CA1082686A - Novel d-homosteroids - Google Patents

Abstract

ABSTRACT

Compounds of the general formula (I) wherein the broken lines in the A-ring denote optional carbon-carbon bonds; R1 represents a hydrogen atom or a methyl group; R3 represents an oxo group or, when the A-ring is unsaturated, an oxo, (.alpha.-H, .beta.-OH) or (.alpha.-H, .beta.-O-acyl) group;
R7 represents a hydrogen atom or a methyl group; R17a.beta. represents a hydrogen atom or a C1-10 alkyl, benzyl, cyclohexyl-methyl, acyl, tetrahydropyranyl or cycloalkenyl group; and R17a.alpha. represents a hydrogen atom or a lower alkyl, ethynyl, vinyl or propadienyl group, which are useful for the manufacture of pharmaceutical pre-parations with hormonal activity, and method for the pre-paration thereof.

Description

~ 08 ~ ~ 8 6 RAN 4104/143 The present invention relates to novel D-homosteroidS.
More particularly, the invention is concerned with novel D
-homos~eroids, a process for the manufacture thereof and pharmaceutical preparations containing same.

The novel ~-homosteroids provided by the present invention have the following general formula ,.R17a~

(I) wherein the broken lines in the A-ring denote optional carbon-carbon bonds;
represents a hydrogen atom or a methyl group; R represents an oxo group or, when the A-ring is unsaturated, an oxo, (a-H, ~-OH) or ~a-H, ~-O-acyl) group;
R represents a hydrog~n atom or a methyl group; R17a~ represents à hydrogen atom or a Cl-C10 alkyl, benzyl, cyclohexyl-methyl, acyl, tetrahydropyranyl or cycloalkenyl group; and R17aa represents a hydrogen atom or a lower alkyl, ethynyl, vinyl or propadienyl group.

;~

Me/27.9.1976 ~ ~ _ ~ 8 ~

As used in this specification, the term "acyl" denotes, in particular, acyl groups derived from organic acids; for example, from alkanecarboxylic acids containing up to 11 carbon atoms (especially from lower alkanecarboxylic acids S containing up to 7 carbon atoms) such as acetic acid, propionic acid, caproic acid, valeric acid, oenanthic acid or undecylenic acid; or from oxalic acid, succinic acid or citric acid, or from aromatic carboxylic acids such as benzoic acid, phenyl-acetic acid or phenoxyacetic acid, or from heterocyclic carboxylic acids such as nicotinic acid, or from cycloaliphatic carboxylic acids such as cyclopèntylpropionic acid.

Lower alkyl groups can contain up to 7 carbon atoms and can be straight-chain or branched-chain. Examples o such lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and isomers of the latter. The preferred lower alkyl groups are methyl and ethyl. An alkyl group denoted by R17a~ can contain up to 10 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and decyl.

Cycloalkenyl groups preferably contain from 5 to 8 carbon atoms. Examples of such yroups are cyclopenten-l-yl and cyclohexen-l-yl.

A preferred group of D-homosteroids of formula I
comprises those in which Rl represents a hydrogen atom, R3 represents an oxo group and the A-ring contains a double-bond.
'In addition, those D-homosteroids of formula I in which R17aa represents a hydrogen atom or a methyl or ethyl group and Z~8&i R17a~ represents a hydrogen atom or a lower alkanoyl group are preferred. Examples of D-homosteroids of formula I are:

17a~-(3-Cyclopentyl)propionoxy-D-homoandrosta-4,16-dien--3-one, S 17a~-nlcotinyloxy-D-homoandrosta-4~l6-dien-3-one~
17a~3-propionoxy-D-homoandrosta~1,4,16-trien-3-one, 17a~-hydroxy-7a-methyl-D-homoandrosta-1,4~16-trien-3-one~
la,7a-dimethyl-17a~-hydroxy-D-homoandrosta-4,16-dien-3--one, 17a~-hydroxy-7a-methyl-D-homoandrosta-4,16-dien-3-one, 17a~-hydroxy-7a-methyl-D-homo-5a-androst-16-en-3-one, 17a~-hydroxy-7a-methyl-D-homo-5a-androsta-1,16-dien-3- : `
-one, ; 17a~-hydroxy-1-methyl-D-homo-5a-androsta-1,16-dien-3-one, lS la,l7aa-dimethyl-D-homoandrosta-4,16-dien-3-one, 3~,17a~-dihydroxy-17aa-methyl-D-homo-5a-androsta-1,16--diene, :
17a~-hydroxy-17aa-methyl-D-homo-5a-androsta-1,16-dien-3- .
-one, ; 20 17a~-hydroxy-la,17aa-methyl-D-homo-5a-androst-16-en-3- -one, ; 17a~-hydroxy-17aa-ethyl-D-homo-Sa-androst-16-en-3-one,17aa-ethyl-17a~-hydxoxy-la-methyl-D-homo-5a-androst-16--en-3-one, 17a~-hydroxy-la-methyl-D-homo-5a-androst-16-en-3-one, 17a~-hydroxy-7a,17aa-dimethyl-D-homoandrosta-4,16-dien -3-one, 17a~-pentyloxy-D-homoandrosta-4,16-dien-3-one, 17a~-n-decyloxy-D-homoandrosta-4,16-dien-3-one, ~ ~ 2 ~ ~

17a~-benzyloxy-D-homoandrosta-4,16-dien-3-one, l7a~-cyclohexylmethyl-D-homoandrosta-4~l6-dien-3-one and 17a~-undecanoyloxy-D-homoandrosta-4,16-dien-3-one.

~ccording to the pxocess provided by the present S invention, the D-homosteroids o formula I hereinbefore are manufactured by ~a) oxidislng the 3-hydroxy or 3-hydroxy-~5 grouping in a D-homosteroid of the general formula Q~?17a~
,R17aa ~ (II) HO

, wherein Rl, R17a~ and R17aa have the :
significance given earlier and the broken line in the 5,6-position denotes an optional carbon-carbon bond, to the 3-keto or 3-keto-~4 grouping, or . .
(b) reacting a D-homosteroid of the general formula R3 ~ (~II) , wherein Rl, R3 and the broken lines in the A-ring have the significance given earlier, with an organometallic compound yielding a R17aa group, a .
3-keto group being intermediately protected, or (c) reacting a D-homosteroid of the general formula ol?l7a~
, R17aa g~ (IV) O

, wherein Rl, R and R have the significance given earlier, with a methyl Grignard compound in the presence of copper-I
chloride, ~.
or (d) reacting a D-homosteroid of the general formula ORi7a~
Rl 7 aa ~'W (V) and R have the significance given earlier and the broken line in the 5,6-position denotes an optional carbon-carbon bond, .

with a methyl Grignard compound in the presence of copper-I
chloride and subsequently rearranging a ~5 double bond in the reaction product into the 4,5-position by acid treatment, or (e) acylating the hydroxy group(s) in a D-homosteroid of formula I in which at least one hydroxy group is present in the 3-position or 17a~-position, or (f) subjecting a D-homosteroid of the general formula ~ (VI~

' ' .

, wherein R3 and the broken lines in the A-ring have the significance given earlier and 2 represents an oxo or (oRl7a~ R17a~) group, : 15 to reduction of the 17a-keto group to the hydroxy group (with intermediate protection of a 3-keto group) when Z represents an oxo group, or to reduction of the 3-keto group and a 17a--keto group which may be present to the hydroxy group when R3 represents an oxo group and the A-ring is monounsaturated, or (g) su~jecting a D-homosteroid of formula I which is .
saturated or monounsaturated in the A-ring and in which R3 represents an oxo group to dehydrogenation in the 1,2-position and/or 4,5-position, ~26;~

, or (h) converting the 17a~-hydroxy group in a D-homosteroid of formula I in which R17a~ represents a hydrogen atom and Rl, R3, R7, R17aa and the broken lines in the A-ring have the S significance given earlier into a cycloalkenyl, tetrahydro-pyranyl, Cl-C10 alkyl, benzyl or cyclohexylmethyl ether, or (i) subjecting a D-homosteroid of formula I in which R17a~ represents an acyl, tetrahydropyranyl or cycloalkenyl 1 group and Rl, R3, R7, R17aa and the broken lines in the A-ring have the significance given earlier to saponification of a 17a~-acyloxy group and a 3-acyloxy group which may be present or to cleavage of a 17a~-tetrahydropyranyl or cycloalkenyl ether, or (j) hydrogenating the ethynyl group in a D-homosteroid of the general formula ORl~an ¦ "C- C H
I~ ~ . .
(VII) ''.

: h in Rl R3 R7, R17a~ and the broken lines in the A-ring have the significance given earlier, to the vinyl group. : :

The oxidation according to process embodiment (a) can be carried out in a manner which is known per se-according to the Oppenauer procedure (e.g. uslng aluminium isopropylate or tert.butylate) or by means of oxidlsing agents such as chromium trloxide (e.g. Jones' reagent) or according to the Pfitzner-Moffatt procedure uslng dimethylsulphoxlde/dicyclo-S hexylcarbodiimide (the initially obtained ~5-3-ketone requiring subsequent isomerisation to the ~4-3-ketone) or by means of dimethylsulphoxide/pyridine/sulphur trioxide.

The reaction of a D-homosteroid of formula III with an organometallic compound according to process embodiment (b) can al90 be carried out in a manner whlch is known per se.
The organometallic compound can be a Grignard compound (e.g.
ethynylmagnesium bromide, methylmagnesium bromide or vinyl-magnesium bromide) or an alkali metal organic compound such as sodium, potassium or lithium acetylide or vinyl lithium. A
3-keto group which is simultaneously present can be inter-mediately protected, for example as a ketal, enol ether, enamine or semicarbazone.

The 7-methylation of a D-homosteroid of formula IV and the l-methylation of a D-homosteroid of formula V according to process embodiments (c) and (d) can also be carrled out in a manner known per se by reaction with a methyl Grignard compound. In embodiment ~d) a la-methyl-~5 compound is initially obtained, the ~5 double bond of which can be rearranged into the 4,5-position by treabment with ethanollc sulphuric acid whilst warmlng.
: :
The acylation of a free hydroxy group in the 3-positlon or 17a~-position in a D-homosteroid of formula I can be carried out by trea~ment with a reactive acid der$vative (e.g. an acid halide or acid anhydride) in the presence of a base (e.g.
pyridine or collidine).

The reduction of a 3-keto or 17a-keto group according to process embodiment (f) can be carried out in a ma~mer known per se using a complex metal hydride; for example, a di(lower alkoxy)aluminium hydride such as diisobutoxyaluminium hydride, a tri(lower alkoxy)aluminium such as triisopropoxyaluminium, lithium aluminium hydride, sodium aluminium hydride, sodium borohydride, trimethoxylithium aluminium hydride or tributoxy-lithium aluminium hydride. Suitable solvents for this reduct~on are hydrocarbons (e.g. cyclohexane, benzene or toluene) or ethers (e.g. diethyl ether or tetrahydrofuran).
Where a 17a-keto group is to be reduced alone in the presence of a 3-ke~o group, the 3-keto group is intermediately protected.
A 3-keto group can be protected in the presence of a 4,5--double bond in the form of an enamine or enol ether. A
non-conjugated 3-keto group can be protected as a ketal.
The introduction and splitting off of these protec~ing groups can be carried out according to known procedures.

A 1,2-dehydrogenation according to process embodiment (g) can be carrled out in a manner known per se using a dehydrogenating agent such as selenium dioxide, 2,3-dichloro--5,6-dicyanobenzoquinone, thallium triacetate or lead tetra~
acetate. The 1,2-dehydrogenation can also be carried out ~icrobiologically; for example, using Schizomycetes, in particular those of the genus Arthrobacter (e.g. A. simplex ATCC 6946), Bacillus (e.g. B. lentus ATCC 13805 and :

! . ! ~ .

108;~;~B6 B. sphaericus ATCC 7055), Pseudomonas (e.g. P. aeruginosa IF0 3505), Flavobacterium (e.g. flavenscens IF0 3058), Lacto-bacillus (e.g. L. Brevis IF0 3345) and Nocardia (e.g. N~ opaca ATCC 4276).

S Double bonds can be simultaneously in the 1,2- and 4,5--positions by bromination to give a 2,4-dibromo-3-ketone and dehydrobromination of the latter using lithium carbonata and lithium bromide in dimethylformamide. A 4,5-double bond can also be introduced by brominating a 3-keto-steroid, which is saturated in the A-ring, in glacial acetic acid to give a 2a,4a-dibromo derivative, reducing said derivative with chromium-II chloride to give a 4a-bromo compound and then dehydrobrominating said 4a-bromo compound, via the semi-carbazone, by treatment with succinic acid to give a Q4-3--ketone.

The etherification of a 17a~-hydroxy group according to process embodiment (h) can be carried out, for example, by treatment with dlhydropyran in order to manufacture a tetra-hydropyranyl ether or by treatment with a cycloalkanone ketal "
ln the presence of a ca~alytic amount of acid (e.g. p-toluene-sulphonic acid) in order to manufacture a cycloalkenyl ether.
For the manufacture of a 17a~-Cl-C10 alkyl, benzyl or cyclo-hexylmethyl ether, it is expedient to intermediately protect a 3-keto group. The protection of a 3-keto group is preferably accomplished by ketalisation (e.g. with ethyleneglycol in the presence of a catalytic amount o~ acid such as p-toluene-sulphonic acid). The etherification of the 17a~ hydroxy group can be carried out by conversion into an alkali metal salt ~ : - . .. . . : .

10~826B~

(e.g. the sodium salt) with a strong base (e.g. sodium hydride) followed by reaction wlth a Cl-C10 alkyl, benzyl or cyclohexyl-methyl halide such as pentyl iodlde, benzyl chloride or cyclo-hexylmethyl iodide in a solvent such as dimethylsulphoxide or S benzene.

The saponification of 17a~-acyloxy and 3-acyloxy groups or the cleavage of 17a~-ether groups according to process embodiment (i) can be carried out in a manner known per se.
Acyloxy groups can be saponified, for example, with aqueous--alcoholic bases such as aqueoùs-methanolic potassium carbonate ~, and ether groups can be cleaved by means of aqueous-alcoholic mineral acids or organic acids such as oxalic acid or p--toluenesulphonic acid.

The hydrogenation of the ethynyl group according to process embodiment (j) can be carried out in the presence of a noble-metal catalyst such as palladium/calcium carbonate and, conveniently, a deactivator such as pyridine.

The starting materials used in the foregolng process, insofar as they are not known or insofar as their preparation is not described hereinafter, can be prepared in analogy to known methods or methods described in the Examples hereinafter.

The D-homosteroids of formula I possess hormonal activity.
D-Homosteroids of formula I in which R17aa represents a hydrogen atom or a lower alkyl group possess, in particular, androgenic/anabolic activity. D-Homosterolds of formula I
in which R17aa represents an ethynyl, viny~ or propadienyl ~ . ~ .~ .. . . . . . ..

~ ~ Z 6 ~ ~

group possess, in par~icular, gestation-inhibitlng and ovulàtion-inhibiting activity.

For example, 17a~-hydroxy-D-homoandrosta-4,16-dien-3-one shows, on subcutaneous administration to juvenile male rats, S an androgenic activity which is comparable with the action of testosterone at one third of the dosage. The androgenic activity was determined on the basis of the growth of the prostate gland and the seminal vesicle. 17a~-Phenylacetoxy-and 17a~-phenoxyacetoxy-D-homoandrosta 4,16-dien-3-one showed, on subcutaneous administration to juvenile male rats, an extended period of activity compared with testosterone enanthate.

The D-homosteroids of formula I can be used as medica-ments; for example in the form of pharmaceutical preparations which contain them in association with a compatible pharma-ceutical carrier material. This carrier material can be an organic or inorganic inert carrier material which is suitable for enteral, percutaneous or parenteral administration such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum ielly etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées, supposltorles or capsules) or in a liquid form (e.g. as solutions, suspenstons or emulsions). If necessary, the pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatlves, stabilisers, wetting agents or emulsifiers, salts for modifying the osmotic pressure or buffers. They may also contain other therapeutically ~aluable substances.

~z~

The following Examples illustrate the process provided by the present invention:

Example 1 50.0 g of 3~-hydroxy-D-homoandrosta-5,16-dien-17a-one were dissolved in 1000 ml of cyclohexanone and 3000 ml of toluene. 400 ml of solven~ were evapora~ed off from this solut~on and the solution was cooled to 80C and treated with 60.0 g of aluminium tert.butylate. Whilst stirring and flushing with argon, the mixture was heated to reflux for 2.5 hours under a water separator. For the working-up, the solution was concentrated in vacuo to about 200 ml, poured on to an ice-cold mixture 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 over sodium sulphate, evaporated in vacuo and finally dried at 50C under a high vacuum. The residue was then recrystallised from acetone/hexane. There were obtained 40.7 g of pure D--homoandrosta-4,16-diene-3,17a-dione of melting point 193-194C;
W : ~236 = 21500; ~a]25 C = +60 (c = 0.1 in dioxan).

The starting material was prepared as follows: ;

18.1 g of 3~-acetoxy-D-homoandrost-5-ene-17a-one were dissolved in 800 ml of methanol under argon at 45C. 23.5 g of copper-II bromide were added to this solution and the mixture was heated under reflux for 18 hours. The mixture was cooled to 35C and filtered and the residue was then rinsed thoroughly with chloroform. The combined filtrates were ~1~8Z~

poured on to 1.3 litres of water containing loo g of sodium chloride and 500 g of ice. The mixture was extracted three times with chloroform. The organic phases were washed with sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo. There were obtained 19.8 g of almost pure 17a-bromo-3~-hydroxy-D-homoandrost-5-en-17a-one, which was used directly in the next step.

35.1 g of calcium carbonate were suspended in 290 g of dimethylacetamide. Whilst flushing with argon, 40 ml of dimethylacetamide were distilled off and then 18.7 g of 17a--bromo-3~-hydroxy-D-homoandrost-5-en-17a-one were added over a period of 20 minutes. The mixture ob~ained was then boiled under reflux for 30 minutes. The solution was cooled to 60C
and the preclpitate filtered off. The filtrate was poured on to a mixture of 1.25 litres of water, ~50 g o ice and 170 g of sodium chloride. The mixture was extracted three times with methylene chloride. The extracts were washed with l-N
hydrochloric acid and water, dried over magnesium sulphate and evaporated in vacuo. There were obtained 14.7 g of crude product which was dissolved in 170 ml of ethyl acetate and treated with a small amount of active charcoal. After flltering the solution over Speedex Dicalite, the filtrate was concentrated to 50 ml and left to cxystalliseO There were thus obtained 11.7 g of pure 3~-hydroxy-D-homoandrosta-5,16--dien-17a-one of melting point lgO-193C; UV: E227 ~ 13000;
~a]D5 = -177 (c = 0.1 in dioxan).

Example 2 15.0 g of D-homoandrosta-4,16-dien-3,17a-dione were Tra~e~r~ - 15 -~ 6 - dissolved in lS0 ml of methanol and boiled under reflux for 10 minutes with 8.1 ml of pyrrolidine with the exclusion of air.
The solution was cooled to -10C. The enamine which had crystallised out was filtered off and dried at 20C under a S high vacuum, There were obtained 16.1 g of pure 3~
-pyrrolidinyl)-D-homoandrosta-3,5,16-trien-17a-one of melting point 207-210C; W : F279 = l9S00; E227 = 13000; ~a]D
-295.

16.1 g of the foregoing enamine were dissolved in 750 ml of absolute tetrahydrofuran and added dropwise over a period of lS minutes to a well-stirred solution of 8.0 g of lithium aluminium hydride in 750 ml of absolute ether at 0C. The mixture was then stirred for a further 1 hour at 0C. For the working-up, the solution was initially cautiously treated with 300 ml of moist ether. 40 ml of saturated sodium sulphate solution were then added, the mixture was stirred for a further 10 minutes and the precipitate was filtered off. The filtrate was evaporated in vacuo. There were obtained 15.8 g of substance which was warmed to 50C with a mixture o~ 1000 ml of methanol and 200 ml of 2-N sodium hydroxide solution or 45 minutes while stirring and flushing with argon. The solution was then poured on to 6 litres of ice-watex and 200 ml of acetic acid and extracted three times with methylene chloride.
The organic extract was washed with waterj dried over sodium sulphate and evaporated in vacuo. The residue was chromato-graphed on 650 g of silica gel. Elution w.ith acetone/hexane (1:1) yielded 13.0 g of pure 17a~-hydroxy-D-homoandrosta--4,16-dien-3-one of melting point 183-185C; W : ~241 ~
16200; ~a]25 C = ~76 ~982~

Example 3 A solution of 6.3 g of 17a~-hydroxy-D homoandrosta--4,16-dien-3-one in 60 ml of pyridine and 60 ml of acetic anhydride was maintained at room temperature overnight. The solvent was then removed in vacuo and the residue was xecrystallised from acetone/hexane. There were obtained 6.0 g of pure 17a~-acetoxy-D-homoandrosta-4,16-dien-3-one of melting point 165-167C; W : ~240 = 17000; [~]D = +91 (c = 0.1 ~
ln dioxan). `

The following D-homosteroids were prepared in an analogous manner using the corresponding acid anhydride:

17a~-Propionoxy-D-homoandrosta-4,16-dien-3-one of melting point 139-140C and l7a~-butyroxy-D-homoandrosta-4~l6-dien-3-one of melting 1 lS point 117-118C.

Exam~ 4

2.0 ml of phenylacetyl chloride were added dropwise to a solution of 2.0 g of 17a~-hydroxy-D-homoandrosta-4,16-dien-

-3-one ln 20 ml of pyridine over a period of 15 mLnutes and the mixture was warmed to 60C for 5 hours, For the working--up, the mixture was poured on to water and extracted with methylene chloride. The organic extract was washed neutral with dilute hydrochloric acid, sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on silica gel.

. . .

.. : . . .. .. . ,.. . , ~ . . ,.. ,,., . ~ . .. . . .. . .

- 1~8;~ 6 Elution with hexane/acetone (9:1) yielded 1.7 g of pure 17a~--phenylacetoxy-D-homoandrosta-4~16-dien-3-on~ of melting point 135-136C tfrom acetone/hexane); W : E240 = 17200; [a]D5 C =
~108 (c = 0.1 in dioxan).

S The following D-homosteroids were prepared in an analogous manner using the corresponding chloride:

17a~-Undecanoyloxy-D-homoandrosta-4,6-dien-3-one;
h [a]25C = +80 (c = 0.1 in dioxan); ~240 = 17100~
17a~-heptanoyloxy-D-homoandrosta-4,16-dien-3-one; oily;
~]DS C = ~88 (c = 0.1 in dioxan) and 17a~-phenoxyacetoxy-D-homoandrosta-4,16-dien-3-one of elting point 174-176C.

Example 5 1.0 g of 17a~-hydroxy-D-homoandrosta-4,16-dien-3-one was dissolved in 40 ml of absolute benzene and then 10 ml of benzene were distilled of f . A solution of 5 mg of p-toluene-J suLphonic acid in 10 ml of benzene and 0.6 ml of dihydropyran wa~ added to the remaining solution and the mixture was held fox 30 minutes at room temperature. For the working-up, the solu~ion was washed neutral, in sequence, with sodium hydrogen carbonate solution and watex, dried over sodium sulphate and evaporated in vacuo. The residue was recrys~allised from ether/hexane and gave pure 17a~-tetrahydropyranyloxy-D-homo-androsta-4,16-dien-3-one of melting point 137-138C; W :
16650 [a]25C = +64 (c = 0.1 in dioxan).

.

~82~

ExamPle 6 A solution of 2.0 g of 17a~-hydroxy-D-homoandrosta-4,16--dien-3-one in 40 ml o~ cyclopentanone diethyl ketal was warmed ~o 120C for 6 hours. The solution was evaporated to dryness S in vacuo and the residue was chromatographed on 40 g of aluminium oxide (activity grade II). By elution with benzene there were obtained 1.2 g of pure 17a~-cyclopentenyloxy-D--homoandrosta-4,16-dien-3-one of melting point 135-137C (from h 1) ~a]25C = +100 (c = 0.1 in dioxan); W : ~240 17200.

, ExamPle ?

A solution of 342 mg of 17a~-acetoxy-D-homoandrosta-4,16--dien-3-one and 328 mg of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in 30 ml of benzene was heated under reflux for 24 hours. The solution was cooled and filtered over a column of 10 g of aluminium oxide (activlty grade II). The column was then completely eluted with 200 ml of ethyl acetate. The combined eluates yielded 270 mg of crystallihe materlal which, upon recrystalli~ation from acetone/hexane, yielded pure 17a~-~0 ~acetoxy-D-homoandrosta-1,4,16-trien-3-one of melting point 222-224C; W : ~ = 14800 ~ J25C

17a~-Hydroxy-17aa methyl-D-homoandrosta-1,4,16-trien-3--one was prepared in an analogous manner from 17a~-hydroxy--17a-methyl-D-homoandrosta-4,16-dien-3-one. Melting point 148-150C; W : r245 = 15500; [a]D
,.. ~

: ,:

- lg - ~ .

lO'B2~B~

Example 8 1.95 g of a 50% dispersion of sodium hydride ln oil were dissolved in 45 ml of tetrahydrofuran and 10 ml of dimethyl sulphoxide. The solution was stirred at room temperature for 30 minutes and then 1.3 g of 3,3-ethylenedioxy-17a~-hydroxy-D--homoandrosta-4,16-diene were added. The mixture was stirred for a further 30 minutes and then 3.9 ml of l-iodo-pentane were added. Subsequen~ly, the mixture was stirred at room temperature for 20 hours. For the working-up, the mixture was treated cautiously with water and extracted with methylene chloride. The organic extracts were washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was dissolved in 65 ml of acetone, treated with 6.5 ml of water and 1.3 g of p-toluenesulphonic acid and stirred at room temperature for 2.5 hours. The mix~ure was poured on to water, extracted with methylene chloride, dried over sodium sulphate and evaporated. The residue was chromatographed on 110 g of ~ilica gel. Elution with hexane/acetone (8:1) yielded 0.3 g of pure 17a~-pentyloxy-D-homoandrosta-4,16-dien-3-one of melting point 58-59C (from methanol/water); ~]25 C = +112 (c = 0.1 in dioxan); ~240 = 16700.

The starting materlal was prepared as follows:

3.4 g of 17a~-acetoxy-D-homoandrosta-4,16-dlen-3-one, 100 ml of ethylene glycol, 100 ml of methylene chloride, 15 ml of ethyl orthoformate and 150 mg of p-toluenesulphonic acid were warme~ to 40C for 75 minutes. Usual working-up yielded .2 g of 3,3-ethylenedioxy-17a~-ace~oxy-D-homoandrosta-4,16-- 20 -~

,, : ~ , ,- . . . - . ., ., . ., ,, ., . , . :

-diene which was saponified with 300 ml o~ 5~ methanolic potassium hydroxide in lOo ml of methylene chloride at room temperature to give 3,3-ethylenedioxy-17a~-hydroxy-D-homo-androsta-4,16-diene of melting point 168-173C.

The ollowing D-homosteroids were prepared in a manner analogous to that described in the flrst paragraph of this Example:

17a~-n-Decyloxy-D-homoandrosta-4,16-dien-3 one; oily;
~ ] 25c = ~940 (c = o~l in dioxan); ~240 17a~-benzyloxy-D-homoandrosta-4,16-dien-3-one of melting point 139-141C (from acetone/hexane); [a]25 C = ~130;
E240 = 16600 and 17a~-cyclohexylmethyl-D-homoandrosta-4,16-dien-3-one of melting point 98-99C; [a]25 C = ~112; ~241 = 16700.
., '' .
lS Example 9 ':
A solution of 6.0 g of D-homoandrosta~4,16-dien-3,17a--dione in 100 ml of tetrahydrofuran and 100 ml of ether was added dropwise to a solution of 3.0 g of lithium aluminium hydride in 400 ml of absolute ether while stirring and cooling to 0C and the mixture was then stirred for a further 1 hour at 0-5~C. For the working-up, the mixture was cautiously treated with 300 ml of moist ether and then with 10 ml of saturated sodium sulphate solution. The mixture was stirred ror a further lS minutes and then the precipitate was filtered off and rinsed thoroughly with methylene chloride. The combined filtrates were evaporated in vacuo. The residue was . . -; . :;; -~ ~ 2 ~ ~ 6 chromatographed on 330 g of silica gel and yielded 4.1 g of pure 3~,17a~-dihydroxy-D-homoandrosta-4,16-diene of melting point 158-162C (from acetone/hexane); [a]D C = +23 ~c =
o.l in dioxan).

S A solution of 3.0 g of 3~,17a~-dihydroxy-D-homoandrosta-

-4,16-diene in 50 ml of pyridine and 50 ml of acetic anhydride was maintained at room temperature for 18 hours. The solution was then evaporated in vacuo and the residue was recrystallised from methanol. There was obtained pure 3B,17a~-diacetoxy-D--homoandrosta-4,16-diene of melting point 115-116C; ~a]25 C =
~12, Example 10 '' A solution of 7.0 g of 3,3-dimethoxy-D-homo-5a-androst--16-en-17a-one in 280 ml of ether was added dropwise to a stirred solution, cooled to 0C, of 3.5 g of lithium aluminium hydride ln 420 ml of ether. The mixture was stirred for 1 hour at 0-5C and thèn cautiously treated with 250 ml of water-saturated ether. The mixture was stirred for a further 15 minutes at room temperature and the pure preclpitate was then filtered of. This precipitate was thoroughly extracted with methylene chloride. The filtrate was evaporated in vacuo.
There were obtained 7.0 g of crude product which was dissolved in 140 ml o acetone and treated with a solution of 2~1 g of p-toluenesulphonic acid in 14 ml of water. The solution was maintained at room temperature for 2 hours and then treated with 500 ml of water. The precipitate which separated out was filtered off. For purification, this precipitate was 6~6 chromatographed on a 50-fold amount of silica gel. Following elution with methylene chloride/acetone (95:5) there were obtained S.O g of pure 17a~-hydroxy-D-homo-5a-androst-16-en-3--one of melting point 203-205C (from acetone/hexane);
[a]25C = +1 (c = 0.1 in dioxan).

The starting material was prepared as follows:

3~-Acetoxy-D-homoandrost-5-en-17a-one was reduced in ethanol using palladium/carbon as the catalyst to give 3~--acetoxy-D-homo-Sa-androstan-17a-one of melting point 113-115C.
This was brominated with copper bromide in methanol and converted into 3~-hydroxy-D-homo-androst-16-en-17a-one of melting point 177-179C by treatment with calcium carbonate in dimethylacetamide. Oxidation of the latter compound with Jones' reagent gave D-homo-5a-androst-16-ene-3,17a-dione of melting point 200-202C (~223 = 8700). Reaction of th1s latter compound with methanol and catalytic amounts of p--toluenesulphonic acid at the reflux temperature finally gave 3,3-dimethoxy-D-homo-5a-androst-16-en-17a-one of melting point 125-127C (from ether/hexane); [a]D5 C = -33; ~223 = 8650.

Example 11 A solution of 3.0 g of 3,3 dimethoxy-D-homo-5a-androst--16-en-17a-one in 20 ml of tetrahydrofuran and 20 ml of ether was added to 70 ml of a 2-M solution of methyl lithium ln ether over a period of 30 minutes while stirring. The ; 25 solution was stirred overnight at room temperature and then worked-up in the customary manner. There were obtained 3.2 g ~l~8~:6~;

- of crude product which was dissolved in 50 ml of acetone and treated with a solution of 1.0 g of p-toluenesulphonic acid in

5 ml of water. The mixture was maintained at room temperature for 2 hours, treated with water and extracted with methylene chloride. After chromatography on silica gel, the residue gave pure 17a~-hydroxy-17aa-methyl-D-homo~Sa-androst-16-en-3--one of melting point 211-214C; ~a]25 C = -52 (c = 0.1 in dioxan).

Example 12 2.0 g of 17a~-hydroxy-D-homo-5a-androst-16-en-3-one were acetylated at room temperature with 50 ml of pyridine and 50 ml of acetic anhydride. The 17a-acetate obtained by customary working-up was dissolved in 20 ml of dioxan and, after the addition of 3 drops of 40~ hydrogen bromide/glacial acetic acid solution over a period of 30 minutes, treated with a solution of 0.36 ml of bromine and 570 mg of sodium acetate in 37 ml of glacial acetic acid. The mixture was then poured on to ice-water. The crystals which precipitated out were filtered off under suction, washed with water and dried over potassium hydroxide in vacuo. There were obtained 3.1 g of pxoduct which was dissolved in 20 ml of dimethylacetamide and added over a period of 20 minutes to a boiling mixtuxe of 5.1 g of calcium carbonate and 45 ml of dimethylacetamide. The mixture was subsequently boiled under reflux for a further 30 minutes, then cooled to 60C and the calcium salts were filtered off. The filtrate was diluted with water and extracted with methylene chloride. The organlc extracts were washed with water, dried over sodium sulphate and .

1~326~

evaporated in vacuo. There were obtained 2.2 g of crude product which was chromatographed on a 50-fold amount of silica gel. Elution with methylene chloride yielded 1.2 g of pure 17a~-acetoxy-D-homoandrosta~ 6-dien-3-one of melting point 133-l35C; [a]25 C = +5S; W : 229 = 11100-': ' , Example 13 A solution of 2.5 g of 3~-acetoxy-D-homoandrosta-5,16--dien-17a-one in 15 ml of tetrahydrofuran and 15 ml of ether was added dropwise to 60 ml of a 1.2-M solution of lithium methyl in ether while stirring and flushing with argon over a period of 30 minutes. The mixture was stirred overnight at room temperature, then poured on to ice-water and extracted with ether. The ether extracts were washed with water, dried over sodium sulphate and evaporated in vacuo. After a two-lS -fold recrystallisation from acetone, there was obtained pure 3~,17a~-dihydroxy-17a-methyl-D homoandrosta-5,16-diene of melting point 220-223C; [a]25 C a -169 (c = 0~1 in dioxan).

.
L0 ml of toluene were distilled off from a solution of l.S g of 3~,17a~-dihydroxy-17a-methyl-D-homoandrosta-5,16--diene in 20 ml of cyclohe~anone and 55 ml of toluene. The mixture was then cooled to 100C and 1.73 g of aluminium tert.butylate were added. The mixture was then boiled under reflux for 2 hours under a water separator. Customary working--up (see Example 1) Yielded 2.7 g of crude product which was chromatographed on silica gel. There were obtained 1.2 g of pure 17a~-hydroxy-17aa-methyl-D-homo-androsta-4,16-dien-3-one o melting point 152-154C (from acetone/hexane); W : ~241 =
700 []25C = +18 (c = 0.1 in dioxan).

.:
D` - 25 -- , . . .- - - ~. . , ~. . - ~

~D8Z6~6 Example 14 A solutlon of 2.0 g of 17aB-hydroxy-17aa-methyl-D-homo-androsta-4,16-dien-3-one in 100 ml of absolute tetrahydrofuran and 100 ml of ab~olute ether was added dropwise to a solution, cooled to 0C, of 1.0 g of lithium aluminium hydride in 200 ml of ether. After completion of ~he addition, the mixture was stirred for a further 1 hour at 0C and then worked-up in the customary manner (see Example 2). By recrystallisation of the crude product from acetone/hexane there was obtained pure 3~,17a~-dihydroxy-17aa-methyl-D-homoandrosta-4,16-diene of melting point 137-141C; [a]D5 C = -28 (c = 0.1 in dioxan).

Example 15 Acetylene was passed into a solution of 2.0 g of potassium in 100 ml of liquid ammonia until the solution lS became decolorised. A solution of 3.4 g of 3~-acetoxy-D--homoandrosta-5,16-dien-17a-one in 70 ml of tetrahydrofuran was then added dropwise over a period of 1 hour, a weak stream of acetylene still being passed through the solution. For ` the workin~-up, 30 ml of ammonium chloride solution were slowly added dropwise and the ammonia was allowed to evaporate overnight. The mixture was treated with water and extracted with ether/methylene chloride. The organlc extracts were washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed~on silica gel.
Elution with hexane/acetone (5:1) yielded pure 17aa-ethynyl--3~,17a~-dihydroxy-D-homoandrosta-5,16-diene of melting point 227-229C (from~ace~one/isopropyl ether); [a]25 C = 3070 (c = 0.1 in dioxan).
~ ' ' 1.1 g of 17aa-ethynyl-3~,17a~-dihydroxy-D-homoandrosta--5,16-dlene were dissolved in lS ml of cyclohexanone and 40 ml of toluene. After the distillation of 8 ml of solvent, 1.27 g of aluminium tert.butylate were added and the mixture was heated at reflux for 2 hours under a water separator. The mixture was worked-up in the customary manner and gave 1.5 g of crude product which, after chromatography on silica gel, yielded pure 17a-ethynyl-17a~-hydroxy-D-homoandrosta-4,16--dien-3-one of melting point 247-250C; W : ~239 = 16800;
[a]D5 C = -138 (c = 0.1 in dioxan).

Example 16 649 mg of 17aa-ethynyl-17a~-hydroxy-D-homoandrosta--4,16-dien-3-one were dissolved in 40 ml of ethyl acatate and S ml of pyridine and, after the addition of 300 mg of palladium/calcium carbonate, the mixture was hydrogenated under normal pressure until 1.1 equivalents of hydrogen had been absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallised from acetone/hexane. There was thus obtained pure 17a~-hydroxy--17aa-vinyl-D-homoandrosta-4,16-dien-3-one of melting point 120-122C; W : ~240 = 16500; [a]25 C = -69 tc = 0.1 in dioxan).

Example 17 ;:.

- A solution of 16 g of pyrldine/sulphur trioxide complex in 64 ml of dimethylsulphoxide was added dropwise to 8 g of 3~-hydroxy-la-methyl-17a~-tetrahydropyranyloxy-D-homo-5a-~ 8 ~

-androst-16-ene in 230 ml of dimethylsulphoxide and 21.2 ml of triethylamine at 15C over a period of 45 minutes and the mixture was subsequently stirred for 1 hour at room temperature.
The mixture was poured on ~o ice-water and the precipitate filtered off, washed and taken up in ether. After drying and evaporation, 7.5 g of la-methyl-17a~-tetrahydropyranyloxy-D--homo-5a-androst-16-en-3-one were obtained.

The starting material was prepared as follows:

50 g of 17~-hydroxy-la-mèthyl-5a-androstan-3--one were heated at reflux in 1000 ml of absolute benzene, 125 ml of ethyleneglycol and 1.25 g of p-toluenesulphonic acid for 7 hours while stirring under a water separator. The solution was then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated to dryness.
55 g of 3 3-ethylenedioxy-17~hydroxy-la-methyl-5a-androstane were obtained.

55 g of 3,3-ethylenedioxy-17~-hydroxy-la-methyl-5a--androstane in 550 ml of toluene and 110 ml of cyclohexanone were treated at boiling with a solution of 5.5 g of aluminium isopropylate in 55 ml of toluene and the mlxture was heated or 3 hours with slow distillation. The mixture was then treated with ether, washed with ice-cold dilu~e sulphuric acid an~ water, evaporated and the residue steam-distilled. After extraction with methylene chloride, the resulting product was recrystallised from diisopropyl ether to give 51 g of 3,3--ethylenedioxy-la-methyl-Sa-androstan-17-one of melting point 155.5-156.6C.
: .

51 g of 3,3-ethylenedioxy-la-methyl-5a-androstan-17-one in 1000 ml of dimethylformamide were treated with 51 g of trimethylsulphonium iodide and 27.2 g of potassium tert.butylate were introduced portionwise over a period of 30 minutes while S stirring. After a further 60 minutes, the mlxture was stirred lnto ice-water and the precipitate which had separated out was filtered off, washed thoroughly with water and taken up in methylene chloride. After evapoxation, the residue was chromatographed on silica gel. 36.6 g of 3,3-e~hylenedioxy- `
-la-methyl-5a-androstan~17(~-1')-spiro-3']oxirane were thus obtained. A sample recrystalllsed from diisopropyl ether melted at 165.5-166.5C.

36.6 g of 3,3-ethylenedioxy-la-methyl-5-androstan-~17(~-1')-spiro-3']oxirane in 366 ml of dimethylformamide and 145 ml of water were treated with 41.3 g of sodium azide and the mixture was stirred for 3 hours at 110C. The mix~ure was then stirred into ice-water and the precipitate which had separated out was filtered off, washed with water and taken up in methylene chloride. After evaporation, 38 g o 3,3--ethylenedioxy-17a-azidomethyl-17~-hydroxy-~a-methyl-5a--androstane were obtained.

38 g of 3,3-ethylenedioxy-17a-azidomethyl-17~-hydroxy -la-methyl-5a-androstane in 380 ml of methanol and~38 ml of water were treated with 19 g of oxalic acid and the mixture was heated at reflux for 30 minutes. The solution was treated with water and extracted with ether. The ether phase was washed with water, dried and evaporated. 29.5 g of 17a--azidomethyl-17~-hydroxy-la-methyl-5a-androstan-3-one were obtained as the residue.

: .

.

~Z6~

29 g of lithium alanate were suspended in 350 ml of absolute tetrahydrofuran and a solution of 29 g of 17a-azido-me~hyl-17~-hydroxy-la-methyl-Sa-androstan-3-one in 350 ml of absolute tetrahydrofuran was added dropwise while cooling with ice and stirring. The mixture was subsequently stirred for 1 hour at room temperature. The suspension was then cooled again in an ice-bath and cautiously treated, in sequencP, with 31.7 ml of water, 31.7 ml of 15% sodium hydroxide solution and 94 ml of water. The precipi~ate was filtered off, rinsed with ether and exhaustively extracted with ether in a Soxhlet apparatus. The suction-filtered filtrate was then combined with the extraction solution and evaporated to give 27.5 g of 17-aminomethyl-3~,17~-dihydroxy-la-methyI-5a-androstane.

27 g of 17a-amlnomethyl-3~,17~-dihydroxy-la-methyl-5a--androstane were dissolved in 558 ml of acetic acid and 558 ml of water were treated slowly, while cooling with ice, with 48.5 g of sodium nitrite dissolved in 381 ml of water. The mixture was subsequently stirred for 1 hour at room temperature, diluted with water and the precipitate which had separated out was filtered of. After dissolving the product in methylene chloride, the solution was washed with sodium hydro~en carbonate solution and water, dried and evaporated. The residue was chromatographed on silica gel. 17.5 g of 3~--hydroxy-la-methyl-D-homo-5a-androstan-17~one were thus obtained.

16 g of 3~-hydroxy-la-methyl-D-homo-5a-androstan-17a-one were heated at reflux in 320 ml of absolutP tetrahydrofuran with 22.5 g of copper-II bromide for 90 minutes while stirring.

~8Z68~

The copper-I bromide which had separated out was filtered off, the filtrate diluted with ether, washed with ammonium chloride solution and water, dried and evaporated. 19.5 g of 17~--bromo-3~-hydroxy-la-methyl-D-homo-5a-androstan-l7a-one were obtained.

19.5 g Of crude 17~-bromo-3~-hydroxy-la-methyl-D~homo--5a-androstan-17a-one were stlrred for 18 hours at 90C in 195 ml of dimethylformamide with 11.1 g of lithium carbonate and 13 g of lithium bromide. The mixture wa9 then precipitated in ice-water and the precipitate was filtered off, washed with water, taken up in methylene chloride, dried and evaporated.
The residue was chromatographed on silica gel and there were obtained 11.5 g of 3~-hydroxy-la-methyl-D-homo-Sa~androst-16--en-17a-one; W ~223 760 -lS 11 g of 3~-hydroxy-la-methyl-D-homo-5a-androst-16-en-17a--one in 44 ml of pyridine were left to stand for 18 hours at room temperature with 22 ml of acetlc anhydride. After precipitation in ice-water, the preclpitate was fil~ered off, thoroughly washed out and dried. There were obtalned 11.2 g of 3~-acetoxy-la-methyl-D-homo-5~-androst-16-en-17a-one;
W ~223 = 7200.

11 g of 3~-acetoxy-la-methyl-D-homo-Sa-androst-16-en-17a--one in 110 ml of absolute tetrahydrofuran were treated with 22 g of lithium tri-tert.butoxyalanate while coollng with ice and the mixture was subsequent}y stirred fox 4 hours whiIe cooling with ice. The solution was diluted with ether, washed with dilute sulphuric acid and water, dried and ~ 31 -- : - . ~ .

1082~B6 evaporated. The resldue was chromatographed on silica gel and 8.5 g of 3~-acetoxy-17a~-hydroxy-la-methyl-D-homo-5a--androst-16-ene were obtained.

8.5 g of 3~-acetoxy-l7a~-hydroxy-la-methyl-D-homo-5a S -androst-16-ene in 85 ml of absolute tetrahydrofuran were stirred for 1 hour at .room temperature wlth 8.5 ml of ~,3--dihydro-4H-pyran and 1 drop of phosphorus oxychloride. The mixture was then diluted with ether, washed with saturated sodium hydrogen carbonate solution and water, dried and evaporated. 9.7 g of 3~-acetoxy-la-methyl-17a~-tetxahydro--pyranyloxy-D-homo-5a-androst-16-ene were obtained.

9.5 g of 3~-ac~toxy-la-methyl-17a~-tetrahydropyranyloxy--D-homo-5a-androst-16-ene in 95 ml of methanol and 9.5 ml of water were heated at reflux for 1 hour with 4.75 g of potassium lS carbonate. The mixture was precipitated in ice-water and the precipitate was filtered off, washed and taken up in methylene chloride. After drying and evaporation, 8.1 g of 3~-hydroxy-la-methyl-17a~-tetrahydropyranyloxy-D-homo-5a--androst-16-ene were obtained.
; ~
Exam~le 18 , 7 g of la-methyl-17a~-tetrahydropyranyloxy-D-homo-5a--androst-16-en-3-one in 70 ml of methanol and 7 ml of water ; were heated at reflux for 30 minutes with 3.5 g of oxalic acid. After precipitation with ice-water, the precipitate was filtered off, w~shed and aken up in methylene chloride.
After drying and evaporat~on, the residue was chromatographed on silica gel. Upon recrystallisation from diisopropyl ether, 3.2 g of 17a~-hydroxy-la-me~hyl-D-homo-5a-androst-16--en-3-one of melting point 189-191C were obtained.

Claims (22)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1) A process for the manufacture of D-homosteroids of the general formula I

wherein the broken lines in the A-ring denote optional carbon-carbon bonds; R1 represents a hydrogen atom or a methyl group; R3 represents an oxo group or, when the A-ring is unsaturated, an oxo, (.alpha.-H, .beta.-OH) or (.alpha.-H, .beta.-O-acyl) group;
R7 represents a hydrogen atom or a methyl group; R17a.beta. represents a hydrogen atom or a C1-10 alkyl, benzyl, cyclohexyl-methyl, acyl, tetrahydropyranyl or cycloalkenyl group; and R17a.alpha. represents a hydrogen atom or a lower alkyl, ethynyl, vinyl or propadienyl group, which process comprises (a) oxidising the 3-hydroxy or 3-hydroxy-.DELTA.5 grouping in a D-homosteroid of the general formula (II) ,wherein R1, R17a.beta. and R17a.alpha. have the significance given above and the broken line in the 5,6-position denotes an optional carbon-carbon bond, to the 3-keto or 3-keto-.DELTA.4 grouping, or (b) reacting a D-homosteroid of the general formula (III) , wherein R1 R3 and the broken lines in the A-ring have the significance given above, with an organometallic compound yielding a R17a.alpha. group, a 3-keto group being intermediately protected, or (c) reacting a D-homosteroid of the general formula (IV) , wherein R1 R17a.alpha. and R17a.beta. have the significance given above, with a methyl Grignard compound in the presence of copper-I
chloride, or (d) reacting a D-homosteroid of the general formula (V) , wherein R17a.alpha. and R17a.beta. have the significance given above and the broken line in the 5,6-position denotes an optional carbon-carbon bond, with a methyl Grignard compound in the presence of copper-I
chloride and subsequently rearranging a .DELTA.5 double bond in the reaction product into the 4,5-position by acid treatment, or (e) acylating the hydroxy group(s) in a D-homosteroid of formula I in which at least one hydroxy group is present in the 3-position or 17a.beta.-position, or (f) subjecting a D-homosteroid of the general formula (VI) , wherein R3 and the broken lines in the A-ring have the significance given above and Z represents an oxo or (OR17a.beta., R17a.alpha.) group, to reduction of the 17a-keto group to the hydroxy group (with intermediate protection of a 3-keto group) when Z
represents an oxo group or to reduction of the 3-keto group and a 17a-keto group which may be present to the hydroxy group when R3 represents an oxo group and the A-ring is monounsaturated, or (g) subjecting a D-homosteroid of formula I which is saturated or monounsaturated in the A-ring and in which R3 represents an oxo group to dehydrogenation in the 1,2-position and/or 4,5-position, or (h) converting the 17a.beta.-hydroxy group in a D-homosteroid of formula I in which R17a.beta. represents a hydrogen atom and R1, R3, R7, R17a.alpha. and the broken lines in the A-ring have the significance given above into a cycloalkenyl, tetrahydro-pyranyl, C1-C10 alkyl, benzyl or cyclohexylmethyl ether, or (i) subjecting a D-homosteroid of formula I in which R17a.beta. represents an acyl, tetrahydropyranyl or cycloalkenyl group and R1, R3, R7, R17a.alpha. and the broken lines the A-ring have the significance given above to saponification of a 17a.beta.-acyloxy group and a 3-acyloxy group which may be present or to cleavage of a 17a.beta.-tetrahydropyranyl or cycloalkenyl ether, or (j) hydrogenating the ethynyl group in a D-homosteroid of the general formula (VII) , wherein R1, R3, R7, R17a.beta. and the broken lines in the A-ring have the significance given above, to the vinyl group.

2) A process according to claim 1, wherein there is manu-factured a D-homosteroid of formula I in which R17a.beta. rep-resents a hydrogen atom or an acyl, tetrahydropyranyl or cycloalkenyl group.

3) A process according to claim 1 wherein there is manufactured a D-homosteroid of formula I in which R1 represents a hydrogen atom, R3 represents an oxo group and the A-ring contains a double bond.

4. A process according to claim 1, _ wherein there is manufactured a D-homosteroid of formula 1 in which R17a.alpha. represents a hydrogen atom or a methyl or ethyl group and R17a.beta. represents a hydrogen atom or a lower alkanoyl group.

5. D-Homosteroids of the general formula I

wherein the broken lines in the A-ring denote optional carbon-carbon bonds;
R1 represents a hydrogen atom or a methyl group; R3 represents an oxo group or, when the A-ring is unsaturated, an oxo, (a-H, .beta.-OH) or (.alpha.-H, .beta.-O-acyl) group; R7 represents a hydrogen atom or a methyl group; R17a.beta. represents a hydrogen atom or a C1-10 alkyl, benzyl, cyclohexyl-methyl, acyl, tetrahydro-pyranyl or cycloalkenyl group; and R17a.alpha. represents a hydrogen atom or a lower alkyl, ethynyl, vinyl or propadienyl group, when manufactured by a process as claimed in claim 1 or by an obvious equivalent thereof.

6. D-Homosteroids of formula I given in claim 5, wherein R17a.beta. repre-sents a hydrogen atom or an acyl,tetrahydropyranyl or cycloalkenyl group, whenever prepared by the process as claimed in claim 2 or by an obvious equivalent thereof.

7. D-Homosteroids as set forth in claim 5, wherein R1 represents a hydrogen atom, R3 represents an oxo group and the A-ring contains a double-bond, whenever prepared by the process as claimed in claim 3 or by an obvious equivalent thereof.

8. D-Homosteroids as set forth in claim 5, wherein R17a.alpha. represents a hydrogen atom or a methyl or ethyl group and R17a.beta. represents a hydrogen atom or a lower alkanoyl group, whenever prepared by the process as claimed in claim 4 or by an obvious equivalent thereof.

9. A process according to claim 1(f) for the manufacture of 17a.beta.-hydroxy-D-homoandrosta-4,16-dien-3-one which comprises subjecting D-homoandrosta-4,16-dien-3,17a-dione to a reduction with intermediate protection of the 3-keto group using pyrrolidine.

10. A process according to claim 1(e) for the manufacture of 17a.beta.-propionoxy-D-homoandrosta-4,16-dien-3-one which comprises acylating 17a.beta.-hydroxy-D-homoandrosta-4,16-dien-3-one with propionic anhydride.

11. A process according to claim 1(f) for the manufacture of 3.beta., 17a.beta.-dihydroxy-D-homoandrosta-4,16-diene which comprises reducing D-homoandrosta-4,16-dien-3,17a-dione.

12. A process according to claim 1(f) for the manufacture of 17a.beta.-hydroxy D-homo-5.alpha.-androst-16-en-3-one which comprises reducing D-homo-5.alpha.-androst-16-ene-3,17a-dione.

13. A process according to claim 1(e) and 1(g) for the manufacture of 17a.beta.-acetoxy-D-homoandrosta-1,16-dien-3-one which comprises acetylating l7a.beta.-hydroxy-D-homo-5.alpha.-androst-16-en-3-one and dehydrogenating the obtained acetate in the 1,2-position.

14. A process according to claim 1(a) for the manufacture of 17a.beta.-hydroxy-17a.alpha.-methyl-D-homo-androsta-4,16-diene-3-oone which comprises oxidizing 3.beta.,17a.beta.-dihydroxy-17a.alpha.-methyl-D-homoandrosta-5,16-diene.

15. A process according to claim 1(f) for the manufacture of 3.beta., 17a.beta.-dihydroxy-17a.alpha.-methyl-D-homoandrosta-4,16-diene which comprises reducing 17a.beta.-hydroxy-17a.alpha.-methyl-D-homoandrosta-4,16-dien-3-one.

16. 17a.beta.-Hydroxy-D-homoandrosta-4,16-dien-3-one whenever prepared by the process of claim 9 or an obvious chemical equivalent thereof.

17. 17a.beta.-Propionoxy-D-homoandrosta-4,16-dien-3-one whenever prepared by the process of claim 10 or an obvious chemical equivalent thereof.

18. 3.beta., 17a.beta.-Dihydroxy-D-homoandrosta-4,16-diene whenever prepared by the process of claim 11 or an obvious chemical equivalent thereof.

19. 17a.beta.-Hydroxy-D-homo-5.alpha.-androst-16-en-3-one whenever prepared by the process of claim 12 or an obvious chemical equivalent thereof.

20. 17a.beta.-Acetoxy-D-homoandrosta-1,16-dien-3-one whenever prepared by thc process of claim 13 or an obvious chemical equivalent thereof.

21. 17a.beta.-Hydroxy-17a.alpha.-methyl-D-homo-androsta-4,16-diene-3-one whenever prepared by the process of claim 14 or an obvious chemical equivalent thereof.

22. 3.beta.,17a.beta.-Dihydroxy-17a.alpha.-methyl-D-homoandrosta-4,16-diene whenever praparad by the process of claim 15 or an obvious chemical equivalent thereof.