NO761308L - - 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-

• -YES,:. 1. 3 tative C-C bonds; R is hydrogen or methyl; R oxo or, in case ring A is unsaturated, oxo, (a-H,p-OH) or"(a-H, p-O-acyl); R<7>hydrogen or methyl; R17aP hydrogen, acyl, tetrahydropyranyl or cycloalkyl;

and R<J>"<7aa>hydrogen, lower alkyl, ethynyl, vinyl or propadienyl.

The term "acyl" shall particularly denote organic acid residues, e.g. residues of lower (up to containing 7 C atoms) alkane carboxylic acids1 such as 'acetic acid, propionic acid, caproic acid, valeric acid, onantic acid; or oxalic acid, succinic acid, citric acid; or residues of aromatic carboxylic acids such as benzoic acid, phenylacetic acid or phenolic acetic acid; or heterocyclic carboxylic acids such as nicotinic acid; j.ell.er: xcycloaliphatic carboxylic acids such as cyclopentylpropionic acid iir i. -V. K^..:c

Lower alkyl esters can contain up to 7 C atoms and be straight-chain or branched. Examples of this are methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. The preferred lower alkyl esters are methyl and ethyl.

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

A preferred connecting group within formula I is de

13

compounds in which R is hydrogen and R is oxo and the ring A contains a double bond. Furthermore, such compounds with formula I are preferred, in which R<*7aa> is hydrogen, methyl or

ethyl and R<17a>^ 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,

17ap-propionoxy-D-homo-androsta-1,4,16-trien-3-one,

17α-hydroxy -7α-methyl-D-homo-androsta-1,4,16-trien-3-one,

1α,7α-dimethyl-17αβ-hydroxy-D-homo-androsta-4,16-dien-3-one,

17α-hydroxy-7α-methyl-D-homo-androsta-4,16-dien-3-one,

17a(3-hydroxy-7a-methyl-D-homo-5a-androst-16-en-3-one,

17α-hydroxy-7α-methyl-D-homo-5-androsta-1,16-dien-3-one,

17a|3-hydroxy-1-methyl-D-homo-androsta-1,16-dien-3-one,

1a,17aa-dimethyl-D-homo-androsta-4,16-dien-3-one,

3(3,17a(3-dihydroxy-17a-methyl-D-homo-5a-androsta-1, 16-diene,

17a(3-hydroxy-17a-methyl-D-homo-5a-androsta-1, 16-dien-3-one,

17a(3-hydroxy-1a, 17a-methyl-D-h6mo-5a-androst-16-en-3-one,

17αp-hydroxy-17α-ethyl-D-homo-5α-androst-16-en-3-one,

17aa-ethyl-17a-hydroxy-1a-methyl-D-homo-5a-androst-16-en-3-one,

17a(3-hydroxy-1a-methyl-D-homo-5a-andros t-16-en-3-one,

17a(3-hydroxy-7a, 17a-dimethyl-D-homo-androsta-4,16-dien-3-one.

According to the invention, the D-homosteroids of formula I can be obtained by • -

a) in a D homosteroid of formula

. „1 „17aR „17aa , , ., ^ , .

in which R , R M and R have the stated meaning and 5

-the double bond is facultative» oxidizes the 3-hydroxy-respectively 3-hydroxy-Zf grouping to the 3-keto-respectively 3-ketoZ^ grouping, or that one

b) reacts a D homosteroid with the formula

in which R 1 , R 3 and the dashed lines in the A ring have

the stated meaning,

under intermediate protection of a 3-keto group with an organometallic compound which releases the residue R^"7aa, or that one

c) reacts a D homosteroid with the formula

wherein R17atI and R<17aP> have the indicated meaning

with a methyl-grignard compound in the presence of copper I chloride, or that one

d) reacts a compound of formula

wherein R and R have the indicated meaning and /\

double bondfl is optional,

with a methyl-grignard compound in the presence of copper I chloride and then rearranges a ^-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-homosteroid of formula I, wherein at least one hydroxy group is present in

The 3 or 17a position or that one

f) in a D homosteroid with the formula

wherein R 3 and the dotted lines have the aforementioned meaning and Z is oxo or (0R<1>7a^,R17aa), when Z is oxo reducing the 17a-keto group under intermediate protection of a 3-keto group to the hydroxy group or, when R 3 forms o<*>kso and the A ring is singly unsaturated, =..-*• reduces the 3-keto group and a possibly present 17a-keto group to a hydroxy group, or that one

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

or the 4.5 position or that one

h) in a D homosteroid of formula I in which R^"<7a>^ constitutes hydrogen and R^, R<7>, R"^<7aa>and the dashed lines in the A ring

. has the stated meaning, transfers the 17a-hydroxy group in a cycloalkenyl or tetrahydropyranyl ether, or that one

i) in a D homosteroid of formula I in which R<*>"<7a>^ constitutes

1 3 7 acyl, tetrahydropyranyl or cycloalkenyl and R , R , R , R<17aa>Qg ^e dotted lines in the A ring have the indicated meaning saponify the 17a-acyloxy group and a possibly present 3-acyloxy group or cleave a 17a- tetrahydropyranyl or -cycloalkenyl ether, or that one j) in a D-homosteroid with formula

in which R<1>, R<3>, R7, R17aP and the dashed lines in the A ring have the meaning,

hydrogenates the ethynyl group to the vinyl group.

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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 Jones reagent); or according to Pfitzner-Moffatt

with the help of dimethylsulfoxide/dicyclohexylcarbodiimide (whereby the primarily obtained ^4<5->3-ketone must subsequently isomerise to the /\4-3-ketone) or carried out with the help of dimethylsulfoxide/pyridine/SO^.

The reaction of the R"<L7a->keto group in a compound of formula II

with an organometallic compound according to a process variant

b) can also be carried out in a known manner. The organomethyl compound may be a Grignard compound (e.g. ethynyl magnesium bromide, methyl magnesium bromide, vinyl magnesium bromide)

or an alkali metal organic compound such as sodium, potassium or lithium acetylide, or vinyllithium. A simultaneously present 3-keto group can be intermediately protected, for example as a ketal, enolet, enamine or semicarbazone.

The 6-methylation of a compound of formula IV and the 1-methylation of a compound of formula V according to the process variants

c) and d) can likewise be carried out in a known manner by reaction with a methyl Grignard compound. Thereby, first one is obtained

la-methyl -compound', if/\^-double bond on treatment

i with ethanolic sulfuric acid under heating can be rearranged in the 4,5 position.

The acylation of a 3- or 17a-standing free hydroxy group i

a D-homosteroid of formula I can be carried out in treatment

with a reactive acid derivative, e.g. an acid halide or acid anhydride in the presence of a base such as pyridine or collidine.

The reduction of a 3- or 17a-keto group according to process variants f) or j) can be carried out in a known manner using complex metal hydrides, e.g. di(lower alkoxy)aluminum hydrides such as diisobutylaluminum hydride, tri-(lower alkoxy)aluminum such as triisopropoxyaluminum; lithium aluminum hydride;

sodium aluminum hydride or sodium borohydride; or trimmed-

oxy- or tributoxylithium 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 in the presence of a 4,5-double bond can 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 process 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 done microbiologically, for example with the help of schizpmycetes, especially those of the Arthrobacter species, e.g. A. simplex ATCC 6946; bacillus, e.g.

B. lentus ATCC 13805 and B. spherikus ATCC 7055; pseudomonas, e.g. P. aeruginosa IFO 3505, flavobacterium, e.g. flavens-cens IFO 3058; lactobacillus, e.g. L. brevis IFO 3345 and ' nocardia, e.g. N. opaque ATCC .4276.

Double bonds in the .1,2 and 4,5 position can be introduced simultaneously

by bromination to 2,4-dibromo3-ketone and dehydrobromination to the latter using lithium carbonate and lithium bromide in

dimethylformamide. A 4,5-double bond can also be introduced

thereby brominating a saturated 3-keto steroid in the A ring

in glacial acetic acid to the 2a,4a-dibromo derivative and reduces this by

chromium II chloride to the 4a-tro m compound. The last connection

■can then dehydrobromate the semicarbazone by treatment \

by succinic acid to the Z_f-3 ketone.

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

h) can happen e.g. by treatment with dehydropyran (for the production 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.

The saponification of 17a- and 3-acyloxy groups. respectively 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

are decomposed using aqueous alcoholic mineral acids or organic acids such as oxalic acid or p-coluenesulfonic 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 methods described below.

The compounds of formula I have a hormonal effect. Compounds of formula I in which R<17aa> is hydrogen or lower alkyl are particularly androgenic/anabolically active. Compounds of formula I in which R<17aa> is ethynyl, vinyl or propadienyl are particularly progestogenic

and ovulation-inhibiting agents.

For example, the 17aR-hydroxy-D-homo-androsta-4,16-dien-3-one showed, when subcutaneously applied to juvenile male rats, a similar androgenic activity to the effect of testosterone at a third part of the dosage. The androgenic activity was thereby determined by the growth of the prostate and seminal vesicles. 17aR-phenylacetoxy- and 17a(3-phenoloxyacetoxy-D-homo-androsta-4,16-dien-3-one showed a prolonged duration of action compared to testosterone onanthate when subcutaneously applied to juvenile male rats.

The process products can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations containing them in mixture in a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or patenteral application, such as e.g. 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 auxiliaries such as preservatives, stabilisers, thickeners or emulsifiers, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

Example 1

50.0 g of 3R-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 were evaporated, the solution 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 approx. 200 ml, poured onto an ice-cold solution of 1500 ml water and 50 ml concentrated hydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried with Na^SO^ and evaporated under vacuum, finally dried in high vacuum at 90°. The residue was then recrystallized from acetone-hexane. 40.7 g of pure D-homo-androsta-4,16-diene^3,17a-dione were obtained with smn. 193-194°.

Preparation of starting materials:

18.1 g of 3R-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 the mixture was heated for 18 hours under

backflow. The reaction mixture was cooled to 35°, filtered

and the residue well washed with chloroform. The combined filtrates were poured into 1.3 l of water containing 100 g of table salt 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 17a-bromo-3R-hydroxy-D-homo-androst-5-en-17a-one was obtained, 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-3R-hydroxy-D-homo-androst-5-ene-17a-

was added over the course of 20 minutes and the mixture boiled for 30 minutes under reflux. The reaction mixture was then cooled to 60° and the precipitate filtered off. The filtrate was poured on

a mixture of 1.25 1 water, 450 g ice and 170 g table salt. The

was extracted three times with methylene chloride. The extracts were washed with 1N hydrochloric acid and water, dried with magnesium sulfate and evaporated in vacuo. 14.7 g of crude product was obtained, which was dissolved in 170 ml of ethyl acetate and treated with a little activated charcoal. After filtration and settling 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 were thus obtained, m.p. 190-193°.

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 run 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°.

16.1 g of these enamides 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 then carefully mixed with 300 ml of wet ether. Then 40 ml of saturated Na2SO4 solution was added thereto, stirred for another 10 minutes and the precipitate filtered off. 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 17α(3-hydroxv-D-homo-androsta-4,16-dien-3-one could be eluted. SmD. 183-185°.

Example 3

A solution of 6.3 g of 17αR-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. The solvent was then removed in vacuo and the residue recrystallized from acetone-hexane. 6.0 g of pure 17αR-acetoxy-D-homo-androsta-4,16-dien-3-one were obtained, m.p. 165-.167°.

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

17aR-propionoxy-D-homo-androsta-4,16rdien-3-one,

m.p. 139-140°,

17αR-butyroxy-D-homo-androsta-4,16-dien-3-one,

m.p. 117-118°.

Example 4

A solution of 2.0 g of 17αR-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 neutral with dilute hydrochloric acid, NaHCO 3 solution and water, dried with Na 2 SO 3 and evaporated in vacuo. The residue was chromatographed over silica gel. With hexane-acetone 9:1, 1.7 g of pure 17αR-phenylacetoxy-D-homo-androsta-4,16-dien-3-one were eluted, m.p. 135-136°

(acetone-hexane) o

Following the same method using the corresponding acid chloride was prepared: 17aR-heptanoyloxy-D-homo-androsta^4,16-dien-3-one;

25° o

oil-like, a = +88 (c = 0.1 in dioxane),

17aR-phenoxyaceoxy-D-homo-androsat-4,16-dien-3-one,

m.p. 174-176°.

Example 5

1.0 g of 17aR-hydroxy-D-homo-androsta-4,16-dien-3-one was dissolved 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 ^£30^ and evaporated in vacuo. The residue was recrystallized from ether-hexane and gave pure 17αR-tetrahydropyranyloxy-D-homo-androsta-4,16-dien-3-one, m.p. 137-138°.

E xample l 6

A solution of 2.0 g of 17aR-hydroxy-D-homo-androsta-4,16-dien-3-one in 40 ml of cyclopentahone 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 aluminum oxide act. II. But benzene 1.2 g of pure 17aR-cyclopentenyloxy-D-homo-androsta-4,16-dien-3-one could be isolated. Temp. 135-137° (methanol), tojp<5>° = +100°. (c - 0.1 in dioxane). UV spectrum:<cf>240<=>17200.

Example 7

A solution of 342 mg of 17aR-acetoxy-D-homo-androsta-4,16-dien-3-one and 328 mg of 2,3-dichloro-5,6-dicyano-benzo-quinone (DDQ) in 30 ml of benzene was heated 24 hours under reflux. The solution

was cooled and filtered through a soyle of 10 g aluminum oxide act. II. The soil was finally completely eluted with

200 ml ethyl acetate. The combined eluates gave 270 mg of crystalline material which recrystallized from acetone-hexane gave pure 17αR-acetoxy-B-homo-androsta-,1,4,16-trien-3-one. Temp. 222-

According to this method, from 17a(3-hydroxy-17a-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 prepd.

Smn. 148-150°.

Example 8

A solution of 342 mg of 17aR-acetoxy-D-homo-androsta-4,16-dien-3-one and 328 mg of 2,3-dichloro-5,6-dicyano-benzoquinone in 30 ml of benzene was heated under reflux for 24 hours . The solution was . cooled and filtered through a soyle of 10 g aluminum oxide act. II. The soil 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 17αR-acetoxy-D-homo-androsta-1,4.16-trien-3-one. Temp. 222-224°,

Example 9

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, 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 ^£50^ solution. 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 yielded 4.1 g of pure 3(3,17αR-dihydroxy-D-homo-androsta-4,16-diene, m.p. 158-162° (acetone-hexane).[a]^ 5° = +23° (c = 0.1 in dioxane).

A solution of 3.0 g of 3R,17aR-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 3R,17aR-diacetoxy-D-homo-androsta-4,16-diene was obtained, m.p. 115-116°.

Example 10

o

A solution of 7.0 g of 3,3-dimethoxy-D-homo-5a-androst-16-en-17a-one 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 500 ml of water. Mon

filtered off the precipitate. This was for cleansing

chromatographed "over 50 times the amount of silica gel. With methylene chloride-acetone 95:5, 5.0 g of pure 17αR-hydroxy-D-homo-5α-androst-16-en-3-one could be obtained.

Temp. 203-205° (acetone-hexane), [α}^<5>= +1° (c = 0.1 in dioxane).

Starting material was prepared as follows: 3R-acetoxy-D-homo-androst-5-en-17a-one was reduced in ethanol with. Pd/C as a catalyst for 3R-acetoxy-D-homo-5a-androstan-17a-one, m.p. 113-115°. This was brominated with copper bromide in methanol and transferred by treatment with calcium carbonate in dimethylacetamide into 3R-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° (6~223= 8700)• The reaction of this compound with methanol and catalytic amounts of p-toluenesulfonic acid at reflux temperature finally gave 3,3-dimethoxysv-D-homo-5a-androst-16-en-17a-one. sitting time 125-127° (ether-hexane).

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-homo-5a-androst-16-en-17a-one was added with stirring over the course of 30 minutes in 20 ml of tetrahydrofuran and 20 ml of ether. The solution was stirred overnight at room temperature and then worked up as usual. 3.2 g of crude product was obtained which was dissolved in 50 ml of acetone also 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 17αR-hydroxysv-17α-methyl-D-homo-5α-androst-16-en-3-one. smn. 211-

Example 12

2.0 g of 17αR-hydroxy-D-nomo-5α-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 of dioxane and, after the addition of 3 drops of 40% HBr glacial acetic acid, the solution was mixed with a solution of 0.36 ml of bromine over the course of 30 minutes. 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 vacuo 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 the calcium salts filtered off. 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 amount of silica gel. With methylene chloride, 1.2 g of pure 17αR-acetoxy-D-homo-androsta-yl, 16-dien-3-one could be eluted. Temp. 133-135°.

Example 13

To 60 ml of a 1.2-molar lithium methyl solution in ether, a solution of 2.5 g of 3R-acetoxy-D-homo-androsta-5,16-dien- 17a-one in 15 ml of tetrahydrofuran and 15 ml of ether. The reaction mixture was stirred overnight at room temperature, then poured onto 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, by recrystallization twice from acetone, gave pure 3R,17aR-dihydroxy-17a-methyl-D-homo-androsta-5,16-diene, m.p. 220-223°.

£<aj>25° = _169° (c = 0.1 in dioxane) .

From a solution of 1.5 g of 3(3, 17a(3-dihydroxy-17a-methyl-D-homo-androsta-5, 16-diene in 20 ml of cyclohexanone' and 55 ml of toluene, 10 ml of toluene was distilled off. Then was cooled 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. Normal processing

(see example 1) gave 2.7 g of crude product, which was chromatographed over silica gel. 1.2 g of pure 17αR-hydroxy-17α-methyl-D-homo-androsta-4,]6-dien-3-one were obtained. Temp. 152-154° (acetone-hexane) . UV: <?241= 16700. Ca]^<5>° = +18° (c = 0.1 in dioxane).

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Example 14

To a 0° cooled solution of 1.0 g of lithium aluminum hydride i

A solution of 2.0 g of 17a|3-hydroxy-17a-methyl-D-homo-androsta-4/16-dien-3-one in 100 ml abs. was added dropwise to 200 ml of ether. tetrahydrofuran and 100 ml abs. ether. After finishing the addition •

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(3,17aR-dihydroxy-17a-methyl-D-homo-androsta-4,16-diene could be obtained. Mp. 137-141°. Ia]^<50>= _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 3R-acetoxy-D-homo-androsta-5,16-dien-17a-one in 70 ml of tetrahydrofuran was added dropwise over the course of 1 hour, whereby a weak stream of acetylene was then passed through the reaction solution .. For work-up, 30 ml of ammonium chloride solution was added slowly and the ammonia was allowed to evaporate overnight. The reaction mixture was mixed with water and extracted with ether-methylene chloride. The organic extracts were washed with water, dried with Na9S0 and evaporated in vacuo. The residue was chromatographed over silica gel. But hexane-acetone 5:1 pure 17aa-ethynyl-3R-17α-dihydroxy-D-homo-androsta-5, 16-diene was eluted.

Temp. 227-229° (acetone-isopropyl ether). a 25. ° = -307 o(c =0.1

in dioxane).

1.1 g of 17aa-ethynyl-3R,17a-dihydroxy-D-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-hydroxy-D-homo-androsta-4,16-dien-3-oneT M.p. 247-250°.

UV: <°oon = 16800. [ali;5<=>-138° (c = 0.1 in dioxane).

fairy

Example number 16

649 mg 17aa-ethynyl-17a-hydroxy-D-homo-androsta-4,16-dien-3-

was dissolved in 40 ml of ethyl acetate and 5 ml of pyridine and after adding

addition of 300 ml of Pd/CaCO^ hydrogenated at normal pressure until 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. 17α|3-hydroxy-17α-vinyl-D-homo-androsta-4,16-dien-3-one was obtained with m.p. 120-122°.

i" 1 25° o

UV: f 240 = 16500-1-°"d = ~69 (c = 0.1 in dioxane).

Example 17

To 8 g of 3y-hydroxy-1a-methyl-17aR-tetrahydropuranyloxy-D-homo-5a-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-SO3~ complex in 64 ml of dimethyl sulphoxide and then stirred for 1 hour at room temperature. It is poured into ice water, the precipitate is filtered off, washed and taken up in ether. After drying and evaporation, 7.5 g of 1a-methyl-17aR-tetrahydropyranyloxy-D-homo-5a-androst-16-en-3-one are obtained.

Preparation of the starting material:

50 g of 17R-hydroxy-la-methyl-5a-androstan-3-one is heated in 1000 ml

IN

abs. benzene, 125 ml of ethylene ethylene glycol and 1.25 g of p-toluenesulfonic acid for 7 hours under stirring in a water separator at reflux. The reaction solution is then diluted with ether, washed with sodium bicarbonate solution and water, dried and evaporated to dryness. 55 g of 3,3-ethylenedioxy-17R-hydroxy-1a-methyl-5a-androstane are obtained. 55 g of 3,3-ethylenedioxy-17R-hydroxy-la-methyl-5a-androstane in 550 ml of toluene and 110 ml of cyclohexanone at the boiling point are mixed with a solution of 5.5 g of aluminum isoproylate in 55 ml of toluene and heated for 3 hours by slow distillation . It is then mixed with ether,

washed with ice-cold diluted syovellic 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-5a-androstan-17-one with m.p. 155.5-156.5°.

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

1000 ml of dimethylformamide with 51 g of trimethylsulfonium iodide and, with stirring, introduce over 30 minutes 27.2 g of potassium tert.-.

butylate in portions. 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 evaporation, the residue is chromatographed on silica gel. One obtains

thus 36.6 g of 3,3-ethylenedioxy-1-methyl-5a-androstane (17((3-11 )

-spiro-35 oxirane. A sample recrystallized from diisopropyl-

ether melts at 165.5-166.5°.

36.6 g of 3,3-ethylenedioxy-loc-methyl-5a-androstane [17.((3-1')-spira-

st oxirane is mixed in 366 ml of dimethylformamide and 145 ml of water with 41.3 g of sodium azide and stirred for 3 hours at 110°. It is then stirred into ice water, the precipitate that has formed is filtered off, washed with water and taken up in methylene chloride. After evaporation, 38 g of 3,3-ethylenedioxy-17a-azidomethyl-17R-hydroxy-la^methyl-5a-

androstane.

38 g of 3,3-ethylenedioxy-17a-azidomethyl-17R-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 in . with water, dried and evaporated. As a residue, 29.5 g of 17a-azidomethyl-17R-hydroxy-1a-methyl-5a-androstan-3-one are obtained.

29 g of lithium alanate are suspended in 350 ml of abs. tetrahydrofuran and

a solution of 29 g of 17a-azidomethyl-17R-hydroxy-1a-methyl-5a-androstan-.3-one in 350 ml abs tetrahydrofuran is added dropwise while cooling and stirring. Then stir 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% sodium bicarbonate and 94 ml of water. The residue is filtered off, washed with ether and extracted completely in the beaker with ether. The aspirated filtrate is then combined with the extraction solution, evaporated and 27.5 g of 17a-aminomethyl-k3,17R-dihydroxy-1a-methyl-5a-androstane are obtained.

27 g 17a-aminomethyl-3^, 17(3-dihydroxy-1a-methyl-5a-androstane

dissolve in 558 ml of acetic acid and 558 ml of water and mix slowly under ice-cooling with 48.5 g of sodium nitrite dissolved in 381 ml of water. Then stir for 1 hour. At room temperature, dilute with water and filter off the precipitate. After dissolving in methylene chloride, wash with sodium bicarbonate solution and water, dry and evaporate. The remainder is chromatographed over silica gel. 17.5 g of 3^-hydroxy-1-methyl-D-homo-5a-androstan-17-one are thus obtained.

16 g of 3^-hydroxy-la-methyl-D-homo-5a-androstan-17a-one is heated in

320 ml abs. tetrahydrofuran with 22.5 g of copper II bromide 90 minutes under reflux stirring. It is filtered off from separated kdpper-I bromide, diluted with ether, washed with ammonium chloride solution and water, dried and evaporated. 19.5 g of 17-bromo-35-hydroxy-1-methyl-D-homo-5a-androstan-17a-one are obtained.

19.5 g of crude 17j-bromo-3j-hydroxy-la-methyl-D-homo-5a-androstan-17a-one is stirred in 195 ml of dimethylformamide with 11.1 g of lithium carbonate and 13 g of lithium bromide for 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 3j-hydroxy-1-methyl-D-homo-5a-androst-16-en-17a-one is obtained.

UV: ^223= 7600. 11 g of 3j-hydroxy-la-methyl-D-homo-5a-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 ice water precipitation, the precipitate is filtered off, washed well and dried. 11.2 g of 3-acetoxy-1-methyl-D-homo-5a-androst[16-ene 17a-one are obtained.

UV: e223 = 7200. 11 g of 3^-acetoxy-la-methyl-D-homo-5a-androst-16-en-17a-one are mixed in 110 ml abs. tetrahydrofuran under ice-cooling with 22 g of lithium tri-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-17a(3-hydroxy-1a-methyl-D-homo-5a-androst-16-ene are obtained.

8.5 g of 3^-acetoxy-17aR-hydroxy-1a-methyl-D-homo-5a-androst-16-

one is stirred in 85 ml 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 3β-acetoxy-1α-methyl-17αR-tetrahydro-pyranyloxy-D-homo-5α-androst-16-ene are obtained.

9.5 g of 3^-acetoxy-1a-methyl-17aR-tetrahydropyranyloxy-D-homo-5a-androst-16-ene are heated in 95 ml and 9.5 ml of water with 4.75 g of potassium carbonate for 1 hour at reflux. It is poured into ice water, the precipitate is filtered off, washed and taken up in methylene chloride.

After drying and evaporation, 8.1 g of 3^-hydroxy-1a-methyl-17aR-tetrahydro-pyranyloxy-D-homo-5a-androst-16-ene are obtained.

Example 18

7 g of 1a-methyl-17aR-tetrahydropyranyloxy-D-homo-5a-androst-16-en-3-one are 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 17aR-hydroxyl-methyl-D-homo-5a-androst-16-en-3-one are obtained with m.p. 189-191°.

Claims (1)

1) Method for the production of D-homosteroids with formula wherein the dashed lines in the A ring denote facultative C-C bonds; R means hydrogen or methyl; R 3 oxo or , in case ring A is unsaturated, oxo, (α-H,R-OH) or (α-H, R-O-acyl); R<7> hydrogen or methyl; R"*"7a^ hydrogen, acyl, tetrahydropyranyl or cycloalkenyl; and R17aa hydrogen, lower-alkyl/ ethynyl, vinyl or propadienyl, characterized in that mana) in a D homosteroid of the formula ; in which R1, R17aP and R<17aa> have the indicated meaning and the Z1.5-double bonds are facultative, oxidizes the 3-hydroxy-respectively the 3-hydroxy-Z^-grouping to the 3-keto-respectively 3-keto,Zf-grouping, or that one b) prepares a D-homosteroid with the formula ;13 in which R , R and the dashed lines in the A ring have the stated meaning, and under an infermedial protection of a 3-keto group. reacts with an organometallic compound which releases the residue R^7aa,c) reacts a D-homosteroid of formula ;, . _17aa _,l7a6 , ... , . where R and R r have the indicated meaning, with a methyl jrignard compound in the presence of copper I chloride, or that mand) reacts a compound of the formula ; in which R and R ^ have the indicated meaning and /\ the double bond is facultative, with a methyl Grignard compound in the presence of copper I chloride and then rearranges a zA\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 the 3- or 17a-position or that one f) in a D homosteroid with the formula ; in which R 3 and the dashed lines have the aforementioned meaning and Z constitutes oxo or (0R^"7a^, R^7aa) , when Z is oxo, the 17a-keto group is reduced to a hydroxy group under intermediate protection by a 3-keto group or, when R is oxo and the A ring is monounsaturated, the 3-ketb group and a possibly present 17a-keto group are reduced to a hydroxy group, or that one g) dehydrogenates a D-homosteroid saturated or monounsaturated in the A ring with the formula I in which R <3> is oxo in the 1,2- and/or 4,5-position or that one h) in a D homosteroid of formula I in which R^ <7a> ^ constitutes hydrogen and R , R , R7, R17aa and the dashed lines in the A ring have the indicated meaning, transfers the 17a-hydroxy group in a cycloalkenyl or tetrahydropyranyl ether , or that one i) in a D homosteroid of formula I in which R^ <7a> ^ is <or> acyl, tetrahydropyranyl or cycloalkenyl and R1, R3, R7, R <1> 7aa and the dashed lines in the A ring have the indicated meaning , saponifies the 17a-a^ cyloxy group and an optionally present 3-acyloxy group or cleaves a 17a-tetrahydropyranyl- or -cycloalkenyl ether, or that one j) in a D homosteroid with the formula ;in which R <1> , R <3> , R7, R173!3 and the dashed lines in the A ring have the meaning, hydrogenates the ethynyl group to the vinyl group.;2) Method according to claim 1, characterized in that compounds of formula I are prepared, in which R 1 is hydrogen and R in oxo and the ring A contains a double bond.;3) Method according to claims 1 or 2, characterized by preparing the compounds of formula I in which R^"7aau is hydrogen, methyl or ethyl and R^"<7a> ^ hydrogen or lower-alkanoyl.;4) . D homosteroids of formula I characterized in that they have a constitution as defined in claim 1.;5) D homosteroids of formula I according to the definition of constitution in claim 1, characterized in that R 1 is hydrogen and R 3 is oxo and ring A contains a double bond.;6) D-homosteroids of formula I according to the definition of the constitution in claim 1, characterized in that R 17 <aa> is hydrogen, methyl or ethyl and R"*"7a^ hydrogen or lower-alkanoyl. 7) Pharmaceutical preparations, characterized in that they contain a D-homosteroid of formula I according to the definition of constitution in claim 1.