DE2651364A1 - NEW D-HOMOSTEROIDS - Google Patents

Description

Patent attorneys "

Dr, Franz teacher Dipl.-Inij. F. Meyer district Munich 80

Lucile-Grahn-Str. 22, Tel. (039) 472S47

I 0. Nova

RAN 4104/143

F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

New D-homosteroids

The invention relates to new D-homosteroids of the formula

17ass

, 17aa

wherein the dotted lines in the A ring indicate optional CC bonds; R ^{1 is} hydrogen or methyl; R ⁵ oxo or, if the ring A is unsaturated, oxo, (ct-H, β-OH) or (aH, β-O-acyl);

Hydrogen or methyl; R.

^17a ß water

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substance, C,, ..- alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R ^{act is} hydrogen, lower-alkyl, ethynyl, vinyl or propadienyl.

The term “acyl” is intended to denote, in particular, organic acid residues, for example residues of up to 11 carbon atoms containing alkanecarboxylic acids, in particular residues of lower (containing up to 7 carbon atoms) alkanecarboxylic acid, such as Acetic acid, propionic acid, caproic acid, valeric acid, oenanthic acid, undecylic acid; or oxalic acid, succinic acid, Citric acid; or residues of aromatic carboxylic acids such as benzoic acid, phenylacetic acid, or phenoxyacetic acid; or heterocyclic carboxylic acids such as nicotinic acid; or cycloaliphatic carboxylic acids, such as cyclopenty! propionic acid.

Lower alkyl radicals can contain up to 7 carbon atoms and be straight-chain or branched. Examples are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred lower alkyl radicals are methyl and ethyl. An alkyl radical R can contain up to 10 carbon atoms. Examples such radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and decyl.

Cycloalkenyl radicals preferably contain 5-8 carbon atoms. Examples are cyclopenten-1-yl and cyclohexen-1-yl.

A preferred group of compounds within Formula I.

1 "5

are the compounds in which R is hydrogen and R is oxo and ring A contains a double bond. Furthermore, those compounds of the formula I are preferred in which R ^{a is} hydrogen, methyl or ethyl and R ^ is hydrogen or lower-alkanoyl. Examples of compounds of formula I are

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17ass- (3-Cyclopentyl) propionoxy-D-h.omo-and.ros ta-4,16-

dien-3-on,

17ass-nieotinyloxy-D-homo-androsta-4,16-dien-3-one, lTaß-Propionoxy-D-liomo-androsta-l ^ jlö-trien - ^ - on, 17ass-Hydroxy-7a-methyl-I) -h.oiiio-androsta-l, 4,16-triene-

la, 7a-dimethyl-17ass-hydroxy-D-liomo-androsta-4,16-

dien-5-on,

17ass-Hydroxy-7a-meth.yl-D-liomo-androsta-4, l6-dien-3-one, ^ aß-Hydroxy ^ a-methyl-D-homo ^ a-androst-lö-en - ^ - on, 17ass-Hydroxy-7a-meth.yl-D-homo-5a-andros ta-1,16-diene-

17ass-Hydroxy-1-methyl-D-h.omo-5a-androsta-1, 16-dien-3-one la, 17aa-dimethyl-D-homo-androsta-4, l6-dien-3-one, 3 β, 17ass-Dih.ydroxy-17aa-methyl-D-homo-5a-androsta-l, 16-

17ass-Hydroxy-17a a-methyl-D-homo-5a-andros ta-1,16-diene-

17ass-Hydroxy-la, 17aa-methyl-D-hoino-5a-andros t-16-en-

^ aß-Hydroxy- ^ aa-äthyl-D-homo-Sa-androst-ie-en-S-on, ^ aa-Aethyl- ^ aß-hydroxy-la-methyl-D-homo-Sa-androst-

l6-en-3-one,

17ass-Hydroxy-la-methyl-D-homo-5a-androst-l6-en-3-one, 17ass-Hydroxy-7a, 17aα-dimethyl-D-homo-androsta-4,16-

dien-3-on.

17aß-pentyloxy-D-homo-androsta-4,16-dien-3-one, 17a / 3-n-decyloxy-D-hoπιo-androsta-4 _f 16-dien-3-one, 17aß-benzyloxy-D- homo-androsta-4,16-dien-3-one, 17ass-cyclohexylmet ± iyl-D-homo-androsta-4, le-dien-S-one, 17aJ3-undecanoyloxy-D-homo-androsta-4 _/ 16- dien-3-on.

The D-homosteroids of the formula I can according to the invention are obtained by one

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in a D-homosteroid of the formula

, 17 ate

II

wherein R, R ^P and R are as defined and the Δ double bond is optional
the 3-hydroxy or 3-hydroxy-Δ grouping to the 3-keto or

3-Keto- ^ group is oxidized, or that one

b) a D-homosteroid of the formula

III

1 3
where R, R and the dotted lines in the Α-ring have the meaning given,

with intermediate protection of a 3-Eeto group with a one Reacts radical R donating organometallic compound, or that one

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a D-homosteroid of the formula

, 17ass

17aa

IV

in which R ¹ , _R ^17aa _and r ¹⁷ ^ have _the meaning given,

with a methyl Grignard compound in the presence of copper (I) chloride implements, or that one

a compound of the formula

, 17 ate

17 aa

in which R and R ^ have the meaning given and the Δ double bond is optional,

with a methyl G-rignard compound in the presence of copper-I chloride and a Δ double bond in the reaction product is then rearranged into the 4,5-position by acid treatment, or that one

7 ο ο ^f - \ ι q / 1 ο Β 1

e) the hydroxyl group (η) in a D-homosteroid of the formula I, in which at least one hydroxyl group in 3- or 17a3-position is present, acylated, or that one

f) in a D-homosteroid of the formula

Vl

in the R ^ and the dotted lines the Have the meaning mentioned and Z Oxo or

(0R ^17aß , R ^17aa ) represents,

if Z represents oxo, the 17a-keto group among intermediate Protection of a 3-eeto group reduced to the hydroxyl group or, if R is oxo and the Α ring is monounsaturated, the 3-keto group and any 17a-keto group that may be present reduced to the hydroxyl group, or that one

g) a saturated or monounsaturated D-homosteroid of the formula I, in which R is oxo, in 1,2- and / or 4,5-position dehydrated, or that one

h) in a D-homosteroid of the formula I, in which R ^{aß is} hydrogen and R ¹ , R ³ , R ⁷ , R ^17aa and the dotted lines in the A ring have the meaning given, the 17a / 3-hydroxy group in one Cycloalkenyl, tetrahydropyranyl, Ci _1n -alkyl, benzyl or cyclohexylmethyl ether transferred, or that one

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i) in a D-homosteroid of the formula I in which R is acyl,

13 7 represents tetrahydropyranyl or cycloalkenyl and R, R, R -, R ^α and the dotted lines in the Α ring have the meaning given, the 17ass-acyloxy group and any 3-acyloxy group saponified or a 17ass-tetrahydropyranyl or cycloalkenyl ether splits, or that one

j) in a D-homosteroid of the formula

0R ^l7ass

^ I

Ri

. I 1 y

VII

wherein R, R, R , R ¹ ' ⁰ X ₁₁₁ Q a ± e dotted lines in the Α ring have the meaning given, hydrogenating the ethynyl group to the vinyl group.

The oxidation according to process variant a) can be carried out in a manner known per se according to Oppenauer, for example by means of aluminum isopropylate or -ter-butylate; or with oxidizing agents such as chromium trioxide (eg Jones reagent); or according to Pfitzner-Moffatt by means of dimethyl sulfoxide / dicyclohexylcarbodiimide (whereby the Λ -3-ketone obtained primarily must then be isomerized to the Δ - J-ketone) or by means of dimethyl sulfoxide / pyridine / S0 ~.

17a
The reaction of the R keto group of a compound of

Formula II with an organometallic compound according to process variant b) can also be used in a manner known per se

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be performed. The organometallic compound can be a G-rignard compound (e.g. ethynyl magnesium bromide, methyl magnesium bromide, Vinyl magnesium bromide) or an organic alkali metal compound such as sodium, potassium or lithium acetylide, or Be vinyl lithium. A 3-keto group present at the same time can be protected intermediately, e.g. as a ketal, enol ether, enamine or semicarbazone.

The 7-methylation of a compound of formula IV and the 1-methylation of a compound of the formula V according to the Process variants c) and d) can also be carried out in a manner known per se by reaction with a methyl Grignard compound be performed. First a la-methyl-

λ 5 λ5

Δ compound obtained, the Δ double bond of which can be rearranged into the 4.5 position by treatment with ethanic sulfuric acid with heating.

The acylation of a 3- or 17ass-free hydroxyl group in a D-homosteroid of the formula I can be carried out by Treatment with a reactive acid derivative, e.g. an acid halide or acid anhydride, in the presence of a base such as pyridine or collidine.

The reduction of a 3- or 17a-keto group according to process variant f) can be carried out in a manner known per se using complex metal hydrides, for example di (lower alkoxy) aluminum hydrides such as diisobutoxyaluminum hydride, tri- (lower alkoxy) aluminum such as triisopropoxyaluminum ; Lithium aluminum hydride ; Sodium aluminum hydride or sodium borohydride \ or trimethoxy- or Tributoxylithiumaluminiumhydrid be performed. Suitable solvents for this purpose are hydrocarbons, such as cyclohexane, benzene, toluene \ or ether, for example diethyl ether or tetrahydrofuran. If a 17a-keto group is to be reduced in the presence of a 3-keto group alone, the 3-keto group is

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■ η.

group intermediately protected. A 3-keto group can if present a 4,5 double bond in the form of an enamine or enolether. A non-conjugated 3-keto group can be protected as a ketal. The introduction and removal of such protective groups can be carried out according to known methods Working methods.

A 1,2-dehydrogenation according to process variant g) can be carried out in a manner known per se using dehydrogenating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, thallium triacetate or lead tetraacetate. The 1,2-dehydration can also be carried out microbiologically, for example by means of schizomycetes, in particular those of the Arthrobacter genera, for example A ”, simplex ATCC 6946; Bacillus, eg, B. lentus ATCC 13805 and B. sphaericus ATCC 7055 ^ »Pseudomonas such as P. aeruginosa IiO 3505, Flavobacterium, for example flavenscens Ii ¹ O 3058. Lactobacillus such as L. brevis Ii O ¹ 3345 and Nocardia, including N. opaca ATCC 4276.

Double bonds in 1,2 and 4,5 positions can be used at the same time by bromination to the 2,4-dibromo-3-ketone and dehydrobromination of the latter using lithium carbonate and lithium bromide be introduced into dimethylformamide. A 4,5 double bond can also be introduced by having one in the A-ring saturated 3-Eeto-steroid in glacial acetic acid to the 2a, 4a-dibromo derivative brominated and this with chromium-II-chloride to the 4a-bromine compound reduced. The latter compound can then be dehydrobrominated to the Δ -3-ketone via the semicarbazone by treatment with succinic acid will.

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The etherification of a 17ass-hydroxy group according to process variant h) can, for example, by treatment with dihydropyran (for the purpose of producing the tetrahydropyranyl ether) or by treatment with a cycloalkanone ketal in the presence of a catalytic amount of acid, such as p-toluenesulfonic acid (for the purpose of producing a cycloalkenyl ether) take place. A 3-oxo group is expediently protected as an intermediate for the preparation of a 17ass-C, _, _{n-alkyl, benzyl or cyclohexyl methyl ether.} The 3-oxo group is preferably protected by ketalization, for example with ethylene glycol in the presence of a catalytic amount of acid, such as p-toluenesulfonic acid. The etherification of the 17a / 3-hydroxy group can be carried out by conversion into an alkali metal salt, for example the sodium salt, with a strong base, for example sodium hydride, and reaction with a C 1-6 alkyl, benzyl or cyclohexylmethyl halide, such as pentyl iodide, benzyl chloride or cyclohexyl methyl iodide , be accomplished in a solvent such as dimethyl sulfoxide or benzene.

The saponification of 17a and 3-acyloxy groups and the Cleavage of 17a-ether groups (process variant i) can take place in a manner known per se. Acyloxy groups can e.g. Aqueous-alcoholic bases, such as aqueous-methanolic potassium carbonate, can be saponified, ether groups can be saponified by means of aqueous-alcoholic mineral acids or organic acids such as oxalic acid or p-toluenesulfonic acid are cleaved. The hydrogenation the ethynyl group according to process variant j) can in the presence of precious metal catalysts, such as Pd / CaCCL and, expediently, a deactivator such as pyridine.

The starting materials for the preparation according to the invention of the compounds of the formula I can, insofar as they are not are known or their preparation is described here, by methods known per se or in analogy to those below

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methods described are produced.

The compounds of the formula I are hormonally active. Compounds of the formula I in which R ^{a is} hydrogen or lower-alkyl are in particular androgenic / anabolic. Compounds of the formula I in which R is ethynyl, vinyl or propadienyl are particularly gestagenic and inhibitory to ovulation.

For example, the 17ass-hydroxy-D-homo-androsta-4, showed 16-dien-3-one when administered subcutaneously to juvenile male rats, an effect comparable to that of testosterone androgenic activity at one third of the dose. The androgenic activity was based on the growth of the prostate and Seminal vesicle determined. The 17ass-phenylacetoxy- and the 17ass-phenoxyacetoxy-D-homo-ändrosta-4, 16-dien-3-one showed when administered subcutaneously to juvenile male rats Testosterone oenanthate has a prolonged duration of action.

The products of the process can be used as remedies, for example in Form of pharmaceutical preparations find use, which they are mixed with one for enteral, percutaneous or pharmaceutical, organic or inorganic inert carrier material suitable for parenteral administration, such as water, Gelatin, gum arabic, lactose, starch, magnesium

stearate, talc, vegetable oils, polyethylene glycols, vaseline, etc. included. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, Capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, Stabilizing agents, wetting agents or emulsifying agents, salts for changing the osmotic pressure or buffers. You can also contain other therapeutically valuable substances.

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example 1

50.0 g of 3j3-hydroxy-D-homo-androsta-5,16-dien-17a-one were dissolved in 1000 ml of cyclohexanone and 3000 ml of toluene. 400 ml of solvent were evaporated from this solution, the solution was cooled to 80 ° and 60.0 g of aluminum tert-butoxide were added. While stirring and gassing with argon, the mixture was heated to reflux on a water separator for 2 1/2 hours. For work-up, the reaction solution was concentrated in vacuo to approx. 200 ml, concentrated on an ice-cold mixture of 1500 ml of water and 50 ml. Poured hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, washed with Na SO. dried and evaporated in vacuo; finally dried in a high vacuum at 90 °. The residue was then recrystallized from acetone-hexane. 40.7 g of pure D-homo-androsta-4,16-diene-3,17a-dione with a melting point of 193-194 ° were obtained. UV: ε ₂₃₆ = 21500; Ea] ^ ⁵ = + 60 ° (c = 0.1 in dioxane).

Production of the raw material:

18.1 g of 30-acetoxy-D-homo-androst-5-en-17a-one were dissolved in 800 ml of methanol under argon at 45 ° C Solution was given 23.5 g of copper (II) bromide and heated Mixture under reflux for 18 hours. The reaction mixture was cooled to 35 °, filtered and the residue was taken with it Washed off chloroform. The combined filtrates were poured into 1.3 l of water containing 100 g of sodium chloride and 500 g of ice. It was extracted three times with chloroform. The organic phases were washed with NaCl solution, with magnesium sulfate dried and evaporated in vacuo. 19.8 g of almost pure 17a-bromo-30-hydroxy-D-homo-androst-5-en-17a-one, the was used directly in the next stage.

35.1 g of calcium carbonate was suspended in 290 g of dimethylacetamide. 40 ml of dimethylacetamide were added while gassing with argon distilled off, then 18.7 g of 17a-bromo-30-hydroxy-D-homo-androst-5-en-17a-one added within 20 minutes

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XI.

and reflux the mixture for 30 minutes. The reaction solution was then cooled to 60 and the precipitate filtered off. The filtrate was poured onto a mixture of 1.25 l of water, 450 g of ice and 170 g of common salt. It was extracted three times with methylene chloride. The extracts were washed with 1N hydrochloric acid and water, dried with magnesium sulfate and evaporated in vacuo. 14.7 g of crude product were obtained, which was dissolved in 170 ml of ethyl acetate and treated with a little activated charcoal. After filtering the solution through Speedex Dicalite, it was concentrated to 50 ml and allowed to crystallize. This gave 11.7 g of pure 3β-hydroxy-D-homo-androsta-5,16-dien-17a-one, melting point 190-193 °.
UV: Z ₂₂₁ = 13000. [A] ^ ⁵ = -177 ° (c = 0.1 in dioxane).

Example 2

15.0 g of D-homo-androsta-4,16-diene-3,17a-dione were dissolved in 150 ml of methanol and refluxed with 8.1 ml of pyrrolidine in the absence of air for 10 minutes. The reaction solution was cooled to -10 °. The enamine which had crystallized out was suction filtered and dried at 20 in a high vacuum. 16.1 g of pure 3- (1-pyrrolidinyl) -D-homo-androsta 3,5,16-trien-17a-one, melting point 207 ° -210 °, were obtained.
UV: ε _{2? 9} = 19500; S ₃₃₇ = 13000. [Α] ^ ⁵ = -295 °.

16.1 g of this enamine were abs in 750 ml. Tetrahydrofuran dissolved and within 15 minutes to a well-stirred solution of 8.0 g of lithium aluminum hydride in 750 ml of abs. Ether added dropwise at 0 °. The mixture was then stirred at 0 for a further hour. The reaction solution was initially used for working up 300 ml of moist ether are carefully added. Then 40 ml of saturated Na SO. Solution were added and the mixture was stirred for a further 10 minutes and filtered off the precipitate. The filtrate was evaporated in vacuo. 15.8 g of substance were obtained with a mixture of 1000 ml of methanol and 200 ml of 2N sodium hydroxide solution heated to 50 for 45 minutes while stirring and gassing with argon became. The reaction solution was then added to 6 l of ice water and

7 C ^{! ::} L 1 9 / ^Λ 0 M

Poured 200 ml of acetic acid and extracted three times with methylene chloride. The organic extract was washed with water, _{dried with Na 3} SO ₄ and evaporated in vacuo. The residue was chromatographed on 650 g of silica gel. 13.0 g of pure 17aj3-hydroxy-D-homo-androsta-4,16-dien-3-one could be eluted with acetone-hexane 1: 1. 183-185 °.

UV: ε ₂₄₁ = 16200. [Α] £ ⁵ = + 76 °.

Example 3

A solution of 6.3 g of 17ass-hydroxy-D-homo-androsta-4,16-dien-3-one in 60 ml of pyridine and 60 ml of acetic anhydride was kept at room temperature overnight. Then it became The solvent was removed in vacuo and the residue was recrystallized from acetone / hexane. 6.0 g of pure 17 a / 3 - Ac et oxy were obtained D-homo-androsta-4,16-dien-3-one, m.p. 165-167 °.

UV: ε ₂₄₀ = 17000. Ca] "= +91 (c = 0.1 in dioxane)"

Using the same method, using the appropriate acid anhydride, the following were prepared:

17ass-Propionoxy-D-homo-androsta-4,16-dien-3-one, M.p. 139-140 °,

17ass-butyroxy-D-homo-androsta-4,16-dien-3-one, 117-118 °.

Example 4

To a solution of 2.0 g of 17a / 3-hydroxy-D-homo-androsta-4,16-dien-3-one 2.0 ml of phenylacetyl chloride in 20 ml of pyridine were added dropwise within 15 minutes and the mixture

ο ^L
Heated to 60 for 5 hours. For work-up, the mixture was poured into water and extracted with methylene chloride. The organic extract was washed neutral with dilute hydrochloric acid, NaHCO ₃ solution and water, dried with Na 3 SO ₄ and evaporated in vacuo. The residue was chromatographed on silica gel. With hexane-acetone 9: 1, 1.7 g of pure 17aj3-phenyl-

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acetoxy-D-homo-androsta ^^ ö-dien-S-one, m.p. 135-136 (acetone-hexane).

UV: ε ₂₄₀ = 17200. [Α] "= +108 (c = 0.1 in dioxane).

Using the same method, using the appropriate acid chloride, the following were prepared:

17 a / 3-Undecanoy loxy-D-homo-andros ta-4,16-dien-3-one; amorphous; [α] = + 80 ° (c = 0.1 in dioxane); ε ₂₄₀ = 17100,

17a / 3-heptanoyloxy-D-homo-androsta-4,16-dien-3-one;

ocO r,

oily, Ca] "= + 88 ° (c = 0.1 in dioxane),

17aJ3-Phenoxyacetoxy-D-homo-androsta-4,16-dien-3-one, M.p. 174-176 °.

Example 5

1.0 g of 17ass-hydroxy-d-homo-androsta-4,16-dien-3-one was dissolved in 40 ml of abs. Dissolved benzene and then distilled off 10 ml of benzene. A solution of 5 mg of p-toluenesulfonic acid in 10 ml of benzene and 0.6 ml of dihydropyran was added to the remaining solution and the hybrid was kept for 30 minutes at room temperature. For work-up, the reaction solution was washed neutral in _{succession with NaHCO 3 solution and water, dried with Na 2} SO ₄ and evaporated in vacuo. The residue was recrystallized from ether-hexane and gave pure 17a / 3-tetrahydropyranyloxy-D-homo-androsta-4,16-dien-3-one, mp.

137-138 °. UV: ε _24ο = 16650, [α] ^ ⁵ ° = + 64 ° (c = 0.1 in dioxane).

Example 6

A solution of 2.0 g of 17ass-Hydroxy-D-homo-androsta-4,16-dien-3-one in 40 ml of cyclopentanone diethyl ketal was heated to 120 for 6 hours. The reaction solution was im Evaporated to dryness in vacuo and the residue chromatographed through 40 g of aluminum oxide act. II. With benzene could 1.2 g of pure ^ aß-cyclopentenyloxy-D-homo-androsta- ^ ie-diene

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3-on to be isolated. M.p. 135-137 ° (methanol), Ca] ^ ⁵ = + 100 ° (c = 0.1 in dioxane). UV spectrum: ε ₂₄₀ = 17200.

Example 7

A solution of 342 mg of 17ass-acetoxy-D-homo-androsta-4,16-dien-3-one and 328 mg of 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) in 30 ml of benzene was 24 hours heated under reflux. The solution was cooled and filtered through a column of 10 g of alumina Akt. II. The column was finally completely eluted with 200 ml of ethyl acetate. The combined eluates yielded 270 mg of crystalline material which, recrystallized from acetone-hexane, yielded pure 17ass-acetoxy-D-homo-androsta-1,416-trien-3-one. M.p. 222-224 °, UV: ε ₂₄₄ = 14800, [α] ^ ⁵ = + 53 °.

According to this method, 17a / 3-hydroxy-17a-methyl-D-homo-androsta-l, 4.16 was obtained from 17ass-hydroxy-17aa-methyl D-homo-androsta-4,16-dien-3-one -trien-3-one manufactured. M.p. 148-150 °, UV: ε ₂₄₅ = 15500, [α] ^ ⁵ = -34 °.

Example 8

1.95 g of sodium hydride oil dispersion (50%) were dissolved in 45 ml of tetrahydrofuran and 10 ml of dimethyl sulfoxide. the The solution was stirred for 30 minutes at room temperature, then 1.3 g of 3,3-ethylenedioxy-17ass-hydroxy-D-homo-androsta-4,16-diene were added to, stirred again for 30 minutes and then gave 3.9 ml of 1-iodo-pentane to. The mixture was stirred at room temperature for 20 hours. For work-up, water was carefully added and the mixture was added Extracted methylene chloride. The organic extracts were washed with water, dried with sodium sulfate and evaporated in the Vacuum a. The residue was dissolved in 65 ml of acetone, mixed with 6.5 ml of water and 1.3 g of p-toluenesulfonic acid and

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Stirred for 2 1/2 hours at room temperature. The reaction mixture was poured into water, extracted with methylene chloride, _{dried with Na2SO 4} and evaporated. The residue was chromatographed on 110 g of silica gel. 0.73 g of pure 17a3-pentyloxy-D-homo-androsta-4,16-dien-3-one were eluted with hexane-acetone (8: 1). M.p. 58-59 ° (from methanol-water). p = +112 (c = 0.1 in dioxane). ε _24ο = 16700.

The starting material was prepared as follows:

3.4 g of 17ass-acetoxy-D-homo-androsta-4,16-dien-3-one, 100 ml of ethylene glycol, 100 ml of methylene chloride, 15 ml of ethyl orthoformate and 150 mg of p-toluenesulfonic acid were heated to 40 for 75 minutes. The usual work-up provided 5.2 g of 3,3-ethylenedioxy-17ass-acetoxy-D-homo-androsta-4,16-diene, which with 300 ml of 5% methanolic KOH and 100 ml Methylene chloride at room temperature to 3,3-ethylenedioxy-17aj3-hydroxy-D-homo-androsta-4,16-diene was saponified from m.p. 168-173.

The same method was used to produce:

17a0-n-decyloxy-D-homo-androsta-4,16-dien-3-one, oily, [cc] q ⁵ = + 94 ° (c = 0.1 in dioxane) ε _24ο = 16650;

17ass-benzyloxy-D-homo-androsta-4,16-dien-3-one; M.p. 139-141 ° (from acetone-hexane) [a] ^ = + 130 °; ε _24ο = 166OOj

17a3-Cyclohexylmethyl-D-homo-androsta-4,16-dien-3-one. M.p. 98-99 °; [cc] "= + 112 °; ε ₂₄₁ = 16700.

Example 9

To a solution of 3.0 g of lithium aluminum hydride in ml of abs. Aether was added dropwise with stirring and cooling a solution of 6.0 g of D-homo-Androsta-4,16-diene-3,17a-dione in 100 ml of tetrahydrofuran and 100 ml of ether and stirred the

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Then mix for 1 hour at 0-5 °. For working up, 300 ml of moist ether and then 10 ml of saturated Na 2 SO solution were carefully added. The reaction mixture was stirred for a further 15 minutes, then the precipitate was filtered off and washed thoroughly with methylene chloride. The combined filtrates were evaporated in vacuo. The residue was chromatographed on 330 g of silica gel and gave 4.1 g of pure 3j3, ^ aß-dihydroxy-D-homo-androsta ^, 16-diene, m.p. 158-162 ° (acetone-hexane). [cc] £ ⁵ = + 23 ° (c = 0.1 in dioxane).

A solution of 3.0 g of 30,17ass-dihydroxy-D-homo-androsta-4,16-diene in 50 ml of pyridine and 50 ml of acetic anhydride was kept at room temperature for 18 hours. The solution was then evaporated in vacuo and the residue was recrystallized from methanol. Pure 3/3, ^ aß-diacetoxy-D-homo-androsta-4,16-diene, m.p. 115-116 °. [a] ^ ⁵ = + 12 °.

Example 10

To a stirred solution, cooled to 0 °, of 3.5 g of LiAlH. in 420 ml of ether was added dropwise a solution of 7.0 g 2, 3-dimethoxy-D-homo-5a-androst-16-en-17-one in 280 ml of ether. The reaction mixture was stirred for 1 hour at 0-5 and then 250 ml of water-saturated ether were carefully added. The mixture was stirred for a further 15 minutes at room temperature and then the pure precipitate was filtered off. This was washed out well with methylene chloride. The filtrate was evaporated in vacuo. 7.0 g of crude product were obtained, which was dissolved in 140 ml of acetone and treated with a solution of 2.1 g of p-toluenesulfonic acid in 14 ml of water. The solution was kept at room temperature for 2 hours and then 500 ml of water were added. The precipitate formed was sucked off. For purification, this was chromatographed on 50 times the amount of silica gel. With methylene chloride-acetone 95: 5, 5.0 g of pure 17ass-hydroxy-D-homo-5cc-androst-16-en-3-one could be obtained. 203-205 (acetone-hexane), [α] "= +1 (c = 0.1 in dioxane).

0 9 3 19/1061

265136V

-a.

The starting material was prepared as follows:

30-Acetoxy ~ D-home-androst-5-en-17a-one was in ethanol with Pd / C as a catalyst to form Sß-acetoxy-D-homo-Sa-androstan-17a-one, m.p. 113-115 °, reduced. This was brominated with copper bromide in methanol and converted into 3β-hydroxy-D-homo ~ androst-16-en-17a-one, melting point 177-179 °, by treatment with calcium carbonate in dimethylacetamide. Jones oxidation of this substance gave D-homo-5a-androst-16-en-3,17a-dione of melting point 200-202 ° (ε ₂₂ 3 - 8700). Reaction of this compound with methanol and catalytic amounts of p-toluenesulfonic acid at reflux temperature finally gave 3, S-dimethoxy-D-homo-Sa-androst-16-en-17a-one, melting point 125-127 (ether-hexane). Ea] ^ = -33. = 8650.

Example 11

A solution of 3.0 g of 3,3-dimethoxy-D-homo-5a-androst-16-en-17a-one in 20 ml was added with stirring to 70 ml of a 2 molar solution of methyllithium in ether within 30 minutes Tetrahydrofuran and 20 ml of ether. The solution was stirred overnight at room temperature and then worked up as usual. 3.2 g of crude product were obtained, which was dissolved in 50 ml of acetone and then admixed with a solution of 1.0 g of p-toluenesulfonic acid in 5 ml of water. The mixture was kept at room temperature for 2 hours, water was added and the mixture was extracted with methylene chloride. After chromatography on silica gel, the residue gave pure 17a3-hydroxy-17acr-methyl-D-hoitio-5a-androst-16-en-3-one, m.p. 211-214 °, [ajp ⁵ ° = -52 ° (c = 0.1 in dioxane).

Example 12

2.0 g of 17a / 3-hydroxy-D-homo-5a-androst-16-en-3-one were acetylated with 50 ml of pyridine and 50 ml of acetic anhydride at room temperature. The 17a-acetate obtained by conventional work-up was dissolved in 20 ml of dioxane and after adding 3 drops of 40% HBr-glacial acetic acid solution within 30 minutes with a solution of

7 0 9 8 19/1061

0.36 ml of bromine and 570 mg of sodium acetate in 37 ml of glacial acetic acid were added. The reaction mixture was then poured onto ice water. The precipitated crystals were filtered off with suction, washed with water and dried in vacuo over KOH. 3.1 g of product were obtained which, dissolved in 20 ml of dimethylacetamide, were added within 20 minutes to a boiling mixture of 5.1 g of calcium carbonate and 45 ml of dimethylacetamide. The mixture was then refluxed for a further 30 minutes, then cooled to 60 and the calcium salts were filtered off. The filtrate was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, with Na SO, dried and evaporated in vacuo. 2.2 g of crude product were obtained, which was chromatographed on 50 times the amount of silica gel. 1.2 g of pure 17a3-acetoxy-D-homoandrosta-l, 16-dien-3-one could be eluted with methylene chloride. 133-135 °. = + 55 °. UV spectrum: ε ₂₂₉ = 11100.

Example 13

A solution of 2.5 g of 3/3-acetoxy-D-homo-androsta-5,16-diene-17a- on in 15 ml of tetrahydrofuran and 15 ml of ether. The reaction mixture was stirred at room temperature overnight, then poured onto ice water and extracted with ether. The ether extracts were washed with water, dried with Na ₃ SO ₄ and evaporated in vacuo. The residue afforded by recrystallization twice from acetone 3j3,17a pure / 3-dihydroxy-17aa-methyl-D-homo-androsta-5, 16-diene, mp. 220-223 ° _[a] 25 _ _i69 ° _(C = o , l in dioxane).

From a solution of 1.5 g of 3 / 3.17a | 3-dihydroxy-17aa-methyl D-homo-androsta-5,16-diene in 20 ml of cyclohexanone and 55 ml of toluene, 10 ml of toluene were distilled off. Then it was set to 100 ° cooled and 1.73 g of aluminum tert-butoxide were added. the The mixture was then refluxed on a water separator for 2 hours. Usual work-up (see example 1)

70 9 8 19/1061

provided 2.7 g of crude product which was chromatographed on silica gel. 1.2 g of pure 17 a / 3 -hydroxy-17 aa-me thy lD-homoandrosta-4,16-dien-3-one were obtained. M.p. 152-154 ° (acetone-hexane). UV: B ₂₄₁ = 16,700. [Α] 25 = + 18 ° ( _c = 0.1 in dioxane).

Example 14

A solution of 2.0 g of 17a3-hydroxy-17aa-methyl-D-homo-androsta-4,16-dien-3-one in 100 was added dropwise to a solution, cooled to 0, of 1.0 g of lithium aluminum hydride in 200 ml of ether ml abs. Tetrahydrofuran and 100 ml of abs. Ether. After the addition had ended, the mixture was stirred at 0 ° for a further hour and then worked up as usual (see Example 2). Pure 3β, 17a / 3-dihydroxy-17aa-methyl-D-homo-androsta-4 _/ 16-diene could be obtained by recrystallization of the crude product from acetone-hexane.

137-141 °. ia] ^ ⁵ ° = -28 ° (c = 0.1 in dioxane)

Example 15

Acetylene was passed into a solution of 2.0 g of potassium in 100 ml of liquid ammonia until the solution was discolored. A solution of 3.4 g of 3β-acetoxy-D-homo-androsta 5,16-dien-17a-one in 70 ml of tetrahydrofuran was then added dropwise over the course of 1 hour, a weak stream of acetylene still being passed through the reaction solution. For work-up, 30 ml of ammonium chloride solution were slowly added dropwise and the ammonia was allowed to evaporate overnight. The reaction mixture was mixed with water and extracted with ether-methylene chloride. The organic extracts were washed with water, dried with Na ₉ SO ₄ and evaporated in vacuo. The residue was on

£ fs

Chromatographed silica gel. Pure 17aa-ethynyl-3β, 17ass-dihydroxy-D-homo-androsta-5,16-diene was eluted with hexane-acetone 5: 1. M.p. 227-229 ° (acetone-isopropyl ether). [a] ^ ⁵ = -307 ° (c = 0.1 in dioxane).

1.1 g of 17aa-ethynyl-3ß, ^ aß-dihydroxy-D-homo-androsta-5,16-diene were dissolved in 15 ml of cyclohexanone and 40 ml of toluene,

709919/1061

After 8 ml of solvent had been distilled off, 1.27 g of aluminum tert-butoxide were added and the mixture was refluxed for 2 hours using a water separator. The reaction mixture was worked up as usual and gave 1.5 g of crude product, the Pure 17aa-ethynyl-IVa) 3-hydroxy-D-homo-androsta-4,16-dien-3-one chromatographed on silica gel delivered. M.p. 247-250 °.

UV: e _23g = 15800. Ca] ^ ⁵ ° = -138 ° (c = 0.1 in dioxane).

Example 16

649 mg of 17aa-ethynyl-17ass-hydroxy-D-homo-androsta-4,16-dien-3-one were dissolved in 40 ml of ethyl acetate and 5 ml of pyridine and, after addition of 300 mg of Pd / CaCO., Hydrogenated at normal pressure until 1.1 equivalents of hydrogen were absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallized from acetone-hexane. Pure ^ aß-hydroxy- ^ acc-vinyl-D-homo-androsta ^ iedien-3-one of melting point 120-122 ° was obtained. UV: ^ ₂ AO ^{= 16500} * [cc] ^ ⁵ ° = -69 ° (c = 0.1 in dioxane).

Example 17

To 8 g of 3 ^ -hydroxy-la-methyl-17a3-tetrahydropyranyloxy-D-homo-5a-androst-16-ene become a solution in 230 ml of dimethyl sulfoxide and 21.2 ml of triethylamine at 15 within 45 minutes of 16 g of pyridine-SO - ^ - complex in 64 ml of dimethyl sulfoxide was added dropwise and then stirred for 1 hour at room temperature. It is precipitated in ice water, the precipitate is filtered off and washed and taken up in ether. After drying and evaporation, 7.5 g of la-methyl-17a3-tetrahydropyranyloxy-D-homo-5cc-androst-16-en-3-one are obtained obtain.

Production of the raw material:

50 g of 17β-hydroxy-la-methyl-5cc-androstan-3-one are in 1000 ml of absolute benzene, 125 ml of ethylene glycol and 1.25 g of p-toluenesulfonic acid 7 hours while stirring with a water separator

709 ^ 19/1061

heated to reflux. The reaction solution is then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated to dryness. There are 55 g of 3,3-ethylenedioxy-17β-hydroxy-la-methyl-5a-androstane obtain.

55 g of 3, S-ethylenedioxy- ^ ß-hydroxy-la-methyl-sot-androstane are in 550 ml of toluene and 110 ml of cyclohexanone at the boiling point with a solution of 5.5 g of aluminum isopropoxide in 55 ml Toluene is added and the mixture is heated for 3 hours while slowly distilling off. It is then mixed with ether, diluted with ice-cold Washed sulfuric acid and water, evaporated and the residue was distilled with steam. After extraction of methylene chloride the product obtained is recrystallized from diisopropyl ether and there are 51 g of 3,3-ethylenedioxy-la-methyl-5a-androstan-17-one obtained from melting point 155.5-156.5 °.

51 g of 3,3-ethylenedioxy-la-methyl-5a-androstan-17-one become 51 g of trimethylsulfonium iodide are added in 1000 ml of dimethylformamide and 27.2 g of potassium tert-butoxide are added with stirring over 30 minutes entered in portions. After a further 60 minutes of reaction time, the precipitated water is stirred into ice water The precipitate is filtered off, washed well with water and taken up in methylene chloride. After evaporation, the Chromatographed residue on silica gel. 36.6 g are obtained in this way 3,3-ethylenedioxy-lcc-methyl-5a-androstane [17 (0-1 ') -spiro-3'] oxirane. A sample recrystallized from diisopropyl ether melts at 165.5-166.5 °.

36.6 g of 3,3-ethylenedioxy-la-methyl-5a-androstane [17 (ß-1 ¹ ) -spiro-3 '] oxirane are mixed with 41.3 g of sodium azide in 366 ml of dimethylformamide and 145 ml of water and 3 Stirred at 110 ° for hours. It is then stirred into ice water, the deposited precipitate is filtered off, washed with water and taken up in methylene chloride. After evaporation, 38 g of S ^ -Aethylendioxy- ^ a-azidomethyl- ^ ß-hydroxy-la-methyl-5a-androstane are obtained.

7 0 9 8 19/1061

38 g of S ^ -Aethylendioxy- ^ a-azidomethyl- ^ ß-hydroxy-lamethyl-5a-androstane 19 g of oxalic acid are added in 380 ml of methanol and 38 ml of water and the mixture is refluxed for 30 minutes. The reaction solution is mixed with water and extracted with ether. The ether phase is washed with water and dried and evaporated. The residue is 29.5 g of 17a-azidomethyl-17/3-hydroxy-la-methyl-5a-androstan-3-one obtain.

29 g of lithium alanate are in 350 ml of abs. Suspended tetrahydrofuran and, with ice cooling and stirring, a solution of 29 g of lTa-azidomethyl-IVβ-hydroxy-la-methyl-Sa-androstan-S-one in 350 ml abs. Tetrahydrofuran was added dropwise. The mixture is then stirred at room temperature for 1 hour. The suspension will then cooled again in an ice bath and carefully washed one after the other with 31.7 ml of water, 31.7 ml of 15% sodium hydroxide solution and 94 ml Water added. The precipitate is filtered off with suction, washed with ether and extracted exhaustively with ether in a Soxhlet. The filtered off filtrate is then with the extraction solution combined, evaporated and there are 27.5 g of 17α-Απιϊηοΐη6 ^ γ1-3ξ, 17ß-dihydroxy-la-methyl-5a-androstane was obtained.

27 g of 17a-aminomethyl-3 ^, 17ß-dihydroxy-la-methyl-5aandrostane are dissolved in 558 ml of acetic acid and 558 ml of water and, while cooling with ice, with 48.5 g of sodium nitrite are dissolved in 381 ml Water slowly added. The mixture is then stirred for 1 hour at room temperature, diluted with water and the precipitated Filtered off precipitate. After dissolving in methylene chloride, it is washed with sodium hydrogen carbonate solution and water, dried and evaporated. The residue is chromatographed on silica gel. 17.5 g of 3 ^ -hydroxy-lame are obtained in this way thy 1-D-homo- 5a- androstan- 17 -one.

16 g of 35-hydroxy-la-methyl-D-homo-5a-androstan-17a-one are in 320 ml abs. Tetrahydrofuran with 22.5 g of copper (II) bromide Heated to reflux for 90 minutes with stirring. It is filtered off from the precipitated copper-I-bromide, with ether diluted, washed with ammonium chloride solution and water,

7 0 9 819/1061

dried and evaporated. 19.5 g of hydroxy-lcc-methy 1-D-homo-5 a-andros tan-17 a-one are obtained.

19.5 g raw

androstan-17a-one are in 195 ml of dimethylformamide with 11.1 g of lithium carbonate and 13 g of lithium bromide for 18 hours at 90 ° touched. It is then precipitated in ice water, the precipitate is filtered off, washed with water, taken up in methylene chloride, dried and evaporated. The residue is chromatographed on silica gel and 11.5 g of 3j-hydroxy-lamethyl-D-homo-5a-androst-16-en-17a-one are obtained obtain. UV: ε ~~ - «= 7600.

11 g of SS-hydroxy-la-methyl-D-homo-Sa-androst-ie-en- ^ a-one are left to stand for 18 hours at room temperature in 44 ml of pyridine with 22 ml of acetic anhydride. After ice water precipitation, the precipitate is filtered off, washed well and dried. 11.2 g of S ^ -acetoxy-la-methyl-D-homo-Sa-androst-lö-en-17a-one are obtained.
UV: ε ₂₂₃ = 7200.

11 g of 3 ^ -acetoxy-la-methyl-D-homo-5a-androst-16-en-17a-one are in 110 ml of abs. Tetrahydrofuran with ice cooling with 22 g of lithium tri-tert-butoxyalanate are added and 4 hours stirred with ice cooling. The reaction solution is diluted with ether, washed with dilute sulfuric acid and water, dried and evaporated. The residue is chromatographed on silica gel and 8.5 g of 3) -acetoxy-17ass-hydroxy-la-methy1-D-homo-5a-androst-16-ene are obtained obtain.

8.5 g of 3 ^ -acetoxy-17ass-hydroxy-la-methyl-D-homo-5a-androst-16-en are in 85 ml of abs. Tetrahydrofuran with 8.5 ml of 2,3-dihydro-4H-pyran and stirred 1 drop of phosphorus oxychloride for 1 hour at room temperature. It is then diluted with ether, washed with saturated sodium hydrogen carbonate solution and water, dried and evaporated. 9.7 g are obtained

709 ^Q 1 9 / 1QR1

3 S -Acetoxy- Ια-methyl-17 a / 3-th tr ahy dro-py r any loxy-D-homo- 5 ctandrost-16-en.

9.5 g of 3 $ -acetoxy-la-methyl-17a0-tetrahydropyranyloxy-D-homo-5a-androst-16-ene are refluxed for 1 hour in 95 ml of methanol and 9.5 ml of water with 4.75 g of potassium carbonate. It will precipitated in ice water, the precipitate filtered off, washed and taken up in methylene chloride. After drying and 8.1 g of 3 $ -hydroxy-la-methyl-17ass-tetrahydropyranyloxy-D-homo-5a-androst-16-ene are evaporated obtain.

Example 18

7 g of la-methyl-17ass-tetrahydropyranyloxy-D-homo-5a-androst-16-en-3-one are refluxed for 30 minutes with 3.5 g of oxalic acid in 70 ml of methanol and 7 ml of water. After ice water precipitation the precipitate is filtered off, washed and taken up in methylene chloride. After drying and evaporation the residue is chromatographed on silica gel. By recrystallization 3.2 g of 17ass-hydroxy-la-methyl-D-homo-5a-androst-16-en-3-one are obtained from diisopropyl ether from melting point 189-191 °.

703819/1061

Claims (7)

Claims 1) Process for the preparation of D-homosteroids of the formula > 17ass 17aa wherein the dotted lines in the A ring indicate optional CC bonds; R ¹ hydrogen or methyl, Έ? Oxo or, if the ring A is unsaturated, oxo, (aH, β-OH) or (aH, β-O-acyl); R is hydrogen or methyl; R '^ is hydrogen, C ₁ _ _lQ alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R ^{ac (} hydrogen, lower-alkyl, ethynyl, vinyl or propadienyl mean,
characterized in that one a) in a D-homosteroid of the formula , 17 ate _R 17aa II 709819/1061 ORIGINAL INSPECTED - »he wherein R ¹ , R ^17ass and R ^17aa are as defined, and the -Δ double bonds are optional the 3-hydroxy or 3-hydroxy Λ group to the 3-keto or 3-Eeto- Δ ^ group is oxidized, or that one a D-homosteroid of the formula III 1 "5
where R, R and the dotted lines in the Α-ring have the meaning given, with intermediate protection of a 3-keto group with a one The remainder of the R-releasing organometallic compound a D-homosteroid of the formula 17ass I7aa IV .17acc , 17 ate in which R " ¹ -, R""*" and R- ¹ "'""have the meaning given,
with a methyl Grignard compound in the presence of copper I 709819/1061 chloride converts, or that one a compound of the formula 17 ate in the R and E ⁷ ^ the specified a 5 Have meaning and the tx double bond is optional with a methyl Grignard compound in the presence of copper (I) chloride converts and then a Δ double bond in the reaction product rearranged into the 4,5 position by acid treatment, or that one e) the hydroxyl group (s) in a D-homosteroid of the formula I, in which at least one hydroxyl group in the 3- or 17ass-position is present, acylated, or that one in a D-homosteroid of the formula VI η r. ·. -: .- · ο / ι <■ "■ f in which R and the dotted lines have the meaning mentioned and Z Oxo or (OR ^17a0 , R ^{17ac (} ) represents, if Z represents oxo, the 17a-keto group among intermediate Protection of a 3-keto group reduced to the hydroxyl group or, if R represents oxo and the Α ring is monounsaturated, the 3-keto group and an optionally present 17a-keto group for Hydroxy group reduced, or that one g) a saturated or monounsaturated D-homosteroid of the formula I, in which R is oxo, in 1,2- and / or 4,5-position dehydrated, or that one in a D-homosteroid of the formula I, in which R ^act and the dotted 13 7
Represents hydrogen and R, R, R, Lines in the A-ring have the meaning given, the 17ass-hydroxy group converted into a cycloalkenyl, tetrahydropyranl, C,, alkyl, benzyl or cyclohexylmethyl ether, or that one i) in a D-homosteroid of the formula I in which R is acyl, 13 7 represents tetrahydropyranyl or cycloalkenyl and R, R, R, R ^act and the dotted lines in the A ring have the meaning given, the 17a / 3-acyloxy group and any 3-acyloxy group saponified or a 17a-tetrahydropyranyl or - Cycloalkenyl ether cleaves, or that one in a D-homosteroid of the formula 17aB CHCH VII 705H19 / 1061 where R, R, R, R and the dotted lines in the Α ring have the meaning given, the ethynyl group is hydrogenated to the vinyl group. 2) Process according to claim 1, characterized in that compounds of the formula I are prepared in which R is hydrogen, never
Means cycloalkenyl. R is hydrogen, lower-alkanoyl, tetrahydropyranyl or 3) Method according to claim 1 or 2, characterized in that that compounds of the formula I are prepared in which R is hydrogen and R is oxo and the ring A is a double bond contains. 4) Process according to claims 1, 2 or 3, characterized in that compounds of the formula I are prepared in which R ^{17act is} hydrogen, methyl or ethyl and R ^{17a / 3 is} hydrogen or lower-alkanoyl. 70981 9/108 1 5) Process for the production of preparations with hormonal effects, characterized in that one is a D-homosteroid of the formula I as defined in claim 1 as an active ingredient with suitable for therapeutic administration, non-toxic, inert solid and liquid carriers and / or excipients which are customary in such preparations mixed. 70 9 819/1061 Λ- 6) Preparations with a hormonal effect, characterized by a content of a D-homosteroid of the formula I as defined in claim 1. 709819/1 OBI 7) D-homosteroids of the formula 17ass 17aa wherein the dotted lines in the A ring indicate optional CC bonds; R is hydrogen or methyl; R is oxo or, if ring A is unsaturated, oxo, (σ-Η, ß-OH) or (aH, / 3-0-acyl); R ^{7 is} hydrogen or methyl; R ^17ass hydrogen, C 1-6 alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R ^{acc is} hydrogen, lower-alkyl, ethynyl, vinyl or propadienyl. 8) D-homosteroids of the formula I according to claim 7, wherein R represents hydrogen, lower alkanoyl, tetrahydropyranyl or cycloalkenyl. 9) D-homosteroids of the formula I as defined in ι 7 or 8, wherein R is hydrogen and the ring A contains a double bond. Claim 7 or 8, wherein R is hydrogen and R is oxo 10) D-homosteroids of the formula I as defined in claim 7, 8 or 9, wherein R ^{σ is} hydrogen, methyl or ethyl and R is hydrogen or lower-alkanoyl. 70981 9/1061 11) D-homo-andros ta-4,16-diene-3,17 a-dione. 12) 17ass-Hydroxy-D-homo-androsta-4,16-dien-3-one. 13) 17a3-acetoxy-D-homo-androsta-4,16-dien-3-one. 14) 17ass-Propionoxy-D-homo-androsta-4,16-dien-3-one. 15) 17a / 3-butyroxy-D-homo-androsta-4 _/ 16-dien-3-one. 16) 17ass-Phenyl-acetoxy-D-homo-androsta-4,16-dien-3-one. 17) 17a / 3-Undecanoyloxy-D-homo-androsta-4 , 16-dien-3-one. 18) ^ aß-Heptanoyloxy-D-homo-androsta ^^ e-dien-S-on. 19) 17ass-Phenoxyacetoxy-D-homo-androsta-4 _/ 16-dien-3-one. 20) ^ aß-Tetrahydropyranyloxy-D-homo-androsta ^, 16-dien-3-one. 21) 17a0-cyclopentenyloxy-D-homo-androsta-4,16-dien-3-one. 22) 17a0-acetoxy-D-homo-androsta-1, 4,16-trien-3-one. 23) 17aj3-Hydroxy-17aa-methyl-D-homo-androsta-1 _/ 4,16-trien-3-one. 24) 17a / 3-pentyloxy-D-homo-androsta-4,16-dien-3-one. 25) 17ass-n-Deeyloxy-D-homo-androsta-4,16-dien-3-one. 26) 17ass-Benzyloxy-D-homo-androsta-4 _/ 16-dien-3-one. 27) 17ass-Cyclohexylmethyl-D-homo-androsta-4,16-dien-3-one. 28) 3β _f 17ass-dihydroxy-D-homo-androsta-4,16-diene. 7 0 8 8 19/1061 29) 3/3, lTaß-Diacetoxy-D-homo-androsta- ^ ie-diene. 30) ^ aß-Hydroxy-D-homo-Sa-androst-lö-en ^ -on. 31) lTaß-Hydroxy-iyaa-methyl-D-homo-Sa-androst-ie-en ^ -one. 32) ^ aß-Acetoxy-D-hoino-androsta-ljie-dien ^ -on. 33) 17a0-hydroxy-17aα-ynethyl-D-homo-androsta-4,16-dien-3-one. 34) 3β, 17ass-dihydroxy-17aa-methyl-D-home-androsta-4,16-diene. 35) 17aa-ethynyl-17a3-hydroxy-D-homo-androsta-4,16-diene-3- 36) 17ass-Hydroxy-17aa-vinyl-D-homo-androsta-4,16-dien-3-one. 37) α-Methyl-17ass-tetrahydrGpyranyloxy-D-homo-5a-androst-16-en-3-one. 38) ^ aß-Hydroxy-la-methyl-D-homo-Sa-androst-ie-en-S-one. 7 0 9 3 19/1061