RS49915B - 16-KETOSTEROIDES OF THE ESTRATRIAN AND ANDROSTEN SERIES SUBSTITUTED - Google Patents

Abstract

New 16-keto-17-substituted-ester-1,3,5 (10) -triene and 16-keto-17-substituted-5-androstenic derivatives of general fonnula I in which R is methyl or benzyl radical and X has the following structure wherein R2 is hydrogen, 1-4 carbon alkyl radical, acyl radical, alkylsulfonyloxy radical or aryl radical. The application contains 1 dependent request.

Description

1. TECHNICAL FIELD

The invention belongs to the field of organic heraic technology, more precisely to the field of making synthetic steroids with biological activity. According to the international classification of patents, the invention belongs to classes C07 J 51/00, A 61 K 31/56, A 61 K 31/575, A 61 K 31/58.

This application was separated from the basic application P-604/96.

2. DEFINED PROBLEM

This invention includes new, hitherto unknown estrone and androstene derivatives with anti-estrogen and anti-androgen activity, 16-keto-17-substituted derivatives in the estrone and androstene series, as well as the process for their preparation starting from the corresponding 17-keto-16-oximes.

3. STATE OF THE ART

D-seco steroids are of great interest both because of their possible biological activity (Baran, J.S., J.Med. Chem. 1967, 10, 1039), and because of the role they may have on certain biochemical processes (Hu, Y. et al, Steroids, 1995, 60, 491). D-seco-estrone and D-seco androstene derivatives can be obtained in different ways. For the first time, when determining the structure of estrogen hormones (Marrian and Haslewood, J.Soc.Chem.Ind., 1932, 51, 279T), D-sec dicarboxylic acid of the gross formula C18H22O5 was obtained by treating estriol with alkalis. In the same way, estradiol and estrone give D-seco monocarboxylic acid (Heer et al., Helv.Chim. Acta, 1945, 28, 156).

Huffman et al. (J.Biol.Chem., 1952, 196, 367) isolated 3-methoxyestra-1,3,5(10)-triene-17-hydroxy-16-one with lead tetraacetate in acetic acid after 24 hours as the main product 3-Methoxy-17-oxo-16,17-seco-estra-1,3,5(10)-triene-16-carboxylic acid. D-secosteroids can also be obtained by Beckman fragmentation of oximes or their derivatives using dimethylsulfoxide and trifluoroacetic acids as reagents (Fenselau et al., J.Org.Chem. Soc. (C) 1956, 3887). D-sec cyano aldehyde in the androstene series was obtained by the action of p-toluenesulfonyl chloride at room temperature in pyridine (Miljković et al., J.Org.Chem. 1973, 38, 3585), and the corresponding derivative in the estrone series was obtained in good yield (Miljković et al., J.Org.Chem. 1977, 42, 2101), under similar conditions starting from 3-Methoxyestra-1,3,5(10)-trien-16-oximino-17P-ol.

Various 17-alkyloxy-, 17-acyloxy-, diarylhalogenarylalkyloxy-, arylsulfonyloxy-, alkylsulfonyloxy-16,17-secoestra-1,3,5(10)-triene derivatives were obtained using Beckman fragmentation under mild conditions (Pejanović et al., patent YU 46859; Petrović et al., Steroids 1990, 27, 276).

In our earlier work, 3|3,17P-dihydroxy-16-oximino-17-picolyl-5-androstene was synthesized (Miljković and Gaši, Chimica Chronica, New Series, 1980, 9, 325), which under very mild reaction conditions, using titanium trichloride in an acidic medium, gives a seco cyano derivative at room temperature 3P-hydroxy-16,17-seco-16-nitrile-17-keto-17-picolyl-5-androstene (Miljković and Gaši, Bull. Soc. Chim. Belgrade, 1981, 46, 263).

The compounds known so far have shown certain biological activities, which could be increased after certain modifications.

4. SOLUTION DESCRIPTION

For the above reasons, and based on the previous knowledge about the biological activity of this type of compound and the relationship between structure and biological activity, we synthesized a number of new compounds in the estrone and androstene series in the expectation that these new compounds will have improved biological activity, which was shown in the biological tests whose results we cite.

The subject of the invention are compounds 16-keto-17-substituted-estra-1,3,5(10)-triene and 16-keto-17-substituted-5-androstene derivatives of the general formula I in which R represents a methyl or benzyl residue, and X has the following structure:

where R2 is hydrogen, an alkyl radical with 1 - 4 carbons, an acid radical, an alkylsulfonyloxy radical or an aryl radical and the procedure for their preparation.

According to the invention, the 17-keto group of the 17-keto-16-oxime of the general formula III

where X has the aforementioned meanings,

the addition of RLi or RMgJ, where R has the aforementioned meaning, in tetrahydrofuran at a temperature of -20° to -10°C, whereby 16-oximino-17-substituted steroids of the estrone and androstene series of the general formula II are obtained

in which R, X and R2 have the aforementioned meaning.

The obtained compounds can be isolated and represent new biological compounds or they can be used as intermediates further in the process by treating them with acidic aqueous titanium trichloride, whereby the hydrolysis of the 16-oximino group into the corresponding 16-keto group occurs with the simultaneous migration of the R group from the 17a to the 17(3 position when obtaining 16-keto-17-substituted derivatives in both series, general formula I, in which R and X have the previously stated meaning.

The invention will be further illustrated by the following examples without intending to be limited thereto.

Example 1

3f!, l 7a- dihydroxy- 16- keto- l 7p- benzyl- 5- androstene

3β,17β-dihydroxy-16-oximino-17α-methyl-5-androstene (1 g) was dissolved in ethanol (100 ml). A solution of titanium trichloride (0.72 g of titanium is heated for one hour at the boiling point with hydrochloric acid (1:1, 72 ml)) and then n-hexane (20 ml) are added to the resulting solution. The reaction mixture is left at room temperature for 12 hours, poured into water, neutralized with aqueous sodium bicarbonate solution to pH 7 and extracted with ether. The organic layer is washed with water, dried and evaporated to dryness in vacuo. The obtained crude product was recrystallized from methanol to give pure 3β,17α-dihydroxy-16-keto-17β-benzyl-5-androstene (0.78 g; 81.2%), m.p. 185°-187°C.

Example 2

3- methoxy- 16- keto- 17a- hydroxy- 17f}- benzyl-estral- 3, 5(10)-triene

3-Methoxy-17α-benzyl-17|3-hydoxy-16-oxyminoestra-1,3,5(10)4riene (1.0 g) was dissolved in ethanol (240 ml) and a mixture of concentrated HCl and ethanol (1:1; 73 ml) and titanium trichloride solution (0.7 g of titanium was heated for one hour at the boiling point with hydrochloric acid/1:1; 71 ml/) and then n-hexane (40 ml) was added. The reaction mixture is left at room temperature for 18 hours, poured into water, neutralized with an aqueous sodium bicarbonate solution to pH 7 and extracted with ether. The organic layer is washed with water, dried and evaporated to dryness in vacuo. The obtained crude compound was purified by silica gel column chromatography (hexane : ethyl acetate /8:2/) and pure 3-methoxy-16-keto-17a-hydroxy-17P-benzyl-estra-1,3,5(10)-triene (0.57 g; 51%) was obtained.

Example 3

3fi, l 7a- dihydroxy- 16- keto- l 7fi- methyl- 5- androstene

3β,17β-dihydroxy-16-oximino-17α-methyl-5-androstene (1 g) was dissolved in ethanol (150 ml) and a mixture of concentrated HCl and ethanol (1:1; 30 ml) was added to the solution. A solution of titanium trichloride (0.6 g of titanium is heated for one hour at the boiling point with hydrochloric acid (1:1; 60 ml)) and then n-hexane (30 ml) are added to the resulting solution. The reaction mixture is left at room temperature for 12 hours, poured into water, neutralized with an aqueous sodium bicarbonate solution to pH 7 and extracted with ether. The organic layer is washed with water, dried and evaporated to dryness in vacuo. The resulting crude product was recrystallized from methanol to give pure 3β,17α-dihydroxy-16-keto-17β-methyl-5-androstene (0.83 g; 87.32%), m.p. 272°-275°C.

Example 4

3- methoxy- 16- keto- 1 7a- hydroxy- 1 7p- methyl- estra- 1, 3, 5(10)- triene

From 3-methoxy-17a-benzyl-17p-hydroxy-16-oxyminoestra-1,3,5(10)-triene (1.0 g), in the same way as in example 2, a crude product is obtained, which after crystallization from methanol gives pure 3-methoxy-16-keto-17a-hydroxy-17p-methyl-estra-1,3,5(10)-triene (0.8 g; 84.2%), wt. 185°-187°C.

Claims (2)

1. New 16-keto-17-substituted-estra-1,3,5(10)-trienic and 16-keto-17-substituted-5- androstene derivatives of general fonnule I in which R is a methyl or benzyl radical and X has the following structure where R2 is hydrogen, an alkyl radical with 1-4 carbons, an acyl radical, an alkylsulfonyloxy radical or an aryl radical. 2. Process for obtaining new 16-keto-17-substituted steroids of the estrone and androstene series of the general formula I, according to claim 1, where the 17-keto group of the 17-keto-16-oxime of the formula III in which X has the previously mentioned meaning, the addition of compounds of the type RLi or RMgJ, where R has the previously mentioned meanings, in tetrahydrofuran, at a temperature of -20° to -10°C, whereby a compound of the general formula II is obtained wherein R and X have the aforementioned meanings, characterized by the fact that it is further treated with acidic, aqueous titanium trichloride, during which the 16-oximino group is hydrolyzed into the corresponding 16-keto group with the simultaneous migration of the R group from the 17a to the 17p position when a 16-keto-17-substituted derivative is obtained in both series.