Halogen substituted mercaptoacylamino acids

The invention relates to a process for the preparation of some derivatives of mercaptoac, lproline of general formula I:

^\_C/^R‘

R $ R_i H, C^/ (I)

II II

R-S- (CH) -CH-CO-N-CH-COOR, prepared by coupling an L -proline ester with a 3-acylthioalkanoic acid (Patent, RSR, No. 69941).

The process, according to the invention, extends the range of pr'oline derivatives with new compounds¹, which is prepared by coupling a carboxylic acid having the general formula II:

In the cases R represents a lower alkanoyl group W, n is 0 or 1, R 1 represents hydrogen or lower alkyl, R a and R 1 represents each nn hydrogen or halogen atom, R 1 represents hydrogen, lower alkyl or CF 1, and¹ ts when n * = l, R j also represents halogen, R 4 represents a hydrogen atom, a lower alkyl radical or trifluoromethyl, which, at least one of the substituents · R?, R'a, R3 and R4 being halogen ²⁰or CF; j depending on the above meaning of the symbols and only R, and R'a being both halogenous atoms.

Breast known various derivatives of pro- ²⁵of the substituted line to the nitrogen atom. Among these closer kin sines. 1- (3-alkanoylthioalkane) -r -proline, 1- (3-aroylthiolalkanoyl) - l -proline and 30 1 - (3-aryloxyloylthioalkanoyl) - j_ -propylene

II

R-S- (CH) CH-COOH (II) with an amino acid of general formula III:

R

HcC

NH · /^C\

R'a.

CH, (HI)

-CH — COOR, wherein the symbionts Ri, Ra, RȚ Rs, R₄ and n have the above meanings, the reaction taking place at temperatures between 0 ° C and room temperature, in dichloromethane medium, using diicyclohexylcarbodylimide cia coupling agent or using cairlboxylic acid of formula II as acid chloride in basic aqueous medium, at pH 8.0 ... 8.4 and, if R is

The price of LEI 25.91 lower alkanoyl, can be hydrolyzed by conventional methods the product obtained to convert it into the product where R is hydrogen, the final product possibly being transformed by methods known in its salts with inorganic or organic bases.

The process of preparation according to the present invention is carried out as described in the following 7 examples.

Example 1

aj. 3- (4-Methoxyenzyl) -thi-2-triyluormethylpropanoic acid

A homogeneous mixture of 3.9 g of 1-trifluoromethyleryl acid and 4.3 g of 4-methoxybenzylthioe is stirred for one hour at 100 to 110 ° C, then the mixture is allowed to cool to temperature. the chamber and the solid substance are recrystallized from cyclohexane; mp 72 ... 74 ° C.

b). [3 ~ (4-Methoxybenzyl) -thio-2-tritluoromethylpropanoyl] - tert-butyl ester -_IT-pralinei

A solution of 6.5 g of 3- (4-meftoxybensyl) -thio-2-trifluoromethylpropanoic acid and 3.76 g of proline I-butyl ester in 500 ml of dichloromethane, is stirred at 0 ° C and treated with 4 , 53 g dicyclohexylcarbodiimide. The mixture is maintained for 30 min at 0^sC and overnight at room temperature, after which the filtrate is filtered and washed until neutral reaction. The organic layer is dried and concentrated in vacuo until dry. Thin-layer chromatographic analysis [, silica gel, methylene chloride / ethyl acetate (95: 5)] shows two large spots with R / 0.46 and 0.51, corresponding to the two diastereomers.

c). l (3-Mercapto - 2 - tritiuormetiipropanoii) -_IT proline

A solution of 4.47 g of tert -butyl ester of 1-! [3- (4-mietoxybenzyl) -thio2-trifluoromethylpropane] - /.- proline (prepared in Example 2) and 10 ml of anisole is cooled to 0 ° C. and add 100 ml of acid (trifluoroacetic acid then 3.18 g of mercury acetate. The bath is removed and the mixture is stirred for one hour at room temperature. Then the mixture is concentrated in vacuo to dryness and the residue is triturated with hexane-hexane. . The insoluble material is brought into aqueous suspension and the suspension is bubbled for 10 min. The precipitate is removed by filtration and the filtrate is dried by freezing to give 1- (3-mercapto-2-trifluoromethylpropanoyl) - /, proline as an amorphous solid. R / = 0.29 ... 0.31 (silicabenzene gel; acetic acid, 7: 1).

Example 2.

a), cis-] -fD-3- (Acetylthio) -2-methylpropanoyl) -4-yloro-y -proline

4.5 g (0.021 mol) of cis-4-fluoro-λ-proline hydrochloride are reacted in 50 ml of water with 4.2 g (0.023 mol) of n -3-acylthylthio-2-methylpropanoic acid chloride in the presence Sodium carbonate to maintain the ρ 8 Take a value of 8.0 ... 8.2 during the acylation reaction (about 20 min). After another hour, the mixture is processed by washing with 2X50 ml of ethyl acetate, it is covered with an ethyl acetate powder, it is acidified with hydrochloric acid to pyl-2. it is saturated with sodium chloride, then separating the layers. The aqueous phase is extracted with another amount of ethyl acetate, the organic extracts are combined, dried and evaporated. The solid residue remaining after evaporation of ethyl acetate is triturated with ether and evaporation is repeated. 5.4 g (93%) of colorless product is obtained; mp 146 ... 48 ° C (sintering 133 ° C); mp = -132 ° (o = l; methanol). The diyclohexylamine salt is prepared by adding dicyclohexylamine to cfs-1- [d -3- (acetylphio) -2-methylpropanoyl] -4-fluoro-1-proline in 70 ml of ethyl acetate to give 8.1 'g S crystalline melting point 202 ... 204 ° C (sintering 187 ° C); [a] “= -72 (c = l, metainol). By crystallization from 90 ml isopropanol, 7.0 g of melting point 205 ... 207 ° C are obtained (sintering Î9O ° C).

a] p = -74 °. A test crystallized from ethanol does not show any change in melting point and rotation [a]_D .

16.9 g of dicyclohexylamine salt is converted again to free acid by distributing this amount of salt between a solution of 10% potassium bisulphate and ethyl acetate (60 ml 10% KHSO «; extraction with 4X50 ml ethyl acetate) . The organic layers merge and evaporate to dryness. 4.1 g (71,%) colorless free acid is obtained, m.p. 154 ... 156 ° C (sintering 140 ° C), [α] -142 ° (c = l, methanol).

b). cis-1 - (ο-3-Mercapto-2-methylpropanoyl) -4-iluc <r- l-proline

7? 22

3.9 g (0.014 mol) cis-1- (z) -3- (acetylthio) 2-methylpropanoyl] -4-fluoro-z-proline is subjected to a hydrolysis reaction in 22 ml of water containing 9 ml of hydroxide. concentrated ammonium. The reaction mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated to dryness resulting in 3.3 g of glass product, which crystallizes incest when dried at a pressure of 0.2 mm at 50 ° C. The material is triturated with 20 ml ethyl alcohol (under slight heating in argon atmosphere), diluted with 25 ml of hexane, triturated and cooled overnight (under argon). Filtration under argon, washing with hexane and drying under vacuum give 2.8 g, (85%) cis-4-fluoro-1- (z> -3-mercapto2-meiylpropanoyl) -z -proline, colorless solid, point Melting point 135 ... 137 ° C. (sense (129 ° C), βα] = -116 ° (c-1; methanol).

Example 3.

a). 1- (3- (Acetylthio) -2-chlorophanoyl] 1 -proline (isomer A)

1.44 gz -proline and 667 mg of sodium carbonate are dissolved in 17 ml of water and stirred in an ice bath. To the mixture is added 2 g of sodium carbonate in 8.5 mg of water, followed by immediate addition of 2.5 g of acid chloride.

3- acetylthio - 2 - chlorpropanoic. The ice bath is removed and after 30 minutes a precipitate is formed which is added to the solution by adding 17 ml of water to the mixture. After a total of 1.5 hours, the reaction mixture was extracted twice with ethyl acetate, the aqueous layer was cooled, acidified with concentrated hydrochloric acid, saturated with sodium chloride, extracted with ethyl acetate, dry over magnesium sulfate and concentrate in vacuo to dryness, yielding 3.3 g of crude oil. It is passed through a column filled with 100 g of silica gel, eluted with 7: 1 benzene / acetic acid, resulting in 2 g of product, which crystallizes from water. 450 mg of [3- (acdtilithio) -2-chloropropanoylj-z -proline is obtained, with a melting point 111 ... 113 ° C, [«]_D = —171Γ tc-1 ethanol).

b). 1- (3- (Acetylthio) -2- chloropropyl] L -proline (isomer B),

The aqueous mum solution of the example is lyophilized and chromatographed on silica gel with benzene / acetic acid 7: 1. The fractions containing the UV absorbing material and which are homogeneous from the point of view of the thin layer chromatograph-6 are combined, concentrated to dryness and crystallized from water. Yield 800 mg,

- melting 90 ... 109 ° C. [«] £ = -4 ° (c-2.1;⁵ ethanol). Mum solutions were concentrated to dryness by lyophilization and the remaining [3- (acetylthio) 2-chloropropanoyl] - z -protein (isomer B) crystallized from ether-hexane to give 380 mg; point¹⁰ melting 1O8., -1O ° G; («] □ = + 17.6 ° (c = l, 25, ethanol).

Example 4

₁₅ 1- (3- (Acetylthio) -2-brompropanoyl]_IT -proline substituting in the process according to the example 3a 3-acetylthio-220-chlorpropanoic acid chloride with -3-acetylthio-2-brompropanoic acid chloride gives [3 (acetylthio) -2-broanpropanoil] - z -proline with melting point 109 ...^it110 "C; [ "]_D -162 ° (c-1.39, ethanol).

Example! 5.

trans - 1 - (o -3- (Acetylthio) -2-methyl-loxopropyl] -4-fluoro-z -proline

a), trans -1-Carbobenzyloxy - 4-chloride30 L-proline

A solution of 6.2 g of medical ester of trans-1-o-aerobobenzyl Ioxi-4-yl-z -proline in 50 ml of methanol was treated dropwise at 0-5 ° C with

11.5 ml of 2 n sodium hydroxide solution, is kept for one hour at a temperature of 0 ° C, after which it is allowed to warm overnight at room temperature. The reaction mixture is concentrated under reduced pressure to about half the initial volume, which is diluted with 400 ml of water. The aqueous reaction mixture is then extracted with ether and the ether extracts are discarded. The aqueous solution is acidified under dilution with dilute hydrochloric acid, at nH = 2, which is extracted with 4 Y50 ml of ehl acetate. Extracts in acetate₅₀ The combined ethyl was dried over anhydrous magnesium sulfate and concentrated under reduced irresolution to obtain the sulfur product, which was purified by passing through light cyclohexyl 55; mp 194 ... 196 ° C, -44 ° (c-1% in methanol).

The free acid is obtained by bringing the salt _θ0 of ctelohexylamine in suspension with 25 ml of ethyl acetate and 22 ml of hydrochloric acid 1 n, followed by the extraction of the aqueous layer with 4χ35 ml of ethyl acetate. extraction_β5 The combined ephthalate acetate sheets are dried over anhydrous and loose magnesium sulfate? 2 to 7 the wind is removed under reduced pressure to give the desired frans-1-carbobenzyloxy-4-fluar- χ -protinja desired.

b). Trans-4-Huorhydrochloride, proh'nâ

A mixture of 3 g trans-1-cor bobenzyloxy-4-Huorz-z-proline with 15 ml of hydrobromic acid in acetic acid (30 ... 32%) is stirred for one hour, then added. 150 ml anhydrous ether. The solvent is decanted from the precipitate, after which it is triturated with fresh ether and finally with methylethyl ketone. Trans-4-fluoro-z-proline hydrochloride has a melting point of 162 ... 164 ° C (decomposition) (a] g = -30 °, (c - 1% in methanol).

c). trans-1- [D- (3-Acetylthio) -2-methyl-1-oxopropyl-4-yloro-1-proline

To a solution maintained under stirring containing 1.9 g of 4-fluorine hydrobromide l -proline in 25 ml of cold water was added 1 g of sodium carbonate to bring the pH of the solution to 8.2. Then below. cooling (5 ° C) and continuous stirring, dropwise dropwise add 1.8 g of z> -3-'-acetylthio-2-methylpropionyl chloride to

2.5 ml ether, in which (the pH of the solution is maintained at about 8.2 ... 8.3 with an aqueous solution of carbonate. 25% sodium dropwise added. After the addition is complete ,. stirring and cooling are continued for another hour, after which the reaction mixture is extracted with 2χ25 ml of ethyl acetate and the extracts are discarded. To the aqueous layer was added 50 ml of ethyl acetate and then under stirring and cooling dropwise concentrated hydrochloric acid to pH = 2 was added, the aqueous layer was saturated with sodium chloride and the ethyl acetate extract was separated. The aqueous layer was extracted with another amount of ethyl acetate (3X25 ml); The ethyl acetate extracts are combined, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the desired product. The dietary salt of a hexane is prepared by dissolving the product in 25 m ethyl acetate and adding 1.8 g dicyclohexyamine to 35 ml ethyl acetate to the solution. The precipitated salt is filtered and recrystallized from lysopropanobyl to give the dicyclohexylamine a / vw-l-fD3- (acetddithio) - 2-methyl-1-oxopropyl) -4-fluoro-z-proline salt, · melting point 209. 211; (a) “= -85 ° (c-1% methanol).

The free acid is recovered by dissolving the dicyclohexylamine salt but with a 5% aqueous solution of potassium bisulphite and extracting the solution with efiiil acetate. The solution of ethyl ketate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give trans-1 [z) -3- (acetylphio) -2-methyl1-o.^!xoprapi^!I} -4-fIuor z -proline desired.

d). trans - 4 - Fluoro-1 (η-3-mercapto2-methyl-1-oxopropyl) - z-proline

Within a cold solution of 4.2 ml of ammonium hydroxide concentrated in 16 ml of water, an argon stream is passed. To this solution was added under stirring in argon atmosphere 1.8 g irans-l-z> -3- (acetylthio) -2-methyl-1-oxoprop'yl] -4-fluoro -proline. The reaction mixture is stirred for another two hours, then extracted with ethyl acetate which is discarded. The aqueous state is stirred, 30 ml of ethyl acetate is added to it, then the aqueous layer is acidified with concentrated hydrochloric acid. After this, the aqueous layer is saturated with sodium chloride and the ethyl acetate extract is separated. The aqueous layer is extracted with 3X30 ml of ethyl acetate, the free extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure, obtained irans-4-fluoro-1-yl-3-mjercapto-2-methyl-1 - oxoplropyl) - z -proline desired; [α] = -112 ° (c = 1% in methanol).

Example! 6.

1- [D-3- (Acetylthio) -2-methyl-1-oxopropyl] -4,4-ditiuor-z-proline. a). 1-Carbobenzyloxy-4,4-difluoro-z-proline methyl ester

To a cooled solution, kept under stirring, containing 3.3 g of methyl ester of 1-catbobenzylloxy-4-keto-z -proline in 80 ml of methylene chloride was added dropwise with 3,3 ml of diethylninotrifluoride of sulfur. The reaction mixture is kept overnight at room temperature, about 100 g of ice is added to the mixture and the reaction mixture is further stirred for 45 g. The organic layer is separated and the aqueous layer is extracted with 2X40 ml methylene chloride. The extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired methyl ester of curbobemethoxy - 4,4 - difluoro-z-protein.

b). 1-Carbobenzioxy - 4,4 - diiluor_IT proline

A solution of 5.6 g methyl ester of 1-carbobenzyloxy - 4,4-ditiuor- z -proline

In 50 ml of methanol, the temperature of 0-5 ° C with droplet is treated dropwise

11.5 ml of sodium hydroxide 2 n. The reaction mixture is kept for 1 h at 0 ° C and then allowed to warm overnight at room temperature. The reaction mixture is concentrated under reduced pressure to about half its initial volume, then diluted with 100 ml of water. The aqueous reaction mixture is extracted with ether and the ether extracts are discarded. The aqueous solution is acidified under cooling with dilute hydrochloric acid to pill-2, then extracted with 3X50 ml of ethyl acetate. The extracts in ethyl acetate were combined, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated, yielding cadbobememyloxy - 4,4 - difluoro-1-proline moiety. This is purified by its passage into the cyclohexylamine salt ϊ mp 18O ... 185 ° C, [«] ® = -24 ° C (c = 1% in ethanol).

The free acid is obtained by treating an aqueous solution of the cyclohexyl lamina salt with hydrochloric acid and extracting the mixture with 4X30 ml of ethyl acetate. The eityl acetate extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired carbobenzyloxy-4,4-difluoro-1-proline.

c). 4,4-Difluoro-1-proline hydrochloride

A mixture of 2.4 g 1-carbobenzyloxy4.4- ddfluor-z -proline and 12 ml hydrochloric acid in acetic acid (30-32%) was stirred for 30 minutes at room temperature. add 300 ml of anhydrous ether.The mixture is cooled, the solid precipitate is filtered and dried under reduced pressure.The obtained 4,4-difluoro-1-proline hydrochloride has a melting point of 163 ... 165 (decomposition); («J p = -14 ° (c = 1% in methanol).

d). 1-0-3- (Acetylthio) - 2 - meW-Î-oxopropiJJ - 4,4 - difluoro- l-praline

To a solution of 2.7 g of hydrobromide

4.4- difluoro- τ -proline in 30 ml of water under stirring and cooled to 5 ° C, solid sodium carbonate is added to bring the pH of the solution to 8.4. Then, under cooling and continuous stirring, 2.4 g of d -3-acetyl-2-methylpr 2-chloride in 3 ml are added dropwise with anhydrous solution, during which time by adding an aqueous solution of carbohydrate. 25% sodium pH of the reaction mixture is maintained at 8.1., 8.3. After the addition is complete, the mixture is stirred and cooled in it. continued for one hour. The mixture dn. The reaction is extracted with 2X25 ml ethyl acetate and the extracts are discarded. To the aqueous layer was added 50 ml of ethyl acetate and, under stirring and cooling, drop by drop of concentrated hydrochloric acid to pH = 2. The aqueous layer is saturated with sodium chloride and the ethyl acetate layer is separated; the aqueous layer is extracted with 3X25 ml of ethyl acetate. The extracts in ethyl acetate are combined, dried over anhydrous magnesium isulfate and concentrated under reduced pressure to obtain the desired product. The dicyclohexylamine salt is prepared by dissolving the product in 40 ml of ethyl acetate and adding a solution of 2.3 g of dicyclohexylamine in 5 ml of ethyl acetate. The precipitated salt is filtered and recrystallized from ethanol. The dicyclohexylamine salt of p-3- (acetylthio) -2nratyl-1-oxopropyl] -4,4-difluoro-1-prolix has a melting point at 225, 227 ° C, W d -70 ° (o- 0.05% in methanol).

The free acid is recovered by dissolving the dicyclohexylamine salt in a 5% aqueous solution of potassium bisulphate ds and extracting with ethyl acetate. The ethyl lactate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1 - [(p-3- (n-ketylthio) - 2-methyl-loxopifopyl] - 4,4. Difluor-τ, - desired proline.

e). 4,4-Difhior - 1 - (p-3-mercapto-2-methyl-1-oxoprc.pi!) -_IT proline

Through a cold solution of 4.6 g ml of ammonium hydroxide concentrated in 11 ml of water, an argon stream is passed. To this solution was added under stirring in an atmosphere of argon 2.1 g 1- [n-3 (acetylphio) -2-methyl-1-oxopropyl] -4,4-difluoro-1-proline. The reaction mixture was further stirred for 2 h, then extracted with ethyl acetate, which was discarded. The aqueous layer is stirred, 30 ml of ethyl ether and added. the aqueous layer is acidified with concentrated hydrochloric acid. After this the aqueous layer is saturated with sodium chloride and the ethyl acetate layer is separated. The aqueous layer was extracted with 3X25 ml of ethyl acetate. The extracts _ in ethyl acetate were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-1 (η-3-mercapito-2-methyl-1-oxo77228 propyl). - the desired protein, in the form of a syrup; rotational optio β α] “--85 ° (c =

1, methanol).

Example 7.

a). cis-4-Chloro -Ί- (3-acetylthio-2- o-methylpropanol) - l -proline

3.15 g of cis-4-chloro-1-proline hydrochloride and 2.8 g of p -3-acetylthio-2-methylpropionyl chloride in 40 ml of water containing 2.3 g of sodium carbonate (chlorofluoride) are reacted. acid was previously dissolved in 4 ml ether). The reaction mixture is maintained at pH = 8.2 ... 8.4 by adding 8 ml of a 25% sodium carbonate solution within 10 minutes. The reaction mixture is stirred for an additional hour, then the product is extracted with ethyl acetate to give 3.6 g of viscous gel, which forms a dicyclohexylamine salt in ethyl acetate, m.p. 189 ... 192 ° C (sintering 185 ° C) and even recrystallized from isopropanol has a melting point 19O ... 192 ° C (sintered 188 ° cj.

b). cis - 4 - Chloro-1 (3-mercapto-2-methylpropanoyl) - l-proline

1.6 g of the product prepared in Example 7a is hydrolyzed in 9 ml of water containing 4 ml of concentrated ammonium hydroxide, yielding 1.2 g of product; after truncation with hexane, this product gave 1.1 g of a colorless solid compound, m.p. 138-140 ° C; [a] “= -79 ° C (c -1, methane).

In the preparation of compounds of the general formula I, those compounds wherein R represents a hydrogen atom or a lower aldanoyl radical, especially hydrogen or acetyl; R 1 represents a hydrogen atom or a lower alkyl radical, preferably hydrogen; Ra and R 'each represent a hydrogen or halogen atom, preferably hydrogen or fluorine; Ra and R / represent each hydrogen, trifluoromethyl or lower alkyl, one of Rs or R * being trifluoromethyl, and the other a hydrogen atom when R 1 and R 2 are hydrogen atoms, · n equals 0 or 1, preferably 1 .

For the proline esfé group, especially the configuration prefer.

Acids having the general formula II with rra-l can be obtained by adding an R-SH thioacid to a substituted / corresponding acrylic acid. For the temporary protection of the mercapto group in compounds of general formula II, R may be a p-toetoxybenzyl group. This group is then removed with trifluoroacetic acid and mercury acetate. Acids of general formula Ii with n = 0 are obtained by a substitution reaction using an R-SH thioacid and a 2-halogenated acid.

When R 1 represents an ester moiety (ie R 1 represents a lower alkyl, obtained when an ester of amino acid III is used as the starting material), the esetric group can be removed. by conventional techniques. For example, when R 1 is tert-butoxy or tert-butyloxy, treatment of the ester having general forinula 1 with trifluoracet-ic acid and anisole will give the corresponding free acid. If other alkoxy groups are present, the corresponding acid will be obtained by alkaline hydrolysis.

If an arpinoadfd having the general formula III in which IL-H is used as starting material or if the final product is obtained as a free carboxylic acid, this acid can be converted into the respective ester, for example by esterification with a diazoalkane, such as exe). for example diazetanethane, or with an alkyl-3-p-tolyltriazine such as 1-n-butyl-3-p-tolyltriazine, etc.

Compounds having the formula, general I have one or more asymmetric centers, the basic center being indicated in formula 1 by an asterisk. Accordingly, the compounds exist in stereoisomeric forms or in racemic mixtures thereof. All these forms are within the scope of the present invention. The synthesis described above may use as the starting material the racemate or one of the enantiomers. When a starting material is used in the synthesis process [racemic, the stereoisomers obtained in the product may be separated by conventional methods such as cuomartogto.ie or fractional crystallization. In general, the preferred isomer form is the omer isomer, considered against the basic asymmetric carbon.

The compounds of the present invention form salts with different inorganic bases and. organic. Such salts include ammonium salts, metal salts of the like, sodium and potassium salts (preferred), alkaline-earth metal salts, for example calcium, magnesium salts, salts with organic bases, for example, salts of organic bases. dicyclohexylamine, benzatin, N-methyl-pglucamine, hydrabamine, salts with a^Jgloves like arginine, lysine etc. Non-toxic, physiologically acceptable salts are preferred, although the other salts are useful, for example for the purification of the product for its isolation.

The salts are conventionally prepared by reacting the free acid form of the product with one or more equivalents of a suitable base, which provides the desired salt ion, in a solvent or mixture in which the salt is insoluble, or in water. , after which it is removed by freeze drying. By neutralizing the slurry with an insoluble acid such as an H + -changing resin (for example, a polystyrene-sulfonic acid resin, such as Dowex 50) or with an aqueous acid and extracting with an organic solvent, for example ethyl acetate, dichloromethane, etc., if possible. obtain the free acid form and, if desired, another salt may be formed;

The compounds of this invention are used as hypotensive agents. Their action is explained by the inhibition of the conversion of the decapeptide called angiotensin I into angiotensin II, which is why they are useful for reducing or alleviating hypertension, the cause of which is angiotensin, the action of the enzyme called renin on angiotbetosinogenesis, a pseudogiobulin I. Angiofensitna I is transformed by angiotensin converting enzyme (ACE) into angiophysin II. The latter is an active substance of pressure, considered as the causative agent in it, the different forms of hypertension in different species of mammals, such as the rat and in dogs. The compounds of the present invention interview in the sequence of angiotensinogen - * (rdniine) - + angioitensin I -► (ACE) - * angiotensis II inhibiting angioltensin transforming enzyme and reducing or eliminating the formation of the angiotenisin II pressure substance. Thus, by administering a composition, which contains a compound or combination of compounds of general formula I or their physiologically acceptable salts, angiotensin-dependent hypertension in mammalian species suffering from this condition is attenuated. A dose dose, or - preferably - daily doses divided into two to the extent, provided on a basis of about 0.1 to 100 mg per kilogram body per day, preferably about 1 to 50 mg per kilogram body per day, exits a dose sufficient to reduce blood pressure in the manner indicated in the animal model experiments, described by SL Eingeî, TR Sehaeffer, MH Waugh and B. Rubi | n, in Pnoc, Soc. Exp. Biol. Med. 143 (1973). The substance is administered by oral preference, but the parenteral routes are used, for example

It is subcutaneous, intramuscular, intravenous and intraperitoneal.

The compounds prepared according to the present invention can be used to reduce blood pressure by conditioning in galenic forms such as: tablets, capsules or elixirs for oral administration or sterile solutions or suspensions for parenteral administration. About 10 to. 500 mg campus or mixture of compounds of general formula 1 or physiologically acceptable salts thereof, is mixed with a carrier, a carrier, an excipient, a binder, a preservative !, a stabilizer, with flavoring substances, etc., all physiologically acceptable, in a dosage unit form according to pharmaceutical practice. The amount of active substance in these compositions or preparations is thus chosen to integrate into the indicated field.

Adjuvants! which can be incorporated into tablets, capsules, etc., are as follows: as a gum tragacanth, acacia, podium starch or gelatin; as excipient dicalcium phosphate or microcrystalline cellulose; as disintegrating agent, corn starch, potato starch, alginic acid, etc., as magnesium stearate ointment; as a sucrose, Iactose or saccharin sweetening agent; as a flavoring substance: mint, raspberry or cherry oil. If the dosage unit is a capsule, the latter may in addition to these substances provide a liquid support such as a fat rod. Various other substances) may be present as coating materials or otherwise altering the physical form of the dosage unit. For example, tablets can be coated in shell, sugar or both. The syrup or elixir may contain the active compound, sucrose a sweetening agent and a preservative !, a coloring agent for airomatting, for example, cherry or orange flavoring.

Sterile compositions for injections can be prepared, according to conventional pharmaceutical practice, by dissolving or making a suspension of the active substance. in a vehicle such as: water for injections, a natural vegetable oil such as sesame oil, coconut, peanuts, cotton seeds, etc.

The following conditional examples are illustrative for these compositions.

a). For each 1000 tablets containing 100 mg 1- (n-3-mercap, topropanoil) -cfs-4-fluoro-λ-proline the following ingredients are used, in g;

- l -S-Mercaptopropanoyl) cis-4-fluoro- £ -pirt> One. . . 100;

- corn starch ' . . . 50;

- gelatin. . . . . . 7.5;

- poultry (mycrocrystalline cellulose) .... 25.0;

- magnesium stearate. . . 2.5.

1 (o-3-Mercaptopropanoyl) - cis - 4-fluoro-1-praline and cornstarch are mixed with a solution of gelatin in water. The mixture is dried and ground to a fine powder. After the choice add avicel and then magnesium stearate of certain granules®. The whole mixture is compressed into a tablet press, yielding 1000 tablets, each containing 100 mg of active ingredient.

bj. For 1000 tablets each containing 200 mg of [o-3- (acetylthio) - 2 - mefci'Ipropanoiîțl-ciS - 4 -. the following ingredients are used in g:

- 1-J) p-3- (Acylthiol) -2-methylpropanoyl] -c / s-4-fluoro-? -Proline. . ' two hundred;

- lactose. . . . . . . 100;

- poultry ....... 150;

- corn starch . . . 50;

- magnesium stearate. . . 5.

1- [o-3 - (Acetylthio) -2-methylpropanoyl] -cis-4-fluoro-2-propane, lactose and poultry are mixed, then ground together with corn starch. The dry mixture is compressed into a tablet press, forming 1000 tablets of 505 mg, each containing 200 mg of active ingredient. The tablets are coated with a solution of Methacel E15 (methylcellulose) in which a dye containing a yellow color H6 is included.

cj, Capsules of two-part gallium H1, each giving 250 mg l (3miercaplto-4,4,4-trifluorobultamoyl) praline, are filled with a mixture of the following ingredients, in mg;

- 1,3-Mercapto-4,4,4, frifluorobutanyl) -7.

proline ...... 250;

- magnesium stearalt. . . 7;

- lactose. ... . 193.

d). Ό solution for injection is obtained as follows (in mg):

- cis-1 - [d-3 - (Mercapto) -2-m ethyl propanoyl]

-cis- 4-fluoro- l -proline. . 500;

- · methylparaben ..... 5;

- propylparaben. . . . . ί;

- sodium chloride . . . . 25;

- water for injection qs. . 5 1

The active substance, preservatives! and the sodium chloride dioxide is dissolved in 3 1 water for injection, then the volume is brought to 5 1. The solution is filtered through the sterile filter and aseptically filled with the pre-sterilized vials, which are then closed with the pressurized rubber caps. Each vial contains 5 ml of solution having a concentration of 100 mg of active ingredient per ml of solution for injection.

Each of the compounds in the preparation examples can be conditioned similarly to those described in ^ examples a) ... d) above.

The process according to the invention for the preparation of halogenated derivatives of mercapfoac'i'ipralitoieâ offers the advantage of being able to obtain a wide range of new substances with hypotensive action.