HU176884B - Process for preparing/thio-propionyl/-amino-acid derivatives - Google Patents

Description

United States

Process for the preparation of thiopropionyl amino acid derivatives

The present invention relates to novel thiopropionyl amino acid derivatives of the general formula (I). In the general formula I

R 1 and R 1 each independently represent a lower alkyl group or together form a five membered ring, and

R ₂ and R _{3 are} hydrogen,

R _{4 is} hydrogen, lower alkanoyl or benzoyl.

Similar thioalkanoyl amino acid derivatives are disclosed in U.S. Patent 4,046,889, but the carbon atom adjacent to the carboxyl group is not substituted.

A lower alkyl group is a straight or branched hydrocarbon group having up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. C 1-2 alkyl is preferred.

Examples of lower alkanoyl groups include acetyl, propionyl, butyryl, isobutyryl. Acetyl is preferred.

Preferred compounds of formula I according to the invention are those wherein R 1, when attached to R, forms a five membered ring.

The compounds of formula I are prepared from the amino acids of formula II, R, R 1 and R ₂ as defined above, by reaction with a halopropionyl halide of formula III, X being a halogen atom, preferably a chlorine or bromine atom, R _{3 being} as defined above. . The resulting intermediate of formula IV - R, R 1, E-2 'R ₃ and X as defined above - is reacted with a mercaptan of formula V - lower alkanoyl or benzoyl group of R _{4 to} give the product of formula I - wherein

R ₄ is lower alkanoyl or benzoyl.

The acid derivative of the formula I is reacted with ammonia or concentrated ammonium hydroxide to give a compound of the formula I wherein R ₄ is hydrogen.

Further experimental data can be found in the following illustrative examples.

The compounds of the present invention are inhibitors of the angiotensin converting enzyme and are useful as hypotensive agents, in particular for reducing angiotensin-induced hypertension. Administration of a composition comprising the angiotensin converting enzyme inhibitor of the invention, alone or in combination, to a mammal suffering from hypertension enters the renin-angiotensin I to angiotensin II conversion pathway and reduces or eliminates hypertension.

Approximately 1 to 1000 mg / kg body weight / day and especially about 10 to 200 mg / kg body weight / day in single or 2-4 divided doses are suitable for the reduction of hypertension. Animal data from Engel et al., FProc. Soc Exp Bioi. Med., 143, 483 (1973)].

The composition is preferably administered orally, but may also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. For oral administration, the compound or compounds of Formula I may be formulated as tablets, capsules, elixirs. For parenteral administration, sterile solutions or suspensions may be used.

Approximately 50 to 1500 mg of the compound (s) of Formula (I) are admixed with a physiologically acceptable carrier, excipient, excipient, binder, preservative, stabilizer, flavor, and the like in a conventional unit dosage form according to accepted pharmaceutical practice. The amount of active ingredient is selected to ensure delivery within the indicated range.

The following examples illustrate the invention and are preferred. Temperature data is given in ° C.

Example I

2 - [(3-Benzoylthio-propionyl) amino] -2-methyl-propionic acid

5.15 g of N-amino-butyric acid is dissolved in 59 ml of 0.85 N sodium hydroxide solution with stirring in an ice bath. To the solution was added 25 ml of 2N sodium hydroxide solution followed by 8.5 g of 3-bromopropionyl chloride. The cooling bath was removed and the pH was adjusted to 7.3 with 2N sodium hydroxide solution. After 2 hours, a solution of 7.5 g of thiobenzoic acid and 4.8 g of potassium carbonate in 50 ml of water was added. The reaction mixture was stirred overnight at room temperature, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness to give 13.1 g. The product, 2 - [(3-benzoylthio-propionyl) -amino] -2-methyl-propionic acid, was crystallized from ethyl acetate: ether. Yield: 5.4 g; mp 142-143?

Example 2

2 [(3-mercaptopropionyl) amino-2-methyl-propionic acid

2.8 g of the product of Example 1 are reacted with 20 ml of water and 20 ml of concentrated ammonium hydroxide solution for 1 hour under argon. The benzamide precipitate was filtered off. and the filtrate was extracted twice with ethyl acetate. The aqueous phase was concentrated in vacuo, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness in vacuo, and the remaining 2 - [(3 * m -captopropionyl) amino] -2-methylpropionic acid was recrystallized from acetonitrile. Yield: 1.2 g. Melting point: 169-170?

Example 3 1-KS-Acetylthio-propionyl-D-amino-cyclopentanecarboxylic acid

6.45 g of 1-aminocyclopentane-1-carboxylic acid are dissolved in 50 ml of 1N sodium hydroxide solution with stirring. To this was added 25 ml of 2N sodium hydroxide solution followed by 8.5 g of 3-bromopropionyl chloride. The cooling bath was removed; the pH of the solution is about 7. Some crystals precipitate out of solution. After stirring at room temperature for 3.5 hours, 54 ml of a 1N sodium hydroxide solution are added until a solution is formed. Subsequently 4.12 g of thioacetic acid were added immediately and the pH was maintained at about 8 with a further 5 ml of 1 N sodium hydroxide solution. After standing overnight, the reaction mixture was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The 1 - [(3-acetylthiopropionyl) amino] cyclopentanecarboxylic acid product is first crystallized from a mixture of ethyl acetate and hexane. The product was recrystallized from ethyl acetate. Yield: 3.655 g; 127-128 °.

Example 4

I - [(3-Mercapto-propionyl) amino] -cyclopentanecarboxylic

The product of Example 3 (1.04 g) was stirred for 1 hour under a argon atmosphere with a mixture of 2.4 ml of water and 1.6 ml of concentrated ammonium hydroxide solution. The reaction mixture was diluted with water, extracted twice with ethyl acetate, the aqueous phase was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous manganese sulfate and concentrated in vacuo. The product 1 - [(3-mercaptopropionyl) amino] cyclopentanecarboxylic acid is crystallized from ethyl acetate and recrystallized from acetonitrile. Yield: 343 mg; mp 175-176?

Claims (1)

A process for the preparation of thiopropionyl> amino40 acid derivatives of the formula wherein R and R1 independently represent a lower alkyl group or together form a five membered ring, R ₂ and R _{3 are} hydrogen; and R _{4 is} hydrogen or lower-alkanoyl 45 or benzoyl, wherein an amino acid of formula II, wherein R, R 1 and R _{2 are} as defined above, is reacted with a halogen-propionyl halide of general formula with the above meaning, And X is a halogen atom, and then the resulting propionylaminocarboxylic acid of formula IV, wherein R, R 1, R ₂ , R ₃ and X are as defined above, is reacted with a thiol of formula V ₄ -lower alkanoyl or benzoyl groups - and the resulting compound of formula I wherein R, R _1, R ₂ and R ₃ are R ₄ -lower alkanoyl or benzoyl, is optionally reacted with ammonia.