Certain tetrahydropyridine-2-carboxylic acids and pyrroline-2-carboxylic acids and derivatives thereof

The present invention relates to new compounds corresponding to the general formula:

(I)

H₂VS

CH ^r1'^s-^(ch2 > nI II

CH-C- N (CH) * It \ / ^{2 m} o CH * loOR in which R and R ^ each represent a hydrogen atom or a lower alkyl group, R ^ represents a hydrogen atom, a lower alkanoyl group or a group of formula:

R.

h₂vs

CH

-S- (CH-) -CH— Cz m,.

(ck₉) m

CH

I

COOR while m and n each represent 0 or 1.

The asterisks indicate asymmetric carbon atoms. The carbon atom of the acyclic side chain is asymmetric when R₂ is different from hydrogen.

The present invention relates to derivatives of 3,4-dehydroproline and 4? 5-dehydropipecolic acid corresponding to formula I above.

Preferred are the compounds of formula I in which R and R₂ each represents a hydrogen atom or a lower alkyl group, in particular, a hydrogen atom or a methyl group, R ^ representing a hydrogen atom or a lower alkanoyl group, in particular, a hydrogen atom or a acetyl group while m is equal to 0 or 1, in particular, equal to 0 and n is equal to 0 or 1, in particular, equal to 1.

The L configuration for the cyclic imino acid is particularly preferred.

Among the lower alkyl groups involved in one or the other of the variants, there are the straight and branched chain hydrocarbon radicals chosen from methyl to heptyl groups, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, isopentyl group and the like. Groups containing 1 to 4 carbon atoms, in particular, 1 and 2 carbon atoms are preferred.

Lower alkanoyl groups are those having the acyl radicals of lower fatty acids containing 2 to 7 carbon atoms, for example, the acetyl group, the propionyl group, the butyryl group, the isobutyryl group and the like. Likewise, lower alkanoyl groups containing up to 4 carbon atoms are preferred, in particular the acetyl group.

The products corresponding to formula I can be prepared by different synthesis methods.

As a general rule, the synthesis of these compounds can be carried out by coupling the acid of formula:

(II) R₂

I

R -S- (CH₂)_not-CH-COOH or its chemical equivalent to the cyclic imino acid of formula:

(III) î / b

HC CH

II

HN (CH ,.) \ / ^2mCH i

COOR by any process that can be adopted to form amido bonds (see, for example, Methoden der Organischen Chemie ”(Houben-Kevl), part 1, pages 735 et seq., Part II, pages 1 et seq. (1974) ) · According to a process, an acid or i 'i - an ester of formula III is coupled with a haloalkanoic acid of formula:

(IV) p

X— (CH „) -CH-COOH ^x 2 'n in which X represents a halogen atom, preferably a chlorine atom or a bromine atom, by one of the known methods in which the acid of formula IV is activated before the reaction with the acid of formula III, by forming a mixed anhydride, a symmetrical anhydride, an acid chloride or an active ester, or alternatively by using the reagent K from WoodAvard, namely K-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, or like.

The product of this reaction is a compound corresponding to the formula:

(V)

X- (CH) -CH '2 n

VS

II ^H2^VS i

- N \ / CH

CH (CH,

COOR

This product is subjected to a displacement reaction with the anion of a thioacid of formula:

(VI) '

R ^ -CO-SH in which represents a lower alkyl group, to obtain a product of formula:

(VII)

R:

H / X

H₂C ch

R₃-CO-S- (CH)_not-CK-C

<img file="LU80925A1_D0001.tif" />

(CH₂)

CH

COOR

<img file="LU80925A1_D0002.tif" />

which can then be transformed into a product of formula (VIII)

HS- (CH_) zn

<img file="LU80925A1_D0003.tif" />

/ X

CH &lt;ch₂)_:

CH

I

COOR by ammonolysis or alkaline hydrolysis. When OR is an ester group (i.e. when R is a lower alkyl group), the latter can be removed by conventional methods. For example, when R is a tert-butoxy group or a tert-amyloxy group, by treating the ester of formula VII or of formula VIII with trifluoroacetic acid and anisole, the free acid is obtained corresponding. In the presence of other alkoxy groups, by alkaline hydrolysis of the compound of formula VII or of formula VIII, the free acid is obtained.

When an acid of formula III is used as a starting material or when the final product is obtained in the form of the free carboxylic acid, this acid can be converted into its ester, for example, by esterification with a diazoalkane such as diazomethane, an 1-alkyl-3-p-tolyl-triazene such as 1-n-butyl3-p-tolyltriazene or the like.

According to another variant, an ester, preferably the methyl ester or t-butyl ester of formula III, is treated in an anhydrous medium such as dichloromethane, tetrahydrofuran, dioxane or the like, with an acylthioalkanoic acid of formula :

(IX) _R

R. - CO - S - (CH₉) - CH - COOH &amp; n in which represents a lower alkyl group, in the presence of dicyclohexylcarbodiimide, K, K'-carbonylbisimidazole, ethoxvacetylene, diphenvlphosphoryl azide or analogous coupling agents at a temperature between about 0 and 10 ° C.

The ester group can then be removed, for example, by treatment with trifluoroacetic acid and anisole at approximately room temperature, to obtain the free acid (R = H).

Alternatively, an ester of formula III (for example, in which R represents a lower alkyl group, in particular a t-butyl group) can be reacted with a thiolactone, for example, β-propiothiolactone, α -methyl-ß-propiothiolactone or the like in an anhydrous solvent such as tetrahydrofuran, dioxane, methylene chloride or the like, at a temperature between about 0 ° C and about room temperature. The ester group can be removed with anisole and trifluoroacetic acid as described above.

The synthesis of compounds of formula I is carried out in which represents a group of formula:

_ H / X

R, h_c ch

I ²i I

-S- (CH,) —CH — CN (CH_) ²ⁿ II \_CH- ^2m⁰ I

COOR by direct oxidation of a compound of formula I in which R ^ represents a hydrogen atom, for example, with iodine, to obtain the symmetrical bis-compound.

The products of formula I contain an asymmetric carbon atom and they have two if R is different from hydrogen. These carbon atoms are indicated by an asterisk in formula I. Consequently, these compounds exist in stereoisomeric forms or in the form of racemic mixtures

All these compounds fall within the scope of the present invention. In the syntheses described above, the racemate or one of the enantiomers can be used as starting material. When the racemic starting material is used in the process of i

In synthesis, the stereoisomers obtained in the product can be separated by conventional methods of chromatography or fractional crystallization. Generally, the L isomer vis-à-vis the carbon atom of the amino acid is the preferred isomer form.

The compounds of the present invention form basic salts with different organic and inorganic bases also falling within the scope of the present invention. Among these salts are ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases, for example, dicyclohexylamine salts, benzathine, N-methyl-D-glucamine hydrabamine, salts formed with amino acids such as arginine, lysine and the like. Non-toxic and physiologically acceptable salts are preferred, although other salts are also useful, for example, to isolate or purify the product.

The salts are formed in the usual manner by reacting the product in the form of its free acid with one or more equivalents of the appropriate base, forming the desired cation in a solvent or in a medium in which the salt is insoluble, or alternatively in water, then removing it by lyophilization. By neutralizing the salt with an insoluble acid such as a cation exchange resin in the hydrogenated form (for example, a polystyrene-sulfonic acid resin such as the Dowex 50 resin) or with an aqueous acid, as well as extracting with an organic solvent, for example, ethyl acetate, dichloromethane or the like, the free acid can be obtained and optionally another salt is formed.

Additional experimental details are given in the examples illustrating preferred embodiments and also serving as models for the preparation of other members of the group.

The compounds of the present invention are useful as hypotensive agents. They inhibit the transformation of the "angiotensin I" decapeptide into "" angiotensin II "and, therefore, they are useful in alleviating or relieving hypertension due to angiotensin. The action of the enzyme "renin" on angiotensinogen which is a pseudoglobulin of the blood plasma, produces angiotensin I. Angiotensin I is transformed into angiotensin II by the enzyme of transformation of angiotensin. Angiotensin II is an active vasomotor substance that has been implicated as a causative agent in different forms of hypertension in various species of mammals, for example, rats and dogs. The compounds of the present invention are involved in the angiotensinogen sequence -> (renin) -> angiotensin I -> angiotensin transforming enzyme -> angiotensin II, by inhibiting the angiotensin transforming enzyme and by reducing or reducing suppressing the formation of the vasomotor substance '' angiotensin II. Thus, by administering a composition containing a compound of formula I or a combination of compounds of formula I; or their physiologically acceptable salts, hypertension due to angiotensin is reduced in mammalian species which suffer from it. A single dose or, preferably, two to four doses spread over the day and established on the basis of approximately 0.1 to 100 mg per kg per day (preferably approximately 1 to 50 mg per kg per day) are suitable for reducing blood pressure, as has been found in the animal experiments described by SL Engel, TR Schaeffer, MH Vaugh and B. Rubin, Proc. Soc. Exp. Biol. Med. ”143, 483 (1973). Preferably, the substance is administered orally, but parenteral modes of administration can also be adopted, for example, subcutaneously, intramuscularly, intravenously or intraperitoneally.

The compounds of the present invention may be used to reduce blood pressure by formulation in compositions such as tablets, capsules or elixirs for oral administration, or in sterile suspensions or solutions for parenteral administration. We combine about 10 to 5θθ^mg of a compound or a mixture of compounds of formula I or their physiologically acceptable salts with a vehicle, a support, an excipient, a binder, a preservative, a stabilizer, a flavoring agent, etc., physiologically acceptable in unit dosage form in accordance with accepted pharmaceutical practice. The amount of active substance contained in these compositions or preparations is calculated so as to obtain an appropriate dosage falling within the indicated range.

The following examples illustrate the present invention and constitute particularly preferred embodiments. All temperatures are given in degrees Celsius.

Example 1

1- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline methyl ester

3.75 g of DL-3,4dehydroproline methyl ester are dissolved in 40 ml of dichloromethane and the solution thus obtained is cooled in an ice-water bath. A solution of 6.18 g of dicyclohexvlcarbodiimide in 21 ml of dichloromethane is added, then 4.45 g of 3-acetylthiopropanoic acid is immediately added. After having stirred for 15 minutes in the ice-water bath and for 16 hours at room temperature, the precipitate is separated by filtration and the filtrate is concentrated in vacuo until dry. The residue is dissolved in ethyl acetate and washed until neutral. The organic layer is dried over magnesium sulfate and concentrated to dryness to obtain the methyl ester of 1- (3-acetylthiopropanoyl) -DL-3,4dehydroproline.

Example 2 - (3-mercaptopropanoyl) -DL-3,4-dehydroproline

2.5 g of 1- (3acetylthiopropanoyl) -DL-3,4-dehydroproline methyl ester are dissolved in a mixture of 10 ml of methanol and 20 ml of normal sodium hydroxide. The mixture is stirred at room temperature under a nitrogen atmosphere for 2 hours, diluted with water and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulphate and concentrated to dryness to obtain l- (3-mercaptopropanoyl) -DL-3,4-dehydroproline with a melting point of 166 -163 ° C (sintering : 143 °) in the form of the dicyclohexylamine salt; 0.33, silica gel; acetate¹ethyl / pyridine / acetic acid / water (45: 20: 0: 11).

Example 3 l- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline

5 g of 3-acetylthiopropanoyl chloride and 15 ml of 2K sodium hydroxide are added to a solution of 3.4 g of DL-3.4 “dehydroproline in 30 ml of normal sodium hydroxide, this solution being cooled in an ice water bath. After stirring for 3 hours at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to obtain l- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline with a melting point of 156-1S8 ° C ( sintering: 152 °) in the form of the dicyclohexylamine salt. R ~ 0.38; silica gel; ethyl acetate / pyridine / acetic acid / water (45: 20: 6: 11).

Example 4

Acid 2-έ · Ε1ιγ1-3-Βθβ · Εγ1-ΕΗχορι? ΟρΗηοΐηηβ

For 4 hours, 6.6l g of thioacetic acid, 6.25 g of ethyl acrylic acid and a few crystals of 2,2'-azobis- (2-methyl-propionitrile) are refluxed, then allowed to stand. mix at room temperature for 48 hours.

The reaction mixture is concentrated to dryness and the residue is again evaporated twice in toluene to obtain 7> 88 g of 2-ethyl-3-acetylthiopropanoic acid.

Example 5

2-ethyl-3-acetylthiopropanoyl chloride

7> S8 g of 2-ethyl-3-acetylthiopropanoic acid are dissolved in 6.14 g of thionyl chloride and the solution thus obtained is stirred at room temperature for 15 hours. By distillation, 2-ethyl-3-acetylthiopropanoyl chloride is obtained in the form of a clear yellow oil; yield: 4, S g; boiling point: 50-60 ° (0.04 ™ Hg).

Example 6

1- (3-acetylthio-2-éthylpropanoyl) -L ~ 3,4-dehydroproline

3> 4 g of L-3,4-dehydroproline are dissolved in .30 ml of normal sodium hydroxide and the solution thus obtained is cooled in a water bath.¹ frozen water. 5.84 g of 3-acetylthio-2-ethyl-propanoyl chloride and 15 ml of 2N sodium hydroxide are added, then the solution is stirred at room temperature for 3 hours. The mixture is extracted with ether, it is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to obtain 1- (3-acetylthio-2-ethyl-propanoyl) -L-3,4-dehydroproline.

Example 7

- (2-ethyl-3-mercaptopropanoyl) -L-3,4-dehydroproline

3 gd® 1— (3-acetylthio-2-ethylpropanoyl) -L-3,4-dehydroproline are dissolved in a mixture of 10 ml of water and 10 ml of concentrated ammonia under a nitrogen atmosphere.

After 25 minutes, the reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to obtain 1- (2-ethyl-3-mercaptopropanoyl) -L-3,4-dehydroproline.

Example 8

1- (2-acetylthiopropanoyl) -L-3,4-dehydroline

5.65 g of L-3,4-dehydroproline are dissolved in 50 ml of normal aqueous sodium hydroxide, then the solution thus obtained is cooled in an ice-water bath while stirring.

25 ml of 2K sodium hydroxide and 8.57 g of sodium chloride are added.

2- bromopropanoyl. The mixture is stirred at room temperature for one hour. A mixture of 4.1θ g of thioacetic acid and 4.8 g of potassium carbonate in 50 ml of water is added, then this mixture is stirred at room temperature for 18 hours. After acidification, the mixture is extracted with ethyl acetate The organic layer is dried over magnesium sulfate and concentrated in vacuo to dryness to give 1- (2-acetylthiopropanoyl) -L-3,4-dehydroproline.

Example 9

1- (2-mercaptopropanoyl) -L-3,4-dehydroproline

By substituting 1 - (2-aet.ylthiopropanoyl) -L3,4-dehydroproline for l- (3-acetylthio-2-ethylpropanoyl) -L-3,4 ~ dehydroproline in the process of Example 7j the l- (2mercaptopropanoyl) -L-3,4-dehydroproline.

Example 10

1- (3-ac6tylthio-2-methylpropanoyl) -DL-4,5-dehydropiperidine2-carboxylic acid "

5.4 g of 3-acetylthio2-methylpropanoyl chloride and 15 ml of 2N sodium hydroxide are added to a solution of 4 g of DL-4,5-dehydropiperidine-2-carboxylic acid in 3θ ml of sodium hydroxide. normal sodium, this solution being cooled in an ice water bath. After stirring for 3 hours at room temperature, the mixture is extracted with ether, acidified and again extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to dryness to obtain 1- (3-acotylthio-2-methylpropanoyl) -DL-4,5-dehydropiperidine-2-carboxylic acid.

Example 11

1- (3-Mercapto-2-methylpropanovl) -DL-4,5-dehydropiperidine2-carboxylic acid.

By substituting 1- (3-acetylthio-2-methylpropanoyl) -DL-4,5-dehydropiperidine-2-carboxylic acid for 1- (3-acetylthio-2-ethylpropanoyl) -L-3,4-dehydroproline in the method of Example 7, 1- (3-mercapto-2-methylpropanoyl) DL-4,5-dehydropiperidine-2-carboxylic acid is obtained.

Example 12

1- (3-Mercapto-2-ethylpropanoyl) -DL-4,5-dehydropiperidine-2carboxylic acid.

By substituting DL-4,5-dehydropiperidine2-carboxylic acid for L-3,4-dehydr-oproline in the process of Example 6 and by subjecting the product to the process of Example 7> 1 'is obtained 1- (3-mercapto-2-ethylpropanoyl) -DL-4,5-dehydropiperidine-2-carboxylic acid.

Example 13

1- (2-Mercaptopropanoyl) -DL-4,5-dehydropiperidLne-2-carboxylic acid.

By substituting DL-4,5-dehydropiperidine2-carboxylic acid for L-3,4-dehydroproline in the process of Example 8, then subjecting the product to the process of Example 9? l- (2-mercaptopropanoyl) -DL-4,5-dehydropiperidine-2c acid is obtained at rb ox yli that.

Example 14, 1 '-F dithiobis- (2-methyl-3-propanoyl) Ί-bis-L-3,4-dehydroproline

1 g of 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline is dissolved in water and the pH is adjusted to 6.5 with normal sodium hydroxide. An ethanolic iodine solution is added dropwise while maintaining the pH between 6 and 7 by carefully adding normal sodium hydroxide. When a permanent yellow color is obtained, the addition of iodine is stopped and the coloring is eliminated with sodium thiosulfate. The reaction mixture is acidified and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to obtain l, l - [ditbiobis- (2methyl-3-propanoyl)] - bis-L-3,4-dehydroproline.

Example 15

Acid 1.1'— fdithiobis- (2-methyl-3-propanoyl) Ί-bis-DL-4,5-dehydropi peridin-2-carboxylic.

By substituting 1- (3-mercapto-2-methylpropanoyl) -DL-4,5-dehydropiperidine-2-carboxylic acid for 1- (3-mercapto 2-methylpropanoyl) -L-3,4-dehydroproline in the process of Example 14, 1.1 '- [dithiobis- (2-methyl-3-propanoyl)] bis-DL-4,5-debydropiperidine-2-carboxylic acid is obtained.

Example 16

1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline

By substituting L-3,4-dehydroproline for 4,5-dehydropiperidine-2-carboxylic acid in the process of Example 10. then subjecting the product to the process of Example 7> ^we obtains 1- (3-mercapto-2-methylpropanoyl) -L-3,4^-dehydroproline.

Example 17

1- (3-Mercapto-2-methylpropanoyl) -L-3,4-dehydroproline sodium salt.

An aqueous solution of l- (3mercapto-2-methylpropanoyl) -L-3,4-dehydroproline is neutralized with IN sodium hydroxide, then the water is removed by lyophilization to obtain the sodium salt of l- (3-mercapto-2-methylpropanoyl) -L-3,4déhydroproline.

Example 18

1- (3-Mercapto-2-methylpropanoyl) L-3,4-dehydroproline dicyclohexylammonium salt.

An equimolar amount of dicyclohexylamine is added to a solution of 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehvdroproline in ethyl acetate. The precipitate formed is isolated by centrifugation to obtain the dicyclohexylammonium salt of 1- (3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline.

Example 19 - (3-acetylthiopropanoyl) -DL-3,4-dehydroproline

1.02 g of DL-3,4-dehydroproline is dissolved in 9 ml of 1N aqueous sodium hydroxide and the solution thus obtained is cooled in an ice bath. 1.5 g of acetylthiopropionvl chloride in 3 ml of ether are then added. 4.8 ml of 2K sodium hydroxide are gradually added while maintaining the pH at approximately S. The aqueous solution is extracted with ethyl acetate. The pH of the aqueous solution is lowered to 1.5, thus separating an oil which is eliminated. The aqueous solution is washed with ethyl acetate and the ethyl acetate wash is added to the separated oil. The solvent is removed and the residue is dissolved in 7 ml of acetonitrile. 1.9 ml of dicyclohexylamine are added, followed by 20 ml of ether. The product under heading (dicyclohexylamine salt) separates in the form of crystals (2.5 g) with a melting point of 156-158 ° C.

Analysis for C₉.₉H_vsNOT₉O, S:

2235^1X2^U4'

Calculated:

Find :

C 62.38; H 8.33; N 6.61 d S 7.57 C 62.05; H 8.47; N 6.61; S 7.57

Example 20

- (3-acetylthiopropanoyl) -DL-3,4-dehydroproline.

A mixture of SOO mg of DL-3,4-dehydroproline, 2.45 g of the p-nitrophenyl ester of acetylthiopropionic acid and 1.1 ml of triethylamine in 30 ml of dimethylformamide is stirred for 72 hours. and 8 ml of water. The solvents are eliminated and the residue is subjected to chromatography on silica gel (Baker ”, 2Ό0 g) using the following solvent system: ethyl acetate / pyridine / acetic acid / water (60: 20: 6: 11 ) to obtain 1.27 g of a product with a melting point of 156-3L58 ° C (dicyclohexylamine salt).

Example 21

1- (3-mercaptopropanoyl) -DL-3,4-dehydroproline

3 g of 1— (3-acetylthiopropanoyl) -DL3,4-dehydroproline are dissolved in 15 ml of methanolic ammonia (5.5 k) and the solution thus obtained is kept at room temperature for 45 minutes. The solvent is removed, the residue is dissolved in water, it is passed through a resin ”AG-50^not, freeze-dried and subjected to chromatography on 50 g of silica gel using the benzene / acetic acid solvent system (8: 2) to obtain 0.8 g of a product with a melting point of 101 - 103 ° C (sintering: 143 °) in the form of the dicyclohexylamine salt. Analysis for CgH ^ NO ^ S:

Calculated:

Find :

C 47.74; H 5.51 5 K 6.96; S 15.93 C 48.09 3 H 5.73 3 N 6.86 3 S 15.65

Example 22

1- (D-3 ~ (acetylthio) -2-methyl-propanoyl) -DL-3,4-dehydroproline

3.39 g of DL-3,4-dehydroproline are dissolved in aqueous sodium carbonate and the solution thus obtained is cooled in an ice bath. Then added, in two portions, 5.5 g of D-3-acetyl-thio-2-methylpropionyl chloride in 10 ml of ether. 16 ml of a 4N sodium carbonate solution are added over 15 minutes while maintaining the pH at around 7.5. The solution is then stirred for one hour, extracted with ethyl acetate (which is eliminated), acidified to a pH of 2, saturated with sodium chloride and l extract with ethyl acetate. The ethyl acetate extract is concentrated, it is applied in a column of 300 g of silica gel and it is eluted with a 10: 2 mixture of benzene and acetic acid to obtain 5.7 g of the product under heading [α] ρ5 = -69.1 ° (c = 2, CH ^ OH). Rf = 0.34 (silica gel; benzene / acetic acid (7: 1)).

Analysis for ^ NO ^ SH, 0:

Calculated: C 47.99; H 6.22; N 5.09; S 11.69

Found: C 48.20 h H 6.29; R 4.91; S 11.34

Example 23

1- (D-3- (acetylthio) -2-méthvlpropanoyl) -L-3,4-dehydroproline

To a stirred solution of 4.7 g of the product of Example 22 in 100 ml of acetonitrile, 4 4L of dicyclohexylamine are added. The solution is kept cold overnight, the crystallized material is filtered and it is recrystallized from acetonitrile to obtain 2.5 g of a product in the form of the dicyclohexylamine salt, [ccl ^ = -222 ° (c = 2, CH (OH); melting point (dicyclohexylamine salt): 188-19O ° C.

2.7 g of the dicyclohexylamine salt are dissolved in 25 ml of water and the solution thus obtained is treated with an i-resin AG-50 '¹ (Ht) (bed volume: 9θ nil), then filter. The resin is washed properly with 200 ml of water, 100 ml of a mixture

- 1: 1 of methanol and water, as well as 200 ml of methanol. The detergents are combined and evaporated to dryness to obtain 1.45 g of the product under heading, = -326 ° (c = 1, CH ^ OH).

R. £ = 0.36; silica gel; benzene / acetic acid (7: 2).

Analysis for C ^^ H ^^ NO ^ S:

Calculated: C 51.35; H 5.88; N 5.44; S 12.46

Found: C 51.30; H 6.20; N 5.43; S 12.16.

Example 24 1- (D-3-mercapto-2-methylpropanoyl) -L-3,4-dehydroproline.

1.2 g of a sample of the product under the heading of Example 23 are dissolved in 10 ml of methanol and, to the solution thus obtained, under an atmosphere of argon, 8 ml of ammonium hydroxide are added aqueous 13.5N. The solution is kept at room temperature for 35 minutes, evaporated, dissolved in 20 ml of water and acidified to a pH of 1.5, then extracted with acetate. 'ethyl. The ethyl acetate extract is evaporated to obtain 629 mg of a product with a melting point of 121-124 ° (sintering: 116 °), [c] p⁵ = -352 (c = 1.2, CH 0H).

Analysis for C ^ H ^ NO ^ S:

Calculated: C 50.22; H 6.09 K 6.51 S 14.89

Found: C 49.93 5H 5.84 5 N 6.28; S 14.87.

Example 25

1- (D-3-acetylthlo-2-n] ethylpr'opionyl) -4,5-dehydropipecolic acid

To an ice-cold solution of 290 mg of L-4,5 dehydropipecolic acid in 2.3 ml of IN aqueous sodium carbonate, 0.332 g of D-3-acetylthio-2-methylpropionyl chloride in 1 ml of ether is added. The pH is maintained at around 7.5 (consumption of 1.1 ml of Ka_oC0 „2K in three hours). The reaction mixture is extracted with ether (which is eliminated), it is acidified to a pH of 2 and it is extracted with ethyl acetate. The ethyl acetate extract is subjected to chromatography on 10 g of silica gel using the benzene / acetic acid solvent system (10: 1) to obtain 126 mg of a product in the form of a homogeneous oil . R_f = 0.32; silica gel; benzene / acetic acid (10: 1).

Example 26

1- (D-3-niercapto-2-methylpropionyl) -4,5-dehydropipecolic acid

For 30 minutes, a solution of 91 mg of 1- (D-3-acetylthio-2-methylpropionyl) -4,5-dehydropipecolic acid in 0.5 mg is maintained at room temperature and under an argon atmosphere. ml of methanolic ammonia 5.5N. This solution is evaporated, dissolved in water, acidified to a pH of 2 and extracted with ethyl acetate. The ethyl acetate is evaporated and 74 mg of a semi-solid product are obtained with a melting point of 150-152 ° (sintering: 144 °) (dicyclohexylamine salt). R ^ = 0.32; benzene / acetic acid silica gel (10: 1).