FR2478632A1 - MERCOPTOACYLATED DERIVATIVES OF PROLINE AND PIPECOLIC ACID WITH CETONIC FUNCTION WITH ANTI-HYPERTENSIVE ACTION - Google Patents

Abstract

COMPOUNDS OF THE FORMULA: (CF DRAWING IN BOPI) AS WELL AS THEIR PHYSIOLOGICALLY ACCEPTABLE SALTS, IN THE FORMULA IN WHICH: R IS A HYDROGEN ATOM OR A LOWER RADICAL ALKYL; R AND R ARE SELECTED INDEPENDENTLY BETWEEN HYDROGEN ATOMS AND LOWER ALKYL RADICALS, ALKYLTH THESE COMPOUNDS ARE USEFUL FOR THE TREATMENT OF HYPERTENSION.

Description

Mercaptoacylated derivatives of proline and functional pipecolic acid

  The present invention relates to derivatives

  ketones of proline and mercapto pipecolic acid

  acyl, of formula (I), and their salts. In formula (I): ## STR2 ##

i3 1 he ...

R4-S- (CH)> C- C N C; COOR

4. I

I * H

  R 2 and R 2 are independently selected from hydrogen and lower alkyl, wherein R 2 can be lower alkyl only if R 1 is also lower alkyl; R1 and R3 are independently selected between

  hydrogen atoms and lower alkyl, alkyl-

  lower thio, - (CH2) n-SH, and halo-lower alkyl; R4 is a hydrogen atom, a hydrolytically removable protecting group, a chemically removable protecting group, or when R1 and R3 are other than - (CH2) n -SH, a sulfide of the formula:

C

(H2C) p (CH2) q

R3 R1 I

I I1 It *

-S- (CH) -C-C-C N C-COOR

R2 H

  R2H m is zero, one or two; n is equal to one, two or three, and p and q are respectively equal to one or two,

  but can not both be equal to two.

  In the preceding formula, the asterisk indicates a center of asymmetry in the cycle. In the case of proline, that is to say when p and q are both equal to one, this center is in the levorotatory configuration (L). In the case of pipecolic acid, that is when p or q is

  equal to two, this center is in the dextrogyric configuration

  levoayre (D, L) or in the L configuration. Centers of asymmetry may also be present in the mercaptoacyl side chain, as defined by R1, R2 and R3. The products may therefore exist in stereoisomeric forms or in form of racemic mixtures. All these products fall within the scope of the invention. The synthesis described below may use the racemate or one of the enantiomers as the starting material. When it is the racemate that is used as a starting material in the

  procedure of synthesis, one can separate the stereo-

  - Isomers obtained in the final product by conventional methods of chromatography or fractional crystallization. Preferably, if there is a center of asymmetry in the mercaptoacyl side chain, it is in the D configuration. The present invention, in its broadest aspects, relates to the mercaptoacyl derivatives of proline and pipecolic acid. , having the formula I above, as well as their salts, compositions containing such compounds,

  and the use of these compounds as anti-

  hypertensives. The term "lower alkyl" as used to define the symbols R 1, R 1, R 2 and R 3 denotes straight or branched hydrocarbon radicals up to seven carbon atoms, for example, methyl or ethyl radicals. , clean, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, etc. Preferred lower alkyl radicals have up to four carbon atoms, with methyl and ethyl being the best choices. Likewise, throughout the specification, the terms "lower alkoxy" and "lower alkylthio" refer to such lower alkyl radicals attached to an oxygen or sulfur atom. The term "halo-lower alkyl" refers to lower alkyl radicals as defined above in which one or more hydrogen atoms have been replaced by chlorine, bromine or fluorine atoms, for example radicals. trifluoromethyl, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, and the like. The term "hydrolysis-removable protecting group" used to define R4 refers to a group which can be removed by conventional hydrolysis or ammonolysis. For this purpose, the acyl radicals of formula ## STR2 ## R 5 may be a lower alkyl radical of one to seven carbon atoms, a lower alkyl radical substituted by one or more chlorine, bromine or fluorine atoms, a radical - (CH 2) r -cycloalkyl, the cycloalkyl part of which is a saturated ring of 3 to 7 carbon atoms, preferably the cyclohexyl radical, an aryl radical such as - (CH 2) <, a heterocyclic radical such as - (CH 2) r, or - (CH2) r, or is equal to

N X

  zero, one, two or three; R 6 is a hydrogen atom, a lower alkyl radical of 1 to 4 carbon atoms, in particular the methyl radical, a lower alkoxy radical of 1 to 4 carbon atoms, in particular the methoxy radical, a lower alkylthio radical of 1 at 4 carbon atoms, in particular the methylthio radical, a chlorine, bromine or fluorine atom, the trifluoromethyl radical, or the hydroxyl group; and X is an oxygen or sulfur atom. The preferred radicals are lower alkanoyl radicals having up to 4 carbon atoms, in particular

  the acetyl radical, and the benzoyl radical.

  The term "chemically removable protecting group" used to define R4 refers to

  radicals such as para-methoxy, para-methoxy-

  benzylcarbonyl, trityl, tert-butoxycarbonyl, etc. These radicals can be removed, after the end of the acvlation reaction, by various means, for example by treatment.

  with trifluoroacetic acid and anisole.

  The preferred compounds of formula I are the derivatives containing the Lproline ring, that is to say those in which

  p and q are both equal to one and R is a hydrogen atom.

  As regards the mercapto-lateral chain

  acyl, compounds in which R4 is a hydrogen atom are preferred as end products; m is zero or one; R 3 is a hydrogen atom, and R 1 and R 2 are both lower alkyl radicals of 1 to 4 carbon atoms, in particular both are methyl radicals, or R 2 is a hydrogen atom and R 1 is an atom hydrogen, a lower alkyl radical of 1 to 4 carbon atoms, in particular the methyl radical, a trifluoromethyl radical, methylthio or mercaptomethyl radical. The above-mentioned side chains, in which R 4 is a lower alkanoyl radical of 1 to 4 carbon atoms, are particularly preferred as intermediates and end products.

  the acetyl radical, or the benzoyl radical.

  Especially preferred are products

  compounds of formula I with a mercapto

  acyl wherein R4 is a hydrogen atom; m is equal to one; R3 and R are hydrogen atoms; R2 is the methyl radical or a hydrogen atom; and when R2 is methyl, the asymmetric carbon atom to which R2 is attached is in the D configuration. The compounds of formula I are obtained by condensing a ketone-functional proline or pipecolic acid of the formula:

(II) N

  C (H 2 C) p (CH 2) q HN qC-COOR I H with an acid, or its chemical equivalent, of formula (III) 13

R4'-S- (CH) - C - COOH

  ! Wherein R 1 is a hydrogen atom or a protecting group which can be removed by hydrolysis or chemically, to obtain the product of formula: (IV)

R R <H C) (CH

  c3 i H2) p. 2 q R-s4 - (CH) C-CO - N q-COOR

I

  This reaction can be carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or a similar agent, or the acid can be activated by forming its mixed anhydride, its symmetrical anhydride, its acid halide, its active ester. or using the

  Woodward's K reagent, N-ethoxycarbonyl-2-ethoxy-l, 2-

  dihydroquinoline, or a similar agent. For the various acylation processes, see Methoden der Organischen Chemie (Houben-Weyl), Vol. XV, part II, page 1 and seq. (1974). Preferably, the acid halide, in particular the acid chloride, of formula III is reacted

with the acid of formula II.

  If the proline or pipecolic acid of formula II is reacted in the form of the ester, the resulting ester can be converted to the free acid, i.e. the product in which R is a hydrogen atom, by conventional means. For example, if R is the ethyl radical, this ester protecting group can be removed

by saponification.

  It is preferable to isolate and purify the product of formula IV by crystallization, for example by forming the dicyclohexylamine salt and then passing this salt in the form of the free acid by treating with an aqueous solution of an acid for example potassium sulphate. The product of formula IV, bearing the acyl group R 5 -CO-, can be converted into the product of formula I in which R 4 is a hydrogen atom, by hydrolysis or

classical ammonolysis.

  The products of formula I in which R 1 and R 3 are other than - (CH 2) n -SH and R 4 are: ## STR2 ##

-S- (CH) - CO - N C; COOH

m I

-1 H

  R2 by oxidizing directly, using iodine, a product of

  formula I wherein R4 is a hydrogen atom.

  The esters of formula I in which R is a lower alkyl radical can be obtained from the corresponding carboxylic acids, that is to say compounds in which R is a hydrogen atom, by conventional esterification processes, for example by

  esterification with a diazoalkane such as diazo

  methane, a 1-alkyl-3-para-tolyltriazene, such as 1-n-

  butyl-3-para-tolyltriazene, or a like product.

247863-

  Compounds of formula

  I by eliminating, according to classical methods, the

  a ketone-functional proline or pipecolic acid of formula I, the ketone function of which is protected by conventional protective groups, such as, for example, an acetal protective group, for example a dialkoxy acetal, such as for example a compound of formula:

(V) H3C CH3

0 \ / 0

c

(H C) (CH2)

l0 / R3 R1 2 P (I2 q

R4 -S- (CH) -CO-N C-COOR

  Wherein the protecting group can be removed by hydrolysis, for example with the aid of an aqueous solution of acid

  hydrochloric acid at room temperature.

  The compounds of formula V can be prepared starting from a proline or an N-carbobenzyloxy and ketone-substituted pipecolic acid of formula II which is treated with methanol in the presence of trimethylorthoformate and concentrated sulfuric acid, and then removing the nitrogen-protecting group by hydrogenolysis in the presence of a palladium-on-charcoal catalyst, to obtain the dimethoxylated intermediate of formula: (VI)

H3C CH3

(H2C) / (CH 2) q

I I

HN C COOR

I *

  The intermediate of formula VI is then combined with an acid, or its chemical equivalent, of formula III to give the dimethoxylated compound of formula V. Reference will also be made to the following publications for a discussion of various methods of obtaining the products of starting and intermediates: US Patents 4,046,889, 4,105,776, 4,154,935 and 4,166. 962; Can. J.

  Biochem. & Physiol. 37, 583-587, (1959); JACS 79, p. 185-

  192, (1957); JACS 79, p. 192-197, (1957); Bull. Soc. Chem., 1965 (8), p. 2253-2259; and Aus. J. Chem. 20, p. 1493-1509,

(1967).

  The procedures set forth herein can be used as general methods of compound synthesis and isomer separation that can be used in the invention described in this patent application. Further details can be found in the examples that serve as models for the preparation of the other members of the group. The compounds according to the invention form basic salts with different inorganic or organic bases. The salt-forming ions derived from these bases may be metal ions, for example aluminum ions, alkali metal ions, for example sodium and potassium ions, alkaline earth metal ions such as calcium and magnesium ions. or an amine salt ion, a number of which are known for this, for example the

  aralkylamines such as dibenzylamine, N, N-dibenzylethylene

  diamine, lower alkylamines such as methylamine,

  tert-butylamine, procaine, lower alkvl-

  piperidines such as N-ethylpiperidine, cycloalkylamines

  such as cyclohexylamine or dicyclohexylamine, 1-

  adamantanamine, benzathine, or salts derived from amino acids such as arginine, lysine, etc. Physiologically acceptable salts such as sodium or potassium salts can be used in medicine, as described below, and are preferred. These salts, as well as other salts that are not necessarily physiologically acceptable, can be used to isolate or purify an acceptable product for the purposes described below, as illustrated with the dicyclohexylamine salt in the examples. These salts are obtained by reacting the acid form of the compound with one equivalent of the base providing the desired basic ion in a medium in which the salt precipitates either in an aqueous medium and then freeze-drying. The free acid form can be obtained from the salt by conventional neutralization techniques, for example using potassium bisulfate, hydrochloric acid, etc. The compounds of formula I in which R4 is a

0

  hydrogen atom, an R5-C- group, or the disulfide substituent, in particular those in which R4 is a

  hydrogen atom, are useful as anti-

  hypertensives. They inhibit the transformation of angiotensi-

  sine 1, a decapeptide, to angiotensin II, and are therefore

  useful for relieving hypertension due to angiotensin.

  The action of an enzyme, renin, on angiotensinogen, a pseudoglobulin in blood plasma, produces angiotensin I. Angiotensin I is transformed by the enzyme

  transformation of angiotensin (ETA) into angiotensin II.

  The latter is an active presser that has been made responsible for various forms of hypertension in different species of mammals, for example rats and dogs. The compounds according to the invention are involved in

  the angiotensinogenic sequence - (renin) - angiotensin I -

  (ETA) -> angiotensin II by inhibiting the angiotensin converting enzyme and reducing or eliminating the formation of the pressing product, angiotensin II. Thus, by administering a composition containing at least one compound of formula I, angiotensin-induced hypertension is relieved in the mammalian species that suffers from it. A single dose, or preferably two to four staggered daily doses, administered at a rate of about 0.1 to 100 ai / kg body weight per day, preferably at about 1 to 15 ai / kg body weight. bodily and daily, is appropriate for reducing blood pressure. This material is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes may be used as well. The compounds according to the invention can also be combined with a diuretic for the treatment of hypertension. An association comprising a compound according to the invention and a diuretic may be administered in a useful amount which comprises (for a 70 kg person) a total daily dosage of about 30 to 600 mg, preferably about 30 to 300 mg , a compound according to the invention, and from about 15 to 300 mg, preferably from about 15 to 200 mg, diuretic, to a mammalian species with hypertension. Examples of diuretics which are contemplated for use in combination with a compound according to the invention are thiazides, for example chlorthiazide, hydrochlorothiazide, flumethiazide,

  Hydrochlorothiazide, benzdroflumethiazide, meth-

  thiazide, trichlormethiazide, polythiazide or benzene

  thiazide, as well as ethacrynic acid, ticrynafene, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone, as well as

salts of these same compounds.

  The compounds of formula I may be packaged for the purpose of reducing blood pressure in the form of compositions such as tablets, capsules or elixirs for oral administration, or in the form of sterile solutions or suspensions for the purpose of parenteral administration. About 10 to 500 mg of a compound or mixture of compounds of formula I are combined with a physiologically acceptable carrier, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. in a unit dosage form as required by the recognized pharmaceutical practice. The amount of active ingredient in these compositions or preparations is such that a suitable dosage is obtained in

the indicated interval.

  Preparation details will be given in the following examples for the various reactions. These examples are preferred embodiments and also serve as models for the preparation of other compounds according to the invention. Temperatures are expressed in degrees Celsius.

EXAMPLE 1

  1- [3- (Acetylthio) -1-oxopropyl] -4-oxo-L-proline a) N-Carbobenzyloxy-4-hydroxy-L-proline

  26.5 g (0.02 mol) of 4-hydroxy-L-

  proline and 32.8 ml (0.23 mol) of benzyl chloroformate in 200 ml of water and 100 ml of acetone in the presence of 20 g (0.02 mol) of potassium bicarbonate and 69.2 g ( 0.50 moles) of potassium carbonate, and the whole is worked with 90 ml of concentrated hydrochloric acid as described in Can. J. Biochem. & Physiol. 37, 584 (1959), to give Ncarbobenzyloxy-4-hydroxy-L-proline. This product is reacted with cyclohexylamine to form the cyclohexylamine salt, yield 69 g, m.p. f. 193-195. The salt (34 g) is neutralized with N hydrochloric acid to give 27 g of free acid as a colorless glass;

  [α] 26 ° C (c: 1% in chloroform).

  D (b) N-Carbobenzyloxy-4-keto-L-proline

  21.5 g (0.81 mol) of N-carbobenzyloxy-4-

  hydroxy-L-proline in 1.2 liters of acetone with 83 ml of 8 N chromic acid in sulfuric acid as described in J.A.C.S. 79, 189 (1957). In order to facilitate the subsequent filtration of the chromium salts, 30 g of "Celite" (diatomaceous earth) are added to the acetone solution before

  to introduce the oxidizing agent. An air stirrer is used.

  The reaction mixture is filtered and the acetone filtrate is concentrated to about 300 ml before diluting with one liter of chloroform. The solution is washed with 300 ml of saturated sodium chloride (four times), dried (McSO4), filtered, and filtered.

  the solvent is evaporated to give 22.8 g of N-carbon.

  benzyloxy-4-keto-L-proline which is crystallized from a mixture of 50 ml of ether and 150 ml of hexane to give 17.2 g (81%) of product, m.p. 99-101, [a] 26 + 17 'D

(c, 1% in chloroform).

c) 4-Keto-L-Proline Hydrobromide

  To 4.0 g (0.015 mole) of N-carbobenzyloxy-4-keto-L-

  20 ml of hydrobromic acid in acetic acid (3032%) are added. The mixture is swirled several times for eight minutes. At the end of this period (the effervescence has ceased), the yellow-orange solution is covered with 250 ml of ether, triturating the gummy product. The ether is discarded and the resulting tacky solid is triturated with fresh ether and finally with 50 ml.

  of acetonitrile to give the 4-keto-L-hydrobromide

  proline as a crystalline solid weighing 2.7 g (85%), m.p. 153-155 (decomposition), [a] - 49 (c, 1%)

'' 26

in water).

  d) 1- [3-Acetylthio) -1-oxopropyl] -4-oxo-L-proline Cooled to a stirred solution of 4.1 g (0.0195 moles) of 4-keto-L-proline hydrobromide. in 50 ml of water, and treated in fractions with solid sodium carbonate (foaming is prevented by adding a few coats of ether) to pH 8.0 (about 2 g is required). Then, while stirring and cooling, a solution of 3.5 g (0.012 mole) of 3-acetylthiopropionyl chloride in 5 ml of ethyl acetate is pipetted into portions; while maintaining the pH between 7.0 and 8.0 by adding dropwise 25% (w / v) sodium carbonate solution (about 10 ml is required). After approximately 10 minutes, the pH stabilizes at 8.0-8.4. After continuing the cooling and stirring for a total of one hour, the solution is washed with ethyl acetate (twice 50 ml), covered with 50 ml of ethyl acetate, shaken It is cooled, carefully acidified to pH 2.0 with concentrated hydrochloric acid, saturated with sodium chloride, and the layers are separated. The aqueous phase is extracted with a supplement of ethyl acetate (three times 50 ml), the combined organic layers are dried (gSO4) and the solvent is evaporated, finally under 0.2 mm.

  mercury, to obtain 4.8 g of an orange-yellow vitreous residue.

  This residue is dissolved in 35 ml of ethyl acetate and treated with a solution of 3.5 g of dicyclohexylamine in 5 ml of ethyl acetate. By priming the crystallization and rubbing the walls of the container, the

  crystals of the dicyclohexylamine salt of 1- [3- (acetylthio)

  1-oxopropyl)] -4-oxo-L-proline, which weigh 2.7 g after a cooling night (almost colorless), m.p. 191-193 (decomposition), [a] D6 - 24 (c, 1% in CHCl3) This salt of dicyclohexylamine is converted to a free acid by suspending it in ethyl acetate and treating it with 45 ml of 10% potassium bisulfate and stirring until two layers are obtained. After separation, the aqueous phase is extracted with ethyl acetate (four times 75 ml), the organic layers are combined, dried over MgSO 4, and the solvent is evaporated to obtain 3.7 g.

  of a pale yellow vitreous substance.

Analysis calculated for C10H13NO5S:

  C, 46.32; H, 5.05; N, 5.40; S, 12.37.

  Found: C, 47.05; H, 5.50; N, 5.18; S, 12.07.

EXAMPLE 2

  1- (3-Mercapto-1-oxopropyl) -4-oxo-L-proline Argon was passed through a cold solution of 9 ml of concentrated ammonia in 22 ml of water for 30 minutes.

  minutes. This solution is then added while cooling

  under argon coverage, to 3.65 g (0.014 mole) of 1- [3 (acetylthio) -1-oxopropyl] -4-oxo-L-proline. It takes about 30 minutes to dissolve the proline by helping at the beginning of a magnetic stirrer. The stirring is continued under argon at room temperature for a further two hours, after which the solution is extracted with 30 ml of ethyl acetate (this operation, as well as the subsequent operations, are carried out as far as possible under argon atmosphere). The aqueous layer is cooled, stirred, covered with 30 ml of ethyl acetate, and

  it is acidified in fractions with 1: 1 hydrochloric acid.

  Sodium chloride is added, the layers are separated, and the aqueous phase is extracted with a supplement of ethyl acetate (three times 30 ml). A brown gummy fraction remains insoluble in both phases. After drying over MgSO 4, the combined ethyl acetate layers are evaporated to give a largely solid residue which becomes an amorphous solid when triturated with ether, and the evaporation is repeated to obtain 1 , 4 c of a

pale yellow substance.

  1.3 g of this substance is rubbed with 50 ml of ether, cooled under argon for one hour, filtered, washed with ether and dried in vacuo to give 1.0 g of -mercapto-1-oxopropyl) -4-oxo-L-proline, Rf 0.67 (methanol on silica gel, visualization in iodine vapor). Analysis calculated for C8H11NO4S. 0.5 H 2 O:

  C, 42.46; H, 5.35; N, 6.19; S, 13.71.

  Found: C, 42.66; H, 5.39; N, 6.30; S, 13.30.

EXAMPLE 3

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

EXAMPLE 4

  (S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline The product of Example 3 is treated with ammonia

  according to the procedure of Example 2 to obtain the (S) -

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

EXAMPLE 5

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

  Proline a) D, L-3- (Acetylthio) -2-trifluoromethylpropionic acid Atrifluoromethylacrylic acid (10 g, 0.071 mole) (prepared according to the procedure) is cooled in a bath of salt, ice and water. indicated in J. Chem. Soc., 1954, p. 371], stirred, and fractionated with 5.7 ml (0.075 mol) of 97% thiolacetic acid. After the addition, the yellow liquid is stirred cold for one hour, allowed to warm to room temperature, and distilled to obtain 14 g (91%) of D, L-3- acid ( acetylthio) -2-trifluoromethylpropionic acid in the form of a light yellow oil, eg 149-153 at 13 mm Hg. This substance solidifies by rest at

low temperature.

  b) D, L-3- (acetylthio) -2-trifluoromethylpropionyl chloride

  D, L-3- (acetylthio) -2-trifluoro-

  methylpropionic acid (7 cc, 0.032 mol) per 18 ml (0.25 mol) of redistilled thionyl chloride, and the melanae was refluxed for 3 hours. After removing the excess thionyl chloride using a rotary evaporator, the

  residue to obtain 6.8% of D, L-3- (acetylthio) chloride -

  2-trifluoromethylpropionyl as a yellow oil

  blade; p.e. 80-82 under 16 mm Hg.

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

proline

  The chloride of D, L-3- (acetylthio) -2-

  trifluoromethylpropionyl with 4-keto-L-hydrobromide

  proline according to the procedure of Example 1 (d), for

  obtain 1 - [(3-acetylthio) -2-trifluoromethyl-1-oxopropyl] -4-

  oxo-L-proline. We can then separate this mixture of

  diastereoisomers by conventional techniques.

EXAMPLE 6

  1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline The mixture is hydrolysed with concentrated ammonia.

  product of Example 5 (in the form of the diastereo-

  isomers or in the form of separated isomers), according to

  procedure of Example 2 to obtain 1- (3-mercapto)

  2-trifluoromethyl-l-oxopropyl) -4-oxo-L-proline.

EXAMPLE 7

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

  a) (S) -1- [3- (Acetylthio) -2- (acetylthiomethyl) -1-oxopropyl-4-

  oxo-L-proline By following the procedure of Example 1 but replacing the 3-acetylthiopropionyl chloride by D-3-acetylthiomethyl-3-acetylthiopropionyl chloride in

  part (d) gives (S) -1- [3- (acetylthio) -2-acetyl-

  thiomethyl) -l-oxopropyl] -4-oxo-L-proline.

  b) (S) -1- (3-Mercapto-2-mercaptomethyl-1-oxopropyl) -4-oxo-L-proline The product of part (a) is hydrolyzed using ammonia

  concentrated, according to the procedure of the Example

  2, to obtain (S) -1- (3-mercapto-2-mercaptomethyl-1-oxo

propyl) -4-oxo-L-proline.

EXAMPLE 8

  1- (3-Flercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline a) Acid 3 (acetylthio) -2- (methylthio) propionic The mixture is stirred with 1 N aqueous sodium hydroxide (94 ml) 12.5 g (0.094 mol) of methyl 2- (methylthio) acrylate [prepared from methyl 2-chloroacrylate according to the procedure of Gundesmann et al., Chemische Berichte 94, 3254 (1916)], with cooling in ice. The mixture is allowed to warm to room temperature and stirred for 5 hours. The resulting solution is washed with ether and acidified to pH 2 with concentrated hydrochloric acid. The solid precipitate is extracted with methylene chloride and the solution is washed with saturated sodium chloride and the solvent is evaporated. The solid residue is used immediately in the next reaction,

  2- (methylthio) acrylic acid, m.p. 70-75.

  Equimolar amounts of 2- (methylthio) acrylic acid and thiolacetic acid are mixed under argon, and the mixture is stirred at 80 for

  obtain 3- (acetylthio) -2- (methylthio) propionic acid.

  b) 3- (Acetylthio) -2- (methylthio) propionic acid chloride

  The 3- (acetylthio) -2- (methyl)

  thio) propionic in thionyl chloride for two hours. The reaction mixture is distilled to remove excess thionyl chloride and the product is distilled off.

  vacuum to obtain 3- (acetylthio) -2- (methyl-

thio) propionic acid.

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

proline

  3- (Acetylthio) acid chloride is reacted

  2- (methylthio) propionic with 4-keto-L-hydrobromide

  proline, according to the procedure of Example 1 (d), for

  obtain 1- [3- (acetylthio) -2-methylthio-1-oxopropyl] -4-oxo

L-proline.

  d) 1- (3-Mrercapto-2-methylthio-1-oxopropyl) -4-oxo-L-proline The product of part (c) is hydrolyzed with concentrated ammonia according to the procedure of the Example

Z478632

  2, to obtain 1- (3-mercapto-2-methylthio-1-oxopropyl) -

4-oxo-L-proline.

EXAMPLE 9

  1- (4-Mercapto-1-oxobutyl) -4-oxo-L-proline a) 1- [4- (Acetylthio) -1-oxobutyl] -4-oxo-L-proline Following the procedure of Example 1 but

  by replacing in part (d) 3-acetylthio chloride

  propionyl by 4-acetylthiobutyroyl chloride,

  1- [4- (acetylthio) -1-oxobutyl] -4-oxo-L-proline is obtained.

  b) 1- (4-Mercapto-1-oxobutyl) -4-oxo-L-proline The product of part (a) is hydrolyzed with concentrated ammonia according to the procedure of the Example

  2, to obtain 1- (4-mercapto-1-oxobutyl) -4-oxo-L-proline.

EXAMPLE 10

  1- (2-Mercapto-1-oxoethyl) -4-oxo-L-proline a) 1- [2- (Acetylthio) -1-oxoethyl] -4-oxo-L-proline Following the procedure of Example 1 but

  by replacing in part (d) 3-acetylthio chloride

  propionyl with acetylthioacetyl chloride, the

  1- [2- (Acetylthio) -l-oxoethyl] -4-oxo-L-proline.

  b) 1- (2-Mercapto-1-oxoethyl) -4-oxo-L-proline The product of part (a) is hydrolyzed with concentrated ammonia according to the procedure of the Example

  2, to obtain 1- (2-mercapto-1-oxoethyl) -4-oxo-L-proline.

EXAMPLE 11

  1- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -4-oxo-L-proline a) 1- [3 (Acetylthio) -2,2-dimethyl-1-oxopropyl] -4-oxo L-proline Following the procedure of Example 1 but

  by replacing in part (d) 3-acetylthio chloride

  propionyl with 3-acetylthio-2,2-dimethylchloride

  propionyl, 1- [3- (acetylthio) -2,2-dimethyl-1-

  oxopropyll-4-oxo-L-proline. b) 1- (3-Mercapto-2,2-dimethyl-1-oxopropyl) -4oxo-L-proline The product of part (a) is hydrolyzed with concentrated ammonia according to the procedure of the Example

  2, to obtain 1- (3-mercapto-2,2-dimethyl-1-oxopropyl) -4-

oxo-L-proline.

EXAMPLE 12

  (S) -1- (3-Mercapto-2-ethyl-1-oxopropyl) -4-oxo-L-proline a) (S) -1- [3 (Acetylthio) -2-ethyl-11-oxopropyl] -4 -oxo-L-proline Following the procedure of Example 1 but

  by replacing in part (d) 3-acetylthio chloride

  propionyl with D-3-acetylthio-2-ethyl chloride

  propionyl gives (S) -1- [3- (acetylthio) -2-ethyl-1-

  oxopropyl] -4-oxo-L-proline. b) (S) -1- (3-Mercapto-2-ethyl-1-oxopropyl) -4-Lproline The product of part (a) is hydrolyzed with concentrated ammonia according to the procedure of the Example

* 2, to obtain (S) -1- (3-mercapto-2-ethyl-1-oxopropyl) -4-

oxo-L-proline.

EXAMPLE 13

  1- (3-Mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid a) 1- [3 (acetylthio) -1-oxopropyl] -4-oxo-L-pipecolic acid Following the procedure of the Example 1 but replacing in part (d) 4-keto-proline by

  4-keto-L-pipecolic acid, 1- [3- (acetyl)

  thio) -l-oxopropyl] -4-oxo-L-pipecolic. b) 1- (3-Mercapto-1-oxopropyl) -4-oxo-L-pipecolic acid The product of part (a) is hydrolyzed with

  concentrated ammonia to obtain 1- (3-mercapto-1-

oxopropyl) -4-oxo-L-pipecolic.

EXAMPLE 14

  (S) -1- (3-mercapto-2-methyl-1-oxopropyl) -5-oxo-L-acid

pipecolic

  a) (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -5-oxoacetate

  L-pipecolic By following the procedure of Example 1 but replacing in part (d) 4-keto-L-proline by

  5-keto-L-pipecolic acid, and acetylthio chloride

  propionyl by D-3-acetylthio-2-methyl-

  propionyl, the acid (S) -1- [3- (acetylthio-2-methyl)

  1-oxopropyl] -5-keto-L-pipecolic.

  b) (S) -1- (3-Mercapto-2-methyl-1-oxopropyl) -5-keto-L-acid

  The product of part (a) is hydrolyzed with concentrated ammonia according to the procedure of the Example

  2, to obtain the acid (S) -1- (3-mercapto-2-methyl-1

oxopropyl) -5-keto-L-pipecolic.

EXAMPLE 15

  1- (3-Mercapto-2-trifluoromethyl-1-oxopropyl) -4-oxo-L-proline a) 3 - [[(4-Methoxy) phenylmethyl] thio] -2-trifluoromethylpropionyl chloride The reaction mixture is stirred at 100.degree. For one hour, a pure mixture of 3.9 g of 1-trifluoromethylacrylic acid and 4.3 g of 4-methoxybenzylthiol. This mixture is allowed to cool to room temperature and the solid is recrystallized

  cyclohexane to give 3 - [[(4-methoxy) phenylmethyl] -

  thio] -2-trifluorométhylpropionique; m.p. 72-74.

  The treatment of this acid with chloride

  thionyl gives 3 - [[(4-methoxy) phenylmethyl] -

thio] -2-trifluorométhylpropionyle.

  b) 1- [3 - [[(4-Methoxy) phenylmethyl] thio] -2-trifluoromethyl-1

oxopropyl] -4-oxo-L-proline

  The chloride of 3 - [[(4-methoxy) - is reacted

  phenylmethyl] thio] -2-trifluoromethylpropionyl of the part

  (a) with 4-keto-L-proline to obtain l- [3 - [[(4-

  methoxy) phenylmethyl] thio] -2-trifluoromethyl-1-oxopropyl] -4-

oxo-L-proline.

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

  proline The product of part (b) is mixed with trifluoroacetic acid and anisole under nitrogen. Hunting

  solvents under vacuum to obtain as residue the 1- (3-

  mercapto-2-trifluoromethyl-1-oxopropvl) -4-oxo-L-proline.

EXAMPLE 16

  (S) -1- (3-Mercapto-3-methyl-1-oxopropyl) -4-oxo-L-proline a) (S) -1- [3 (Acetylthio) -3-methyl-1-oxopropyl] - 4-oxo-L-proline Following the procedure of Example 1 but

  by replacing in part (d) 3-acetylthio chloride

  propionyl with D-3-acetylthio-3-methylpropionyl chloride,

  (S) -1- [3- (acetylthio) -3-methyl-1-oxopropyl] -4 is obtained

  oxo-L-proline b) (S) -1- (3-Mercapto-3-methyl-1-oxopropyl) -4-oxo-L-proline The product of part (a) is hydrolyzed with

  concentrated ammonia to obtain (S) -1- (3-mercapto-3-

  methyl-l-oxopropyl) -4-oxo-L-proline.

EXAMPLES 17-25

  Following the procedure of Example 1, but replacing the 3-acetylthiopropionyl chloride with the acid chloride indicated below in column I, the mercaptoacyl derivative indicated below is obtained in FIG.

column II.

  Column I 3-Benzoylthiopropionyl Chloride D-3-benzoylthio-2-methylpropionyl Chloride

  D-3 - [[(2-thienyl) carbonyl] thio chloride] -

2-methylpropionyl

  3 - [[(2,2,2-trichloroethyl) carbonyl] chloride -

thio] propionyl

  D-3 chloride - [[(2-furyl) carbonyl] thio] -2-

methylpropionyl

  3 - [[(4-pyridyl) carbonyl] thio chloride] -

propionyl

  D-3 - [[(4-methylphenyl) carbonyl] chloride -

Thico] -2-methylpropionyl

  2 - [[(phenylmethyl) carbonyl] thio chloride] -

acetyl

  4 - [[(cyclohexyl) carbonyl] thio] chloride -

  butyroyl Column II 1- [3- (benzoylthio) -1-oxopropyl] -4-oxo-L-proline

  (S) -1- [3- (benzoylthio) -2-methyl-1-oxopropyl] -4-

oxo-L-proline

  (S) -1- [3 - [[(2-thienyl) carbonyl] thio] -2-methyl-

1-oxopropyl] -4-oxo-L-proline

  1- [3 - [[(2,2,2-trichloréthyl) carbonyl] thio] -1

oxopropyl] -4-oxo-L-proline

  (S) -1- [3 - [[(2-furyl) carbonyl] thio] -2-methyl-1-

oxopropyl] -4-oxo-L-proline

  1- [3 - [[(4-pyridyl) carbonyl] thio] -1-oxopropyl] -

4-oxo-L-proline

  (S) -1- [3 - [[(4-methylphenyl) carbonyl] thio] -2-

  mnéthyl-l-oxopropyl] -4-oxo-L-proline

  1- [2 - [[(phenylmethyl) carbonyl] thio] -1-oxoethyl] -

4-oxo-L-proline

  1- [4 - [[(cyclohexyl) carbonyl] thio] -1-oxobutyl] -

4-oxo-L-proline Co Do L "You have

EXAMPLE 26

  1-Adamantanamine salt of (S) -1- (3-mercapto-2-meth)

  1-oxopropyl) -4-oxo-L-proline The product of Example 4 can be prepared by the following procedure.

  a) Methyl ester of N-carbobenzyloxy-4,4-dimethoxy-L-

  A stirred solution of 7.8 g (0.03 mol) of Ncarbobenzyloxy-4-keto-L-proline of Example 1 in 60 ml of methanol was treated with 96 ml of trimethyl orthoformate, followed by 0.6 nl of concentrated sulfuric acid, and allowed to

  stand overnight at room temperature.

  The pale yellow solution is stirred, treated with 1.5 g of potassium carbonate and then with 30 ml of water, and the bulk of the solvent is removed using a rotary evaporator to obtain a residue. syrupy which is shaken with 30 ml of water and 30 ml of chloroform. After separating the layers, the aqueous phase is extracted with additional chloroform (three times 30 ml) and the combined organic layers are washed with 45 ml of saturated sodium chloride solution and then dried over magnesium sulfate. Evaporation of the solvent gives 8.4 g (88%)

  methyl ester of N-carbobenzyloxy-4,4-dimethoxy-L-

  proline. b) N-Carbobenzyloxy-4,4-dimethoxy-L-proline The ester (8.4 g, 0.026 mole) of part (a) is dissolved in 80 ml of methanol, treated dropwise between - 1 and 4 with 18 ml (0.036 mole) of 2N sodium hydroxide maintained at 0 for one hour, then at room temperature overnight. After having removed about half of the solvent using a rotary evaporator, the solution is diluted with 150 ml of water, washed with 100 ml of ether (the washings are discarded), acidified to pH 2, while cooling, with 63 ml of hydrochloric acid 1: 1, and extracted with ethyl acetate (four times 750 ml). The combined extracts are washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, and the solvent is evaporated to give 8.0 g of a pale yellow viscous oil. This oil is dissolved in 35 ml of ethanol, treated with 3.0 g of cyclohexylamine in

  ml of ethanol and diluted to 500 ml with ether.

  Upon initiation of crystallization and rubbing, the crystalline N-carbobenzyloxy-4,4-dimethoxy-L-proline cyclohexylamine salt separates; after cooling overnight, it weighs 7.0 g, m.p. 157159 (sintering at 151), [α] 6 - 34 (c, 1% in ethanol). This material is recrystallized from 100 ml of acetonitrile to give the salt as a colorless solid, m.p. 158-160 (frittace at 154),

  2o] 6 - 330 (c, 1% in ethanol).

  The cyclohexylamine salt of the N-carbohydrate is

  benzyloxy-4,4-dimethoxy-L-proline suspended in 40 ml of ethyl acetate, stirred and treated with 25 ml of 1N hydrochloric acid. Once two clear layers have been obtained, they are separated, the aqueous phase is extracted with a supplement of ethyl acetate (three times 40 ml), the combined organic layers are dried over magnesium sulphate, and the solvent is evaporated, finally under 0.2 mm of mercury

  and at 40, to obtain 7.2 c (70%) of N-carbobenzyloxy-4,4-

  dimethoxy-L-proline as a pale yellow viscous syrup. c) 4,4-Dimethoxy-L-proline A solution of N-carbobenzyloxy-4,4-dimethoxy-L-proline (72 g, 0.022 mole) in 210 ml of titanium dioxide was treated with 2.3 g of 5% palladium on carbon. a 2: 1 mixture of methanol and water, and shaken in a Parr hydrogenation apparatus for 6 hours. The catalyst is filtered off under nitrogen, washed with methanol, and the combined filtrates are evaporated, finally 0.1-0.2 mm Hg, to obtain a partially crystalline residue. We take this

  residue in 200 ml of methanol and the evaporation is repeated.

  When rubbing the solid under ether (repeat again

  evaporation), 3.6 g (95%) of 4,4-dimethoxy-L-

  proline almost colorless, m.p. 192-194 (decomposition);

  [a] 26 - 47 (c, 1% in methanol).

  A sample recrystallized from a mixture of methanol and ether is colorless and melts at 197-] 98

  (decomposition); [a] 26 - 490 (c, 1% in methanol).

  d) (S) -1- [3- (Acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-

  L-Proline It is cooled to a stirred solution of 3.3 g (0.019 mole) of 4,4-dimethoxy-L-proline in 50 ml of water and is brought to pH 8.5 by adding a solution. 25% sodium carbonate (weight / volume). Then, while continuing to shake and cool, add

  a solution of 3.8 c (0.021 mol) of D-3 chloride

  acetylthio-2-methylpropanoyl in 5 ml of ether, while maintaining the pH between 7.5 and 8.5 by adding dropwise 25% sodium carbonate solution. Once the pH has stabilized at 8.2 to 8.4 (at the end of about 15 minutes), stirring and cooling are continued for a total of one hour. The solution is then washed with 50 ml of ethyl acetate (the washings are discarded), overlaid with 50 ml of ethyl acetate, cooled, stirred and acidified with water. Precaution with 1: 1 hydrochloric acid to pH 2.0, saturated with sodium chloride, and the layers separated. The aqueous phase is extracted with a supplement of ethyl acetate (three times ml), the combined organic layers are dried over magnesium sulphate and the solvent is evaporated, finally

  0.2 mm Hg, to obtain 6.7% of a syrupy product.

  This product is treated in 70 ml of ethyl acetate per 3.9 g.

  of dicyclohexylamine to give 6.5 g of dicyclo

  (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4 hexylamine

  colorless dimethoxy-L-proline, in two crops (3.1 g and 3.4 c), (frittaoe 26 mp 158-160 (sintering 145), [a] D 710 (cl% in

ethanol).

  After recrystallization from a warm mixture of ml of ethyl acetate and 60 ml of hexane, the colorless solid salt weighed 6.0 g, m.p. 158-166 (sintering at 155), [a] 25

- 69 (c, 1% in ethanol.

  The dicyclohexylamine salt is converted to the free acid by suspending 5.0 g in 50 ml of ethyl acetate, cooling and treating with 60 ml of a 10% potassium bisulfate solution so that get two clear layers. After separation, the aqueous phase is extracted with ethyl acetate (three times 50 ml), the combined organic layers are dried over magnesium sulphate and the solvent is evaporated, finally 0.1-0.2 mm. of mercury and at 45, to obtain 4.1 g (69%) of (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-dimethoxy-L-proline in the form of a viscous and almost vitreous substance,

  a] 25-112 (c, 1% in ethanol).

[oD

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

  proline Argon is passed through a cold solution of 8.5 ml of concentrated ammonia in 20 ml of water for a quarter of an hour. This solution is then added, while cooling and under an argon blanket, to 4.1 g (0.013 g).

  mole) of (S) -1- [3- (acetylthio) -2-methyl-1-oxopropyl] -4,4-

  dimethoxy-L-proline, and the mixture is swirled in an ice bath until a pale yellow solution (about 15 minutes) is obtained. Stirring is continued under argon at room temperature for a further 2 hours, then the solution is extracted with 30 ml of ethyl acetate (this operation, as well as the subsequent operations, are carried out as far as possible in an atmosphere argon). The aqueous layer is cooled, stirred, overlaid with 30 ml 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 supplement of ethyl acetate (three times 30 ml), the ethyl acetate layers are dried over magnesium sulphate and

  evaporate the solvent to obtain 3.5 g (100%) of (S) -1- (3-

  mercapto-2-methyl-1-oxopropyl) -4,4-dimethoxy-L-proline as a colorless viscous syrup, [?] D25-72 (c, 1% in ethanol). This syrup (3.4 g) is triturated with 20 ml of ethyl acetate, rubbed, diluted with 30 ml of hexane, and

  cool to obtain a colorless solid weighing 2.6 g, m.p.

  108-110, [α] 25-770 (c, 1% in ethanol) D

  f) 1-Adamantanamine salt of (S) -1- (3-mercapto-2-methyl)

1-oxopropyl) -4-oxo-L-proline

  (S) -1- (3-mercapto-2-methyl-1-oxo)

  propyl) -4,4-dimethoxy-L-proline (0.4 to 0.0014 moles) to 8 ml of N-hydrochloric acid, in which argon was first passed for 10 minutes. Once a solution is obtained, the flask is sealed under argon and kept overnight at room temperature. The following operations are also carried out under an argon atmosphere, as far as possible. To the stirred solution is added 20 ml of methylene chloride, and after saturating with sodium chloride, the layers are separated. The aqueous phase is extracted with additional methylene chloride (three times 15 ml), the organic layers are combined, dried over magnesium sulphate and the solvents are evaporated to give a foamy residue. After trituration with ether (the evaporation is repeated), 0.26 g of (S) -1- (3mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline are obtained.

  in the form of an amorphous (hycroscopic) solid.

  0.245 g of this product is dissolved in 7 ml of acetonitrile.

  nitrile and treated with 0.17 g of 1-adamantanamine to precipitate the salt as a bulky solid. After cooling overnight, the colorless material was filtered, washed with cold acetonitrile and ether and dried in vacuo to give 0.36 g of (S) -1-1-adamantanamine salt. (3-Mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline (1: 1), mp 188-190 (decomposition), frittaoe at 184, [a] 25,130 [D]

(c, 1% in methanol).

  Analysis calculated for C9H13NO4S. C10H17N. 0.25 H2O:

  C, 58.96; H, 8.02; N, 7.24; S, 8.29.

  Found: C, 58.60; H, 8.37; N, 7.16; S, 8.29.

EXAMPLE 27

  1,1 '- [Dithiobis (1-oxo-3,1-propanediyl)] bis [4-oxo-L-proline] The product of Example 2 is dissolved in water and the pH is adjusted to 6. By adding 1N sodium hydroxide To this stirred solution is added dropwise a solution of 0.5M iodine in 95% ethanol (6.34% iodine in 50 ml of solution), while maintaining the pH between 5.5 and 6.5 using

  of 1N sodium hydroxide. The excess of iodine is removed by thio-

  diluted sodium sulphate and concentrate the solution,

  It is cooled and acidified with 1: 1 hydrochloric acid.

  A solvent is added and the layers are separated. The organic layer is dried over magnesium sulphate and evaporated.

  the solvent to obtain the residue as 1,1 '- [dithiobis (1-oxo)

  3,1-propanediyl)] bis [4-oxo-L-proline].

EXAMPLE 28

  1- [3- (acetylthio) -1-oxopropyl] -4-oxo methyl ester

  L-Proline A solution of the product of Example 1 in ether is treated with a slight excess of diazomethane. After standing at room temperature for 2 hours, the mixture is evaporated

  the solvent to obtain the methyl ester of 1- [3- (acetyl)

thio) -l-oxopropyl] -4-oxo-L-proline.

EXAMPLE 29

  Methyl ester of 1- (3-mercapto-1-oxopropyl) -4-oxo-L-

  proline The product of Example 28 is hydrolyzed with concentrated ammonia according to the procedure of the Example

  2, to obtain the methyl ester of 1- (3-mercapto-1-

oxopropyl) -4-oxo-L-proline.

EXAMPLE 30

  Sodium salt of 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline 1.0 c of the product of Example 2 is dissolved in 10 ml of water, and the solution is treated with an equivalent of

  sodium bicarbonate. The solution is subjected to cryo-

  desiccation to obtain the sodium salt of 1- (3-

  mercapto-l-oxopropyl) -4-oxo-L-proline. In the same way, using baking soda

  potassium, the corresponding potassium salt is obtained.

EXAMPLE 31

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

  oxo-L-proline 1.0 g of the product of Example 4 is dissolved in 10 ml of water and the solution is treated with one equivalent of sodium bicarbonate. The solution is freeze-dried

  to obtain the sodium salt of 1- (3-mercapto-2-methyl-1-

  oxopropyl) -4-oxo-L-proline. In the same way, by using baking s

  potassium, the corresponding potassium salt is obtained.

EXAMPLE 32

  1000 tablets each containing the following ingredients are prepared (from sufficient total quantities)

1- (3-mercapto-1-oxopropyl) -4-oxo-

  L-proline 100 ma Corn starch 50 mg Gelatin 7.5 mg "Avicel" (microcrystalline cellulose) 25 mg Magnesium stearate 2.5 mg Total 185 mg

fisan-

  by mixing 1- (3-mercapto-1-oxopropyl) -4-oxo-L-proline

  and corn starch with an aqueous solution of gelatin.

  The mixture is dried and ground into a fine powder. The "Avicel" and then the magnesium stearate are granulated. This mixture is then compressed in a tablet press to form 1000 tablets each containing 100 mg

of active ingredient.

EXAMPLE 33

  As obtained in Example 32, tablets are obtained

  each containing 100 mg of (S) -1- (3-mercapto-2-methyl-1-oxo)

propyl) -4-oxo-L-proline.

EXAMPLE 34

  We obtain, from the following ingredients, 1000

  tablets each containing 50 mg of 1- (3-mercapto-1-oxopropyl) -

4-oxo-L-proline:

1-3-mercapto-1-oxopropyl) -4-oxo-

  L-proline 50 Lactose 100 to "Avicel" 150 g Corn starch 50 g Magnesium stearate 5 g

  1- (3-Mercapto-1-oxopropyl) -4-oxo-L-

  proline, lactose, and "Avicel", and then corn starch is added to them. Magnesium stearate is added. The dry mixture is compressed in a tablet press to form 1000 tablets of 355 mg each containing 50 mg of active ingredient. These tablets are coated with a solution of "i" ethocel E 15 "(methyl cellulose) containing, as a colorant, a lacquer

containing yellow n 6.

EXAMPLE 35

  Prepared as described in Example 34 tablets

  each containing 50 mg of (S) -1- (3-mercapto-2-methyl-1-oxo)

propyl) -4-oxo-L-proline.

EXAMPLE 36

  The following ingredients are filled with the following ingredients: # 1 gelatin capsules in two pieces each containing

  mc of sodium salt of 1- (3-mercapto-1-oxopropyl) -4-oxo

  L-Proline: 1- (3-mercapto-1-oxopropyl) -4-oxo L-Proline - 100 mg Magnesium Stearate 7 mg Lactose 193 mg

EXAMPLE 37

  As prepared in Example 36, gelatin capsules each containing 100 mg of sodium salt were prepared.

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

EXAMPLE 38

  An injectable solution is prepared as follows:

1- (3-mercapto-1-oxopropyl) -4-oxo-

  L-proline 500 g Methyl paraben 5 g Propyl paraben 1 g Sodium chloride 25 g Water for injection, enough to make 5 1 The active ingredient, preservatives and sodium chloride are dissolved in 3 l of water, then The volume is brought to 5 liters. The solution is filtered through a sterile filter and aseptically filled with pre-sterilized flasks, which are then closed with pre-sterilized catchesouc closures. Each vial contains 5 ml of solution at a concentration of 100 mg of active ingredient per ml of solution

for injection.

EXAMPLE 39

  A solution is prepared as described in Example 38

  injectable containing (S) -1- (3-mercapto-2-methyl-1

oxopropyl) -4-oxo-L-proline.

EXAMPLE 40

  Sixty tablets, each containing the following ingredients, are prepared from sufficient global quantities:

1- (3-mercapto-1-oxopropyl) -4-oxo-

L-proline 100 mg

"Avicel" (micro cellulose)

  crystalline 100 mg Hydrochlorothiazide 12.5 mg Lactose U.S.P. (United States Pharmacopoeia) 113 mg starch U.S.P. 17.5 mg Stearic acid U.S.P. 7 mg Total 350 mg

  forming disks of 1- (3-mercapto-1-oxopropyl) -4-oxo

  L-proline, "Avicel", and some of the stearic acid. These discs are crushed and made to

  through a No. 2 sieve, then mixed with the hydrochloro

  thiazide, lactose, mal starch and the remainder of stearic acid. The mixture is compressed into 350 mg capsule-shaped tablets in a tablet press. We groove

  the tablets in their middle to make them scored.

EXAMPLE 41

  It is possible to prepare as described in Example 40

  tablets each containing (S) -1- (3-mercapto-2-methyl)

  1-oxopropyl) -4-oxo-L-proline and hydrochlorothiazide.

  The products of Examples 1, 3, 5 to 25 and 27 to 29 may be packaged according to the procedures of the Examples

32 to 41.

Claims (41)

1. Compounds of formula: O It C   C / R 1 R 1 O (H 2 C) p (CH 2) 3 1 21 p 2q R - S - (CH) - C -C - N C-COOR 4 m l H   R2 and their physiologically acceptable salts, in the formula of which: R is a hydrogen atom or a lower alkyl radical; R 1 and R 3 are independently selected from hydrogen atoms and lower alkyl, lower alkylthio, - (CH 2) n -SH, and halo lower alkyl; R2 is a hydrogen atom or a lower alkyl radical, R2 can not be a lower alkyl radical than when R1 is itself a lower alkyl radical m is zero, one or two; n is one, two or three; p and q are respectively equal to one or two, but can not both be equal to two; and R4 is a hydrogen atom, a hydrolytically removable protecting group, a chemically removable protecting group, or provided that neither R1 nor R3 are - (CH2) n -SH, or 3R3O (H2C) (CH2) 31 1 I l 1 p -S- (CH) -C- C- N C-COOR. I! m H | R2 H   2. Compound according to claim 1, wherein p is equal to two and q is one.   3. Compound according to claim 1, wherein p is equal to to one and q is equal to two.   4. The compound of claim 1 wherein p and q are both are equal to one.   5. Compounds according to claim 1, of formula: -R O | He He R4-S- (CH2) -C C N COOH I H (L)   R2 and their physiologically acceptable salts, in the formula of which: R1 and R2 are both lower alkyl radicals of 1 to 4 carbon atoms or R2 is a hydrogen atom and R1 is a hydrogen atom, a radical; lower alkyl of   1 to 4 carbon atoms, a trifluoromethyl radical, methyl   thio or mercaptomethyl; m is zero or one; and R4 is a hydrogen atom, an alkanoyl radical   lower by 1 to 4 carbon atoms, or a benzoyl radical.   6. Compound according to claim 5, wherein R1 and R2   both are methyl radicals and m is one.   7. A compound according to claim 5, wherein R2 is a hydrogen atom, R1 is trifluoromethyl radical, and m is ecal to one.   8. A compound according to claim 5 wherein R2 is hydrogen, R1 is methylthio, and m is one. 9. The compound according to claim 5, wherein R2 is a hydrogen atom, R1 is the mercaptomethyl radical, and m is equal to one.   10. Compound according to claim 5, wherein R1 and R2   both are hydrogen atoms.   11. Compound according to claim 10, wherein m is equal to one. 12. Composed according to the acetyl radical. 13. Composed according to a hydrocene atom. 14. Composed according to equal to zero.   15. Compound according to hydrogen atom, R1 is one. 16. Composed according to acetyl radical. 17. Composed according to hydrogen atom.   18. The compound according to claim 11, wherein R4 is claim 11, wherein R4 is claim 10, om is methyl, wherein R2 is one and m is equal to claim 15, wherein R4 is claim 15 R4 is one of claim 17 which is (S) -1- (3mercapto-2-methyl-1-oxopropyl) -4-oxo-L-proline. 19. Hypertension treatment composition,   characterized in that it comprises a pharmaceutical carrier-   and one or more antihypertensive agents, or physiologically acceptable salts thereof, of the formula: ## STR2 ## R4-S- (CH) -   R1 C- R2 C (H2C) P (CH2) q il I _ _ _ 1 C- - N C-COOR   Wherein R is a hydrogen atom or a lower alkyl radical; R 1 and R 3 are independently selected from hydrogen atoms and lower alkyl, lower alkylthio, - (CH 2) n -SH, and halo-lower alkyl radicals; R 2 is a hydrogen atom or a lower alkyl radical, R 2 can not be a lower alkyl radical than when R 1 is itself a lower alkyl radical; m is zero, one or two; n is one, two or three; p and q are respectively equal to one or two, but can not both be equal to two; R4 is a hydrogen atom, a protecting group which may be removed by hydrolysis, or provided that neither R nor R are - (CH2) n -SH, Si3-C2) nS R -S- (CH)   m o He 1c x He | (H2C) (CH2) q R l o 2 q C Il N C C - C N. C-COOR   R2 R2 H H 20. Composition according to claim 19, characterized in that the antihypertensive agent has the formula: o R1 O I II R4-S- (CH2) -C -   In which R 1 and R 2 are both lower alkyl radicals of 1 to 4 carbon atoms, or R 2 is a hydrogen atom and R 1 is a hydrogen atom, a lower alkyl radical; from 1 to 4 carbon atoms, the trifluoromethyl, methylthio or mercaptomethyl radical; m is zero or one; and R4 is a hydrogen atom, an alkanoyl radical   lower than 1 to 4 carbon atoms, or the benzoyl radical.   21. Composition according to claim 20, characterized in that R1, R2 and R4 are atoms of hydrogen and m is equal to one.   22. Composition according to claim 20, characterized in that R1 is the methyl radical, R2 and R4.   are hydrogen atoms and m is equal to one.   23. Composition according to claim 19,   characterized in that it also contains a diuretic.   24. A process for preparing a proline or a ketone-functional pipecolic acid of the formula: ## STR2 ## COOR I I H R2 H   or one of its physiologically acceptable salts, in the formula of which: R is a hydrogen atom or a lower alkyl radical; R 1 and R 3 are independently selected from hydrogen atoms and lower alkyl, lower alkylthio, - (CH 2) n -SH, and lower haloalkyl radicals; R 2 is a hydrogen atom or a lower alkyl radical, R 2 can not be a lower alkyl radical than when R 1 is itself a lower alkyl radical; m is zero, one or two; n is one, two or three; p and q are respectively equal to one or two, but can not both be equal to two; and R4 is a hydrogen atom, a hydrolytically removable protecting group, a chemically removable protecting group, or provided that neither R1 nor R3 are - (CH2) n-SH, R3 -S- (CH) - o It c R1O (H2C) (CH2) q He I - C-C-N-N C-COOR.   Characterized in that: a ketone-functional proline or pipecolic acid of the formula: C) q - COOR   with an acid or its chemical equivalent, of formula: R3 CR1   Wherein R4 is a hydrogen atom or a hydrolytically or chemically removable protecting group to form a product wherein R4 is a hydrogen atom or a hydrogen atom, or R4 is a hydrogen atom or a protecting group which may be removed by hydrolysis or chemically; protecting group which can be removed by hydrolysis or chemically; and, where appropriate, said protecting group is removed, and, in the case where R1 and R3 are other than - (CH2) n-SH, said product in which R4 is hydrogen is oxidized with the aid of iodine, to form a product in which R4 is: o II / xl 3 l 2 1 H2q R H   R2 or else: it is desired in that in that the protective group of the product is eliminated in that   get, whose ketone function is protected.   25. The method of claim 24, characterized   p is equal to two and q is one.   26. Process according to claim 24, characterized   p is equal to one and q is equal to two.   27. The method of claim 24, characterized p and q are both equal to one.   28. The process as claimed in claim 24, wherein a product of formula is obtained: ## STR2 ## N COOH   H (L) or a physiologically acceptable salt thereof, wherein R1 and R2 are both lower alkyl radicals of 1 to 4 carbon atoms or R2 is a hydrogen atom and R1 is a hydrogen atom. hydrogen atom, an alkyl radical   1 to 4 carbon atoms, the trifluoro-   methyl, methylthio or mercaptomethyl; m is zero or one; and R4 is a hydrogen atom, an alkanoyl radical   lower than 1 to 4 carbon atoms, or the benzoyl radical.   29. The method of claim 28, characterized in that R1 and R2 are both methyl and am radicals. is ecal to one.   30. Process according to claim 28, characterized in that R2 is a hydrogen atom, R1 is the trifluoromethyl radical, and m is equal to one. 31. Process according to claim 28, characterized in that R2 is a hydrogen atom, R1 is the radical methylthio, and m is equal to one.   32. Process according to claim 28, characterized in that R is a hydrogen atom, R1 is the radical   mercaptomethyl, and m is equal to one.   33. The method of claim 28, characterized   in that R1 and R2 are both hydrogen atoms.   34. Process according to claim 33, characterized in that m is equal to one.   35. Process according to Claim 34, characterized   in that R4 is the acetyl radical.   36. Process according to claim 34, characterized   in that R4 is a hydrogen atom.   37. Process according to claim 34, characterized in that m is zero.   38. Process according to claim 28, characterized in that R2 is a hydrogen atom, R1 is the radical methyl and m is equal to one.   39. Process according to claim 38, characterized   in that R4 is the acetyl radical.   40. Process according to claim 38, characterized   in that R4 is a hydrogen atom.   41. Process according to claim 40, characterized   in that the product obtained is (S) -1- (3-mercapto-2-methyl) 1-oxopropyl) -4-oxo-L-proline.