IL31443A - 3-cyclopentyl ethers of gonatrienes and tetraenes,their preparation and pharmaceutical compositions containing them - Google Patents

Description

31443/3 oni» o^aon ninp i *»n*wani onaan 3-Cyclopentyl others of gonatrlenes and tetraenes, their preparation and pharmaoeutloal compositions containing them AMERICAN HOME PRODUCTS CORPORATION 0. 29732 31443/2 This invention relates to gonatrienes and gonatetraenes and more particularly to certain novel 3-cyclopentyl ethers of gonatrienes and gonatetraenes, to processes for preparing, them and pharmaceutical compositions containing them. In particular, it is concerned with certain 13-methyl or ethyl-3-cyclopentyloxy gona-1 , 3 ,5 ( 10) , 8-tetraenes ; 13-ethyl-3-r'cyclopentyloxy-8a-gona- 1 , 3 » 5 ( 10 )-trienes ; 13-ethyl-3-cyclope.ntyloxy-l6oc-hydroxygona- 1 , 3 , 5 ( 10)-trienes 13-ethyl-3-5yclopentyloxy ona-1 , , 5 ( 10 )- trienes; and 13-ethyl-3-cyclopentyloxy-gona-l,3,5(lO) ,16- as 3144;i/2 - 3 i whic B?~ is a methyl or ethyl group, Z is a carbonyl or hydroxymethylene group, R is a lower alkyl, ethy.yl or 2 ¾ chloroethynyl group and R is a lower alkanoyloxy {roup. As employed herein, the terms "lower alkyl" and "lower alkanoyloxy" mean moieties containing from one to eight carbon atoms. Typical examples of the compounds of this invention are: 3-cyclopentyloxy- 13P-ethyl-8oc-gona-l, 3 ,5(10)-trien-17-one ; 3-cyclopentyloxy-13P-ethyl-17a-ethynylgona-l,3,5(10)-trien-16a,17 -diol; and 17a-chloroethynyl-3-cyclopentyloxy-13 -e hylgona-l , 3 , 5 10) -ΐΓΐβη-Γ7β-ol.

. The novel 3-cyclopentyloxy steroids of th; present invention may be prepared by the process which comprises (1) reducing a 3-cyclopentyloxy steroid of general formula in which (a) 2 has the meaning given above, the dotted line 1 ' indicates a double bond in the' 14-position and. R is methyl or ethyl, to give a 3-cyclopentyloxy-gona-13 -methyl or ethyl- . l,3t5(10),8-tetraen-17-one or 17-ol, or (b) Z has the meaning ! givenabove, the dotted line indicates an optional double bond in the 14-position and R is ethyl to give a 3-cyclopentyldxy-13P-ethyl-gona-l,3,5(lO)-trien-17-one or 17-ol, or a 3-oyclopentyloxy- ; AHP-* 5^2-f etherifying with an etherifying agent containing the cyclo pentyl group the 3-hydroxy group of a 3-hydroxy steroid of general formula 1 A to F where X has one of the meanings /given above for X or is or required and if desired/ oxidising a resulting 17-ol to a 17-ketone, reducing a 17-ketone to a 17-ol, alkylating, ethynylating or chloroethynyl-ating a 17-ketone to a 17a-alkyl, ethynyl or chloroethynyl-17P-ol, enol acylating a 17-ketone to a ^^.-17-alkanoyloxy compound, or oxidising a ^"^-17-alkanoyloxy compound to a l6a-hydroxy- 17-ketone or l6a,17-diol„ It is to be understood that in the above procedures any keto group in the 17-position or hydroxy group in the l6 and/or 17-position may be protected by formation of a suitable derivative and the protecting group removed subsequently,.

Depending upon the reaction conditions, reduction of the gona-pentaene or gonatetraene steroid of formula (II) can give a gona-1,3,5(10) ,8-tetraene, a gona-1,3, 5 ( 10)-triene or an 8a-gona-1,3, 5(10) -triene. For example catalytic hydrogenation of the gonapentaene or gonatetraene provides an 8a-gona-l,3,5(lO)-triene while a gona-1, 3, 5(lO) ,8-tetraene can be obtained by catalytic reduction of the gona AHP-^^-f of hydrogen has been absorbed,, A gona-l,3,5(lO)-triene may be obtained by reducing the gonatetraene with, for example, an alkali metal in liquid ammonia0 The etherification of the 3-hydroxy steroid (III) may be effected by, for example, contacting the steroid (III) with a cyclo- pentyl halide, in the presence of an alkali metal alkoxide, e.g. sodium methoxide and potassium ethoxide in an alkanol, e.g. methanol, ethanol and isopropanol, at a temperature range from about 50°C. to about reflux temperatures for a period of about one to about five hours. Preferably, this reaction is conducted with cyclopentyl bromide, in the presence of sodium methoxide, in absolute ethanol at reflux temperatures0 When the reaction is complete, the resulting 3-cyclopentyloxy steroid may be separated by standard recovery procedures. For example, the reaction mixture may be cooled, concentrated, digested with a water-immiscible organic solvent mixture, then the organic layer dried, evaporated to dryness and the residue recrystallised from a suitable solvent to afford the product.

Where the product of the reduction process (1) or the ether- ification process (2) is a compound of formula (I) other than the desired compound or is a compound of formula the desired compound of formula (I) may be obtained by a subsequent after-process„ For example, the 3-cyclopentyl ethers of 13-poly- ethyl earbonalltyigonatrien-17~ols and 13-polycarbonalkylgonatetraen-17- ols may be prepared by the reduction of the corresponding 3-cyclo- carbohalkylgonatetraen-17-onesi. This reaction may be effected by con-jQicting an appropriate 3-cyclopentylether of a 13-ethyl-alk lgonatrien-17--one: or 13-ethylgonatetraen-17~one with an alkali ratal borohydride, .g. in an alkanol at about room t empera-ture fo several hours. When the reduction is complete, the resul in; product may be separated by conventional procedures. For example, the reaction mixture is admixed x/ith water to precipitate the product which is then collected by filtration and recrystalljse from a suitable solvent, e.g» an alkanol. ¾ .·.'. .3-cyqio ©ntyloxy-17 k©to steroid of formula (I) can be obtained from the corresponding 17-hydroxy steroid by an oxidation, for exanple, by an Oppenauer oxidation.

The 3-cyclopontyloxy-17a-ethynyl-13-methyi or ethyl-l,3,5(lO),a-tetraen*-17P-"Olsi the 13-ethyl-3-cyclopentyloxy-17a-ethynyi-Sa-gona-l, ,5 (I0)-trien-r#-ol J the 13-ethyi-3-cyclo-'pentyloxy-17a-©thynylgona-l 3,5 (10)-trien-16a,17^-diols ; and the i3-ethyl-3-cyclopentyloxy-17c~ethynyigona-l,3»5(10)~trien-17P-ols of this invention may be prepared by ethynylating (e.g. withlan organoroetfillic ethynyl compound) the corresponding 17-keto-steroid. The 17-keto, steroid may be contacted with an excess Of lithium acetylide-ethylene diamine in dry dimethylsulphoxide under an atmosphere of acetylene at about room temperature for a period of about fifteen minutes to about four hours. When the reaction is complete* the appropriate 17a-ethynyl-17^~hydroxy-storoid may be separated by routine methods. For example, the reaction mixture may be poured into ice-water, extracted with a water-immiscible solvent, which is then washed, dried and evaporated to dryness to afford the product as a residue.

In particular certain 3-cyclopentyloxy steroids of this invention, which have a 17a-ethynyls a 17x-chloroethynyl or a 17a-lower alkyl substituent have been shown to exhibit utility as oestrogenic agents in standard pharmacological tests0 Surprisingly it has been found that many \ thf.se 3-cyclopentyl ethers of the invention especially ¾3^«gt¾iyl roTnpxranchEr, of formula (I) where X is (C) or (F) ehow an oestrogenic response of prolonged duration„ Compounds in which X is (C) belong to the general class of steroids disclosed in U0K0 Specification No„ Ι,ΙΙΙ., +7 and those of formula (F) belong to the general class of steroids disclosed in U0K0 Specification l„01fli)277o Specification 101119 *7 doee not suggest prolonged oestrogenic activity and Specification merely proposes its compounds ae intermediates for other steroids„ One pharmacological test in which oestrogenic activity of prolonged activity was demonstrated was carried out as follows: Spayed rats are administered 1 mg<, of compounds on day 0 and vaginal smears are taken on the afternoon of successive days,, The proportion of rats responding with cornified vaginal smears is increased by active compounds„ Prolonged duration of activity is shown by compounds exhibiting positive smears at least several days from day 00 In this procedure dl-3-cyclopentyloxy~13P-ethyl~17a°-ethynylgona- (Compound I)s dl-3-cyclopentyloxy-17a-chloro-ethynyl-13 -ethylgona-l,3,5(10)-trien-17P-ol (Compound II) and dl-3-cyclopentyloxy-13P-ethyl-17a-ethynyl-8a=gona-l¾3s5(lO)"=trien'=17P- 01 (Compound III) produced the data in the following tables Long-term Rat Vaginal Smear Test No. of positive smears out of total of 5 pe Compound 0 1 2 3 if 5 6 7 8 9 10 11 12 13 I 0 0 0 0 if 5 5 2 3 1 3 3 3 1 2 II 0 0 0 1 if 3 if 5 1 0 . 0 3 3 3 2 III 0 0 0 0 5 5 1 0 3 1 if 3 3 2 2 AHP-^2-f Many of the compounds of the present invention are of particular value as oestrogenic agents because they exhibit excellent oestrogenic response, have a rapid onset of action, long lasting effect and low activity. Many show the long lasting oestrogenic activity when orally administered,, As oestrogenic agents, the 3-cyclopentyloxy steroid compounds of this invention of formula (I) where X is (A), (C), (E) or (F) are medicinally useful in replacement therapy in oestrogen deficiency0 They may also be employed in prostatic carcinoma and inoperable mammary carcinoma, especially in postmenopausal women,. Further, they may be used in chlorinoepithelioma, urinary bladder malignancy, senile sebaceous adenoma of the skin, suppression of lactation, prophylaxis and treatment of mumps orchitis, treatment of atherosclerosis and senile osteoporosis,. For veterinary purposes, the 3-cyclopentyl-oxy steroids of this invention may be used in replacement therapy for underdeveloped females; incontinence, vaginitis of spayed bitches, in uterine inertia, pyometra and in retained fetal membranes<> The compounds of the invention in which X has the structure (B), (D) or (Q) are useful as intermediates for the preparation of the 17ct-ethynyl, 17a-chloroethynyl or l?a-lower alkyl derivatives in which X is (C) or (E) „ The pharmaceutical preparations of the invention are ones comprising a compound of structure I in which X is (A), (C), (E) or (F) in association with a pharmaceutically acceptable carrier. Such a preparation is prepared by a process in which the compound is mixed or otherwise brought into association with a pharmaceutically acceptable carrier„ The compounds may also be administered alone„ When administered in combination with pharmaceutically acceptable carriers, the proportion of carrier is determined by the solubility and chemical AEP- 5 2~f pharmacological practice0 For example, the compounds may be ( administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay, and so fortho They may also be administered orally in the form of solutions which may contain colouring and flavouring agents or "they may be injected parenterally0 For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonico The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen0 Furthermore, it will vary with the particular subject under treatment Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound0 Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached,, In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 0„02 mcgm. to about 500 mcgm*> per kilo per day, although as aforementioned variations will occur and it may be desirable to employ a dosage level of more than 500 mcgm0 per kilo per day. However, a dosage level that is in the range of from about Oo 0 mcgm0 to about 200 mcgm0 per kilo per day is most desirably employed in order to achieve effective resultso The following Examples illustrate the invention., EXAMPLE I diss ethanol (50 mlo), cyclopentyl bromide (2„5 g°) is added and the AHP-^5½-f ethanol removed in vacuo and the residue digested with water and ethyl acetateo The organic layer is washed with water, brine and dried over anhydrous sodium sulphate.. After filtration the solvent is removed in vacuo and the residue treated in tetrahydro-furan solution with Nuchar charcoal,, After filtration through supercel the solvent is removed _in vacuo and the residue dissolved in ether0 After standing the mixture is filtered, the ether removed from the filtrate in vacuo and the residue recrystal-lised from isopropanol. The crystals are filtered off to obtain loOO g0 of ∞3-cyclopentyloxy-13 -ethylgona-l,3, lO)~triene-l6a, l? -diol as an isopropanol solvate, m„p. 99-100 C; 3,13 V·» ΓΠΟ.Χ Analysis ; Calcd for C^H^O^C^HgO: C, 75 «31; H, 9»83» Found; EXAMPLE II dl-13P-Ethyl-3-hydroxy-8a-gona-l,3,5(lO)-trien-17=one (6„00 g0 ) is dissolved in a solution of sodium methoxide (lo30 g0 ) in absolute ethanol (260 ml0) and stirred at reflux temperature to completely dissolve the solidso Cyclopentyl bromide (7oO g0) is added and the mixture refluxed for four hourso After cooling, the ethanol is removed in vacuo and the residue digested with water and ethyl acetateo The organic layer is washed with water and brine then dried over anhydrous sodium sulphate, filtered, the solvent removed in vacuo and the residue dissolved in benzene0 The solution is passed through a column of Florex XXS, the solvent removed in vacuo and the residue dissolved in chloroform,. The solution is passed through a column of silica gel, the solvent removed in vacuo and the residue crystallised from methanol to obtain 3<>78 go of the product0 A sample (loOO g0 ) is dissolved in methylene chloride, treated with ΑΗΡ« '2 -f with isopropanol by boilingo The solution is seeded and allowed, to stand to obtain 0.89 g. of the pure dl-3-cyclopentyloxy-13P-. ■ ethyl-8o-gona-l,3,5(lO)-trieni-17-one, m.p, 133-131*0», λ Jjj^ .78 μ. Analysis; Calcdo for C^H^! C, 81.77 ; H, 9.17.

Found: C, 81.62? H, 9.00» . ' ' . ■■ ·. '■ · . - » EXAMPLE III . \ . dl-3-Cyclopentyloxy-13P-ethyl-8<x-gona-l, 3 ♦ 5 ( 0)-trien~17~one (2o00 g„) is added to methanol (150 ml,'), the mixture stirred and eodium borohydride (2.0 g.) in small portions is added to the reaction over a period of one hour. The reaction is stirred at room i temperature for a further two hours then water (200' ml.) ie added dropwise to completely precipitate the product., The solid is , filtered off and dried and then dissolved in methylene chloride, treated with Nuchar charcoal, filtered through superoel and the solvent removed in vacuo. The residue is dissolved in methanol then water is added' dropwise with stirring to precipitate the product. The product is recovered by filtration and dried to obtain 1.27 g. of dl-3-cyclopentyloxy-133-ethyl-8a m.po 100-101 Ci A max 3.02 μ. Analysis; Calcd. for C^tt^O^.

C, 6Ί 8 H, 9 8, EXAMPLE IV · i ^-3-Cyclopentyloxy~13P»-ethylgona-l,3,5(10)-trier) ' 17«»one (3.00 g) is dissolved in dry dimethylsulphoxide (80 ml.) and saturated with purified acetylene by bubbling the gas through the for half an hour.. Lithium acetylide-ethylene diamine (1.5 g.) is added and 3 43/2 ί , the reaction stirred under an atmosphere of acetylene at room temperature for one and a half hours, A further quantity of lithium acetylide-ethylene diamine (1,5 g.) is added and the reaction stirred for another one and a half hours* The reaction mixture is poured onto ice and the mixture extracted with ether-ethyl acetate and the extract washed with water and brine,. The solution is dried over anhydrous sodium sulphate, filtered and the solvent removed in yacuo, The .oil is dissolved in benzene, the solution passed through a column of Florex XXS and the solvent , removed in vacuo to obtain 1„75 g» of dl-3-cyclopentyloxy-13P-ethyl- ■ , 17a-ethynyle0na-l93,5(10)-trien-17P-ol; 3.0 and 3,1 EXAMPLE V I dl-13P~Ethyl-17-methylgona-ls3,5(10)-triene-3s17P diol (5.00 g) is dissolved in a solution of sodium methoxide (l„50 g„ ) in absolute · ' ethanol (100 ml.), cyclopentyl bromide (5,0 g.) added and the mixture; refluxed for two hours. After cooling the solvent is removed in i vacuo, the residue digested with water and ethyl acetate; the organic ! layer is washed with water and brine and then dried over anhydrous sodium sulphate. The mixture is filtered and the solvent evaporated in vacuo to afford dl-3-cyclopentyloxy-133-ethyl- 7a-methylgona-l , 3 , 5 (10)-trien-17p-ol .

In like manner, dl-13 , 17a-diethylgona-l,3 , 5(iO)-triene-3 ,173 diol is converted to dl-3-cyclopentyloxy-»13t3'.17g-diethylgona-1, 3 , 5 (10)-trien-17P-ol.

EXAMPLE VI dl-3-Cyclopentyloxy-13P-ethyl~8a-gona-ls3,5(10)-trien-17-one ' AHP-45½-f purified acetylene gas is bubbled through the stirred solution, for forty-five minutes. · Lithium acetylide-ethylene diamine . ( 2 o 0 go ) . is added and the mixture stirred under acetylene at room temperature for two hours. The reaction mixture is poured into water, the resulting solid filtered onto super eel and the mixture air dried. The mixture of solids is extracted with methylene chloride, filtered and the solvent removed in vacuo0 The resulting oil is dissolved in l s l-hexane-benzene mixture and the solution, passed through a column of Florex XXS and the solvent then removed in vacuo o The resulting oil is dissolved in hexane and the above treatment repeated to obtain 1.05 g. of dl~3-cyclopentyloxy-13p- max 2o96 5X1(1 o0 μ0 Analysis: Calcd. ' for C^H^O^ C, 82 9 5 H, 9 ° 05 , Found: C, 82.61 ; H, 9 » 30 » ,! EXAMPLE VII dl-3-Cyclopentyloxy~13β-ethylgona-l, 3 , ( 10)-trien-17-one ( 5.OOg) ' is dissolved in isopropenyl acetate (50 mlo ) then 5 ml, of a solution prepared by carefully mixing concentrated siilphuii; jacid ( 10 drops) with isopropenyl acetate ( 10 ml o ) is added0 The reaction is ' refluxed for one hour then slowly distilled over a period of five ··'.. hours to remove 5k ml. of distillate. After cooling, the distillate is diluted with benzene then the extract is washed with saturated ! - •.60dium bicarbonate solution, water, brine and dried over anhydrous sodium sulphate. After filtration, the solvent is removed in vacuo and the residue dissolved in boiling hexane. The solution is . cooled and passed through a column of Florex XXS. The solvent is removed in vacuo, the residue triturated with 'methanol and filtered ■ to obtain 3o 00 g. of dl-3-cyclopentyloxy-.13p-ethylgona-l, 3,5 ( 10) 5 l6- 31443/2 < tetraen»17-ol-, acetate, m.p. 120-121°C; C, 79.15; H, 8.69. Found: C, 79ol2? .

EXAMPLg^VIir * dl-.3-Cyclopentylox -13P-eth lGona-l,3',5(10),l6--t.etraen- 7-oi," acetate, prepared by the procedure of Example VII, 050 g.). is . diss9lved in, benzene (100 mlo), cooled with an ice-bath, and m- chloroperbenzoic acid (2«0 g.) addedo The mixture is stirred at room temperature for four hours, then diluted with ether, washed with 5% potassium carbonate solution, water and brine ad dried over . anhydrous sodium sulphate. The mixture is filtered, the solvent ' removed in vacuo and the resulting oil dissolved in methanol (250. ml.) containing 3 molar sulphuric acid (75 ml„). The reaction mixture is allowed to stand at room temperature for four days then the solvent is evaporated to one-third volume in vacuo. The mixture is diluted with water, filtered and the resulting white crystalline solid is air dried. The1 solid is dissolved in methylene chloride, treated with charcoal and filtered. The solvent is removed in vacuo and the residue crystallised from methanol to obtain 1„59 g of product; hup. l60-l62°Co A 0o 0 go sample is further purified by the above procedure to obtain from isopropanol, 0022 go of dl~3-cyclopentyl- oxy-13 ~ethyl-l6a«hydroxyg0na-l,3,5(lO)-trien-17-one, m„p. l63-].65°C; max and 5·75-μ· Analysis; Calcd. for 78,22; ' H, 8,75« Founds C, 77.93; H, 8.78. ' . ' .51443/2 ; dissolved i 50-50 petroleum ether-benzene and filtered through f Grade 1 neutral alumina. The filtrate is evaporated under vacuum to obtain dL-3-cyclopentyloxy-17ot-chlorpethynyl-13p-ethylgona- KBr l,3,5(lO)-trien-17P-ol, as a white glass (0.175· g.)? mx 3·0, i. 0, 6.25 . Analysis. Calcd. for C^R-^CIO^ C, 76.00; H, 7.60; CI, 7o59o Founds C, 76.665 H, 8.22; CI, 7. 8» ' EXAMPLE XI * d-3-Cyclopentyloxy-13P-ethylgona-l,395(10) ,8-tetraeu»17-one (lo5 go ) » is dissolved in dry dimethyl sulphoxide (60 mlo) and purified acetylene gas is bubbled through the stirred solution for one half hour. Lithium acetylide-ethylene diamine (2.0 g.).is then added and the mixture stirred at room temperature for two hours. The reaction mixture is poured onto ice with stirring and extracted with ether. The latter is washed, dried and evaporated and the residue filtered through a column pf Florex using benzene. The solvent is removed and the product is recrystallised twice from i methanol to provide d-3-cyclopentyloxy-17a-ethynyl-13P~ethylgona- ■ I, 3»5(10) ,8-tetraen-17P-ol as an alcoholate (0 70 g.), rn.p. II6- 117°, X KBr 2 .02; , .max .92 , 3.10, 6.25 , 8 Ε τ (£ maΐ0xΗ 278 η 19,000) ,' . 2 o Co] D; a -13^ (C=2,chf), d-3-Cyclopentyloxy-13p-methyl-17ct-ethynyl-' gona-l,3,5(10) ,8-tetraen-17P-ol (rn.p, 12^-125°) is prepared by a . similar procedure.

. *: - EXAMPLE XII ·. , Repe tin the procedure of Example X by reacting an appropriate 13@-ethyl-3-jCyclopentyloxygon-17»one with lith um chloro-acetyiide, the following compounds are prepared? dl-17a-chloroethynyl-3-cyclopentyloxy-13P-ethylgona- 1,3,5(10) ,8-tetraen-17p-ol; - - - - » It is understood that in all the Examples either the dl-steroids or specific d-isomers may be employed as starting material with like results,, The following Example illustrates pharmaceutical compositions according to the inventione EXAMPLE XIII * Tablets are prepared in conventional manner such that each contains the following ingredients! dl-3~cyclopentyloxy-13P-ethyl-17a°-ethynylgona- 1 , 5, 10)-triene L?β-οΐ o Spray dried lactose 75 nig.

Methylcellulose (*f00 cps) 12 mg.

Stearic acid powder 6 mg.

Talc 2 mg.

Claims (1)

1. alk l or chloroeth n l. j 31443/2 . . * ' . '"* - k, A steroid as claimed in Claim 2 wherein R is ethynylo 5 o . A steroid as claimed in Claim 1 wherein X has the structure (C). . '. '- .·". ' · ■ ' ·. ■ ··. 6. A steroid as claimed in Claim 1 wherein X has the structure (E).; \ 7o A steroid as claimed -in Claim 6 wherein R is lower alkyl or ethynylo. 8. A steroid as claimed in Claim 6 wherein R is chloroet.hynyl. 9. A steroid as claimed in Claim 1 wherein X has the structure -(F) „ 10. A steroid as claimed in Claim 9 wherein R is lower alkyl or ethynyl. 11. A steroid as claimed in Claim 9 wherein R is chloroethynyl. · 12 o A steroid as claimed in Claim 1 wherein X has the structure (B). 13. A steroid as claimed in Claim 12 wherein Z is a carbonyl group, l^o A steroid as claimed in Claim 12 wherein Z is a hydroxymethylenjs • group. 15. A steroid as claimed in Claim 1.wherein X has the structure- (D). 16. A' steroid as claimed in Claim 1 wherein X has the structure (G). 17." 3-Cyclopentyloxy-13 -ethyl-17a-ethynylgona-lV3,5(10)-trien-17 ol. ■ ■ ' 18. 3-Cyclopentyloxy-13 -ethyl-17 -ethynyl-8 -,-r0na.it f5(io)-ΐΠβη-17β-ο1. 9i. .3-Ογο1ορθηίγ1ο γ-13β-θΐ1ιγ1-17α-βΐή3Γη3τ½οχ»-1,3,5(10)--_ triene-l6a,17pMiiol. 2~0V 17a-Chloroethynyl-3-cyclopentyloxy-13 -ethylgona- l,3,5(10)-trien-17P-ol. . . . 2Ϊ. ^-Cyclopentyloxy-^ -e hyl ona-l^'.SdO^-triene-iea.^ - diol. _ - 22. ! 3-0yclopontyloxy-13P~ethyl-8a-eona-l,3,5(10)-trien-17-one or ' ; i7P-oi. 23. 3-Cyclopentyloxy-13P-ethyl-l6a~hydroxygona-l,3.5(lp)-'tri*en-17-ono. .t . · .■'. - · .. ■· . ■ ' . -,, i · '- " ' ' 2 . 3-Cyclopentyloxy-13P-othylgona-l,3»5(10),l6-tetraen-17-ol, acetate. 25. 3-Cyclopentyloxy-13P-ethyl or methyl-17a-ethynylgona-1,3»5(10) , ; 8-tetraen-17P-ol. I « .· ·' . ' 26. I The racemate. of a 3-cyclopentyloxy steroid as claimed in any one j of the preceding claims and its lja-enantiomer. , j : . ' .. ' . . 27. A 3-cyclopentyloxy Gtoroid of general formula (I) substantially as described herein and shown with reference to any one of Examples I 1 to X or XII. 28« i A 3-cyclopentyloxy steroid of general formula (I) eubetantially as described herein and shown with reference to Example XI. 29. j n • J ) I»:-- -J .\ ΛΛ. > Lti-ri l -i-l '' ' |J „iu,», 31443/2 - 23 - dotted line indicates a double bond in the 14-poaition and R is methyl or ethyl, to give a 3-cyclopentylox'y-13 -methyl or ethylgona-, 1,3,5(10) ,8-tetraen-17-one or 17-ol, or (b) Z has the meaning given in Claim 1, the dotted line indicates an optional double bond in the 13-cyclopentyloxy-13β-ethyl-Sa-gona-l , 3 , 5 (10 )-trien-17-one or 17-ol (2) etherifying with an etherifying agent containing the cyclo-pentyl group the 3-hydroxy group of a 3-hydroxy steroid of general formula has one of the meanings A to F given in Claim 1 for X or and if dasired or required, oxidising a resulting 17-ol. to a 17-ketone, reducing a 17-ketone to a 17-ol, alkylating, et ynylating or chloroethynylating a 17-ketone to a 17a-alkyl, ethynyl.or chloro- 16 ethynyl-17β-ol, enol acylating a 17-ketone to a -17-a.lkanoyloxy • 16 ' \ compound or oxidising a Δ -17-alkanoyloxy compound to a 16oc-hydroxy- 17-ketone or 16a,l7-diol. 30. A process as claimed in Claim 29 in which a 3-hydroxy steroid of general formula (where X has one of the meanings B to P given in Claim 1 or has the meaning A given in Claim 1 in. which is an ethyl^oup) is etherified with a cyclopentyl halide. 31. A process as claimed in Claim 30 in which the cyclopentyl halide is cyclopentyl bromide. 32· A process for preparing 3-cyclopentyloxy-13P-ethyl-8a-gona-1,f3,5(10)-trien-17-ol or 3-cyclopentyloxy-13P-ethyl-gona-1,3*5(10)-triene-16a,l7P-diol claimed in Claim 1 wherein the corresponding 17-ketone compound is reduced. 33· A. process as claimed in Claim 32 wherein the 17-ketone compound is reduced by a hydride transfer agent. 34· A process as claimed in Claim 33 wherein the hydride · transfer agent is an alkali metal borohydride. 35· A process for preparing a 3-cyclopentyloxy-13P~ethyl- 17a-lower alkyl-, ethynyl- or chloroethynyl- gonai,3.5(l0) ,8r tetraen-17P-ol, a 3-cyclopentyloxy-13P-ethyl-17a-lower alky].-, ethynyl- or chloroethylnyl-8a-gona-l,3,5(10)-trien-17P-ol, a 3-cyclopentyloxy-13P-ethyl-17a-lower alkyl-, ethynyl- or chloro-ethynyl-gona^3,5(10).-triene-16 ,17p-aiol or a 3-cyclopentyloxy-13 -ethyl-17a-lower alkyl-, ethynyl- or chloroethynyl-gona-l,3,50.0) trien-17P-ol claimed in Claim 1 in which the corresponding 17-keton is lower alkylated, ethynylated or chloroethynylated. 36. A process as claimed in Claim 35 wherein the 17-ketone is alkylated, ethynylated or chloroethynylated with an organometallic alkyl, ethynyl or chloroethynyl compound. 37. A process or preparing a 3-cyclopentyloxy-13P-ethyl-17-lower alkanoyloxy-gona-1,3,5(10),16-tetraene claimed in Claim 1 wher A process as claimed in Claim 39 in which the gonatetraene is oxidised with a per-acid and the resulting, 3.6a,17<x-epoxide is hydrolysed. A process for preparing a 3-cyclopentyloxy steroid compound of "■„. general formula (I) substantially as described herein and shown with.. I reference to any one of Examples I to X and XII» i ' · '■ ■ .'■ 1 A process for preparing a 3-cyclopentyloxy steroid compound of , j < ! general formula (I) substantially as described herein and shown ! with reference to Example XI A 3-cyclopentyloxy steroid whenever prepared by the process claimed in any one of Claims 29 to 42. A pharmaceutical preparation comprising a 3™cyclopentyloxy steroid as claimed in Claim 1, wherein X is (A), (C), (E) or (F) in association with a pharmaceutically acceptable cari'ier. A pharmaceutical preparation comprising a 3-cyclopentyloxy .steroid as claimed in any one of Claims 2 to h in association with a ' pharmaceutically acceptable carrier,, I A pharmaceutical preparation comprising a 3-cyclopentyloxy steroid , as claimed in Claim 5 in association with a pharmaceutically acceptable carrier, A pharmaceutical preparatio comprisin a 3-c clo ent lox steroid 31443/2 - 26 - ■48. A pharmaceutical preparation eomprioing a 3- cyclopentyloxy steroid as claimed in any one of Claims 9 to 11 in association with a pharmaceutically acceptable carrier. 49· A pharmaceutical preparation comprising a 3- cyclopentyloxy steroid as claimed in any one of Claims 17 to 20 or 27 in association with a pharmaceutically acceptable carrier. 50. A pharmaceutioal preparation comprising a racemate of a 3-cyclopentyloxy steroid as claimed in any one of Claims 2 to 17 to 20 and its 13«-enantiomer in association with a pharmaceuti cally acceptable carrier. For the Applicants' jfl-.R33INHOLD J3QH AMD PARTNERS By: ■ ΐ IX* />