IL28411A - 9alpha-unsubstituted 11beta-chloro-19-nor-steroids and their preparation - Google Patents

Description

a-UNSUBSTITUTED HB-CHL0R0-19-N0R- STEROIDS AND THEIR PREPARATION onaanl 9 tt mppa The present invention relates to' novel chlorine-substituted steroids and to a process for their preparation.

We have found that 9a-unsubstitu ed 11β-οη1θΓθ-19-ηόΓ-steroids, which are a new class ^af -compounds j; '.possess valuable hormonal activity, for. example progestational or anabolic activity- According to the present invention therefore we provide 9a-unsubstituted-ll3-chloro-19-nor-steroids.

The new steroids according to the invention may carry various ring substituents , for example in the 17-position a hydroxyl group, a protected hydroxyl group, an oxo group, or a protected oxo group, or an aliphatic, araliphatic, acetyl or acyloxyacetyl group in the presence or absence of a hydroxy! or protected hydroxyl group; in the 16-position' a methylene group; in the 6-position a chlorine or fluorine atom or a methyl group; in the 3-position an oxo, protected oxo, hydroxyl or protected hydroxyl group. The steroids may possess double bonds; for. example, the A-ring may be fully aromatic or may possess double bonds in the 1,2-position and/or the 4, 5-positioh. The B-ring may also be unsaturated, for example with a double bond in the 5,6- or 6,7- position. In general the 4- and 16- positions are preferably unsubstituted and the A, B, C and D rings are preferably not condensed with further rings.

Where acyloxy groups are present these may be substituted or unsubstituted aliphatic, cycloaliphatic , araliphatic or aryl acyloxy groups, for example acetoxy ,proplo:i^ i eK β-phenylpropionyloxy or benzoyloxy groups. aryloxy groups, especially arylmethoxy groups such as benzyloxy groups. Protected oxo groups include ketal groups, e.g. ethylene-dioxy groups and enol ether groups such as enol methyl ether groups, or enol ethyl ether groups.

The aliphatic groups which ma be present in the 17-position preferably contain 1-9 carbon atoms and may, for example, be substituted or contain unsaturation. Substituents which ma be present include for example, halogen atoms ( e .g. ' chlorine ) or hydroxy or acyloxy groups. Useful aliphatic substituents thus include methyl, ethyl, propyl, vinyl, 2-methyl-prop-2-enyl, 1-methyl-prop-2-enyl, but-2-enyl, allyl, ethynyl, chloroethynyl groups etc.

Particularly useful steroids according to the invention include the 3-οχο-Δ -ll£-chloro-19-nor-steroids and Ιΐβ-chloro-oestr-4-ene-3,17-dione, while possessing hormonal activity, is especially useful as an intermediate in the preparation of related compounds having other substituents in the 3- and/or 17- positions.

Further particularly interesting compounds include 17a-acetoxy-l^-chloro-19-nor-pregn-4-ene-3 , 20-dione 5 Ιΐβ-chloro-19-nor-pregn-4-ene-3, 20-dione; 17a-acetoxy-3-ethoxy-6 , 11β- ■ dichloro-19-nor-pregna-3 ,5-dien-20-one ; 17a-acetoxy-6 , 11β-dichloro-19-nor-pregna-4 ,6-diene-3, 20-dione } 17a-acetoxy-6a, l^-dichloro-19-nor-pregn-4-ene-3 , 20-dione ; Ιΐβ-chloro-3-ethoxy-17a-ethynyloestra-3, 11β-ο1ι1θΓθ-17α-θ h n l-17β-hydroxy-3-methox oeθtra-3 ,5-diene ; 17a-ethynyl', 17a-allyl-, 17a(2-me h l-prop-2-renyl)-, 17a-(l-meth l-prop-r2-enyl)- and 17a-but-2-enyl- llβ-chloro-17β-hydroxy-oestr-4-en-3-one; llβ-chloro-17a-ethyn l-17β-hydrox -oestra-4,6-dien-3-one ; 6 , l^-dichloro-17a-ethynyl-3^-hydroxyoestra-4 , 6-dien-3-one ; 6a, llβ-dic■hloro-17α-et ynyl-17β-hydroxyoestr-4-en-3-.one ; The new steroids according to the invention may be prepared in any convenient way. According, to a still further feature of the invention there is provided a process for the preparation of 9a-unsubstituted ll3-chloro-19-nor-steroids in which a 9a-unsubetituted lla-hydroxy-19-nor-steroid is reacted with a reagent of the general formula H3 -R5 ' ' 7 N - C - C - R' I R2 R4 R6 1 2 where R and R , which may be the same or different, are alkyl groups having 1-5 carbon atoms or aralkyl or aryl groups or, together with the nitrogen atom to which they are attached, comprise a heterocyclic radical which may, if desired, contain further hetero-atoms, 3 R is a chlorine or fluorine atom, R is a chlorine or fluorine atom 4 5 and R is hydrogen or R and R together represent a carbon-carbon bond; .

R is a chlorine or fluorine atom and 7 R is a chlorine or fluorine atom or a trifluoro-methyl groμp, the reaction being effected in the presence 3 of,.chloride ions when R and R are both fluorine . 3 / 4 Where R^ and/or R are chlorine, the compound of formula I· acts directly as a chlorinating agent but where 3 4 neither R nor is chlorine, it is necessary to carry out the reaction in the presence of chloride ions. While it is not wished to., be bound by theoretical considerations it is believed that the reagent of formula I reacts with the 11a- The chloride ion is more strongly nucleophilic than the fluoride ion so that even when neither R 3 nor R4 is chlorine, reaction in the presence of chloride ions results in the introduction of chlorine at the 11-position.

The reaction according to the invention is particularly useful because no methods have previously "been described for the preparation of Ιΐβ-chloro-steroids with a 9a-hydrogen atom and the method previously proposed for production of the analogous Ιΐβ-fluoro-steroids in the 10-methyl series having a 9a-hydrogen atom tends to give the 9,11 unsaturated product.

The source of chloride ions in the variation .of the reaction in which neither R 3.nor R4 is chlorine is preferably a salt soluble in organic solvents biit the cationic portion should be inert to the reagent of formula I for example, the cation of a tertiary or quaternary nitrogen base, e.g. triethyl-amine., trimethylamine , pyridine, collidine ,-tetrabulyl ammoniumhydroxide etc . h general, however the preferred scurce ofchloride ions is lithium chloride. i The reagents of formula I in which neither R nor R is chlorine include N-(2-chloro-l,l,2-trifluoroethyl) diethylamine , N-( 1,1 , 2 , 2-tetrafluoroethy1 )diethylamine , N-(2-chloro-l,l,2-trifluoroethyl).dimethylamine , N-(2-chlor o-l,l,2-trifluoroethyl)dipropylamine, N-(2-chloro-l,l,2-trifluoroethyl)diisobutylamine , N-(2-chloro-l,l,2-trifluoroethyl) dioctylamine , N-( 2-chloro-l, 1 , 2-trifluoro-ethyl)methylethylamine , N-( 2, 2-dichloro-l,l-difluoroethyl) die hylamine , N-( 1, 1, 2 , 3 , 3 , 3-hexafluo opropyl)diethylamine and N-( 1,1, 2 ,2-tetrafluoroethyl) diisopropylamine .

The reagent f choice is N-(2-chlorq-l,l,2-trifluoroethyl)- vinylamine .

The reaction is preferably effected in an inert solvent that is any solvent which does not react with the reagent of formula I, for example aromatic and aliphatic hydrocarbons, halogenated hydrocarbons, esters, ketones, nitriles, ethers and tertiary alcohols. Examples of such solvents are benzene, toluene, chlorobenzene , methylene chloride, pentane, hexane, cyclohexane, ethyl acetate, butyl acetate, acetonitrile , acetone, methyl ethyl ketone, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, t-butyl alcohol, t-amyl alcohol, and the like. Since the starting materials are frequently only slightly soluble in non-polar solvents, a polar solvent such as tetrahydrofuran is preferred.

Unless further chlorine substituents are required, reactive hydroxyl groups initially present in the steroid should be protected, for example by esterification, etherification etc.

The lip-chloro-19-nor-steroids according to the invention can also be prepared by reacting the corresponding lltx-aryl-sulphonate or lla-alkylsulphonate with a source of chloride ions, for example a chloride of an alkali metal e.g. lithium chloride, or a hydrochloride of a tertiary organic base such as triethylamine or a chloride of a quaternary organic base such as tetrabutyl ammonium chloride advantageously in an inert polar solvent such as tetrahydrofuran. The above, lla-sulphon-ates may be prepared by reacting the corresponding lla-hydroxy compound with an alkyl- or aryl-sulphonyl halide.

The li -chloro-19-nor-steroids according^ to the invention may also be prepared by reaction of a 9a-unsubstituted-lloc- ' compounds are the lla-hydroxy-J-oxo-A^-^-nor-steroids; of these lloc-hydroxy-oestr-4~ene-3 » 17-dione , is of especial interest in view of the importance of the corresponding Ιΐβ-chloro-compound.

The 9a-unsubstituted-lla-hydroxy-19-nor-steroids may be prepared in any convenient way. Thus, for example, the llo-hydroxy group may "be introduced into a 19-nor-steroid having no 11-substituent by microbiological methods e.g. using organisms such as Aspergillus ochraceus and Rhizopus nigricans .

The preferred method of preparing the lloc-hydroxy steroids used as starting compounds is to react a 9-dehydro steroid with diborane followed by reaction of the boron complex so formed with, for example, alkaline hydrogen peroxide as described' in our published Dutch Patent Specification No. 6611525.

The reactions according to the inventiqn and a number of subsequent reactions designed to produce various groupings into the steroid molecule are shown in the following drawings : - The 11α ,17ft-dihydroxy-19-norpregn'-4—ene-3 ,20-dione VIII used as starting material may be prepared from the relatively readily available 21-iodo-prednisolone by reduction ·e .g.' with a sulphite reducing agent, to 11β,17α-dihydroxypregna-l,4-diene-3»20-dione which may then be converted, b treatment with an N-halo-amide or N-haloimide, e.g. N-bromosuccinimide or N-chlorosuccinimide , in the presence of a tertiary organic base such as pyridine, quinoline etc. followed by treatment with sulphur dioxide to yield 17a-hydroxy-pregna-l, ,9-triene-3,20-dione which is then aromatised, for example, by reaction with activated zinc in wet pyridine, to 3il7o-dihydroxy-19-norpregna-1,3,5,(10) ,9-"fcetraen-20-one which is reacted with an alkylating agent, e.g. an alkyl halide or dialkyl sulphate such as ethyl iodide or dimethyl sulphate to form the corresponding 3-alkoxy derivative (e.g. the -me hoxy compound) which is then reacted with a ketone protecting reagent, for example a glycol e.g. ethylene glycol, to protect the 20-keto group followed by reaction with diborane and subs-ejquent treatment with alkaline hydrogen peroxide to form the corresponding 11a-hydroxy compound which may then be reduced and hydrolysed, e.g. by reaction with a metal/ammonia reducing agent , such as lithium in liquid ammonia, in the presence of a proton-source, such as an alcohol, followed by acid hydrolysis to form the desired product VIII.

As shown in the above drawings, lla-hydroxy-oestr- -en-3,17-dione (II, R = H) may be reacted with a reagent of the mesylate (II, R "» CH^SO^-) may be reacted with a source of chloride ions. Δ -l^-0hloro~19-nor-steroid-3,17-diones such as compound III can he treated further to introduce various groupings at the 17-position, where necessary after selective protection of the 3-oxo-group. Thus, for example it is possible to convert to the corresponding 3-enol ether, for example compound IV, e.g. by reaction with an enol-etherifying agent such as a gem-dialkoxy-alkane e.g. 2,2-dimethoxypropane or an alkyl orthoformate , e.g. methyl or ethyl orthoformate , in the presence of acid, e.g. a mineral acid such as hydrochloric or sulphuric acid or an organic acid such as toluene- sulphosalicylic acid p_-sulphonic acid/ or benzene sulphonic acid. The double bonds in the enol ether are in the 3 and 5(6)-positions. Other methods of protecting the 3-oxo-group include formation of a ketal or thioketal such as an ethylene, propylene or butylene ketal or thioketal or a hydrazone such as a semicarbazone , phenylhydrazone etc. The nature of the protecting system will clearly be chosen having regard to the subsequent reactions which are to be effected.

The 3-enol ethers may then, for example, be reduced e.g. with a borohydride reducing agent, such as an alkali metal borohydride e.g. sodium, potassium or lithium borohydride, to convert the 17-oxo group to hydroxyl, as in compound V. .The 17-hydroxy-3-enol ether can then be 4. converted to the corresponding 3-οχο-Δ -steroid by hydro- ' lysis e.g. with a mineral acid such as hydrochloric, hydrobromic or sulphuric acid. If desired, the 17- V or propionic anhydride or acetyl or propionyl chloride or bromide .

The 17-oxo-3-enol ethers can also be reacted with organo-metallic reagents to introduce a 17oc-hydrocarbon substituent together with a 17P-hydroxy group. Thus, for example, an acetylide, e.g. an alkali metal acetylide, such as sodium or potassium acetylide, may be used to give the extremely useful 17oc-ethynyl-17P-hydroxy derivative, for example compound VI or reaction with a G-rignard reagent, e.g. an aliphatic magnesium chloride, bromide or iodide., may be used to give the 17a-aliphatic-17P-hydroxy-compound e.g. a 17a-methyl derivative such as compound 711 or the corresponding 17 -allyi, 2-methyl-prop-2-enyl , l-methyl-prop-2-enyl or but-2-enyl compounds. . Again the 17-hydroxy group can, if desired, be acylated before or after hydrolysis of the enol ether grouping.

The 3-oxo steroids can be converted into the corresponding enol esters by reaction with an acylating agent, such as an anhydride e.g. acetic or propionic anhydride, in the presence of an acid e.g. perchloric acid, toluene—p_-sulphonic acid or sulphosalicylic acid. The reaction may be effected in an inert organic solvent, e.g. a hydrocarbon, halogenated hydrocarbon or ester solvent, or an excess of the anhydride may be used as solvent. This reaction, as h applied to 3-οχο-Δ -steroids, leads to the corresponding x 5 3-acyloxy-A ' ^-steroids. Where there is a free hydroxyl group present, e.g. at the 17-position, this may be acylated simultaneously. acylation using an appropriate acyl anhydride or halide will yield the corresponding 3~ and/or 17-acyloxy derivative, for example the acetate or benzoate. The borohydride reduction can be carried out in the presence of a conjugated double bond and, for example, Δ -3-ketones can be, reduced in this way.

Where it is desired to produce the 3- and/or 17-acyloxy compounds according to the invention or the corresponding 3-and/or 17- ethers, these can be prepared by reaction of the corresponding 3- and/or 17- hydroxy steroids or 3-oxo-steroids with an acylating agent for example an acyl halide or anhydride, e.g. acetic, propionic or benzoic anhydride or chloride, or an etherifying agent for example an alkyl or aralkyl halide, sulphate or arylsulphonate. 3-Oxo steroids will, of course, form the corresponding enol or dienol ethers or esters as indicated above.

The 6β-ο1ι1θΓθ-3-οχο-Δ -steroids according to the invention are of particular importance. They can be prepared by reaction of a 3-acyloxy or 3-alkoxy-A^,^-llp-chloro-19- ' nor-steroid with a chlorinating agent such as molecular chlorine preferably in the presence of a carboxylic acid such as acetic, propionic or pivalic acid and a tertiary base such as trimethylamine , triethylamine or pyridine, or with an N-chloro-amide or -imide e.g. N-chlorosuccinimide or N-chloro-acetamide, preferably in the presence of an inorganic or organic base, e.g. an alkali metal acetate such as sodium or potassium acetate or a tertiary amine such as triethylamine, trimethylamine or pyridine in the presence of a carboxylic methoxy or ethoxy group. h.

The 6a-chloro-3-oxo-A -steroids according to the invention are also of particular interest and these can "be obtained from the corresponding 6p-chloro-steroids "by converting to the enol ethers or esters, e.g. using the methods described above followed by hydrolysis, e.g. acid hydrolysis, for example using a mineral acid such as hydrochloric, hydrobromic or sulphuric acid or an organic acid such as acetic, propionic or toluene-p_-sulphonic acid, to remove the 3-ether or ester group. 4- 6 3-0χο-Δ ' -steroids according to the invention can be prepared by reaction of. a corresponding 3-acyloxy or 3-alkoxy-Δ ' -steroid with a reagent capable of converting an or ester enol ether/into a conjugated ketone, for example chloranil or manganese dioxide. 17a-Acyloxy-3-keto-A -steroids according to the invention may be obtained from the corresponding 3β » 17α-diacyloxy-Δ^' ^-steroids by selective hydrolysis at the 3-position e.g. usin a basic reagent such as an alkali metal or an acidic reagent, e.g. an organic or mineral acid, hydroxide, e.g. sodium or potassium hydroxide/ preferably in a polar solvent medium such as methanol, ethanol, dioxah, tetrahydrofuran etc.

There is now given the preferred method of preparation of a number of particularly important compounds according to the inventions The compound li -chloro-17a-ethynyl-17 -b.ydroxy-3-methoxy-oestra-3 , 5-diene XX (R » CH^) may conveniently be prepared by reaction of 113-chloro-3-niethoxy-oestra-3 , 5-dien- conveniently together with a co-solvent, for example, diethyl ether, dioxan or tetrahydrofuran. This compound is also of use as an intermediate in preparing ll ~chloro-17a~ ethynyl-17 -hydroxyoestr- -en-3-one. l^-Chloro-17a-ethynyl-3-ethoxyoestra-5 , 5-dien-173~ol XX (R = 0^3.^ m y be prepared by a method analogous to that described above for the corresponding 3~methoxy compound by reaction of lip-chloro-3-ethoxyoestr-3 , 5-dien-17-one XIX (R = CgH^) with an acetylide. The starting material may be prepared by reacting l^-chloro-oestr-4~en-3 , 17-dione III with an ethylating agent e.g. a transetherification agent such as ethyl orthoformate in the presence of an acid catalyst e.g. a mineral acid such as hydrochloric or sulphuric acid or an organic acid such as toluene-£-sulphonic acid or sulphosalicylic acid. 6 , lip-Dichloro-17a-ethynyl-17 -hydroxyoestr-^—en-3-one XXII may be prepared by reaction of a corresponding 3-alkoxy-3 , 5-diene with a chlorinating agent such as an N-chloro-amlde or-imide, e.g. N-chlorosuccinimide as described above. The 3-alkoxy group may, for example, be a methoxy or ethoxy group A 6β-οη1θΓθ-4·-θη-3-οηθ can be converted into the corresponding 6cx-chloro compound by enol alkylation, e.g. etherification using an alkyl orthoformate and acid,or enol esterification, e.g. using an acid anhydride and an acid catalyst followed by hydrolysis of the resulting 6-chloro-3 , 5-diene, e.g. in an acid medium. The acid may be an organi acid, e.g. acetic or propionic acid, or a mineral acid, e.g. hydrochloric acid. The conditions may be mild and standing eth.ynyl-17P-hyd.FOxyoestr- -en-3-oiie with an alkyl ortho-formate followed by hydrolysis of the resulting 6,11β-dichloro-3»5-diene XXIII with acetic acid. l^-Chloro-17a-ethynyl-^-hydroxyoestra- ,6-dien-3-one XXI may be prepared from an li -chloro-17a-ethynyl-3~ alkoxy or 3-acyloxy by reaction with a reagent capable of converting an enol ether or ester to a conjugated ketone, e.g. chloranil or manganese dioxide, the latter reagent being preferred where enol esters are to be dehydrqgenated. 17a-Acetoxy-l^-chloro-19-norpregn-4-ene-3,20-dione XI may be prepared conveniently by hydrolytic de-acetylation at the 3-position of 3,17a-diacetoxy-l^-chloro-19-norpregna-3,5-<3.ien-20-one, X. The hydrolysis can be effected under acidic or basic conditions e.g. using aqueous mineral acid, for example hydrochloric or sulphuric acid, or an alkali metal hydroxide, preferably in a polar solvent medium such as methanol, ethanol, dioxan, tetrahydrofuran etc.

The 3»17a-diacetoxy-l^-chloro~19-norpregna-3,5-dien-20-one X used as starting material may conveniently be prepared by acetylation of l^-chloro-17a-hydroxy-19-nor-pregn- -ene-3»20-dione IX, e.g. using an acetyl halide or acetic anhydride preferably in the presence of an acid^ catalyst e.g. a sulphonic acid such as toluene-p_-sulphonic or methane-sulphonic acid.

The l^-chlor0-17a-hydroxy-19-norpregn- -ene-3 ,20-dione IX starting material is conveniently prepared by reaction of the corresponding 11a-hydroxy compound VIII with 3 , 17a-Diacetoxy-lip-chloro-19-E.orpregna-3 , 5-dien-20-one X may also be used as starting material for the preparation of ^-chloro-derivatives , which are also of interest in "the progestational field, by reaction with a chlorinating agent. Molecular chlorine, preferably in the presence of triethylamine and acetic acid, yields a mixture of the desired dichloro-compound, 17oc-acetoxy-6p, 11 -dichloro-19-norpregn-4~ene-3,20-dione XV with one or more of the tri-chloro-compounds, 3 ξ , 17a-diacetoxy-34 , 6p,li -trichloro-19-norpregn-4—en-20-one XIII and 3 , 17oc-diacetoxy-54 ,6P,l^-trichloro-19-norpregn-3-en-20-one XIV. The trichloro compounds yield the dichloro-compound XV by treatment with acid, e.g. acetic acid.

Compound XV may be converted into the corresponding 3-alkoxy-3 , 5-diene , e.g. by reaction with an alkyl orthofor-mate in the presence of an acid catalyst such as toluene-jD-sulphonic or sulphosalicylic acid. Thus triethylortho-formate yields 17a-acetoxy-3-ethoxy-6,li -dichloro-19-nor-pregna-3 , 5-dien-20-one XVI. The 3-alkoxy-3 , 5-diene may then be. converted into the corresponding 17 Compound XVI may be converted into 17a-ace(toxy-6a'li -dichloro-19-norpregn- -ene-3»20-dione XII by hydrolysis in an acid medium. The acid may be an organic acid, e.g. acetic or propionic acid, or a mineral acid, e.g. hydrochloric acid. The conditions may be mild and standing at room temperature in acetic acid is normally effective.

P. A. 28^11/11 According' o a still further feature of the invention we provide pharmaceutical compositions comprising one or more ?a-unsubstituted-11 -chloro-19-nor-steroids together with a pharmaceutical carrier or excipient and/or one or more further active compounds e.g. hormones. Compounds having progestational activity may advantageously he formulated in conjunction with one or more hormones having oestrogenic activity. .

The compositions according to the invention are intended for administration to both humans and animals. The term "pharmaceutical" as used herein to describe compositions and carriers means therefore that these are of use in both human and veterinary medicine.

The compositions are .preferably in the form of dosage units and may be formulated for daily oral administration in such forms as tablets, capsules, sachets etc., either for taking directly or with a draught. Suppositories for rectal absorption may also be employed. Injection preparations may be formulated, preferably for more prolonged action, while implantation pellets may be formulated having the advantage of requiring very infrequent administration.

Conventional pharmaceutical excipients for solid preparations may for instance include sugar alcohols, sugars, starch, magnesium stearate, gelatine, polyethylene glycols and suitable colouring agents. Tablets may be coated for protection, colour distinction or elegance by conventional methods such as film coating or sugar or pearl coating.

Suppositories may be prepared, using conventional bases such . as glyco-gelatine , cocoabutter, or water-dispersible bases with a melting point above body temperature, such as poly-glycols. ΪΟΓ injection purposes, preparations for intramuscular or subcutaneous administration may be prepared in conventional sterile oily, aqueous or emulsion bases, in solution and/or suspension. Vehicles preferably include physiologically acceptable vegetable oils, e.g. arachis oil, fractionated coconut oil; oily esters, e.g. isopropyl-myristate ; nonaqueous solvents, e.g. propylene glycol; aqueous vehicles such as sterile water or physiological saline; together with suitable formulatory agents such as suspending agents, e.g. aluminium stearate for oily materials, carboxymethyl cellu-lose for aqueous preparations; physiologically acceptable emulsifying agents, e.g. "Tween" 81, buffering agents for pH control, anti-oxidants , stabilising and solubilising agents. The injections may be formulated for immediate use, or as quantity of active material.

Each dosage unit for daily administration to humans preferably contains 0.05 to 5.0 mg. active material according to the invention, advantageously 0.2 to 2.0 mg.

Implantation pellets would in general contain a much higher dosage to cover prolonged activity for preferably several months. Implants may be prepared aseptically from sterile material, by fusion or heavy compression, preferably without the addition of other substances.

For veterinary use in particular, long acting vaginal inserts such as tampons and pessaries may be prepared in a conventional manner. The dosage required for animal treat-ment will of course, vary according to the size of the animal .

The following compounds according to the invention have given particularly good results in tests demonstrating hormonal activity: - 17a-Acetoxyr-li -chloro-19-nor-pregn- -ene-3,20 dione XI 3,17a-Diacetoxy-li -chloro-19-nor-pregna-3 ,5-dien-20-one X l^-Chloro^l9-nor-pregn~ -ene-3»20-dione XXV 17a-Acetoxy-3-ethoxy-6,li -dichloro-19-nor-pregna-3,5-dien-20-one XVI 17a-Acet'oxy-6, li -dichloro-19^nor-pregna- ,6-diene-3,20-dione XVII 17a-Acetoxy-6a , li -dichloro-19-nor-pregn- -ene-3 » 20-dione XII li -Ohloro-17 -ethynyl-17 -hydroxy-3-methoxyoestra-3,5-diene XX(R=CH,) liP-Chloro-17 -ethynyl-17 -hydro3 yoestr- -en-3-one l^-Chloro-3-ethoxyoest:i¾.-3,5~dien«-17-one IXCR^CgH^) lip~Chloro-3-methoxyoest%i3 IV lip-Chloro-oestr-4--ene-3,17-dione . Ill Compounds III, IV and XIX have shown good anabolic/ ratios androgenic activity/ All the rest of the above compounds possess progestational and antioestrogenic activity several times greater than that of progesterone. Compounds XI and XVII have shown exceptional progestational activity and compound XXV has shown exceptional antioestrogenic activity.

The progestational compounds listed above may be employed as oral contraceptives, preferably either in continuous daily doses of 0.05 to 0.5 mg. or given intermittently at higher doses mixed with an oestrogen (0.05 nig. ethynyl oestradiol plus Ο.5-5 mg. progestagen). Apart from their use as oral contraceptives these progestagens may be employed clinically in the following conditions; dysmenorrhoea, functional uterine bleeding, pre-menstrual tension, diagnosis of pregnancy, endometriosis and threatened or habitual abortion.

For the better understanding of the invention the following Examples are given by way of illustration onlyj all temperatures are in °G.

Example 1 Preparation of Ιΐβ-chloro-oestr~4"-ene- ^ 17-dione from ( a) lla-hydrox.yoestr-" --ene-3 , 17-dione and Ν,Ν-diethyl- triohlorovinylamine lla-Hydroxyoestr-4-ene-3 ,17-dione (6 g.), prepared as in Example 3 of our Dutch. ¾1aat Applicatlm,NoJ6611525 in tetrahydrofuran (350 ml.) was heated under reflux in an atmosphere of nitrogen with Ν,Ν-diethyltriohlorovinylamine (40 ml., 9 mole equivs.). After 24 hr. , the solvents were removed in vacuo and the crude product was isolated in chloroform and purified by chromatography on magnesium silicate (350 g.).

Elution with 0 ethyl acetate/benzene gave Ιΐβ-chloro·-· oestr-4-ene-3»17-dione (1.58 g,, 25$) which crystallised as prisms (methanol), m.p. 185-7°. It had spectral data resembling that of the authentic specimen prepared by the method described below. . Addition of lithium chloride (3.6 mole equivs* ) to this reaction mixture resulted in a similar reaction to yield Ιΐβ-chloro compound. (b) lla-Hydrox.yoestr-4~ene-3.17-dione and N~(2~chloro-l,l,2~ trifluoro-ethyp-diethylamine in presence of lithium chloride A mixture of lla-hydroxyoestr-4-ene-3 , 17-dione (5 g.) in tetrahydrofuran (100 ml.) with N-(2-chloro~l,l,2-trifluoro~ ethyl )-diethylamine (10 ml., 3.1 mole equivs.) and anhydrous lithium chloride (25 g», 35 mole equivs.) was heated under chroniatographed on magnesium silicate (250 g.). Elution with 25 ethyl acetate in benzene gave ll -chloro-oestr-4-ene-3 ,17- dione (1.8 g., 3 %) which crystallised from methanol as prisms m.p. 188-189% /"a_7D + 199° (c 0.7 chloroform), max, 237 αΐμ (e 17,600) (Found: C, 70.4; H, 7.7; CI, 11.5. ci8H23C102 requires C, 70.5} H, 7.6; CI, 11.6 ). (c) llq-Mesyloxyoestr-4-ene- , 17-dione and lithium chloride lla-Mesyloxyoestr-4-ene-3 , 17-dione (0.05 g. ) in tetrahydrofuran (5 ml.) was heated under reflux (3 days) with anhydrous lithium chloride (0.25 g.). Evaporation of the solvent in vacuo and isolation of the product in ethyl acetate gave ll|3-chloro-oestr-4-ene-3 , 17-dione which had similar spectral characteristics to the products described above .

Example 2 ll6-Chloro-3-methox oestra-3. ( )-dien-17-one .. A mixture of ll -chloro-oestr-4-ene-3, 17-dione (2.51 g. ) dime hoxypropane (12,5 ml.), dimethylformamide (12.5 ml.), methanol (0.5 ml.) and toluene jD-sulphonic acid (0.077 g. ) was heated under reflux for 4 hr. The cooled solution was poured into water containing some sodium hydrogen carbonate and the product, after isolation in ether, was crystallised from methanol containing a little pyridine to give rectangular prisms of ll -chloro-3-methoxyoestra-3,5(6)-dlen-17-one (0.97 g., 37 ), m.p. 133-134°, Z~a7D + 1° (c 0.8 dioxan), Xmax. 241 πιμ (e 19,800). (Pound: C, 71.1; H, 7.6; CI, 11.2.

C19H25C102 re(luires c> 71.1; H, 7.9; CI, 11.1%).

Example 3 (0.212 g.) in methanol (20 ml.) was added sodium (ca 0.2 g. ) followed by sodium borohydride (0.25 g. ) and the mixture was heated under reflux (2 nr.). Evaporation of the solvents in vacuo and trituration of the residue with water gave a filterable product which was dried and crystallised from methanol (containing a little pyridine) to give 11β-οη1θΓθ-3-methoxyoestra-3 , 5(6 )-dien-17B-ol (0.07 g. , 33 ) as rectangular prisms, m.p. 78-80°; max. 240 πιμ (e 17,800). Spectral data accorded with the above structure.

Example 4 llB-Chloro-17a-eth.ynyl-17B-h.ydroxyoestr-4-en-3-one A solution of, sodium acetylide in liquid ammonia was made by passing acetylene (3 hr.) through a solution of sodamide in liquid ammonia, made from sodium (0.47 g. ) dissolved in liquid ammonia (60 ml.), and catalysed by ferric nitrate (6 mg.). To the solution was added ll -chloro-3^methoxyoestra-3,5(6 )-dien-17-one (0.42 g.) in ether-tetrahydrofuran (1:1, 40 ml.) followed, (after 12 hr, ) , by ammonium chloride (jc_a 2 g.).

After evaporation of the ammonia and solvents in vacuo, the product was isolated in ethyl acetate and tre.ated with a solution of concentrated hydrochloric acid (0.3 ml.) in water (10 ml.), and methanol (50 ml.) at the boiling point (1 hr.). Evaporation of the solvents in vacuo and crystallis-ation of the residue twice from ether-acetone gave 11β-chloro-17α-et ynyl-17β-h droxyoestr-4-en-3-one (0.15 g., 33$), m.p. 230-232° ( crystal change at 215°), ~α-_¾ + 64° (c 0.6 chloroform). Xmax. 239 πιμ (e 16,500). (Pound: C, 72.1; H, 7.5; CI, 10.6. C H C10 requires G, 72.2; Example 5 llB~Chloro-17B"liyclroxy-17a-meth.yloea r-4-en-3-one llB-Chloro-3-methoxyoestra-3, 5(6 )-dien-17-one (0.49 g. ) in tetrahydrofuran (14 ml.) was added dropwise to a solution of methylmagnesium iodide, made from magnesium (0.58 g.) and methyl iodide (1.5 ml.) in ether (14 ml.). The reaction mixture was heated under reflux for 2 hr., and a saturated solution of ammonium chloride was then added. The product (0.5 g.) was isolated in ether and hydrolysed in methanol (35 ml.) by a solution of concentrated hydrochloric acid (0.3 ml.) in water (10 ml.). The product was chromatographed on magnesium silicate (100 g.), elution with 5 o ethyl acetate in benzene giving a crude specimen of llB-chloro-17B-hydroxy-17a-methyloestr-4-en-3-one which was contaminated with ca. 25$ of 17-ketonic material as indicated by the inf ared spectrum.

Example 6 llB-Ohloro-17a~ethynyl-17B-hydroxy-3-methoxyoestra- .5-diene (XX R = CH^) llB-0hloro-3-methoxyoestra-3,5-dien-17-one XIX (R = CH5) (1.4 g. ) in tetrahydrofuran (80 ml.) was added to a solution of lithium acetylide made by passing acetylene (5 hr.), through a solution of lithium aluminium hydride (5 g.) in tetrahydrofuran (250 ml.). After 16 hr. the excess of acetylide was decomposed by a saturated solution of sodium potassium tartrate and the solution was dried over magnesium sulphate. Evaporation of the solvent and crystallisation of the residue from isopropanol-water, and then from ether-light 3,5-dieneXX (R = OE^) (0.107 g. , 15/ , m.p. 131-133°, max. 240 ιημ (e 18,400). (Pound: C, 72.4; H, 7.8; CI, 10.2.

C21H27C102 re¾ulres c» 72.7; H, 7.85; CI, 10.2#).

Example 7 llB-Chlor,o-3-ethoxyoestra-3,5-dien-r7-one XIX. (R =. C Hc ) Toluene-jD-sulphonic acid (42 mg.) and ethyl, ortho- formate (3 ml.) were added under nitrogen to Ιΐβ-chloro- oestr-4-ene 3,17-dione XVIII (3 g.) in dioxan (15 ml.).

After 70 min. , pyridine (10 drops) was added and the reaction mixture was partitioned between dilute aqueous sodium hydrogen carbonate and ether containing a trace of pyridine. Evaporation of the ether layer to dryness and crystallisation ,of the residue from ether-light petroleum (tup. 40-60°) gave llB-chloro-3-ethoxy-oestra-3 , 5-dien-17- one (1.8 g.). Recrystallisation from ether gave prisms, m.p. 144-145°, max. (in EtOH) 241 nm (e.20, 700).

Example 8 llB-Chloro-17a-ethynyl-3-ethox.voestra-3t 5-dien-17B-ol.

Sodium (1 g.) was added to liquid ammonia (ca. 200 ml.) containing ferric nitrate (20 mg. ) and the solution was stirred for 75 min., and then acetylene was passed through the solution for 2 hr. A solution of ll3-chloro-3-ethoxy- oestra-3,5-dien-17-one XIX (R = C2H"5) (2 g. ) in tetrahydro- furan (60 ml.) was added and acetylene was passed through the solution for a further 21 hr. during which time the ammonia evaporated.

Ammonium chloride was added, followed by 2N-sodium methanol containing a trace of pyridine gave 11β-οη1θΓθ-17α-ethynyl-3-ethoxyoestra-3,5-dien-^-ol XX (R = C2H5)(1.2 g.), m.p. 122-126°, Z~a_7D 240.5 nm. (e 21,600) .(Pound: C, requires C, 72.3; H, 8.I96).

Example 9 6β ,llS-I)ichloro-17a-eth.yn.yl-17B-h[ydrox.yoestr-4--en-3-one XXII a) From llp-Chloro-17a-ethynyl-3-ethoxyoe8tra-5 , 5- dien-l7B-ol XX (R = C.2¾) Sodium acetate (0.5 g. ) in water (5 ml.) was added to l^-chloro-17a-ethynyl-17 -hydroxy-3-ethoxyoestra-3 , 5-diene XX (R = C2H^) (1 g. ) in acetone (40 ml.). The solution was cooled to 0° in an atmosphere of nitrogen and N-chloro-succinimide (560 mg.) was added, followed immediately by acetic acid (0.5 ml.). The solution was stirred at 0° for 30 min. and poured into ice cold water. The white precipitate was collected and crystallised from aqueous acetone to give 6β , llβ-d chloro-17α-ethynyl-17β-hydrox oestr- -en-3·-one XXII (0.55 g.), m.p. 189-192°. (Pound: C, 65.6; H, 6.35? 01, I9.3. C20H24C12°2 re¾uires c» 65. » H, 6.6; CI, 19.3$)· b) Prom llB-chloro-17a-ethynyl-3-methoxyoestra-3f 5- dien-176-ol XX (R = CH^) Sodium acetate (0.45 g.) in water (4.5 ml.) was added to llβ-chloro-17α-ethynyl-3-methoxyoestra-3 , -dien-17β-ol XX (R = CH5) (0.868 g.) in acetone (30 ml.) at 0°. N-chloro-succinimide (0.55 g.) and acetic acid (0.45 ml.) were added and after 2 hr. the mixture was diluted with water. The precipitate was collected . and crystallised from ether to dioxan), XmQV (in EtOH) 237 nm (e 14,400) (Found: C, 64.8; H, 7.0; 01, 19.0. C20H24G12°2 re¾uires c» 55.4; H, 6.6; CI, 19.3 ).

Example 10 6. llB-Dichloro-17a-ethynyl-3-ethoxyoestra-3.5-dien-17B-ol XXIII 6β , ll -Dichloro-17a-ethynyl-17p-hydroxyoestr-4-en-3-one.

XXII (200 mg. ) was dissolved in dioxan (5 ml.) and triethyl-orthoformate (0.2 ml.) and sulphosalicylic acid (20 mg. ) were added under nitrogen. The solution was stirred at room temperature for 90 min. and then poured into sodium bicarbonate solution. The steroid was extracted with ether containing a trace of pyridine and crystallised from aqueous methanol to XXIII (150 mg.), m.p. 110-114°, Xmov (in EtOH) 251 nm (e 23,280).

Example 11 6qt llB-Dichloro-17a-ethynyl-17B-h,vdroxyoestr-4-en-3~one XXIV .6 , ll -Dichloro-17a-ethynyl-3-ethoxyoestra-3 , 5=dien-17p-ol XXIII (260 mg. ) was dissolved in acetic acid (10 ml.) and the solution was allowed to stand at room temperature for 17 nr.

The reaction mixture was poured into sodium bicarbonate solution and the white solid was filtered off, washed with water and dried. Crystallisation from acetone/petroleum ether (40-60°) gave 6a, ll3-dichloro-17a-ethynyl-17 -hydroxyoestr-4-en-3-one XXIV (90 mg.), m.p. 172-174°, mav (in EtOH) 233 nm, (e 14,970). (Found: C, 65.4; H, 6.6. C20H24012°2 recluires c» 65.4; H, 6.6%), Example 12 llB-Chloro-17a-ethynyl-17B-hydroxyoestra-4.6-dien-3-one XXI - - - - - ,; - - - - nitrogen for 3 r. , ethyl acetate was added and the solution was washed with 2N-sodium hydroxide, water, dried (MgSO^) and evaporated. Trituration of the residue with ether and crystallisation from aqueous methanol gave llp-chloro-17a-ethynyl-17£-hydroxyoestra-4,6-dien-3-one XXI (100 mg.), m.p. 255-260° (decomp.), ·λ_deβlA„. o . (in EtOH) 280 nm (e 28,000).

^J^ + 50° (c, 0.5 in dioxan) (Found: C, 72.5; H, 7.0.

C20H23C12°2 re¾uires °» 72.6; H, 7.0 ).

Example 13 17a-Acetoxy-6B ,llB-dichloro-19-norpregn-4-ene-3 ,20-dione XV 3, 17a-Diacetoxy-llB-chloro-19-norpregna-3 , -dien-20-one X (329 mg. ) in dry, ethanol-free , chloroform (10 ml.), dry triethylamine (1.2 ml.) and dry glacial acetic acid (1.8 ml.) at 0° was treated with a 0.147M solution of chlorine in carbon tetrachloride (5.5 ml., 1.05 mole equivalents).

The solution was stirred at 0° for 1 hr. before being partitioned between chloroform and dilute aqueous sodium bicarbonate. The chloroform layer was dried (MgSO^), filtered and evaporated under reduced pressure to leave a white foam. This was subjected to preparative thin layer chromatography on silica gel containing ultraviolet fluorescing agents.

Two main bands were isolated, the more polar (76 mg.) being the desired 17a-acetoxy-6B , llB-dichloro-19-norpregn-4-ene-3.20-dione ■ XV. The less polar substance (215 mg. ) failed to exhibit the absorption characteristic of an α,β-unsaturated ketone when the chromatogram was examined by an ultra-violet lamp emitting at 254 nm and hence may be presumed to contain only isolated chromophores .

XIV or a mixture of these compounds. When dissolved in glacial acetic acid (10 ml.), heated on a steam-hath for 30 minutes and isolated by the removal of the solvent under reduced pressure this material afforded 17α-acetoxy-6β,llβ-dichloro-19-norpregn-4-ene-3 ,20-dione identical in all respects with that obtained above. This crystallised on trituration with ether to give white prisms, m.p. 183-185° dec. O.J^ + 3.9° (dioxan, 0.89), av (in EtOH) 237 nm (e 15,500). Found: C, 61.2} H, 6.6} 01, 16.05. C22H28C120 , H2° re¾uires °» 61.15; H, 6.65} CI, 16.45%).

Example 14 17a-Aoetoxy-3-ethoxy- 1 llB-dichloro-19-norpregn- « 5-dien-20-one. XVI 17a-Acetoxy-6B ,ΙΙβ-dichlor o-19-norpregn-4-ene-3, 20-dlone XV (144 mg. ) and triethyl orthoformate (2 ml.) in dry dioxan (5 ml.) were treated with sulphosalicylic acid (38 mg. ). After 2· hr, at room temperature, pyridine (5 drops) was added to the solution which was then partitioned between ether and water. The ether layer was washed twice with water, dried over magnesium sulphate, filtered and evaporated to leave a colourless foam. This was crystallised from ether to afford 17a-acetoxy-3-ethoxy-6t llB-dichloro-19-norpregna-3 s 5-dien-20-one XVI (84 mg. ) as colourless prisme, m.p. 128° dec, ^ ^ - 78,2°, (c, 0.71, in dioxan), max (in EtOH) 251 nm, (e, 21,950) (Pound: C, 63.4} H, 7.0} Gl, 15.05 C24H32C12°4 re(luires G» 63.25} H, 7.1} CI, 15.5.5%).

Example 15 acid (5 mle) and the solution was allowed to stand at room temperature overnight. The solvent was removed under reduced pressure an,d the residual gum was subjected to preparative thin layer chromatography. This afforded two products, the more polar (82 mg,) being identical with 17a-acetoxy-6β , ll -dichloro-19-norpregn-4-ene-3, 20-dione XV. The less polar product (55 mg.), which crystallised as prisms on contact with ether, was characterised as the desired 17a-acetoxy-6a, llB-dichloro-19-norpregn-4-ene-3 , 20-dione XII by its proton magnetic resonance spectrum (in CDCl^) which showed signals at f5.62 (broad multiplet, protons at and Clla respectively), γ 4.46 (singlet, 1 proton at C^). Example 16 17a-Acetoxy-6 ,llB-dichloro-19-norpregna-4,6-diene-3120-dione XVII 17a-Acetoxy-6 ,llB-dichloro-3-ethoxy-19-norpregn-3 , 5-dien-20-one XVI (196 mg.) in dry ji-butanol (50 ml.) was treated with chloranil (187 mg.). The mixture was refluxed with stirring for 2½· hr, the solvent was removed under reduced pressure and the residue was taken up in ether (300 ml:. ) and washed with 2N aqueous sodium hydroxide followed by water. The ethereal solution was dried (MgSO^) and evaporated to afford a foam (100 mg.)» This was subjected to preparative thin layer chromatography to give 17a-acetoxy-6,l^-dichloro-19-norpregna-4,6-dien-3, 20-dione XVII, XfflOT (in EtOH) 280 nm (e 19,600) as a colourless foam (35 mg. ) .

Example 17 llB-0hloro-17a-hydroxy-19-norpregn÷4-ene- t 20-dione IX and anhydrous lithium chloride (500 mg. ) were stirred together in dr tetrahydrofuran (10 ml.) for 2 hours at room temperature The reaction mixture was partitioned between chloroform and water and the organic layer was dried and evaporated to leave a gum. This was subjected to preparative thin-layer chromatography which afforded the main product as crystals.

These were recrystallised from acetone/petroleum ether (60-80°) to give llB-chloro-17a-hydroxy-19-norpregn-4-ene- , 20-dione IX (61 mg. , 55%) as prisms, m. p.196-198° , Ζ~α_7ρ + 128° (dioxah, o 0.64), XmQ„ 232.5 nm. (ε 17,400) in tetrahydrofuran, (Pound: C, 68.4; H, 7.75} CI, 9.64. C20H2yC105 requires C, 68.4; H, 7.8; CI, 10.1%). (86 mg.) and toluene-p-sulphonic acid monohydrate (79 mg.) in dichloro-me thane (2 ml.) were treated with acetic anhydride (2 ml.). After 6 hours at room temperature, the solution was poured into chloroform and washed with aqueous sodium bicarbonate. The organic layer was dried and evaporated under reduced pressure to give a colourless crystalline residue which on recrystallisation from acetone/petroleum ether (60-80°) afforded 3 17a-diacetoxy-llB-chloro-19-norpregna-3 i -dien-20-one X (46 mg., 47 ) as colourless needles m.p, 219-221°, Z~aJ7D.- 56.6° (dioxan, c 0,64), max 234 nm. (ε 18,400) (Found: C, 66.3; H, 7.2; CI, 8.0. C24H51C105 requires C, 66.3; H, 7,2; CI, 8.15%).

Example 19 1 - etox - l -ohl r -1 -n re n- -ene- 2 -dione XI 1 equivalent of methanolic potassium hydroxide. After 15 minutes the solution was partitioned "between water and ether and the ether layer was dried and evaporated to leave a crystalline residue. · This was recrystalllsed from ace one/cyclohexane to afford 17 -aoetox.y-llB-chloro--19-norpregn-4-ene^3120--dione XI (71 mg., 78$) as colourless needles, m.p. .211-212°, L~ a_7;D + 69.1° (dioxan, c 0.94), Xmax> 237.5 nm. (ε 17,300) (Pound: C, 67.1? H, 7.5; CI. 8.9. C22H2gC104 requires 0, 67.2; H, 7.45; 01, 9.0 ).

Example 20 ll3-0hloro-oestr-4-ene-3 , 17-dione lithium chloride (3.3 g. ) w s added to a solution of lla-hydroxyoestr-4-ene-3,17-dione (5 g.) in tetrahydrofuran (125 ml.) under nitrogen at 0°, followed by N-(2-chloro-l,l,2-trifluproethyl)-diethylamine (5 ml.). After 30 min. the mixture poured into iced water (3 1.) to precipitate 11β-chloro-oestr-4-ene-3, 17-dione (4.68 g.), m.p. 160-164°, (in EtOH) 238 nm. (e 16,200).

Example 21 llB-Chloro-3-methoxyoestra-3 , 5-dien-17-one t ■ Methyl orthoformate (2.5 ml.) and toluene-jD-sulphonic acid (35 mg, ) were added under nitrogen to Ιΐβ-chloro-oestr-4-ene-3, 17-dione (2.5 g. ) in dioxan (12.5 ml.) and the- solution was stirred for 70 min. The reaction mixture was poured into sodium bicarbonate solution and the steroid was extracted with ether containing a trace of pyridine. Removal of solvent from the extract left a gum, which 'was triturated with methanol containin a trace ''of pyridine to give l^-chloro-3-methoxy- Example 22 llB-Chloro-17a-ethynyl-5-methoxyoeatra-5, 5-dien-176-ol Sodium (1.25 g. ) ' was . added to liquid ammonia (ca. 250 ml.) containing ferric nitrate (25 mg.), the solution was stirred for 90 min. , and the acetylene was passed through the solution for 2 hr. A solution of llB-chloro-3-methoxyoestra-3 , 5-dien —-17-one (2.65 g. ) in tetrahydirofuran (75 ml..) was added and acetylene was passed through the solution for 20 hr., during which time the ammonia evaporated.

Ammonium chloride was added, followed "by sodium bicarbonate solution and the steroid was extracted with ether containing a trace of pyridine. Crystallisation from methanol containing a trace of pyridine gave llB-chloro-17a-ethynyl-3-methoxyoestra-3, -dien-17p-ol (1.55 g.)» m.p. 139-144°; λ_ον (in EtOH) 240 nm. (e 18,400).

Example 25 ' f llB-;Chloro-3-ethoxyoestra-3 » 5-dien-17-one ,'Ethyl orthoformate (12.1 ml.) and toluene-jD-sulphonic acid (168 mg, ) were added under nitrogen to Ιΐβ-chloro-oestr- 4-ene-3,17-dione (12.1 g. ) in dioxan (60 ml.) and the solution was stirred for 90 min. The reaction mixture was poured into sodium bicarbonate solution and the steroid was extracted with ether containing a trace of pyridine. The solvent was removed from the extract to leave a gum, which was. triturated with methanol containing a trace of pyridine to give llB-chloro-3-ethoxyoestra-3,5-dien-17-one (7.7 g.), m. p. 142-146°, ~a__D + 1° (c, 1.0 in dioxan); "kmaX t 240 nm. (ε 20,400) (Pound: C, 71.9; H, 7.9; CI, 10.6. 020Η2γ0102 requires C, 71.7; H, 8.1; CI, 10.6 ); ol (500 mg. ) was dissolvedin t-butanol (50 ml.) and ' (500 mg. ) was added. The solution was refluxed under nitrogen for 3·5 nr., ethyl acetate was added and the solution was washed with N-sodium hydroxide, water, dried (MgSO^) and evaporated.

The crude product was chromatographed on silica and crystallised from aqueous methanol to give 6 , llp-dichloro-17a-ethynyl-17 -hydroxyoestra-4,6-dien-3-one (84 mg.), m.p. 242-248° (decomp), max. 281 nm* £ 20»500) (Found.- C, 65.5; H, 5.8. C20H2201202 requires C, 65.7; H, 6.1 ).

Example 25 (a) 3-Ethoxy-lla-hydroxyoestra-3. -dien-17-one Toluene-jD-sulphonic acid(240mg. ) and ethyl orthoformate (4 ml.) were added under nitrogen to lla-hydroxyoestr-4-ene-3 , 17-dione (4 g.) in dioxan (100 ml.). After 3 hr. the reaction mixture was poured into sodium bicarbonate solution and the steroid was extracted with ether containing a trace of pyridine. Crystallisation from methanol containing a trace of pyridine gave 3-ethoxy-lla-hydroxyoestra-3i5-dien-17-one (2,86 g.), m.p. o (in EtOH) 241 nm. (ε 18,500), (Pound: C, 74.9; H, 9.2. 020H2803.1AH20 requires C, 75.1; H, 8.9 )» (b) lla-Hydroxyoestra-4 , 6-diene-3117-dione 3-Ethoxy-lla-hydroxyoe stra-3, 5-dien-17-one (250 mg.) was dissolved in t-butanol (25 ml.) and chloranil (250 mg. ) was added. The solution was heated under nitrogen at 50° for 45 min. , ethyl acetate was added and the solution was washed with N.-sodium hydroxide, water, dried (MgSO^) and evaporated. The crude product was chromatographed on silica and crystallised from acetone/petroleum ether (b.p. 40-60°) to give lla-hydroxyoestra- 4, 6-diene-3, 17-dione (20 mg.'), m.p.192-196, . (in EtOH) 282 nm. ( c) ll3-Chloro-oestra-4.6-diene-3.17-dione v- between chloroform and water and the organic layer was dried (MgSO^) and evaporated to give a gum. This was chromatographe.d to give llB-chloro-oestra-4 ,6-diene-3 , 17-dione (25 mg.), m.p. 168-172*, av (in EtOH.) 280 nm. (e 19,400) (Pound: CI, 11.3.

G18H21 C102 re(luires CI,, 11.6 ).

Example 26 17a-Acetoxy-6qt llB-dichloro-19-norpregn-4-ene- .20-dione 17a-Acetoxy-6β , ll3-dichloro-19-norpregn-4-ene-3, 20-dione (1.152 g. ) in dry dioxan (35 ml.) was treated with ethyl orthoformate (15 ml.) and eulphosalicylic acid (120 mg.). The solution was stirred for 2 hr. at room temperature, after which pyridine (1 ml.) was added and the reaction mixture was poured into ether. The solution was washed with dilute aqueous sodium 'bicarbonate then water, dried (MgSO^) and evaporated to afford crude 17a-acetoxy-6,ll -dichloro-3-ethoxy-19-norpregn-3 , 5-dien-20-one as a golden gum. This was dissolved in acetic acid (20 ml.) containing a few drops of water.

After 3 hr. at room temperature the solvents were removed under reduced pressure, and the residual foam (1.146 g, ) was subjected tb preparative thin layer chromatography to afford pure 17a-aoetoxy-6a,ll3-dichloro-19-norpregn-4-ene-3, 0-dione as colourless prisms. Recrystallisation from acetone/light petroleum afforded prisms (358 mg.), m.p. 167-168° dec, "a_D + 17° (Dioxan, c 0.74), ax, 233 nm. (e 15,700) (Pound: C, 61.6; H, 6.9; CI, 16.7. C22H28C120 re¾uires C, 61.7; H, 6.6, CI, 16.6 )..

Example 27 17a-Acetoxy-6 ,llB-dichloro-19-norpregna- 6-diene-3 , 20-dione Chloranil (320 mg. ) was added over 30 min. to 17ά- nitrogen. After a further 90 min. the reaction mixture was poured into a mixture of ether (300 ml.), benzene (100 ml.) and ethyl acetate (100 ml.). The solution was washed with IN aqueous sodium hydroxide (4 x 50 ml.), with water (4 x 50 ml.) and with saturated brine (2 x 100 ml. ) before being evaporated to leave a pale brown foam (388 mg.")".

This was subjected to preparative thin layer chromatography to afford 17a-acetoxy-6 , l^-dichloro-19-norpregna-4,6-diene-3, 20-dione (82 mg. ) as a colourless foam, ~a_7D + 74° (Dioxan, c 0.58) (Pound: C, 62.05; H, 6.1} Gl, 16.2. C22H26G1204 requires C, 62.1; H, 6.2; 01, 16.7 ).

Example 28 17a-Acetoxy-6 , llB-dichloro-19-norpregna-4.6-diene-3 ^ 20-dione 17a-Acetoxy-6 , llB-dichloro-3-ethoxy-19-norpregna-3 , -dien-20-one (204 mg. ) and precipitated manganese dioxide (1.024 g.) were stirred together and a mixture of glacial acetic acid (10 ml.) and water (1 ml.) was added. After 12 min. at room temperature the mixture was filtered, the manganese dioxide was. washed with acetone and the combined filtrate and washings were evaporated under reduced pressure to afford a pale brown foam (220 mg.). This was chromatographed to give 17a-acetoxy- , llB-dichloro-19-norpregna-4 , 6-diene-3 , 20-dione (116 mg. ) as a colourless foam, which on crystallisation from aqueous dioxan gave a 1:1 dioxan/steroid solvate m.p. 120-130° dec, after softening at 114-116° (cap. corr.), Ό>^7" + 61.7° (Dioxan, c 1.08), \ av 280 nm. (e 22 , 700) (Found : CI, 13.8. σ22Η26012°4·σ4Η8°2 requires CI, 13.8$).

Example 29 - - - - - - - - - were dissolved in propionic anhydride (10 ml.) and methylene chloride (10 ml.). After 6 hr. at room temperature the solution was poured into ether and washed with dilute aqueous sodium "bicarbonate and water. The ether layer was dried (MgSO^) and evaporated under reduced pressure to leave a solid residue. A portion of this was crystallised from acetone/cyclohexane to afford l^-chloro-5 , 17a-dipropionyloxy-19-norpregna-3 , 5-dien-20-one, XmaXi 233 nm. (e 15,700) , Ό max< (in CS2) 1752 (enol ester), 1738 (ester), 1718 (carbonyl) cm"1.

Example Q llB-Chloro-17c.-propionyloxy-19-norpregn-4-ene-3.20-dione The crude product from Example 29 was dissolved in "~ methanol and treated with 2N aqueous sodium hydroxide until examination by thin layer chromatography indicated that the enol-ester group had been hydrolysed. The solution was poured into water and the product was extracted into ether and purified by chromatography to afford ll -chloro-17a-propionyloxy-19-nor-pregn-4-ene-3, 20-dione as a white foam, Xmov 237 nm. (e 16,200), ^max. in CS2? 1758 (ester)» 1708 (saturated carbonyl), 1672 cm"1, (unsaturated carbonyl). (Found: C, 68.0; H, 7.6. OgjHj^OlO^ requires C, 67.9} H, 7.7 ).

Example 31 (a) llq-Hydroxy-19-norpregn-4-ene-3 > 0-dione .

A solution of 20 , 20-ethylenedioxy-3-methoxy-19-nor-pregna-1, 3» 5(10)-trien-lla-ol (2.24 g. , 6 mmole.) in dry tetrahydrofuran (70 ml.) was added to a stirred mixture of liquid ammonia (140 ml.) and dry t-butanol (70 ml.). Lithium (2,24 g.) was added and the mixture was stirred for 6 hr.

Ethanol (70 ml. was- then added and the ammonia and s lvent and evaporated. A solution of the residue in methanol (70 ml.), water (26 ml.) and concentrated hydrochloric acid (7 ml.) was heated under reflux for 3 hr. The reaction mixture was cooled and partitioned between chloroform and water. The chloroform layer was washed with water and dried (MgSO^). Evaporation of the extract left a residue (2 g. ) which on purification by chromatography and crystallisation from acetone-petroleum ether (b.p. 60-80°) gave lla-hydroxy-19-nor-pregn-4-ene-3,20-dione (1 g. , 53$) , m.p. 166-167°, Z~a_7D + 15.5°, (CHC15), XmaXo 240 nm. (e 17,150). (b) ilB-0hloro-19-norpregn-4-ene- , 20-dione A mixture of lla-hydroxy-19-norpregn-4-ene-3 , 20-dione (0.474 g., 1.5 mmole.), lithium chloride (2 g.), 2-chloro-1,1,2-trifluorotriethylamine (0.57 ml. 3.7 mmole.) and dry tetrahydrofuran (20 ml.) was stirred at 0° for 3 hr, and at room temperature for a further 2 hr. The reaction mixture was poured into water and extracted with ohloroform. The extract was- washed with water, dried (MgSO^) and evaporated. The residue (1.17 g.) was purified by chromatography and crystallisation from aoetone-petroleum ether (b.p, 60-80°) to give ll3-chloro-19-norpregn-4-ene-3,20-dione (0.246 g,, 50$). m.p. 135-136°, Z~a_D + 218° (CHClj), Xmax# 237 nm. (ε 17,400), (Pound: C, 71.7} H, 8.3} 01, 10.6. C20H27C102 requires 0, 71.7} H, 8.1} CI, 10.6$).

Example 32 ll8-Chloro-3-ethoxy-17a-( 2-methylpro -2-en.yl )oestra-315-dien-17B-ol l^-Chloro-3-ethoxyoestra-3, 5r-dien-17-one (639 mg.) in methylprop-2-ene (1.2 ml„ ) and magnesium turnings (0.32 g. ) in anhydrous ether (30 ml.). The reaction temperature was kept below 10° during the additions. The mixture was allowed to reach room temperature and stirred for a further 2 hr.

Saturated ammonium chloride solution (5 ml.) was added slowly with stirring followed by pyridine (2 drops) and water (30 ml.). Isolation by extraction with ether gave a yellow oil (840 mg. ) which crystallised from aqueous methanol (containing a trace of pyridine) to give l^-chloro-3-ethoxy-17a-( 2-methylprop-2- enyl)-oestra-3,5-dien-17p-ol (220 mg.), m.p. 62-64°, Z"a__7D - 16° (C, 0.94 dioxan), max> (in EtOH) 240 nm. (e 17,300).

Example 33 llB-0hloro-176-hydroxy-17a-(2-methylprop-2-enyl)oestr~ 4-en-3-one Crude llB-chloro-3-ethoxy-17a-(2-methylprop-2-enyl) oestra-3,5-dien-17B-ol (820 mg.) was dissolved in acetone (10 ml.) and 2N hydrochloric acid (1 ml.) and stirred at ° for 30 min. The solution was then concentrated by evaporation, diluted with water and extracted with ether to yield a white froth (663 mg.), which on chromatography and crystallisation from ether-petroleum ether (b.p. 40-60°) gave llB-chloro-17B-hydroxy;-17a-( 2-methylprop-2-enyl )-oestr-4-en-3-one (137 mg. ) , as a hemihydrate, m.p, 132°, + 95° (C, 0.78 dioxan) Xmax< (in EtOH) 240 nm. (ε 18,050) (Pound: 0, 71.lj H, 8.6} 01, 9.6. O22H5.j_ClQ20O.5H2O requires. C, 71.1? H, 8.5? CI, 9o5#).

Example 34 (prop-2-enyl )-oestra-3 , 5-diene by the Grignard reagent prepared from l-chloroprqp-2-ene and magnesium using a method similar to that described in Example 32. The crude llp-chloro-^-ethoxy-17a-(prop-2-enyl)-oestra-3, 5-dien-17B-ol was obtained as a yellow froth (806 mg.), showing infrared absorption at 1650 and 1630 cm."1 (3, 5-diene).

Example 35 llS-Chloro-17B-hydrox,y-17a-(prop~2-enyl)-oestr.r-4-en-3-one Crude ll3-chloro-3-ethoxy-17a-(prop-2-enyl)-oestra-3, 5-dien-173-ol (800 mg„) was hydrolysed with hydrochloric acid in aqueous acetone to give a white froth (663 mg.), whioh was purified by chromatography and crystallisation from ether-petroleum ether (b.p. 40-60°) to give llB-chloro-17B-hydroxy-17a-(prop-2-enyl)-oestr-4-en-3-one (265 mg.), m.p. 125°, *α7 + 95.5° (0, 1.06 dioxan), \mov (EtOH) 239 nm. , (e 19,350) (Pound: C, 72el; H, 8.5} CI, 9.9. C21H2gCl02 requires C, 72.3; H, 8.4} CI, 10.2 ).

Example 36 llB-Chloro-17B-hydroxy-17a-( l-me hylprop-2-enyl )-oestr-4-en- 1 3-one and ll6-chloro-17a-(but-2-enyl)-176-hydroxy-oestr-4-en-3-one ' llB-Chloro-3-ethoxy-oe3tra-3, 5-dien-17-one (640 mg.) was converted into a mixture (809 mg. ) of' the enol ethers of the titled compounds by the Grignard reagent prepared from l-bromobut-2-ene and magnesium using a method similar to that described in Example 32, The crude mixture of enol ethers was hydrolysed with hydrochloric acid in aqueous acetone to give a yellow froth The less polar fraction (313 mg. ) was crystallised from ether to give llp-chloro-173-hydroxy-17a-( l-me hylprop-2~enyl )-oestr-4-en-3-one (67 mg.), m.p. 162.5-164.5°, JT^J-Q + 92° (C, 0.44 dioxan), m„v (in EtOH) 238 nm. (e 18,000) with an infrared spectrum showing absorption at 900 cm."^ (vinylidene ) .

The more polar fraction (235 mg. ) was crystallised from ether-petroleum ether (b.p. 40-60°) to give ll -chloro-17p~ hydroxy-17a-(but-2-enyl)-oestr-4-en-3-one (12 mg,), m.p. 167.5°, ma . (in EtOH) 239 nm. (e 17,550), with an infrared spectrum showing absorption at 960 cm,"^ (trans disubstituted double bond).

Example 37 llB-Chloro-oestr-4-ene-3.17-dione from llq-hydroxy-oestr-4-ene« 3,17-dione using triphenylphosphine-carbon tetrachloride The hydroxysteroid (0.842 g.) was dissolved by refluxing under nitrogen in carbon tetrachloride (25 ml.) and tetrahydro-furan (15 ml.). Triphenylphosphine (1.3 g. ) and chloroform (4 ml.) were added and the solution was refluxed for 3 nr., during which time a crystalline product precipitated. The solution was filtered and the filtrate was washed with water, dried and evaporated to give an oil (1.98 g.). This was chromatographed on silica gel, and crystallised from methanol to give l^-chloro-oestr-4-«ne-3 , 17-dione (0.225 g.) as colourless prisms, m.p. 189-190°, + 189° (c, 0.71 CHOI,), λ„, v (in EtOH) 237 nm. (e 17,100) (Pound: C, 70.2; H, 7.3; CI, 11.5. Calc for C18H250102. C, 70.5.; H, 7.6; CI, 11.6 . ■ " Example 58 (101 mg. ) and precipitated manganese dioxide (505 mg. ) were stirred together. Acetic acid (5 ml.) containing water (0.5 ml.) was added and the mixture was stirred at room temperature for 20 min. The manganese dioxide was filtered, off and washed with acetone. The cpmbined filtrate and washings were evaporated under reduced pressure to give a pale brown foam. This was subjected to preparative thin layer chromatography to afford pure 17a-aoetoxy-l^-ohloro-19-norpregna- , 6-diene-3 , 20-dione (47 mg.) as a colourless foam, λ_ ■ (in EtOH) 279 nm. (e 20,200).

Example 39 17a-H.ydroxypregna-l , .9-triene-3 % 20-dione . 11β, 17a-Dihydroxypregna-l,4-diene-3, 20-dione . , (55.5 g. ), (prepared' by the reduotion of 21-iodo-prednisolone . with sodium metabisulphite in aqueous dioxan) in anhydrous pyridine (825 ml.) at 14 to 16° was treated with dry recrystallised N-bromo-succinimide (40.2 g.). The solution was stirred at 14 to 16° for 25 minutes in the absence of light „ Sulphur dioxide was blown gently over the surface of the stirred solution until there was no reaction to acidified starch/ iodide paper. Water- (3 1.) was added, dropwise at first and then more rapidly. The mixture was poured into an excess of 2N-aqueous hydrochloric acid (about 5 1.) and stirred for a few minutes,, and the product was collected, washed thoroughly with water and dried over phosphorus pentoxide in vacuo to yield 46.9 g. (89$) of 17a-hydroxy-pregna-l .4.9- triene- .20-dione m.p. 187-192¾ Recrystallisation of a small quantity from acetone afforded material, m.p. 215-217° Ad ivtilcaL- Example 40 31 l?g-Dlhydroxy'-Tl9-norpregna-l , 3 , 5 , (10) , 9-tetraen-20-one 17 -Hydroxypregna-l,4,9 - triene - 3, 20-dione (64 g) , zinc chloride . (47 g. ) , activated zinc (1 kg.), dr industrial methylated spirits (5 1.)» pyridine (500 ml.) and water (50 ml.) were r;efluxed gently with stirring for 3 hours.

The zinc was filtered off and washed with hot industrial methylated spirits and the combined washings and filtrate were evaporated under reduced pressure to about 700 ml. The solution was poured into water (10 1.) containing an excess of hydrochloric acid and after stirring for some minutes the product was collected, washed thoroughly with water and dried to give 59.5 g. (97$) of 3117<¾.-dihydroxy-19-norpregna- 1,3*5 (10) .9-tetraen-20-one m.p. 211-214° A small amount of this material crystallised from acetone to yield the pure phenol as pale yellow prisms, m.p. 234r236°, Γ a 7-n + 151° (dioxan, c 0.88); XmQV .263 nm. (e 18,500) and 299 nm (e 2,900) (Found: 0, 76.6, 76.4; H, 8.1, 7.8. C20H24°3 re¾uirea c» 76.9; H,7.75#).

Example 41 17q-Hydroxy-3-methoxy--19-norpregna-l , 3i 5 (10) , 9-tetraen-20-one , 3 , 17a-Dihydroxy-19-no'rpregn.a-l,3,5(10), 9-tetraen-20-one . " (5945 g.) anhydrous potassium carbonate (250 g.), dimethyl sulphate (150 ml.) and acetone (2 1.) were refluxed. gently with stirring for 4 hours. Water (3 1.) was added slowly and the mixture was allowed to cool slowly with stirring overnight. The crystalline product was collected, washed thoroughly with water and dried over phosphorus as colourless leaves m.p. 188-191°. Recrystallisation of a small quantity from acetone/cyclohexane afforded a pure sample m.p. 201-203° C + 150° (dioxan, G 0.81), vmax„ . 262nm. (ε 19,900) and 298 nm. (e 2,900) (Pound: C, 77.3; H, 7.9 C21H2603 requires 0, 77.25; H, 8.050.

Example 42 .20-Ethylenedioxy 5-methoxy-19-norTregna -1, , 5 (10) .9-tetraen-17q-ol . 17a-Hydroxy-3-methoxy-19-norpregna-l , 3 , 5 ( 10) , 9-tetraen-20-one (20 g.), pyridine hydrochloride (2.2 g.), dry ethylene glycol (200 ml.) and dry diglyme (400 ml.) were adjusted to pH 4 with concentrated hydrochloric acid and the solution was distilled very slowly at 120-130° under nitrogen at 220 mm. until examination by thin-layer chromatography indicated that the reaction was complete. The reaction mixture was poured into very dilute sodium hydroxide (5 1.) and the precipitated crude 20, 20- ethylenedioxy-3-methoxy-19-norpregna -1,3,5(10) , 9-tetraen-17q - ol was collected, washed thoroughly and dried to afford an amorphous powder (21.9 g., 96#).

Recrystallisation of a small amount frommethanol containing a trace of pyridine gave the pure ketal as colourless prisms, m.p. 164-166C , "^7j) + 93° (dioxan, , c 0.83)» λ„ον 262 nm (e 19,400) and 298 nm. (inflexion, e 3,300) (Found: C, 74.7; H, 8.0. °23H30°4 requires C, 74.55; H, Example 43 , 20-Ethylenediox -3-methox -1 -nor re na-l 3 5 10 )-triene- 9 - tetraen-17a,-ol (21 g.) in dry diglyme (400 ml,) was treated at 0° with a stream of diborane generated externally in dry nitrogen. The diborane was generated by the slow addition of boron trifluoride etherate (100 ml.) in anhydrous tether (100 ml.) and dry diglyme (100 ml.) to a stirred slurry of sodium borohydride (40 g.) and diglyme (400 ml.). After 2 hours the reaction mixture was allowed to warm to room temperature and the addition of diborane was continued for a further 3 hours. The solution was cooled and 2N-sodium hydroxide (200 ml.) was added, followed by $ hydrogen peroxide (50 ml.). The mixture was allowed to stand at room temperature for 20 minutes and was partitioned between ether and water. The ether layer was washed well with water,- 5$ aqueous ferrous sulphate, again with water and dried over magnesium sulphate, and the solution was evaporated to leave a colourless foam. Chroma ography over siliea gel afforded pure 20, 20-eth.ylenedioxy-3-methox.y-19-norpregna-1 , 3 5 ( 10) triene-llq,, 17 -diol as a colourless froth (12 g., 55$). A small quantity was crystallised from ether to give colourless prisms, m. p. 104-106°, "a _7D - 49° (dioxan, ~c™ 1.0), 276.5 nm. (ε 1,690) and 282.5 nm. (e 1,570) (Pound: C, 71.1; H, 8.3. ¾H32° re¾uires C, 71.1; H, 8.3$).

Example 44 lift , 17q~Dih.ydrox.y-19-norpregna-4-ene- , 20-dione VIII , 20-Ethylenedioxy-3-methoxy-19-norpregna-l ,3,5(10)-triene-lla ,17a-diol (12 g) in dry tetrahydrofuran (400 ml.) Ethanol (400 ml.) was added and the ammonia was allowed to evaporate overnight. The remaining solvents were removed under reduced pressure and the residue was partitioned between ether and water. The ether layer was evaporated and the residual, gum was refluxed for 3 hours in methanol (400 ml.) containing water (150 ml.) and concentrated hydrochloric acid (40 ml.). The yellow solution was partitioned between chloroform and water, the organic phase wa3 washed with water, dried and evaporated and the colourless residue was - crystallised twice from ethyl acetate/cyclohexane to afford ll , 17a~ dihydroxy-19-norpregn-4-ene- , 20-dione Till (4.5 g. , 47$) as colourless prisms.

A small amount v/as recrystallised to afford an analytica sample, m.p. 182-183°, CJ^ - 21° (dioxan, c. 0.94), λ ■ 240.5 nm. (e 15,900) (Found: C, 72.15; H, 8.4. · C20H28°4 re¾uires °f 72.25; H, 8.5 ).

Example 45 - ll0-Chloro-17a-chloroethyn,yl-170-hydroxyoestr-4-en-3-one cis-Dichloroethylene (1.8 g. ) in ether (10 ml.) was added dropwise over 15 min. to a suspension of sodamide (from 0.855 g. sodium) in ammonia (250 ml.) and the mixture was stirred under reflux for 1 hr. i^-chloro-3-ethoxyoestra-355-dien-17-one (1.2 g. ) in tetrahydrofuran (30 ml.) was added and the mixture was stirred under reflux for 17 hr. Ammonium chloride v/as 'added, the ammonia was evaporated and then water was added. Isolation by extraction with ether gave 11β- chloro-17a-chloroe thynyl-3-ethoxyoestra-3, 5-dien-170-ol '■(1.03 g..) as a brown froth with infrared absorption at 1640.

P.A. 28¾11/II infrared absorption at 1640 and 1660 om (enol ether).

This enol ether in acetone (15 ml.) was treated with 2N-hydrochloric acid (2 ml.) for 1 nr. at 25°. Isolation as in Example 33 and crystallisation from ether gave ll3-chloro-17a-chloroethynyl-173-hydroxyoestr-4-en-3-one,. ra. p. 169-171°, ^ ^ + 18 (°» °·9Θ dioxan), maXt (in BtOH) 238 nnw (e 17,100) (Pound: CI, 18.8.

C20H24C12°2 re¾uires CI, 19.3/0.

Example lla-Mesyloxyoestr-4-ene~3.17-dione lla-fiydroxyoestr-4-ene-3,17-dione (1.76 g. ) in pyridine (33 ml.) was treated with methanesulphonyl chloride (2.5 ml.) at 25° for 4 hr. The reaction mixture was concentrated in, vacuo and shaken with chloroform and water. The chloroform layer was evaporated to dryness and the product was purified by chromatography and crystallisation from acetone to give lla-mesyloxyoestr-4-ene-3,17-dione, m.p. 179-180°, Z"aJ7D+43° (c, 1.0 in CHClj), \max> (in EtOH) 236-237 nm. (e 17,100) (Found: C, 62.3; H, 6.9; S, 8.6. ClgH2605S requires C, 62.3; H, 7.2; S, 8.8 )..

The following Examples · illustrate pharmaceutical compositions according to the invention:- A. Oral tablets (continuous daily administration) (a) 17a - acetoxy - 6, 11β - dichloro ·- 19 nor pregna- 4, 6 -diene - 3, 20 dione. (microfine) 0.25 mg Starch (60 mesh) 10.0 mg Lactose (60 mesh) 64.0 mg Magnesium stearate (100 mesh.) 0.75 mg Ball mill (a) with twice the weight of lactose to a very fine powder all below 5 microns. Dilute with 5 successive portions of lactose, milling between each. Triturate with the starch and blend in the remaining lactose to form a homogeneous powder. Granulate with 50 ethanol in water and pass through a No. 12 mesh B.S. sieve. Dry the granules to constant weight and pass through a No. 20 mesh B.S. sieve and blend in the magnesium stearate prior to compression at 75 mg. per tablet on 7/32 inch punches, preferably engraved punches for identification of the tablets. Pressure is adjusted so that the tablets disintegrate within 10 mins. The tablets may be film, coated for colour distinction and should be released for publio use, only in specially designed packs to strictly regulate the use of the tablets.

B. Oral tablets (for intermittent administration) (b) 17a - acetoxy - 11β - chloro - 19 2.0 mg nor - pregn - A - ene 3, 20 dione (microfine) (c) Ethynyl oestradiol (microfine.) 0.05mg Starch (60 mesh) 10.5 mg Ball mill (b) and (o) separately with very small quantities of lactose, mix together and proceed as in exampleA-, treating the mixture of (b) and (c) as for (a) in example fa The tablets will of course be compressed on different punches at 80 mg per tablet, and may be subsequently coated if required.

Lon^ Acting Injection (Deep intra muscular) (d) 17a - acetoxy - 6, 11β — dichloro - 19 nor pregna τ 4, 6 - diene - 3, 20 dione. (Sterile) 10.0 mg Aluminium stearate 1.5$ w/w gelled in winterised arachis oil to produce 0.5 ml, Prepare the base by heating together the aluminium stearate dispersed in the arachis oil until solution is effected and thickening occurs about 90°C. Close the vessel and with continued stirring, sterilise the base by heating at 150°C for one hour. Cool rapidly to 55°C. Aseptically triturate the (d) with the base and pass through a refining mill and to obtain a homogeneous dispersion. Pack into unit cartridges.

A¾eous Injection (long acting.) (e) 17a - acetoxy - 11β - chloro - 19- nor - pregn - 4 - ene - 3, 20 dione 10.0 mg (f ) Sodium carboxy - methyl - cellulose 10 mg (g) Nonex, 5 ■ ■ (a polyethylene glycol oleate supplied by Union Carbide of Grafton S ., London W.1. ) 0.01$ w/v , (in final injection) (h) Formalised starch 20 mg Vehicle (in separate- container) A sterile sorbitol solution 10$ w/w 1 ml Sterile (f) and (h)separately by dry heat. Dissolve (g) in a little chloroform, sterilise by filtration and disperse over the mixed, sterilised powders (f) and (h) . Remove the chloroform and blend the powders in a ball mill to give a homogeneous mix.

Prepare sterile crystals of (e) in 2 particle size ranges, approximately, 15 - 25 microns and 50 - 40 microns, taking about equal portions of each. Blend these crystals with the base and aseptically distribute 55 mgs of the resultant dry mjx into sterile vials and close hermetically. Reconstitute the injection immediately before use, by adding 1 ml of the sorbitol vehicle to the dry mix and shaking to obtain a suspension.

Tablet Implant (3) 17a - acetoxy - 11β - chloro - 19 - nor - pregn - 4 - ene - 3,20 dione (microfine) 60 mg Tablets .implants may be prepared by conventional methods such as heavy compression of the pure sterile material or by fusion, by melting and casting into shape in a mould.

The implants are packed into sterile moisture proof The quantity of active ingredient in an implant will be related to the duration required; shape and surface area Intravaginal pessary for veterinary use. (For sheep) (k) 17β - acetoxy - 6, ΙΙβ - dichloro - 19-noE- pregr.a- 4, 6 - diene - 3, 20 dione. 20.0 mgs.

Dissolve (k) in sufficient ethanol and sterilise by filtration. The pessaries or tampons may be prepared in a conventional manner by absorbing the required amount of ethanolic solution onto sterile gauze rolls or fine porous plastic sponges, evaporating the ethanol under vacuum and protecting the vaginal insert in a sterile pack, suitable for administration. The dosage required for veterinary preparations, will, of course, be related to the size of the animal being treated.

Claims (1)

1. IS CLAIMED of the Steroids ae clairaod in Claim 1 having in the a hydroxyl hydroxyl oxo or a protected or an aliphatic araliphatic in presence or absence of hydroxyl or protected hydroxyl tho hydrogen chlorine or fluorine atom or a methyl an protected hydroxyl or protected hydroxyl 2 S as claimed Claim 1 or having one or more double bonds the A Steroids claimed in Claim 1 having a and a bond or double bonds in both the and poeitions or a or group and double bonds in the Steroids as in Claim having a or in the presence or absence a group a Steroids as claimed any of the preceding claims having a chlorine atom in the Steroids claimed in any of the preceding claims in which any acyloxy present are araliphatic or acyloxy Steroide as claimed in Claim 7 in which said acyloxy are acetoxy groups or propionyloxy Steroids as claimed in any of Claims 2 8 in which vaid protected hydroxyl are alkoxy groups having carbon aralkoxy aryloxy groups and said oxo are or ether Steroids as claimed Claim 9 in which said groups are or groups protected oxo ethylene dioxy or enol ether or enol ethyl ether Steroids as any of or possessing at the a saturated or unsaturated aliphatic group with carbon Steroids as claimed in claim 9 possessing at the position a chloroethynyl or acetyl Steroids as claimed in claim 9 possessing at the position a or Steroids as claimed in any of the preceding claims which are unsubstituted at the Steroids as claimed in any of the preceding claims which are unsubstituted at the Steroids as claimed in any of the preceding claims in which the C and D rings are condensed with no further rings ll Ot Compounds as in 1 as described in any the Examples with exception of of Claims 17 to A process for the preparation of in which a is reacted with reagent of the general N C C R where and which may be the same or are alkyl groups having carbon atoms or or groups together with the atom to which they are comprise a heterocyclic radical which contain further a chlorine or fluorine is a chlorine ine atom and is hydrogen or R or R together represent a is a chlorine or fluorine and is a chlorine or fluorine atom or a methyl the reaction being offected in the presence of chloride ions when and are both A process as claimed in claim in which said source of chloride ions is lithium process as claimed in claim or claim in which the reagent of formula I used in conjunction with chloride ions is one or more of diethylamine methylethylamine and A process as claimed in claim in which the reagent of formula I is A process as claimed in any of claims to in which the reaction solvent is an aromatic or aliphatic halogenated ether or tertiary alcohol A process as claimed in 6 in which the reaction solvent is A process for the preparation of compounds as claimed in claim 1 in which a or is reacted with a source of chloride A process as claimed in claim in which the source of chloride ions is lithium A process for the preparation of compounds as claimed in claim 1 in which a A process claimed in claim 50 in which the steroid is reacted with triphenyl phosphine in carbon process for the preparation of hydroxy and steroids as claimed in claim 1 in which a as claimed in claim 1 is reacted with a borohydride reducing agen A process as claimed in claim which the steroid starting material is a A process for the preparation of steroids as claimed in claim 1 or the corresponding in which the corresponding steroid or steroid is reacted with an acylating or etherifying A process as claimed in claim in which the acylating agent is an acyl halide or process as claimed in claim in which the acylating agent is propionic or benzoic anhydride or A process as claimed in claim in which the steroid is reacted with a or alkyl orthoformate in the presence of A process as claimed in any of claims to 56 carried out in the presence of an organic or inorganic A process as claimed in in which the acid benzene sulphonic acid suiphosaiicyiic A process as claimed in claim in which the hydroxy steroid is reacted with an alkyl or aralkyl sulphate or A process for the preparation of metallic A process as claimed in claim l the metallic reagent is an alkali metal acetylide or a carbon magnesium A process as claimed in claim 62 which the alkali metal acetylide is sodium or potassium A process as claimed in claim 62 which the carbon magnesium halide is a or magnesium bromide or A process for the preparation of a steroid as claimed in claim 1 in which a or is reacted with a chlorinating A process as claimed in claim 65 in which the ing agent is molecular chlorine or an A process as claimed in claim 66 in which chlorination is effected with molecular chlorine in the presence of a carboxylic acid and a tertiary organic A process as claimed in claim 66 in which chlorination is effected with an or in the presence of a carboxylic acid and an inorganic or tertiary organic A process as claimed in any of claims 65 to 68 in which the starting steroid is a or a 3 A process for the preparation of steroids as claimed in claim 1 in which a Δ as claimed in claim 1 is subjected to enol A process as claimed in claim 70 in which enol or esterifxcation is effected using an alkyl or acyl anhydride in the presence of acid and hydrolysis is effected in an acid 4 6 A process for the preparation of as claimed in claim 1 in which a or steroid as claimed in claim 1 is reacted with a reagent capable of converting an enol ether a conjugated A process as claimed in claim 72 in which the said reagent is or manganese 4 A process for the preparation of a steroid as claimed in claim 1 wherein a steroid as claimed in claim 1 is subjected to selective hydrolytic deacylation at the A process as claimed in claim in which the selective hydrolysis is effected under basic process as claimed in any to 75 stantially as herein A process as claimed in any of Claims to 75 stantially as herein described with reference to any of Examples 1 to Compounds as claimed in claim 1 whenever prepared by process as claimed in any of 2 to Pharmaceutical compositions comprising one or more together with a pharmaceutical carrier or excipien one or more further active Compositions as claimed in claim 79 which said further active compounds are Compositions as claimed in claim 79 or claim 80 in the form of dosage Compositions as claimed in claim 81 in the form of injection preparations or implantation Compositions as claimed in claim 79 or claim 80 comprising as carrier or excipient one or more of the sugar magnesium polyethylene glycols and colouring or bases with a melting point above body sterile or emulsion physiologically acceptable vegetable oily sterile or physiological suspending physiologically acceptable emulsifying buffering stabilising and solublising Compositions as claimed in olaim 79 or claim so as a dry powder reconstitution before use with a separate Compositions as in claim 81 containing to of active material according to the invention per dosage Compositions as claimed in 17 containing Composi ions as claimed Claim 79 or Claim for veterinary use in in the form of long acting inser Compositions as claimed i Claim 87 in the form of tampons or Pharmaceutical compositions as claimed in Claim 79 substantially as described compositions as claimed Claim 79 eubstantially as described herei reference to any of A to of the and pregnane substantially as hereinbefore described and reference to any of the insufficientOCRQuality