CH643566A5 - 25-ALKYL CHOLESTEROL DERIVATIVES. - Google Patents

Description

The present invention relates to a group of 25-alkylcholesterol derivatives of the formula

CH.

R.

CH.

wherein R: an alkyl radical with 1 to 4 carbon atoms, R hydrogen, an alkanoyl radical with 2 to 7 carbon atoms or a radical of the formula

O

0

CH.

R,

CH.

R and X are hydrogen, alkanoyl radicals having 2 to 7 carbon atoms or radicals of the formula

0 0

5 II II

H0-C- (CH2) n-C-

wherein n is an integer less than 4 and the wavy line represents R or S stereo configuration, io A further embodiment of the invention consists of compounds of the formula

R,

25th

CH.

wherein Ra is an alkyl radical with 1 to 4 carbon atoms, Ri is hydrogen, R is hydrogen, an alkanoyl radical with 2 to 7 carbon atoms or a radical of the formula

O

O

HO-C- (CH :) "- C-

where n is an integer less than 4, Y is the methylene or carbonyl radical, where if Y is the carbonyl radical, Ri is hydrogen and if Y is the methylene radical, Ri is the radical-OX, where X is hydrogen Alkanoyl radical with 2 to 7 carbon atoms or a radical of the formula

O O

II II

HO-C- (CH2) n-C-

where n is an integer less than 4 and the wavy line represents R or S stereo configuration.

One embodiment of the invention consists in compounds of the formula ## STR1 ## in which Rz is an alkyl radical having 1 to 4 carbon atoms,

30 HO-C- (CH2) n-C-

where n is an integer less than 4, and the wavy line represents R or S stereo configuration.

The compounds according to the invention are useful due to their valuable pharmacological properties. For example, they inhibit the activity of ß-hydroxy-ß-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that controls the rate of cholesterol synthesis in mammalian liver (one of the two main sources of 40 serum cholesterol).

An important risk factor in the development of atherosclerotic diseases and related clinical conditions is the amount of circulating serum cholesterol. With an increase in total serum cholesterol 45 rins above 180 mg / ml, the risk of atherosclerosis also increases. The low density lipoproteins, which are high in cholesterol, are the primary carrier for cholesterol which is deposited in tissues.

The majority of arterial cholesterol in athero-50 sclerotic patients appears to be of endogenous origin. A decrease in the speed of cholesterol biosynthesis leads to a decrease in serum cholesterol levels. The rate-limiting step in the biosynthesis of cholesterol is the enzymatic reduction of 55 ß-hydroxy-ß-methylglutaryl-CoA (HMG-CoA) to mevalonic acid (MVA) by the enzyme HMG-CoA reductase. The regulation of cholesterol biosynthesis by suppressing the activity of HMG-CoA reductase therefore leads to a lowering of the serum cholesterol level. The compounds according to the invention inhibit the activity of the HMG-CoA reductase. This efficacy is particularly useful in combating type II hypercholesterolemia, an inherited disorder caused by an autosomal dominant mutation in a single gene site 65 (Brown and Goldstein, pp. 191, 150 [1976]).

The reduction in the activity of HMG-Co A reductase by the compounds according to the invention is demonstrated as follows:

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Male Charles River rats of the CD strain, initially weighing 180 to 250 g, are fed normal laboratory food. The rats are kept in a room with the lighting cycle reversed for 3 to 6 days. 20,25-diaza cholesterol is administered at a dose of 5 mg / kg / day (IG) for a total of 6 days. For the past three days, the test compound is given along with the 20,25-diaza cholesterol. Both compounds are given two hours before the test on the last day. The rats are anesthetized with ether and killed, then the livers are removed. After homogenization, the liver microsomes are collected by differential centrifugation. The liver microsomes are used as the source of the HMG-CoA reductase. The experimental set-up was developed by L.W. White and H. Rudney, Biochemistry, 9.2713 (1970); Brown et al., J. Biol. Chem. 248, 4731 (1973) and C.A. Edwards, Biochem. Biophys. Acta 409.39 (1975). The percentage change in the formation of [! 4C] -mevalonic acid from [14C] -HMG-CoA is used as a measure of the enzyme activity in the treated groups compared to the comparison groups. If the treated groups show less activity and the decrease at 0.05 is statistically significant, the compound is considered active.

The compounds 25-methylcholest-5-en-3ß, 22-diol and 3ß-hydroxy-25-methylcholest-5-en-7-one according to the invention were found to be effective in the above test in doses of 5 mg / kg (IG). The corresponding compounds of the natural series, without 25-methyl group, i.e. the cholest-5-en-3ß, 22-diol and 3ß-hydroxycholest-5-en-7-one, were both in the above test at doses of 30 mg / kg (IG) and (SC) inactive. The explanation for the different biological activity of the synthetic versus the natural series presumably goes back to the different degradation rates of the two series, see Counsell at al., J. of Lipid Research, 18, No. 1,24-31 (1977). These results are surprising in view of the work of M.S. Brown and J.L. Goldstein, J. of Biol. Chem, 249, No. 22; 7306-7314, 7308 (1974), according to which the addition of a methyl or ethyl group to position 24 of the cholesterol noticeably reduces the inhibitory effect on HMG-CoA reductase.

The compound 25-methylcholest-5-en-3ß-ol-3ß-acetate according to the present invention was described by Elser, W. et al., Mol. Crys. and Liq. Crys. 13,255-270 (1971). In this article, the mesomorphic behavior of modified cholesterols is described, whereas there is no indication of pharmaceutical usefulness or pharmaceutical preparations.

The compounds according to the invention can be processed in a known manner with pharmaceutically reliable carriers to give new pharmaceutical preparations. The concentration of active substance in such preparations is not critical, but is preferably 1 to 80%. These preparations can be administered orally, suitable forms for such administration being among other things tablets, troches, capsules, dragees, pills, powders, solutions, suspensions and syrups. Pharmaceutically acceptable carriers are, for example, gelatin capsules, sugars such as lactose or cane sugar, starches such as corn starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose or cellulose acetate phthalate, gelatin, talcum, calcium phosphates such as dicalcium phosphate or tricalcium phosphate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate Gum acacia, polyvinyl alcohol, stearic acid, alkaline earth stearates such as magnesium stearate, oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, theobroma oil, water, agar,

Alginic acid and benzyl alcohol and other non-toxic and compatible substances common in pharmaceutical formulations.

In addition to the stated usability, the compounds according to the invention can also be used as antiprotozoal agents, in particular as agents against Trichomonas vaginalis.

The compounds according to the invention are usually derived from the 6β-methoxy-3a, 5-cyclo-5a-23,24-bis-norcholan-22-al [Steroids, 15, 113 (1970)] of the formula

CH'O

OCH

produced. The 6β-methoxy-3cc, 5-cyclo-5a-23,24-bisnor-cholan-22-al is expediently alkylated with the addition of a 3,3-dimethylalkylmagnesium halide of the formula

CH3

I.

X-Mg-CHa-CH-C-Ri

I.

CHj wherein X represents a halogen and R2 represents an alkyl radical with 1 to 4 carbon atoms. The resulting i-steroid alcohol of the formula

CH

OCH

is rearranged by heating in aqueous dioxane with an acid such as 4-methylbenzenesulfonic acid monohydrate, with a diol of the formula

HO

receives.

5

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30th

35

40

45

50

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65

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If a compound of the formula II is heated with an alkane carboxylic acid, a 3-ester of the formula according to the invention is obtained

OH

IV

0

alkyl-CO

while when heating a compound of formula III in pyridine with an alkane carboxylic acid anhydride or chloride, an ester mixture according to the invention of the formulas

O

alkyl-CO

V

O

II

alkyl-CO

O

II

OC alkyl

VI

obtained, which can be broken down by chromatography on silica gel while eluting with methylbenzene and mixtures of methylbenzene and increasing amounts of ethyl acetate. If a compound of the formula III is heated in pyridine with a methyl-O-chloro-fi-oxoalkanoate, a mixture of esters of the formulas is obtained

O

II

0

C ^ OC alkylene -CO

OH

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O

O

CH3OC alkylene. -CO

VIII

which can also be broken down by chromatography on silica gel as described above. If one heats an ester of formula VII or VIII with lithium iodide in

Pyridine, 2,6-dimethylpyridine or 2,4,6-trimethylpyridine, this gives an ester of the formula according to the invention

O O

. II 'II

HOC alkylene: -CO

OH

O

respectively.

IX

^ Ikylen -'.- COH C = 0

X

O 0

il II

HOC-alkylerx -CO

If a compound of the formula VI or X is heated with sodium bicarbonate in aqueous ethanol, a 22-ester of the formula according to the invention is obtained

XI

HO

7

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wherein Z represents an I-oxoalkyl or Q-carboxy-1-oxoalkyl radical. Finally, when a compound of the formula IX is heated in pyridine with an alkane carboxylic acid anhydride or chloride, a mixed ester of the formula according to the invention is obtained

ü

OC alkyl

O

HOC-alkylene.i-CO

As an exception to the above process, a compound of formula IX in which the esterified group is a 3-carboxy-2'1-oxopropyl group is preferably prepared by heating a compound of formula III with butanedioic anhydride in pyridine. In all formulas I to XII, R2 represents an alkyl radical, preferably having fewer than 5 carbon atoms, and the wavy line means R or S stereoconfiguration.

The alkylation of the compound of the formula I can also optionally be carried out by adding a 3,3-dimethylalkyltriphenylphosphonium iodide, giving a compound of the formula 30

XII

alkyl

receives the 7-keto-35 compound of the formula according to the invention upon contact with chromium oxide and pyridine in methylene chloride under nitrogen

XIII

OCH-

40

45

o alkyl-CO

XVI

receives that result in the hydrogenation over 5% palladium / carbon.

Compound of formula

If one heats an ester of the formula XVI with sodium bicarbonate in aqueous ethanol, the corresponding 3β-hydroxy compound according to the present invention is obtained, which is the formula

CH.

\

XIV

CH-

OCH-

; returns The latter can be rearranged by heating with an alkane carboxylic acid, whereby compounds of the

CH_ CH3

! 1 I '

c = - <CH2CH2CH2C R

CH-

XVII

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If a compound of the formula XVII is heated in pyridine with a methyl £ 2-chloro-f2-oxoalkanoate and the resulting mixed ester of the formula

XVIII

CH-iOC-alkylene-i-CO

With lithium iodide in pyridine, 2,6-dimethyl pyridine or 2,4,6-trimethyl pyridine, an ester of the formula according to the invention is obtained

XIX

0 0

II H

HOC alkylene'-CO

As an exception to the above process, a compound of formula XIX wherein the esterifying residue is the 3-carboxy-l-oxopropyl residue is preferably prepared by heating a compound of formula XVII with butanedioic anhydride ss in pyridine.

In the above formulas XIII to XIX, R2 represents an alkyl radical having 1 to 4 carbon atoms, the wavy line means R or S stereo configuration.

In the following examples, amounts of material40 refer to parts by weight, unless parts by volume are specifically mentioned. The relationship between parts by weight and parts by volume corresponds to the relationship between grams and milliliters.

45

example 1

50 parts by volume of 1.35 molar 3,3-dimethylbutylmagnesium chloride solution become a solution of 13.4 parts of 6β-methoxy-3a, 5-cyclo-5oc-23,24-bisnorcholan-22-al in 100 vol. parts of tetrahydrofuran added dropwise under nitrogen at 0 to 5 ° C. When the addition is complete, the cooling bath is removed and the reaction mixture is stirred at room temperature for about 1 hour. Then 100 parts by volume of saturated ammonium chloride solution are added. 100 parts by volume of ether are then added to the hydrolyzed reaction mixture and the phases are separated. The aqueous phase is extracted with a further portion of ether, and the combined extracts are washed with saturated saline and dried over sodium sulfate. After removal of the solvent, the 6β-methoxy-25-methyl-3cc, 5-cyclo-5a-cholestan-22-ol is obtained as an oil, which was used in this crude form in the following reactions.

Example 2

17.2 parts of the compound prepared according to Example I were added to 75 parts by volume of glacial acetic acid and heated on a steam bath for 3 hours. The reaction mixture was cooled and 300 parts by volume of water were added, an oily

50

55

Solid was formed. This oily solid was extracted with ether and the ether extracts were washed with 5% sodium bicarbonate solution until the aqueous extract remained basic. The organic phase was dried over sodium sulfate and freed from the solvent. The solid product was recrystallized from acetone to give two fractions. Another product fraction was obtained by chromatographing the mother liquors. Recrystallization from acetone gave the analytically pure 25-methylcholest-5-en-3ß, 22-diol-3-acetate of mp 185 to 187 ° C. •

Example 3

0.1 part of tosyl acid hydrate was added to a solution of 2.5 parts of 6β-methoxy-25-methyl-3a, 5-cyclo-5a-cholestan-22-ol in 60 parts by volume of dioxane and 20 parts by volume of water, and the reaction mixture was heated on the steam bath for 5 hours. Then water was added to the reaction mixture and the solution was extracted with ether. The combined ether extracts were washed with saturated saline and dried over sodium sulfate. The solvent was removed and an oil was obtained which gave a solid product when triturated with ethanol. The pure 25-methylcholest-5-en-3β, 22-diol of mp 191 to 193 ° C. was obtained by recrystallization from aqueous ethanol. 25-Methyl-cholest-5-en-3ß, 22-diol was also prepared in the following way:

5 parts by volume of 5% sodium hydroxide solution were added to a solution of 1.0 part of 25-methylcholest-5-en-3β, 22-diol-3-acetate in 20 parts by volume of ethanol and the reaction mixture was stirred for 1 hour Reflux heated. The hot reaction mixture was filtered and a little water was added to the filtrate. After cooling, the product was obtained in two fractions. The pure compound of melting point 187 to 191 ° C. was obtained by recrystallization from ethanol.

Example 4

To 1.6 parts of 25-methylcholest-5-en-3ß, 22-diol in 25

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Parts by volume of pyridine were added to 1.0 part of succinic anhydride and the reaction mixture was heated on the steam bath for 18 hours. Water was added to the cooled reaction mixture and an oil separated out, which solidified on stirring. The solid was recrystallized from aqueous ethanol and then from ethyl acetate / hexane to give 25-methylcholest-5-en-3ß, 22-diol-3ß-hemisuccinate, melting at 190-193 ° C.

Example 5

10 parts by volume of acetic anhydride were added to 2.5 parts of 25-methylcholest-5-en-3β, 22-diol-3ß-acetate in 20 parts by volume of pyridine and the reaction mixture was left to stand for 5 hours at room temperature. Then the mixture was heated on the steam bath for 1 hour. After cooling, 200 parts by volume of water were added to the reaction mixture. The solid which formed was recrystallized from ethanol, the 25-methylcholest-5-en-3ß, 22-diol-3ß, 22-diacetate having a melting point of 175 to 177 ° C. was obtained.

Example 6

To 200 parts by volume of methylene chloride, which contained 15.8 parts of pyridine, 10 parts of chromic acid (previously dried over phosphorus pentoxide) were added in portions at room temperature in a nitrogen atmosphere. The burgundy solution was stirred for 30 minutes, then 2.7 parts of 25-methylcholest-5-en-3β, 22-diol-3ß, 22-diacetate in 15 parts by volume of methylene chloride were added rapidly. The reaction mixture was stirred at room temperature for 20 hours and then decanted from the insoluble residue. The residue was washed several times with ether, the ether wash solutions were combined with the decantate. This ether solution was treated with «Florex» and filtered through diatomaceous earth. The filtrate was washed with 1N hydrochloric acid and then with saturated brine, dried over sodium sulfate, treated with activated carbon and filtered. The solvent was removed and the crude solid was recrystallized from ethanol. The pure 3ß, 22-dihydroxy-25-methylcholest-5-en-7-one-3ß, 22-diacetate of mp 260 to 262 ° C was obtained.

Example 7

To 1.3 parts of 3ß, 22-dihydroxy-25-methylcholest-5-en-7-one-3ß, 22-diacetate in 130 parts by volume of ethanol was added 13 parts by volume of 5% sodium bicarbonate solution, then the reaction mixture was 2Vi Heated at reflux. After cooling, the orange solution was acidified with a little acetic acid and 200 parts by volume of water were added. The precipitate that formed was recrystallized from ethanol in two fractions. These were combined and recrystallized twice from ether / hexane to give the 3β, 22-dihydroxy-25-methylcholest-5-en-7-one-22-acetate of mp 217-218 ° C.

Example 8

5.0 parts by volume of 5% sodium bicarbonate solution was added to 50 parts by volume of ethanol containing 1.0 part of 25-methylcholest-5-en-3ß, 22-diol-3ß, 22-diacetate, then the mixture became 2 Heated at reflux for Vi hours. After adding water, the solid product was collected and recrystallized from ethanol, giving the 25-methylcholest-5-en-3β, 22-diol-22-acetate of mp 210 to 211.5 ° C.

Example 9

To 0.4 part of 25-methylcholest-5-en-3β, 22-diol-3-acetate, which was suspended in 15 parts by volume of acetone at room temperature, 0.35 part of Jones reagent was added, and the reaction mixture was then stirred for 30 min was stirred. Excess reagent was destroyed with a little isopropanol, then the reaction mixture was decanted from the insoluble residue. When water was added to the decantate, a solid formed which was collected and recrystallized from ethanol. This gave the 3ß-hydroxy-25-methyl-cholest-5-en-22-one-3ß-acetate of mp 187 to 187.5 ° C.

Example 10

To 1.3 parts of 3β-hydroxy-25-methylcholest-5-en-22-one-lo 3ß-acetate in 40 parts by volume of ethylene glycol, 7.0 parts of hydrazine hydrate (65% hydrazine) and 10 parts by volume of ethanol are added, then the reaction mixture is refluxed for 1 hour, after which it is homogeneous. 3.0 parts of potassium hydroxide pellets are added and the solution is heated to 15 190 ° C. and kept at this temperature in a nitrogen atmosphere for 16 hours. A further 3.0 parts of sodium hydroxide are then added, followed by heating for another 24 hours. Water is added to the cooled solution and the precipitate is collected. It is dissolved in a 20 1: 1 ether / pentane mixture and the solution is filtered through a cake made of magnesium sulfate. The solvent is removed from the filtrate and the solid product is recrystallized from acetone and then from methanol. This gives the 25-methylcholest-5-en-3ß-ol of mp 25 153 to 165 ° C.

Example 11

5.0 parts by volume of acetic anhydride are added to 0.9 part of 25-methylcholest-5-en-3β-ol in 12 parts by volume of pyridine and the reaction mixture is left to stand for 16 hours. Then water is added, the precipitate is collected and recrystallized from methanol, giving the 25-methylcho-lest-5-en-3ß-ol-3ß-acetate of melting point 146 to 148 ° C.

35 Example 12

To 70 parts by volume of methylene chloride, which contains 7.8 parts of pyridine, 5.0 parts of chromium oxide are added in portions at room temperature in a nitrogen atmosphere. After the burgundy solution has been stirred vigorously, 1.0 part of 40 25-methylcholest-5-en-3β-ol-3ß-acetatin and 5 parts by volume of methylene chloride are added and the reaction mixture is stirred at room temperature for 16 hours. Then 3 volumes of ether are added to the reaction mixture and the solution is decanted from the insoluble residue. 45 "Florex" is added to the solution, then it is filtered through diatomaceous earth. The filtrate is washed with 1N hydrochloric acid, then with 5% sodium bicarbonate solution and then with saturated saline. The solution is dried over sodium sulfate, the solvent is removed, giving an oily residue. When recrystallizing from ethanol containing little water, the 3ß-hydroxy-25-methyl-cholest-5-en-7-one-3ß-acetate of mp 183 to 186 ° C is obtained.

Example 13

55 To 0.48 parts of 3β-hydroxy-25-methylcholest-5-en-7-one-3ß-acetate in 40 parts by volume of ethanol, 4.0 parts by volume of 5% sodium bicarbonate solution are added and the reaction mixture is 3 hours. heated at reflux. After cooling, the base is neutralized with a little acetic acid, then 60 parts by volume of water are added 60, whereupon a precipitate forms. The precipitate is collected and chromatographed on Woelm silica gel while eluting with ethyl acetate in benzene. Recrystallization from aqueous ethanol gives the 3β-hydroxy-25-methylcholest-5-en-7 s one with a melting point of 176 to 178 ° C.

Example 14

To 0.2 parts of 3β-hydroxy-25-methylcholest-5-en-7-one in 6

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Vol parts of pyridine are added 0.5 parts of succinic anhydride and the reaction mixture is heated on the steam bath for 18 hours. After cooling, water is added and then 1N hydrochloric acid is added. The solid is collected and dissolved in ether. The ether solution is washed with 1N hydrochloric acid and saturated brine, dried over sodium sulfate and filtered. The solvent is removed and the product is recrystallized from methanol, giving the 3β-hydroxy-25-methylcholest-5-en-7-one-3ß-hemisuccinate of mp 211 to 212 ° C.

Example 15

To 7.8 parts of 3,3-dimethylbutyltriphenylphosphinium iodide in 75 parts by volume of tetrahydrofuran are added 9.4 parts by volume of a 1.75-molar phenyllithium solution over 5 minutes under nitrogen, then the orange-red solution stirred at room temperature for 15 minutes. After cooling the solution to -70 ° C, 4.0 parts of 6β-methoxy-3a, 5-cyclo-5a-23,24-bisnorcholan-22-al are added in 25 parts by volume of tetrahydrofuran over the course of 5 minutes. , then the reaction mixture is stirred at -70 ° C. for 30 minutes, then the cooling bath is removed and the mixture is allowed to warm to room temperature. Then add saturated ammonium chloride solution and then ether, then the phases are separated. The aqueous phase is extracted with further ether, and the combined extracts are washed with saturated saline and dried over sodium sulfate solution. After removing the solvent, an oil is obtained which is taken up in pentane and after stirring for several minutes at room temperature, the precipitate formed is filtered off. The filtrate volume is reduced to half and the precipitate which has formed again is filtered off. This precipitate consists of tri-phenylphosphine oxide. After removal of the solvent from the filtrate, the 6β-methoxy-25-methyl-3a, 5-cyclo-5a-cholest-22-ene is obtained as an oil, which was used in crude form for the further reactions.

Example 16

4.8 parts of 6β-methoxy-25-methyl-3a, 5-cyclo-5a-cholest-22-ene in 200 parts by volume of ethanol were at 2.45 kg / cm2 and room temperature over 4.8 parts of 5% palladium / Coal is hydrogenated until 1 equivalent of hydrogen is consumed. The catalyst was filtered off and after removal of the solvent from the filtrate, 6β-methoxy-25-methyl-3a, 5-cyclo-5a-cholestane was obtained.

Example 17

4.3 parts of crude 6β-methoxy-25-methyl-3a, 5-cyclo-5a-cholestane in 30 parts by volume of glacial acetic acid were heated on the steam bath for 2 hours. Then 30 parts of methanol was added to the solution, and after cooling, a crystalline product was obtained. After removal of the solvent, the product was recrystallized from ether / methanol, giving the pure 25-methylcholest-5-en-3ß-ol-3ß-acetate from F. 152 to 153 ° C.

Example 18

To a solution of 4 parts of 25-methylcholest-5-en-3β, 22-diol in 25 parts of pyridine was added a solution of 1 part of acetyl chloride in 5 parts of pyridine. The resulting mixture was stirred at room temperature for 6 hours and then diluted with an equal volume of water. The mixture thus obtained was extracted with ether, the extract was washed successively with 5% hydrochloric acid and then with water, then the

Stripped solvent by vacuum distillation. The residue was taken up in methylbenzene and the methylbenzene solution was chromatographed on silica gel using methylbenzene and mixtures of methylbenzene and increasing amounts of ethyl acetate for development. From the eluates selected by thin-layer chromatography and freed from the solvent by vacuum distillation, 25-methylcholest-5-en-3ß, 22-diol-3-acetate and 25-methylcholest-5-en-3ß, 22-diol-3,22-diacetate were used Residues isolated that melted after recrystallization from ethanol at 185 to 187 or 175 to 177 ° C (the less polar diester was eluted first).

Example 19

A. To a solution of 4 parts of 25-methylcholest-5-en-3β, 22-diol in 25 parts of pyridine was added a solution of 2 parts of 3-methoxy-3-oxopropanoyl chloride in 5 parts of pyridine. The resulting mixture was stirred at 90 to 95 ° C for 3 hours and then diluted with an equal volume of water. Then the mixture was extracted with ether, the extract was washed successively with 5% hydrochloric acid and water, and the solvent was stripped off by vacuum distillation. The residue was taken up in methylbenzene, the methylbenzene solution was chromatographed on silica gel using methylbenzene and mixtures of methylbenzene and increasing amounts of ethyl acetate for development. From the eluates selected by thin layer chromatography and freed from the solvent by vacuum distillation, the 25-methylcholest-5-en-3ß, 22-diol-3- (3-methoxy-3-oxo propanoate) and -3,22-bis (3rd -methoxy-3-oxopropanoate) as residues (the less polar diester was eluted first).

B. A mixture of 4 parts of 25-methylchoest-5-en-3ß, 22-diol-3,22-bis (3-methoxy-3-oxopropanoate), 12 parts of lithium iodide and 30 parts of 2,6-dimethylpyridine was refluxed with stirring overnight, after which an equal volume of water was added. The solid precipitate was filtered off, washed with water and air dried. In this way, the 25-methyl-cholest-5-en-3β, 22-diol-3- (hydrogen propanedioate) was isolated.

Example 20

A mixture of 1 part of 25-methylcholest-5-en-3ß, 22-diol-3ß-hemisuccinate, 10 parts of pyridine and 5 parts of acetic anhydride was stirred at room temperature overnight, then diluted with an equal volume of water. The solid precipitate that formed was filtered off, washed with water and air-dried. The 25-methylcholest-5-en-3β, 22-diol-22-acetate-3ß-hemisuccinate was isolated in this way.

Example 21

A. To a solution of 4 parts of 3ß-hydroxy-25-methyl-cholest-5-en-7-one in 25 parts of pyridine was added a solution of 2 parts of 3-methoxy-3-oxopropanoyl chloride in 5 parts. The resulting mixture was stirred at 90 to 95 ° C for 3 hours and then diluted with the same volume of water. The mixture was then extracted with ether, the extract was washed successively with 5% hydrochloric acid and water and then the solvent was removed by vacuum distillation. The 3β-hydroxy-25-methylcholest-5-en-7-one-3- (3-methoxy-3-oxopropanoate) was obtained as residue.

B. A mixture of 4 parts of 3β-hydroxy-25-methylcho-lest-5-en-7-one-3- (3-methoxy-3-oxopropanoate), 12 parts

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Lithium iodide and 30 parts of 2,6-dimethylpyridine were refluxed with stirring overnight, then an equal volume of water was added and the solid precipitate that formed was filtered off, washed with water and air dried. The 3β-hydroxy-25-methylcholest-5-en-7-one-3- (3-hydrogen propanedioate) was isolated in this way.

Example 22

Pharmaceutical preparations were produced in the following manner, the amounts being based on 1000 tablets, capsules, suppositories or parenteral products.

Tablets

500 g of an active ingredient, for example 25-methylcholest-5-en-3ß, 22-diol, were combined with 265 g lactose, 200 g corn starch and 30 g polyvinylpyrrolidone, mixed thoroughly and sieved through a sieve with a 0.42 mm mesh size . The mixture was then granulated with isopropyl alcohol, spread on trays and dried at 49 ° C for 16 hours. The dried granules were sieved again, the granules were carefully mixed with 5 g of magnesium stearate and the mixture was compressed into tablets of the appropriate size. In this way, 1000 tablets with 500 mg of active ingredient / tablet were produced.

Capsules

500 g of 25-methylcholest-5-en-3ß, 22-diol were carefully mixed with 87.5 g of corn starch and 87.5 g of lactose, sieved through a sieve with a 0.42 mm mesh size and mixed again. Then, 75 g of talc was added and the mixture was mixed thoroughly and filled by hand or by machine into size 00 hard gelatin capsules in an amount of 750 mg / capsule. A product with 500 mg of active ingredient / capsule was obtained.

In the manufacture of tablets and capsules from the compounds according to the invention, extenders can be used. These include the following:

Sugars such as lactose, cane sugar, mannitol or sorbitol, starches such as corn starch, tapioca starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose or methyl cellulose, gelatin, calcium phosphate such as dicalcium phosphate or tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinylpyralolidine acid Magnesium stearate, vegetable oils such as peanut oil, cottonseed oil,

Sesame oil, olive oil, corn oil, surface active (non-ionic, cationic, anionic), ethylene glycol polymers, ß-cyclodextrin, fatty alcohols, hydrolyzed cereal solids and other non-toxic and compatible fillers, binders, disintegrants and lubricants, which are common in pharmaceutical formulations.

Suppositories

500 g cocoa butter are melted in a water or steam bath (to avoid local overheating), then 500 g 25-methylcholest-5-en-3ß, 22-diol are emulsified or suspended in the melt. Finally, the mass is poured into chrome-plated, cooled metal molds, in which the suppositories quickly solidify. In this way, 1000 suppositories with 500 mg of active ingredient per piece are obtained.

Numerous carriers and raw materials can be used in the production of suppositories from compounds according to the invention. These include:

20th

Triglycerides of oleic acid, palmitic acid and stearic acid (cocoa butter), partially hydrogenated cottonseed oil, branched-chain saturated fatty alcohols such as suppository base G, hydrogenated coconut oil triglycerides of Ci2-Ci8-fatty acids, water-dispersible carriers such as polyethylene glycol, gelatin, glycerol -40 stearate and polyethylene-4-sorbitan monostearate and substances which can increase the melting point of the suppository base, such as beeswax, spermacet and the like.

30th

Parenteral products

10 g of 25-methylcholest-5-en-3ß, 22-diol are dissolved in 1000 ml of ethyl alcohol and a total volume of 5000 ml is produced with sesame oil. The mixture is filtered 35 and filled into ampoules, which are sealed. The ampoules are sterilized in a suitable manner. This gives 1000 ampoules with a concentration of 10 mg of active ingredient per 5 ml.

Numerous carriers and solubilizers can be used in the production of parenteral products from compounds according to the invention. These include:

Vegetable oils such as peanut oil, corn oil, cottonseed oil, sesame oil, benzyl alcohol, saline, phosphate buffer, 4s water, ethylene glycol polymers, urea, dimethylacetamide, triton, dioxolanes, ethyl carbonate, ethyl acetate, glycerin, formal, isopropyl myristate, surface active, ionic ionization Polyalcohols and ethanol.

B

Claims (10)

643566 2nd PATENT CLAIMS I. Compound of formula R 3rd 643566 wherein R: has the meaning given above, with water in the presence of tosyl acid hydrate. 3. A compound according to claim 1 of the formula R, CH. R. CH. CH. R, CH. wherein Ri is an alkyl radical with 1 to 4 carbon atoms, R is hydrogen, an alkanoyl radical having 2 to 7 carbon atoms or a radical of the formula O O II II HOC- (CH2) n-C- where n is an integer less than 4, Y is the methylene or carbonyl radical, where if Y is the carbonyl radical, Ri is hydrogen and if Y is the methylene radical, Ri is -OX, where X is hydrogen, an alkanoyl radical having 2 to 7 carbon atoms or a radical of the formula O O il II HOC- (CH2) n-C- Is where Rz is an alkyl radical having 1 to 4 carbon atoms, Ri is hydrogen and R is hydrogen, an alkanoyl radical with 2 to 7 carbon atoms or a radical of the formula O O HOC- (CH2) "- C- where n is an integer less than 4, and the wavy line represents R or S stereo configuration. 25 4. 25-Methylcholest-5-en-3ß, 22-diol as a compound according to claim 1. 5. 25-Methylcholest-5-en-3ß, 22-diol-3ß-hemisuccinate as a compound according to claim 1. 6. 25-methylcholest-5-en-3β, 22-diol-3- (hydrogen propane-30 dioate as a compound according to claim 1. 7. 3β-hydroxy-25-methylcholest-5-en-7-one-3ß-hemisuc-cinate as a compound according to claim 1. 8. A process for the preparation of compounds according to claim 1 of formula A. 35 OH RO wherein R2 is an alkyl radical having 1 to 4 carbon atoms and R and X are hydrogen, alkanoyl radicals having 2 to 7 carbon atoms or radicals of the formula O O II II HOC- (CH2) "- C- where n is an integer less than 4, and the wavy line represents R or S stereo configuration. OH OCH. 9. The method according to claim 8 for the preparation of 25-methylcholest-5-en-3ß, 22-diol, characterized in that 6ß-methoxy-25-methyl-3a, 5-cyclo-5ct-cholestan-22-ol with Reacts water in the presence of tosyl acid hydrate. 10. Pharmaceutical or veterinary preparations containing one or more of the compound (s) of claims 1 to 7.