HU179780B - Process for preparing thiazolidine-carboxylic acid derivatives - Google Patents

Abstract

New substituted derivatives of thiazolidine-, thiazaneand related carboxylic acids which have the general formula are useful as angiotensin converting enzyme inhibitors.

Description

The present invention relates to novel thiazolidine carboxylic acid derivatives of general formula (I) and their salts. In this ye formula

R 1 and R _{5 are} hydrogen, R ₂ and R _{6 are} lower alkyl, or

R ₂ and R _{6 are} hydrogen, R 1 and R _{5 are} lower alkyl,

R _{3 is} hydrogen or lower alkyl,

R _{4 is} hydrogen or lower alkanoyl, p is 0 or 1.

Stars represent asymmetric carbon atoms.

Thiazolidinecarboxylic acid derivatives are described, for example, in Z. Naturforsch. 176, 765 (1962); J. Bioi. Chem. 1957, 607, and Belgian Patent No. 861,454.

The lower alkyl group is straight or branched

and may have from one to four carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. The lower alkanoyl group has an acidic residue of a carboxylic acid having few (up to 4) carbon atoms, such as acetyl, propionyl, butyryl, with acetyl being preferred.

Throughout the specification, the symbols have the same meaning as above.

The compounds of formula I can be prepared as follows.

- Acylating an acid of formula II or a salt thereof - R _p R ₂ , R ₅ and R ₆ as defined above - with an acid of formula III - R ₃ , R ₄ and pa above.

The acid of formula JII may be activated before reacting with the acid of formula II; this activation may be mixed anhydride, symmetric anhydride, acid chloride, reactive ester formation, with Woodward K 5 reagent, Ν, Ν'-carbonylbis-imidazole, EED () (N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline) and the like.

An overview of these methods is given in Methoden dér OrgSnischen Chemie [Houben-Weyl, XV. Volume 10, Parts 1 and 2 (1974)].

The resulting compound, when R _{4 is a} lower alkanoyl group, may be hydrolyzed with a base such as ammonium hydroxide; R _{4 is} hydrogen. (Formula IV).

Of course, the acid of formula II can also be acylated batchwise.

The compounds of formula I may have at least 1 and at most 3 asymmetric carbon atoms. These asymmetric carbon atoms in formula I are denoted by 20 stars. Accordingly, these compounds may exist in diastereoisomeric forms or as racemic mixtures thereof. All these forms are within the scope of the invention. In the syntheses described above, the racemate or one of the enantiomers may be used as starting material. When used in the synthesis, the stereoisomers of the product obtained can be separated by conventional chromatography or fractional crystallization techniques. Generally, the L-isomer per amino acid carbon atom is preferred.

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The compounds of the present invention form basic salts with various inorganic and organic bases and are within the scope of the invention. Examples of such salts are ammonium salts, alkali metal salts such as sodium and potassium salts (these are preferred), alkaline earth metal salts such as calcium and magnesium salts, with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamine , amino acids such as arginine, lysine, etc. formed salts. Non-toxic, physiologically acceptable salts are preferred, although other salts may also be useful, for example, for product isolation or purification, such as the dicyclohexylamine salt.

Salts are prepared by conventionally reacting the compound in the free acid form with one or more equivalents of a suitable base to provide the desired cation in a solvent or medium in which the salt formed is insoluble and is isolated by filtration or water and frozen remove by drying. The salt is neutralized with an insoluble acid such as a cation exchange resin in a hydrogen form such as Dowex 50 polystyrene sulfonic acid resin (Mikes, Laboratory Handbook of Chromatographic Methods, Van Nostrand, p. 256 (1961)) or with an aqueous acid, e.g. -acetate, dichloromethane, etc. extracted to give the free acid and, if desired, convert it to another salt.

Further details are given in the Examples, which illustrate preferred embodiments of the invention, and serve as a model for the production of other members of the compound.

The compounds of the invention inhibit the conversion of angiotensin I-decapeptide to angiotensin II and can therefore be used to reduce or alleviate angiotensin-induced hypertension by the action of the renin enzyme pseudoglobulin on the plasma, angiotensinogen. Angiotensin I is converted by angiotensin converting enzyme (ACE) into angiotensin ΙΙ. The latter is an effective antihypertensive agent and is used in a variety of mammalian species such as rats, dogs and the like. is considered to be the cause of hypertension in various forms. The compounds of the present invention inhibit angiotensinogen-angiotensin I-angiotensin II conversion by inhibiting the action of the angiotensin converting enzyme and reducing or eliminating the production of angiotensin II which increases blood pressure.

Cushman and Cheung, Biochem. Pharmacol. 20, 1637 (1971)] using an angiotensin converting enzyme isolated from a rabbit lung and a smooth muscle probe excised by E. O'Keefe et al. (Federation Proc., 31, 511 (1972)). inhibition of the angiotensin converting enzyme. In these studies, the compounds of Formula I have been shown to be very effective in inhibiting the vasoconstrictor effect of angiotensin I and promoting the vasoconstrictor effect of bradykinin.

Administration of a pharmaceutical composition containing one or more of the compounds of Formula I or a physiologically acceptable salt thereof to mammalian hypertensive patients will alleviate or reduce hypertension induced by angiotensin. 5-1000 mg / kg, preferably 10-500 mg / kg, of the compounds administered in a single dose or preferably in 2 to 4 divided doses per day are suitable for lowering blood pressure. Az S. L. Engel, T. R. Schaeffer, Μ. H. Waugh and B. Rubin, Proc. Soc Exp Bioi. Med., 143, 483 (1973)]. serve.

The compounds are preferably administered orally, but parenteral, for example, subcutaneous, intramuscular, intravenous or intraperitoneal administration may also be employed.

The compounds of the invention are suitable for peroral tablets to lower blood pressure, to medicinal t _t in sterile solutions or suspensions in capsules, or by parenteral clixírek form bea'dás can be used as ones. One to more than 500 mg of one or more compounds of Formula I, or a physiologically acceptable salt thereof, with a physiologically acceptable solvent, carrier, tablet compound, excipient, preservative, stabilizer, flavoring agent, and the like. mixed in dosage units according to accepted pharmaceutical practice. The amount of active ingredient in these pharmaceutical compositions is such that an effective dosage amount is obtained within the indicated limits.

The following examples further illustrate the invention. Temperature data is given in degrees Celsius.

Example 1

3- (3-acetylthio-propanoyl) -2,2-dimethyl-4-L-thiazolidine carboxylic acid

5.74 g of 2,2-dimethylthiazolidine-4-carboxylic acid are dissolved in 58 ml of anhydrous pyridine with heating, and the solution is cooled in an ice bath and 4.814 g of 3-acetylthiopropanoyl chloride are added dropwise with stirring. After removing the ice bath, the reaction mixture was allowed to stand overnight at room temperature, and the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with 10% potassium hydrogen sulfate solution and water, then the ethyl acetate extract was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diethyl ether and filtered off. evaporation of the filtrate and recrystallization of the dry residue from acetonitrile gave 2.63 g of 3- (3-acetylthiopropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid. 126-127 °. * •

Example 2 *

3- (3-mercapto-propanoyl) -2,2-dimethyl-4-L-thiazolidine carboxylic acid

5.82 g of 3- (3-acetylthio-propanoyl) -2,2-dinyl-ethyl-4-L-thiazolidinecarboxylic acid are dissolved in 15 ml of water and 15 ml of concentrated ammonium hydroxide under argon and allowed to stand for 30 minutes at room temperature. and acidified with concentrated hydrochloric acid while cooling. The precipitated crystals were cooled and separated by filtration and washed with water to give 4.79 g of product. 132-136 °. This product was dissolved in hot acetonitrile and the turbidity removed by filtration. The filtrate gave 3.4 g of the title compound. 135-136 °.

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Example 3

3- (3-acetylthio-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidine carboxylic acid isomer A

19.8 g of 2,2-dimethyl-4-thiazolidinecarboxylic acid hydrochloride are dissolved in 200 ml of anhydrous pyridine, cooled in an ice-bath, and 18.0 g of 3-acetylthio-2-methylpropanoyl chloride are added dropwise and the reaction mixture is stirred overnight. stir at room temperature. The precipitate was collected by filtration and the filtrate was concentrated in vacuo. The dry residue was dissolved in ethyl acetate, washed with 10% potassium hydrogen sulfate solution, then water, dried over magnesium sulfate and evaporated in vacuo to give 31 g of crude 3- (3-acetylthio-15-2-methylpropanoyl) -2,2-dimethyl-4-L. thiazolidine carboxylic acid A isomer is obtained. Addition of this free acid and dicyclohexylamine to acetonitrile gives 24 g of dicyclohexylamine salt. The salt was recrystallized from 700 ml of acetonitrile to give 18.2 g of product. M.p. 197-198 °.

The salt can be converted to the free acid by dissolving in ethyl acetate, adding 10% potassium hydrogen sulfate solution and recrystallizing from 100 mL of acetonitrile. Yield 8.9 g. 171-172 ° C.

Example 4

3- (3-Acetylthio-2-methyl-propanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid B isomer

The mother liquors obtained in the procedure of Example 3 for the preparation of the dicyclohexylamine salt were evaporated in vacuo. The residue was added to ethyl acetate and 10% potassium hydrogen sulfate solution and then recrystallized from 80 ml acetonitrile to give 7.5 g of 3- (3-acetylthio-2-methylpropanoyl) -2,2-dimethyl-4-L-. thiazolidinecarboxylic acid B isomer is obtained. 156-157 °.

Example 5

3- (3-Mercapto-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid A isomer was dissolved in a cooled mixture of water (15 mL) and concentrated ammonium hydroxide (15 mL) under argon. 3-Acetylthio-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid A and after 30 minutes the solution was acidified with concentrated hydrochloric acid with cooling. The crystalline precipitate was collected by filtration and washed with water, then recrystallized from 40 ml of acetonitrile and the turbidity removed by filtration, 4.2 g of 3- (3-mercapto-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidine. the carboxylic acid A isomer is obtained. Mp 55-174-175 °.

Example 6

3- (3-Mercapto-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid B isomer B is dissolved in 4 g of 3- (3-acetylthio) in a cold mixture of water and 6 ml of concentrated ammonium hydroxide under argon. -2-methyl-propanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid B isomer. After 30 minutes at room temperature, the reaction mixture was acidified with concentrated hydrochloric acid with cooling. The crystalline product was isolated by filtration, washed with water, recrystallized from acetonitrile (removing insoluble matter by filtration), 3.7 g of 3- (3-mercapto-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid -B isomer is obtained. M.p. 197-198 °.

Example 7

3- (3-acetylthio-propanoyl) -5,5-dimethyl-DL-4-thiazolidine carboxylic acid

A) DL-penicillamine (5,5-dimethyl-4-thiazolidinecarboxylic acid) (134 mmol) was dissolved in 134 ml of n-hydrochloric acid at room temperature and 40 ml of 20% (492 mmol) of a 37% formaldehyde solution was added. After 30 minutes, sodium acetate (11 g, 134 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with ice-cold 50% aqueous ethanol and dried in vacuo to give 14.4 g of 5,5-dimethyl-4-thiazolidinecarboxylic acid. M.p. 209-210 °. The mother liquor was evaporated in vacuo and the dry residue triturated with 95% ethanol to give an additional 1.4 g of product. Total yield 15.8 g (73%). M.p. 30-212-213 °.

B) 3- (3-Acetylthio-propanoyl) -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid

The product (6 g, 37.2 mmol) obtained in Step A was dissolved in a mixture of tetrahydrofuran (42 mL) and water (41 mL) containing sodium bicarbonate (3.5 g, 41.4 mmol) and added dropwise to 5.5 mL (41.1 mmol). of acetylthiopropanoyl chloride in 5.5 ml of diethyl ether and 2N sodium hydroxide were maintained at pH 6-7. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes, 100 ml of hydrochloric acid was added, the mixture was extracted with ethyl acetate (2 x 250 ml) and the combined organic extracts were washed with water (100 ml) and brine, dried (Na2 SO4). The residual oil solidifies upon standing at room temperature. The resulting crude product (11.0 g) was recrystallized from diethyl ether / petroleum ether (50 g) to give the title compound (7.9 g, 73%). Melting point 99-100.5 °.

Example 8

3- (3-mercapto-propanoyl) -5,5-dimethyl-DL-4-thiazolidine carboxylic acid

A suspension of 2.91 g (10 mmol) of 3- (3-acetylthiopropanoyl) -5,5-dimethyl-4-thiazolidinecarboxylic acid in 8 ml of water was stirred rapidly at room temperature under argon and 8 ml of 58% aqueous ammonium hydroxide solution. The heterogeneous solution was then stirred under argon for a further 30 minutes, then cooled and acidified with concentrated hydrochloric acid. The aqueous solution was extracted with ethyl acetate (40 mL) and ethyl acetate (30 mL), and the combined organic extracts were washed with water (5 mL) and then with potassium chloride (10 mL). After drying over sodium sulfate and evaporation in vacuo, 2.74 g of crude oil are obtained. Addition of ethyl acetate / hexane (4: 6) (50 mL) and rapid crystallization by trituration gave the title compound (1.88 g, 75%) as a light white powder. M.p. 100-101.5 °. Chromatography on silica gel (TLC) and eluting with ethyl acetate / pyridine / methanol / water ₍ 60:20: 6:11), R _{f =} 0.46.

Claims (8)

A process for the preparation of a racemic or stereoisomeric thiazolidine carboxylic acid derivative of the Formula I or a salt thereof, wherein R 1 and R _{5 are} hydrogen, R ₂ and R _{6 are} lower alkyl, or R ₂ and R _{6 are} hydrogen, R 1 and R _{5 are} lower carbon atoms. alkyl, R _{3 is} hydrogen or lower alkyl, R _{4 is} hydrogen or lower alkanoyl, p is 0 or 1, characterized in that an acid of formula II - in which R 1, R ₂ , R 5 and R _{b are} as defined above - or a salt thereof with an acid of formula III - R ₃ and pa are acylated with a lower C ₄ alkanoyl group or a reactive derivative thereof, preferably a halide thereof, optionally hydrolyzing the resulting compound of formula I wherein R _{4 is a} lower C 35 alkanoyl group, optionally with the resulting compound of formula I compound is converted to its salt and / or separated into its stereoisomers. Process for the preparation of 3- (3-acetylthiopropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid according to claim 1, characterized in that 2,2-dimethylthiazolidine-4-carboxylic acid is 3 -acetylthio-propagate Reaction with 5 noyl chloride. 3. A process according to claim 1 for the preparation of 3- (3-mercaptopropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, characterized in that 3- (acetylthiopropanoyl) -2,2- dimethyl-4-L-thiazolidine-carboxylic 10 Bonic acids are hydrolyzed. The process of claim 1 for the preparation of 3- (3-acetylthio-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, characterized in that 2,2-dimethyl-4- thiazolidinecarboxylic acid is reacted with 3-acetylthio-2-methylpropanoyl chloride. The process of claim 1 for the preparation of 3- (3-mercapto-2-methylpropanoyl) -2,2-dimethyl-4-L-thiazolidinecarboxylic acid, characterized in that 3- (3-acetylthio-2) methyl-propanoyl) -2,2-dimethyl-4-L- 20-Thiazolidinecarboxylic acid is hydrolyzed. 6. A process for preparing 3- (3-acetylthiopropanoyl) -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid according to claim 1, wherein 5,5-dimethyl-4-thiazolidinecarboxylic acid is 3 -acetylthio-propagate Reaction with 25 noyl chloride. The process of claim 1 for the preparation of 3- (3-mercaptopropanoyl) -5,5-dimethyl-4-DL-thiazolidinecarboxylic acid, characterized in that 3- (3-acetylthiopropanoyl) -5, 5-dimethyl-thiazolidine-4-DL 30-carboxylic acid is hydrolyzed. 8. A process for the preparation of a thiazolidinecarboxylic acid derivative of the Formula I or a salt thereof, wherein For the preparation of a pharmaceutical composition comprising R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and p as claimed in claim 1, characterized in that the active ingredient produced by the process according to any one of claims 1 to a is a carrier, diluent , filler and / or other excipients.