IL30491A - Halogenated steroids of the pregnane series,their manufacture and pharmaceutical compositions containing them - Google Patents

Description

30491/2 onικ o* »s»n ninpii »i»©-» i tnis** Halogenated steroids of the pregnane series, their manufacture and pharmaceutical compositions containing them SPARA EDICA AG 0:28745 — - 30491/2. - la - , RAN 4104/48-21 This Invention relates to novel halogenated steroids formula wherein Rg is hydrogen, hydroxy or lower alkanoyloxy? ^Q is methylene, a-halomethyl, or a-halo; ^ is hydroxy or lower alkanoyloxy; and X and n have the same meaning as above; and to a process f or tie preparation thereof.

As used herein the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon moieties having up, to eight carbon atoms, such as metjiyi, ethyl, t-butyl, n-octyl or tiie like. Lower, alkanoyl similarly comprehends residue* of lower alkane oarboxylic acids such as acetyl, butyryl, caprylyl or the like. When used as part of the definition of 1Q, halo comprehends chloro or fluoro.

Compounds of formula I having a grouping A^ are useful as progestational agents. When ^ is hydrogen cr hydroxy, the compounds can be administered parenterally, and when R, is lower alkanoyloxy the compounds can bS administered orally or paren erally Preferred compounds are those having a grouping A^ wherein ^ is lower alkanoyloxy f R^ is methylene and n is 0.

Compounds of formula I having a grouping Ag wherein X is . an unsaturation between the 1- and 2-posltion are useful as glucocorticoids, ie. , as anti-inflammatory and thymolytic agents. 30491/2 The process for the preparation of the compounds of this invention comprises ■ .'··- ( ; a) treating a Steroid of the- formula · ■ ν/herein· A' is one of the groupings and wherein n is 0, i.e. X and X' are absent, and has the same meaning as in formula I above, with chlorine and a proton acceptor, or wi,th. a chlorinating agent ; or -b) dehydrogenating a steroid of the formula I having a groupin wherein n is 0, in the l(2)-position; or c) oxidizing the 11-hydroxy group in a steroid corresponding to the formula I haying a grouping A^ wherein the ll-keto group is replaced by a hydroxymethylene group, to form a carbonyl group; or d) esterifying a steroid of formula I having at least one free hydroxy group in the position 17 and 21; or e) saponifying a 17- and/or 21-esterified steroid of formula I;j'or f ) treatin a steroid of the formula ; wherein R, and RQ have the same meaning as above and X' is hydrogen or chloro, with a strong acid.

. The .chlorination p rocedure according to process variant ; (a) is suitably effected by intramixing chlorine and a reaction medium which contains the starting material steroid of formula II, preferably in solution. The treatment with chlorine can be conducted in. the presence of a proton acceptor, for example, an N,N-di-lower alkyl-lower alkanpyl-amide such as dimethyl- formamide or dimethylacetamide; . a lower alkylene oxide such as ethylene oxide or. propylene oxide; or the like; in a solvent such as lower alkanoic acids such as propionic acid or acetic acid. Alternatively, the proton acceptor can be added subsequent to the intramixing of the chlorine and starting material steroid. In this case the initial chlorination product is an intermediate of the formula A wherein R1 and A have the same meaning as above.

Conveniently, this intermediate is not purified but is dehydro-chlorinated by treatment with a proton acceptor such as nitrogen-containing heterocyclic base such as picoline, pyridine or the like .

When the proton acceptor is initially present during the chlorination, it can also serve as the solvent for the starting material steroid of formula II. Alternatively, and preferably, 30491/2 - 6 can be convenient inert organic solvents, for example, ethers, such as lower alkyl ethers, for. example, ethyl ether, or dioxane; chlorinated hydrocarbons such as chloroform or carbon tetrachloride; or the like. The chlorine can be introduced into the reaction mixture by conventional techniques, e.g., a solution containing the chlorine can be introduced into the reaction mixture. A chlorine-containing,, lower alkanoic acid solution", for example, chlorine in propionic acid, is suitable for this purpose. The treatment with chlorine is suitably effected at a low temperature, preferably between. about -40°C and room temperature, more advantageously between about -;jO°C and about 0°C. Another embodiment is to treat with chlorine in carbon tetrachloride using chloroform as a solvent for the starting material, preferably between about 0°C and room temperature, followed by removal of the solvent and treatment with a heterocyclic nitrogen-containing base such as pyridine, picoline or the like.

Hydroxy groups present, in the. starting material molecule, i.e., comprehended by the moieties' symbolized by M, can be esterified after the chiorination procedure; .alternatively., the chiorination procedure can. be effected on starting materials containing ester moieties.[ ~ In addition to the foregoing, other known techniques can he used to protect labile groups prior to the chlorination procedure.

It should be noted that the above chlorination procedure when applied to 2-unsubstituted l(2)-saturated starting steroids may yield, as a by-product, , -ehloro-eteroids of formula I, 2,4- ichloro compounds of formula X can also be obtained by chlorination of a 2-unsubstituted l(2)-saturated 4-chloro compound of formula X by means of a chlorinating agent such as chlorine or N-ohloro-eucoinimide· The dehydrogenatlon procedure according to process variant (b) can be brought about bytreatment with selenlous acid or by a reaction s equence consisting of chlorination and dehydrochlorination, the latter step being carried out e.g. by treatment with lithium chloride in dimethylformamlde.

The oxidation of an ll-hydroxymethylene group according to process varian (c) can be effected by means known per se, e.g. with chromic acid The esterification of a free hydroxy group according to process variant (d) can be effected In a known manner e*g. using a reactive acid derivate such as a halogenide or an anhydride. The saponification of a 17- or 21-esterified hydroxy group (process variant e) can be effected with weak basic agents, such as an alkali metal carbonate or dicarbonate.

The clevage of the l6a,17a-oxido moiety and subsequent f dehydration according to process variant (i.) can.be effected by treating the starting, steroid in an anhydrous solvent in the presence of a strong acid, such as trifluoroacetic acid.

The compounds of this invention are characterized by. a .. high degree of endocrinological usefulness with a selectivity of. action characterized by minimal side effects. Thus, the endocrinologically useful compounds of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements, in the form of conventional pharmaceutical preparations; for example, they can be administered in conventional pharmaceutical solid or liquid forms, such as tablets, pills, capsules, solutions, suspensions, emulsions, or the like. These pharmaceutical preparations can contain conventional pharmaceutical carriers and excipients, such as, water, talc, corn starch, polyalkylene glycols, emulsifying agents, buffering agents, agents for. the adjustment of osmotic pressure, Vaseline, and the like. Though it is preferred to administer the endocrinologically useful compounds of this invention internally, those having progestational, or anti-inflammatory usefulness can also be administered topically. For this purpose, i.e., topical administration, these compounds can be- administered in conventional topical administrat conventional topical carriers such as petrolatum, stearic acid or the like. Also compositions containing an active ingredient of ' this invention can be subjected to conventional pharmaceutical processes', such as, sterilization or the like. Also, the pharmaceutical compositions of this invention can contain othe active ingredients . Moreover, . the endocrihologically active compounds can be administered as feed additives, and for this purpose can be admixed with conventional animal feeds or conventional animal feed premixes.

The following examples are illustrative of this invention but not limitative thereof. Most of the starting material •compounds . are known compounds or members of■ known classes of compounds. In any event, the starting materials can be prepared by known methods as, for example, those in certain instances exemplified in the followin examples. All temperatures in the examples are stated in degrees Centigrade.

■ Example 1 To a solution of 3 . 9 g of ' 6-chloro- 17c-acetoxy- 10-methylene-pregna-4 , 6-dien-3 , 20-dione .in .25 ml of alcohol-free chloroform was added dropwise (at 0° ) 11 . ml ( 5$ excess) of a Ο.87 molar solution of chlorine in carbon tetrachloride. The resultant solution was stirred for one hour at 0° and the solvents were then removed under reduced pressure. The resulting foam was treated wi h 10 ml of dry pyridine and then stirred at room tem erature for 2 hours. Ether 200 ml was added and chloric acid. The ether solution was then dried and the solven was removed under reduced pressure. The residue was triturated with ether to give 2.4 g of material which was chromatographed on 100 g of silica gel. Elutioh wit 2% ethyl acetate-benzene gave 2o,4 , 6-trichloro-17<*-acetoxy-lo-rnethylenepregna-4 , 6-dien-3 , 20-dione which upon crystallization from methylene chloride-ether melted at 235-238°d. (dec. begins 225° ) . .

Further elution with 5» ethyl acetate-benzene gave 4, 6-dichloro-r7< -ace toxy- l6-methylenepregna-4, 6-diener 3,20-dione which upon crystallization from methylene chloride-ether melted at 218-219° .

Example 2 A solution of 0.250 g of 2 ,4, 6-trichloro- 17o<.-acetoxy-l6-methylenepregna-4 6-dien-3 , 20-dione, 0. 1 g of lithium chloride, and 3 of■ dry dimethylformamide was refluxed for one half hour under a nitrogen atmosphere. The solution was then cooled and poured into 100 ml of ice water. The product was filtered and air-dried. The so-obtained crude material was chromatographed on 6 g of neutral alumina (grade I). Elution with a 1 : 1 solution of petroleum ether ( 60-90°) and methylene chloride and finally methylene chloride gave jC-dichloro- /*-acetoxy-lS-rnethylene-pregna-l^, 6- riene-3 , 0-dione as a light yellow product which upon crystallization from ether-methylene chloride melted at 225-228° . 30491/2 -* Example 3 ■ . To I.05 g of 6-chloro-10o^-17 -isopropylidenedioxypregna " ,6-diene-3,20-dione in 10 ml of alcohol-free chloroform at 0 l is added 2.8 ml of 1.0 M solution. of chlorine in. carbon tetra- chloride. After 1 hour at 3°, solvents are removed under reduced pressure and the residue treated with .12 ml of pyridine. After standing at room temperature for 2 hour, the pyridine is removed under vacuum and the residue taken up in methylene chloride, washed with 2 N hydrochloric acid, water, dried ' . (MsS04).and concentrated under reduced pressure. The residue is- chro atographed on silica gel and the purified · roduct is recrystallized from acetone/hexane to yield ^.,6-dichloro-l6«-, 17«--isopropylldenedi0xypregna-4 , 6-diene-3»20-dione . -12- 30491/2 < Example ' ■ A solution of 1.00 g of 6-chloro-l6 The starting steroids can be prepared as follows: A mixture of 15 S f l6o-chloromethyl-17o<-acetoxy-progesterone, 150 ml of dioxane (purified over alumina), '20 ml of triethyl orthoformate, .10 ml of ethanol and 1.5 ml of concentrated sulfuric acid is stirred at room temperature in the absence of light. After 2 hours the reaction mixture is poured with stirring into .3 liters of ice and water' containing excess sodium bicarbonate. The resultant precipitate is collected by filtration, washed well with water and dissolved' in dichloro-methane. This solution is dried and concentrated to a semisolid residue which could be crystallized from ether to give 17 According to the above procedure treatment of: {%) 21-acetoxy-17oi-hydroxy-l6-methylene-4-pregnene- j 11, 20-trione yields 21-acetoxy-3-ethoxy-17o<-hydroxy-l6-methylene-pregna- ,5-diene-ll,20-dione .('2 ) ±1*.- (2-chloroethyrayl ) -17/¾-hydroxy-androa )|-ΘηΘ· 3-°ne yields 17"<-(2-chloroethynyl)r-3.etho.yy-17¾- yrirr y androo a *5 dieno.

A solution of the foregoing crude enol ether prepared from 15· g of lo^-chloromethyl-^ix-acetoxyprogesterone in 670 mi of acetone is cooled to 5°· A solution of 14.2 g of sodium acetate in 240 ml of water is added thereto, followed by 27·β g of N-chl rosuccinimide .and 17.2 ml of acetic acid. After stirring for an additional ±.5 hours the reaction mixture is poured into 8 liters of water and ice. After stirring for an additional hour the slurry is filtered and the precipitate is and crystallization of the residue from dichloromethane-ether gives 6P-chloro- l6 -chloromethyl- 17<*-acetoxyprogesterone .

According to the above procedure treatment of: {%) 21-acetoxy- 3-ethoxy-YJO-hydroxy-lb-rnethylene-pre na-3, -diene-lli 20-dione yields 21-acetoxy-6/3-chloro- 17e-hydroxy- l6-rnethylene-4-pregnene-3 , 11 , 20- trione; ethynyl ) - 17|fi-hydroy.y-androst- -ene-3-one .

A mixture of 10. 0 g of the foregoing β/3-chloro compound, 50 ml of tetrahydrofuran (purified over alumina), l8 ml of triethyl orthoformate, .5 ml of ethanol and 100 mg of p-toluene-sulfonic acid is stirred at room temperature for 1. hours in the absence . of light. The reaction mixture is then added in the course of 10 minutes to a stirred suspension , of 45 g of activated manganese dioxide in 4 0 ml of acetic acid and 5 ml of. water. The resultant mixture is stirred for' an additional hour and then filtered. The solid is washed well with dichloro-methane and the combined filtrates are concentrated under vacuum. The oily residue is diluted with dichlorome thane, washed three times with 5$ sodium bicarbonate solution, once with water, dried and concentrated. The residue is crystallized with ether and then recrystallized from acetone-hexane to give purified 6-chloro-lw-chloromethyl-6-dehydro- 17<*.-acetoxyprogeste one .

According to the above procedure treatment of : -. ( L ) 21-, ' methanol was added 83 . 0 g of semicarbazide hydrochloride and 104 ml of pyridine. The reaction mixture was refluxed overnight (nitrogen atmosphere). Approximately one half of the solvent was then removed under reduced pressure and the mixture was allowed to digest for 15 minutes, filtered, washed well with water and dried under reduced pressure to yield 69.0 g of solid 3 , 20-bis-3emicarbazone .

A solution of 69Ό g of the preceding bis-semicarbazone in 690 ml of trifluoroaoetic acid was stirred. and refluxed for 85 minutes. The reaction mixture was then cooled to room temperature and the. solvent removed under reduced pressure to yield an oil . .

The crude oil was dissolved in.1.4 liters of $0% acetic acid. To this solution was added l40 ml of 5 % pyruvic, acid and 69.Ο g of sodium acetate (anhydrous ) . The reaction.'mixture was allowed to stir and heat at 100°C for 75 minutes unde nitrogen. The reaction mixture was cooled to room temperature and poured into · 2 liters of water. The resulting mixture was extracted two times with chloroform.. The organic layers were washed once with water, . twice with 10% p tassiurn bicarbonate · and once with brine. The combined organic layers were- dried over sodium sulfate and concentrated to dryness under reduced pressure to yield 60 g of an oil.

The above oil was dissolved in 300 ml of dry pyridine an 60 ml of distilled acetic anhydride. The, solution was allowed to stand at room temperature for 3 hours and was then added to 3 liters of 3 hydrochloric acid and 500 g of ice. The mixture was extracted three' times with 3 : 1 ether : ethylene chloride. combined organic layers were dried ( a^SO^) and concentrated under reduced pressure to give 52.0 g of 6-chloro~21-acetoxy-pregna-4,6, l6-triene-3, 11, 20-trione as a pale yellow foam.

A solution of diazomethane (from 105 g of nitrosomethyl, urea) in 1. 1 of ether was added to a solution of 52.0 g of 6-chloro-21-acetoxypregna-4 , 6, l6-triene-3 , 11,20-trione in 520. ml of dry tetrahydrofuran over a ten minute period. The reaction mixture was allowed to stand at room temperature · for 90 minutes whereupon a precipitate emerged. The .solvent was removed under reduced pressure to give a yellow solid which was crystallized once from methylene chloride-ether to yield 44.0 g of 6-chloro-21i-acetoxy-l6iXJ 17«x--methi''leneazopregna- J6-diene-3, 11,20-trione as yellow crystals, mp 194-197°C (dec).

Forty four grams of crystallized pyrazoline was placed in an evacuated three liter flask which was heated in an oil bath at 175-188°, for 30 minutes. The reaction mixture was then cooled to room temperature. The resulting crude oil was crystallized once from methylene chloride-ether to yield 20.28 g o 6-chloro-21-acetoxy-l6-methylpregha-4,6, l6-triene-3, 11·,20- · trione as yellow crystals, mp 1 5-l6o°. An additional 13.5 S of product was obtained from the mother liquors.

A solution of 5.0 g of 6-chlcro-21-acetoxy-lo-methyl-pregna-4, 6, 16-triene-3, 11,-20-trione in 0 ml of alcohol free chloroform was cooled to 0°C. To this solution was added 11.6 ml of 1.10 Molar chlorine solut on in car on a o d whereupon the solvent was removed under reduced pressure. The resulting pale yellow solid was crystallized once from methylene chloride-ether to yield 3 · 59 S of 4, 5,6-trichloro-2.1-acetoxy-l6.-methylpregna-6, l6-diene-3 , ' 11, 20-trione as pale yellow o crystals, mp 211-213. C.

To a cooled ( 0°C) solution of 3,40 g of 4 , 5 , 6- trichloro-21-acetoxy-l6-methylpregna-o, l6-diene-3 , 11 , 20-trione 'in..140 ml of methylene chloride was added 26.0 g of disodium hydrogen, phosphate. To the stirred suspension was added rapidly 8.20 ml of the peroxytrifluoroacetic acid solution (prepared by adding, ·' over a 10 minute period, ·' 5 · 1 -ml' of trifluoroacetic . acid, to a cold solution, of 0.82 ml of 90$ hydrogen peroxide in 5 ml. of . methylene chloride ) . The reaction mixture was allowed to stir at 0°C for 3 · 5 hours and was then, diluted with 400' -ml Of .water . The resulting. mixture was extracted twice with methylene chloride . The organic layers were washed once with water and · once with brine, combined, dried (Na^SO^ )·. and concentrated under reduced pressure to yield 3·6θ g of colorless oil.

The above oil was dissolved in 27 ml of dry pyridine and was allowed to stand at room temperature for 90 minutes whereupon the pyridine was removed under reduced' pressure . The residue was' dissolved in methylene chloride and the organic solution was washed twice with IN hydrochloric acid solution, once with 5έ sodium bicarbonate solution and once with brine. The organic layers were combined, dried (Na^SO^) and concentrated under - - - - 6 Example / A solution of 1.00 g of 2J4,6-tri.chloro-21-acetoxy-l6 , 17<*-oxido-l6/3-methylpregna-4 ,6-diene-3, 11.,20-trione in 25 ml dry benzene and'5«0 ml trifluoroacetic acid was refluxed under nitrogen for ten hours. The reaction mixture was cooled to room. temperature and was diluted with ^il ether-meth lene chloride. The mixture . was washed twice with 5 sodium bicarbonate solution and once with brine. The organic layers were combined, dried (Na^SO^), and concentrated to yield an oil which was chromatographed oyer silica gel in benzene. Elutions with benzene : ethyl acetate, and evaporation of the solvent gave the crude product. Crystallization from ethyl acetate-ether gave 230 mg of 2,4, 6- trichloro-21-acetoxy- 17c -hydroxy- l6-methylene-pregna-4,6-diene-3, 11,20- trione, . mp 271-274°.

Preparation of the starting steroid: A 0.90 Molar solution of chlorine (3,30 mi) in glacial . acetic acid was added dropwise over two minutes, to a solution of 1.20 g of 4,.6-dichloro-21-acetoxy-l6o<,17=<-oxido-l 3-met¾rl-pregna-4 , 6-diene-3 , 11,20- trio e in 20 ml of glacial acetic acid. The. reaction mixture was allowed to stand at room temperature for one hour and was then diluted with 75 ml of water. The resulting precipitate was filtered, washed with water, and · dried to yield. I.l8 g of 2, ,6-trichloro-21-acetoxy-l6<- 17^-oxido-l63-methylpregna-4,6-diene-3, 11,20- trione as a colorless ' solid. 30491/2 Example $ To a stirred solution, of 140 mg of 2 > 4 J 6-trichloro-21-acetoxy-17'-hydroxy^l6-raethylenepregrja-il, 6-dlene-3 J 11^ 20-trione in 3 .0'ml of dry dimethylformamide was added 100. mg of anhydrous lithium carbonate. The reaction mixture was allowed to stir and heat under nitrogen at 125°C for 4· hours and at . 151°C 'for ; 15 minutes. The cooled reaction mixture was. diluted with water and was extracted twice with, methylene chloride . · The organic layers were washed with brine, combined, dried (Na2S0^.) and concentrated. The resulting oil (140 mg) was . dissolved in one ml of pyridine and.0..2Q ml of. acetic anhydride. The reaction mixture was allowed to stand at. room temperature for three hours and was then diluted with cold"3N: hydrochloric acid. The mixture was extracted once 'with 3 :1 ether-methylene, chloride and once with methylene chloride. The organic layers were washed once with IN hydrochloric acid, once with 5% sodium bicarbonate solution .and once with brine. The combined organic layers were dried . (Na^SO^ ) and concentrated to yield an oil which was. chromatographed on 10.0,g of Florisil in benzene..

Elution with benzene-ethyl acetate gave · the product which was crystallized price from ethyl acetate:ether to yield , 6-di-' ohloro-21-acetoxy-17»«.-hydroxy-l6-methylenepregna-l, 6-triene- . 3 , 11 , 20-trione. 8 EXAMPLE ύ solution of 2.5 g of potassium hydroxide in 100 ml. of methanol was added 2.5 g of 4j6-dichloro-17a-hydroxy-16-methylene-pregna-l r6-triener3»20-dione acetate. After approximately 10 minutes solution occurred. After stirring at .1 room temperature fo 1.5 nr. (precipitation of product "began approximately 0.5 hr. after solution occurred), a solution of 8 g of potassium dihydrogen phosphate in 150 ml of water was added. The precipitate was filtered and dried overnight under vacuum. The product was dissolved in a minimum of acetone* dried (MgSO^), decolorized (charcoal) and filtered. Hexane was added to the filtrate and the solvent was removed at atmospheric pressure until crystallization occurred. ..This procedure gave 1.3 g of 4,6-dichloro-lTa-hydroxy-lSmethylenepregna-l, ,6-triene-3,20^dione , m.p 258-260°. A second crop (0.6 g) of product obtained from the raother liquors had m.p. 256-258°. 9 EXAMPLE d A tablet formulation: Per Tablet 17a~acetoxy-4,6-diohloro-16-methylenepregna- 4,6-diene-3, 0-dione 2.0 mg Lactose 121.5 mg 5r Corn Starch 70.5 rng' Pregelatinized Corn Starch . 8.0 rng Calcium Stearate 3.0 mg Total Weight 205.O mg Example l/6 A capsule formulation: 17 -acetoxy- , 6-dichloro-l6-methylenepregna- 4,6-diene-3,20-dione 5 rag " Lactose ·' ·;.·■■ -.178 mg Corn Starch 37 mg Talc ' 3. mg Total Weight.. 22¾ mg VJ-1 a.'....( -1 ' L'*, ...J 30491/2 - - -

Claims (21)

1. Halogenated steroids of the general formula • A wherein R^ is fluorine or chlorine and A is a grouping of one J L wherein Rg le hydrogen, hydroxy or lower alkanoyloxy; 1Q is methylene, a-halomethyl, or oc-halo; ia ,hydroxy or lower alkanoyloxy; and X and n have the same meaning ae above »

2. Asteroid of formula I having a grouping A^ wherein R. is chlorine or fluorine, R, is lower alkanoyloxy R. is methylene and n is 0. yoxy

3. A 4,6-dichloro-17a-lower alkanoyl-l6-methylene-pregna-4 , 6-diene-3 , 20-dione .

4. 4 , 6-Dichloro-17a-acetoxy-l6-methylene-pregna-4 ,6- • iene-3 , 20-dione .

5. 4,6-Dichloro-17oc-acetoxy-l6-methylene-pregna-l,4,6-triene-3,20-dione .

6. 2ai4,6-Trichloro-17a-acetoxy-l6-methylene-pregna-4,6-diene-3, 0-dione. ' .. '

7. ' 4,6-Diehjj.uO~21-acetoxy-17a-hydroxy-16-methylene-pregna- ,6-diene-3 , 11, 20-trione .

8. 2i{4,6-Trichloro-21-acetoxy-17a-hydroxy-l6-methylene- 20-pregna-4 , 6-diene-3 , 11 Arione . 30491/2. wherein A' is one of the groupings A.^ and Ag wherein n is 0, i.e. X and X' are absent and has' the same meaning as in Claim

9. I, is treated with chlorine and a proton acceptor, or with a chlorinating agent.

10. A process for the preparation < a halogenated steroid of the formula I in Claim 1, wherein a steroid of the formula I having a grouping A^ wherein n is 0, is dehydrogenated in the l(2)-position.

11. II. A process for the preparation of a halogenated steroid of the formula I in Claim 1, wherein ah 11-hydroxy-steroid correspondirgt0" he formula I in Claim 1 having a grouping wherein the 11-keto group is replaced by an hydroxymethylene. group, is ■ oxidized to form an 11-carbonyl group. ·

12. A process for the preparation c a halogenated steroid of the formula Ϊ in Claim 1, ν,-herein a steroid of formula I having at least one free hydroxy group in the position 17 and -21 is esterified.

13. A process for the preparation1 of a halogenated steroid of the formula I in Claim 1, wherein a 17- and/or 21-esterified steroid of formula I is saponified.

14. A process for the preparation, of a halogenated steroid of the formula I in Claim 1, wherein a steroid of the ' formula wherein and have the same meaning as in Claim 1 and * is hydrogen or chloro is treated with a strong acid;

15. · A process according to Claim 9 wherein a steroid • '. wherein of formula II ha.ving a grouping A^, / is lower, alkanoyloxy, is methylene and n is 0, is chlorinated.

16. A process according to Claim 15 wherein a 6-chloro- 17oc-lower alkanoyloxy-16-methylene-pregna-4 , 6-diene-3 , 20-dione is chlorinated.

17. A process according to Claim 1 herein 4,6-dichloro-21- acetoxy-l6 , 17a-oxido-16 -methylpregna-4 , 6-diene-3 , 11 , 20-trione is treated with trifluoro acetic acid.

18. A process according to Claim 14 wherein 2,4,6-trichlorO' -acetoxy-l6 , 17a-oxido-l6 -methylpregna-4 , 6-diene-3 , 11', 20-trione is treated withtrifluoro acetic , acid . 30491/2

19. A process according to any of Claims 9 to 18 for the & ■ In Claim 1 preparation o f halogenated slfroids of formula lf as hereinbefore particularly described, especially with reference to the foregoing Examples.

20. Halogenated steroids of the formula I in Claim 1 whenever prepared by a method according to any me cf Claims 9 to 19«

21. Compositions having endocrinologically useful properties containing as active ingredient a halogenated steroid of formula I in Claim 1 and one or more nontoxic, inert, therapeutically compatible solid or liquid carriers and/or excipients. For the Applicants HD:BH