IE49179B1 - 17a-acetylene derivatives of androst-4-ene - Google Patents

Description

(54) 17a-ACETYLENE DERIVATIVES OF ANUR0ST-4-ENE THE BRITISH LIBRARY OCT 1985 SCIENCE REFERENCE LIBRARY PATENT APPLICATION BY (71) R0USSEL.UCLAFj A FRENCH g0DY CORPORATE, OF 35 BOULEVARD DES INVALIDES, PARIS 7EME, FRANCE.

Price 9Op - 4 917B - -3a17a-acetylene derivatives of androst-4-ene This invention relates to new 17 In one aspect the invention provides the compounds of the sreneral formula: wherein R^ represents an alkyl radical containing from 2 to 3 carbon 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 1? carbon atoms; f represents a hydrogen atom, a fluorine atom or a methyl radical; and the dotted lines in the A and R rings represent optional second carbor.-carbon bonds at the 1(2) and 6(7) positions, wi th the proviso that when represents a methyl radical 48178 E represents a saturated or unsaturated aliphatic hydrocarbyl radical and the B ring is saturated, Y represents a methyl radical.

Preferably substituent R·1· represents a methyl or ethyl radical, and a particularly preferred group of compounds of the invention comprises those compounds wherein R1 represents a methyl radical.

When R represents a saturated hydrocarbyl radical, this is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. n-pentyl, n-hexyl, 2-methyl-pentyl, 2,3-dimethyl-butyl, n-octyl or 2,2-dimethylhexyl radical.

When R represents an unsaturated hydrocarbyl radical, this is preferably a vinyl, isoprorer.yl, isobutenyl.allyl 2 or 2-methylallyl radical. When S' represents an aryl radical 2 this is preferably the phenyl radical and vzhen E represents an aralkyl radical this is preferably the benzyl radical.

Among the compounds of the invention particularly preferred 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.

Specific preferred compounds of the invention are those compounds for which preparations are set out hereinafter in the Examples, and most especially lip,17p~dihydroxy- 49179 -5’ 17«-21-methyl-4)regna-l ,4,6-trien-20-yn-3-one.

The invention also provides a process for preparing the compounds of general formula I, in which a compound. t y (II) (wherein R^, Y and the dotted lines are as before), is reacted with a conpound of the HCSCR4* defined hereingeneral formula: p (wherein R is as defined hereinbefore) in the presence of a tertiary alcoholate, to obtain a compound of general formula I.

In a preferred embodiment of this process, for preparing l,R-dienes of general formula I, the starting product is a compound of the general formula: keeps the wherein R same meaning as above.

In a preferred method of carrying out the process tbe ' 48170 -zitertiary alcoholate is an alkali metal teributoxid e or a pcn+a-notaj! ter. ,such as sodium, potassium or lithium (ΜπΊα-ηβω* tenbutoxid e or ter.

The invention also provides an alternative process for 5 preparing the compounds of general formula I, in which a compound either of the General formula: or of the general formula: y (iv) P (wherein, in each case E ,H' and Y are as defined hereinbefore, K represents a blocked ketone function in the form 1θ 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 a When K represents a ketal group this is preferably either a cyclic alkylketal e~oup having from 2 to 4 carbon atoms and especially a ethyleneketal or propyleneketal group, or a dialkylketal such as a dimethylketal or diethylketal group.

When X represents an oxime this is preferably an =ROH or =ROalk group, alk representing an alkyl radical containing from 1 to 4 carbon atoms.

The alkyl group L preferably represents a methyl, ethyl or n-propyl radical.

Tbe 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 paratoluenesulphonic acid.

The afent capable of releasin- the ketone function and of creating a Λ 4,6 system used in the preparation of compounds Ig is preferably a derivative of p-benzoquinone such as 2,3-dichloro-5»6~dicyanobenzoquinone or chloranil, with the reaction taking place in an aqueous solution of -7ne'tor.e. Ηο-eve-, it is also possible, to create a ‘•'.,6 system by a biochemical route - for example, hy usin- the bacterium Arthrobacte Simplex.

The agent capable of eleasinr the ketone function and 5 of c-eating a 1 1,4,6 system used in the preparation of compounds Iq is preferably a derivative of p-henzocuinone such cs chloranil or r,3-dichloro“5,6-dicyar.obenzoouinone, with the epcricn taking place in benzene.

The starting materials of general formula III and IV 1C may conveniently hr prepared by reacting a compound either cf --ρ mene-'l formula: or c ° «-''r.e-a? formula: TC — 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.

Vhen substituent T in general formula VII recresents a 5 radical -HalMg, the halogen atom is preferably a bromine atom.

The compounds of general formulae II, V and VI which are used ps starting materials in the processes of the invention are, in general, known compounds. They can be prepared, for example, by processes as described in French 1C Patents Nos. 1,359,611 and 1,222,424 or in U.S. Patents ffcs. 5,010,957 and 3,072,684. *-ethoxy-lip-hydroxy-6-methy1-androsta-3,5~dien-17~one, a compound of general formula VI, is however a new compound, for which a preparation is described in detail hereinafter in the Examples. Furthermore, that compound is the subject of Patent Specification No. 4-91 #0 divided hsrefban.

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 rolyarthritis, 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 invention extends, therefore, to the compounds of 48178 -9formula I. as medicaments for line in treatment of the human or animal body, especially as medicaments intended for administration by a topical route.

Freferred medicaments are those classes of compounds 5 and specific compounds mentioned hereinbefore as being preferred.

Before using the compounds in medicine however, it is preferred to form them into pharmaceutical compositions, by association with suitable pharmaceutical vehicles, Accordingly, in a further aspect, this invention provides pharmaceutical compositions containing as active ingredient one or more compounds of general formula I, in association with a pharmaceutical vehicle.

The compositions of the invention preferably contain one or more of those compounds mentioned hereinbefore as beins preferred. * The description pharmaceutical is used herein to exclude any possibility that the nature of the vehicle, considered of course in relation to the route by which 2C tie composition is to be administered, could be harmful to the patient to be treated. The choice of a suitable vehicle is believed to be within the competence of those accustomed to the preparation of pharmaceutical formulations.

The compositions can be administered by a buccal, rectal, or parenteral route, or most preferably locally by topical application to the skin or mucous membranes. -10' 48170 The pharmaceutical vehicle may he, for example: a) the ingestible excipient of a tablet or pill, such as a plain or coated compressed tablet; the ingestible container of a capsule or cachet; the ingestible pulverulent solid carrier of a powder or granules; or the ingestible liquid medium of a syrup, solution or suspension; b) the solid or liquid medium of a paste, cream, ointment or gel, or the liquified propellant gas of an aerosol; c) a sterile injectable liquid solution or suspension medium; or d) a base material of a suppository.

Whilst the pharmaceutical vehicles just listed represent those most likely to be employed, they do not necessarily exhaust all possibilities.

The oharmaceutical compositions nay be prepared by known methods usinm excipients commonly employed in the formulation of pharmaceutical compositions. Such excipients may be solid or licuid as appropriate to the pharmaceutical form chosen, and may include a wide range of organic and ino-ganic solids, and aciueous and nonaqueous liquids; examples include talc, gum arabic, starch, lactose, magnesium stearate or fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These compositions may also contain one or more wetting, dispersing or emulsifying agents and/or one or more preservatives. -114917S The dosage of the active ingredient to be administered to a patient will of course vary with the compound concerned, the complaint and the patient being treated and the route of administration chosen. By way of illustration it may be said that a useful dose for an adult comprises from 1 to 4 applications daily of an ointment containing from 0.1% to % of the compound prepared in Example 2.

When the same compound is administered by oral route the dose may be, for example, rrom 1C mg to lg. -12The following Examples, Test Results and Formulation are now given, though only by way of illustration, to show certain aspects of the invention in more detail. 17«Bxample 1: 113173-dihydroxy-21-methyl-43regna-4,6-dien-20-yn~3-one 17«.Stage A s 5~ethoxy-113,173-dihydroxy-21-methyl-/pregna5,5~dien-2O-yn cm^ of a 0.75 M solution of ethyl magnesium bromide in tetrahydrofuran was cooled to 0°C, and propyne was bubbled in for two hours. The solution was allowed to heat up to ambient temperature. 3.4-5 E of 3-ethoxy-llg-hydroxy-androsta-3,5-dien-17-one (described in Belgian Patent No. 864,170) and 14 cm^ of dry tetrahydrofuran were added. The reaction solution was kept at from 20°C to °C for 45 minutes, then poured into a cold solution of ammonium chloride and extracted with ether. The ethereal phase was washed with a saturated solution of sodium bicarbonate, dried on sodium sulphate, and the solvent was evaporated off under reduced pressure to obtain the desired product, which was used in this form in the following stage. etStage B : 113.17fl-dihydroxy-21-methyl-£regna-4,6-dien-20-yn-3-one 17«4 g of 3-ethoxy-llp-17P-dihydroxy-21-methyl-X>regnaz -3,5-dien-2O-ynewas dissolved in 100 cur of acetone. cn^ of distilled water were added followed by 4.8 g of 2,3-dichloro-5,6-dicyanobenzoquinone, and the mixture was -1348179 agitated at ambient temperature for one hour. It was then poured into a saturated solution of sodium bicarbonate and extracted with methylene chloride. The organic phase was washed with a O.JM solution of sodium thiosulphate, dried on sodium sulphate and concentrated to dryness to obtain 3.8 r of a product which was chromatographed on silica (eluant: benzene/ethyl acetate, 5θ:5θ)· The product of Rf = 0.25 was isolated and purified by recrystallisation from diisopropyl ether to obtain the desired product, meltinp- at 200°C.

ANALYSIS : C22H2803 = 340.466 Calculated: 0% 77.6 8.29 Found : 77-8 8.3 17«EXANPLE 2: 1131173-dihydroxy-21-methyl-/pregna-l ,ί!, 615 -trien-20-yn-3-one Under agitation and under a current of nitrogen, a solution containing 3.7 g of 3-ethoxy-113,17p-dihydroxy17*- -21-methyl-^)regna-3,5-dien-2O-yne and 5θ cur of benzene was poured into a solution containing 6.8 g of 2-3-dichloro -5,6-dicyanobenzoquinone. After agitation for 25 minutes the mixture was washed with a saturated solution of aqueous sodium bicarbonate, then with a 0.5 H solution of sodium thiosulphate, and the organic phase was dried on sodium sulphate. The solvent was evaporated off under reduced pressure to obtain 2.75 g of a crude product which was chromatographed on silica (eluant: benzene/ethyl acetate, 49178 1450:50). 1.2 g of a product of Rf = 0.20 were isolated which were recrystallised from a mixture of diisopropyl ether, acetone and methylene chloride to obtain 819 mg of the desired product, melting at 216°C.

ANALYSIS Calculated Found θ22^26θ3 s 558.4-5 C% 78.07 H% 7-74 77.9 7.7 17«EXAMPLE 5: llg,17P-dihydroxy-21-phenyl-ypregna-l,4-dien-20-yn-3-one Under agitation and at ambient temperatue, 2.91 g of potassium tenbutoxitt.e and 2.75 cm^ of phenyl acetylene z were added to IOC cnr of dioxan. The agitation was maintained for one hour and then 3 g of Ιΐβ-'hydroxy-androsta-l,4-dien-3,17~4ione (prepared according to the process indicated in U.S. Patent No. 3,OIC,957) and 30 cm^ of dioxan were introduced. After agitation of the suspension thus obtained for 2 hours an aqueous solution of. acetic acid was added, and the mixture was diluted with water and extracted with methylene chloride. The organic phase was washed with a saturated solution of sodium bicarbonate and dried on sodium sulphate to obtain 4.25 B of a crude product which was chromatographed on silica (eluant: benzene/ /ethyl acetate, 6:4). 1.265 g of a product of Rf = 0.20 were isolated and recrystallised from a mixture of methylene chloride and diisopropyl ether to obtain the desired product, melting at 262°C. 40170 -15[aJD = -21° ί 2° (0.7%, CHClj) -17«*EXAMPLE 4: 113,173~dihydroxy-21-trifluoromethyl/pregna-1,A-dien-20-yn-3-one At -70°C under an atmosphere of nitrogen a solution containing 2.1 g of 113-hydroxy-androsta-l,4-diene-3,173 3 -dione, 35 cr/ of anhydrous tetrahydrofuran and 3.5 cm of hexamethylphosphotriamide was agitated.· A current of trifluoromethylacetylene gas was bubbled in, then drop by drop, a solution containing 3.4 g of 96% potassium 1C tenbutox ide, 70 cm'’ of tetrahydrofuran and 3.5 cra^ of hexamethylphosphotriamide was added. The product ohtained was poured into an aqueous solution of ammonium chloride, and the whole was extracted with diethyl ether. The organic phase was dried and the solvent was evaporated off.

The product obtained was chromatographed cn silica (eluant: benzene/ethyl acetate, 6:4) and 2.7 g of a product were isolated which were recrystallised from a mixture of diisopropyl ether and methylene chloride to obtain 2.248 g of the desired product, melting at 254-255°C. [cx]D = -6.5° ± 1.5° (0.7%, CHC1 ) 17: 113,173~dihydroxy-6a-21-dimethyl-7pregna-l,4-dien-20-yn-5-one Propyne was bubbled for 1 hour 30 minutes into a solution z containing 200 cm of tetrahydrofuran and 10.3 g of 96% potassium terhut oxide. The mixture was thereafter agitated 48179 16for a few hours and 20 cm^ of hexamethylphosphotriaraide were added. The mixture was brought to -15°C and at this temperature a solution containing.75 E °f 11β“ -hydroxy-6a-methyl-androsta-l,h-dien-3,17-dione in 60 cm^ of tetrahydrofuran (prepared according to the process indicated in French Patent 1,35^,611) was added, with agitation being maintained at -15°C for 4 hours.

The mixture was then poured into an aqueous solution of hydrochloric acid, extracted with diethyl ether, washed with water and dried to obtain 6.C5 g of a product which was purified by chromatography on silica (eluant: methylene chloride/acetone, 8:2), then a second time by chromatography on silica (eluant: benzene/ethyl acetate, 6:4). After recrystallisation from diisopropyl ether, 1.105 g of the desired product was obtained.

M.Pt. = 196°C. aD = -14° Ϊ 2° (0.%, CHC13) 17«*EXAMPEE 6: llB,17B-dihydroxy-6-21-dimethyl-/pregna4,6-dien-20-yn-5-one At 0°C, under agitation and under a current of nitrogen, a current of propyne was bubbled into a 1.15K solution of ethyl magnesium bromide in tetrahydrofuran. The solution was allowed to return to ambient temperature and agitated again for one hour thirty minutes. 6.3 g of 3-ethoxy-lip-hydroxy-6-methyl-androsta-3,5-dien-17~one (prepared as described hereinafter) were added, and agitation was -17maintained for one hour thirty minutes. The mixture was then poured into an aqueous solution of ammonium chloride, chilled and extracted with diethyl ether. The organic phase was washed with an aqueous solution of sodium bicarbo5 nate and dried. The solveit was evaporated off under reduced pressure to isolate 4.7 g of a product which was dissolved in a solution containing 100 cm'’ of acetone and 5 cm^ of water. 2.5 g of 2,3-diehloro-5,6-dicyanobenzoquinone were added. The reaction mixture was then poured into an aoueous solution of sodium bicarbonate and extracted with methylene chloride. The organic phase was washed, with sodium thiosulphate, dried on sodium sulphate and the solvent evaporated off under reduced pressure. After chromatography of the product obtained on silica (eluant: benzene/ethyl acetate, 1:1) 2.95 S of the desired product were obtained.

N.K.H. Spectrum : (CDCl^) 60 KHz CII5 = 81.5 Hz, 71.5 Hz, 110 Hz H at 270 Hz Ethylenic H at 352 Hz.

ANALYSIS : C H,„0, = 354.47 - 23 3° 3 Calculated: C% 76-76 H% 8.57 Found : 76.6 8.7 17aEXAKELE 7: llg,17g-dihydroxy-21-phenyl-/>regna-4-en-20-yn-3-one 3 Drop by drop, at 0 C, 7-2 cm of phenylacetylene were 48179 -18z added to a solution containing 40 cm of a 1.3E solution z of n-butyl lithium m hexane and 40 cur of anhydrous tetrahydrofuran. 3 g of 3-sthoxy-lip-hydroxy-androsta-3,5-dien-l?-one were then added and the mixture was agitated at ambient temperature for 17 hours, then poured into an aqueous solution of ammonium chloride and extracted with diethyl ether. After chromatography on silica (eluant: benzene/ethyl acetate, containing 0.2% of triethylamine) a product of Rf = 0.35 was isolated which was then treated for 30 minutes with a solution containing z z 125 co of methyl alcohol and 25 cnr of a normal solution of hydrochloric acid. The formed mixture was poured into water, ext-acted with methylene chloride and dried on sodium sulphate. The solvents were evanorated off and after purification by chromatography 1.1 g of the desired product we-e obtained. a?° = -4° ί 20 (c = C.7% CHCl^) 17«EXAKPLS 8: 11β,173-dihydroxy-6,Ql-dimethyl-7p-egna-1,4,6-trien-20-yn-3-one Propyiie was bubbled at 0°C, under agitation for 30 minutes and under a current of inert gas, into a 1.15M solution of ethyl magnesium bromide in tetrahydrofuran.

The temperature was allowed to rise again, with the bubbling-in maintained for 1 hour 30 minutes. 4.5 g of 3-ethoxy-lip-hydroxy-6-methyl-androsta-3,5-dien-17~one were added and the reaction mixture was agitated for ' 4917© -191 hour at 20°C, then poured into an aqueous solution of ammonium chloride at 0°C and extracted with diethyl ether. The organic phase was washed with an aqueous solution of sodium bicarbonate and dried. The solvent was evaporated off to obtain 4.3 g of a product which was dissolved in X cm of benzene. To this was added a solution of 9 g of z 2,3-dichloro-5,S-dicyano-benzoquinone in 200 cjjr q£ benzene, and the whole was agitated for 3θ minutes at ?0°C. The reaction mixture was then poured into an aqueous solution of sodium bicarbonate and extracted with ether. (Phe organic phase was washed with a 0.5 N solution of sodium thiosulphate, then with a solution of sodium bicarbonate, dried and the solvent evaporated off to obtain 3-4 g of crude product which was chromatographed on Silica, eluting with a mixture of benzene and ethyl acetate (3:7)· 2.95 g of the desired product were obtained and recrystallised from methanol. K.Ft. = lzi8°C ANALYSIS : C23H?gC5, UeCH Calculated: C% 74.97 H% 8.39 Found : 75-5 8.4 Ι.Γ. Spectrum (CHC1^) Presence of OH, -C—C-CS^, C = 0 (1660 - 1653 cm-1) c = c (1608 cm-1) U.V. Spectrum (EtOH) Fax. 228 nm (ε = 12 700) Infl. 250 nm (ε = 8 600) Kax. 504 nm (ε = 10 700) -20Preparation of 3-ethoxy-llS-hydroxy-6-methyl-androsta-3,5-dien-17-one, used in Examples 6 and 8 1.80 g of 113-hydroxy-6a-methyl-androst-4-ene-3,17-dione were suspended in a solution containing 10 cur 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 paratoluenesulphonic acid in 5θ cm of ethanol were added. After 5 minutes 0.4 cm^ of triethylamine were added and the whole was cooled in an ice hath. Water was added, drop hy drop, and the formed precipitate was vacuum-filtered off, with a 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).

TEST RESULTS: Pharmacological study of the compounds prepared in Examples ? and 4, referred to hereinafter as compounds A and P respectively Compounds A and 3 were used in an aqueous dispersant containing 0.25;' of carboxymethylcellulose and 0.20% of Folysorbate 80. 1. Study of the anti-inflammatory activity by oral route.

The anti-inflammatory activity was investigated according to the standard granuloma test.

In the technique used, a modification of the method of H. HEIEi·. and Colleagues (Experientia, 1^50 , 6 , 469), conventional female Wistar rats weighing from 100 to 110 g -21received .an implant of two pellets of cottonwool, each of 10 mg, beneath the skin of the thorax; the oral treatment, which begins immediately after this implantation, lasted for two days, at the rate of two administrations per day, Sixteen hours after the last ingestion - that is, on the third day - the animals are sacrificed.

The pellets, surrounded by granuloma tissue fopined, were weighed whilst fresh, then after standing for eighteen hours at 60°C. The weight of the granuloma was obtained by deduction of the initial weight of the cottonwool.

The results, expressed in terms of AD 5θ (that is to say, the dose causing an inhibition of the granuloma by 50/=), are as follows : AD 50 Compound A 10 mg/kg Compound B 4 mg/kg CONCLUSION: Compounds A and B have pood activity when they are administered by oral route. 2C 2. Study of the dermal activity The dermal activity was investigated by the test of oedema caused by croton.

The technique employed was inspired by that of TONELLI et al. (Endocrinology 1965 22» Ρ·625): oedema 25 is caused in the mouse by application of croton oil to -22I an ear. Mice were divided into two batches.

- To the mice of the first batch a solution of croton oil was applied to the right ear.

- To the mice of the second batch a solution of croton oil mixed with compound A or B was applied to the right ear.

- No active material was arplied to the left ears of the mice.

At the end of six hours the ears were cut off and weighed. The difference in weight between the right ear and the left ear gave the degree of inflammation.

The results below are expressed in terms of AC 50 (active concentration which reduces by half the oedema caused by the croton oil in the controls).

AC 50 Compound A 0.07 sg/kg Compound B 0.3 mg/kg CONCLUSION: Compounds A and B have remarkable activity when administered by local route Formulation: Ointment An ointment for topical application was prepared from the following: Compound A............................1.5 g Excipient q.s.v. ...........100 g Details of the excipient : lanolin and Vaseline! T+ade. Merfc),

Claims (28)

1. The compounds of the general formula: 1 to 3 carbon atoms; R represents a saturated or unsaturated aliphatic hydrocarbyl radical containing from 5 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 E rinses represent optional 1C second carbon-carbon bonds at the 1(2) and 6(7) .positions, with the proviso that when 3^ represents a methyl radical, f represents a saturated or unsaturated aliphatic hydrocarbyl radical and the P ring is saturated, Y represents a methyl radical. 15 2. A compound as claimed in claim 1, wherein R^ represents a methyl radical. 3. A compound as claimed in claim 1 or claim 2, wherein 3 represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, 2-methyl-pentyl,

2. C 2,

3. -dimethyl-butyl, n-octyl, 2,2-dimethylhexyl, vinyl, -2449479 isopropenyl, isobutenyl, allyl, 2-methylallyl, phenyl or benzyl radical

4. A compound as claimed in any of claims 1 to 3, wherein the A ring is ethylenically unsaturated at the 1(2) position.

5. 5- A compound as claimed in 'my of claims 1 to 4, wherein the B ring is ethylenically unsaturated at the 6(7) position.

6. A compound as claimed in any of claims 1 to 5, wherein Y represents a hydrogen atom. 1C

7. - A compound as claimed in any of claims 1 to 5» wherein Y represents a methyl radical. 17ct

8. 11β, 17,3-hihydroxy-21~methyl-4)regna-l,4,6-trien-2C-yn-3-one.

9. - A process for preparing the compounds of general formula I, in which a compound of the general formula: (II) defined in general the presence claim 1) is reacted with a compound of the formula: HC aCH 2 (wherein fr is as defined hereinbefore) in 20 of a tertiary alcoholate, to obtain a compound of general formula I.

10. A nrocess as claimed in claim 9» in which the -2549179 starting material is a compound of the general formula:

11. A process as clained in claim 9 or claim 10, in which the tertiary alcoholate is an alkali metal tenbutoxide or |x τΛα-ηοΡοίβ 5 ter,

12. A process for preparing the compounds of general formula I, in whi'h a compound either of the general 4BIV9 -26claim 1, K represents a blocked ketone function in the form of a ketal or oxime and L represents an alkyl groun having from 1 to 12 carbon atoms) is reacted: either with an acid hydrolysis agent to obtain a compound 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: ι p 10 (wherein fi , R and Y are as defined in claim 1); or with an a~ent capable of releasing the ketone function and of creating a Δ 1,4,6 double bond system to obtain a. compound of the general formula: -2748179 C=CR?· 1 2 wherein R , R and Y are as defined in claim 1

13. A process as claimed in claim 12, in which K represents a cyclic alkylketal group having from 2 to 4 carbon atoms or a dialkylketal. 5

14. A process as claimed in claim 13, in which K represents a ethyleneketal, propyleneketal dimethylketal or diethylketal group.

15. A process as claimed in claim 12, wherein E represents an =ΚΟΗ or =TiOalk group, alk representing an alkyl radical 10 containing from 1 to 4 carbon atoms.

16. A process as claimed in claim 12, wherein L represents a methyl, ethyl or n-propyl radical.

17. A process as claimed in an;z of claims 12 to 16, in which the acid hydrolysis agent used in the preparation of 15 compounds is hydrochloric, sulphuric,acetic, citric or paratoluenesulphonic acid.

18. A process as claimed in any of claims 12 to 16, in which the agent capable of releasing the ketone function and of creating a Δ 4,6 system used in the preparation of 2C compounds Ι β is 2,3 - dichloro-5,&-dicyanobenzoquinone or chloranil, with the reaction taking place in an aqueous -28solution of acetone.

19. - A process as claimed in any of claims 12 to 16, in which the agent capable of releasing the ketone function and of creating a Δ 1,4,6 system used in the preparation of compounds Ιθ is chloranil or 2,3-dichloro~5,65 -dicyanobenzoquinone, with the reaction taking place in benzene.

20. A process as claimed in any of claims 12 to 19, in which the starting material of general formula III or IV is prepared by reacting a compound either of the general 10 formula: with a compound of the general formula: TCSCR 2 - 29 2 wherein R is as defined in claim 1 and T represents a lithium or potassium atom or a radical -HalMg, Hal representing a halogen atom.

21. A process as claimed in claim 20, wherein when T 5 represents -HalMg, Hal represents a bromine atom.

22. A process for preparing a compound of general formula I defined in claim 1, substantially as described herein with reference to any one of the Examples.

23. A compound of general formula I as defined' in claim 1 W whenever prepared by a process as claimed in any of claims 9 to 22.

24. The compound of general formula I defined in claim 1, for use in therapeutic treatment of the human or animal body . 15

25. A compound as defined in any of claims 2 to 8, for use in therapeutic treatment of the human or animal body.

26. Pharmaceutical compositions containing as active ingredient one or more compounds of general formula I defined in claim 1, in association with a pharmaceutical 20 vehicle.

27. A composition as claimed in claim 26, in which the active ingredient is or includes one or more compounds as claimed in any of claims 2 to 8.

28. A pharmaceutical composition substantially as 25 described herein with reference to the Formulation. Dated this 8th day of August, 1979.