NL8201145A - METHOD FOR PREPARING A PHARMACEUTICAL PREPARATION AND METHOD FOR PREPARING SUITABLE COMPOUNDS - Google Patents

Description

i? a - 1 -

Process for "preparation of a pharmaceutical preparation as well as process for" preparation of suitable compounds.

The invention relates to a process for the preparation or manufacture of a pharmaceutical composition having an antihypertensive effect by a compound of the formula 1 of the formula sheet, wherein R is a hydroxyl or lower alkoxy group, R1 and R2 each a hydrogen atom or a lower alkyl group, R ^ a hydrogen atom, a lower alkyl or mercapto-lower alkylene group, R ^ a hydrogen atom, lower alkanoyl or benzoyl group or a group of the formula 1a and XS, SO or SOg and m * 1, 2 or 3 , n = 0, 1 or 2 and m + ns 3, and 10 p ss 0, or 1, or a salt thereof in a form suitable for therapeutic administration.

Namely, it has been found that these compounds are suitable for effectively combating high blood pressure. The new compounds are able to inhibit the enzyme, which converts angiotensin I, which is produced in our body, into angiotensin II, which has an antihypertensive effect.

Inhibition of the angiotensin converting enzyme by the compounds of formula 1 can be measured in vitro with isolated rabbit lung angiotensin converting enzyme according to the procedure described by Cushman and Cheung [Biochem. Pharmacol., 20, 1637 (1971) / and using an assay method on a excised smooth muscle E.E. O'Keefe et al., Federation Proc. 311, 511 (1972W, these compounds have been shown to be potent inhibitors of angiotensin I contraction activity and enhancers of bradykinin contraction activity.

The administration of a composition containing one or more compounds of the formula 1 and / or one or more physiologically acceptable salts thereof to a hypertensive mammal inhibits or reduces the angiotensin-induced 8201145 hypertension. A single dose, or preferably 2 ¼ daily divided doses, in an amount of about 5-1000 mg per kg per day, preferably about 10-500 mg per kg per day, is suitable for reducing blood pressure. The animal model tests described by S.L. Engel, T.R. Schaeffer, M.H. Waugh and B. Rubin, Proc.

Soc. Exp. Biol. Med. 1) -83 (1973), serve as a useful guide.

The substance is preferably administered orally, but parenteral routes of administration such as subcutaneous, intramuscular, intravenous or intraperitoneal may also be used.

The compounds of the invention can be used for lowering blood pressure in the form of preparations such as tablets, capsules or elixirs for oral administration or in sterile solution or suspensions for parenteral administration. About 10-500 mg of a compound or mixtures of compounds of the formula 1 or physiologically acceptable salts thereof are mixed with a physiologically acceptable vehicle, carrier material, excipient, binder, preservative, stabilizing agent, flavoring agent, etc., in unit dosage form as usually desired in pharmaceutical practice. The amount of active ingredient in these preparations is such that an appropriate dose is obtained within the indicated range.

The invention also relates to the preparation of the compounds of the formula I in a manner customary for such compounds. Thus, a compound of the formula II, wherein R represents a hydroxyl group, can be acylated with an acid of the formula III, optionally after conversion of this acid into a mixed anhydride, symmetrical anhydride, acid chloride, active ester, Woodward reagent K, N. N'-carbonyl bisimidazole, EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) or the like.

In this connection reference can be made to Methods of Organic Chemistry (Houben-Weyl), Vol. XV, parts 1 and 2 (197¼).

The acid of the formula II can, of course, be acylated stepwise. For example, a portion of the 8201145 <3 - 3 - acylating agent 3 may first be attached to the acid of the formula 2, for example, by reacting this acid with a haloacyl halide of the formula 3a, wherein halogen, preferably chlorine or bromine , for example, 3-bromopropanoyl-5 chloride. A product of the formula 3b is obtained. The reaction of this intermediate with a thiol R 1 -SH then gives the desired product of the formula 1. This stepwise acylation is illustrated in the examples.

When the product obtained is an ester, for example, when R represents lower alkoxy, the ester can be converted to the free carboxy group by alkaline hydrolysis or by treatment with trifluoroacetic acid and anisole. Conversely, the free acid can be esterified using conventional procedures.

The disulfides, ie when R 1 represents a group of the formula Ia, are obtained by oxidation of a compound of the formula 4, for example with an alcoholic solution of iodine.

Products of formula 1 have at least 20 asymmetric carbon atoms and may contain up to 4 asymmetric carbon atoms. These carbon atoms are indicated by an asterisk in formula 1. The compounds exist therein in diastereoisomeric forms or in racemic mixtures thereof. All these isomeric forms are within the scope of the invention. In the above-described syntheses, the starting material may use the racemate or one of the enantiomers.

When the racemic starting material is used in the synthesis, the stereoisomers obtained in the product can be separated by conventional chromatographic or fractional crystallization methods. Generally, with respect to the carbon atom of the amino acid, the L isomer is the preferred isomer form.

The compounds of the invention form basic salts with various inorganic and organic bases, which are also within the scope of the invention. Such 8201145-U salts include ammonium salt and alkali metal salts such as sodium and potassium salts (preferred), alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexyiamine salt, benza-thine, N-methyl-D-glutamine, hydrabamine salts, amino acid salts such as arginine, lysine and the like. The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, for example, in the isolation or purification of the product, such as in the case of the dicyclohexyiamine salt.

The salts are conventionally formed by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or medium in which the salt is insoluble and filtration or in water , after which the water is removed by freeze drying. By neutralizing the salt with an insoluble acid, such as a cation exchange resin in the hydrogen form, for example, polystyrene sulfonic acid resin Dowex 50 (Mikes, Laboratory Handbook of Chromatographic Methods, Van Nostrand, 1961, p. 20 256_ / or with an aqueous acid extraction organic solvent, for example ethyl acetate, dichloromethane or the like, the free acid form can be obtained and, if desired, another salt can be formed.

The preparation of the compounds used according to the invention is further illustrated in the following examples.

Example I

U- (3-Acetylthiopropanoyl) -3-methyl-1, H-thiazane-5-carboxylic acid.

3-Acetylthiopropanoyl chloride (8.3 g) is added to a mixture of 3-methyl-1, U-thiazane-5-carboxylic acid Acta. Chem. Scand. 13,623 (1959) ⁄ (8 g) in dimethylacetamide while maintaining the temperature below 25 ° C. N-Methylmorpholine (10.1 g) is added and the mixture is heated on a steam bath for 1 h. After cooling to room temperature, the resulting precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with 10% potassium hydrogen sulfate. The organic layer is dried and evaporated to dryness to give 4- (3-acetylthiopropanoyl) -5 3-methyl-1-thiazane-carboxylic acid.

Example II

h- (3-Mercaptopropanoyl) -3-methyl-1,1-thiazane-5-carboxylic acid.

By dissolving 1 g of the compound obtained in Example I in a mixture of 3 ml of water and 3 ml of concentrated ammonia in an argon atmosphere and stirring this mixture for 30 min at room temperature and then acidifying with concentrated hydrochloric acid the 3-acetyl group is split off. The organic layer is dried and evaporated to dryness in vacuo to give 4- (3-mercaptopropanoyl) -3-methyl-1,3-thiazane-5-carboxylic acid.

Example III

H- (3-Mercaptopropanoyl) -3-methyl-1-thiazane-5-carboxylic acid.

When using 3-acetylthio-2-methylpropanoyl chloride instead of 3-acetylthiopropanoyl chloride in the procedure of Example I, and subsequent treatment of the product according to the procedure of Example II, H- (3-acetylthio-2 -methylpropanoyl) -3-methyl-1Λ-thiazane-5-carboxylic acid and ^ - (3-25 mercaptopropanoyl) -3-methyl-1,4-thiazane-5-carboxylic acid.

Example IV

b - / - (2-Mercaptomethyl) -3-mercaptopropanoyl / - 3-methyl-1. U-thiazane-5-carboxylic acid.

When 2- (acetylthiomethyl) -3-acetylthiopropanoic acid chloride is used instead of 3-acetylthiopropanoyl chloride in the procedure of Example I and subsequent treatment of the product according to the procedure of Example II, k - / - (2-acetylthiomethyl) -3- (acetylthio) propanoyl / - 3-methyl-35 l-1-thiazane-5-carboxylic acid and k- (2-mercaptomethyl) -3-mercapto-8201145-6-propanoyl-3-methyl-1 1-thiazane-5-carboxylic acid.

Example V

4- (3-Mercapto-2-methylpropanoyl) -1-oxo-1,1 * -L-thiazane-5-carboxylic acid.

5 When using 3-acetylthio-2-methylpropanoyl chloride instead of 3-acetylthiopropanoyl chloride and 1-oxo

1,4-thiazane-5-carboxylic acid J_CA, 55 (1961) 9580 i / in place of 3-methyl-1.-Thiazane-5-carboxylic acid in the procedure of Example I and subsequent treatment of the product according to the procedure of Example II, U- (3-acetylthio-2-methylpropanoyl) -1-oxo-1UL-thiazane-5-carboxylic acid and! + - (3-mercapto-2-methylpropanoyl) -1-oxo-1,4 -L-thiazane-5-carboxylic acid is obtained. Example VI

1.1- Dioxo-3-methyl-1.H-thiazane-5-carboxylic acid 15 -

A solution of 3-methyl-1U-thiazane-5-carboxylic acid (6 g) in acetic acid (300 ml) is stirred at ^ 5 ° C for 6 hours while adding 30% hydrogen peroxide (25 ml) in an amount of 5 ml / l. The solution is allowed to stand overnight and the solvent is removed in vacuo to give 1,1-dioxo-3-methyl-1U-thiazane-5-carboxylic acid.

Example VII

1.1- Dioxo-1 * - (3-mercapto-2-methylpropanoyl) -3-methyl-1,1-thiazane-25-carboxylic acid.

When using 1,1-dioxo-3-methyl-1Λ-thiazane-5-carboxylic acid instead of 3-methyl-1U-thiazane-5-carboxylic acid in the procedure of Example III and subsequent treatment of the product according to the procedure of Example II, 1,1-dioxo - - - (3-acetylthio-2-methylpropanoyl) -3-methyl-1Λ-thiazane-5-carboxylic acid and 1,1-dioxo-1- (3-mercapto-2-methylpropanoyl) -3-methyl-1Λ-thiazane-5-carboxylic acid.

Example VIII

35 ^ - (3-Mercaptopropanoyl) -L-1H-thiazane-5-carboxylic acid.

8201145 - 7 -

Aqueous ammonia (13 ml concentrated ammonium hydroxide in 30 ml water) is stirred in a nitrogen atmosphere for 15 min and solid 1 * - (3-acetylthiopr.opanoyl) -L-1 th-thiazane-5-carboxylic acid (6.8 g) (0.02U m) is added. A clear solution is immediately formed at 5-10 ° C. The solution is stirred in a nitrogen atmosphere at room temperature for 1 hour. The solution is extracted with 100 ml of ethyl acetate and the aqueous layer is made strongly acidic with 20% hydrochloric acid. The precipitated oil is extracted with 3 x 150 ml of ethyl acetate. The extracts are combined and dried over magnesium sulfate and then the solvent is removed to yield 5.6 g of a semi-crystalline mass, which is found to contain a substantial amount of the starting material. The recovered material (5.6 g) is hydrolyzed again in the manner described above with 12 ml of concentrated ammonium hydroxide in 25 ml of water for an additional 2 hours. This solution is acidified and the precipitated oil is extracted with 3 x 150 ml of ethyl acetate. The extracts are combined and dried over magnesium sulfate and then the solvent is removed, yielding 2.7 g (1 * 8%) 1 * - (3-mercaptopropano-yl) -L-1.1 * thiazane-5-carboxylic acid are obtained as a viscous mass after drying overnight at room temperature and 1 mm. Anal .: Calculated for C 8 H 13 HO 3 S: N 5.95% 9 C 1 * 0.82%, H 5.56% S 27.25%, SH 100% 25 Found: N 6.13%, C 1 * 0.85% t H 5.1 * 6 l, S 27.38%, SH 96%.

Example IX

3- (3-Mercaptopropanoyl) -1,3-thiazane-1 * -carboxylic acid.

To a solution of 1,3-thiazan1 * -carboxylic acid (J.Biol. Chem. 607 (1957)) (7.1 * g) in a 1 N sodium hydroxide solution (50 ml), which is cooled in an ice bath, are 2 N sodium hydroxide (25 ml) and 3-bromopropionyl chloride (8.5 g) are added in this order with vigorous stirring. After 3 hours, a suspension of thiobenzoic acid (7.5 g) and potassium carbonate (1 *, 8 g) in 8 2 0 1 1 4 5 - δ - water (50 ml) is added. The reaction mixture is stirred at room temperature overnight and filtered. The filtrate is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and evaporated to dryness. The residue is purified by silica gel chromatography (benzene acetic acid 7: 1) and the purified material is crystallized from ethyl acetate-ether-hexane to give 3- (3-benzoylthiopropanoyl) -1,3-thiazane-U-carboxylic acid.

7.7 g of this compound are dissolved in a mixture of 15 ml of water and 7.5 ml of concentrated ammonia in an argon atmosphere. After standing at room temperature for 1 hour, the reaction mixture is diluted with 20 ml of water and filtered. The filtrate is extracted with ethyl acetate, acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. The second ethyl acetate extract. is dried and evaporated to dryness.

The residue 3- (3-mercaptopropanoyl) -1,3-thiazane-1-carboxylic acid is crystallized from ethyl acetate.

Example X.

3- (3-Mercapto-2-methylpropanoyl) -1,3-thiazane - ^ - carboxylic acid.

20 Λ g of 3-Acetylthio-2-methylpropanoic acid chloride (prepared from 3-acetylthio-2-methylpropanoic acid and thionyl chloride; boiling point 80 ° C) and 15 ml of 2 N sodium hydroxide solution are added to a solution of 0.8 g of 1,3-thiazane -lt-carboxylic acid 25 in 30 ml of 1 N sodium hydroxide solution, which is cooled in an ice-water bath. After stirring at room temperature for 3 hours, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo to give 3- (3-30 acetylthio-2-methylpropanoyl) -1,3-thiazane-U-carboxylic acid.

1 g of this compound, dissolved in a mixture of 3 ml of water and 3 ml of concentrated ammonia in an argon atmosphere, is stirred at room temperature for 30 min and acidified with concentrated hydrochloric acid. The organic layer 8201145

V

- 9 - is dried and evaporated to dryness in vacuo, whereby 3- (3-mercapto

2-methylpropanoyl) -1S-thiazane-^ -carboxylic acid is obtained. Example XI

3- / (2-Mercaptomethyl) -3-mercaptopropanoyl / 1,3-thiazane-1 + -carboxylic acid.

To a solution of 1.8 g of 1,3-thiazane-H-carboxylic acid and 2.7 g of sodium carbonate in 25 ml of water in an ice bath, 3.9 g of 2- (acetylthiomethyl-3-acetyl) are added -10 thiopropanoic acid and thionyl chloride prepared 2- (acetylthiomethyl) -3-acetylthiopropanoic acid chloride The mixture is stirred intensively at room temperature for 2 hours and then extracted with ethyl acetate, then the aqueous layer is acidified and extracted with ethyl acetate. The layer is dried and evaporated to dryness to give 3- / (2-acetyl-thiomethyl) -3-acetylthiopropanoyl / 1,3-thiazane-carboxylic acid.

1 g of this compound is dissolved in a mixture of 3 ml of water and concentrated ammonia in an argon-20 atmosphere. The mixture is then stirred at room temperature for 30 min and then acidified with concentrated hydrochloric acid. The organic layer is dried and dried in vacuo to give 3-7 (2-mercaptomethyl) -3-mercaptopropano-yl-1,3-thiazane-carboxylic acid.

25 8201145

Claims (2)

A process for the preparation or manufacture of a pharmaceutical preparation having an antihypertensive effect, characterized in that a compound of the formula 1, wherein a hydroxyl or lower alkoxy group, R 1 and R 5 each is a hydrogen atom or a lower alkyl group, R ^ represents a hydrogen atom, a lower alkyl or mercapto-lower alkylene group, R ^ represents a hydrogen atom, lower alkanoyl or benzoyl group or a group of the formula 1a and XS, SO or SO 2 and m * 1, 2 or 3, n » 0, 1 or 2 and 10 m + n = 3, and p = 0 or 1, or bring a salt thereof into a form suitable for therapeutic administration. 2. Process for preparing a compound suitable for use in the process according to claim 1, characterized in that a compound of the formula 15. wherein X, m, n, p, R, R 1, R 2 , R 1 and R 1 have the same meaning as in claim 1, prepared in a manner conventional for such compounds. 20 8201145