DK143448B - ANALOGY PROCEDURE FOR THE PREPARATION OF 13-ALKYL-D HOMOGONADIA - Google Patents

Description

(19) DENMARK (i®?) \ Ra /

^ (12) PUBLICATION MANUAL od 143448 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 859/77 (51) intCI.3 C 07 J 63/00 (22) Filing date 25 · Feb. 1977 (24) Race day 17 · Oct · 1975 (41) Aim. available Feb 25 1977 (44) Posted Aug 24 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) Master Application No. 4699/75

(30) Priority Oct 18 1974, 15989/74, CH

(71) Applicant F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, CH-4002 Basel, CH.

(72) Inventor Andor Fuerst, CH: Marcel Mueller, CH: Juerg Albert

Walter Gutzwiller, CH: Ulrich Kerb, DE: Rudolf Wlechert, DE.

(74) Plougmann & Vlngtoft's Patent Office · (54) Analogy for manufacturing®

Young of 15-alkyl-D-homogonadlene.

The present invention relates to an analogous procedure for the preparation of novel 13-alkyl-D-homogonadienes of the general formula I

OR17af5 CQ R13! Wherein R is (H, H) or (aH, β-O-acyl having not more than 7 carbon atoms), alkyl having not more than 7 carbon atoms, R represents acyl having not more than 7 carbon atoms; 10) position, which method is peculiar in that

a D-homosteroid of the general formula III

13 0

FRS

wherein R, R and the dotted line in the A-ring have the meaning given above, are reacted with a metal-organic-releasing group R and a won D-homosteroid of formula I wherein R p is hydrogen, if desired , be eschewed.

The term "acyl" in this specification refers in particular to organic acid residues, e.g. residues of alkanecarboxylic acids such as acetic acid, propionic acid, capric acid and valeric acid, or oxalic acid, succinic acid, citric acid or aromatic carboxylic acid residues such as benzoic acid.

Alkyl groups containing up to 7 carbon atoms can be straight or branched chain. Examples thereof are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred groups R are methyl and ethyl.

3 U3U8

A preferred class of compounds encompassed by Formula I are 13 such compounds wherein R is methyl or ethyl and the double bond in ring A sits in the 4,5-position. Furthermore, such compounds of formula I are preferred in which R is ethynyl or 80-chloro or chloroethynyl and R p is hydrogen.

Examples of compounds of formula I are: 17a3-Hydroxy-13-methyl-D-homogona-4,16-diene, 17aa-ethynyl-17afi-hydroxy-13-methyl-D-homogona-4,16-diene, 17aa- ethynyl-13-ethyl-17a3-hydroxy-D-homogona-4,16-diene, 17af} -acetoxy-17aa-ethynyl-13-ethyl-D-homogona-4,16-diene, 3 &, 17a3-diacetoxy-13 '-Methyl-D-homogona-4,6-diene, 3 | 3,17a | 3-diacetoxy-17aa-ethynyl-13-methyl-D-homogona-4,6-diene and 3 (3,17a3-diacetoxy) 17a-ethynyl-13-ethyl-D-hoinogona-4,6-diene.

The reaction of the 17α-keto group in a compound of formula XII with a metal-organic compound can be carried out in a manner known per se. The metal-organic compound may be a Grignard compound, e.g. ethynylmagnesium bromide or propynylmagnesium bromide, or an alkali metal organic compound, e.g. sodium, potassium or lithium acetylide, or vinyllithium.

The D-homosteroids of formula III used as starting material can be prepared as described in the Examples or by analogy therewith.

The compounds of formula I are hormonally active, e.g. is highly proactive. For example, they can used as cycle regulators. For this purpose dosages of 0.01 -0.1 mg / kg can be used. Furthermore, an androgenic effect can be observed.

The compounds prepared by the process of the present invention can be used in pharmaceutical formulations containing them in admixture with a pharmaceutically, organically or inorganically inert carrier suitable for enteral or parenteral application.

In contrast to the steroids described in Danish Patent Specification No. 132031, the compounds of formula I contain a double bond at the 16.17 position. The latter compounds are superior to the known compounds, so it has e.g. In the Clauberg test, it was found that 17aa-ethynyl-13 (3-ethyl-17a-hydroxy-D-homogona-4,16-diene (compound A in the table below), 33-acetoxy-17aa-ethynyl-13 ' ethyl 17a-hydroxy-D-homogona-4,16-diene (Compound B) and 38-ace-toxy-17a, 18-dimethyl-D-homoestra-4,16-diene-17aB-ol (Compound C) have more potent progestogenic effect than 17aa-ethynyl-13β-ethyl-D-ho-mogon-4-ene-17a-ol-3-one (D-homonorgestrel) The results are shown in the table below:

Compound Dose Mc Phail Index mg (for rabbits A 0.3 oral 2.5 0.1 oral 1.4 B 0.3 oral 2.2 C 0.1 subcutaneously 3.7 0.03 subcutaneous 2.9 D Homonorgestrel 0.3 Oral 1.3 0.1 Oral 1.0 Due to the particularly good effect exhibited by such compounds, preferred variants of the process of the invention are to prepare D-homosteroids of formula I wherein Rx is ethynyl that compounds of formula 13 I are prepared in which R is ethyl and the double bond of the A-ring is in the 4,5-position and that such compounds of formula I are prepared in which R .

The process according to the invention is further illustrated by the following examples: U3U8 5

Example 1.

To a solution of 2.6 g of 13-ethyl-D-homogona-4,16-diene-17a-one in 50 ml of absolute tetrahydrofuran is added 1.66 g of lithium acetylide-ethylenediamine coruplex and the mixture is stirred with continuous flow of acetylene. for 90 minutes at room temperature. For work-up, pour the mixture gently into 250 ml of water and extract three times with ether. The ether extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is chromatographed on 100 g of silica gel. With 95: 5 hexane-acetone elute 1.8 g of pure 17aa-ethynyl-13-ethyl-17a-hydroxy-D-homogona-4,16-diene, mp 95-97 ° C (ether-hexane), [α] D 19 -193 ° (c = 1.0 in dioxane).

The starting material can be prepared as follows:

To a solution of 3.14 g of 13-ethyl-3-methoxy-D-homogona-2,5 (10), 16-trien-17α-ol in 150 ml of methanol is added 10 ml of IN and 3 ml of concentrated aqueous hydrochloric acid. and stir for 12 hours at 25 ° C. The methanol is evaporated on a rotary evaporator and the aqueous residue is extracted three times with dichloromethane. After washing of the organic phases with hydrogen carbonate solution, drying over sodium sulfate and evaporation on a rotary evaporator, 2.9 g of 13-ethyl-17a mp 191 - 192 ° C.

4.0 g of 17a3-hydroxy-13-ethyl-D-homogona-4,16-dien-3-one is reacted with ethanedithiol in methanol and boron trifluoride etherate as catalyst to form 3,3-ethylenedithio-13-ethyl-17af3-hydroxy - D-homogona-4,16-diene, mp 156 - 158 ° C. This substance is dissolved in tetrahydrofuran, added to a mixture of 150 ml of liquid ammonia and 30 ml of tetrahydrofuran at -50 ° C and then reduced by the addition of 800 mg of lithium in 50 ml of liquid ammonia to amorphous 13-ethyl-17aP-hydroxy-D homogona-4,16-diene. 1.90 g of this substance is dissolved in 65 ml of acetone, cooled to 0 ° C and treated over 5 minutes with 2.0 ml of Jones reagent (CrO 3 in 8n h 2 SO 4). After recrystallization of the crude product 1.3 g of pure 13-ethyl-D-homo-gona-4,16-diene-17a-one, mp 78-79 ° C (methanol); [α] ρ5 = -10.1 ° (c = 1.0 in dioxane); ^ 225 = ^ 870 ·

Claims (3)

Example 2 Analogously to Example 1, 3β-acetoxy-13-ethyl-17α-hydroxy-17α-methyl-D-homogona-4,16-diene is prepared, mp 119-121 ° C, [α] = -103 ° (c. = 1.0 in dioxane). claims, 1. Analogous Process for Preparation of 13-alkyl-D-Homogonadiene of General Formula I 13 OR17ai3 R ILVcict represents H or acyl of not more than 7 carbon atoms, Rx represents alkyl of not more than 7 carbon atoms, ethynyl, 1-propynyl or chloro-ethynyl, and the dotted line in the A-ring represents an additional carbon-carbon bond of 4.5 - or the 5 (10) position, characterized in that a D-homosteroid of the general formula III O R13 j A '1 R III