DE2422317A1 - NEW COMPOUND WITH HYPOLIPAEMIC EFFECT AND PROCESS FOR ITS PRODUCTION - Google Patents

Description

PATENT LAWYERS

PROF. DR. DR. J. REITSTÖTTER

DR.-ING. WOLFRAM BUNTE

DR. WERNER KINZEBACH

D-eOOO MUNICH 4O, BAUERSTRASSE 22 FERNRUF (OBO) 37 OS Θ3 TKLKX 02102ΟΘ ISAR POSTAL ADDRESSl D-eOOO MÜNCHEN 43, POSTFACH 7ΘΟ

May 8, 1974 M / 15

LABOEATORIOS FEREER S.L. Avda, Captain Lopez Varela, Barcelona (3), Spain

106

! New compound with hypolipemic effects and procedures too ; their manufacture.

The invention relates to the 24ß-ethyl-A5-cholesten-3ß-ol-ester 2- (4-chlorophenoxy) -2-methylpropionic acid, ß-sitosteryl clofibrinate for short called, the formula:

CH,

CH,

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; a new process for making this compound and from it manufactured pharmaceuticals.

ß-sitosteryl-elofibrinate has hypolipemic effects and is therefore very suitable for the therapy of hyperlipamia, in particular of hypercholesterolemia, to prevent atherosclerosis and premature myocardial infarction.

There are already other esters of 2- (4-chlorophenoxy) -2-methylpropionic acid known, the best known is the ethyl ester with the international abbreviation "Clofibrate".

Surprisingly catfish has now been found that the erfindungsge- '' Permitted connection significantly affects more antihyperlipämisch and antihypercholesterolemic than the known drugs in this field.

The new compound is mainly made by esterifying ß-sitosterol and 2- (4-chlorophenoxy) -2-methylpropionic acid and their derivatives produced. The new compound is obtained by reacting the alcohol ß-sitosterol with 2- (4-chlorophenoxy) -2-methylpropionic acid in the presence of esterification catalysts or condensation agents, such as mineral acids, Dicyclohexylcarbodiimide, carbonyldiimidazole etc. But you can also a reactive derivative of the acid, e.g. a symmetrical anhydride, an acid chloride, bromide etc. for the conversion. Use setting with the ß-sitosterol. For more detailed information Some examples of the preparation according to the invention are given below.

example 1

10 g (0.024 mol) of 24β-ethyl-Ä5-cholesten-3β-ol are dissolved in 25 ml , boiling pyridine. 15 g (0.036 mol) of 2- (p-chlorophenoxy) -2-methylpropionic anhydride are added to this solution. This solution let it boil for 2 hours, then this mixture is added

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m / 15 258 3 2A22317

to 100 ml of an aqueous solution of 18% hydrochloric acid. This new one Mixture must be shaken vigorously for 30 minutes. The crystals formed in this way can be, by suction in a Separate the frit. The crystallized material obtained in this way is dissolved in 100 ml of benzene, the remaining water separates and is separated, e.g. in a separating funnel. The benzene solution is washed twice with an aqueous 20% sodium carbonate solution and three times with distilled water.

The benzene solution thus obtained is added to 400 ml of methanol, then it is vigorously shaken. After a few seconds, siph very quickly forms 2- (p-chlorophenoxy) -2-methylpropionate of 24ß-ethyl-A5-cholesten-3ß-ol in the form of white crystals, which are filtered off, washed in methanol and then dried.

Yield: 12.5 g (0.0204 mol) =

Example 2 ι

i Dissolve 5 g (0.012 mol) of 24β-ethyl-A5-cholesten-3β-ol in 20 ml of |

boiling pyridine. To this solution are added 3.3 g (0.014 mol),

2- (p-Chlorophenoxy) -2-methylpropionic acid chloride. This mixture;

is kept boiling for 2 hours and then as in the previous ■

going trap treated. ■ '

Yield: 6.3 g (0.0103 mol) = $ 86. i

Example 3 'i

A solution of 5 g (0.012 mol) of 24β-ethyl-A5-cholestenr 3-β-ol in 50 ml of benzene is prepared, and 2.6 g of 2- (p-chlorophenoxy) -2-methylpropionic acid are added and also 2.9 g of dicyclohexylcarbodiimide. This solution must be ^{shaken at 40 °} C. for 15 hours, it is filtered, the filtrate is washed twice with an aqueous 20% sodium carbonate solution and two more times! with water and then add it to 200 ml of methanol. The crystals

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which then arise immediately, are filtered off, washed with methanol and dried.

j Yield: 6.1 g (0.010 mol) = $ 83.

The product obtained, the ß-sitosteryl clofibrinate, has a Molecular weight of 611.35, the empirical formula C ^ qHcq0, C1 and the structural formula given above. This compound represents a white, slightly yellowish powder with a melting point : from 105 to 106 ° and is soluble in ether, benzene, chloro- ' form, η-hexane, olive oil and non-polar solvents, but insoluble in water, acids, alkalis and alcohol.

! Element ar analysis: Calculated: C 76.6 # H 9.73 $ ^: Found: C 76.7 # H 9

The UV spectrum has two maxima, the first at 281 m / u and that second at 288.5 m / u; one shoulder after 274 m / rev and one

Minimum at 340 m / u; E ₁ ; ": 281 m / u in n-hexane: 21.4 + 0.2

i The IR spectrum is characteristic and has no OH band, the j

0 ι

-1 Ϊ

-C-Esterbande is 1726 cm. i

The thin layer chromatogram shows a single spot, Rf » 0.63 (ethyl acetate / cyclohexane 1: 1).

Free ciofibric acid: 0 #

Water (Karl Fischer method): 1 $>

JT ~ CJ = - 16 ° (concentration = 2 g / l, diluent chloroform.

Pharmacological effect

The acute toxicity of ß-sitosteryl clofibrinate is extremely low; it was found that when administered orally to albino mice, the DLc _{0 is} higher than 10 g / kg.

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Prolonged toxicity test results in albino mice after oral administration of the compound of the invention were found after more than 30 days of treatment no change in the normal behavior of the animals and also no phatological changes Changes to the organs.

The ß-sitosteryl clofibrinate was also tested on female rabbits that were given an aterogenic diet for 2 months had fed (according to Kritchewisky). After these 2 months the aterogenic diet was stopped and the rabbits were divided into six groups. Group A animals were sacrificed to obtain samples of the organs and tissues. Group B was fed a control diet, while the other groups C, D, E and F were fed different diets with the control diet Doses of ß-sitosteryl clofibrinate and ethyl clofibrinate (clofibrate) for comparison.

During the experiment, serum lipid levels were determined in each rabbit as well as total and free cholesterol levels! of triglycerides, proteins, lipidic phosphorus and free Fatty acids determined; Weight and food intake were also checked. The results of this experiment show that the medicament according to the invention, ß-sitosteryl clofibrinate, is much more active than the ethyl clofibrinate (clofibrate) in Relation to the depletion of plasma cholesterol, hepatic cholesterol and the degree of atherosclerosis in the aorta.

The compound according to the invention was also tested clinically, the effect of this compound in the treatment of hyperlipemia, in particular hypercholesterolemia and hypertriglyceridemia, being investigated in 25 cases. Each patient was given the same dose, 2.7 g per day, divided into three doses for 2 months. The results were extremely satisfactory, since the average cholesterol value could be reduced from 369 mg fi to 303 mg #.

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M / 15 258 ₆

The patients who suffered from "hypertriglyceridemia" had j average triglyceride level - of 947 mg #; after the first A remarkable reduction had already been achieved after the month of treatment and the value was in the range of 350 mg ^, after the second month it was 310 mg #. Although this is not the j represents a normal value, the reduction achieved is very satisfactory. j

I ■ 'ι

The decrease in serum levels for total lipids was Also noteworthy, the level rose from 1100 mg ^ to 750 mg # decreased

will.

The tolerability of the medicament according to the invention was excellent in all cases, only one patient showed negative

symptoms, [which, however, disappear after a few days disappeared from. Γ

The compound according to the invention lowers the lipid blood level in two ways: First, it inhibits the enzymatic systems in the body that are responsible for lipid synthesis are (endogenous lipids) and secondly, it reduces the absorption of lipids in the intestinal tract from food (exogenous lipids). Because of this double effect, the compound according to the invention has a maximum influence on the Decrease in lipid blood levels, especially on the of cholesterol and is therefore involved in lipid metabolic disorders indexed.

The compound of the invention is therefore useful for the therapy of hyperlipemia and xanthomatosis, for the treatment of hyperlipemia associated with atherosclerosis, for diabetic hypercholesterolemia and for hypercholesterolemia associated with nephrotic syndromes, for myocardial infarction Angina and hypertension.

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The compound according to the invention can be used with conventional pharmacological; gically compatible carriers, diluents and binders and mixed into pharmaceutical preparations in the form of, for example Tablets, capsules or suspensions that can be administered orally can be processed. Tablets of e.g. 1,200 g may contain 0.450 g of the compound of the invention; 100,000 cnr suspension can e.g. 20 g according to the invention Connection included. 4 to 6 tablets or 4 to 5 spoons of 5 can be taken daily with the meal can be taken, but the dose can be increased or decreased depending on the circumstances.

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Claims (6)

M / 15 258 PATENT PROBLEMS 1. 24ß-ethyl-A5-cholesten-3ß-ol-ester of 2- (4-chlorophenoxy) -2-methylpropionic acid. 2. Process for the preparation of the compound of claim 1, characterized in that 24ß-ethyl-A5-cholesten-3ß-ol (ß-sitosterol) with 2- (4-chlorophenoxy) 2-methylpropionic acid or a reactive derivative of this acid. 3. The method according to claim 2, characterized in that in the esterification of the free 2- (4-chlorophenoxy) -2-methylpropionic acid an esterification catalyst or a condensing agent is used. 4. The method according to claim 3, characterized in that there is a mineral acid as the esterification catalyst and as Condensing agents dicyclohexylcarbodiimide or carbonyldiimidazole used. 5. The method according to claim 2, characterized in that a symmetrical anhydride is used for the esterification 409 847/1 1 5 3 h / 15 258 j _r9 , 242231V 2- (4-chlorophenoxy) -2-methylpropionic acid or an acid halide this acid is used. t. 6. Medicament consisting of the compound according to claim 1 and customary pharmaceutically acceptable carriers, Diluents and / or formulations. 409847/1153