DE2434337A1 - 4-PHENYLBUTTERIC ACID GLYCERINESTERS AND THEIR DERIVATIVES, A PROCESS FOR THE MANUFACTURE OF THE SAME AND PHARMACEUTICAL PREPARATION - Google Patents

Description

LAWYERS

DR. JUR. DIPL-CHEAA. WALTER BY ALFRED HOEPPENER

DR. JUR. DIPL-CHEAA. H.-J. WOlFP DR. JUR. HANS CHR. AX

023 FRANKFURT AM AAAlN-HÖCHST

AOHONSTBASSEM

July 16, 1974

Our no. 19 399

F / La

C. M. Industries Paris / France

Glycerine esters of phenyl butyric acid and its Derivatives, a method for producing the same as pharmaceutical preparation

The present invention relates to glycerol esters of 4-phenylbutyric acid and their derivatives of the general formula I

^R 3 ^R 4

C-Ch ₉ -CH ₉ -CO-CH ₀ -CH-CH ₀ -OH ^Δ II ^z I ^Z

O OH

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where R _{1 is} a phenyl, substituted phenyl or cyclohexyl group, R "is a hydrogen atom or a halogen atom, preferably a chlorine atom, and R _{1 and R 1 are} hydrogen atoms or together are an oxygen atom; a process for the production of these compounds as well as pharmaceutical preparations, if R _{1 is} a substituted phenyl group, the substituent is a halogen atom or an alkoxy group with 1 to ¹ carbon atoms, preferably a chlorine or fluorine atom or a methoxy group, which in para position are located.

The compounds of the invention are analytical and anti-inflammatory agents which can be used in human and veterinary medicine.

Examples of compounds according to the invention are following:

TABLE I. ^R 2 O Example no. ^R l Cl O 3 and 4 cyclo-C H H H / H 5 ^C 6 ^E T H H / H 1 CVcIo-CgH ₁₁ Cl O 2 CVCIo-CgH ₁₁ H O 6th PF-CgH ₁ , H O 7th P-CH ₃ O-CgH ₁₁ H 8th D-Cl-C ^ H ₁₁

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The process for the preparation of the compounds of the formula I according to the invention is characterized in that a lower alkyl ester or an acid or an acid chloride of the general formula II is ^{mixed with the ketal 2,2-dimethyl-1} l-oxymethyl-dioxolane of the formula III (hereinafter briefly referred to as glycerol acetonide) and hydrolyzed the resulting ester of formula IV. This procedure is based on the following equation:

RjA / - C-CH-CH ₉ -CO-A + HO-CH ₀ -CH-CH ₀ >

\ · / Z. Δ Z λ t Z ^^

° χ / ° C

/ \ (III)

H ₃ C CH ₃

C-CH ₂ -CH ₂ -CO-O-CH ₂ -ClI-Cn ₂

uv j H ^ C CH ^

wherein A is a chlorine atom, a lower alkyl or a hydroxyl group, and FL, R ₂ , R and R ^ have the meaning given above.

When R ₇ and R j together represent an oxygen atom, it becomes an ester (II; A = lower alkyl group) because it is difficult to produce an acid chloride in such a case. For this purpose, an alkyl ester,

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preferably a methyl or ethyl ester, prepared by reacting the acid with an alkanol, preferably methanol or ethanol in the presence of an acid such as sulfuric acid, after which the ester obtained is transesterified with glycerol acetonide in an inert solvent such as toluene at reflux temperature will. The reaction is preferably carried out in the presence of a small amount of metallic sodium or sodium hydride. When R, = R ₁ ^ = H, it is easy to prepare the acid chlorides (II; A = Cl) from a conventional agent, such as thionyl chloride, and an acid (II; Λ = OH) by being in an inert Solvent, such as benzene, works. The chloride thus obtained is then reacted with glycerol acetonide to produce compound IV.

The compound IV can also be obtained directly from the acid (II; A = OH) by esterification with glycerol acetonide in one anhydrous solvents such as p-toluenesulfonic acid, are produced, the water formed during the reaction in the form of an azeotrope when it is formed is removed from the reaction mixture.

To hydrolyze the esters of the general formula IV the desired esters of general formula I under favorable conditions, it is desirable to boric acid in ethylene glycol monomethyl ether to be used as a medium.

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The following examples explain the preparation of compounds according to the invention in more detail.

example 1 2,3-Dihydroxypropyl- * J - (* 1-cyclohexyl-phenyl) -butyrate

(a) ² I- (k -cyclohexyl-phenyl) -butyric acid chloride

A solution of 50 g of H- (* I-cyclohexyl-phenyl) -butyric acid in 200 ml of anhydrous benzene was added dropwise to 60 g of thionyl chloride with stirring, taking care that the temperature did not rise above * t5 ° C. At the end of the addition, the mixture was refluxed for one hour and the benzene was distilled off in vacuo without the temperature of the mixture being allowed to rise above 50.degree. The crude acid chloride thus obtained was used directly in the subsequent step.

(b) £ (2,2-Dimethyl-dioxolanyl- (il)) -methyl] -i | - (4-cyclohexyl-pheny1) -butyrate

The acid chloride obtained in step (a) was dissolved in 100 ml of carbon tetrachloride with stirring at room temperature dropwise to a stirred solution of 20 g glycerol acetonide in 200 ml carbon tetrachloride and 50 ml of pyridine were added.

The mixture was stirred overnight, the precipitated pyridine hydrochloride was filtered off and washed with carbon tetrachloride washed. The organic solution was then twice with 250 ml of a 10 # aqueous Solution of sodium bicarbonate extracted and washed with water / water

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washed until neutral.

The solution was dried, the solvent was evaporated. 50 g of a brown one are considered to have been which was used in the next step without further purification.

(c) 2,3-Dihydroxy-propyl- ¹ J - (* t-cyclohexyl-phenyl) -butyrate

The Ql obtained in step (b) was dissolved in 300 ml of 2-methoxyethanol. Refluxed for 1 1/2 hours with 50 g of boric acid. After cooling, the boric acid was filtered off and the solution was diluted with 500 ml of water. The diluted solution was extracted with ether, and the ethereal phase was separated off. This phase was washed with an aqueous solution of sodium bicarbonate and then with water until it was neutral. After drying, the solvent was evaporated. The residue crystallized out on cooling. It was recrystallized from isopropyl ether. The desired compound is obtained in the form of fine, colorless crystals; P = 5 ¹ J ⁰ C The yield for the three stages was 55 . %.

Example 2

2,3-dihydroxy-propyl ⁱ ~ ⁽¹ l-cyclohexyl-3-ehlorphenyl) - butyrate

The procedure of Example 1 was followed, but 4- ( ¹ J-cyclohexyl-phenyl) -butyric acid by a

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equivalent amount of l | - (3-chloro- * l-cyclohexyl-phenyl) -butyric acid was replaced.

The desired ester was obtained as colorless crystals with a weight of US g, a melting point of 80 to 82 ° C. (from isopropyl ether) and in a yield of 68 % .

Example 3

2,3-Dihydroxy-propyl- ⁱ »- (3-chloro-4-cyclohexyl-phenyl) - ¹ l-

oxo-buty rat »; _i __ _>

(a) Methyl ¹ ! - (3-chloro-'l-cyclohexyl-phenyl) ^-1 -oxo-butyrate

100 g of 4- (3-chloro-IJ-cyclohexyl-phenyl) - ⁱ l-oxo-butyric acid, dissolved in 6OO ml of methanol for 3 hours were refluxed together with 10 ml of concentrated sulfuric acid. After evaporation of methanol, the residue was taken up in 500 ml of chloroform and 1 l of water. The organic phase was separated and the aqueous phase was extracted again with 500 ml of chloroform. The chloroform extracts were combined, washed with water until neutral, dried over sodium sulfate and the solvent was evaporated.

The residue crystallized on cooling: mp -49 ° C

The crude methyl ester was used directly for the next step.

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(b) [(2,2-Dimethy1-dioxolany1- (4)) - methyl] - ^ - (3-chloro-Jl-cyclohexyl-phenyD-iJ-oxo-butyrate

A mixture of 6θ g of the obtained in step (a) Methylesters, ¹ IO g Glycerinacetonid and 2 g of sodium hydride as a 50 £ strength oily suspension one hour were maintained long in one liter of anhydrous toluene at reflux. Heating was continued while the ibluene-methanol azeotrope (boiling point: 63 ° C) was distilled off. When the temperature at the top of the column reached 110 ° C, heating was stopped. After the mixture had cooled, it was poured into 2 liters of water. The organic phase was separated off and the aqueous phase was extracted twice with 250 ml of ether each time.

The organic extracts were combined, washed with water, dried and concentrated. The residue which crystallized out on cooling was recrystallized from isopropyl ether. 50 g of a colorless pesticide with a melting point of 75 to 76 ° C. were obtained; Yield: 65 %.

(c) ^{2,3-dihydroxy-propyl-I} l- (3-chloro-i | -cyclohexyl-phenyl) -4-oxo-butyrate

The dioxolane obtained in Example 3 (b) was hydrolyzed as in § Example 1 (c) described ^ to give colorless crystals of melting point 7 ¹ I to 75 ° C (from isopropyl ether). Yield 90 %.

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Example 1

This example concerns the same compound as example 3.

(a) [2,2-Dimethyl-dioxolanyl- (4)) - methyl] -ii- (3-chloro-i | - cyclohexyl-phenyD-iJ-oxo-butyrate

A flask fitted with a thermometer and a water separator with a reflux cooler was charged with 100 g of 4- (3-chloro-i | -cyclohexyl-phenyl) ^-1 l-oxo-butyric acid, 1 g of p-toluenesulfonic acid and 500 ml of xylene. The mixture was refluxed for one hour to dehydrate the reactants and then 80 grams of glycerol acetonide was added rapidly. It was refluxed for a further 4 hours.

In the meantime, water in the expected approximate theoretical amount of 6 ml had separated out.

The xylene was distilled off under reduced pressure, and the oily residue was dissolved in 1 liter of ether and a 10 JSigen aqueous solution of sodium bicarbonate (2 1) added. After stirring for one hour, the ethereal phase was separated and twice with an aqueous 10% solution of sodium bicarbonate and then washed with water until neutral. The ether solution was made over sodium sulfate dried and the solvent was evaporated to dryness. The residue was dissolved in 100 ml of boiling isopropyl ether recorded. After cooling and centrifugation, 71 g of colorless crystals with a melting point of 75 ~ 76 ° C were obtained obtain. The compound was identical to that of Example 3 (b).

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The alkaline, aqueous extracts were combined and acidified with concentrated hydrochloric acid. They were extracted with ethyl acetate; the organic phase was washed with water and dried over sodium sulfate; the solvent was evaporated in vacuo. In this way, 22 g of unreacted starting acid was obtained. The yield was 67.3 % based on the acid actually converted.

(b) The dioxolane was hydrolyzed as described in Example 1 (c); the desired compound was obtained in a yield of 90 % ; P. = 7 ¹ I - 75 ° C (from isopropyl ether).

Example 5

2,3-dihydroxypropyl-4-biphenylyl-4-oxo-butyrate

The procedure in this example was the same as in Example 3, except that instead of ^ - (3-chloro-i | - cyclohexyl-phenylJ-Jl-oxo-butyric acid Ί-biphenyIyI- ¹ I-oxo-butyric acid was used in an equivalent amount became.

The following compounds were obtained in sequence: '

a) The methyl ester: F. = 101 ⁰ C; Yield: 97 %;

b) The C (2,2-dimethyl-dioxolany 1- ( ¹ I)) -methyl3-4-biphenyIyI-Ί-oxo-butyric acid ester; P, = 6 * 1 - 65 C (from isopropyl ether); Yield: 51 %;

c) The desired title compound: P. = 108-110 ° C (from ethyl acetate); Yield: 75 JS.

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Example 6

2,3-dihydroxy-propyl- ¹ J- ( ¹ »-p-fluorophenyl-phenyl) -4-oxo butyrate ; ] __

(a) A mixture of 26.3 g of ^ - (^ - p-fluorophenyl-phenyl) -oxo-butyric acid, 500 mg p-toluenesulfonic acid and 26 g glycerol acetonide, dissolved in 500 ml anhydrous xylene, was heated under reflux for 20 hours, during which the water which formed was removed azeotropically. After cooling down 16.5 g of unreacted starting acid were filtered off. The remaining organic phase was washed with a bicarbonate solution and then washed with water until neutral, dried and concentrated. The residue became from a Mixture of isopropyl ether and ethanol in a ratio of 75: recrystallized. 6.5 g of the acetonide with a melting point of 75 ° C. were obtained; Yield: 17.5 56.

(b) The 6.5 g of the acetonide formed in step (a) was dissolved in 100 ml x acetic acid containing 5 % water and the solution was allowed to stand for MO hours at ambient temperature. The solution was then concentrated to dryness, the residue was taken up in methylene chloride and the organic phase was washed with water and concentrated. The residue was recrystallized from ethyl acetate, whereby k g of a colorless compound with a melting point of 115 ° C. (ethyl acetate) were obtained. Yield: 69 55.

Elemental analysis : (calc. (%) C found. (%)

65 , 88 H 5 , 52 65 , 77 5 , 64 66 , 06 5 , 61

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Example 7

2,3-dihydroxypropyl * l- (4-p-anisyl-phenyl) - ¹ t-oxo-butyrate

(a) A solution of 30 g of methyl ¹ * - (Mp-anisyl-phenyl) -oxobutyrate and 15.8 g of glycerol acetonide in 25 "O ml of dry toluene was heated under reflux for one hour in the presence of 0.5 g of sodium hydride. the condenser was then replaced by a distillation column, and the solvent was distilled very slowly until the temperature at the head of the column reached 110 ⁰ C. the slow distillation was continued, and the port of the reaction was monitored by plate chromatography. After completion of the reaction was the mixture was taken up in water, neutralized with acetic acid and extracted with ether. The organic phase was washed with water until neutral, dried, passed over charcoal (3 SA) and then concentrated. The residue obtained was recrystallized from methanol, whereby 26. g of a yellowish compound; as a result of the chromatography it still contained some starting ester.

(b) 13 g of the acetonide formed in step (a) was dissolved in 100 ml of acetic acid containing 5 % water and the solution was allowed to stand for 2 days at ambient temperature. The acetic acid was then concentrated and the residue was chromatographed over silica gel. The starting methyl ester was thus isolated in the first place, together with about 4 g of the glycerol ester; F. = 125 - 130 ⁰ C.

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After recrystallization from acetonitrile, 3.2 g of a colorless compound were obtained: mp = 130 ° C. (acetonitrile); insoluble in water; soluble in benzene and acetic acid.

Elemental analysis: (C. ? 0 ^H 22 V ber. (%) C. cL \ J
67 cc. 0
, 02 found (%) 67 , 26 67 , 11 Example 8

H 6.19 6.08 6.32

2,3 Dihydroxypropyl - ^ - fty-p-chlorophenyl-phenyD-ty-oxo-butyrate

(a) A solution of 30 g of methyl - ^ - Cl-p-chlorophenyl-phenyl) -oxo-butyrate and 16 g of glycerol acetonide in 250 ml of dry toluene was refluxed for one hour in the presence of 600 mg of sodium hydride heated. The condenser was then replaced with a distillation column and the solvent was very slowly distilled off until the temperature at the top of the column reached 110.degree.

The brown solution obtained as residue was hydrolyzed, neutralized with a few cubic centimeters of acetic acid and extracted with ether. The organic phase was up to Neutrality washed, dried and passed over charcoal; then it was evaporated.

The crystalline residue was recrystallized twice from methanol, whereby 15 g of a yellowish product were obtained.

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(b) 15 g of boric acid and 200 ml of methyl cellosolve were added added to the 15 g of the product prepared in step (a). The mixture was refluxed for 3 hours and then left to cool. The precipitated boric acid was filtered off, and the resulting light yellow Solution was hydrolyzed and then extracted with ethyl acetate. The organic phase was washed up with water washed to neutrality, dried and concentrated to dryness.

The residue was washed with a 100 g silica containing Chromatographed column.

Elution with benzene containing 5 % ether made it possible to remove the starting methyl ester.

Elution with a solution of ether which contained 25% methanol gave, after recrystallization from methanol, 9.6 g of the glycerol ester; Yield: 26 %, P. = 124 to 125 ° C (methanol); insoluble in water; very slightly soluble in cold alcohols and soluble in hot alcohols.

Element aranalyse: (C ₁ 62 ₁₉ cio
,8th 5> 5 , 27 ber. (Z) J
e 62 , 54 j
H 5 , 22 found (Ji) 62 , 42 5 , 29

The new compounds were examined pharmacologically, with the following results:

I. Acute toxicity (Column A of Table II)

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The acute. Toxicity was determined in mice after intraperitoneal and oral administration.

Groups of 10 animals were randomly formed from a homogeneous population.

1. Intraperitoneal toxicity:

The compounds were administered in a suitable solvent at increasing doses, with each dose increasing 10 mice each was tested. Mortality was observed for 8 hours.

2. Oral toxicity:

The products were administered in a suitable solvent with the aid of a nasogastric tube. The mortality was observed for 72 hours.

For the most interesting compounds, the average lethal dose LD_ _{0 was} calculated using the method of Miller and Tainter ^ Proceedings of the Society for Experimental Biology and Medicine, Vol. 57, Page 261, (19M) J

II. Analgesic effect (column B)

The analgesic effect was determined by the method of Koster and Anderson [Federation Proceedings, Vol. 18, p.412 (1959) J examined on the basis of pain in the bowels.

Groups of 5 starving mice each were subjected to Injection of dilute acetic acid caused pertitoneal irritation. The animal responds to the pain with an extension of the abdomen and extension of the hind legs. The analgesic effect of the subject to be examined

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Compound administered orally 30 minutes before acetic acid shows a decrease in number of the abdomen extensions, which are counted in 2 periods of 5 minutes.

Each product was administered in a certain dose range and the ED ^ ₀ was calculated using the "probits" method for the most effective compounds (dose which halves the number of stretching movements compared with the reference animals).

III. Anti-inflammatory effect

The anti-inflammatory effect of the products according to the invention was determined by the various methods 1, 2A and 2B determined.

1. Experimental granuloma in the rat, oral administration (column C)

It was tested by Hersberger and Calhoun £ Endocrinology, Vol. 60, page 153> (1957) J using Worked cotton pellets; the test animals were male rats with an average weight of 200 g.

Each animal received ¹ l of cotton pellets subcutaneously (2 on the back, 2 on the abdomen). The rats were then randomly divided into groups of 10 each. Oral treatment was started on the day of implantation and continued for 5 days. The rats were sacrificed on the day of the last treatment. The granulomas were removed, dried for 8 hours, and then weighed.

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Then the weight of the granulomas of treated animals was compared with the weight of the granulomas of the comparison animals by calculating the coefficient t according to Student (Statistical Tables for biological, agricultural and medical Research, editors SR Fischer, Oliver and Boyd, 1957). The results are given in % of the change in the granuloma weight in the treated rats, based on the granuloma weight in the comparison animals.

2. Effect on edema formation

A) Edema on the hind paw of rats, due to carraghenin

caused (column D)

It was prepared following the procedure of Winter et al., £ Proceedings of the Society for Experimental Biology and Medicine, Vol. Ill, page 5M, (1962) J. There were 0.05 ml of a 1% carraghenin suspension was injected into the paw pad of the right hind leg of the rat. That The volume of the paw was later determined using a plethysmograph.

The compounds of the invention were administered orally for 5 consecutive days. The edema was caused on the 5th day, 1 hour after the last administration. The volume of the paw was before the carragheenin-injection, measured then 3 and finally 2 I ¹ hours after administration.

In comparison animals and treated animals, the Difference in paw volume before and after administration of the carraghenin certainly. Then the percentage off

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softening of the volume in treated animals on the volume in the comparison animals. The percentage value is negative if the volume becomes smaller, when enlarged it is positive.

B) abscess with carraghenin after 24 hours (column E)

The local inflammatory edema produced by subcutaneous injection of 0.5 ml of a 2% carraghenin suspension was measured in male rats. The abscess thus formed receives significant amounts of exudate after 2 I ¹ hours. However, it is sufficiently demarcated to be removed and weighed immediately.

The compounds were administered orally in 2 servings: immediately after the carraghenin injection, then 6 hours later. The rats (males of I ¹ JO _ + 10 g) were sacrificed 2k hours after the injection, then the abscesses were weighed.

The results are given in % of the deviations in the weight of the abscesses in treated rats compared with the weight of the abscesses in the comparison animals. The Student coefficient was also calculated.

The results of the various pharmacological studies are summarized in Table II.

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TABEL

II

"C D anti-inflammatory effects

Carraghenin abscess

Product No. 009 acute toxicity (mg / kg) Analgesic Dose, oral Percentage Ab - dose , 24 hours Percentage I. ro 010 mouse orally effect administered softening orally deviation ; 34337 038 ^LD 50 50 % (mg / kg) (mg / kg / day) Granuloma Carraghenin- (mg / kg) -45 ⁺ 50 VO
I. cn 037 intrape- (5 days) edema -24.9 ⁺ 100 ο
co ritoneal > 1000 3 hours - 2.6 50 00 > 1000 50 37/1 18 * 31 between
250 and
500 > 1000 between 25
and 50 50 -28 ⁺ -36, I ⁺ -49, I ⁺ 31 > 500 1000 25th 50 -20.9 ⁺ -58.5 ⁺ -25.6 ⁺ 31 > 500 25th 50 - 5.3 + 7.6 -20.6 ⁺ 31 > 500 between 6
and 12 50 -17.4 + 16 -45.5

243A337

The symbol indicates that the values obtained with the treated animals differ from those observed with the control animals by a significant threshold value of at least 5 % .

On the basis of the pharmacological results compiled above, the compounds according to the invention can are used in particular as analgesics and / or anti-inflammatory agents in human and veterinary medicine.

Another object of the present invention is a pharmaceutical composition containing a or more of the compounds according to formula I as active ingredient, together with a pharmacologically usable carrier.

Examples of suitable carriers are starch, talc, gum arabic, magnesium stearate and carboxymethyl cellulose.

The compositions are used in oral, endorectal, Forms suitable for parenteral or local use. In particular, such forms can be gelatin capsules or tablets containing 10 to 500 mg of active ingredient per unit. The daily dose for the aforementioned Compounds can be on the order of 20 mg to 3 g per day. By topical preparations, e.g. Ointments, which preferably contain 2 to 15% by weight of active ingredient local administration can be used.

The following examples illustrate pharmaceutical compositions according to the invention:

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Example 9

The following ingredients were compressed into tablets:

2,3-dihydroxypropyl-4- (3-chloro-i | -cyclohexyl-phenyl) -

il-oxo-butyrate (see Example 3) 250 mg

Microcrystalline cellulose 100 mg

Rice starch 20 mg

Potassium methacrylate 10 mg

Magnesium stearate 5 mg

Talc 5 mg

The tablets can be produced by the usual method of double compression or granulation using an aqueous rubber solution or a non-aqueous solvent such as ethyl alcohol will. The tablets can be made by glutination or by coating with a substance that opposes resistant to the action of gastric juice, e.g. made jenteric with cellulose acetophthalate to avoid the action of gastric hydrochloric acid on the active substance or possible gastric disturbances. The tablets can, but need not, be coated with sugar; they can be opaque and optionally colored be.

Example 10

The following ingredients were made into an ointment for local administration:

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2,3-dihydroxypropyl-4- (3-chloro-cyclohexyl-phenyl) - ^1-f .oxo-butyrate (. Cf. Example 3) 6 g

Perhydrosqualene 20 g

Wax (Sipol AO wax) 17 g

distilled water ad. 100 g

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Claims (1)

Patent claims : 1. Glycerol phenylbutyrate of the general formula I. C-CH _O -CH _O -C: O-CH _O -CH-CH _O -OH (I) ZZn ZkZ O OH in the R. a phenyl, substituted phenyl or cyclohexyl radical, R ₀ a hydrogen or halogen atom, and R 1 and R 1 hydrogen atoms or together an oxygen atom 2. 2,3-dihydroxypropyl ^I l- (ll-cyclohexy 1-pheny l) butyrate 3. 2,3-Dihydroxypropyl ¹ L- ( ¹ L-cyclohexyl-3-chlorophenyl) butyrate ¹ 1. 2, 3-dihydroxypropy 1-4- (3-chloro-Ί-cy clohexy 1-pheny 1) 4-oxo-butyrate 5. 2,3 ~ Dihydroxypropyl- ¹ l-biphenyl-M-oxo-butyrate 6.2,3-Dihydroxypropy l-'l- ( ⁱ »-p-fluorophenyl-phenyl) - ⁱ l -oxobutyrate 7. 2 _> 3-dihydroxypropyl-'l- (ll-p-anisy 1-phenyl) -4-oxo-butyrate, 8. 2,3-Dihydroxypropy 1-U- (4-p-chloropheny1-pheny1) M-oxobutyrate. 509807/1184 - 2k - 9. A process for the preparation of the compounds according to claim 1, characterized in that a lower one Alkyl esters or an acid or an acid chloride of the general formula II R- R. ο 4 ^Λ '—C-CH ₂ -CH ₉ -CO-A CH) in which A is a chlorine atom, a lower alkyl or a hydroxyl group, and R., R_, R_ and R ₁ . have the meanings given in claim 1, reacts with glycerol acetonide and hydrolyzes the ester obtained. 10. The method according to claim 9, characterized in that a methyl or ethyl ester of the formula II is used in which R ₁ and R 1. together mean an oxygen atom. 11. The method according to claim 10, characterized in that the reaction with glycerol acetonide is carried out in an inert solvent at its reflux temperature. 12. The method according to claim 11, characterized in that there is used as the inert solvent toluene. 13. The method according to claim 10, characterized in that the reaction with glycerol acetonide in the presence of a small amount of metallic sodium or sodium hydride. 509 807/1 184 14. The method according to claim 9> characterized in that that the free acid is used as the compound of formula II, and the reaction with glycerol acetonide in Performs in the presence of an anhydrous solvent. 15. The method according to claim I ¹ I, characterized in that the anhydrous solvent used is p-toluenesulfonic acid. 16. The method according to claim 9 »characterized in that the hydrolysis with boric acid in ethylene glycol monomethyl ether performs as a medium. 17. A pharmaceutical composition containing one or several of the compounds according to claim 1 as active ingredient and one or more pharmacologically usable carriers. For: CM. Industries Dr.H.J.Wolff Attorney at Law 509807/1184