IL45483A - 3-oxo-d-homo-21,24-dinor-17aalpha-chol-4-ene-23,17a lactone derivatives their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

1450884 D-homosteroids F HOFFMANNLA ROCHE & CO AG 25 Sept 1974 [26 Sept 1973] 41706/74 Heading C2U The invention comprises compounds of formula wherein the 1,2-bond is single, R<SP>10</SP> being H or Me, or double, R<SP>10</SP> being Me; the 6,7-bond is single, R<SP>7</SP> being H, mercapto, acylthio, alkylthio, cycloalkylthio or aralkylthio, or double, R<SP>7</SP> being H; and the 16,17-bond is single or double. Compounds I (R<SP>7</SP>=H) are prepared (a) from the corresponding #<SP>5</SP> (or #<SP>5,16</SP>)-3#-ols by oxidation to give a #<SP>4</SP>, #<SP>4,6</SP> or #<SP>1,4,6</SP>-3-oxo grouping, e.g. with CrO 3 , DCC/DMS, SO 3 /py, Br 2 /LiBr/Li 2 CO 3 /DMF or with Al(OPr<SP>i</SP>) 3 or Al(OBu<SP>t</SP>) 3 optionally in the presence of DDQ; or (b) from the corresponding #<SP>5(10)</SP> or #<SP>5(10)</SP>,<SP>16</SP>-3- ones by acid or base #<SP>5(10)</SP>##<SP>4</SP> isomerization; and are interconvertible by chemical or microbial 1,2- and/or 6,7-dehydrogenation. Compounds I (R<SP>7</SP> is other than H) are prepared from the corresponding 6,7-dehydro compounds (where R<SP>7</SP>=H) by reacting with H 2 S, a mercaptan or a thiocarboxylic acid, optionally followed by 1,2-dehydrogenation. The starting materials are prepared as described in Specifications 1,450,885 and 1,450,886. Compounds I are said to affect body mineral reserves, and may be made up with carriers into pharmaceutical compositions for oral, parenteral rectal and topical administration. [GB1450884A]

Description

45483/2 - ai7,23-TK-4-'7iD-aa 7-TiJ'» -24,21-,»ain- D-iopiK-3 nn m iniR o' aon ninpn 'wani 7 man , op"? 3 - Oxo-D-hono-2l,24-dinor-17att-chol-4-ene-23,17a lactone derivatives, their preparation and pharmaceutical compositions containing them SPARAMEDIGA, 0(J.

Co 43533 45483/2 The present invention relates to steroids. More particularly, the invention is concerned with D-homosteroids a process for the manufacture thereof and pharmaceutical preparations containing same.

The D-homosteroids provided by the present invention have the following general formula wherein the broken lines in the 1*2-, 6i7- and 16il7-positions denote optional bonds* represents a hydrogen atom or a methyl group when a single bond is present in the l»2~position or a methyl group when a double bond is present in the 1,2-position and R represents a hydrogen atom or a lower alkanoylthic or alkylthio group when a single bond is present in the 6»7-position or a hydrogen atom when a double bond is present in the 6»7-Posi"fcion. 45483/2 Of particular interest are D-homosteroids of formula I in which represents a methyl group and those in which a single bond is present in the l» 2-position. Examples of such preferred compounds are 3-oxo-D-homo-21,24-dinor-17aa-chola--4» 6-diene-23> 17a-lactone and 7a-acetylthio-3-oxo-D-homo-21,24-- 17a-lactone. Examples of D-homosteroids of formula I in which represents a hydrogen atom are 3-oxo-19» 21»24-trinor--D-homo-17ao-chol-4-ene-23 , 17a-lactone, 3-oxo-19 » 21,24-trinor--D-homo-17aot-chola-4» 6-diene-23 , 17a-lactone , 3-oxo-19i 21 , 24--trinor-D-homo-17aa-chola-4»6, 16-triene-23 > 17a-lactone, 3-oxo--19 , 21 ,24-trinor-D-homo-17aa-chola-l,4» 6-triene-23 , 17a-lactone and 7a-acetylthio-3-oxo-19>21,2 -trinor-D-homo-17aa-chola- il^ diene-23»17a-lactone.

According to the process provided by the present invention, the D-homosteroids of formula I hereinbefore are manufactured by a) oxidising the 3-hydroxy-A^ grouping in a D-homosteroid of the general formula , wherein R and the broken line in 16,17-position have the significance given earlier, to the 3-keto-Az*" or S-keto-A^'^ grouping or, insofar as R10 -represents a methyl group, also to the 3-keto-A 1* '6 grouping, or b) dehydrogenating a D-homosteroid of the general formula - in the 1,2- and or 6,7-position (in the l»2-position only in the case when represents a methyl group), or c) isomerising the 5,10-double "bond in a D-homosteroid of wherein the broken line in 16,17-position has the significance given earlier, into the » 5-position* or d) reacting a D-homosteroid of the general formula , wherein R and the broken line in 16,17-position have the significance given earlier, with a compound of the formula R^-H in which R? has the significance given earlier and, if desired, dehydrogenating the product in the 1,2-position.

The oxidation of a D-homosteroid of formula II in accordance with embodiment a) of the process can be carried out according to the Oppenauer procedure (e.g. by means of aluminium isopropylate) , or using an oxidising agent such as chromium trioxide (e.g. Jones' reagent)? or according to the Pfitzner-Moffatt procedure using dimethyl sulphoxide/dicyclo-hexylcarbodiimide (the initially obtained Δ^-3-ketone requiring subsequent isomerisation to the Δ^-3-ketone) » or using pyridine/ sulphur trioxide. When an aforementioned oxidising agent such as Brg/LiBr/LigCO-j in dimethylformamide is used or when the oxidation is carried out according to the Oppenauer procedure in the presence of benzoquinone there is obtained a D-homo- li 6 steroid containing a 3-keto-A rouping. 2, 3-Dichloro-5*6- -dicyano-benzoquinone is, for example* suitable for the 1 4- 6 oxidation to a D-homosteroid containing a 3-keto-A grouping.

The 1,2-dehydrogenation of a D-homosteroid of formula III in accordance with embodiment b) of the process can be carried out in a manner known per se ; for example , in a microbiological manner or using a dehydrogenating agent such as selenium dioxide* 2, 3-dichloro-5*6-dicyano-benzoquinone, chloranil, thallium triacetate or lead tetraacetate. Suitable microorganisms for the 1,2-dehydrogenation are, for example, Schizomycetes, especially those of the genera Arthrobacter (e.g. A. simplex ATCC 694-6), Bacillus (e.g. B. lentus ATCC 13805 and B. sphaericus ATCC 7055) » Pseudomonas (e.g. P. aeruginosa IFO 3505) , Flavobacterium (e.g. F. flavescens IFO 3058) , Lactobacillus (e.g. L. brevis IFO 334-5) and Nocardia (e.g. N. opaca ATCC 4276).

The introduction of a A6-double bond into a 6,7- W -saturated D-homosteroid of formula III can be carried out, for example, using a substituted-benzoquinone such as chloranil [see J. Am. Chem. Soc.82, 4293 (i960); 81, 5951 (1959)1 or using 2,3-dichloro-5»6-dicyano-benzoquinone or using manganese dioxide [see J. Am. Chem. Soc.2, 5932 (1953)].

A 1,4-,6-trisdehydro D-homosteroid can be obtained directly from a 6,7-saturated D-homosteroid of formula III in which R10 represents a methyl group using 2,3-dichloro-5»6- -dicyano-benzoquinone or chloranil.

The isomerisation of a D-homosteroid of formula IV in accordance with embodiment c) of the process can be carried out in a manner known per se; for example, by treatment with acidic or basic agents, suitably by warming with mineral acids such as 6-N hydrochloric acid or with an alkali such as aqueous-alcoholic sodium hydroxide or potassium hydroxide at room temperature.

The introduction of a substituent denoted by R' into a D-homosteroid of formula V in accordance with embodiment d) can be carried out in a manner known per se by reaction with ■hyiflanraQe sulphide, a mercaptan or a thiocarboxylic acid. The reaction can be carried out in an inert solvent such as an ether (e.g. dioxane or tetrahydrofuran) , an alcohol (e.g. methanol or ethanol) or a chlorinated hydrocarbon (e.g. chloroform). The reagent (e.g. the thiocarboxylic acid) is expediently used in excess amounts and can thereby serve as the solvent.

The D-homosteroid starting materials can be prepared as^& follows : A Grignard compound is prepared from 17aa-ethynyl-33-» 17a--dihydroxy-D-homo-androst-5-ene in a manner known per se and is converted into the propiolic acid derivative with carbon dioxide. The sodium salt of the thus-obtained propiolic acid derivative is hydrogenated using palladium-on-carbon in aqueous ethanol until one mol equivalent of hydrogen has been taken up. The resulting acrylic acid derivative lactonises spontaneously and is hydrogenated with the uptake of a second mOl equivalent of hydrogen to give a D-homosteroid of formula II in which a single bond is present in the 16, 17-position and in which R"^ represents a methyl group. D-homosteroid starting materials of formula II in which a single bond is present in the 16, 17-position and in which R10 represents a hydrogen atom can be prepared as follows: D-homocestrone methyl ether is reduced according to the Birch procedure to give D-homo-2, 5(10)-oestradiene-3 » 17a3-diol-3--methyl ether* this is oxidised (e.g. according to the Pfitzner-Moffatt procedure) to the 17a-ketone and the ketone is reacted with an ethynyl-Grignard compound. Weak acidic hydrolysis thereof (e.g. using oxalic acid) yields D-homo-17ao --ethynyl-17a-hydroxy-5(10)-oestren-3-one from which* by a Grignard reaction using carbon dioxide and hydrogenation as described earlier in connection with the 10-methyl compound* there is obtained 3-(D-homo-3 » 17a -dihy<3roxy-5(10)-oestren--17aa-yl)-propionic acid lactone. Oxidation (e.g. according to the Pfitzner-Moffatt procedure) yields 3-(D-homo-17a --hydroxy-3-oxo-5(l0)-oestren-17aa-yl)-propionic acid lactone, i.e. a D-homosteroid of formula IV in which a single bond is 45483/2 D-homosteroid starting materials which contain a double bond in the 16,17-position are expediently prepared by introducing a unit at the 17a-position of a D-homo-5,16- -androstadien-33-ol-17a-one (for the preparation of starting materials in which represents a methyl group) in a manner known per se; for example, by reaction with a Grignard reagent such or, preferably, with the corre d, converting the protected- -aldehyde function into an acid function and lactonising the resulting product by acidification. In an analogous manner, D-homosteroid starting materials in which a double bond is present in the 16,17-position and in which represents a hydrogen atom can be prepared by introducing a 16,17-double bond into D-homooestrone methyl ether by bromination and dehydrobromination and then, in a manner analogous to that described earlier, carrying out a Birch reduction on the aromatic ring, oxidising a 17a-hydroxy group* introducing a propionic acid side-chain by means of a Grignard reaction or condensation with propiolic acid in the presence of potassium ✓ hydroxide, lactonising the propionic acid side-chain and hydrol sing the 3-ether group.

The D-homosteroids of formula I hereinbefore possess pharmacological activity, their activity on the mineral reserves of the body being of particular interest. They may be used, inter alia, for flushing oedemas which are caused, for example, by heart insufficiencies.

D-homosteroid starting materials which contain a double1 "bond in the 16, 17-position are expediently prepared by introducing a unit at the 17a-position of a D-homo-5,16- -androstadien-33-ol-17a-one (for the preparation of starting materials in which R"^ represents a methyl group) in a manner known per se; for example* by reaction with a Grignard reagent such or, preferably, with the corresponding lithium compound, converting the protected--aldehyde function into an acid function and lactonising the resulting product by acidification. In an analogous manner, D-homosteroid starting materials in which a double bond is present in the 16» 17-position and in which R10 represents a hydrogen atom can be prepared by introducing a 16, 17-double bond into D-homooestrone methyl ether by bromination and dehydrobromination and then, in a manner analogous to that described earlier, carrying out a Birch reduction on the aromatic ring, oxidising a 17a-hydroxy group, introducing a propionic acid side-chain by means of a Grignard reaction or condensation with propiolic acid in the presence of potassium hydroxide, lactonising the propionic acid side-chain and hydrol sing the 3-ether group.

The D-homosteroids of formulae II-V hereinbefore are novel and it will be appreciated that they also form part of the present invention.

The D-homosteroids of formula I hereinbefore possess pharmacological activity, their activity on the mineral reserves of the body being of particular interest. They may be used, inter alia, for flushing oedemas which are caused, for example, by heart insufficiencies.

The D-homosteroids of formula I hereinbefore may be used as medicaments; for example* in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier. This carrier can be an inert organic or inorganic carrier material suitable for enteral* percutaneous or parenteral administration such as* for example, water, gelatine* gum arabic* lactose* starch* magnesium stearate* talc* vegetable oils* polyalkyleneglycols, petroleum jelly and the like. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets* dragees* suppositories or capsules)* in a semi-solid form (e.g. as salves) or in a liquid form (e.g. as solution* suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatives* stabilisers, wetting agents* emulsifiers* salts for varying the osmotic pressure or buffers. The pharmaceutical preparations may also contain therapeutically valuable substances other than the D-homosteroids provided by the present invention.

The pharmaceutical preparations can be prepared in a manner known per se by mixing a D-homosteroid of formula I with non-toxic* solid and or liquid carrier materials which are customary in pharmaceutical preparations and which are suitable for therapeutic administration (e.g. those carrier materials mentioned hereinbefore) and* if desired, transforming the mixture into the desired pharmaceutical dosage form. As a dosage guideline a daily dosage of 10-200 mg may be employed depending en the individual needs, the mode of administration and the professional Judgement of the person supervising the administration of the subject compounds.

The following Examples illustrate the process provided by the present invention: Example 1 80 ml of solvent were distilled off while stirring and gassing with argon from a mixture of 12.50 g of 33-hydroxy-D- -homo-21,2 -dinor-17aa-chol-5-ene-23» 17a-lactone, 160 ml of cyclohexanone and 400 ml of toluene. 15· 0 g of aluminium tertbutylate were then added and the mixture was heated for 2 hours under reflux and under a water-separator. For the working-up» the mixture was evaporated to a volume of ca 200 ml, poured on to ice-water/dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride extract was washed with water* dried over sodium sulphate and evaporated in vacuo. The residue was freed from solvent and low molecular in a high vacuum weight condensation products at 140°C/and then chromatographed on silica gel. By elution with methylene chloride/acetone (95: 5) » there were isolated 10.3 g of pure 3-oxo-D-homo-21 ,24--dinor-17a -chol-4-ene-23 , 17a-lactone of melting point 220°--221°C (from acetone/isopropyl ether); ε2 ΐ = 16600; Ca] 5 = +72° .

The starting material was prepared as follows: 3β-Acetoxy-17α-eth nyl-17-h dΓo y-D-homo-androst- -e e was converted using butyl-lithium into the lithium salt which was reacted with carbon dioxide to give 3β » 17a -dihydroxy-D--homopregn-5-en-20-yne-21-carboxylic acid of melting point 194°-196°C; Ιά1 Ώ = -123° . This acid was catalytically hydrogenated in alkaline solution and, after acidification, yielded 3P-hydroxy-D-homo-21,2 -dinor-17aa-chola-5i 20-diene- ^ -23, 17a-lactone of melting point 205°-207°C; [a]D = -43° · This lactone was catalytically hydrogenated using palladium--on-car on in ethanol to give 33-hydroxy-D-homo-21 ,24-dinor--17aa-chol-5-ene-23* 17a-lactone of melting point 240°-243°C [a D » -99° (c = 0.1 in dioxane).

Example 2 A solution of 4.0 g of 3-oxo-D-homo-21,24-dinor-17aa--chol-4-ene-23,17a-lactone in 200 ml of dioxane containing 6.506 HC1 was treated over a period of 3 minutes with a solution of 3.1 g of 2,3-dichloro-5»6-dicyano-benzoquinone in 50 ml of dioxane containing 6. $ HC1. The mixture was then stirred for 7 minutes at room temperature, treated with 50 g of sodium bicarbonate, stirred for a further 3 minutes at room temperature and then heated under reflux for 30 minutes. The mixture was cooled, the precipitate filtered off and the filtrate filtered through 100 g of Alox II, final elution being carried out with ethyl acetate. The combined filtrates were evaporated in vacuo. The residue was chromatographed on 200 g of silica gel. By elution with methylene chloride/ acetone (97: 3) i there was isolated pure 3-oxo-D-homo-21,24--dinor-17aa-chola-4,6-diene-23, 17a-lactone of melting point 242°-244°C; = 27200; [a]D = +25° (c = 0.1 in dioxane).

By elution with methylene chloride/acetone (9:1)» there was finally obtained 3-oxo-D-homo-21,24-dinor-17aa-chola-l,4,6--triene-23 , 17a-lactone of melting point 179°-180°C; e222 = 11600, ε255 = 9300, ε298 = 12500; [α]^5 = +15° (c = 0.1 in dioxane) .

Example 3 A solution of 0.50 g of 3-oxo-19-nor-D-homo-21,24--dinor-17aa-chol-5(lO)-ene-23>17a-lactone in 50 ml of dioxane containing 2 HC1 was held at room temperature for 2 hours. For the working-up, the mixture was poured on to ice-water and extracted with methylene chloride. The methylene chloride extract was washed neutral with water» dried over sodium sulphate and evaporated in vacuo. After recrystallisation of the residue from acetone hexane, there was obtained pure 3--oxo-19-nor-D-homo-21,2 -dinor-17aa-chol- -ene-23, 17a-lactone ; e240 a 16800· The starting material was prepared as follows: D-homooestrone methyl ether was reduced according to the Birch procedure and subsequently oxidised according to the Pfitzner-Moffatt procedure to give 3-methoxy-D-homooestra--2,5(l0)-dien-17a-one. This was ethynylated using potassium acetylide to give 17aa-ethynyl-17-hydroxy-3-niethoxy-I)-homo-oestra-2»5(10)-clieiie which was reacted* via the corresponding lithium compound, with carbon dioxide to give 17a3-hydroxy-3--methoxy-19-nor-D-homo-pregna-2* 5(10)-dien-20a-yne-21- -carboxylic acid. Partial catalytic hydrogenation of this carboxylic acid in alkaline solution and subsequent treatment with oxalic acid in dioxane yielded 3-oxo-19-nor-D-homo-21,2--dinor-17aa-chola-5(10) »20-diene-23,17a-lactone which was converted by selective catalytic hydrogenation into 3-oxo- -19-nor-D-homo-21,2 -dinor-17aa-chol-5(10)-ene-23»17a-lactone.

Example A solution of 1.0 g of 3-oxo-D-homo-21,24-dinor-.17aa--chola-4»6-diene-23» 17a-lactone in 6 ml of thioacetic acid was held at room temperature for 3 hours. The mixture was poured on to ice-water and extracted with ether. The ether extract was washed with dilute sodium hydroxide and water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed over silica gel. Elution with ether/hexane (1 : 1) yielded pure 7a-acetylthio-3-oxo-D-homo-21,24-dinor-17aa--chol-4-ene-23, 17a-lactone of melting point 1930-195°C (from methanol); ^236 β 90°» = -26° (c = °· 1 in dioxane).

Example 5 1.4 g of 3 -hydroxy-D-homo-21,2 -dinor-17aa-chol-5-ene--23,l?a-lactone, 1.8 g of lithium bromide and 1.8 g of lithium carbonate were warmed to 80°C in 30 ml of dimethyl-formamide and treated over a period of 45 minutes with a solution of I. 32 g of bromine in 9·2 ml of dioxane. The mixture was subsequently warmed to 80°C for a further 2 hours. The mixture was then poured on to water and acidified with acetic acid. The precipitate was filtered off and recrystallised twice from acetone hexane. There was obtained pure 3-oxo-D--homo-21,24-dinor-17aa-chola- i 6-diene-23 , 17a-lactone of melting point 242°-244°C.

Example 6 1.5 g of 3-oxo-D-homo-21,24-dinor-17aa-chola-»4»6-diene -23> 17a-lactone were dissolved in 50 m of tetrahydrofuran containing 2% o HC1. This solution was treated with 1»2 g of 2, 3-dichloro-5»6-dicyano-benzoquinone and the mixture stirred at room temperature for 16 hours. Working-up in the usual manner yielded a product which, after recrystallisation from acetone heatane, gave pure 3-oxo-D-homo-21,24-dinor-17aa-chola--l, »6-triene-23 » 17a-lactone of melting point 179°-180°C.

Example 7 5.0 g of 33-hydroxy-D-homo-21,2 -dinor-17aa-chola-5»16--diene-23> 17a-lactone were dissolved in 25 ml of dimethyl sulphoxide and 25 ml of benzene. 1.2 ml of pyridine and 0.6 ml of trifluoroacetic acid were added while stirring and gassing with argon. 7·6 g of N^N'-dicyclohexylcarbodiimide were then added and the mixture was stirred overnight at room temperature. A mixture of 3·4 g of oxalic acid, 31 ml of methanol and 35P ml of ether was then added to the slightly yellowish suspension and the resulting mixture was stirred for a further 1 hour. For the working-up, the mixture was treated with 400 ml of water, stirred for 15 minutes and then filtered. The filtrate was washed successively with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The crude product was dissolved in 1 0 ml of acetic acid and 15 ml of 2-N hydrochloric acid and held at room temperature for 1 hour. The solution was then poured on to ice-water, extracted with methylene chloride and the methylene chloride extracts washed with sodium carbonate solution and water. After drying over sodium sulphate, the solvent was evaporated in vacuo and the residue recrystallised from acetone/hexane. There was obtained pure 3-oxo-D-homo-21 , 24- -oinor-17aa-chola-4»16-diene-23,17a-lactone of melting point 218°-219°C; εΡ.η - 16650.

The starting material was prepared as follows: 33-Acetoxy-D-homo-androst-5-en-17a-one was brominated with CuB^ and, by subsequent treatment with calcium carbonate in dimethylacetamide and acetylation with acetic anhydride/ pyridine, converted into 3 -acetoxy-D-homoandrosta-5>16-dien- -17a-one. This compound was converted* by treatment with 3β- -ethylenedioxy-n-propyl-magnesium bromide and subsequent acetylation, into 3P-acetoxy-17aa-( 3 ' » 3 ' -ethylenedioxa-propyl)- -17a-hydroxy-D~homoandrost-5-ene. Acid saponification of this ethylene ketal, oxidation according to the Jones procedure, saponification of the 3P-acetoxy group with potassium carbonate and subsequent treatment with acid yielded 3P-hydroxy-D-homo- -21,24-dinor-17aoc-chola-5* 16-diene-23 , 17a-lactone.

Example 8 In a manner analogous to that described in Example 5» from 33-hydroxy-D-homo-21, 24—dinor-17aoc-chola-5i 16-diene-23 , 17a- -lactone there was obtained 3-oxo-D-homo-21,24-dinor-17aoc- -chola-4,6,16-triene-23, 27a-lactone of melting point 214°--214.5°C Example 9 manner analogous to that described in Example 4, -lactone there was obtained 7a-acetylthio-3-oxo 1» - nor--17aa-chola- »16-diene-23, 17a-lactone. M.p. 143-143, 5 ° (from acetone/isopropyl ether).

Example 10 A mixture of 5-6 g of 3-oxo-D-homo-17aa-pregna-4, 6,16--triene-21,17a-carbolactone, 16.5 ml of ethyl mercaptan and 1.7 ml of piperidine was heated to reflux for 3 days. The solvent was then evaporated in vacuo and the residue crystallized from methanol. There was obtained 3 ·1 g of 7a-(ethylthio )-3-oxo-D-homo-17aa-pregna-4,l6-diene-21,17a-carbo-lactone: UV : λ 240 nm, £ = 16000. 1 max '

Claims (9)

1. 45483/2 CLAIMS: 1. A process for the manufacture of D-homoeteroide of the general formula wherein the broken lines in the 1,2-, 6,7- and 16,17-positions denote optional bonds, represents a hydrogen atom or a methyl group when a single bond is present in the 1,2-position or a methyl group when a double bond is present in the 1,2-position 7 and R represents a hydrogen atom or a lower alkanoylthio or alkylthio group when a single bond is present in the 6,7-position or a hydrogen atom when a double bond is present in the 6,7-position, which process comprises a) oxidising the 3-hydroxy- A^-grouping in a D-homosteroid of the general formula » wherein R and the broken line in 16,17-position have the significance given in claim 1, to the 3- eto-A^ °r 3-keto-A^'^ grouping or, insofar as R10 represents a methyl group» also to the 3-keto-A * grouping* or b) dehydrogenating a B-homosteroid of the general formula , wherein R and the broken lines in 6,7- and 16,17- position have the significance given in claim 1, in the 1»2- and or 6,7-position (in the 1,2-position only in the case when represents a methyl group), or c) isomerising the 5>10-double bond in a D-homosteroid of the general formula wherein the broken line In 16,17-position has the significance given earlier, into the 4,5-position, or d) reaoting a D-homoeteroid of the general formula wherein R and the broken line in 16,17-position have the significance given in claim 1, 7 7 with a compound of the formula R -H in which R' has the significance given in claim 1 and, if desired, dehydrogenating the product in the 1,2-position.

2. A prooess according to claim 1, wherein a D-homo-steroid of formula II in which R10 represents a methyl group is oxidised to a D-homosteroid of formula I containing a 3-keto--A* or 3-keto-A^'6 grouping.

3. A process according to claim 1, wherein a 6,7-satura-ted D-homosteroid of formula III in which R1^ represents a methyl group is dehydrogenated in the 6,7-position. 4· A prooess according to claim 1, wherein a D-homosteroid of formula V in which R10 represents a methyl group is reaoted with thioacetic acid. 5. A prooess for the manufacture of the D-homosteroids of formula I given in claim 1, substantially as hereinbefore described with reference to any one of the foregoing Examples· 6. Process for the manufacture of pharmaceutical preparations characterized in that a D-homosteroid of formula I given in claim 1 is mixed, as active substance, with nontoxic, inert, therapeutically compatible solid or liquid carriers, commonly used in suoh preparations, and/or excipients. 7. A pharmaceutical preparation containing a D-homosteroid of formula I given in claim 1 in association with a compatible pharmaceutical carrier. 45483/2 8, D-homoeteroida of the general formula ' wherein the broken lines in the 1,2-, 6,7- and 16,17-positions denote optional bonds, represents a hydrogen atom or a methyl group when a single bond is present in. the 1,2-position or a methyl group when a double bond is present in the 1,2-position 7 and R represents a hydrogen atom or a lower alkanoylthio or alkylthio group when a single bond is present in the 6,7-position or a hydrogen atom when a double bond is present in the 6,7-position, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 9. D-homosteroids according to claim 8, wherein R represents a methyl group, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 10. D-homosteroids according to claim 9, wherein a single bond is present in the 1,2-position and a double bond is present in the 16,17-position, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof, 11. 3-Oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 12. 3-0xo-D-homo-21,24-dinor-17aa-chola-4,6-diene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 13. 3-0xo-19-nor-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 14· 7a-Acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23»17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 1 . 3-0xo-D-homo-21,24-dinor-17aa-ohola-l, ,6-triene-23,17a-laotone , whenever prepared according to any one of olaims 1-5 or by an obvious chemical equivalent thereof. 45483/2 16. 3-0xo-D-homo-21f24-dinor-17aa-chola-4 ,16-diene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious ohemical equivalent thereof. 17. 7a-Acetylthio-3-oxo-D-homo-21 , 24-dinor-17aa-chola-4 ,16 diene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 18. 3-0xo-D-homo-21,24-dinor-17aa-ohola-4,6,16-triene-23,17a-lactone, whenever prepared according to any one of claims 1-5 or by an obvious chemical equivalent thereof. 45483/2 D-homoeteroide of the general formula wherein the broken lines in the 1,2-, 6,7- and 16,17-positions denote optional bonds, R"1"0 represents a hydrogen atom or a methyl group when a single bond is present in the 1,2-poBition or a methyl group when a double bond is present in the 1,2-position 7 and R represents a hydrogen atom or a lower alkanoylthio or alkylthio group when a single bond is present in the 6,7-position or a hydrogen atom when a double bond is present in the 6,7-poeition. 20. D-homosteroids according to claim 19, wherein R10 represents a methyl group. 21. D-homosteroids according to claim 20, wherein a single bond is present in the 1,2-position and a double bond is present in the 16,17-position. 45483/2 22. 3-0xo-D-homo-21,24-dinor-i7aa-chol-4-ene-23,17a-lactone. 23. 3-0xo-D-homo-21,24-dinor-17acr-chola-4,6-diene-23,17a-lactone· 2

4. 3-0xo-19-nor-D-homo-21f24-dinor-17aa-chol-4-ene-23f 17a-lactone. 2

5. 7a-Acetylthio-3-oxo-D-homo-21,24-dinor-17aa-chol-4-ene-23,17a-lactone. 2

6. 3-0xo-D-homo-21,24-dinor-17aa-chola-l,4, 6-triene-23,17a-lactone. 2

7. 3-0xo-D-homo-21,24-dinor-17aa-chola-4,16-diene-23,17a-lac one. 2

8. 7a-Acetylthio-3-OXO -D-homo-21 , 24-dinor-17aa-chol 4 , 16-diene-23 , 17a-lactone . 2

9. 3-Oxo-D-homo-21,24-dinor-17aa-chola-4, 6,16- riene 3,17a-lactone. the Rpp4icants