DK145197B - ANALOGIFREMGANGSMAADE OF PRODUCING testosterone esters - Google Patents

Description

in 145197

The invention relates to an analogous method for the preparation of novel testosterone esters of the general formula I

O-CO-X-O-CO-R

(D

wherein R represents an alkyl group of 8-23 carbon atoms and X represents an alkylene group of 1-3 carbon atoms.

Testosterone esters are already known. Some esters, such as, for example, testosterone propionate and testosterone nanthate, are used in the medicine as depot preparations to replace androgens. The esters also have interesting androgenic effects in the case of oral administration in the presence of a lipidic material, which can be traced back to the lyra = 10 phatic resorption. Admittedly, the lymphatically resorbed and hydrolytically released and thus effective part of the dose is very poor in animals and humans, e.g. after oral administration of testosterone undecylate.

As with the continuous oral ingestion, the active substance from the depot preparation must be made available in unchanged quantity over an extended period of time. With the known test cheese esters, a uniform and sustained release cannot be achieved. For example, after intramuscular administration, the testosterone nanthate shows initially a high testosterone mirror, which then rapidly declines. Long-chain esters, such as, for example, testosterone undecylate, which show a somewhat more uniform release, are only cleaved slowly and inadequately in the plasma. Because of this delayed cleavage of the testosterone esters, they may exhibit an undesirable - because it is not natural - steroid ester effect per se.

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In order to deliver a greater proportion of the dose to the body after oral administration by lymphatic route, testosterone esters must be lipophilic as far as possible. It is also known that the depot effect of intramuscularly administered steroid esters stays the longer the lipophilic ester is. The known highly lipophilic fatty acid esters of testosterone (eg testosterone undecylate and testosterone palmitate) have the serious disadvantage that the more effective the testosterone is released from the ester sterile, the slower the lipophilic 10 fatty acid used.

It has now been found that the novel testosterone esters of general formula I have a uniform and sustained effect as depot preparations. After release from the depot, the esters in question are rapidly cleaved in the plasma.

They can therefore be used with good use of the active substance, especially parenterally.

In order to achieve an androgenic depot effect, the esters of the invention are administered, for example, intramuscularly in oily solution. As a solvent, vegatable and animal oils are considered. For example, castor oil, sesame oil, sunflower oil, olive oil, soybean oil, flaxseed oil, peanut oil, etc. Also suitable are synthetic and semi-synthetic mono-, di- and triglycerides of fatty acids, glyce = rolethers, glycols, etc.

The oily solutions may be added to solvents such as benzyl alcohol or benzyl benzoate, thickeners such as gelatin, preservatives, emulsifiers, stabilizers, wetting agents, etc.

The concentration of. The ester prepared according to the invention in the oily solution is 1-50% by weight.

The uniform sustained release of testosterone from the esters of the invention can be detected by radioimmunoassay through determination of the testosterone concentration in plasm 3 145197.

To this end, two female baboons were each intramuscularly administered 50 mg of testosterone glycohexacanoate in 1 ml of castor = oil / benzyl benzoate (6: 4). Testosterone plasma levels ranged from 2 to 40 days between 15 and 25 ng / ml plasma. The testosterone was released almost completely from the depot.

For androgen substitution in men with androgen deficiency, at intervals of approx. 4 weeks intramuscularly administer 50 to 400 mg of the esters of the invention.

Furthermore, oral administration of the testosterone esters prepared according to the invention is also discussed. The most advantageous form of (oral administration) is also the oily solution. For easier handling, the oily solution containing the active substance and any additives may, for example, be filled into gelatin capsules or encapsulated in microcapsules.

The concentration of the esters of the invention in the dosage unit varies widely and is from 1 to 50% by weight.

For oral replacement therapy, 10-200 mg of testosterone ester is required daily.

The testosterone esters prepared by the process of the invention contain 2 alkanoyloxy groups in the ester moiety.

If the steroid alcohol testosterone is designated by the formula St-OH, the following formula is obtained for the testosterone esters in question:

St-O-CO-X-O-CO-R.

These esters are cleaved stepwise:

St-O-CO-X-O-CO-R 1, Step> St-O-CO-X-OH 2 '> St-OH.

It is believed that the stepwise cleavage is responsible for the very uniform and long-lasting effect of the esters of the invention.

Following intramuscular administration of e.g. 47 mg of testosterone glycotridecanoate in 1 ml of castor oil / benzyl benzoate (6: 4) (= 25 mg of testosterone) for female baboons, the time course of the 5 testosterone concentration in the plasma was measured by radioimmunoassay. The extent to which the testosterone is available was calculated from the surface under the curve of the plasma mirror.

With testosterone glycotride decanoate (17β- (O-tridecanoylglycoloyl = oxy) -4-androsten-3-one) prepared according to the invention, uniform, at least 56 days of sustained physiological testosterone plasma mirrors are obtained. After administration of 29.8 mg of testosterone propionate (= 25 mg of testosterone), the intramuscular depot was depleted already after 15 days, and after administration of 34.7 mg of testosterone nanthate (= 25 mg of testosterone), the 15 depot was depleted after 30-35 days. . Only testosterone undecylate also resulted in a duration of action of approx. 56 days.

These advantages of the esters of the invention are particularly evident in the case of oral administration.

The alkanoyloxycarboxylic acid esters of the invention result in higher testosterone plasma levels after oral administration than the recognized well-functioning testosterone undecylate.

The temporal course of the testosterone concentration in the plasma of female dogs weighing approx. 10 kg was measured after 25 oral administration of 50 mg of testosterone glycohexadecanoate (= 25 mg of testosterone) and of 40 mg of testosterone undecylate (= 25 mg of testosterone) in comparison with oral administration of 25 mg of testosterone. Testosterone determination in plasma was done by radioimmunoassay. For administration 50, the test compounds were dissolved in groundnut oil.

145197 5

The extent to which testosterone is available was calculated as the ratio between the area under the testosterone plasma mirror curve (0-8 hours) after oral administration of the test compounds and the area under the testosterone plasma mirror curve after 5 intramuscular administration of testosterone.

The following table shows that the esters (testosterone glycohexadecanoate) are 7-8 times more effective than testosterone and 3-4 times more effective than the well-known testosterone undecylate.

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The process of the invention is characterized by esterification of testosterone with the acid R-CO-O-X-COOH or a derivative thereof in the usual manner. As derivatives, the acid halides and anhydrides are particularly suitable.

The reaction of testosterone with the acid halide, e.g. chloride, is carried out in the usual manner in a solvent such as acetone, hexane, benzene, toluene, pyridine and in the presence of a tertiary amine such as pyridine, dimethylaminopyridine, di-methylaniline or triethylamine. In a preferred embodiment, pyridine simultaneously acts as a hydrogen halide displaying agent. j agent and as solvent for the reaction participants.

The reaction of testosterone with the desired acid anhydride is carried out according to known methods in a solvent, such as pentane, hexane, benzene, toluene, pyridine, and in the presence of a basic or acidic catalyst. Thus, pyridine can simultaneously act as a solvent and a basic catalyst.

The esterification can also be done by reacting the steroid alcohol with the acid in a solvent such as acetonitrile in the presence of a condensing agent such as dicyclohexylcarbo = 20 diimide.

The acids R-CO-O-X-COOH are a commonly known linking group. For example, undecanoyloxyacetic acid is described in Canadian Journal and Chemistry 47 (1969) 853. The acids used for the esterification can also be prepared in a manner known per se, e.g. from the hydroxyalkanecarboxylic acids HO-X-COOH and the aliphatic acyl chlorides R-CO-C1.

In principle, one may also initially esterify testosterone with a lower acyloxyalkanecarboxylic acid, then partially saponify the lower acyloxy group and then esterify with the last desired acid R-CO-OH or a derivative of this acid. For example, acyloxyacetic acid and acyloxyacetyl chloride are described in Ber. 36 (1903) 466 - 468. The preparation of α = acetoxypropionic acid is described in Compt. Fuck. 140, 938.

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Example 1 50 g of glycolic acid are dissolved under nitrogen in 500 ml of pyridine and slowly added with stirring 180 g of palmitic acid chloride. After adding approx. 2/3 a white precipitate appeared. 5 was stirred for 20 hours at room temperature and then poured into 1.2 L of 6N sulfuric acid with stirring and ice cooling. The precipitated product was aspirated, the filter cake was washed neutral with water and dried in vacuo over phosphorus pentoxide. After recrystallization from acetone, 170 g of 0-hexade = 10 canoylglycolic acid is obtained, mp 84-85 ° C.

21 g of O-hexadecanoylglycolic acid is dissolved under nitrogen in 60 ml of benzene and the solution is distilled until the water is azeotropically removed. Then 0.1 ml of dimethylformamide is added and 23.7 g of thionyl chloride are added dropwise with stirring. It is heated under reflux for 15 hours, then the benzene and excess thionyl chloride are distilled off in vacuo. The semi-solid residue is recrystallized from hexane. 16 g of 0-hexadecanoylgly = coloyl chloride are obtained, mp 39-40 ° C.

<3 g of 17f3-hydroxy-4-androsten-3-one is dissolved in 15 ml of pyridine and 20, under nitrogen and stirring, 10.4 g of 0-hexadecanoylglycoloyl chloride is added. After 15 hours, the reaction solution is poured into ice-cooled oxalic acid solution (2 equivalents to pyridine) and the precipitated product is suctioned off, washed neutral and dried. After filtration over silica gel with hexane, 4.3 g of 17β- (O-hexadecanoylglycoloyloxy) -4-androsten-3-one are obtained. Melting point: 41-42 ° C, UV: ε241 = 15,000.

Example 2 Dissolve 17 g of 3-hydroxy-4-androsten-3-one in 15 ml of pyridine under nitrogen and 5.3 g of O-tridecanoylglycoloyl chloride are added. After 15 min. is poured into ice-cooled oxalic acid solution and the precipitated product is extracted with methylene chloride.

The organic phase is washed neutral, dried with sodium sulfate 9.19197 and evaporated. The residual oil is chromatographed over silica gel with methylene chloride. 4.85 g of 170- (0 ~ tride = canoylglycoloyloxy) -4-androsten-3-one is obtained as colorless oil. UV: ε240 = 16 · 000 · 5 Example 3

Analogously to Example 2, 3 g of 170-hydroxy-4-androsten-3-one is reacted with β-tridecanoyloxypropionyl chloride. 4.7 g of 170- (δ-tridecanoyloxypropionyloxy) -4-androsten-3-one is obtained as colorless oil. UV: & 24Q = 15 · 800 * 10 Example 4

Analogously to Example 2, 3 g of 170-hydroxy-4-androsten-3-one is reacted with γ-hexadecanoyloxybutyryl chloride. 5.1 g of 170- (γ-hexadecanoyloxybutyryloxy) -4-androsten-3-one are obtained. Melting point: 42-50 ° C. UV: £ 240 = Example 5

Analogously to Example 2, 3 g of 170-hydroxy-4-androsten-3-one is reacted with O-undecanoylglycolic acid chloride. 4.9 g of 170- (O-undecanoylglycoloyloxy) -4-androsten-3-one is obtained as colorless oil.

UV: ε240 = 16,000.

Example 6

Analogously to Example 2, 16 g of 170-hydroxy-4-androsten-3-one is reacted with O-nonanoylglycolic acid chloride. 9.7 g of 170- (O-nonanoylglycoloyloxy) -4-androsten-3-one is obtained as colorless oil.

UV: ε 240 = 15,800.

Example 7

Analogously to Example 2, 6 g of 170-hydroxy-4-androsten-3-one is applied with O-octadecanoylglycoloyl chloride. 9.5 g of 170- (O-octadecanoylglycoloyloxy) -4-androsten-3-one is obtained. Melting point: 43-45 ° C. UV: ε241 = 15,200.