / γ / / -L-proline.

d) trans-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4 - // (dimethyl-amino) carbonyl7-/ /γ / -L-proline.

By treating the material of part c with an equivalent amount of D-3-acetylthio-2-methylpropanoyl chloride according to the method described in Example I, part f, trans-1 / D- (3-acetylthio) - 2-methyl-1-oxopropyl / -4- / 7- (dimethylamino) carbonyl-7ox-7-L-proline.

8000206 22

Example XXIII

trans-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7- (pyrrolldino) -carbonyl7oxy7-L-proline,

Using the procedure described in the preparation of Example XXII, but replacing the dimethylamino-carbamyl chloride in part a with pyrrolidinocarbamoyl chloride, trans-1 / D- {3-acety1thio) -2-methyl-1 -oxopropy-4- / 7- (pyrrolidine) carbonyl7oxy7-L-proline.

10 Example XXIV

trans-1- (p- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7 ™ (piperidino) -carbonyl7oxy7-L-proline.

Using the procedure described in the preparation of Example XXII, but replacing the di-methylaminocarbamoyl chloride in part a with piperidinocarbamyl chloride, trans-1- / p- (3-acetylthio) -2-methyl-1 is obtained -oxopropyl7-4- / 7 ™ (piperidino) carbonyl7oxy7-L-proline.

Example XXV

20 trans-1- (p- (3-Acetylthio) -2-methyl-1-oxopropyl-4 -4- (morphollno) carbonyl7oxy7-L-proline.

Using the method used in the preparation of Example XXII, but replacing the dimethylaminocarbamoyl chloride in part a with morpholinocarbamyl chloride, trans-1 - / - d- (3-acetylthio) -2-methyl- 1-oxopropyl7-4 - // - (morpholino) carbonyl7oxy7-L-proline.

Example XXVI

trans-1- (2-Acetylthio-1-oxoethyl) -4- / 7 ™ (methylamino) carbonyl7oxy7-30 L-proline.

Using the procedure described in the preparation of Example I, but replacing the D- (3-acetylthio) -2-methylpropanoyl chloride in part f with 2-acetylthioacetyl chloride, trans-1- (2-acetylthio-) 1-oxoethyl) -4 - // (rahylamino) carbonyl7oxy7-L-proline.

• * 8000206 ΐ 23

Example XXVII

trans-1- (4-Acetylthlo-1-oxobutyl) -4 - // ** (mathylamlno) carbonyl / oxy7-D-proline.

Using the method described in the preparation of Example I, but replacing the trans-4-hydroxy-L-proline in part a with trans-4-hydroxy-D-proline and the D- (3-acetylthio) -2-methylpropanoyl chloride in part f by 4-acetyl-thiobutyroyl chloride trans-1- (4-acetylthio-1-oxobutyl) -4- // ** (methylaino) carbonyl7oxyl-D-proline is obtained.

10

Example XXVIII

cls-1 ((4-Acetylthlo-4-mathyl-1-oxdbutyl) -3- (methyl) carbonyl7-oxy7-L-prollne.

Using the procedure described in the preparation of Example III, however, replacing the D-3- (acetyl thic> -3-methylpropionyl chloride in part e with 4-ecetylthio-valeroyl chloride) gives cis-1- (4-acetylthio -4-methyl-1-oxobutyl) - 3 - // (methylaino) carbonyl7oxy7-L-proline.

20 Example XXIX

trans-1- (L- (3-Acetylthlo) -2-ethyl-1-oocopropyl-7-3- (7-methylamino) -carbonyl-7oxy-7-prollne.

Using the procedure of Example I, but replacing the trans-4-hydroxy-L-proline in part a 25 with trans-3-hydroxy-L-proline and the D-3- (acetylthio) -3-methylpro -pionyl chloride in part f by L- (3-acetylthio) -2-ethylpropionyl chloride, trams-1 / ~ L- (3-acetylthio) -2-ethyl-1-oxopropyl7-3- // ~ ( methyl amino) carbonyl 7oxy 7-L-proline.

30

Example XXX

trans-1- (D- (3-Acetylthio) -2-methyl-1-oxopropyl-7-4- / "(amino carbonyl) -oxy7-L-prollne.

a) The methyl ester of trans-M-carfaobenzyloxy-4- / (aminocarbonyl) -oxy7-L-prollne «8000206> 24

A solution of equivalent amounts of the methyl ester of N-carbobenzyloxy-trans-4-hydroxy-L-proline of Example I, part b, and dinethylaniline was treated with a solution of phosgene in toluene. After the reaction mixture was left overnight stand, an equivalent amount of ammonia is passed through the solution of the methyl ester of trans-N-carbobenzyloxy-4 - / "(chlorocarbonyl) oxy / -L-proline. After standing at room temperature for 12 hours, the resulting solution was washed with water, dried over magnesium sulfate, filtrated hair and the solvent was distilled off, yielding the methyl ester of trans-N-carbobenzyloxy-4 - / (amino-carbonyl) oxy7-L -proline obtained.

b) trans-N-carbobenzyloxy-4 - / '* (aminocarbonyl) -oxy / -L-proline.

By hydrolysis of the methyl ester of part a with a solution of sodium hydroxide in the manner described in Example I, part c, trans-N-carbobenzyloxy-4 - / "(amino-mm carbonyl) oxy-L-proline is obtained .

c) trans-4- / (Aminocarbonyl) oxyZ-L-proline.

By hydrogenation of the material of part b according to the method described in example I, part e, trans-4- (aminocarbonyl) oxy7-L-proline is obtained.

mmd) trans-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / (aminocarbonyl) oxy7-L-proline.

By treating the material of part c with an equivalent amount of D-3-acetylthio-2-methylpropanoyl chloride according to the method described in Example I, part f, trans-1- / ~ D- (3-acetylthio) -2- methyl-1-oxopropyl / -4- / (aminocarbonyl) -30 oxy7-L-proline.

Example XXXI

trans-1 - / p- (3-Acetylthio) -2-methyl-1-oxopropyl / -4 - // (diisgpropyl-amino) carbonyVoxy? -! * - pro line.

Using the procedure of Example XXX, 8000206, however, replacing the ammonia in part a with d ± isopropylamine, trans-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl7- 4 - // “(diisopropylamino) carbonyl7oxy] -1-proline obtained ·

5 Example XXXII

trans-1- / D- (3-Acetylthlo) -2-aethyl-1-oxopropyl / -4- / 7 ~ (cycloprftfl-amino) carbonyl / oxy7-L-proline ♦

Using the procedure described in Example XXX, however, replacing the ammonia in part a 10 with cyclopropylamine, trans-1- / D- (3-acetylthio) -2-methyl-m

1-oxopropy-4 - // ** (cyclopropylamino) carbonyl7oxy7-L-proline. Example XXXIII

trans-1-Z 2 D- (3-Acetylthio) -2-methyl-1-oxopropy1 / -4 - // (n-butylamino) -15 carbonyl7oxy7-L-proline.

Using the procedure of Example XXX, but replacing the ammonia in part a with n-butylamine, trans-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl7-4 - // ( n-butylamino) carbonyl7oxy7-1-proline.

20

Example XXXIV

trans-1- / D- (3-Acetylthio) -2-methyl-1-oxopropyl7-4- / 7 (propargylamino) -cagonyvoxy / -L-prollne.

However, using the procedure of Example XXX, 25, replacing the ammonia in part a with propargyl amine, trans-1- (10- (3-acetylthio) -2-methyl-1-oxopropyl-7-4) is obtained. // (propargylamino) carbonyl7oxy7-L-proline.

Example XXXV

The methyl ester of trans-1- (p- (3-acetylthio) -2-ethyl-1-oxopropyl-7-4- (7-methylamino) -curbonyl-7oxy-7-proline.

A small excess of diazonethane was added to the solution of the material of Example 1 in diethyl ether.

After the reaction mixture was stirred at room temperature for 2 hours, the solvent was distilled off to yield the methyl ester of 8000206 26 trans-1- / d- (3-acetylthio) -2-methyl-1-oxopropyl7-4 - // (Methylamino) carbonyloxoxyl-L-proline.

Example XXXVI

The S, S dimer of trans-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (methylamino) carbony 17oxy / -1 proline.

They treated a stirred solution of the material of Example II in ethanol with a solution of one equivalent of iodine in ethanol. The pH of this solution was kept between 6 and 7 by addition of an IN sodium hydroxide solution. The solvent was then evaporated and the residue obtained was extracted with ethyl acetate. After drying over magnesium sulfate, the solution was filtered and the solvent was removed, yielding the S, S dimer of trans-1- (D-3-mercapto-2-methyl-1-oxopropy1) -4- / 7 "(methylamino) -15 carbony 17oxy7-I-proline.

Example XXXVII

The S, S dimer of cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 "(methylamino) carbonyl-7oxo-L-proline.

Oxidation of the material of Example IV with a solution of iodine according to the method used in Example XXXVI gave the S, S dimer of cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) - 4- / 7 ”(methylamino) carbonyl7oxo7-I *. proline.

Example XXXVIII

The sodium salt of trans-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl7-4 / 7 (methylamino) carbonyl7oxy7-L-prollne.

They treated a solution of 2.9 g of the material of Example I in 25 ml of water with 0.84 g of sodium bicarbonate.

Freeze-drying of the resulting solution gave the sodium salt of trans-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl7-4- / 7 (methylamino) carbonyl-17-ox-7-L-proline .

Example XXXIX

1000 tablets were made, each containing 100 mg of active 8000206 27 ingredient from the following ingredients; cis-1 - (D-3-mercapto-2-methyl-1-oxopropyl) - 4- / 7 (aethy laol nol carbonyl7ox ^ 7 ”L'-proline 100 mg 5 corn starch 50 g gelatin 7.5 g

Avicel (microcrystalline cellulose) 25 g magnesium loop stearate 2.5 g 10 The cis-1 - (D-3-mercapto-2-methyl-1-oxopropyl) -4 - // (methylamino) carbonyl / oxy / - was mixed L-proline and corn starch with an aqueous solution of the gelatin. This mixture was dried and ground to a fine powder. The Avicel and then the magnesium stearate were then mixed with the granulated product. This is then pressed into a tablet press to form 1000 tablets, each containing 100 mg of the active ingredient.

Example XL

1000 tablets were made, each containing 200 mg of trans-1- (D-3-mercapto-1-oxopropyl) -4 - // (methylamino) carbonyl / ox-L-proline from the following ingredients: trans- 1- (D-3-mercapto-1-oxopropyl) -4- / 7 (methylamino) carbonyl7oxy7-I * -proline 200 g 25 lactose 100 g

Avicel 150 g corn starch 50 g magnesium stearate 5 g 30 The trans-1- (D-3-mercapto-1-oxopropyl) -4- // (methylamino) carbonyl / ox / l-proline, the lactose and the Avicel and then mixed the mixture thus obtained with corn starch. Magnesium stearate was then added. The resulting dry mixture was pressed in a tablet press to 1000 tablets of 505 mg, each containing 200 mg of active ingredient. The tablets were coated 8000206 28 with a solution of Methocel £ 15 (ethyl cellulose) containing a yellow # 6 lacquer as colorant.

Example XL ·! 5 Two-part φφΐ gelatin capsules, each containing 250 mg of trans-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (methyl-amino) carbonyl7oxy7-L-proline, were filled with a mixture of the following ingredients: 1o trans-1- (D-3-mercapto-2-methyl-1-oxopropyl) - 4- / 7 (methylamino) carbonyl7ox ^ 7-L-proline 125mg magnesium stearate 3mg USP lactose 100 mg

Example XLII

An injectable solution was prepared in the following manner from the following ingredients: trans-1- (D-3-mercapto-2-methyH-oxopropyl) -20 4 - // "(methylamino) carbonyl7oxy7" * proline 500 g methyl paraben 5 g propyl paraben 1 g sodium chloride 25 g water for injection qs 51 25

The active ingredient, the preservatives and the sodium chloride were dissolved in 3 L of water for injection purposes and then the volume was adjusted to 5 L. Then this solution was filtered through a stereo filter and aseptically introduced into pre-sterilized vials which were then sealed with sterilized rubber caps. Each vial contained 5 ml of solution at a concentration of 100 mg of active ingredient per ml of solution, 6000206

Claims (24)

Compounds according to claim 1, wherein R represents a hydrogen atom. Compounds according to any one of the preceding claims, wherein n 1. Compounds according to any one of the preceding claims, wherein R 1 represents a hydrogen atom. Compounds according to any one of the preceding claims, wherein R2 represents a lower alkyl group. 6. Compounds according to any one of the preceding claims, wherein R & represents a lower alkyl group. Compounds according to any one of the preceding claims, wherein R4 represents a group of formula la. Compounds according to any one of the preceding claims, wherein the amide group is at the meta site relative to both the COOR group as the nitrogen atom of the pyrrolidine ring, wherein R, R, R., R_, R_, R. and n have the same meanings as 0 12 3 4 in claim 1. 9. Compounds according to claim 8, wherein R is a hydrogen atom or a lower alkyl group, R and R, independently of each other, an alkyl group with at most 4 carbon atoms, R 1 and R 8, 8000206 independent of each other, a hydrogen atom or an alkyl group with at most 4 carbon atoms, R 1 a hydrogen atom, a lower alkanoyl or benzyl group and n represent 0 or 1, Compounds according to claim 8, wherein R and 5 each represent a hydrogen atom, Rq and, independently of each other, an alkyl group with at most 4 carbon atoms, R 1 and R 2, independently, a hydrogen atom or a methyl group and η 1, Compounds according to claim 8, wherein R, R 1, R and R each represent a hydrogen atom, R and R 4 each represent the methyl group and n 10. Compounds according to claim 8, wherein R, R ^ and R ^ each represent a hydrogen atom, Rq and R ^ each represent the methyl group, R ^ an acetyl group and η 1. 13. Trans-1- / D- (3-acetylthio) 2-methyl-1-oxopropyl / 4 - // (methylamino) carbonyl / oxy / -L-proline according to claim 8. Trans-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- / 7 (methylamino) carbonyl-7oxy / -L-proline according to claim 8. Cis-1- / D- (3-acetylthio) -2-methyl-1-oxopropyl / -4- / 7 "(methylamino) carbonyl-7oxy-7-proline according to claim 8. Cis-1- (D-3-mercapto-2-methyl-1-oxopropyl) -4- (7-methylamino) carbonyl-7oxy-7 "-proline according to claim 8. The compound of formula 9, wherein R and R. have the same meanings as in claim 1. 18. A compound according to claim 17, wherein R 1 is a lower alkyl group. The compound of claim 17, wherein R represents the O methyl group and R 1 represents a hydrogen atom. 20. A method of preparing a medicament for lowering blood pressure, characterized in that one or a number of compounds according to claim 1, wherein the substituents and symbols have the meanings indicated in claim 1, and / or a salt into a dosage form suitable for such application, 21. A method according to claim 20, characterized in that the pharmaceutical also comprises a pharmaceutically acceptable 8000206 '* *>> carrier, 22, Process according to claim 20 or 21, characterized in that one of the compounds according to claims 2-19 and / or a salt thereof is used, A method for lowering blood pressure in hypertensive mammals, characterized in that a medicament according to claims 20-22 is administered to these mammals. 24. Methods, as described in the description and / or the examples. 25, Shaped drugs, obtained using a method according to claims 20, 21, 22 and 24. / 8000206 / v -OCO-N f. «. r ^ T xr, i —S- (ChI -CH— CO - NL- CO OR y'R · OCO-N \ 'x R1 1a s — Mh | -CH — CO— N-1 — COOR 1 Λ1 * * * r ° f0H r ° fH 3 HN-L COOH - Cbz - N-1— COOH y Re OH OCOtY l ^ xT fX \ r, 5 Cbz-N -— COOR Cbz — NL COOR 4 ^ OCOCl D r ^ x / ö I haL - CO - N Cbz - N-1 — COOR -. \ - 0 R1 7 / Ro ^ OCON 0 ° ° Nx • rx \ rx Ri Cbz - NL COOH g HN - C00H R> * Rs _co - s - (ch) w— CH-COOH Ί0 R. OCO-NC Rj Rz XX x-Ri Rs CO —S - (CH 2 CH-CO —N-LCOOH 11 8000206 ER SQUIBB & SONS, INC., Princeton, New Jersey, USA, America