CH626638A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids which have endocrine activity and the formula <IMAGE> in which R<18> is hydrogen or methyl; R<17a beta > is hydrogen, acyl, lower alkyl, cycloalkyl-lower-alkyl; benzyl, furfuryl or tetrahydropyranyl and R<17a alpha > is hydrogen, lower alkyl, aethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadiynyl or chloroethynyl, are prepared. They can be obtained by heating a corresponding 11-hydroxy-D-homosteroid-4,9(10),16-triene with an acid. Resulting compounds of the formula I in which R<17a beta > is hydrogen can be acylated, and those in which R<17a beta > is acyl can be hydrolysed.

Description

The invention relates to a process for the preparation of new D-homosteroids of the formula wherein R18 is hydrogen or methyl; R17afi is hydrogen, acyl, lower alkyl, cycloalkyl lower alkyl; Benzyl, furfuryl or tetrahydropyranyl and R17aa are hydrogen, lower alkyl, ethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadiynyl or chloroethynyl.

The term "acyl" is intended in particular to denote organic acid residues, e.g. Residues of lower (up to 7 carbon atoms) alkane carboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oenanthic acid; or oxalic acid, succinic acid, citric acid; or residues of preferably monocyclic aromatic carboxylic acids such as benzoic acid, phenylacetic acid, or phenoxyacetic acid; or heterocyclic carboxylic acids such as nicotinic acid or cycloaliphatic carboxylic acids e.g. Cycloalkylalkanecarboxylic acids such as cyclopentylpropionic acid, cyclohexylacetic acid, cyclopropylacetic acid; or cycloalkyl carboxylic acids such as cyclopropyl, cyclopentyl or cyclohexyl carboxylic acid.

Lower alkyl radicals can contain up to 7 carbon atoms and can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred lower alkyl radicals are methyl and ethyl.

A preferred connecting group within the formula I are the compounds in which RI7aa are hydrogen, methyl or ethynyl and R17ass is hydrogen, lower alkanoyl, lower alkyl or benzyl. Of particular interest are the 17a-hydroxy-D-homo-19-nor-17aa-pregna-4,9,11,16-tetraen-20-in-3-one and the 17ass-hydroxy-17a-methyl-D- homo-ostra-4,9, ll, 16-tetraen-3-one. Further examples of compounds of formula I are

13-ethyl-l 7 a-hydroxy-D-homo-18,19-dinor-17 aa-pre-gna-4,9, ll, 16-tetraen-20-in-3-one,

17 aβ-hydroxy-D-homo-19-noröstra-4,9,11,16-tetraen-3-

on,

13-ethyl-17ass-hydroxy-D-homogona-4,9, ll, 16-tetraen-3-one,

13-ethyl-17 a-hydroxy-17a-methyl-D -homogona-4,9,11,16-tetraen-3-one,

17ass-benzyloxy-D-homoöstra-4,9, ll, 16-tetraen-3-one,

13-ethyl-17ass-benzyloxy-D-homogona-4,9,11,16-tetra-en-3-one,

17ass-amyloxy-D-homo- 19-noröstra-4,9,11,16-tetraen-3 -

on,

13-ethyl-17-aß-amyloxy-D-homogona-4,9,11,16-tetraen-3-one,

17ass-acetoxy-D-homoöstra-4,9, ll, 16-tetraen-3-one,

13-ethyl-17ass-acetoxy-D-homogona-4,9, ll, 16-tetraen-3-one,

17ass- (CyclohexyI) methoxy-D-homo-19-noröstra-4,9, ll, 16-tetraen-3-one,

13-ethyl-17 aß- (cyclohexyl) methoxy-D-homo-19-norgo-na-4,9,11,16-tetraen-3-one.

According to the invention, the D-homosteroids of the formula I can be obtained by using a D-homosteroid of the formula

3rd

626 638

17 a (3rd

17aa il in which R18, RI7aa and R17a | ì have the meaning given, heated with an acid.

In the above process, a compound of formula II is reacted with an acid, e.g. a sulfonic acid such as p-toluenesulfonic acid, a mineral acid such as hydrochloric acid or preferably formic acid, whereupon a compound of the formula I having an unsaturated C ring is obtained (cf. DOS 1 618 810).

A 17a-free hydroxy group in a resulting D-homosteroid of formula I can be obtained by treatment with a reactive acid derivative e.g. an acid halide or acid anhydride in the presence of a base such as pyridine, collidine or 4-diethylaminopyridine.

A 17a-acyloxy group in a D-homostereoid of the formula I obtained can be obtained in a manner known per se, e.g. are saponified with aqueous-alcoholic bases, such as aqueous-methanolic potassium carbonate.

The starting materials for the preparation of the compounds of the formula I according to the invention, if they are not known or their preparation is described here, can be prepared by methods known per se or in analogy to the methods described below. The compounds of formula I are hormonally active. In particular, the compounds of the formula I in which R17aa represent unsaturated radicals have a progressive effect. For example, the 17a-hydroxy-D-homo-19-nor-17aa-pregna-4,9, ll, 16-te-40 traen-20-in-3-one in the Clauberg test at 50 mg / kg p.o. a McPhail value of 3.5; at 20 mg / kg s.c. a McPhail value of 2.8. Such connections are said to e.g. find use as an ovulation inhibitor. Compounds of the formula I in which Ri7aa is hydrogen or lower alkyl can be used as anrogen / anabolic agent. The 17ass-hydroxy-D-homoöstra-4,9, ll, 16-tetraen-3-one was found in the M. leva-

tor ani test with subcutaneous application about 3 times more active than testosterone propionate.

The process products can be used as healing agents e.g. in the form of pharmaceutical preparations which are used in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

example

1.0 g of 17ass acetoxy-11ß-hydroxy-D-homo-oestra-4,9,16-trien-3-one was dissolved in 15 ml of 60% aqueous formic acid and heated to 1000 for 15 minutes. The reaction mixture was poured onto ice water, neutralized with sodium hydroxide solution and extracted with methylene chloride. The organic extract was washed neutral with water, dried with Na2S04 and evaporated in vacuo. The residue was chromatographed on silica gel with benzene-ethyl acetate 2: 1. 0.6 g of pure amorphous 17ass acetoxy-D-homo-oestra-4,9, 11, 16-tetraen-3-one could be eluted, [a] D25 = -3270 (C = 0.1 in dioxane).

The starting material was produced as follows:

With a solution of 5.0 g 17ass acetoxy-D-homo-oestra-5 (10), 9 (ll), 16-trien-3-one in 50 ml abs. Ethanol and 0.05 ml of triethylamine were bubbled with an oxygen stream for 4 hours. The reaction mixture was cooled to 10 0 and the precipitate formed was filtered off with suction. This was washed with methanol, dried at 40 0 in vacuo. This gave 4.5 g of crude 17ass acetoxy-11ß-hydroperoxy-D-homooe-stra-4,9,16-trien-3-one, which was suspended in 30 ml of methanol with 2.5 ml of trimethylphosphite for 30 minutes at room temperature was stirred. The reaction solution was then poured onto a mixture of water and ice, which contained 5% by volume of perhydrol, left to stand at 00 for 20 minutes and then extracted with methylene chloride. Evaporation of the extract and chromatography of the crude product on silica gel gave pure 17a-acetoxy-11ß-hydroxy-D-ho-mo-oestra-4,9,16-trien-3-one.

C.

Claims (5)

626 638 2. The method according to claim 1, characterized in that compounds of the formula I are prepared in which R17aa is hydrogen or methyl and R17afi is hydrogen, lower alkanoyl, lower alkyl or benzyl. 2nd PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula wherein R18 is hydrogen or methyl; R17 is hydrogen, acyl, lower alkyl, cycloalkyl lower alkyl; Benzyl, furfuryl or tetrahydropyranyl and R17act are hydrogen, lower alkyl, ethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadienyl or chloroethynyl, characterized in that a D-homosteroid of the formula in which R18, R17act and Rl7ass have the meaning given, heated with an acid. 45 3. The method according to claim 1, characterized in that compounds of the formula I are prepared in which R17aa ethynyl and R17aP represent hydrogen, lower alkanoyl, lower alkyl or benzyl. 4. The method according to claim 1 for the preparation of a 17ass-acylated D-homosteroids of the formula I, characterized in that a 17ass-hydroxy-D-homosteroid of the formula I obtained is acylated. 5. The method according to claim 1 for the preparation of a 17ass-hydroxy-D-homosteroids of formula I, characterized in that a 17ass-acyloxy-D-homosteroid of 60 formula I obtained is saponified.