IE49180B1

IE49180B1 - Intermediate for use in preparing 17a-acetylene derivatives of androst-4-ene

Info

Publication number: IE49180B1
Application number: IE753/85A
Authority: IE
Original assignee: Roussel Uclaf
Priority date: 1978-07-13
Filing date: 1979-08-08
Publication date: 1985-08-21
Also published as: IE850753L

Description

This invention relates to an intermediate for use in preparing nev/ 17£><-ac.etylene derivatives of androst-^-ene, and tc a process for preparing the intermediate· Ia Paw speuikotim. Me.. 4^^ frcm which thia A^ca-ken is divided there are described and claimed compounds qf the general formula : wherein R~ represents an alkyl radical containing from 2 to 3 caroon atoms; R represents a saturated or unsaturated aliphatic hydrocarbyl radical containing from 1 to 12 carbon atoms, a trifluoromethyl radical, an aryl radical containing from 6 to 12 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms; Y represents a hydrogen atom, a fluorine atom or a methyl radical; and the dotted lines in the A and B rings represent optional second carbon-carbon bonds at tho 1(2) and 6(7) positions, with the proviso that when R^ represents a methyl radical 918 0 -2o R represents a saturated or unsaturated aliphatic hydrocarbyl radical and the B ring is saturated, Y represents a methyl radical.

Preferably substituent R^ represents a methyl or ethyl 5 radical, and a particularly preferred group of compounds of the invention comprises those compounds wherein represents a methyl radical.

When R represents a saturated hydrocarbyl radical, this is preferably a methyl, ethyl, n-propyl, isopropyl, ±0 n-butyl, isobutyl. n-pentyl, n-hexyl, 2-methyl-pentyl, 2,3-dimethyl-butyl, n-octyl or 2,2-dinethylhexyl radical, p 'When E represents an unsaturated hydrocarbyl radical, this is preferably a vinyl, isoorocer.yl·, isobutesyli allyl o or 2-methylallyl radical. When represents an aryl radical 2 this is preferably the phenyl radical and when ?. represents an aralkyl radical this is preferably the benzyl radical.

Among the compounds of the Parent invention particularlypreferred groups of compounds of formula I are those wherein the A ring is ethylenic unsaturated at the 1(2) position and those wherein the B.ring is ethylenic unsaturated at the 6(7) position.

Especially preferred compounds of general formula I are those wherein Y represents a hydrogen atom or a methyl radical.

A specific preferred conpound of the Parent invention is most especially 1.1 β , 17[3-dihydraxy-21-methyl--. 17<Χ— - pregna-1,Ί,6-trien-20-yn-3-one.

The Parent invention also provides a process for preparing - 3 the compounds of general formula I, in which a compound either of the general formula: or of the general formula: y (iv) 2 (wherein, in each case R ,R and Y are as defined herein5 before, K represents a blocked ketone function in the form of a ketal or oxime and L represents an alkyl group having from 1 to 12 carbon atoms) is reacted: either with an acid hydrolysis 3gent to obtain a compound -448180 of the general formula: 2 (wherein 5 , ?. and Y are as defined hereinbefore); cr with an agent capable of releasing the ketone function and of creating a Δ 4,6 double bond system to obtain a compound of the general formula: with an agent capable of releasing the ketone function and of creating a Λ 1,^,6 double bond system to obtain a compound of the general formula: 2 wherein R , R. and Y are as defined hereinbefore, When K represents a ketal group this is preferably either a cyclic alkylketal group having from 2 to 4 carbon atcns and especially a ethyleneketal or propyleneketal group, or a dialkylketal such as a dicethylketal or diethylketal group.

When K represents an oxime this is preferably an =;:CK or =K0alk group, alk representing an alkyl radical containing from 1 to a carbon atoms. 1C The alkyl group L preferably represents a methyl, ethyl or n-propyl radical.

The acid hydrolysis agent used in the preparation of compounds L· is preferably a mineral acid such as hydrochloric or sulphuric acid, an organic carboxylic acid such as acetic or citric acid, or a sulphonic acid such as paratoluenesul phonic ncid.

The agent capable of releasing the ketone function and of creating a Δ k,6 system used in the preparation of conpounds lg is preferably a derivative of js-benzoquinone such as 2,3~dicl'.loro-5j6-dicyanobpnzo -6acetone. However, it is also possible, to create a Δ4,6 system by a biochemical route - for example, by using the bacterium ArthrobacteT Simplex.

The agent capable of releasing the ketone function and 5 of creating a Δ 1,4,6 system used in the preparation of compounds Ις is preferably a derivative of p-benzoouinone such as chloranil or 2,3-dichlorc-5,&-dicyarobensoquinone, with the reaction taking place in benzene.

The starting materials of general formula III and IV 10 may conveniently be prepared by rea (V) (VI) Σ ara as defined he re inbefore) as appropriate with a compound of the general formula - 49180 -7TC — CR2 (VII) wherein R is as defined hereinbefore and T represents a lithium or potassium atom or a radical -HalMg, Hal representing a halogen atom.

When substituent T in general formula VII represents a 5 radical -HalMg, the halogen atom is preferahly a bromine atom The compounds of general formulae II, V and VI which are used as starting materials in the processes of the Parent in\rention are, in general, known compounds. They can be prepared, for example, by processes as described in French 1C Patents Nos. 1,359,611 and 1,222,^24 cr in U.S. Patents Nos. 5,010,957 and 5,072,684. -ethoxy-lig-hydroxy-6-methyl-androsta-3,5~dien-17-one, a compound of general formula VI, is however a new compound, and is the subject of· the present inventiony.15 The compounds of general formula I have interesting pharmacological properties, and especially have displayed remarkable anti-inflammatory activity, mainly when applied by topical route.

The compounds of general formula I may be useful in the treatment of polyarthritis, arthrosis and lumbar pains; they are of especial interest for the treatment of local inflammatory reactions such as oedema, dermatoses, pruritis, various forms of eczema and solar erythema.

The following Example illustrates the invention but docs not limit it. . 8 _ Example Preparation of 3-ethoxy-11-hydroxy-6-methyl-androsta-3 ι 5-dicn-17-one. 1.80 g of 1 yj -hydroxy-6pi-methyl-androst-4-ene-3,175 -dione were suspended in a solution containing 10 cm of ethanol and 2 cm of triethoxymethane. The suspension was agitated at 50°C under a current of nitrogen, then 0.25 cm of a solution containing 480 mg of paratoluenesulphonio acid in 50 cm^ of ethanol were added. After 5 o lo minutes 0.4 cmJ of triethylamine were added and the whole was cooled in an ice bath. Water was added drop by drop, and the formed precipitate was vacuum-filtered off, with .ι 7:3 mixture of ethanol and water and dried to obtain 1.66 g of the desired product. Rf = 0.55 (benzene/ethyl acetate , 1:1).

The product prepared as described above can be used to prepare compounds of formula (I) as described in Examples ό and8 of

Claims

1. CLAIMS'

1. 3-Ethoxy-11^3 -hydroxy-6-methyl-androsta-3,5-dien-17-one.

2. A process for the preparation of the compound according to claim 1, which process comprises reacting 11^-hydroxy5 -methyl-androst-A-ene-3,17-dione with triethoxymethane.

3. - A process for the preparation of the compound according to claim 1 substantially as hereinbefore described with reference to tho specific Example. A. The compound according to claim 1 when prepared by a 10 process according to claim 2 or claim 3·