IL33137A - 3-cyclopentyloxy-13beta-alkyl-17alpha-ethynyl-gona-3,5-dien-17beta-ols and 17beta-acylates,their preparation and pharmaceutical compositions containing them - Google Patents

Description

3-0yclQpentyloxy-13β— alte l— 17ct-ethynyl-gona-3 »5-dien-17p-ols and 17p-acylate?3 i their preparation and pharmaceutical compositions containing them.

AMERICAH HOME fiODOCT CORPufljiTIOlSr C: 31401 AHP-i 850/5850-ClA917A9l7-ClA9l7-C2-f This invention relates to novel steroid compounds having pharmacological activity and utility as intermediates in the preparation of steroid compounds having pharmacological activity, to processes for their preparation^ to preparations containing them, and to methods for prevonting oonooption and ovulation in warm bleodod ovulating vortobrao« The novel steroids are 3-cyclopentyloxy-13-polycarbonalkyl-17a-ethynylgona-3,5-dien-17P-ols, and their acylates of general formula (I) wherein R is alkyl of £x-atn- 2 ataouit>-30 carbon atoms and R are hydrogen or methyl; R is hydrogen or COR where R is alkyl of from about 1 to about 10 carbon atoms, cycloalkyl of from about 3 to about 6 carbon atoms or monocarbocyclic aryl (lower) alkyl.

Particularly preferred compounds within the scope of formula (I) are respectively: dl and d-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3,5-dien-17P-ol, acetate, dl and d-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3, 5-dien-17β-ο1.

Compounds of formula (I) are useful per se, in that they possess hormonal effects in animals as evidenced by standard pharmacological tests, including progestational effects of long duration of activity after oral administration„ In contrast to compounds of the prior art, the instant compounds have a substantially increased duration '33137/2 MP-½50 ' otc-f of activity. .' Especially valuable for this purpose are dl and d-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3,5-dien-17P-ol and. their acetates , ίο β ο compounds of formula ( I) wherein R is ethyl , in their racemic and d-enantiomorphic forms. Furthermore, compounds of formula (I) are of value as intermediates for the preparation of compounds exhibiting hormonal effects in animals by standard pharmacological tests, 6 5 The compounds of formula (I) in which R is CO can be prepared wn to wherein R , R , R , R , R and R are as herein above defined or a 3-enol ester or 3-enol ether thereof is reacted with cyclopentyl alcohol or an ortho'formate or ketal derivative, ' thereof , in the presence of an acid catalys t .' For the general me th ods of the Art reference- in mn.d e to Fieser & Fieser, Steroids , 1959, pages 310 to 312 , and references listed therein; and to Djerassi, Steroid Reactions , 1963, pages 2 to 'v6 and references cited therein. s In an example, the compounds of formula (I) in which R is COR^ can be prepared by ..treating a' 3-enol acylate-17-acylate of general formula v ΑΗΡ- 850 etc-f wherein R, R , R , R , R and R are as hereinabove defined with cyclopentyl alcohol in the presence of an acid catalysto The 3-enol-17-acylates of general formula (III) may be prepared from the corresponding 17-hydroxygon-A-ene compound of the general formula wherein R„ R , R , R and R are as hereinabove defined.

Heretofore it has been proposed to provide 3-cyclopentyl-enol ether 17-esters similar to those of formula (I) by a multi-step process comprising, for example, blocking (protecting) the 3-keto group in the corresponding 17--hydroxygon-4—ene compound, such as by reaction with a ketalising agent, e.g. ethylene glycol, propylene glycol and the like; conversion of the resulting 3-a kylene ketal to the corresponding 3~enol ester of the 17-ester with an excess of an alkanoic anhydride, it being required first to hydrolyse and then to enolesterify the 3-ketal group and simultaneously to esterify the 17-hydroxy group; and finally to exchange the 3-enol ester group for the desired 3-cyclppentyloxy group. A means has now surprisingly been found to accomplish the same conversion in fewer steps, in a much shorter overall timev while avoiding the need to use the preventive steps of protecting the 3-keto group (e0go by ketalijfation) AHP-4850 etc-f then exchanging or removing the protective group (e.go by hydrolysis) which is required in the prior art methods„ In essence there has now been found a combination of reagents and reaction conditions which in only a few minutes will simultaneously esterify the hydroxy group of the 17-position and enolesterify the 3-keto group, avoiding entirely any need to use an exchange reaction between a protecting group (e„g. a ketal radical) and the residue of the employed acid (e.go acetic acid) » The prior art exchange reaction required a minimum of five hours plus additional time to complete precipitation ' of the crystalline diacetate» The invention thus provides a novel process for the preparation of 3-cyclopentyloxy-13-alkyl-17a-ethynylgona-395-dien-17 -ol, acylates of the formula O. O ^ wherein R is alkyl of £# The compounds of general formula I in which R is hydrogen, i.e. the 17-free alcohols, may be prepared by ethynylating a 3-cyclopentyloxy-17-ketone of general formula (IX) 1 3 wherein R, R , R , Hr and R are as hereinabove defined. The 3-cyclo-pentyloxy-17-ketones of general formula (IX) can be prepared by treating the corresponding 3-enol acetate of general formula (X) with cyclopentyl alcohol in presence of an acid catalyst, e.g. p_-toluene-sulphonic acid„ The reaction may be carried out in, for example, refluxing heptane» The 3-enol acetate of general formula (X) may ΑΗΡ- 850 etc-f itself be prepared by enol acetylating the corresponding ^-en-3-one of general formula (XI) The -en-3-one may, for example, be treated with acetic anhydride and perchloric acid in ethyl acetate at about 25°C<> The term "(lower) alkyl" as used herein includes alkyl groups, straight and branched chain and alicyclic of from about 1 to about 6 carbon atoms, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2-methylpentyl, n-hexyl', cyclopentyl, and the like,, "Alkyl groups of from about 1 to about carbon atoms" includes "(lower) alkyl groups" as above defined but e¾oi-w4oo¾ of oou¾^607--6ho--roo1>hyl-fflao33jeT and in addition includes n-octyl, n-nonyl, n-decyl, n-undecyl, n-tetradecyl, n-octadecyl, n-eicosyl and branched chain isomers thereof. "Cycloalkyl of from about 3 to about 6 carbon atoms" includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl as well as cyclopentylmethyl and cyclo-propylethyl. "Monocarbocyclic aryl (lower) alkyl" contemplates (lower) alkyl groups as above defined monosubstituted by phenyl, such as benzyl, phenethyl, oc-methylbenzyl and the like,. Preferably with respect to 1 2 3 the compounds of formula (I), R is the ethyl group, R , R , R and 6 R are hydrogen and R is COCK.,, The term "substantially non-polar, inert organic solvent" when used herein and in the appended claims, contemplates a family of diluents for the reaction which excludes solvents which would react with acetic anhydride. For example, water and alcohols would not be useful; the only water acceptable in step 1(a) is that inherently present in the aqueous perchloric acid.

AHP- 850 etc-f Illustrative solvents are, for example, hydrocarbons, e.g. hexane, heptane, cyclohexane, benzene, toluene, chloroform, carbon tetrachloride and the like§ ethers, eog0 diethyl ether, diiso-propyl ether, and the like; ketones, e0 » acetone, methyl isopropyl ketone and the like; and esters - especially preferred are (lower)alkyl (lower) alkanoates, such as methyl acetate, ethyl acetate, ethyl n-propionate, i-propyl acetate, n-hexyl acetate, ethyl n-hexanoate, n-hexyl n-hexanoate and the like0 The term "acid acceptor" is used in its art-accepted sense to contemplate an acid binding agent suitable to combine with the acid halide, HX, formed by reaction of the acyl halide and a hydroxyl group under esterification conditions of step I(b)0 These comprise, generally, inorganic and organic bases, preferably of weak to moderate strength, such as alkali metal and alkaline earth metal carbonates or bi-carbonates, e«go sodium bicarbonate, lithium carbonate, magnesium carbonate and the like, or organic amines, such as quinoline, dimethylaniline, triethylamine, pyridine and the like. Especially preferred for use in step 1(b) are organic amines and convenient, because it helps the mixture reflux at a preferred temperature and is an especially good solvent, is the tertiary aromatic amine, pyridine. The wavy lines at Cg, C^, and C^g of the formulae herein indicates the contemplation of epimers of either a or β-configuration when methyl-substituted in these positions„ The products of the process will have the same configuration as that of the starting materials0 The 17-hydrox.y~i~ene compounds of general formula IV used as starting materials are conveniently prepared by techniques known to those skilled in the art,, For example, the corresponding 13-alkyl-3-(lower) alko ygona-l, 3,5(lO)-trien-17 "Ol can be subjected to Birch reduction and Oppenauer oxidation to produce the corresponding 13-alkyl-3-(lower) alkoxygona-2, 5(l0)~dien~17-one which, when reacted with alkali metal acetylide or Grignard reagent and then acid hydrolysed with hydro- AHP-4850 etc-f chloric acid, provides the required gon-A—en-3-oneSo These procedures are illustrated in detail in H„ Smith, Hughes, Douglas, Wendt, Buzby, Edgren, Fisher, Foell, Gadsby, Hartley, Herbst, Jansen, Ledig, McLoughlin, McMenamin, Pattison, Phillips, Rees, Siddall, Siude, L. Smith, Tokolics and Watson, J, Chem„ Soc«, 196 , H72-H92. Means are also available to those skilled in the art, which are suitable to prepare starting materials optionally substituted at C-6, C-7, C-10 and C-l6 with methyl groups. For example the 6,13 and 7<> 13-clialkyl-gonatriene compounds of United Kingdom Patent No., 1, 103, 205 can be converted by the route outlined above to the corresponding C-6 and C-7 methyl-substituted gon-A—en-3-ones. The lO -methyl-^-alkylgon- en-3-ones can be provided by converting the ^-alkylgon-A—ene to the -hydroxy-5-bromo derivative, oxidising to the A—keto-5-bromo derivative, dehydrobrorainating across the 5(10) position, adding hydrogen cyanide at 5(10) to obtain the corresponding A-keto-lO-cyano derivative, ketalising to protect the - e o group, reducing the 10-cyano group to a 10-methyl group, hydrolysing to remove the protecting ketal group to provide the 10 -methyl-13"-alkylgonan-i-one, converting this to its 3-hydroxymethylene derivative, converting this to the 3-oximino derivative, hydrolysing the oximino group, mesylating the ^—hydroxy group, c.atalyti-cally hydrogenating the unsaturation at the —position and eliminating ^irg^iT-bu h111-?jr-fea May "19 -¾ (y ; The proper substituents at C-17 are introduced by entirely conventional techniques, such as those outlined U.K. Specification No . 1 , 191 , 347 in H. Smith et al, cited above, and in the said SopiaA-Mou 551 ¾ ί3Ί·7»— The l6-methyl-13-alkyl-17a~ethynylgon-^-en~3-on-17 -ol starting materials are accessible from the corresponding 13 -alkyl-3-alkoxy-l6-methylgona-l,3, 5(lO) ,8-tetraen-17-ones of G„A„ Hughes and H. Smith, UoSo 3, 391 , 169 (Example 76 shows the 13-ethyl compound), which are ΑΗΡ-Λ85Ο etc-f reduced with, for example, sodium borohydride, to the 17 -ols, then treated with alkali metal, e_g» sodium, potassium or lithium in liquid ammonia and excess aniline to form the corresponding 17P-ol-triene, which is converted to the starting material by the route outlined above„ The enolesterification and esterification according to step 1(a) in the instant process is accomplished by contacting the 17-hydroxy^ -ene compound of general formula (IV) with acetic anhydride and aqueous perchloric acid in a substantially non-polar, inert organic solvent, e<>gc, those illustrated above and, preferably, ethyl acetate. The reaction temperature and time are not particularly critical although best results in terms of product purity and yield are obtained at reaction temperature of from about 15°Co to about 0°Co, preferably about 20°Co to 25°C0 during reaction times of from about three to about fifteen minutes although, in most instances, about 5 minutes is entirely satisfactory<> In one manner of proceeding to a solution of 08 parts by volume of acetic acid, 0„ 05 parts by volume of 7 % aqueous perchloric acid and 50 parts by volume of ethyl acetate there is added 1 part by weight of the 13'-alk l-1 α-ethy yl-17 - ydroxygon- -en-3-οηβο The mixture is allowed to stand at about 25°C<> for about 5 minuteso The diacetate is recovered in any standard manner. For example, the reaction mixture can be poured into saturated aqueous sodium bicarbonate solution0 The organic layer is then separated, washed with sodium bicarbonate, water, brine and dried over anhydrous sodium sulphateo The mixture is filtered, the solvent is removed by distillation in a vacuum and then methanol and a small amount of pyridine are addedo Cooling and removing the solvent in a vacuum leaves the diacetate as a residue, which can be recrystallised if desired from an appropriate solvent, e0go a lower alkanol such as methanolo ΑΗΡ- 85Ο etc-f The enolesterification and esterification according to step.1(b) in the instant process is accomplished by heating the corresponding anhydride in admixture with the corresponding acyl halide and an acid acceptor, eog0 as illustrated above and, preferably, pyridine, at. a temperature of from about 50°C0 to about 150°C» until the reaction is substantially complete0 The time required is not particularly critical and, in most instances, if steam bath temperatures are used, i0e. about 90°C0, the reaction is essentially complete in from about 1 to about 2 hourso In one manner of proceeding, 3 parts by weight of the steroid is mixed with about 16 parts by volume of the anhydride and about 8 parts by volume of the acyl halide, then about 0.8 parts of the volume of the acid acceptor is added if, for example, pyridine is usedo The mixture is heated on a steam bath for about 1 to 2 hours. The product is recovered by any of the usual methods, For example, the reaction mixture can be cooled, then mixed with from 5 to 10 volumes of water, then extracted with a water-immiscible organic solvent, such as ether or chloroform, then the solvent is thoroughly dried and evaporated leaving the product as a residue<> It is useful to apply a high vacuum to the residue to remove traces of unreacted anhydride and acyl halide0 The product can be purified, if desired, by chromatography or by crystallisation from an appropriate solvent, for example, a lower alkanol such as methanol0 The exchange reaction between the acyl radical in the 3-position and the cyclopentyl group in step (II) is accomplished by treating the 3-enolacylate (e.g. acetate) 17-acylate (e»g0 diacetate) with cyclopentyl alcohol in the presence of an acid catalyst of enoletherification. The reaction conditions are not particularly critical although for best results it is preferred to carry out this step at a temperature of from about 65°Co to about 175°C0 for from about 5 to about S hours. The acid catalyst required to bring about the exchange reaction can be any of those commonl used to form enol ethers„ These would include AHP-i 850-etc-f toluenesulphonic acid, benzenesulphonic acid, naphthalene sulphonic acid, anthraquinone sulphonic acid and Lewis acids such as stannic chloride or antimony pentachloride. Acid salts of organic bases with mineral acids, e.g. pyridinium chloride are also useful in step (II). £-Toluenesulphonic acid is convenient, economical and preferred. The exchange reaction of step (II) is preferably carried out in an organic solvent which is substantially non-polar„ Solvents such as heptane, iso-octane, benzene, toluene and the xylenes, tetrahydrofuran or dioxane can be used. Halogenated organic solvents, such as ethylene bromide, chloroform or tetrachloroethane also can be used. Heptane is economical, it refluxes at a desirable temperature and is preferred. In one manner of proceeding, a mixture of 1 part by weight of the 3-enol acylate-17-acylate, 0.05 parts by weight of p_-toluenesulphonic acid, 2 parts by volume of cyclopentyl alcohol, and 50 parts by volume of heptane is refluxed into a water-separator for 20 hours. The product can be recovered by any of the usual techniques. For example, the reaction mixture can be cooled to about 25°C. and a small amount of pyridine is added before evaporation to dryness in a vacuum. The residue can be dissolved in methanol the solution filtered and then evaporated to dryness to leave the product as a residue. It may be purified, if desired, by recrystallisation from a suitable solvent, e.g. a lower alkanol, for example, methanol.

The ethynylation of the compounds of general formula (IX) may be accomplished by reacting the 3-cyclopentyloxy-17-ketone with an ethynylating agent, such as an alkali metal acetylide, e.g. potassium or lithium acetylide or a Grignard reagent. It is useful to carry out the reaction in a diluent, for example, with potassium acetylide, liquid ammonia can be used; and with lithium acetylide, dimethyl sulphoxide can be used, and is preferred. In one manner of proceeding, purified acetylene gas is bubbled through a solution of the 3-cyclo- AHP-4850-etc-f pentyloxy-17-ketone in about 75 parts by volume of dimethylsulphoxide (DMSO) per part by weight of substrate. After about ^ minutes about one-half part by weight of lithium acetylide-ethylenediamine per part by weight of steroid is added; and the mixture is stirred for two hours o Then a second portion of lithium acetylide-ethylene-diamine (weighing the same as the first.) is added. After two hours the reaction is substantially complete and the product may be recovered by pouring the mixture into ice-water, and the extracting, e.g. with ether, washing, drying and evaporating the extract, which leaves the product as a residue.. It can, if desired, be purified by chromatography and recrystallisation0 As mentioned above, the compounds of formula (I) provided by this invention possess valuable hormonal activity,. Accordingly the present invention also provides a pharmaceutical preparation comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Such a preparation may be prepared by a process in which the compound of formula (I) is mixed or otherwise brought into association with a pharmaceutically acceptable carrier. In pharmacological tests in rabbits the compounds have been found to be orally-active, potent progestational agents with a prolonged duration of activity. This makes them of value to treat conditions in animals, such as valuable domestic animals, for example, cattle, pigs and dogs, which respond to administration of progestational agents, such as the need to control habitual abortion in cattle and to delay estrus in cattle, pigs and dogs. When used for this purpose or for pharmacological purposes, compounds of formula (I) will be formulated and administered by techniques and at dosages which have become matters of common knowledge and experience for structurally-some-what similar progestational agents, e.g. norethindrone and the 5-enol ethers and 3-enol acetates thereof.

AHP-i 850-etc-f For example^ for progestational deficiencies in a warm blooded animal of 50-100 mgo body weight, a useful regimen would be oral administration of 5-20 mgo daily in the form of a 5-mg» scored tablet, for example, or in admixture with animal feed-stuffso The compounds can be formulated in liquid or solid forms, for instance as capsules, tablets, suppositories, powders, dispensible granules, cachets, and the like by combining them with conventional carriers. Such conventional carriers include magnesium carbonate or stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wa and cocoa butter,. Diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders or tablet-disintegrating agents can be used. Powders or tablets preferably contain 5 to 10 to 9 # of the active constituent. The active steroid can be formulated with an encapsulating material with or without other carriers.

Liquid preparations such as solutions, suspensions or emulsions can also be usedo Such preparations include dispersions in a non-toxic carrier such as arachis oil or sterile water, preferably containing a non-ionic surface active agent such as fatty acid esters of polyhydroxy compounds, e.g. sorbitan, aqueous starch, in sodium carboxymethyl cellulose solutions, aqueous propylene glycol or polyethylene glycol.

Thus a water-propylene glycol solution can be used for parenteral injection and aqueous suspensions suitable for oral use can be made by utilising natural or synthetic gums, resins, methyl cellulose or other well known suspending agents. preventing compositions,, It is a matter of common knowledge and experience to orally administer estrogens/progestogens in admixture or sequentially to ovulating vertebrates to prevent ovulation,, The desired objective in nearly all instances, following daily administration of unit dosages of such well-known progestagens as norethindrone or norethynodrel and such well-known estrogens as mestranol, is to inhibit the production of release of gonadotropins from the pituitary and to suspend ovulation. In this manner, in live-bearing species, a luteoid endometrium is induced and maintained while the composition is taken for the inhibition of ovulation, that is, prevention of conception.

Somewhat less well known is a means to prevent conception by admini stration of a progestogen alone, on a daily basis, and often in very small amounts (the so-called "micro-doses") „ The exact mode-of-action of such materials is not entirely understood, but contraception has been demonstrated at dose levels that do not appear to alter pituitary function and thus do not inhibit ovulation,, It is currently believed that agents of this type are effective by preventing the liquefaction of cervical mucus that occurs at about the time of ovulation. Failure of the mucus to change in the "normal" way results in prevention of sperm migration into the uterus (of live-bearing species) and a prevention of impregnation,, In these circumstances, the cervical mucus is said to be hostile to sperm penetration,, To use this latter method to prevent conception, it has up to now been essential to administer the progestagens on a daily basis and recent reports by workers in this field suggest that duration of cervical action of certain progestagens is even less than 2k hours„ As a result of the necessity for daily dosage (pill) - administration, the patient-failure rate has been high for this approach to contraception and method-failure rate has also been relatively high (compared with conventional oral contraceptives, first above-mentioned) , presumably as a result of the short duration of action.

It' has now been found that the progestogens of formula I can be administered alone and cause a contraceptive effect, and this anti-fertility effect is distinguishable from that produced by the combination of progestogen and estrogen because ovulation still will occur. Furthermore, because all of the prior art daily dosage regimens require extra-ordinary care to insure proper pill-taking (administration) on the part of the subject (or administerer) , it is desirable to provide a wholly different approach to administration0 It has now surprisingly been found possible to administer a novel composition (which will be defined hereinafter) to warm blooded vertebrates and to achieve a biologically meaningful, long acting prevention of conception. This effect is valuable when viewed against current regimens in that it avoids the high failure rates with the frequent (daily) administration of the prior art short-acting contraceptive compositions and the failures seen following missed dosages (pills) with the prior art progestagen/estrogen anovulatory compositions. It follows therefore that the use of the instant compositions will allow very simple regimens for oral contraception. For example, such a composition may be administered once for a brief interval during the cycle, prior to the expected time of ovulation. As a result of the protracted period of action, cervical mucus will be rendered hostile to sperm for a week or more, thus completely encompassing the fertile period, which, in vertebrates of the highest order, extends from about day 10 to day 17 of the normal cycle. Furthermore, even if daily dosages are administered, good results will be obtained, even at lower dosages because the effect lasts longer than 2k hours. However, in a very simple regimen, the - -e c- composition would be administered on days 8-10 of the cycle (before the fertile period), and this will suffice for contraceptive purposes,, In addition to permitting administration on a much simplified basis, the instant compositions are highly effective and their use is accompanied by a minimum of side effects„ Accordingly the present invention also provides a method of t as herein defined) preventing conception in warm-blooded ovulating vertebrae/which comprises the oral administration thereto of a composition comprising a compound of general formula I and a pharmacologically acceptable inert carrier, the amount of said composition administered being at least sufficient to prevent conception,, In addition,, the present invention provides an orally-active, conception-preventing composition comprising a compound of general formula I and a solid, oral, pharmacologically-acceptable carrier9 the amount of the compound in the composition being at, least sufficient to impart orally-active, conception-preventing activity thereto„ Such a preparation may be prepared by a process in which the compound of general formula I is mixed or otherwise brought into association with the carrier0 In these compositions, the active compound is preferably dl- or d~3-cyclopentyloxy~13-ethyl-17a-ethynyl-gona-395-dien-17P-ol or its 17-acetate0 The compositions are preferably administered in the form of a unit dosage comprising from about 0o05 mg0 to about 20 mg0 of active compound and a major amount of carriero The term "preventing conception" contemplates a mechanism whereby the vertebrate does not produce a fertilised egg because the necessary contact with sperm has been inhibited;, In essence, conception is prevented by administration of an agent, which it is believed, modifies the nature of the reproductive tract to such a degree as to provide, a hostile environment for any sperm which might be present0 Merely. by way of illustration, these functions are performed by administration , , AHP-A850-etc-f of a progestational agent, e.g. 3-cyclopentyloxy-13-ethyl-17 To formulate unit dosages for administration according to this aspect of the invention the active ingredient can be compounded into oral dosage forms, such as tablets, capsules and the like. This is done by combining the active ingredient with conventional carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxy-methyl cellulose, low melting wax, cocoa butter, and the like. Diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, tablet-disintegrating agents, and the like may be employed. The active ingredient can be formulated with an encapsulating material with or without other carriers. In all cases, the proportion of active ingredient in the said compositions will be at least sufficient to impart ovulation preventing activity thereto on oral administratione This will range upward from about 00001% by weight of active ingredient in said composition. As is mentioned above the amount of active ingredient especially preferred for each unit dosage (e.g. tablet or capsule) is from about .05 to about 20 mg. of active ingredient (although from about 0.001 to about 100 mg. can be used, if desired).

The dosages will depend on whether or not the administerer wishes to use conventional regimens (administer daily a composition comprising from about 0o05 to about 5 mg° of active ingredient) or to take advantage of the short period-a-month regimen made possible by this invention (administer at daily intervals just before the fertile period, AHP-½850-etc-f .βο days 8-10 of a normal cycle, from about 1 to about 20 mg„ of active ingredient) <, These dosages are based on an average body weight of about 70 kgo , and can be adjusted to the weight of the individual vertebrateo In addition, it has been found that the progestogens of general formula I can be administered in admixture with estrogens» When the prior art estrogens/progestogens have been administered in admixture or sequentially to ovulating vertebrates to prevent ovulation it has been necessary to follow with great precision the established regimen of daily dosages', because failure rates appear to be closely related to the missing of unit dosages, i0e0 tablets, during the treatment period. And this seems to be an especially critical problem with the sequentials (eogo estrogen alone for 10-15 days, followed by progestogen plus estrogen for 5-H days, in warm blooded vertebrates of the highest orders) . Because the existing daily dosage regimens require extraordinary care to insure proper pill-taking (administration) on the part of the subject (or administerer) , it would be desirable to provide a wholly different approach. It has now surprisingly been found possible to administer a novel composition (comprising the progestogens of general formula I and certain estrogens as hereinafter defined) to warm blooded vertebrates and to achieve a biologically meaningful, long acting inhibition of ovulation., This effect is valuable when viewed against current regimens in that it dispenses with the frequent (daily) administration of the prior art anovulatory compositions„ It follows therefore that the use of the instant compositions will allow very · simple regimens for oral contraception,. For example, in vertebrates of the highest order, the initial tablet can be scheduled shortly after completion of menses — by way of illustration — on a Sunday, providing this does not go beyond day 7 of the usual 28 day cycle. The vertebrate then would be administered a unit dosage on the Sunday following the A - 0-etc- menses and on the subsequent 2 Sundays, Because of the surprisingly long duration of activity of the compositions, protection is excellent during about the next week and menses will occur during the second week following the final tablet„ The menses should be complete, in due course, so that tablet administration would be initiated again on the fourth Sunday following the initial tablet. Thus, in this very simple regimen, the composition would be administered on the. same day of the week, three weeks in a row, skipped the next week and initiated again the following week. For convenience of administration an inert tablet (placebo) may be included in a tablet sequence which will have the effect of a skipped administration and increase the ease of the administration regimen., In addition to permitting administration on a much simplified basis, the compositions are highly effective and their use is accompanied by a minimum of side effects.

To this end, therefore, the invention further provides a method of (as herein defined) preventing ovulation in a warm-blooded ovulating vertebrate/which comprises the oral administration thereto of a composition comprising: (a) a compound of the general formula (I) in admixture with (b) a compound of general formula (XII) wherein R is alkyl of from about 1 to about 20- carbon atoms, and the broken line indicates a single bond or a double bond at C,_,-Cg, the amount of said composition administered being at least sufficient to prevent ovulation.. The invention also provides an orally-active, ovulation-preventing composition comprising (a) a compound of general formula (I) in admixture with AKP- 50-etc-f « (b) a compound of general formula (XII), and a solid, oral, pharmacologically-acceptable carrier, the amounts of active ingredients (a) and (b) in said composition being at least sufficient to impart orally-active, ovulation-preventing activity theretoo Such a preparation may be prepared by a process in which the active ingredients (a) and (b) are mixed or otherwise brought into association with the carrier,. These compositions preferably contain from about 0.015 parts to about 2.5 parts by weight of active ingredient (b) per part by weight of active ingredient (a) . The compositions are preferably administered in the form of a unit dosage comprising from about 2 mg„ to about 20 mg. of active ingredient (a) , from about 003 mgo to about 5 mg° of active ingredient, (b) and a major amount of solid, oral, pharmacologically-acceptable carrier. Preferred active ingredients (a) are dl- or d-3-cyclopentyloxy-13-ethyl-17 To formulate unit dosages for administration the active ingredients (a) and (b) can be compounded into oral dosage forms, such as tablets, capsules and the like. This is done by combining the active ingredients with conventional carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, traga-canth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, and the like. Diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, tablet-disintegrating agents, and the like may be employed. The active ingredients can be formulated with an encapsulating material with or without other carriers. In all cases, the proportion of active ingredients in the said compositions will be at least sufficient to impart ovulation preventing activity thereto on oral administration. This will range upward from about 0.001$ by weight of active ingredient (b) [the estrogen] is said composition. As is mentioned above the amount of active ingredients especially preferred for each unit dosage (tablet or capsule) is from about 2 to about 20 mg. of active ingredient (a) [although from about 0,25 to about 100 mg. can be used, if desired] and from about 0.3 to about 5 mg. of active ingredient (b) [although from about 00005 to about 15 mg. can be used, if desired].

The dosages will depend on whether or not the administerer wishes to use conventional regimens [administer daily a composition comprising from about 0o25 to about 10 mg„ of active ingredient (a) and from about OoOl to about loO mg„ of active ingredient (b)] or to take advantage of the once-a-week regime made possible by this aspect of the invention [administer at weekly intervals from about 2 to about 20 mg. of active ingredient (a) and from about 0„3 to about 5 mg. of active ingredient (b)]0 These dosages are based on an average body weight of about 70 kg. and can be adjusted to the weight of the individual vertebrate, The "active ingredients (b)" contemplated by this aspect of the invention are estrogens, specifically, 3-cyclopentyloxy-13-alkyl-17o - 7 ethynylgona-1,3? 5(10) ,trien-17 -ols and -dehydro analogues thereof, which can be prepared by procedures well within the capabilities of those skilled in the art„ For example, the corresponding 3-cyclo- n pentyloxy-13-alkylgona-l,3, 5(10)-trien-17-ones or ^V-dehydro analogues thereof are prepared by reacting the corresponding 3-hydroxy compounds of Ho Smith et al. , J» Chem0 Soc», 196* , ?2- t92, and G0C. Buzby, RoPo. Stein and H„ Smith, Belgian Patent No„ 700, 232 (August 31, 1967) , respectively, with cyclopentyl halide (chloride or bromide) in the presence of a base, e0g0 potassium hydroxide or sodium methoxide.

These then, as will be exemplified in detail hereinafter, can be ethynylated by conventional procedures, e0g» in acetylene-saturated dimethylacetamide with lithium acetylide-ethylenediamine or in acetylene saturated dimethylsulphoxide with lithium acetylide-ethylenediamine. In addition, means are well known to permit partial etherification with cyclopentyl alcohol of the corresponding 17o-ethynylgona-3, 17- As is mentioned hereinabove, the instant active ingredients (a) and (b) possess, respectively, marked intrinsic progestational and estrogenic activities of increased duration, which are of practical value, especially after oral administration because they permit regimens AHP- 50-etc-f to be established for less frequent dosages than presently possible. When used herein and in the appended claims, the term "warm blooded ovulating vertebrates" contemplates female standard laboratory test animals and birds such as mice, rats, guinea pigs, rabbits, monkeys, gibbons, langurs, chickens and the like and valuable domestic animals and birds, such as dogs, cats, rabbits, sheep, cattle, horses, chickens, turkeys and the like, of such an age that ovulation is feasible and normalo The term "solid, oral, pharmacologically-acceptable carriers" contemplates usual and customary solid substances employed to formulate unit dosages for pharmacological purposes „ It also will include, in its broadest aspects, animal feedstuffso One pharmacological test in which progestational activity of prolonged duration was demonstrated for compounds of general formula I was carried out as follows: The orally-administered compound is subjected to a Clauberg assay and the progestational effects are determined 2 days, 5 days and 7 days post-administration. Compounds that maintain biologically meaningful progestational effects for at least several days are deemed to have a prolonged duration of activity. Immature female rabbits (800-1200 g.) are primed with estradiol-17P for 6 dayso On the following day the primed rabbits then receive one administration of the test compound by stomach tube (gavage). The animals are sacrificed at 2 , 5 and 7 days post-treatment. Progestational activity is assayed by histological evaluation of uterine glandular proliferation [Elton and Edgren, Endocrinology, 6 _, S -k72 (1958 ) ] .

In this test dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3 , 5-dien-17P-ol, acetate, a compound of general formula (I), administered at 1 mg» per animal had an assay value (McPhail Index) of 1.8 after 2 days; and lo2 after 5 days ( animals); and at 3 mg. per animal it had an assay value of 1.5 after 2 days; and 1.2 after 5 days (3 animals) and at mg. per animal had an assay value of 1.2 after 2 days (3 animals); 2.9 after 5 days ( animals) ; and 2.0 after 7 days ( animals) ; showing that it maintained biologically meaningful progestational effects even 1 week after a single oral administration of 10 mg. per animal.

Similarly, dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3, 5-dien-17P-ol administered at 1 mg. per animal had an assay value of 2.0 after 2 days and 1.2 after 5 days and at 3 mg» per animal it had an assay value of 2.3 after 2 days and 0o7 after 5 days.

AHP- 50-etc-f ' One pharmacological test in which estrogenic activity of prolonged duration for compounds of general formula (XII) 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 dayso The proportion of rats responding with cornified vaginal smears is increased by active compounds. Prolonged duration of activity is shown by compounds exhibiting a statistically significant ratio of positive smears at least several days from 0„ In this procedure, 3-cyclopentyloxy-13-ethyl-l?a-ethynylgona-l, 3 s 5(lO) , 7-tetraen-l?P-ol, a compound of general formula (XII) , produced the following data: Day 1 2 3 k 5 6 7 8 9 10 11 12 13 Ik + Smears 0 1 15* 20* Ik* 19* 11* k 7* 8 * 3 1 0 1 Total Smears 20 20 20 20 20 20 20 20 20 20 20 . 20 20 20 'Statistically significant at p ^0005» Thus positive estrogenic effects were demonstrated for a period of 8 days (after a latent period) „ - -e c- In the product of a total synthesis which has not included a suitable resolution stage the compounds of the invention will be present as racemates <> Using a convention approved by Fieser & Fieser, "Steroids", p„ 336 (1959) « compounds designated as the d-forms are the enantiomers corresponding in configuration at C-13 to that of the natural hormone estrone - The corresponding enantiomorphs are consequently designated the 1-forms and the racemates the dl-forms. The compounds of the present invention include the d-enantiomers and mixtures of the d-enantiomers with the 1-enantiomers , particularly racemates o The compounds are preferably the d-enantiomers<, For convenience, the formulae drawings in the specification and claims depict the d-enantiomers but it is to be understood that these formulae drawings are employed in a generic manner to include the d-enantiomers and mixtures of the d- and 1- enantiomers, e.go racemates. The d-enantiomers can, of course, be obtained by using appropriate resolved starting materials in the processes described herein.

AHP- 50-etc-f The following Examples illustrate the invention,, EXAMPLE 1 d.l-3-Cyclopentyloxy-13-ethyl-17a-ethynylgona~3¾ 5-iien-17P-Ol. acetate (a) dl-13-Ethyl-17a-ethynylp;ona-3<1^-dien-3 17β-(ϋο1¾ diacetate.' To a solution of acetic anhydride (k8 ml.) and 70% perchloric acid (0o5 mlo) in ethyl acetate (* 00 ml.) add ethyl..acetate to a total volume of 500 ml. then add dl-13-ethyl-17a-ethynyl-17P-hydroxygon-4-en-3-one (1000 go), swirl and let stand at room temperature for 5 minuteso Pour the reaction into saturated sodium bicarbonate solution. Separate the organic layer, wash with sodium bicarbonate, water, brine, and dry over sodium sulphate0 Filter, remove the solvent in vacuo then add methanol and pyridine (2 mle) and boil for 10 minutes. Cool and remove the solvent in vacuo and crystallise the resulting oil from methanolo Filter to obtain 800 g„ of title product, m0p. 162-16^°0. (b) dl-3-Cyclopentyloxy-13-ethyl-17g-ethynylgona-3 , 5-dien-17P-ol, acetate Reflux at about 85°C. a mixture of dl-13-ethyl-17 Obtain an analytical sample by recrystallisation from methanol, m.p. l^-155°0o Et0H 2^3 ιπμ (£ 19, ^00) . Anal. Calcd. for requires C, 79.58 ; Hs 9.06. Found:' C, 79.32; H, 8.77· EXAMPLE 2 d-3-Cyclopentyloxy-13-ethyl-17a-ethynylgona-3 <) 5"dien-17 -olt acetate e/ (a) .d-13-Ethyl-17a-ethynylgona-3 <, 5-dien^-3 ¾ 17P-diol¾ diacetate To a solution of acetic anhydride (65 mle) and 7% perchloric acid (1 ml0) in ethyl acetate (800 ml.) add d-13-ethyl-17a-ethynyl-17P- A - 50-etc- hydroxygon-^-en-3-one (1000 g.) swirl and let stand at room temperature for 3»5 minuteso Pour the reaction into saturated sodium bicarbonate · solutiono Separate the organic layer, wash with sodium bicaronate, water, brine and dry over sodium sulphate. Filter, remove the. solvent in vacuo then add methanol and pyridine (1 ml.) and boil for 10 minutes. Cool and remove the solvent in vacuo. Dissolve the residue in methylene chloride, treat with Nuchar charcoal, filter and remove the solvent in vacuo. Dissolve the residue in hot methanol and let stand to crystallise. Filter to obtain 7.30 g. of the pure title product, m.p. 158-l6l°C; [ctL, - 19^° (c=19-, dioxane), ™Γ 3»θ8 and 5.75 .

Anal, Calcd. for C^H^O^: C, 75.72; H, 8.13. Found: C, 75.66; H, 7.90. (b) d-3-Cyclopentyloxy-13-ethyl-17x-ethynylgona-3« 5-dieri-17 -ol acetate Reflux a mixture of d-13-ethyl-17a-ethynylgona-3,5-die¾il7P-diol, diacetate (7.00 g.) £-toluenesulphonic acid (0,50 g.), cyclopentyl alcohol (30 ml.) and heptane (^00 ml,) into a water separator for 20 hours. Cool, add pyridine (3 ml.) and evaporate the solvent in vacuo.

Dissolve the resulting oil in methanol, filter and evaporate in vacuo z then pump the residue dry. Crystalline the residue from methanol to get I083 go , m.p. ll8-122°C. Treat the solid in hot ether with Nuchar charcoal, filter and remove the solvent in vacuo. Boil the residue z with methanol and let stand to fully crystalline. Filter to get 1.50 g. of pure title product, m.p. ΐ4θ-1^2°0; 3.06 and 5.75 2^3 ιπμ (£20,500); [ot^ -2l ° (c=l.l#, dioxane).

Anal. Calcd. for cZQ^jS° C' 79.58; H, 9.06. Found: C, 79.

H, 8.89.

EXAMPLE 3 The following 17-hydroxygon- —ene compounds: AHP- 50-etc-f S CHjCHgCHg H H H H (CH3)2CH H H H H CHjCHg H H H CH-CH- ■H a-CH^ H H CH,CH_ H H H CH3CH2 ■ H H a-CH- H CH3CH2 . H H P-CH3 H CHjCHg-. . H H H a-CH3 CH,CH_ H H H 2 are treated with acetic anhydride and perchloric acid in ethyl acetate according to the procedure of Example 1, step (a) and the following 3- enol-acetate-17-acetates are obtained: H H CHjCHgCHg H H H H (CH3)2CH H H H H -H- -H- -H- CH-.CH_ CIL H H H CH-CHg H H H AHP-½50-etc-f R £. £ CH3CH2 H CH H H CH3CH2 H H H CH3CH2 H H H CH,CH_ H H H o-CH^ EXAMPLE 5 The ly-hydroxygon-^-ene compounds used as starting materials in Example 3 are heated with appropriately substituted acid anhydrides and acyl halides and an acid acceptor according to the procedure of Example step (a), then the enol esters are converted to the corresponding 3-cyclopentyl enol ethers by the procedure of Example 1, (b) and in this manner the following compounds are obtained: R CH_.CH_ H H H H CH, 3 CH,CH_ H H H H CH2(CH2)gCH3 3 2 CH..CH_ H H H H -CIHC.^CH2 I : 1 CH3CH2 H H H H -0Η(0Η2)^0Η2 CH3CH2CH2 H H H H OH, (CH3)2CH H H H H OH, on (OII2) I8OII2 —H H H H 6¾- A - 50-etc-f R £ £ CH-.CH2 H H H CH5CH2 H OH, H H c¾ CH3CH2 H H H CH3 CH3CH2 H H cc-CH^ H CH5 CH CH2 H H H CH3 CH,CH_ H H H ot-CH^ CH3 .? 2 CH-,CH_ H H H P-CH3 CH3 2 EXAMPLE 6 The procedure of Example 1, step (a) is repeated, respectively at 15°C<> and at i 0°Co Substantially the same results are obtained.

The procedure of Example 1, step (a) , is repeated, respectively, allowing a three minute and a 15 minute reaction time before pouring the mixture into sodium bicarbonate solution. Substantially the same results are obtained.

The procedure of Example 1, step (c), is repeated, substituting for ethyl acetate, equal weights, respectively, of the following (lower)-alkyl (lower) alkanoates: methyl acetate, isopropyl acetate, n-hexyl acetate, ethyl propionate and n-hexyl n-hexanoate. Substantially the same results are obtained.

The procedure of Example 1, step (b), is repeated, respectively at 65°C. and at 175°C„ (in a pressure vessel). Substantially the same results are obtained.

The procedure of Example 1, step (b) , is repeated, respectively, allowing a 5 hour and a 48 hour reaction time. Substantially the same results are obtained.

The procedure of Example 1, step (b) , is repeated, substituting for the p_»toluene sulphonic acid, stoichiometrical amounts of benzene-sulphonic acid, naphthalenesulphonic acid, anthraquinonesulphonic acid AHP-4850-etc-f and stannic chloride, antimony pentachloride and pyridine hydrochlorideo Substantially the same results are obtained., The procedure of Example 1, steps (a) and (b) are repeated, substituting for the ethyl acetate and the heptane, respectively, equivalent amounts of the following substantially non-polar organic solvents: cyclohexane, benzene, iso-octane, tetrahydrofuran, dioxane, ethylene bromide, chloroform and tetrachloroethane. Substantially the same results are obtained,, EXAMPLE 7 dl~3-0yclopentylox.Y-13-ethyl-17X"ethynylgona-3-i5-dien-17P-ol (a) dl-13-Ethyl"-3-hydroxyKona"3c 5"dien-17-one, acetate To a solution of acetic anhydride (25 ml„) and 70$ perchloric acid (0.3 mlo) in ethyl acetate (250 ml0) is added dl-13-ethylgon- -ene-3,17-dione (5<0 g„) the mixture is swirled and allowed to stand at room temperature for 3 minutes, The reaction is quenched with saturated sodium bicarbonate solution then the organic layer is washed and dried. The solvent is removed in vacuo, methanol and pyridine (1/2 ml«) are added to the residue then the mixture is boiled for 10 minutes on the steam bath . After cooling the solvents are removed in vacuo and the residue pumped to dryness,, The residue is triturated with hexane, and filtered to obtain „5 g. of crude product,, The solid in methylene chloride is treated with Nuchar charcoal, filtered and the methylene chloride removed in vacuo. The resulting oil is crystallised from absolute ethanol to obtain 2„80 g. of pure title product, m.p. 1 5-1^8°. ^ 5 o 67 and ο 75μ » Anal. Calcdo for σ21Η28°3: C' 76o795 H» 8 " 59 ; Found: C, 760 6 · ; H, 8.71° (b) dl-°3-Cyclopentyloxy--13~ethylgona--3¾5-dien-17-one A mixture of cyclopentanol (15 ml0), p_-toluenesulphonic acid (250 mgo) and heptane (250 ml0) is refluxed into a water separator for 1 hour AHP- 50-etc-f then dl-13-ethyl-3-hydroxygona- 95"dien-17-one, acetate (3,00 g.) is added and the refluxing into the water separator continued for 16 hours. The water-separator is replaced with a fresh one containing pellets of sodium hydroxide and refluxing is continued for 7 hours. Again the water separator is replaced with a fresh one and refluxing is continued for a further 1.6 hours. After cooling, pyridine (3 ml.) is added, the mixture filtered and the solvent evaporated in vacuo» The residue is pumped dry and triturated with cold methanol,. The mixture is filtered to obtain 2060 o of crude producto The solid is dissolved in ether-THF containing several drops of pyridine, treated with Nuchar and filtered. The solvent is removed in vacuo and the residue crystallised from methanol. After filtering, the solid is dissolved in a large volume of hot methanol, the mixture filtered and let stand to deposit lo26 go of title product, m.p. l4l-l43°« Finally, the solid is dissolved in ether, hexane is added, the mixture boiled to remove the ether, and let stand to deposit 0.69 go of pure title product as flat white prisms, mop. 1 1-1 3° Jj£ 5.77U, ) 243 <πμ ( 20,200).

Analo Calcd. for G^ ll^O^. C, 8.1.31; H, 9->67. Found: C, 81. 7; (c) dl^3-0yclopsnt,yloxy-13-ethyl-17(x-ethynylgona-3<3-dien-17P-ol Purified acetylene gas is bubbled through a solution of dl-3-cyclo-pentyloxy-13-ethylgona-395-dien-17-one (2.00 g„) in dry DMSO (150 ml.) for 45 minutes, then lithium acetylide-ethylene diamine (1.00 g.) is added and the mixture stirred under an atmosphere of acetylene for 2 hours at room temperature. Again lithium acetylide-ethylenediamine (l000 go) is added stirring is continued for 2 hours and the reaction is then poured into ice-water» The mixture is extracted with ether, washed, dried and the extract evaporated in vacuo. The resulting oil is dissolved in hexane and the solution passed through a short column of Florex. The hexane is removed in vacuo, then the residue AHP- 850-etc-f is dissolved in ether and treated with Nuchar charcoalo After filtering the ether is removed in vacuo and the residue pumped under KBr vacuum to complete dryness to get loOO go of the title product ^ ' max 2,95 and 3.07V-* AHP-i 850-etc-f EXAMPLE 8 A tablet for use in the prevention of conception is prepared from the following ingredients: dl-3-cyclopentyloxy-13-ethyl-17a- . ethynylgona-3s 5-d.ien-17P-ol, acetate 5 mg° carboxymethylcellulose ( OO cps) 15 mg0 lactose powder 25 mg„ redried corn starch 25 mg. magnesium stearate powder mg. calcium silicate powder q. s. 200 mg.

The tablet is prepared by dissolving the steroid in benzene, mixing the solution with starch, drying the mix in a current of air, adding the remaining ingredients, mixing and compressing the composition into slugs. The slugs are regranulated and compressed into tablets, each containing 5 mg. of the progestagen.

EXAMPLE 9 Tablets are prepared having the same composition as in Example 8, except that an equal weight of the d-enantiomorph of the progestogen, d-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3s5-dien-17P-ol, acetate is substituted for the dl-racemate. The tablet is prepared by dissolving the steroid in benzene, mixing the solution with the lactose powder and drying the mix in a current of air, then adding the carboxymethylcellulose and half the starch. With the powder thus obtained is mixed starch paste prepared from the remainder of the starch, the mixture is wet-granulated, the granules dried, the stearate added and the composition compressed into tablets.

AHP- 50-etc-f EXAMPLE 10 A capsule for use orally to prevent conception contains, in encapsulating gelatin, the following ingredients: dl-3"Cyclopentyloxy-13-ethyl-17a- ethynylgona-3s 5-(iien»17 -ol, acetate 5 mg. finely divided silica lubricant 5 mg. magnesium stearate powder 5 mg» powdered corn starch 113 mg. lactose powder q„s. 2^5 mg.

EXAMPLE 11 Formulations for prevention of conception are prepared in tablet form consisting of the following ingredients: dl-3-cyclopentyloxy-13-ethyl-17a-ethynyl-gona-3 , 5-dien-17P-ol, acetate 0.05 1, 0 5o0 10.0 20.0 microcrystalline cellulose, N.F. 20.0 2000 20.0 20.0 20.0 magnesium stearate U.S.P. 0.22 0.22 0.22 0.22 0.22 lactose U.S.P. q.s. ad lOOoO 100.0 100.0 100.0 100.0 EXAMPLE 12 Tablets for preventing conception are formulated and prepared according to Example 8 , substituting for dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-35i*-!iien-17 -'Ol, acetate, respectively, an equivalent amount of the corresponding 17β-ο1 and of dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3 , 5-clien-17P-ol, heptanoate.

AHP- 50-etc-f EXAMPLE 13 A tablet for use in the prevention of ovulation is prepared from the following ingredients: dl-3-cyclopentyloxy-13-ethyl-17a- ethynylgona-3, 5-dien-17P-ol, acetate 5 rag. dl-3-cyclopentyloxy-13-ethyl-17a-ethynyl- gona-l, 395(lO) 97-tetraen-17P-ol 1 mg. carboxymethylcellulose (kOO cps) 13 mg. lactose powder 25 mg. redried corn starch 25 mg. magnesium stearate powder k mg. calcium silicate powder q.s. 200 mg.

The tablet is prepared by dissolving the steroids in benzene, mixing the solution with starch, drying the mix in a current of air, adding the remaining ingredients, mixing and compressing the composition into slugs. The slugs are regranulated and compressed into tablets, each containing 5 mg» of the progestogen and 1 mg, of the estrogen.

EXAMPLE Ik Tablets are prepared having the same composition as in Example 13 except that an equal weight of the d-enantiomorph of the progestogen, d-3-cyclopentyloxy-13-ethyl-17cx-ethynylgona-3, 5-dien-17P-ol, acetate is substituted for the dl-racemate. The tablet is prepared by dissolving the steroids in benzene, mixing the solution with the lactose powder and drying the mix in a current of air, then adding the carboxymethylcellulose and half the starch. With the powder thus obtained is mixed starch paste prepared from the remainder of the starch, the mixture is wet-granulated, the granules dried, the stearate added and the composition compressed into tablets.

AHP-½850-etc-f EXAMPLE 15 A capsule for use orally to prevent ovulation contains, in encapsulating gelatine, the following ingredients: dl-3-cyclopentyloxy-13-ethyl-17tx- ethynylgona-395-dien-17P-olj, acetate 3 mg. dl-3-cyclopentyloxy-13-ethyl-17«- ethynylgona-l,395(lO) ,7-tetraen-17 -ol 1 mg0 finely divided silica lubricant 5 m ° magnesium stearate powder 5 mgo powdered corn starch 113 nig. lactose powder q.s. 2^5 mg.

EXAMPLE 16 Formulations for prevention of ovulation are prepared in tablet form consisting of the following ingredients: dl-3-cyclopentyloxy-13-ethyl-17a-ethynyl-gona-3 , 5-dien-17P-ol, acetate 5 9»85 205 2.0 2.0 20.0 20.0 dl-3-cyclopentyloxy- 13-ethyl-17a-ethynyl-gona-l,3 5(lO)-trien-ΐ7β-οΐ 0.075 0ol5 l«o 0o 5 0.3 5.0 macrocrystalline cellulose, N.F. 20.0 20.0 20.0 20.0 20.0 20.0 20.0 magnesium stearate, U.S. P. 0.22 0.22 0.22 0.22 0.22 0.22 0.22 lactose, U0S.P0 q.s. ad 100.0 100.0 100.0 100.0 100.0 100.0 100.0 EXAMPLE 17 Tablets for preventing ovulation are formulated and prepared according to Example 13 > substituting for dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-3, 5-dien-17P-ol, acetate, equivalent amounts of dl-3- AHP- 50-etc-f cyclopentyloxy-13-ethyl-17a-ethynylgona-3, 5-dien-17p-ol, heptanoate and dl-3-cyclopentyloxy-13-ethyl-17 -ethynylgona-3, 5-dien-17 -ol, and for the dl-3-cyclopentyloxy-13-ethyl-17a-ethynylgona-l, 3, 5(lO) , 7-tetraen-17P-ol, respectively, equivalent amounts of d-3-cyclopentyloxy-17a-ethynylestra-l, 3, 5(10) , 7-tetraen-17 -ol; 17 PROCEDURE B (dl) -3-Cyclopentyloxy-13-ethyl-17a-ethynylgona-l«,3 5(lO) , 7-tetraen-17P-ol (Alternative Procedure) Dissolve (-) -3-cyclopentyloxy-13-ethylgona-l, 3 » 5.( 10) , 7-tetraen-17-one (1( 5 go) in dimethylsulphoxide (75 ml.) and saturate the solution with purified acetylene. Add lithium acetylide ethylenediamine (0.90g.) and stir the reaction under acetylene for 1--J hours at room temperature.. Pour the reaction onto ice, extract with ethyl acetate-ether (1:1) and wash, dry and evaporate the extract. Dissolve the residue in warm hexane, and chromatograph the solution on a column of Florex XXS. Elute the product with benzene, remove the solvent AHP-^O-etc-f in vacuo. Treat a methylene chloride solution of the residue with Nuchar charcoal, filter through super eel and remove the solvent in vacuo to obtain the product as a white glass (1.33 g°); max 2.95 and 3° 10 μ.

Analysis for C^H^O^ Calcd, C, 82.93; H, 8.57%. Found: C, 82.56; H, 8 %. d-3-Cyclopentyloxy-17o-ethynylestra-l,3, 5(lO) , 7-tetraen-17P-ol is obtained by entirely analogous procedures (Belgian Patent 700,232, Example 105 ) ° The corresponding 3-cyclopentyloxy-13-alkyl-17oc-ethynylgona-li3s 5(10)-trien-17P-ols are obtained from the corresponding 17-ones of J. Chem. Soc, 1963, 5072-509^ and ibid., 196*t, ¥*72-H92, by entirely analogous procedures. In this manner there are provided 17a-ethynyl-estradiol 3-cyclopentyl ether and 3-cyclopentyloxy-13-ethyl-17

Claims (1)

1. AHP-½850A850-C ^917A 17-Cl 917-C2-fl C L A I S: A compound of the general formula (I) or 3 1 2 5 wherein R is alkyl of Zoom 2 carbon atoms 5 R , R , IT and an 6 ,-5 5 R are hydrogen or methyl/ is hydrogen or COR"^ where R is alkyl of from 1 to 10 carbon atoms, cycloalkyl of from 3 to 6 carbon atoms or monocarbocyclic aryl-(lower) alkyl„ 2o A compound as claimed in claim 1 wherein R. is ethyl„ 3. A compound as claimed in claim 1 or claim 2 wherein R is hydrogene A compound as claimed in any one of the preceding claims wherein R is hydrogen0 A compound as claimed in any one of the preceding claims wherein 2 3 R. and R are hydrogen. A compound as claimed in any one of the preceding claims wherein ^ is hydrogeno A compound as claimed in any one of claims 1 to 5 wherein R^ is CO ^ where R^ has the meaning given in claim 1. 6 8. A compound as claimed in any one of claims 1 to 5 wherein R. is COCH,. A compound as claimed in any one of claims 1 to 6 in the form of the d-enantiomer substantially free of the corresponding l-enantiomer<> 33137/2 - 45 - 3-Cyclopentyloxy-13-ethyl-17a-ethynylgona-3 , 5-(ϋβη-17β-ο1 , acetate or heptanoate. 3-Cyclopentyloxy-13-ethyl-17a-ethynylgona«3,5-dien-17P-ol. A process for the preparation of a 3-cyclopentyloxy-13-alkyl-17