NO763545L - - Google Patents

Description

New. D homosteroids.

The invention relates to new D homosteroids of the formula

in which the dashed lines in the A-ring denote facul-

1 3

tative C-C bondins; R is hydrogen or methyl; R

oxo or, in case ring A is unsaturated, oxo, (α-H, (3-0H). or (α-H, (3-0-acyl); R<7>hydrogen el-

clay methyl; R17aP hydrogen, C1-10 alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R<17a>(<X>hydrogen, lower-alkyl, ethynyl,

vinyl or propadienyl.

The term "acyl" shall in particular denote organic acid residues, e.g. residues of alkanecarboxylic acids containing up to 11 C atoms, especially residues of lower (up to containing 7 C atoms) alkanecarboxylic acids, such as acetic acid, propionic acid, caproic acid, valerian acid, onantic acid, undecyl 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 carboxyl-

acids such as cyclopentyl propionic acid.

Lower alkyl radicals can contain up to 7 C atoms and be straight-chained or branched. Examples of this are methyl, ethyl,

propyl, isopropyl, butyl and isomers thereof. Preferred lower alkyl residues are methyl and ethyl. An alkyl residue R<17aP> may contain

up to 10 C atoms. Examples of such residues are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and decyl.

Cycloalkenyl residues preferably contain 5-8 C atoms. Examples of this are cyclopenten-1-yl and cyclohexen-1-yl.

A preferred group of compounds within the formula I are the compounds in which R 1 is hydrogen and R 3 is oxo, and the ring A contains an eh double bond. Furthermore, such compounds of formula I are preferred, in which R~*"7aof constitutes hydrogen, methyl or ethyl and R^7aP hydrogen or lower-alkanoyl. Examples of compounds of formula I are

17a(3 - (3-cyclopentyl) propionoxy-D-homo-androsta-4 ,16-dien-3-one, 17a(3-nicotinyloxy-D-homo-androsta-4 ,16-dien-3-one, 17a (3-propionoxy-D-homo-androsta-l, 4,16-trien-3-one, " 17a(3-hydroxy-7a-methyl-D-homo-androsta-l, 4,16-trien-3- one, la , 7a-dimethyl-17a(3-hydroxy-D-homo-androsta-4 ,16-dien-3-one, 17a(3-hydroxy-7a-methyl-D-homo-androsta-4,16- dien-3-one, 17α-hydroxy-7α-methyl-D-homo-5α-androst-16-en-3-one, 17α(3-hydroxy-7α-methyl-D-homd-5α-androsta-1, 16-dien-3-one, 17α-hydroxy-1-methyl-D-homo-5α-androsta-1,16-dien-3-one,

1a,17aa-dimethyl-D-homo-androsta-4,16-dien-3-one, 3(3 ,17a|3-dihydroxy-17aormethyl-D-homo-5a-androsta-l, 16-diene, 17ap- hydroxy-17aa-methyl-D-homo-5oc-androsta-l, 16-dien-^ 3-one, 17a|3-hydroxy-la , 17act-methyl-D-homo-5a-androst-16-en-3 -one, 17ap-hydroxy-17ao-ethyl-D-homo-5a-androst-16-en-3-one, 17aa-ethyl-17a(3-hydroxy-la-methyl-D-homo-5a-androst-16 -en-3-one, 17αp-hydroxy-la-methyl-D-homo-5α-androst-16-en-3-one,

17ap-hydroxy-7a,17aa-dimethyl-D-homo-androsta-4,16-dien-3-one, 17a(3-pentyloxy-D-homo-androsta- 4,16-dien-3-one, 17a( 3-n-decyloxy-D-homo-androsta-4,16-dien-3-one, 17a(3-benzyloxy-D-homo-androsta- 4,16-dien-3-one, 17a(3-cyclohexylmethyl- D-homo-androsta-4,16-dien-3-one, 17a(3-undecanoyloxy-D-homo-androsta-4,16-dien-3-one.

The D-homostroids of formula I can, according to the invention, be obtained by mari

IN

a) in a D homosteroid of formula

wherein R<1>, R<17aP>and R17aa have the stated meanings,

and the /^ double bond is facultative,

does not oxidize the 3-hydroxy- or 3-hydroxy-Z\~*-group to the 3-keto- or 3-keto-ZV^-grouping, or that one

b) reacts a D homosteroid with the formula

13

in which R , R and the dashed lines in the A ring

have the meanings indicated,

under intermediate protection of a 3-keto group with an organometallic compound that emits the residue R 17aa, or that one

c) reacts a D homosteroid with the formula

wherein R^", R<17aoc> and R<17a>^ are as indicated, with a methyl Grignard bond in the presence of: of copper I chloride,

or that one

d) reacts a compound of formula

wherein R^7aa and R^<a>^ have the meanings indicated, and the -A5 -double bond is facultative, with a methyl Grignard compound in the presence of copper-I-chloro id and then rearranges a Z^ double bond in the reaction product by acid treatment in the 4,5 position, or that one

e) acylates the hydroxy group(s) of a D-hombsteroid of formula I, in which at least one hydroxy group is present in the 3- or

17a (3 position one, or that one

f) in a D homosteroid with the formula

wherein R 3 and the dotted lines have the aforementioned

meanings and Z constitutes oxo or (0R17a^ , R17aoc) , when Z constitutes oxo reduces the 17a-keto group under intermediate protection of a 3-keto group to the hydroxy group or,

when R 3 is oxo and the A ring is monounsaturated, reduces

the 3-keto group and an optionally present 17a-keto group to hydroxy group,• or that one

g) dehydrogenates an A-ring saturated or monounsaturated D-homosteroid of the formula I, in which R 3 is oxo?i 1,2- and/

or the 4.5 position, or that one

h) in a D homosteroid of formula I, wherein R"<*>"<7aP>is<r>hydrogen and R<1>, R<3>,R<7>,R17ao<f>and the dashed lines .in the A ring

have the indicated meanings, transfer the 17a(3-hydroxy group in a cycloalkenyl- or tetrahydropyranyl-, C-L-10-alkyl-, benzyl- or cyclohexylmethyl ether, or that one

i) in a D-homostroid of formula I, in which R<173!3>is acyl, tetrahydropyranyl or cycloalkenyl, and R"*", R3,R<7>,R"<*>"<7aa>and the the dashed lines in the A ring have the indicated meanings, saponify the 17a(3-acyloxy group and an optionally present 3-acyloxy group or cleave a 17a(3-tetrahydropyranyl- or

-cycloalkenyl ether, or that one

j) in a D homosteroid of formula

wherein R<1>, R<3>, R7, R<17aP>and the dashed lines' in the A ring have the indicated meanings,

hydrogenates the ethynyl group to the vinyl group.

The oxidation according to method variant a) can take place in a known manner according to Oppenauer, e.g. using aluminum isopropylate

or -ter. -butylate; or with an oxidizing agent such as chromium trioxide (eg Jpnes reagent); or according to Pfitzner-Moffatt

with the help of dimethylsulfoxide/dicyclohexylcarbodiimide (whereby the primarily obtained A5-3 ketone must subsequently be isomerized to the A4-3 ketone) or carried out with the help of dimethylsulfoxide/pyridine/SO^•

17a

The reaction of the R -keto group in a compound of formula II with an organometallic compound according to procedure: evariant

b) can also be carried out in a known manner. The organometallic compound may be a Grignard compound (eg, ethynylmagnesium bromide, methylmagnesium bromide, vinylmagnesium bromide) or an alkali metalorganic compound such as sodium, potassium or lithium acetylide, or vinyllithium. A simultaneously present 3-keto group can be intermediately protected, e.g. such as ketal, enolet, enamine or semicarbazone. The 7-methylation of a compound of formula IV and the 1-methylation of a compound of formula V according to process variants c) and d) can likewise be carried out in a known manner by reaction with a methyl Grignard compound. Thereby, an lcc-methyl-A5 compound is first obtained, whose A5 double bond can be rearranged in 4,5- the silent one.

The acylation of a 3- or 17a(3-standing free hydroxy group in a D-homosteroid of formula I can be carried out by treatment with a reactive acid derivative, for example 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 method variants f) can be carried out in a known manner by means of complex metal hydrides, e.g. di(lower-alkoxy)-aluminum hydrides such as di-isobutyloxyaluminum hydride, tri-(lower-alk-oxy)-aluminum, such as triisopropoxyaluminum; lithium aluminum hydride'; sodium aluminum hydride or sodium borohydride; or trimethoxy or trimethoxy lithium aluminum hydride. Suitable solvents for this are hydrocarbons, e.g. cyclohexane, benzene,

toluene; or ether, e.g. 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 intermediately protected. A 3-

keto group can, in the presence of a 4,5-double bond, be protected in the form of an enamine or enolet. An unconjugated 3-keto group can be protected as a ketal. The introduction and removal of such protecting groups can take place according to known methods.

A 1,2-dehydrogenation according to method variant g) can be carried out in a known manner with dehydrogenating agents. such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, thallium triacetate or lead tetraacetate. The 1,2-dehydrogenation can also be carried out microbiologically, for example with the help of schizomycetes, especially those of the Arthrobacter species, e.g. A. simplex ATCC 6946; Bacillus, e.g.

B. lentus ATCC 13805 and B. sphaerLcus ATCC 705 5; Pseudomonas, e.g. P. aeruginosa IFO 3505, Flavobacterium, e.g. flaven scene. IFO 3058; Lactobacillus, e.g. L. brevis IFO 3345 and Nocardia, e.g. N. opaca ATCC 4 276.

Double bonds in the 1,2- and 4,5-position can be introduced simultaneously by bromination to 2,4-dibromo-3-ketori and dehydrobromination to the latter using lithium carbonate and lithium bromide in dimethylformamide. A 4,5-double bond can also be introduced by brominating a 3-keto steroid saturated in the A ring in glacial acetic acid

to the 2a,4a-dibromo derivative and reduces this with chromium II chloride to the 4a-bromo compound. The latter compound can then be dehydrobrominated over the semicarbazone by treatment with succinic acid to the A4-3 ketone.

Etherification of a 17ap hydroxy group according to a method variant

h) can happen e.g. by treatment with dehydropyran (for. preparation of the tetrahydropyranyl ether) or by treatment with

a cycloalkanone ketal in the presence of a catalytic amount of acid, such as p-toluenesulfonic acid (to prepare a cycloalkenyl ether). For the preparation of a 17a(3-C1_10-alkyl, benzyl or cyclohexyl methyl ether, a 3-oxo group is suitably protected as an intermediate. The protection of the 3-oxo group is preferably carried out by ketalization, e.g. with ethylene glycol in the presence of a catalytic amount of acid, which p-toluene-sulfonic acid. The pretreatment of the 17a(3-hydroxy group can be carried out by reaction in an alkali metal salt, e.g. the sodium salt, with a strong base, e.g. sodium hydride, and reaction with a C1--O-alkyl- , benzyl-

or cyclohexylmethyl halide, such as pentyl iodide, benzyl chloride, or cyclohexylmethyl iodide, in a solvent, such as dimethyl sulfoxide or benzene.

The saponification of 17a- and 3-acyloxy groups or the cleavage of 17a-ether groups (method variant i) can take place in a known manner. Acyloxy groups can e.g. saponified with aqueous alcoholic bases, such as aqueous, methanolic potassium carbonate, ether groups can be cleaved with the aid of aqueous alcoholic mineral acids or organic acids such as oxalic acid or p-toluenesulfonic acid. The hydrogenation of the ethynyl group according to method variant j) can be carried out in the presence of noble metal catalysts, such as Pd/CaCO^ and suitably a deactivator such as pyridine.

The starting materials for the preparation according to the invention of compounds of formula I can be prepared, unless it is known or their preparation is described here, according to known methods or in analogy to the subsequently described methods.

The compounds of formula I have a hormonal effect. Connections

with formula I, in which R<17a<>x is hydrogen or lower alkyl, are particularly androgenic/anabolically active. Compounds of formula I, in which R 7aa is ethynyl, vinyl or propadienyl, are particularly progestogenic and ovulation inhibiting.

For example, 17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one) when subcutaneously applied to juvenile male rats showed a similar androgenic activity to the effect of testosterben at a third of the dosage. The androgenic activity was thereby determined by the growth of the prostate and the seminal bladder. 17a(3-phenylacet-oxy- and 17ap-phenoxyacetoxy-D-homo-androsta-4,16-dien-3-one showed, when subcutaneously applied to juvenile male rats, a prolonged duration of action against testosterone onanthate.

The process products can find use as pharmaceuticals

e.g. in the form of pharmaceutical preparations containing them

in mixture in a pharmaceutical, organic or inorganic inert carrier suitable for enteral, percutaneous or patenteral application

material, such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oil, polyalkylene, glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and respectively contain auxiliary substances such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

EXAMPLE 1

50.0 g of 3(3-hydroxy-D-homo-androsta-5,16-dien-17a-one was dissolved in 1000 ml of cyclohexanone and 3000 ml of toluene. From this solution, 400 ml of solvent was evaporated, the solution was cooled to 80° and mixed with 60.0 g of aluminum tert-butylate. Under stirring and argon gassing, it was heated for 2 1/2 hours with a water rinse at reflux. For the work-up, the reaction solution was evaporated in vacuo to about 200 ml, poured into an ice-cold solution of 1500 ml of water and 50 ml of concentrated hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried with Na 2 SO 4 and evaporated in vacuo, finally dried in high vacuum at 90°. The residue was then recrystallized from acetone-hexane. 40.7 g pure D-homo-androsta-4,16-diene-3,17a-dione with mp 193-194°.

UV: ^236= 215005 [«']p = +60° (c = 0.1 in dioxane) .

Preparation of starting materials:

18.1 g of 3(3-acetoxy-D-homo-androst-5-en-17a-one was dissolved under argon at 45° in 800 ml of methanol. 23.5 g of copper II bromide was added to this solution and heated. the mixture was refluxed for 18 hours. The reaction mixture was cooled to 35°C, filtered, and the residue well washed with chloroform. The combined filtrates were poured into 1.3 1 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, dried with magnesium sulfate and evaporated in vacuo. 19.8 g solid pure 17α-bromo-3(3-hydroxy-D-homo-androst-5-ene- 17a-on which was used directly in the next step.

35.1 g of calcium carbonate was suspended in 290 g of dimethylacetamide. Under argon gassing, 40 ml of dimethylacetamide was distilled off, then 18.7 g of 17a-bromo-3(3-hydroxy-D-homo-androst-5-en-17a-one) was added over the course of 20 minutes and the mixture was boiled for 30 minutes under reflux. The reaction mixture was then cooled to 60° and the precipitate was filtered off. The filtrate was poured onto

a mixture of 1.25 1 water, 450 g ice and 170 g table salt. It was extracted three times with methylene chloride. The extracts

washed with 1N hydrochloric acid and water, dried with magnesium sulfate and evaporated in vacuo. 14.7 g of crude product was obtained, which was dissolved in 170 ml of ethyl acetate and treated with a little activated charcoal. After filtering the extract over Speedex Dicalite, it was concentrated to 50 ml and allowed to crystallize. 11.7 g of pure 3(3-hydroxy-D-homo-androsta-5,16-dien-17a-one was thus obtained, m.p. 190-193°.

UV: £227= 13000. [ct]^ = -177 (c =0.1 in dioxane) ..

EXAMPLE 2

15.0 g of D-homo-androsta-4,16-diene-3,17a-dione was dissolved in 150 ml of methanol and boiled with 8.1 ml of pyrrolidine under exclusion of air for 10 minutes under reflux. The reaction mixture was cooled at -10°. The crystallized enamine was filtered off and dried at 20° in high vacuum. 16.1 g of pure 3-(1-pyrrolidinyl)-D-homo-androsta-3,5,16-trien-17a-one were obtained, m.p. 207-210°.

UV: £22g = 19500-, £22713000. [ct]^ = -295°.

16.1 g of these enamines were dissolved in 750 ml abs. tetrahydrofuran and added dropwise over 15 minutes to a well-stirred solution of 8.0 g lithium aluminum hydride in 750 ml abs. ether at 0°.

It was then stirred for another 1 hour at 0°. For work-up, the reaction solution was first carefully mixed with 300 ml of wet ether. Then 40 ml of saturated Na2S0^ solution was added to it, stirred for another 10

minutes and filtered off the precipitate. The filtrate was evaporated in vacuo. 15.8 g of substance was obtained which was heated with a mixture of 1000 ml of methanol and 200 ml of 2N caustic soda for 45 minutes under stirring and argon blowing at 50°. The reaction solution was then poured onto 6 L of ice water and extracted three times with methylene chloride. The organic extract was washed with water, dried with Na 2 SO 4 and evaporated in vacuo. The remainder was chromatographed over 650 g of silica gel. With acetone-hexane 1:1, 13.0 g of pure 17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one could be eluted. Mp. 183-185°. UV: £24116200. La] p5 +76°.

EXAMPLE 3

A solution of 6.3 g of 17α(3-hydroxy-D-homo-androsta-4,16-dien-3-one in 60 ml of pyridine and 60 ml of acetic anhydride was kept overnight at room temperature. Then the solvent was removed in vacuum and the residue recrystallized from acetone-hexane. 6.0 g of pure 17α(3-acetoxy-D-homo^androsta-4,16-dien-3-one were obtained, m.p. 165-167°. UV: £24o = 17000. [cc]^5 = +91° (c = 0.1 in. dioxane).,

Following the same method using the corresponding acid anhydride, it was prepared:

17a(3-propionoxy-D-homo-androst a- 4,16-dien-3-one,

m.p. 139-140°, 17α(3-butyroxy-D-homo-androsta-4,16-dien-3-one, m.p. 117-118°.

, EXAMPLE 4

A solution of 2.0 g of 17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one in 20 ml of pyridine was added dropwise to 2.0 ml of phenylacetyl chloride over 15 minutes and the mixture heated for 5 hours at 60°. For work-up it was poured onto water and extracted with methylene chloride. The organic extract was washed neutrally with dilute hydrochloric acid, NaHCO 3 solution and water, dried with Na 2 SO 4 and evaporated in vacuo. The residue was chromatographed over silica gel. With hexane-acetone 9: 1, 1.7 g of pure 17a(3-phenyl-acetoxy-D-homo-androsta-4,16-dien-3-one, m.p. 135-136° (acetone-hexane) were eluted..

UV: £24o = 17 200. [ a]D = +108 (c = 0.1 in dioxane).

Following the same method using the corresponding acid chloride was prepared: 17a(3-undecanoyloxy-D-homo-androsta-4,16-dien-3-one; amorphous;

"[a]<25>+80° (c = 0.1 in dioxane) ; ^24Q = 17100.

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

oil-like, [<x]p<5>° = +88° (c = 0.1 in dioxane).

17a(3-phenoxyacetoxy-D-homo-androsta-4,16-dien-3-one, m.p. 174-176°.

EXAMPLE 5

1,0 17a|3-hydroxy-D-homo-androsta-4,16-dien-3-one was Jbst in 40 ml of abs. benzene and 10 ml of benzene were then distilled off. 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 mixture was kept for 30 minutes at room temperature. For work-up, the reaction solution was washed neutrally with NaHCO 3 solution and water successively, 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, m.p. 137-138°.

UV: ^24o = 16650, [a]" =<+>64° (c = 0.1 in dioxane).

EXAMPLE 6

A solution of 2.0 g of 17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one in 40 ml of cyclopentanone-diethyl ketal was heated for 6 hours at 120°. The reaction solution was evaporated to dryness in vacuo and the residue chromatographed through 40 g of alumina act II. With benzene 1.2 g of pure 17a(3-cyclopentenyloxy-D-homo-androsta-4,16-dien-3-dn could be isolated, m.p. 135-137 O' (methanol ), [ttJj2j 5° +100° (c = 0.1 in dioxane). UV spectrum: ^ 240 172o°-

EXAMPLE 7

A solution of 342 mg 17a(3-acetoxy-D-homo-androsta-4,16-dien-3-one and 328 mg 2,3-dichloro-5,6-dicyano-benzo-quinone (DDQ) in 30

ml of benzene was heated for 24 hours under reflux. The solution was cooled and filtered through a sieve of 10 g aluminum oxide act. II. The broth was finally completely eluted with 200

ml of ethyl acetate. The combined eluates gave 270 mg of crystalline material which recrystallized from acetone-hexane gave pure 17α(3-acetoxy-D-homo-androsta-1, 4,16-trien-3-one. M.p. 222-224°.

UV: *24414800, [a]£5° = +53°.

According to this method, from 17a(3-hydroxy-17aa-methyl-D-homo-androsta-4,16-dien-3-one the compound 17a(3-hydroxy-17a-methyl-D-homo-androsta-1, 4,16-trien-3-one prepared mp 148-150° D

UV: ^245= 15500, [a]^<5>= -34°.

EXAMPLE 8

1.95 g sodium hydride oil dispersion (50%). was dissolved in 45 ml of tetrahydrofuran and 10 ml of dimethylsulfoxide. The solution was stirred for 30 minutes at room temperature, then 1.3 g of 3,3-ethylenedioxy-17a(3-hydroxy-D-homo-androsta-4,16-diene) was added, stirred for a further 30 minutes and then 3.9 ml 1-iodo-pentane. The mixture was stirred for 20 hours at room temperature. For the work-up, water was carefully added and extracted with methylene chloride. The organic extracts were washed with water, dried with

sodium sulfate and evaporated in vacuo. The residue was dissolved in 65 ml of acetone, 6.5 ml of water and 1.3 g of p-toluenesulfonic acid were added and stirred for 2 1/2 hours at room temperature. The reaction mixture was poured into water, extracted with methylene chloride, dried with Na 2 SO 4 and evaporated. The remainder was chromatographed on .110 silica gel. With hexane-acetone (8:1), 0.73 g of pure 17α(3-pentyloxy-D-homo-androsta-4,16-dien-3-one was eluted. M.p. 58-59° (from methanol-water ).

[oc]D 25^<=><+>112 o (c 0.1 in dioxane). £2i0= 1670°-

The starting material was prepared as follows:

3.4 g 17a(3-acetoxy-D-homo-androsta-4,16-dien-3-one, 100 ml ethylene glycol, 100 ml methylene chloride, 15 ml ethyl orthoformate and 150 mg of p-toluenesulfonic acid was heated for another 75 minutes

40°. Usual work-up gave 5.2 g of 3,3-ethylenedioxy-17a(3-acetoxy-D-homo-androsta-4,16-diene, which was saponified with 300 ml of 5% methanolic KOH and 100 ml of methylene chloride at room temperature to 3 , 3-ethylenedioxy-17a(3-hydroxy-D-homo-androsta-4,16-diene with m.p. 168-173°.

Following the same method was prepared: 17ap-h-decyloxy-D-homo-androsta-4,16-dien-3-one, oily, [cc]<2>p° = +94° (c = 0.1 in dioxane)<±>2iQ = 16650;

17a(3-benzyloxy-D-homo-androsta-4,16-dien-3-one; m.p. 139-141°

(from acetone-hexane) [oc]D = + 130°; ^40= 166o°;

17α-cyclohexylmethyl-D-homo-androsta-4,16-dien-3-one; m.p. 98-99°; [ct]25 + 112°;. ^241 16700.

EXAMPLE 9

To a solution of 3.0 g of lithium aluminum hydride in 400 ml of abs. ether, 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 was added dropwise while stirring and cooling at 0°, the mixture was then stirred for another 1 hour at 0-5°. For work-up, it was carefully mixed with 300 ml of wet ether and then with 10 ml of saturated Na2SO4-16sning. The reaction mixture was stirred for a further 15 minutes, then the precipitate was filtered off and washed with methylene chloride. The combined filtrates were evaporated in vacuo. The residue was chromatographed over 330 g of silica gel and gave 4.1 g of pure 3(3,17a(3-dihydroxy-D-homo-androsta-4,16-diene, m.p. 158-162°

(acetone-hexane), [oc]D 25° = +23 o (c = 0.1 in dioxane).

A solution of 3.0 g of 3(3,17a(3-dihydroxy-D-homo-androsta-4,16-diene in 50 ml of pyridine and 50 ml of acetic anhydride) was kept for 18 hours at room temperature. The solution was then evaporated in vacuo and the residue recrystallized from methanol. Pure 3(3,17a(3-di-acetoxy-D-homo-androsta-4,16-diene) was obtained, m.p. 115-116°.

[aj^<5>° = +12°.

EXAMPLE 10

A solution of 7.0 g of 3,3-dimethoxy-D-homo-5<x-androst-16-ene-17a was added dropwise to a stirred solution of 3.5 g of LiAlH^ in 420 ml of ether at 0° -on in 280 ml of ether. The reaction mixture was stirred for 1 hour at 0-5° and then carefully mixed with 250 ml of water-saturated ether. The mixture was stirred for another 15 minutes at room temperature and the clean precipitate was then filtered off. This was washed well with methylene chloride. The filtrate was evaporated in vacuo. 0.7 g of crude product was obtained, which was dissolved in 140 ml of acetone and mixed with a solution of 2.1 g of p-toluenesulfonic acid in 14 ml of water. The solution was kept for 2 hours at room temperature and then mixed with 5.00 ml of water. The precipitate was filtered off. For purification, this was chromatographed over 50 times the amount of silica gel. With methylene chloride-acetone 95:5, 5.0 g of pure 17a(3-hydroxy-D-homo-5of-androst-16-en-3-one could be obtained.

Temp. 203-205° (acetone-hexane), [cc]D= +1 (c = 0.1 in dioxane).

The starting material was prepared as follows: 3(3-acetoxy-D-homo-androst-5-en-17a-one was reduced in ethanol with Pd/C as catalyst to 3p-acetoxy-D-homo-5a-androstane-17a- on, m.p. 113-115°. This was brominated with copper bromide in methanol and oyerfort by treatment with calcium carbonate in dimethylacetamide i3p<->hydroxy-D-homo-androst-16-en-17a-one, m.p. 177-179° .Jones oxidation of this substance gave D-homo-5a-androst-16-ene-3,17a-dione with m.p. 200-202° (^23= .8700.) .The reaction of this compound with methanol and catalytic amounts p-toluenesulfonic acid at reflux temperature finally gave 3,3-dimethoxy-D-homo-5oc-androst-16-en-17a-one, m.p. 125-127° (ether-hexane). '[oe]25 = -33° 8650.

EXAMPLE 11

To 70 ml of a 2-molar solution of methyllithium in ether, a solution of 3.0 g of 3,3-. dimethoxy-D-homd-5(x-androst-16-en-17a-one in 20 ml tetrahydrofu-

ran 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 was obtained, which was dissolved in 50 ml of acetone and then mixed with a solution of 1.0

g of p-toluenesulfonic acid in 5 ml of water. The mixture was kept for 2 hours

at room temperature, mixed with water and extracted with methylene chloride. The residue gave, after chromatography on silica gel, pure 17a(3-hydroxy-17aa-methyl-D-homb-5<x-androst-16-en-3-one, m.p. 211 —

214° [ct]<25>° -52° (c 0.1 in dioxane) .

EXAMPLE 12

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

ning over the course of 30 minutes mixed with a solution of 0.36 ml of bromine and 570 ml of sodium acetate in 37 ml of glacial acetic acid. The reaction mixture was then poured onto ice water. The precipitated crystals were filtered off, washed with water and dried in vacuum over KOH. 3.1 g of product was obtained which was dissolved in 20 ml of dimethylacetamide over the course of 20 minutes and added to a boiling mixture of 5.1 g of calcium carbonate and 45 ml of dimethylacetamide. It was then boiled for another 30 minutes under reflux, then cooled to 60° and calcium-salt-

ne filtered out. The filtrate was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, dried with Na 2 SO 4 and evaporated in vacuo. 2.2 g of crude product was obtained, which was chromatographed on 50 times the quantity of silica gel.

With methylene chloride, 1.2 g of pure 17α(3-acetoxy-D-homo-androsta-1,16-dien-3-one could be eluted. Mp. 133-135°.

[ <x] at +55°. UV spectrum: «^22g 11100.

EXAMPLE 13

To 60 ml of a 1.2-molar lithium methyl solution in ether, a solution of 2.5 g of 3(3-acetoxy-D-homo-androsta-5,16-diene was added dropwise over the course of 30 minutes with stirring and argon blowing -17a-one in 15 ml of tetrahydrofuran and 15 ml of ether. The reaction mixture was stirred overnight at room temperature, then poured into ice water and extracted with ether. The ether extracts were washed with water, dried with . Na 2 SO 4 and evaporated in vacuo. The residue gave recrystallization twice from acetone pure 3(3,1-7a(3-dihydroxy-17aa-methyl-D-homo-androsta-5,16-diene, m.p. 220-223°).

[α]25 = _i69° (c =0.1 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 cyclohexane and 55 ml of toluene), 10 ml of toluene was distilled off. to 100° and 1.73 g

aluminum tert-butylate was added. The mixture was then boiled for 2 hours under reflux on a water separator. Usual work-up (see example 1) gave 2.7 g of crude product, which was chromatographed over silica gel. 1.2 g of pure 17a(3-hydroxy-17aoc-methyl-D-homo-androsta-4,16-dien-3-one were obtained, mp. 152-154° (acetone-hexane). UV: ^241 = 16700. = +18° (c = 0.1 in dioxane).

EXAMPLE 14 -

A solution of 2.0 g of 17a(3-hydroxy-17acc-methyl-D-homo-androsta-4,16-diene-3- on in 100 ml abs. tetrahydrofuran and 100 ml abs. ether. After the addition was finished, the mixture was stirred for a further 1 hour at 0° and then worked up as normal (see example 2). After recrystallization of the crude product from acetone-hexane, pure 3(3 ,17ap-dihydroxy-17aa-methyl-D-homo-

androsta-4,16-diene is obtained. Temp. 137-141. [a] D 25 = -28

(c = 0.1 in dioxane).

EXAMPLE 15

Into a solution of 2.0 g of potassium in 100 ml of liquid ammonia, acetylene was introduced until the solution was decoloured. Now a solution of 3.4 g of 3(3-acetoxy-D-homo-androsta-5,16-dien-17a-one in 7-0 ml of tetrahydrofuran was added dropwise over the course of 1 hour, whereby further a weak stream of acetylene was passed through the reaction solution. For work-up, 30 ml of ammonium chloride solution was slowly added dropwise and ammonia 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 Na2SO4 and evaporated in vacuo. The residue was chromatographed over silica gel. Pure 17aa-ethynyl-3(3, 17a(3-dihydroxy-D-homo-androsta-5,16-diene) was eluted with hexane-acetone 5:1. M.p. 227-229° (acetone-isopropyl ether) .[a]D -307 (c = 0.1 in dioxane).

1.1 g of 17aa-ethynyl-3(3,17a(3-dihydroxy-D-homb-androsta-5,16-diene was

dissolved in 15 ml of cyclohexanone and 40 ml of toluene. After distilling off 8 ml of solvent, 1.27 g of aluminum tert-butylate was added thereto and heated for 2 hours at reflux using a water separator. The reaction mixture was worked up as usual and gave 1.5 g of crude product which, chromatographed over silica gel, gave pure 17aa-ethynyl-17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one. Mp. 247-250° .

UV: £23g = 16800. [cc]q = -138° (c = 0.1 in dioxane).

EXAMPLE 16

649 mg of 17aa-ethynyl-17a(3-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 to

1.1 equivalent of hydrogen was occupied. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallized from acetone-hexane. 17a(3-hydroxy-17aoc-vinyl-D-homo-androsta-4,16-dien-3-one was obtained with m.p. 120-122°. UV:<£>24o<=>165o°-Wc< 50>=~69° (c = ^ 1 dioxane) •

EXAMPLE 17

To 8 g of 3^-hydroxy-la-methyl-17a(3-tetrahydr.pyranyloxy-D-homo-5(x.-androst-16-ene) is added dropwise in 230 ml of dimethylsulfoxide and 21.2

ml of triethylamine at 15° over the course of 45 minutes a solution of 16 g of pyridine-SO^ complex in 64 ml of dimethylsulfoxide and then stirred for 1 hour at room temperature. It is poured into ice water. the precipitate from the

filtered, washed and taken up in ether. After drying and evaporation, 7.5 g of 1a-methyl-17a(3-tetrahydropyranyloxy-D-homo-5a-androst-16-en-3-one are obtained.

Preparation of the starting material:

50 g of 17(3-hydroxy-la-methyl-5(x-androstan-3-one) is heated in 1000 ml

abs. benzene, 125 ml of ethylene glycol and 1.25 g of p-toluenesulfonic acid

7 hours under rowing at water separators at backflow. The reaction solution is then diluted with ether, washed with sodium bicarbonate solution and water, dried and evaporated to dryness. The recovery

des 55 g .3 , 3-ethylenedioxy-17p-hydroxy-1a-methyl-5(x-androstane.

55 g of 3,3-ethylenedioxy-17β-hydroxy-1(x-methyl-5α-androstane in 550

ml of toluene and 110 ml of cyclohexanone at the boiling point are mixed with a

dissolving 5.5 g of aluminum isopropylate in 55 ml of toluene and heating

mes 3 hours by slow distillation. It is then mixed with ether,

washed with ice-cold dilute sulfuric acid and water, evaporated and the residue distilled with steam. After methylene chloride extraction, the product obtained is recrystallized from diisopropyl ether and 51 g of 3,3-ethylenedioxy-la-methyl-5cc-androstan-17-one with m.p. 155.5-156.5°.

51 g of 3,3-ethylenedioxy-loc-methyl-5a-androstan-17-one are mixed in

1000 ml of dimethylformamide with 51 g of trimethylsulfonium iodide and un-

where stirring is introduced over 30 minutes 27.2 g of potassium tert.-buty-

lazily portionwise. After a further 60 minutes of reaction time, this is stirred into ice water, the precipitate that has formed is filtered off,

washed well with water and taken up in methylene chloride. After in-

the evaporation, the residue is chromatographed on silica gel. One recovers

where thus 36.6 g of 3, 3-ethylenedioxy-1a-methyl-5a-androstane[17 ((3-1')-spiro-3'-yoxirane. A sample recrystallized from diisopropyl-

, ether melts at 165.5-166.5°.

36.6 g of 3,3-ethylenedioxy-loc-methyl-5oc-androstane[17((3-1')-spiro-3'] oxirane are mixed in 366 ml of dimethylformamide and 145 ml of water with 41.3 g of sodium azide and stirred 3 hours at 110°. It is then stirred into ice water, the precipitate that has formed is filtered off, washed with water and Si methylene chloride is taken up. After evaporation, 38 g of 3,3-ethylenedioxy-17a-azidomethyl-17p-hydroxy-1a-methyl- 5oc-andro-stan.

38 g of 3,3-ethylenedioxy-17a-azidomethyl-17(3-hydroxy-1a-methyl-5a-androstane are mixed in 380 ml of methanol and 38 ml of water with 19 g of oxalic acid and heated for 30 minutes at reflux. The reaction solution is mixed with and extracted with ether. The ether phase is washed with water, dried and evaporated. As a residue, 29.5 g of 17a-azidomethyl-17(3-hydroxy-la-methyl-5ct-androstan-3-one are obtained. 29 g of lithium alanate is suspended in 350 ml of abs. tetrahydrofuran. and added dropwise while cooling with ice and stirring a solution of 29 g of 17a-azidomethyl-17(3-hydroxy-1-methyl-5o-androstan-3-one in 350 ml of abs. tetrahydrofuran. Then stirred for 1 hour at room temperature. The suspension is then cooled again in an ice bath and carefully mixed successively with 31.7 ml of water, 31.7 ml of 15% caustic soda and 94 ml of water. The slurry is filtered off, washed with ether and extracted completely in the sox with ether. The aspirated the filtrate is then combined with the extraction solution, evaporated, and 27.5 g of 17a-aminomethyl-3<5,17(3-dihydroxy-1a-methyl-5a-androstane are obtained. 27 g 17a-aminomethyl-3^,17(3-dihydroxy-1a-methyl-5a-androstane is dissolved in 558 ml of acetic acid and 558 ml of water and mixed slowly under ice-cooling with 48.5 g of sodium nitrite dissolved in 381 ml of water. It is then stirred for 1 hour at room temperature, diluted with water and the precipitate that has formed is filtered off. After dissolving in methylene chloride, wash with sodium bicarbonate solution and water, dry and evaporate. The residue is chromatographed over silica gel. One thus obtains 17.5 g of 3^-hydroxy-1-methyl-D-homo-5oc-androstan-17-one. 16 g of 3^-hydroxy-la-methyl-D-homo-5(x-androstan-17a-one is heated in 320 ml of abs. tetrahydrofuran with 22.5 g of copper II bromide for 90 minutes while stirring at reflux. It is filtered off from separated copper-'l-bromide, dilute with ether, wash with ammo- nium chloride solution and water, dried and evaporated. 19.5 g of 17α-bromo-3α-hydroxy-1α-methyl-D-homo-5α-androstan-17α-one is obtained. 19.5 g of crude 17α-bromo-3α-hydroxy-1α-methyl-D-homo-5α-androstan-17α-one is stirred in 195 ml of dimethylformamide with 11.1. g lithium carbonate and 13 g lithium bromide 18 hours at 90°. It is poured into ice water, the precipitate is filtered off, washed with water, taken up in methylene chloride, dried and evaporated. The residue is chromatographed over silica gel and 11.5 g of 3^-hydroxy-la-methyl-D-homo-5a-androst-16-en-17a-one is obtained, UV:<e>223= 7600■ 11 g 3^— Hydroxy-la'-methyl-D-homo-5cx-androst-16-en-17a-one is left to stand in 44 ml of pyridine with 22 ml of acetic anhydride for 18 hours at room temperature. After precipitation with ice water, the precipitate is filtered off, washed well and dried. 11.2 g of 3^-acetoxy-1-methyl-D-homo-5oc-androst-16-en-17a-one are obtained.

UV :<É>223= 7 200. 11 g of 3j-acetoxy-la-methyl-D-homo-5or-androst-16-en-17a-one are mixed in 110 ml of abs. tetrahydrofuran under ice-cooling with 22 g of lithium tert-butoxyalanate and stirred for 4 hours under ice-cooling. The reaction solution is diluted with ether, washed with dilute sulfuric acid and water, dried and evaporated. The residue is chromatographed over silica gel and 8.5 g of 3^-acetoxy-17α|3-hydroxy-lα-methyl-D-homo-5cx-andro st-16-ene are obtained.

8.5 g of 3^-acetoxy-17α-hydroxy-lα-methyl-D-homo-5(x-androst-16-ene) are stirred in 85 ml of abs. tetrahydrofuran with 8.5 ml of 2,3-dihydro-4H- pyran and 1 drop of phosphorus oxychloride for 1 hour, at room temperature. It is then diluted with ether, washed with saturated sodium bicarbonate solution and water, dried and evaporated. 9.7 g of 3|-acetoxy-la-methyl-17ap:-tetrahydro-pyranyloxy- D-homo-5a - andro st-16-en.

9.5 g of 3j;-acetoxy-1a-methyl-17ap-tetrahydropyranyloxy-D-homo-5a-androst-16-ene are heated in .95 ml of methanol and 9.5 ml of water with

4.75 g potassium carbonate 1 hour at reflux. The common in ice-

water, the precipitate is filtered off, washed and taken up in methylene chloride. After drying and evaporation, 8.1 g of 3^-hydroxy-la-methyl-17a(3-, tetrahydro-pyranyloxy-D-homo-5a-androst-16-ene are obtained.

EXAMPLE 18

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

Claims (38)

1. Process for the production of D-homosteroids with formula wherein the dashed lines in the A ring denote facultative C-C bonds; R<1> means hydrogen or methyl; R oxo or, in case ring A is unsaturated, oxo, (a-H,(3-0H) or (oc-H, (3-0-acyl) ; R 7 hydrogen or methyl; R173''3 hydrogen., C1 _l0 -alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R17aa hydrogen, lower-alkyl, ethynyl, vinyl or propadienyl, . characterized in that maria) in a D homosteroid with the formula wherein R <1> , R173!3 R <17a> and c have the indicated meanings, and the A5 double bonds are optional, oxidizing the 3-hydroxy or 3-hydroxy A5 grouping to the 3-keto or 3-keto A4 -grouping, or åt manb) produces a D-homosteroid with the formula 13 in which R , R and the dashed lines in the A ring have the meanings indicated, and under an intermediate protection of a 3-keto group, reacts with an organometallic compound giving off the residue R <17a> °,c) reacts a D-homosteroid of formula wherein R<1> , R17aoc and R17aP have the indicated meanings, with a methyl Grignard compound in the presence of copper I chloride, or that one d) reacts a compound with the formula wherein R^" <7a> ( <X> and R <17aP> have the indicated meanings and the A5 double bond is optional, with a methyl Grignard compound in the presence of copper-I chloride and then rearranges a /a\ 5-double bond in the reaction product by acid treatment in the 4,5-position, or that one e) acylates the hydroxy group(s) in a D-homosteroid of formula I, in which at least one hydroxy group is present in 3- or 17a(3-still3 or that one f) in a D homosteroid with the formula 3 in which R and the dashed lines have the aforementioned meanings, dg Z constitutes oxo or (0R17a^,R17<aQ> ), when Z constitutes oxo, the 17a-keto group reduces to the hydroxy group under intermediate protection of a 3-keto group or, when R <3> is oxo and the A ring is monounsaturated, the 3-keto group and a possibly present 17a-keto group are reduced to a hydroxy group, or that one g) dehydrogenates a saturated or monounsaturated in the A ring tet D-homos■ teroid of the formula I, in which R 3 constitutes, oxo in the 1,2- and/or 4,5-position, or that one h) in a D homosteroid of formula I, in which R^"7aP is hydrogen and R 1, R 3 , R 7 , R 173.a and the dashed lines in the A ring have the indicated meanings, transfers 17a(3- the hydroxy group in a cycloalkenyl or tetrahydropyranyl, C 1-4 alkyl, benzyl or cyclohexyl methyl ether, or that one i) in a D-homosteroid of formula I, in which R^ is <7aP> acyl, tetrahydropyranyl or cycloalkenyl and R <1> , R3, R7, R17acx and the dashed lines in the A ring have the indicated meanings, for soaps 17a(3-acyloxy group and an optionally present 3-acyloxy group or cleaves a 17a(3-tetrahydropyranyl or cycloalkenyl ether, or at least) in a D-homosteroid with the formula wherein R1, R <3> , R7, R <17aP> and the dashed lines in the A ring have the indicated meanings, hydrogenates the ethynyl group to the vinyl group. 2. Process according to claim 1, characterized in that compounds of the formula I are prepared, in which R 7aP means hydrogen, lower alkanoyl, tetrahydropyranyl or cycloalkenyl. 3. Method according to claim 1 or 2, characterized in that compounds of formula I are prepared, in which R 1 is hydrogen and R 3 is oxo and the ring A contains a double bond. in 4. Process according to claims 1, 2 or 3, characterized in that compounds of formula I are prepared, in which R17aocu tgjo <r> hydrogen, methyl or ethyl, and R"*"7a^ hydrogen or lower-alkanoyl.; 5. Process for the production of preparations with a hormonal effect, characterized by mixing a D-homosteroid with the formula I according to the definition in claim 1 as active ingredient with suitable for therapeutic purposes, non-toxic, inert, in and of itself in such preparations usually solid and liquid carriers and/or excipients.; 6. Preparations with hormonal action, characterized by a content of a D-homosteroid with the formula I according to the definition in claim 1.; 7. D-homosteroids of the formula "wherein the dashed lines in the A ring" denote optional C-C bonds, R1 means hydrogen or methyl; R 3 oxo or, if the A ring is unsaturated, oxo, (cc-H, (3 -OH) or (oc-H, (3-0-acyl); R 7 hydrogen or methyl; R <17aP> hydrogen, C1_10 -alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; and R<17aot> hydrogen, lower alkyl, ethynyl, vinyl or propadienyl.; 8. D-homosteroids with the formula I according to claim 7, characterized in that R" <*> " <7a> ^ means hydrogen, lower alkanoyl, tetrahydropyranyl or cycloalkenyl. 9. D-homosteroids with the formula I according to the definition in claim 7 or 8, characterized in that R <1> is hydrogen and R 3 oxo, and ring A contains a double bond. 10. D-homosteroids with the formula according to the definition in claim 7, 8 or 9, characterized in that R 7a<x is hydrogen, methyl or ethyl, and R 7a^ is hydrogen or lower alkanoyl. 11. D-homo-androsta-4,16-diene-3,17a-dione. . 12. 17a(3-hydroxy-D-homo-androsta-4,16-dien-3-one. 13. 17a(3-acetoxy-D-homo-androsta-4,16-dien-3-one. 14. 17a(3-propionoxy-D-homo-androsta-4,16-dien-3-one. 15. 17α|3-butyroxy-D-homo-androsta-4,16-dien-3-one. , 16. 17a(3-phenyl-acetoxy-D-homo-androsta-4,16-dien-3-one. 17. 17a(3-undecanoyloxy-D-homo-androsta-4,16-dien-3-one. 18. 17a(3-heptanoyloxy-D-homo-androsta-4,16-dien-3-one. 19. 17a(3-f enoxyacetoxy-D-homo-androsta-4,16-dien-3-one. 20. 17a(3-tetrahydropyranyloxy-D-homo-androsta-4,16-dien-3-one. 21. 17a(3-cyclopentenyloxy-D-homo-androsta-4,16-dien-3-one. 22. 17a(3-acetoxy-D-homo-androsta-1, 4,16-trien-3-ori. 23. 17ap-Hydroxy-17aoc-methyl-D-homo-androsta-1, 4^L6-tfien-3-one. 24. 17a(3-pentyloxy-D-homo-androsta-4,16-dien-3-one. 25. 17a(3-n-decyloxy-D-homo-androsta-4,16-dien-3-one. 26.. 1'7a(3-benzyloxy-D-homo-androsta-4,16-dien-3-one. 27. 17a(3-cyclohexylmethyl-D-homo-androsta-4,16-dien-3-one. 28. 3p , 17a(3-dihydroxy-D-homo-androsta-4,16-diene. 29. 3(3,17a(3-diacetoxy-D-homo-androsta-4,16-diene. 30. 17a(3-hydroxy-D-homo-5(x-androst-16-en-3-ron. 31. 17a(3-Hydroxy —17ao-methyl-D-homo-5a-androst-16-en-3-one. 3 2. 17a(3-acetoxy-D-homo-androsta-1,. 16-dien-3-one. 33. 17a(3-hydroxy-17aa-methyl-D-homo-androsta-4,16-dien-3-one. 34.. 3(3 , 17a(3-dihydroxy-17aa-methyl-D-homo-androsta-4,16-diene. 35. 17aa-ethynyl-17a(3-hydroxy-D-homo-androsta-,4,16-dien-3-one. 36. 17a(3-hydroxy-17aa-vinyl-D-homo-androsta-4,16-dien-3-one. 37. 1α-methyl-17α(3-tetrahydropyranyloxy-D-homo-5α-androst-16-en-3-one. 38. 17αp-Hydroxy-lα-methyl-D-homo-5α-androst-16-en-3-one.