NO146024B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BRAND CAPTAIN PROPERTY ACESTERS - Google Patents

Description

This invention relates to the production of new carboxymethyl esters of mercaptopropanoic acids with the formula:

and salts thereof.

In formula I and in what follows, the symbols have those below

indicated meanings.

R is hydrogen or lower alkanoyl.

is hydrogen or lower alkyl.

R 2 is hydrogen, lower alkyl, phenyl-lower alkyl

or indolyl-lower alkyl.

The lower alkyl groups are linear or branched hydrocarbon radicals with up to 7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and the like. ci~ c^

and especially C-C-C alkyl groups are preferred. The phenyl lower alkyl and indolyl lower alkyl groups include lower alkyl groups of the same type (with the same preferred groups as indicated above).

The lower alkanoyl groups are the acyl radicals of the lower

(C2_C^) fatty acids, e.g. acetyl, propionyl, butyryl, isobutyryl and the like. The aforementioned groups, and especially acetyl, are preferred.

Preferred compounds of formula I are those where R is hydrogen or lower alkanoyl, especially acetyl; R 1 is hydrogen or lower alkyl, especially methyl; and R 2 is hydrogen, phenyl-lower alkyl or indolyl-lower alkyl, especially phenylmethyl.

The compounds of formula I are prepared according to the invention by acylation of an α-hydroxy acid of the formula with an acid of the formula

by usual esterification methods.

A preferred method involves activating the acid of formula III with carbodiimidazole to form the acylimidazole intermediate of the formula

which is used without insulation. It is also preferred to form a product where R is lower alkanoyl and then treat the acyl derivative with ammonia or concentrated ammonium hydroxide to obtain a product where R is hydrogen.

The carbon atoms marked with an asterisk in formula I are asymmetric if R 1 and R 2 are different from hydrogen. The compounds with asymmetric carbon thus exist as diastereoisomers or as racemic mixtures. All of these are produced according to the invention.

The α-hydroxy acids of formula II are well known in the literature and can be prepared by many available methods.

The i-iercaptopropanoic acids of formula III can be prepared as described in US Patent 4,053,651 and Belgian Patent 851,361, e.g. by reacting a thioacid with the formula

where R. is lower alkyl, with an acrylic acid of the formula

The R^-CO group can be removed at this stage or later by treatment with ammonia or concentrated ammonium hydroxide as described above.

The compounds of formula I form the usual (basic) salts of carboxylic acids, e.g. by reaction with inorganic or organic bases. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and salts with organic bases, e.g. dicyclohexylamine, benzathine, hydrabamine and N-methyl-D-glucamine salts. Since some of the compounds of formula I cannot be readily prepared as crystalline substances with well-defined melting points, the salts (which are not necessarily physiologically acceptable) represent means of isolating and characterizing the product.

Further experimental details will appear from the examples

below.

The compounds produced according to the invention are inhibitors of angiotensin-converting enzyme and are useful as hypotensive agents, particularly for the reduction of renin-angiotensin-dependent hypertension. When administering a preparation containing one or a combination of the angiotensin-converting enzyme inhibitors produced according to the invention to a hypertensive mammal, it affects renin -"angiotensinogen -"

the angiotensin I -» angiotensin II course and the hypertension is reduced or alleviated.

A single dose, or preferably two to four divided daily doses, given on the basis of approx. 1 to 1000 mg per kg per day and especially approx. 10 to 100 mg per kg per day, is appropriate to . achieve a reduction of elevated blood pressure. Animal model experiments described by Engel et al, Proe. Soc. Exp. Biol. Pray. 143, 483

(1973) represent a valuable guideline.

The preparations are preferably administered orally, but can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The compound or compounds of formula I may be prepared as tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for parenteral use.

About. 20 to 1000 mg of a compound or compounds of formula I or physiologically acceptable salts thereof may be mixed with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., in a conventional unit dosage form as required by the application . The amount of active substance is selected as follows

that one achieves a dose in the specified range.

The following examples shall serve to further illustrate the invention and represent preferred embodiments.

forms. All temperatures are in °C.

Example 1

O-(3- acetylthiopropanoyl) glycolic acid

3-(acetylthio)propanoic acid (2.96 g) and 1,1<1->carbonyldiimidazole (3.24 g) are dissolved in 20 ml of dry tetrahydrofuran with stirring at room temperature. After 20 minutes, a solution of glycolic acid (1.52 g) and 2.80 ml of triethylamine in 15 ml of dry tetrahydrofuran is added. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the crude residue is taken up in ethyl acetate, washed with 1N hydrochloric acid and three times with water, dried over magnesium sulfate and 0-(3-acetylthiopropanoyl)glycolic acid is concentrated to dryness in vacuo to give 3.9 g. This is dissolved in ether, and dicyclohexylamine is added. The dicyclohexylamine salt is precipitated, yield 2.85 g, m.p. 150-157°. The salt is converted to the free acid by adding it to ethyl acetate, and then adding a 10% potassium bisulphate solution, yield 1.5 g.

Example 2

O-(3- mercaptopropanoyl) glycolic acid

O-(3-acetylthiopropanoyl)glycolic acid from Example 1

(1.3 g), under a blanket of argon, is treated for 15 minutes with a cold solution of 7 ml of water and 7 ml of concentrated ammonium hydroxide. This is cooled, acidified with concentrated hydrochloric acid and extracted

into ethyl acetate, yield 1.2 g. This product, O-(3-mercaptopropanoyl) glycolic acid, is chromatographed on DEAE Sephadex A25 (polydextran anion exchange resin) with a linear gradient of ammonium bicarbonate. The desired fractions (45-70; UV peak at 254 nm) are collected, concentrated and lyophilized. This ammonium salt of 0-(3-mercaptopropanoyl)glycolic acid is converted to the free acid by treatment with Dowex 50WX2 cation exchange resin, yield 320 mg. The 0-(3-mercaptopropanoyl)glycolic acid is converted to the dicyclohexylamine salt by dissolution in ether and precipitation by addition of dicyclohexylamine, m.p. 14 3-14 4°.

Example 3

O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid

A mixture of thioacetic acid (50 g) and methacrylic acid

(40.7 g) is heated on a steam bath for 1 hour and then stored at room temperature for 18 hours. After confirmation by NMR spectroscopy that complete conversion of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuum, and the desired 3-acetylthio-2-methylpropane acid is separated in the fraction with a boiling point of 128.5-131°

(2.6 mm Hg), yield 64 g.

3-acetylthio-2-methylpropanoic acid (6.48 g) is taken up in 40 ml

dry tetrahydrofuran. 1,1'-carbonyldiimidazole (0.48 g) is added to this solution and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g) and 11.2 ml of triethylamine in 60 ml of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of the solution. The reaction is allowed to take place overnight at room temperature. The crystalline salt is filtered, and the filtrate is concentrated to dryness in vacuo.

The residue is taken up in ethyl acetate, washed with 1N hydrochloric acid and three times

with water, dried over magnesium sulfate and concentrated to dryness in vacuo. This product is converted to its dicyclohexylamine salt by dissolution in ether/hexane and precipitation by addition of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120-122°. This salt is then converted to the free acid, 0-[3-(acetylthio)-2-methylpropanoyl]glycolic acid, by addition to ethyl acetate,

addition of 10% potassium bisulphate solution and then crystallization from ethyl/hexane, yield 2.96 g, m.p. 50-51°.

Example 4

0-(DL-3- mercapto-2- methylpropanoyl) glycolic acid

O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid (1.5 g) is placed under a blanket of argon. To this is added a cold solution of 7.5 ml of concentrated ammonium hydroxide and 7.5 ml of water,

and the mixture is stored for 15 minutes at room temperature. The sour-

is then made with concentrated hydrochloric acid and extracted with ethyl acetate, yield 1.3 g. This product is dissolved in ether/hexane, and dicyclohexylamine is added to precipitate the dicyclohexylamine salt,

yield 2.24 g, m.p. 96-98°. An amount of 1.9 g of the salt is converted to the free 0-(DL-3-mercapto-2-methylpropanoyl)glycolic acid by adding it to ethyl acetate and then adding 10% potassium

bisulphate solution, yield 0.9 g. The product is a heavy oil which is chromatographed on silica gel (benzene 7:2 acetic acid), Rf= 0.49, trace R f = 0.32 and 0.57.

Example 5

O-L-[3-(acetylthio)propanoyl]-3-phenyllactic acid

3-(Acetylthio)propanoic acid (1.48 g) is added to 10 ml of dry tetrahydrofuran with stirring. 1,1'-carbonyldiimidazole (1.62 g) is added to this solution, and the mixture is stirred for 20 minutes at room temperature. L-(-)-3-phenyllactic acid (1.66 g) is added to a solution of 7.5 ml of dry tetrahydrofuran and 1.4 ml of triethylamine. The reaction mixture is stored overnight at room temperature. The tetrahydrofuran is removed in vacuo, the residue is taken up in ethyl acetate, washed with IN hydrochloric acid, three times with water,

dried over magnesium sulfate and concentrated to dryness in vacuo, yield 2.8 g. The obtained O-L-[3-(acetylthio)propanoyl]-3-phenyl-lactic acid is purified on a silica gel column by elution with benzene 7:1 acetic acid, yield 1, 7 g.

Example 6

O-L-(3-mercaptopropanoyl)-3-phenyllactic acid

To 1.5 g of O-L-[3-(acetylthio)propanoyl]-3-phenyllactic acid is added a solution of 7.5 ml of water and 7.5 ml of concentrated ammonium hydroxide under an argon blanket. After 15 minutes, the reaction mixture is cooled, acidified with concentrated hydrochloric acid and extracted into ethyl acetate, yield 1.1 g. The product, O-L-(3-mercaptopropanoyl)-3-phenyllactic acid is purified on a silica gel column by elution with benzene 14:1 acetic acid, yield 357 mg.

A small amount of the semi-solid product is converted to its dicyclohexylamine salt by dissolution in ether/hexane and precipitation with dicyclohexylamine, m.p. 100°.

Example 7

0- DL-( 3- acetylthiopropanoyl)- 3- indole lactic acid

By using DL-3-indolelactic acid instead of L-(3-phenyllactic acid) in the method according to example 5, O-DL-(3-acetylthiopropanoyl)-3-indolelactic acid is obtained.

Example 8

O- DL-( 3- mercaptopropanoyl)- 3- indole lactic acid

By using O-DL-(3-acetylthiopropanoyl)-3-indolelactic acid instead of O-L-(3-acetylthiopropanoyl)-3-phenyllactic acid in the method according to example 6, O-DL-(3-mercaptopropanoyl)-3-indolelactic acid is obtained, as the dicyclohexylamine salt, m.p. 151-153°C.

Claims (1)

Analogous method for the preparation of a therapeutically active compound of the formula where R is hydrogen or lower alkanoyl; R 1 is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, phenyl-lower alkyl or indolyl-lower alkyl; and salts thereof, characterized in that an α-hydroxy acid with the formula where R2 has the above-mentioned meaning is reacted with an acid with the formula where R and R-^ have the above-mentioned meaning, by usual esterification methods.