DE957030C - Process for the preparation of the phenylpropionic acid esters of steroid hormones - Google Patents

Description

ISSUED JANUARY 31, 1957

O 2755 IVb j

is used

The invention relates to a process for the preparation of new derivatives of hormones of the cyclopentane polyhydrophenanthrene series by esterification with / J-phenylpropionic acid.

It is known to convert hormones of the steroid series into esters, the effectiveness of which is greater than that the hormones themselves. As such are the esters of propionic acid, benzoic acid and phenylacetic acid applied. In order to obtain steroid hormones with a longer lasting effectiveness, was also already proposed the esterification with cyclopentylpropionic acid and Perform cyclohexylpropionic acid.

It has now been found that physiologically active steroids with a free hydroxyl group, the can be esterified with a fatty acid, are able to be physiologically active with jS-phenylpropionic acid React derivatives that have a longer duration of action than the previously known derivatives of the corresponding active compounds have and, moreover, in most cases a higher effectiveness than the known derivatives. from

The jÖ-phenylpropionic acid esters are of particular interest of testosterone and estradiol and their derivatives, but also the phenylpropionates of Other steroid hormones have similarly increased effects compared to the previously known esters.

Phenylpropionic acid esters of steroid hormones have not yet been described in the literature. she are able to exert and have a physiological effect over a considerable long period of time in many cases a higher effectiveness than the derivatives of the hormones used up to now. this has the great advantage that fewer injections are required, while the higher one Efficacy makes it possible to maintain a therapeutic effect with much smaller doses.

The table below gives a comparison of the properties of testosterone phenylpropionate with already known testosterone propionate derivatives. The table shows the mean weight of seminal vesicles in mg at various time intervals after a single intramuscular injection of 0.1 ecm castrated rats. The results are given over a range of comparative injections I through V. The different injections in the list were made as follows:

Injection I. testosterone propionate in sesame oil, 2.5 mg in 0.1 ecm oil;

Injection II. Testosterone - /? - phenylpropionate in sesame oil, 2.5 mg in 0.1 ecm oil;

Injection III. Testosterone propionate in ethyl oleate, 2.5 mg in 0.1 ecm oleate;

Injection IV. Testosterone- / J-phenylpropionate in Ethyl oleate, 0.5 mg in 0.1 ecm oleate;

Injection V. Testosterone-jS-phenylpropionate in Ethyl oleate, 2.5 mg in 0.1 ecm oleate.

Tabel
Weight of the seminal vesicles in mg

injection 3 5 7th 9 Days 21 28 35 42 23.4 32.9 36.7 32.6 H 21.7 13.9 14.6 I8.7 I. 33.2 48.1 9M 120.2 30.4 60.2 58.3 50.3 41.6 II 29.6 50.6 69.1 72.1 76.8 21.8 21.7 17.8 24.1 III 22.0 35.7 52.2 53.7 37.9 32.2 25.3 21.0 23.6- IV 29.6 40.8 107.6 122.2 33.4 101.8 70.1 Ö2..0 45.4 V 134.5

From the table above it can be seen that with injection I the maximum effect is achieved in 7 days, while with injection II the maximum effect is achieved in 9 days with a much greater effectiveness. In addition, even after 42 days, activity is generally much greater than what was seen with injection I at any time. A comparison of injections III and IV shows that the effectiveness of the new derivative (injection IV) is such that a fraction ( ¹ I ₅ ) of the active component in injection IV in comparison with injection III gives approximately the same results as with the propionate of the injection III. A comparison of injections III and V shows that with the same amount of active material an even higher maximum effectiveness is achieved after 14 days and a large part of the effectiveness is still retained even after 42 days.
In the following, results of tests with testosterone esters on capons will be shown, in which the phenylpropionic acid ester was compared with the propionate and the cyclopentylpropionate. Six, five or six capons each received 5 mg of the preparation to be examined, dissolved in 0.2 ecm of oil, injected intramuscularly. The table shows the mean percentage increase in the capon comb after 12, 16, 20 and 24 days.

Testosterone phenylpropionate

Testosterone Propionate ..

Testosterone cyclopentyl propionate

To

16 I 20

Days

'275%

210%

314% 70%

258%

24

339% 78%

297%

305% 58%

295%

The above list shows an essential superiority of the biological effect of testosterone phenylpropionate compared to the known comparison substances.

The experiments which relate to estradiol esters are described below.

The following were tested: I. Estradiol-17 / ^ phenylpropionate; II. Estradiol-3, 17-di - ^ - phenylpropionate; III. 17-ethinyl estradiol-3 ß-phenylpropionate.

The duration of the estrogenic effect of the compounds I and II was compared to that of the estradiol-17-monobenzoate, compared that of compound III with the 17-ethinyl estradiol. To determine the effect of a compound, ten castrated rats are administered 0.5 mg of this compound subutaneously. The duration of the effect is the number of

Taken days after injection when 50% of the test animals were still in heat.

The duration of the heat was as follows:

Days

Estradiol 17-monobenzoate 9

Compound I 30

Compound II 62

17-ethinyl estradiol. 9

Compound III 13

These experiments clearly show that the estradiolphenylpropionic acid esters are also outstanding Effect is to be attributed.

The clinical investigations with cortisone phenylpropionate have shown that through the esterification With phenylpropionic acid, a significant increase in the effectiveness of this hormone is also achieved that are similar to these cortisone esters

ao makes derivatives of cortisone superior.

The new hormone esters can, for. B. in a known manner by condensing the steroid hormone with /^P.henylpropionic anhydride with or without use a solvent can be prepared, the reaction time by heating or by Working with a solvent, e.g. B. pyridine, benzene or another suitable solvent or their mixtures can be abbreviated.

You can also use ß-phenylpropionic acid chloride in a solvent such as pyridine or a mixture of benzene and pyridine The latter should contain sufficient pyridine to bind the split off hydrogen chloride. Other common processes for the preparation of carboxylic acid esters can also be used here, z. B. the reaction of a diazoketone with a carboxylic acid or the esterification with the free acid, which leads to the desired product in a manner that is easy to carry out.

The following examples explain the process according to the invention.

example 1

A solution of 10 g of testosterone in 30 ecm of pyridine was cooled in ice, and 7.5 g of α-phenylpropionyl chloride were slowly added with stirring. The solution was then removed from the ice bath, left at room temperature overnight, and then decomposed with ice. The solid ester was recrystallized from methanol; F. = 116 to 117 ⁰ ; [α] g ″ = + 88 ° (c - ι in dioxane).

Example 2

A solution of 10 g of testosterone in 30 ecm of benzene and 10 ecm of pyridine was cooled in ice, and 7.5 g of yS-phenylpropionyl chloride were added dropwise with stirring. The solution was then removed from the ice bath, left at room temperature overnight and then washed with water, dilute soda solution and then with dilute hydrochloric acid. After drying, the benzene solution was evaporated to a dry residue and recrystallized from methanol; F. = 116 to 117 ⁰ .

Example 3

12.5 g of ^ -phenylpropionic anhydride were added to a solution of 10 g of testosterone in 30 ecm of pyridine. After standing overnight at room temperature, the solution is decomposed by adding water and the testosterone phenylpropionate is crystallized from methanol; F. = 116.5 to 117 ⁰ .

Example 4

10 g testosterone and 12.5 g / I-phenylpropionic anhydride were heated together at 100 ° for 5 hours. The melt was then treated with water and the solid mass was washed with dilute soda solution, dried and crystallized from methanol; F. = 116 to 117 ⁰ .

Example 5

2 g of testosterone and 1.5 g of I-phenylpropionic acid were _{heated together under a CO 2} atmosphere to 220 ° for ι hour, the water formed being distilled off. The product was then cooled and extracted with isopropyl ether. The ethereal solution was washed with soda solution and water and then dried over sodium sulfate. After removing the ether, the residue taken up in benzene was chromatographed on aluminum oxide and the benzene eluate was evaporated to dryness. Crystallization from methanol gave 1.8 g of testosterone phenylpropionate; F. = 117 ⁰ . A second fraction could be obtained from the mother liquor.

Example 6
[5-Pregnen-3, 2i-diol-20-one-2i - /? - phenylpropionate] _lQQ

A mixture of 40 g of 21-diazopregnenolone and 130 g of phenylpropionic acid were heated on the steam bath for ι hour. The nitrogen evolution had almost stopped after 25 minutes. The mixture, which solidified on cooling, was 16 hours left to stand, dissolved in warm methanol, cooled rapidly and, with stirring, in aqueous soda solution poured. The precipitate was collected by filtration and washed with warm water until the Filtrate reacted as alkali-free against litmus. The dried crude material (41.5 g) became from methanol crystallized to form a pale yellow amorphous solid; M.p. = 108 to 109.5 °; [α] f? = + 31.5 °; Yield 35.2 °. After recrystallization from methanol, the product had a melting point of 110.5 to 112 °. From this can be determined by Oppenauer oxidation with aluminum apropylate of ii-deoxycorticosterone-2i- / 3-phenylpropionate, Establish [α] f = -f-170.5 °. The product had a melting point from 139 to 139.5 °.

Example 7
Estradiol-3 - /? - phenylpropionate

10 g of "a" r-ostradiol with m.p. = 178 ⁰ were dissolved in 104 ecm warm, pure, dry acetone, and sodium hydroxide solution (24.7 g in 260 ecm) was distilled

Water) added. The solution was then cooled to room temperature. 16 cc of freshly prepared and distilled / J-phenylpropionyl chloride and 6.5 cc of sodium hydroxide solution (i8 g dissolved in 25 cc of distilled water) were added simultaneously over the course of i _^3/4 hours with vigorous stirring. Stirring was continued for 45 minutes to ensure that all of the acid chloride had decomposed. The ester was collected by filtration and, after washing with a sufficient amount of 30% acetone to remove the mother liquor, washed with cold distilled water and finally with warm water until the filtrate reacted free of alkali against red litmus. The ester weighed 14.8 g at this stage.

The mother liquors were then treated as above with 8 ml of iS-phenylpropionyl chloride and 3.25 ml of sodium hydroxide solution, a second small amount of product (2.6 g) being obtained. Another treatment gave a third batch of product (1.2 g). The three amounts of product were combined and crystallized from a mixture of diethyl ether and η-hexane, 16 g of the ester being obtained as colorless crystals; F. = 90.5 to 92 ^0; [α] 2 "= + 62.7 °. A sample, recrystallized from isopropyl ether, had a melting point of 104.5 to 105.5 °.

Example 8 Estradiol 3,17-di-β-phenylpropionate

30 ecm of iS-phenylpropionyl chloride were slowly added, while cooling, to a solution of 10 g of """oestradiol with a temperature of 178 ° in 120 ecm of pyridine. The cherry-red solution was allowed to stand at room temperature for 16 hours, after which it was poured into a mixture of dilute hydrochloric acid and ice. The gummy solid which separated out was dissolved in diethyl ether and washed with soda solution, water, dilute hydrochloric acid and finally again with water. The ethereal solution was evaporated after drying over sodium sulfate to dryness and the residue crystallized from acetone to give 9.8 g of colorless crystals, mp = 125 to 127 ^0, crystallized. Concentration of the filtrate gave a second batch (2.8 g). The mother liquor was evaporated to dryness, the residue was dissolved in benzene and filtered through a column of alumina. Removal of the benzene by distillation with subsequent crystallization of the residue from acetone gave 1.4 g of colorless crystals; F. = 122 to 125 °.

After further crystallization from acetone, the first batch had a melting point of 130 to 130.5 g; [α] ο = + 38.7 ° in dioxane.

From this, by partial hydrolysis with methanolic potassium carbonate, the estradiol 17 - /? - phenylpropionate with a melting point of 119.5 to 12.5 ° (from diethyl ether and η-hexane), [α] f? = + 54.5 g (i ⁿ dioxane), win. Example 9

17 a-methyl-5-androstene-3 ß, 17 /? - diol-

3-jS-phenylpropionate

45 ecm of absolute benzene were added to a solution of 10 g of 17 a-methylandrostenediol in 20 ecm of pyridine. The solution is cooled to - iq ° and a solution of 6 g of 7 g of iS-phenylpropionic acid chloride in 20 ecm of absolute benzene is added dropwise with vigorous stirring. The reaction mixture is then stirred for a further 15 minutes and cooled to about 0 to -5 ° in 24 hours. Then it is poured onto a mixture of ice and water. The benzene layer is separated and washed with 5 ° / _o sulfuric acid until an acid reaction, then washed with 5 ° / _o aqueous sodium hydroxide solution and with water until neutral. The benzene solution is dried over sodium sulfate, evaporated to a small volume and then filtered through a column of 50 g of alumina. The benzene eluates obtained are evaporated to dryness. After recrystallization of the residue from methanol, 10 g of ester with a melting point of 122.5 ° to 124.5 ° are obtained; [a]% = -47 ° (c = ι in dioxane).

Example 10 17-Ethinylestradiol-3-jS-phenylpropionate

10 g ethinyl estradiol are dissolved in 40 ecm pyridine and 10 ecm benzene. To this solution, cooled to -10 °, a solution of 8 g of β-phenylpropionic acid chloride in 20 ecm of benzene is added dropwise with vigorous stirring; After standing for 24 hours to 0 to -5 °, the reaction mixture is poured into a mixture of ice and water. The benzene layer is washed after separation with 5 ° / _o sulfuric acid solution, 5 ° / _o aqueous sodium hydroxide solution and with water. After drying over sodium sulfate, this solution is evaporated to a small volume and filtered through aluminum oxide. The benzene eluates are evaporated to dryness. After recrystallization from benzene petroleum ether, the residue from evaporation gives 11 g of ester with a melting point of 105 to 106 °; [a] | ° = 3.3 ° (c = 0.9 in dioxane).

Example 11

17-Oxy-ii-deoxycorticosterone-2i - /? - phenyl propionate

To a solution, cooled to -10 °, of 5 g of 17-oxy-ii-deoxycorticosterone in 25 ecm of pyridine, a solution of 5 g of I-phenylpropionic acid chloride in 20 ecm of dry benzene is added dropwise with vigorous stirring. The reaction mixture is cooled to a temperature of 0 to -5 ° for 24 hours. After pouring the reaction mixture onto a mixture of ice water and the benzene layer is separated and then / washed with 5 ° _o sulfuric acid solution, 5 ° / _o aqueous sodium hydroxide solution and with water. The benzene solution is then dried over sodium sulfate, evaporated to a small volume and filtered through 25 g of aluminum oxide. The ester is eluted with ether and the resulting solution is evaporated to dryness. After recrystallization from methanol, 5 g of ester with a melting point of 170 to 172 ^° ; [α] f = + ii8 ° (c = 0.8 in dioxane).

Example 12
Oestrone-3-jS-phenylpropionate

A solution of 10 g of estrone in 40 ecm of pyridine is cooled to -10 °. Then become this

10 g of S-phenylpropionic acid chloride in 20 ml of dry benzene were added dropwise with vigorous stirring. After standing for 24 hours at 0 to -5 ^0, the reaction mixture is poured onto a mixture of ice and water. The benzene layer is / then and then washed after separation with 5 _cent sulfuric acid solution, with 5 ° / _o aqueous sodium hydroxide solution with water. The benzene solution is dried over sodium sulfate and filtered through a column of 50 g of aluminum oxide. The benzoeluates are evaporated to dryness. The evaporation residue is recrystallized from acetone, which gives 12.4 g of ester with a melting point of 146 to 148 ° [d \% = + 111 ° (c = 0.9 in dioxane).

Example 13

ii-Dehydro-17-oxycorticosterone-2i - /? - phenylpropionate

3 g of cortisone are dissolved in 40 ecm of pyridine; after cooling to -10 °, a solution of 3 g of α-phenylpropionic acid chloride in 10 ecm of benzene is added dropwise with vigorous stirring. The reaction mixture is left to stand for 24 hours at ^{0 to} -5 0 and then poured into a mixture of ice and water. The benzene layer is separated and then washed it with 5 ° / _o sulfuric acid solution, washed with 5 ^o / cent sodium hydroxide solution and water. After drying over sodium sulfate, the benzene solution is evaporated to a small volume and filtered through a column of 15 g of aluminum oxide. The ester is eluted with a mixture of benzene and ether (50:50) and then the eluates are evaporated to dryness. Finally the evaporation residue is recrystallized from a mixture of acetone and ether. There are 3 g / - = get phenylpropionate, melting at 175 to 177 ^0; [α] | "= + 183 ⁰ (c = 0.5 in dioxane).

Example 14

4-pregnen-ii, 17, 2i-triol-3, 20-dione-2i - /? - phenylpropionate

0.2 ecm / S-phenylpropionic anhydride are added to a solution of 200 mg of Kendall's compound F in 2 ecm of pyridine. The reaction mixture is left to stand overnight at room temperature. The ester is crystallized from aqueous acetone. The crystals have a melting point of 138 to 139 ⁰ ; [α] * ^β = + 136 ⁰ (c = 0.7 in dioxane).

Claims (1)

PATENT CLAIM: Process for the preparation of the phenylpropionic acid esters of steroid hormones, characterized in that that a steroid hormone with | 8-phenylpropionic acid or its functional derivatives esterified in a manner known per se. Considered publications:
German patent specification No. 823 593. © «09 577/480 7.56 (609 777 1.57)