Steroids and a process for the manufacture thereof

The invention relates to new steroids, which correspond to formula 1 (formula figures refer to the attached formula sheet), in which:

X1 and Xg1 independently represent hydrogen, fluorine, chlorine or bromine;

R is hydrogen, lower alkyl, cycloalkyl or acyl;

hydrogen;

R, hydroxyl or 3~hydroxyl and acyl, (lower alkyl), aryl(lower alkyl) and cycloalkyl derivatives thereof, 3-keto, 3-^^θ^ο A »

3-keto 5-keto-A^lo4j 3-keto Δ^{4 v}’^{6 * * * 3 and} '3-keto ^^k4·⁶ 'proposes;

Eg and R^ together with the carbon 2 of the steroid ring form a membered heteroaromatic ring, in which one hetero 7202984

- 2 10

35.

. τ λ 4 λ 4» 6 atom to the carbon atom 3., and/\ and represent its dehydroderivatives;

p_ hydrogen and, when R, 3-keto A^ or 3-keto A . representsγ 5 — represents, hydrogen, acylthio, lower alkylthio or mercapto representsto

The term acyl group used here and below refers to the acid residue of a saturated or unsaturated aliphatic, cycloaliphatic, araliphatic or aromatic carboxylic acid containing up to 20 carbon atoms. Examples of such acids are formic acid, acetic acid, propionic acid, butyric acid, cyclohexane carboxylic acid, oleic acid, palmitic acid, stearic acid, succinic acid, malonic acid, citric acid and benzoic acid.

The term alkoxy group includes aliphatic, cycloaliphatic or araliphatic groups having up to 20 carbon atoms. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, butoxy, tert-butoxy, cyclopentyloxy, cyclohexyloxy and benzyloxy. Alkyl groups are to be understood as meaning branched or unbranched hydrocarbon groups without multiple bonds having up to 20 carbon atoms; the term cycloalkyl group refers to a saturated hydrocarbon having at least one carbocyclic ring containing 3-8 carbon atoms. The term low is used to denote groups of up to 8 carbon atoms. The term heteroaromatic ring includes ring systems of aromatic character, wherein at least one member in the ring is not a carbon atom₀

Preferred compounds of formula 1 are those wherein both radicals represent and hydrogen or fluorine; R -4 acetyl, propionyl, methyl, ethyl or propyl; R_ hydrogen; R_n hydrogen and R₇ 3keto, 3-keto A or 3-keto A⁴ and Rg θη R^ together with the carbon atom 2 of the steroid ring represent a heteroaromatic ring as defined above, in particular an isoxazole ring. >

The compounds of formula 1 are obtained according to the invention in that

a) a methylene or halomethylene group on the 16.17-(double bond) of a steroid of formula 2, wherein

0 2 9 8 4 ^R2

R'

Rg and R'.

X_r Xg, hydrogen;

3-hydroxyl, 3~^hydroxy®n represents acyl, (lower alkyl), aryl(lower alkyl) and cycloalkyl derivatives thereof; together with carbon 2 of the steroid ring represent a 5-membered heteroaromatic ring with one heteroatom bonded to carbon 3, and

R'^y represents acyl, lower alkyl or cycloalkyl, adds or

b) a steroid of formula 3? in which

R'^y, Xl ^and Xg k°^venhave standing meaning and R^ 3-kotOj 3-keto /\4 or 3-k^et° A^4<6 represents with hydrazine or hydroxylamine turnover, or

c) an ether or ester bond at the 3~ and/or 17~ position of a steroid of formula la, wherein

Rg, Ry R'^yj A and Xg have the meaning above, splits, or \

d) oxidizes the 3-hydroxyl group of a steroid of formula Ib, wherein Χ,ρ Xg and R^y have the above meaning to a 3-keto group, or

e) a hydroxyl group in a steroid of formula lc, wherein Rg, Rj and Rjy have the above meaning and at least one hydroxyl group is in the 3 or 17 position, »

acylates or alkylates» or

f) a steroid of formula ld, wherein !5

S^y, X^ and'Xg have the above meaning in at least one of the positions l(2), 4(5) θη 6(7) dehydrogenates, or

g) a steroid of formula le, wherein

X^, Xg and R^y have the meaning above and the l'2-(double bond) is optional, reacts with hydrogen sulfide, a lower alkylthiol or an S-metal salt of a monothiocarboxylic acid, or

h) the acylthio group in a steroid of formula If, where ^f

X^, Xg and, R^y have the meaning above and the 1.2«(double 7202984

- 4 bond) is optional, hydrolyzes, or

i) the 1,2-(double bond) in a steroid of formula Ig, where

X, Xn and S,_ have the above meaning and one or both 1' 2 x?

of the double bonds represented by dashed lines are present selective hydrogenation

Compounds of formula 2 can be prepared from readily available 3-hydroxy-17-ketosteroids (hereinafter referred to as hydroxyketones), eg isoandrosterone, 3-hydroxy-androst 5-θθ*¹ 17-on etc», are prepared. The hydroxy ketones may be treated, for example, with an enolacylating agent such as, for example, isopropenyl acetate, in the presence of a strong acid, eg a mineral acid or an organic sulphonic acid. In this case, the hydroxyl group¹ at the carbon atom 3 S^e~acylated and the ketone in position 17 converted to the enolacylate.

Alternatively, a hydroxy ketone can be converted to the corresponding 17,17' dialkyl ketal by reaction with a ketalizing agent, eg a trialkyl orthomic acid ester, eg trimethyl or triethyl orthomic acid, in the presence of a mineral acid or an organic sulfonic acid. Elimination of the alcohol by heating with a strong acid affords the 17-enol ether. Desirably, the 3-hydroxyl group may be esterified prior to reaction in a conventional manner by treatment with an acylating agent, eg acetic anhydride or acetyl chloride, in the presence of a base, eg pyridine, or etherified by reaction with an alkylating agent as described below.

The hydroxy ketones can be converted to 3-ether 17-ketones by reaction with an alkylating agent, such as eg methyl iodide or benzyl chloride, in the presence of a strong base, eg an alkali metal hydride. The 17-ketone can then be converted to the enol ester by means of an acylating agent as described above. It may be desirable to first protect the 17-ketone group by conversion to a conventional hydrolyzable ketal group. This protecting group can then be removed after etherification of the 3-hydroxyl group.

0 2 9 8 4

The conversion of compounds of formula 2 into compounds of formula 1 according to process embodiment a) can be effected by methods which involve the addition of a methylene or halomethylene group to a double bond to form a cyclopropyl or halocyclopropyl condensed ring system are known in themselves»

For introducing the methylene group, a compound of formula II is used with a reactive dihalomethane, such as diiodo- or dibromoethane, in the presence of a zinc reagent, eg a zinc copper pair or dialkyl zinc, in an inert solvent, preferably an ether or dichloromethane, to . The reaction proceeds stereospecifically and yields cyclopropa/Ï6a.17ce_7 steroids of formula 1, wherein X^ and X₂ propose hydrogen, op.

To introduce a halocyclopropane ring, a monohalogen or dihalocarbene is added to the 16.17-(double bond) which can be formed in situ by a number of methods known per se. For example, difluorocarbene can be prepared in situ by pyrolysis of the sodium salt of chlorodifluoroacetic acid , preferably in a heated solution in an inert organic ether, e.g

in diethylene glycol dimethyl ether, prepare₀ The difluorocarbene prepared in situ in this manner reacts with a steroid of Formula 2 to form a compound of Formula 1, wherein X1 and X_nsuggest fluorine.

Processes for the preparation of monochlorocarbene, dichlorocarbene, monobromocarbene and dibromocarbene are also known.

One method consists in treating these carbenes in situ by treatment of an appropriately substituted di- or trihalomethane, such as eg chloroform, bromoform, methylene chloride or methylene bromide, with a strong base such as eg potassium tert-butylate. Another method consists in preparing the carbene from an appropriately substituted organomercury compound, such as phenylmercury trichloromethane. The carbenes thus prepared "react with the steroid of Formula II to form a compound of Formula I wherein one or both radicals X^ and X₂ . represent chlorine or bromine.

- 6 10

The 5-hydroxymethylene steroids of formula III (which exist in various tautomeric forms) can be prepared, for example, by condensing a compound of formula Id or its /\^~ or /\' derivative with an alkyl formate, such as ethyl formate, in the presence of a base, eg a metal alcoholate, are obtained. This method is preferably used when lower alkyl or cycloalkyl represents. When R1 is acyl, it is preferable to use a 3-ketal of r

treating a compound of formula Id with a Vilsmeier reagent (phosphorus oxychloride and N,N-dimethylformamide) and then cleaving the protecting group at the 3-position under aqueous-acidic conditions. The 17-ester group can be cleaved, if desired, as described below.

The reaction of compounds of the formula III with hydrazine yields in a manner known per se androstano^[ji2,-zJ-pyrazoles of the formula Ih, wherein

R' , X, and X? have the above meaning, and /\^~ and /\y°6derivatives thereof»

Reaction of compounds of formula III with hydroxylamine in the presence of acid affords androstano/2,3-d-7isoxazoles (formula Ii) and reaction with hydroxylamine in the presence of a base affords androstano/3·2-c-7isoxazoles (formula Ij),

ΔΑ

- and . fi . ή¹

6.derivatives thereof.

Other heteroaromatic systems condensed with the steroid ring in the 2.3 position can be prepared analogously by methods known per se. If desired, the above heteroaromatic compounds, wherein R'^y represents acyl, can be converted to the corresponding 17-hydroxy compounds.

According to embodiment c) of the process, the ester group on the carbon atom 3 of the steroid of formula la is selectively hydrolyzed by treatment with an aqueous base, such as eg alkali metal carbonate or alkali metal dicarbonate solution. On the other hand, the selective hydrolysis can also be carried out by treating compounds of formula la esterified in the 3-position with a

0 2 9 8 4 dilute aqueous mineral acid, eg, with dilute hydrochloric acid. Another method for the selective hydrolysis of the ester group at the 3-position consists in adding a steroid of the formula Ia to an activated surface, eg. » activated aluminum oxide, adsorbs»

If there is a benzyloxy or a substituted benzyloxy group on the 3~pl^aats, this group can be hydrogenolyzed to a hydroxyl group under the usual conditions, e.g. by means of hydrogen in the presence of a metal

<img file="NL7202984A_D0001.tif" />

can the ester group on the 3-pl^aacan be selectively hydrolyzed by treatment with an aqueous or an alcoholic base, such as, for example, an alkali metal hydroxide or carbonate. The 3-ester group can additionally be selectively hydrolyzed by reduction with a metal hydride, such as₀lithium aluminum hydride, are removed»

An acyloxy group. at the 3-position and/or 17-position can be hydrolyzed to the corresponding 17-ol or 3&lt;17-&lt;3.iol by treatment with an aqueous base or an aqueous mineral acid. Further methods for removing such groups consist in mixing a compound of formula la with a metal-organic compound and e.g a Grignard compound, such as tert-butylmagnesium chloride, treated or reduced with a metal hydride, such as lithium aluminum hydride.

The oxidation of a compound of formula (Ib (Embodiment d) of the process) can be carried out with the usual oxidizing agents such as, for example, chromium trioxide, potassium dichromate, potassium permanganate, etc. A preferred oxidizing agent is Jones's reagent (chromium trioxide-sulfuric acid). . The oxidation with chromium trioxide-pyridine is particularly preferred when E4 is lower alkyl or cycloalkyl.

<img file="NL7202984A_D0002.tif" />

0 2 9 8 4

<img file="NL7202984A_D0003.tif" />

is hydrogen, mild oxidizing agents such as cyclohexylbodiimide-dimethylsulfoxide can be selectively oxidized. The acying or alkylation of a free hydroxyl group of a compound formula Ic can be accomplished in a manner known per se.

Double bonds can be formed in the 1.2 and/or 4*5 and/or 6.7 position in a manner known per se with dehydrogenating agents, such as

eg DDQ (2,5-dichloro 5.6-dicyan 1,4-benzoquinone) may be introduced.

A

A /^-(double bond) can be in the presence of an A or

Δ⁶ -(double bond) selectively reduced by means of a soluble hydrogenation catalyst such as tris(triphenylphosphine)rhodium chloride, /L g e in the presence of hydrogen. A' ” - or

A ' '* 3-keto-steroids can be used with nucleophilic reagents, eg with

S-metal salts of monothiocarboxylic acids, with lower alkylthiols or hydrogen sulfide in compounds with a 7-^acyl1H10, lower alkylthio or mercapto group are converted. 7-E-®3?o^apphosteroids can be prepared by hydrolysis of the corresponding 7-acylthiosteroids.

The compounds of formula 1 have hormonal properties.

In particular, they have a high degree of anabolic and androgenic activity. Many compounds of formula I have such differentiation in anabolic and androgenic activity that they are particularly useful as anabolic agents. The compounds of formula 1 may be administered orally or parenterally. An approximate daily dose of a compound of Formula 1 for adults is about 2-20 mg.

The products obtainable according to the invention can be used as pharmaceuticals, eg in the form of pharmaceutical preparations, which these are mixed with a pharmaceutically, organically or inorganically inert carrier material suitable for enteral, percutaneous or parenteral administration, such as, for example, water, gelatin, &lt;» contain gum, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations may be in solid form, eg as tablets, dragees, suppositories, capsules; in semi-solid form, eg as ointments; or in liquid form, eg as solutions, suspensions or emulsions, available

0 2 9 8 4 run. Optionally they are sterilized and/or contain auxiliary materials such as preservatives, stabilizers, wetting agents or emulsifiers, salts to alter the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The following examples serve to illustrate the invention.

Example 1

To a solution of 2.9 g copper(II) acetate monohydrate in

29Ο cm° acetic acid was added while heating on a steam bath 195 g of granulated (20 mesh) zinc. The mixture was stirred for 4 minutes and the liquid was aspirated. The residue was washed with 290 ml of hot acetic acid and three times with 290 ml of room temperature ether. The resulting zinc-copper pair was covered with 290 ml of ether, then a solution of 230.8 g was added with stirring.

5f-androst 16-ene 3P(«17P-diol diacetate, 163 ml) (540 g) diiodomethane and 580 ml dichloromethane added as a slow stream. The reaction mixture was refluxed with stirring overnight. The organic phase and two di20 chloromethane washing solutions of the metal were shaken out with ice and a little 1 H hydrochloric acid. The organic phase and two dichloromethane washing solutions of the aqueous phase were combined, dried and evaporated. The residue, after recrystallization from dichloromethane-ether, yielded 64 g (68%) of 3'H-cyclopropa/Ï6a,17oc-5a-androsta 3P'173-8-ol-diacetate with m.p.₀ 185 ~ 188°0; /α/Ζρ· +25.26° (chloroform, c ~ 1.20).

Example II

One solution of 50 g of the diaacetate prepared in Example 1 in 500 ml of tetrahydrofuran was added with stirring over 40 minutes to a dispersion of_s10 g of lithium aluminum hydride in 500 3 cc of ether was added. The reaction mixture was refluxed for 1 hour, then cooled to room temperature, and then saturated sodium sulfate solution was carefully added thereto until the gray color disappeared and the separated inorganic-spacious layer was completely viscous. Be organic layer and a tetrahydrous 7.2 0 2 9 8 4 furan wash solution of. the aqueous residue was combined, dried and partially evaporated. The resulting dispersion was diluted with a little ether and filtered to give 35 ? 4 g (90^) 3'H-cyclopropa2Ï6a.17a-7 5a-androsta 3β.17β-άΐο1 in the form of colorless crystals, the melting point of which varied. Thin layer chromatography with 10% methanol in chloroform or 15% ethyl acetate in benzene showed the presence of a homogeneous material, /α_/_B +¹⁰?49 (tetrahydrofuran., c=1.202).

Example III

To 625 g of benzene-wetted alumina (activated chromatography grade, 80-200 mesh) was added a solution of 25 g of the diacetate prepared in Example 1 in as little benzene as possible. The resulting dispersion was mixed well and excess benzene was evaporated in a nitrogen stream. The aluminum oxide was again well mixed and allowed to stand at room temperature. After 2.5 days, the alumina was applied to a column of 450 g of benzene-wetted alumina. Elution with 505Ó ether in dichloromethane and ether gave 7? 78 g of crystalline material. Recrystallization wick methanol-water afforded 2.617 g of 3'H-cyclopropa/Ï6aol7a_7 5&lt;X-^androstan3p.17P-diol 17-acetate as colorless crystals with M.p₀ 142.5 - 144?5°8. Further recrystallization from ether gave an analytically pure preparation with m.p. 145.5 - 146.5 °C. +13?57° (chloroform, o = 1.157) '

Example IV

To a solution of 50 g of the di3,3 acetate prepared in Example 1 in 500 ml of tetrahydrofuran were added 500 ml of methanol and 10 ml of concentrated hydrochloric acid. The solution was stirred at room temperature and the course of the reaction was monitored by thin layer chromatography. After 7 hours, the amount of reaction product appeared to have reached a maximum. Then 11 cn 2 of pyridine was added. The reaction mixture was diluted with 500 ml of water and the methanol was removed under reduced pressure. The residue was diluted with water and the precipitate was filtered off, washed with water and sucked dry. The solid residue was washed with dichloromethane for several years, the washing solutions were combined. and concentrated. The residue thus obtained was dissolved in benzene and adsorbed on 230 g of silica gel. Elution with 10-30% ether in dichloromethane afforded fractions containing the desired product. Recrystallization from dichloromethane-methanol yielded the 12.39 g of 3'H-cyclopropa/Ï6a.17a_7 5ct'^a&amp;drostan 3β»17β-&amp;1ο1 17-acetate with mp » 138 - 142°C.

Example 7

A mixture of 98 3 5a-androstan 3β-ο1 17-one ethylene ketal, 21 g of a 50% dispersion of sodium hydride in mineral oil and

1 dm-1 dimethyl sulfoxide was stirred at room temperature for 30 minutes.

Then 65 µl of benzyl chloride was added, the reaction mixture was stirred overnight and then poured into 6 dl of ice water.

The resulting precipitate was filtered off and dissolved in dichloromethane. The solution was dried, concentrated and the residue was recrystallized from dichloromethane-ether. One obtained

95.6 S fTZ) 3P-benzyloxy 5cc-androstan 17-one-ethyleneketal with m.p.

153.5 - 155?5°C. Further recrystallization from dichloromethane-acetone gave an analytically pure preparation with mp 15155 153.5 °C. -15.4° (chloroform, c 1.08).

Example VI

A mixture of 102.2 g of the 33 benzyl ether prepared according to Example V, 1200 ml of methanol and 600 ml of dichloromethane was prepared in 3; a steam bath was heated to boiling point and 120 ml of 3 H hydrochloric acid was added thereto. The reaction mixture was heated further and was

3 minutes homogeneous. After a total of 19 minutes, the dichloromethane

- removed under reduced pressure, and the residue was diluted with water. The precipitate was filtered off and air dried to give 91.2 g (100$) 3β-1^θηζ7ΐο^χ7 5a-^androstan 17-one with M.p.

150.5 - 153.5°8. An analytically pure preparation was obtained by recrystallization from dichloromethane-methanol. m.p. 151.5 154°C. 68.9° (chloroform, c = 1.04).

Example VII

To a solution of 91.2 g of the 3,3 benzyl ether ketone prepared in Example 6 in 750 ml benzene and 35 cc isopropenyl acetate was added a solution of 0.85 ml concentrated sulfuric acid in 85 ml/ml isouropenyl acetate. The reaction mixture was allowed to sit for 24 hours. v hit, where 300 cc of solvent was allowed to distill off. Then 500 ml benzene was added, 400 cm. of which was again distilled off over 24 hours. The residue was filtered after cooling to room temperature with dichloromethane over 30 g of aluminum oxide. The light yellow viscous oil obtained after concentrating the eluate was dissolved in hexane and adsorbed on 600 g silica gel. Elution with 50 and 75% benzene in hexane gave fractions from which after crystallization from pentane 46 g (44%) 3P-benzyloxy 5&lt;X10 androst 16-ene 17-ol-acetate in the form of colorless crystals with mp 100-104°C. Recrystallization from ether-pentane gave an analytically pure preparation with mp. 100 1O2°C obtained.+23.3° (chloroform, c = 0.934)

Example VIII

To a zinc-copper pair prepared as described in Example I from 9.8 g of granulated zinc, 30 ml of ether and, over 15 minutes, a solution of 6.4 g of the benzyl ether prepared according to Example VII was added. enol acetate in 60 ml dichloro 3 methane and 8.43 ml diiodomethane. The reaction mixture was refluxed with stirring overnight, then cooled to room temperature and washed with 100 ml saturated ammonium chloride solution® The washing solution was extracted with dichloromethane and the combined organic phases washed with water, dried and concentrated® The residue was dissolved in pentane and adsorbed on 50 g of silica gel® Elue® ring with hexane gave little polar material, elution with benzene then the desired product(s) Crystallization from etherpentane afforded 1.67 g (²5%) 3P"benzyloxy 3 ^!H-cyclopropa/Ï6a. 17&lt;X-/5a-androstan IJ,S-ol-acetate as colorless crystals with Mp® 111.5-=--113.5°C. Recrystallization from pentane afforded an analytically pure preparation with Mp. 113.5 - 115.5°C® +11.9 (chloroform, c - 0.973)°

Example IX

12.4 g of the cyclopropaster oil prepared in Example VIII,

3 ^-

40 cm dichloromethane, 1 dm^J methanol and 1.13 S of ^ and 10%'s phl72 0 2 9 8 4

13 ladium cocatalysts were shaken under a hydrogen atmosphere at room temperature and under normal pressure. Within 30 minutes, 0.03 mol of hydrogen was taken up. Concentration of the catalyst-free solution gave a colorless crystalline residue which, after recrystallization from methanol, contains 7.77 g (79/) 3'H·cyclopropa/Ï6a.17cx.7 .alpha.-androstane. 142.5 - 145.5°^c yielded. Example X

A solution of 11.39 g of the zo cyclopropasteroid prepared in Example 9 in 500 ml of acetone was cooled to 30 and to this was added Jones's reagent (14.5 ml -1 ) dropwise until an orange coloration persisted. Excess Jones's reagent was destroyed by addition of isopropanol and the reaction mixture was filtered through a filter aid. The filter was washed several times with acetone and to the filtrate and the combined washings was added a little solid sodium bicarbonate and sodium sulfate. The solution was again filtered through a filter aid and then concentrated. The residue was recrystallized from dichloromethane-ether-hexane to afford 9.2 g (81/) 3'H-cyclopropa/Ï6oc.17a-75a-^ahdrostan 17β-ο1 3-oh-acetate in the form of colorless crystals with Snip &gt; 163.5 - 167°C. Further recrystallization from ether-hexane gave an analytically pure preparation with m.p. 165.5 - 167°C. +35.61° (chloroform, c = 1.177)o

Example XI

To a solution of 7.28 g of the androstan prepared according to Example 2 in 36 ml of dimethylsulfoxide, 36 ml of benzene and 1.92 ml of pyridine was added 0.96 ml of trifluoroacetic acid and then a solution of 14.85 g of dicyclohexylcarbodiimide in 20 cc of benzene added. The reaction mixture was stirred at room temperature for 2 days and then 600 cc of ether was added thereto. Then a solution of 6.5 g of oxalic acid in 60% of methanol was added, the mixture was stirred vigorously for 38 minutes and then filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried and put in under mild conditions. Z evaporates. To the residue were added 60 cnr pyridine and 3θ cnr acetic acid an7202984 hvdride. The reaction mixture was allowed to stand overnight at room temperature and then poured into 3 dm ice water. The oily precipitate was filtered through a filter aid and dissolved in dichloromethane. The solution was dried and concentrated and the residue was applied to a silica gel column with benzene. . Slugging with mixtures of hexane and benzene and with benzene yielded few polar species; elution with 5/ether in benzene gave 3'H-cyclopropa/lea. 17&lt;X__7 5d^_aadrostan 17β-ο1 3“'°ö^ace'fc^aa-'fc·

The yield after recrystallization from dichloromethane-hexane was 2 g.

Example XII

To a solution of 29.6 g of the androstandiol prepared according to Example II 33 in 225 ^C.I.A pyridine 225 ml propionic anhydride was added. The reaction mixture was kept at room temperature

3 stirred for days, then poured into 54 ml ice water and filtered. The precipitate was dissolved in dichloromethane, the solution was washed three times with water, dried and filtered through 45 g of silica gel. The eluate was concentrated and the residue was recrystallized from dichloromethane-ether-pentane. There was obtained 29.1 g (72fo) 3^!H-cyclopropa/Ï6a.17&amp;_7 5ff-^androstan 3P-17P-4iol dipropionate with Mp. 154.5 - 157.5°C, /5+4.79° (chloroform, o = 1.02). Example XIII

A solution of 29.1 g of the solution according to Example 3 was left

XII prepared dipropionate in 291 ml tetrahydrofuran, 291 ml methanol and 5.2 ml concentrated hydrochloric acid for 6 hours at room temperature and 5 hours in a refrigerator. The reaction mixture was neutralized by adding 6.2 ml pyridine to 100 ml. evaporated under reduced pressure, with 1 dm-⁵ water diluted and filtered. The solid was air dried, dissolved in benzene and adsorbed onto Tlorisil. Elution with 2/2 ether in dichloromethane afforded fractions containing the desired product. These fractions were combined and recrystallized from dichloromethane-hexane.^£: sad. 5.68 g (23[deg.] 3'H-cyclopropa/Ï6a,17a-75a-andrstan 3,17β-ϋο1,17-propionate were obtained in the form of clear crystals with

mp 180 - 182°C. /Ξ_/^ +14.21° (chloroform c = 0.9638).

0 2 9 8 4

- 15 Example XIV

To a solution of 5.3 g of the propionate obtained in Example 13 in 265 ml of Acetone and 35 of tetrahydrofuran at 2^pC added dropwise 5.9 ml Jones reagent. After that,

3 ml of isopropanol was added, the inorganic precipitate was filtered off, the solution was treated with a little sodium bicarbonate and dried over sodium sulfate. The solution was evaporated and the residue crystallized from ether. 2.8 g (55%) of 3'H-cyclopropa/T0 Cl 17a-7 5ct-androstan 17β-ο13-one-propionate was obtained in the form of colorless crystals of m.p. 130.5 - 133.5°C. /a_7p^ +36.0° (chloroform, c = 0.934) » ,

Example XV

A solution of 5.16 g of the ketoacetate described in Example 10 in 80 ml of tetrahydrofuran, 20 ml of water and 3.1 ml of concentrated hydrochloric acid was allowed to stand at room temperature for 16 days. The solution was poured into 1 dl of ice water and the precipitate was filtered off and dissolved in dichloromethane. The solution was washed with water, dried and concentrated. The crystalline residue was recrystallized from dichloromethane-ether to give

2.257 g 3'H-cyclopropa/Ï6a.17a_7 5&amp;-^androstan 17β-ο1 3--one, found to be homo3 on thin layer chromatography with 15% ethyl acetate in benzene. This material was dissolved in 23 ml of pyridine and 23 ml of propionic anhydride was added to the solution. After standing for 3 days at room temperature, the solution was poured into 5 cnr water, the precipitate was filtered off and dissolved in ether.

The solution was washed with water, dried and evaporated. The residue, after recrystallization from ether-pentane and finally from ether, gave 0.89 g of 3'H-cyclopropa/Ï6a.17a_75a~^androstan 17β-ο1 3-one-propionate with m.p. 129.5 - 132.5°C.

Example XVI

A mixture of 3.01 g of 5'H-cyclopropa/10a, 17(XJ 5a-^aa&lt;3.rostan 3 3

17β-ο1 3-one^acetate, 3θ cm^y p-toluenesulfonic acid and 6 ml of ethylene* glycol in 200 ml of benzene was refluxed for 45 minutes, the water resulting from the reaction azeotropically distilled off. The cooled solution was washed with dilute sodium bicarbonate solution, dried and evaporated. The colorless crystalline residue was recrystallized from dichloromethane-ether-hexane to afford 2.94·5'H-cyclopropa/T6a. 17&amp;J 5cx~^ah.drostan 1?β-ο1 3-one-acetate 3,3-ethyleneketal with m.p. 158.5 5 160.5°C and 0.29 g of the same substance with m.p. 155-5 - 15θ?5°. An analytical sample obtained by recrystallization from ether-hexane melted at 159.5 - 1δ0.5°0 = +16.82° (chloroform, c = 0.9896).

Example XVII

To a mixture of 0.5 g of lithium aluminum hydride and 25 ml of ether was added a solution of 1 g of the ethylene ketal prepared in Example XVI and 10 cn^y tetrahydrofuran added. The solution was refluxed with stirring for 1 hour, cooled, diluted with dichloromethane and treated with excess sodium sulfate solution. The organic phase was washed repeatedly with water, dried and concentrated to afford 830 mg of crude 3'H-cyclopropa/Ï6a,17o-7 5a-androstan 17,1-3-OQ·3.5~^ethylene ketal. Beze

3 dust became in 8 c$^y pyridine and to the solution was added 8 ml of propionic anhydride. After standing for 4 days at room temperature, the solution was poured into 200 ml of ice water, the precipitate was filtered off and dissolved in dichloromethane. The solution was dried and evaporated to yield 1.11 g of crude 3'H-cyclopropa/10a. llccj

5a-andrsstan ,οΐ 5.one-propionate 5.3-ethylene ketal op. Substance 3 was dissolved in 20 ml of tetrahydrofuran and to the solution was added 15 x cs / 5 H perchloric acid. The solution was stirred at room temperature for 2 1/4 hours and then poured into 200 ml of water containing 3.8 g of sodium bicarbonate. The precipitate was filtered off and dissolved in dichloromethane, the solution was dried and evaporated to give 786 ml of crude 3'H-cyclopropa._jl/Ï6a:.17a27 5ct-androstan 17β-ο1 3-one-propionate in the form of yellow, oily crystals. Purification of this material gave a product with m.p. 129.5 132.5°C op.

Example XVIII

To a solution of 20 g of 5a-androst 16-ene 3β,17p-diol diacetate in 340 csr dried diethylene glycol dimethyl ether, a solution was added with vigorous stirring and refluxing.

0 2 3 8 4

X of 65 g of sodium chlorodifluoroacetate in 320 ml of diethylene glycol dimethyl ether was added over 30 minutes. The solution was.

refluxed for a further 5 minutes, then 200 ml of solvent was distilled off under reduced pressure over 15 minutes. The reaction mixture was cooled in an ice bath and poured into 3 dm -1 of ice water. The precipitate was filtered off and dissolved in dichloromethane. The solution was dried, filtered through silica gel and evaporated to give a spontaneously crystallizing oil. Recrystallization from dichloromethane-ether-hexane afforded 18.8 g (83%) of 3' 3'-difluoro 3'H-cyclopropa/Ï6awl7a-7 5ct-androstan 3P-17P-diol diacetate as colorless crystals ( 17.1 g with mp 155.5-158.5[deg.] C. 1.7 S with mp 151.5-157.5[deg.] Further recrystallization from ether-hexane afforded an analytical preparation with mp. 157.5 - 159°^c θΡ° -10.37° (chloroform, c = 1.273)o

Example XIX

To a solution of 15.6 g of the difluorocyclopropasteroid prepared in Example XVIII in 75 ml of methanol and 10 ml of tetra3 hydrofuran was added 1.5 ml of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature and after 3.3 ears poured into 1 dm ice water. The precipitate was filtered off and dissolved in dichloromethane. The solution was dried and evaporated to yield crude 3' 3'-difluoro 3'H-cyclopropa/Ϊ6α.17θζ7 5cc-androstan

3β.17β-ϋο1 17-acetate op. A purified sample of this material 0 3 had a melting point of 146 DEG-152 DEG C. The crude product was diluted with 1.7 cm.

X Jones reagent oxidized in 75 ml acetone. After adding a little isopropanol, the reaction mixture was filtered through a filter aid and diluted with water. The organic solvents were removed under reduced pressure and the aqueous suspension filtered. - The solid was dissolved in dichloromethane and the solution was dried and evaporated. Recrystallization from dichloromethane-ether gave 0.6 g (43%) of 3',3'-difluoro 3'H-cyclopropa/Ï6a,17o-7 5a-androstan 17β-ο1,3-oh-acetate, m.p. 196 198°C. /cë_7p^ +15.05° (chloroform, c = 1.083).

Example XX • A mixture of 3 S ^by the cyelo~ . prepared according to example X

0 2 9 8 4 «

propasteroid and 4.08 g of dichlorodicyanbenzoquinone in 90 ml of dioxane were refluxed for 2 hours and 45 minutes. The cooled reaction mixture was filtered, the solid, (2,3-dichloro-5,6-dicyan-hydroquinone), washed with dioxane and the combined phthalates concentrated under reduced pressure. The gummy residue was dissolved in dichloromethane and adsorbed onto 200 g of silica gel. The steroids were eluted with ether and 20/ethyl acetate in ether and again adsorbed on 100 g of silica gel from dichloromethane solution. Practically nothing was eluted with 5/ebher in dichloromethane or less polar solvents. 17p-hydroxy 3'H-cyclopropa 6α.17α-5 cc-androstan 1-ene-3-one acetate was eluted with 250 cc/7/ether in dichloromethane, which crystallized on evaporation. Recrystallization from dichloromethane ether-hexane and finally from ether gave 0.702 g of colorless crystals of m.p. 187 - 188°C at. +57.06° (chloroform, c =

,ογβ).

Further elution with 10, 12, 15 and 17/ether in dichloromethane afforded fractions with 17p-hydroxy 3 ^,H-cyclopropa/Ï6a.17o:-5a-androsta 1,4-diene 3-one acetate. Recrystallization from dichloromethane-ether afforded 0.867 g of colorless crystals of m.p. 218.5 220.5°G. /ö_7²⁵ +54.78° (chloroform, c = 0.9766).

Example XXI

A mixture of 3.43 g of 17P-hydroxy 3'E-cyclopropa/Ï6a.17cc-7 5a-androsta 1,4-diene 3-one acetate, 3.43 g of tris(triphenylphosphine)rhodium chloride, 540 eni benzene and 60 cm. hydrogen at room temperature and shaken under normal pressure. After 3 hours and 45 minutes, the hydrogen uptake decreased markedly and the hydrogenation was terminated. A total of 225 cm 2 was taken up (theoretically 243 cm 2 ). The solution was concentrated under reduced pressure and the residue was dissolved in dichloromethane and passed through a {

aluminum oxide column filtered. Evaporation of the filtrate afforded red crystals which, recrystallized from dichloromethane-ether, afforded a mixture of pale yellow crystals and red solid. By rubbing with dichloromethane only the yellow crystals dissolved₀ The red solid was worn away«, De di72 0 2 9 8 4

19 chloromethane solution was evaporated and the residue recrystallized from dichloromethane ether. There were obtained 2.89 g of 17P-Hydroxy 3&gt;H-cyclopropa/Ï6a.17a-7 androst 4-ene 3-one acetate of m.p. 207 210°C. (Analytical preparation 211-214°C.) +112.79° (chloroform, c = 1.032).

Example XXII

Hydrogen chloride was passed over a solution of 1.47 g of the conjugated ketone prepared in Example 21 in 60 ml of dioxane and a solution of 0.976 g of dichlorodicyanbenzoquinone in 60 ml of dioxane for a few seconds. The two solutions were mixed and stirred with hydrogen chloride being passed over its surface for 2 minutes. Stirring was then continued for 5 minutes. The precipitate (2,3-dicyan 5'6-dichlorohydroquinone) was eg filtered off and the filtrate poured into 1 dl of water. The precipitate was filtered off and dissolved in dichloromethane. The solution was passed through a short column of alumina and concentrated. The resulting oil was crystallized from ether-hexane and dichloromethane-ether-hexane. 0.818 g (56%) of pure 17β-hydroxy-3'H-cyclopropa/Ï6a.17d-/androsta 4-6-diene 3-of-^acetate with m.p. 149+152 °C. +56.9° (chloroform, c = 1.07)»

Example XXIII

To a solution of 594 µg of the dienone prepared in Example XXII in 6 ml of dioxane were added 1.5 µl of ethyl mercaptan and 180 mg of sodium methoxide. The heterogeneous mixture was stirred at room temperature for 7 days and filtered. The filtrate was concentrated in a stream of air and the resulting oil dissolved in dichloromethane. The solution was filtered through a filter aid and concentrated. The residue, after crystallization from ether and dichloromethane-ether, afforded 304 rog (43/) 7a-^ethylthio 17p-hydroxy 3'Hcyclopropa/ï50a.17o-7 androst 4-,3-one-acetate as colorless crystals, M.p., 199-202.5 °C. An analytical preparation had a melting point of 200 - 208^eG. -3.2° (chloroform, c = 0.69)0

Example XXIV

To a warm solution of 100 g of 5&amp;-^aadrostan 3-ο1 17-on7202984

10 acetate in 500 cvZ methanol and 100 cm? methyl ester of orthoformic acid. 1.0 c? concentrated, sulfuric acid added.» The solution was. for a few minutes until completely solidified, then the mixture was allowed to stand for 10 minutes. After adding ~7 10 ml of nyridine, the reaction mixture was stirred, cooled and filtered. The colorless solid was washed with methanol containing some pyridine to give crude 17,17-dimethoxy-5-androstan 3-3-Ol-acetate, m.p. 115 DEG-125 DEG C. Recrystallization from dichloromethane and methanol with a little pyridine afforded 89.6 g of material, mp 144 DEG-149 DEG C. An analytical preparation had m.p. 148-151°C. 1,θ3 (chloroform, c =

0,970).

Example XXV x

This a mixture of 3 dm toluene, 1 g p-toluenesulfonic acid 3,3 monohydrate and 0.426 ml pyridine was distilled off 200 ml of solvent. The solvent was cooled slightly and 89.6 g of the dimethyl metal prepared in Example XXIV was added thereto. The reaction mixture was then heated for a further 1 g hour, during which time 400 ml of solvent was distilled off. After 1 hour, the reaction mixture was cooled slightly and evaporated under reduced pressure to give crude 17-methoxy 5ct-androst 16-ene 3p-ci-^acetate as θθη pale yellow solid remained.

A solution of 2.4 g copper(II) acetate monohydrate in 400 cet acetic acid was heated on a steam bath and 160 g granulated zinc (20 mesh) was added thereto. The mixture was constricted for 3 minutes and the solvent was removed. The residue was washed once with 400 ml of hot acetic acid and three times with room temperature ether. The resulting zinc-copper pair was covered with 100 ml of ether, then a solution of the crude enol ether obtained above in 150 ml of diiodomethane and 250 ml of dichloromethane was added. The reaction mixture was refluxed with stirring overnight, then cooled, and poured onto ice. The lower aqueous layer was separated and the organic phase was washed twice with water, dried and evaporated. The residue was recrystallized from methanol, dichloromethane-methanol and finally from ether-hexane to give 10.4 g of -methoxy 3'H-cyclopropa/Ï6a«17a-7 5a-androstan 3β-ol-acetate as colorless crystals with m.p. 127-130°C. The combined mother liquors were chromatographed on silica gel. Elution with hexane and 20-50% henzene in hexane afforded 27.1 g of further material with m.p. 124 - 129.5°^c· The analytical preparation had m.p. 127 130°C. /ce_7p^ +19.44 (chloroform, c = 0.9004).

Example XXVII

A mixture of 29.1 g of the cyclone prepared in Example XXV ¹ 3 propasteroid, 29.1 g potassium bicarbonate, 1200 cnr methanol and 300 cn 7 water was refluxed for 1 g hour. The methanol was evaporated under reduced pressure and the residue was diluted with water and filtered. The solid was dissolved in dichloromethane, the solution was dried and evaporated. The crystal-shaped

-5 residue was crystallized from dichloromethane-ether to give

21.25 g (θ3%) 173-methoxy 3'H-cyclopropa/Ï^CC. 17&amp;_7 5a~androstan 3β~ol as colorless crystals of m.p. 190 - 194°C. The analytical preparation had m.p. 194.5 - 190.5°E. /ö_7p^ +30.32° (chloroform, c = 1.151).

Example XXVII

To a solution of 92.5 ml of pyridine in 2.75 ml of dichloromethane was gradually added 40.4 g of chromium trioxide and then a solution of 23.1 g of the 3-ol prepared in Example XXVI in 900 ml of dichloromethane. The mixture was stirred for 20 minutes, washed with water, dried and dried over a short period of time^,'Florisil column lined. Evaporation and recrystallization of the residue from dichloromethane-ether-hexane gave 20.57 g (90%) of 17β-1ψάτοχγ 3'H-cyclopropa/Ï6a.17cc_&gt;_7 5a+^aherostan 3-one with m.p. 150 - 153°E. The analytical preparation had m.p. 149.5 - 151°C. /Ö_7p^ +55.44° (chloro30 form, c = 1.048)»

Example XXVIII

To a solution of 3 g of the 3 3 . prepared in Example XXVII

3-ketone in 60 ml of pyridine and 10 ml of ethyl ester of formic acid was added with intensive stirring a sodium methoxide solution prepared from 0.84 g of sodium and 7.8 ml of methanol. The response7202934

The mixture solidified within 1 minute and allowed to stand for 45 minutes.® Then it was diluted with water, neutralized with acetic acid and extracted with dichloromethane®. The dichloromethane extract was dried, filtered over silica gel and evaporated. Crystallization from dichloromethane-ether afforded 2.83 g (.7%) of 2-hydroxymethylene 17,methoxy 3'H-cyclopropa/6a. ?α_7 5&lt;X-androstan 3-°n in the form of colorless crystals with Mp® 174 - 176°C. +75.39 (chloroform, c = 0.470°)

Example XXIX

A mixture of 1.065 g of the compound prepared in Example XXVIII

3 j hydroxymethylene steroid, 25 cm^y methanol and 0.4 cr 85°t'^s hydrazine hydrate was refluxed for 50 minutes. Ka removal of the solvent under reduced pressure and recrystallization. lization from dichloromethane-ether, 917 ®g (θ7%) 17β~ methoxy 3^!H-cyclopropa_J6cc.17ci_J 5a-androstano/3®2-c_7-pyrazole in the form of colorless crystals with Mp® 243 - 245°C® The analytical preparation had Mp. 244 - 246°C® +78.02° (chloroform, c = 1.084)®

Example XXX

To 8.27 g of the hydroxymethylene steroid prepared in Example XXVIII was added 250 ml of hot acetic acid. The reaction vessel was immediately placed in an oil bath preheated to 170°C.

minutes later, a solution of 3.68 g of hydroxylamine hydrochloride and 4.14 g of sodium acetate in 47 ml of water was added. The solution started boiling after 4 minutes and was boiled under 5 minutes

- reflux cooling. The reaction mixture was then cooled in an ice bath and poured into 3.5 dm of water. The resulting precipitate was filtered off and dissolved in dichloromethane. The solution was dried and concentrated under reduced pressure. The residue was dissolved in benzene and adsorbed on silica gel. Solvent elution of benzene to give 57® ether in dichloromethane afforded crystalline fractions which were combined and recrystallized from dichloromethane ether. 4.792 g (58%) of .beta.-methoxy 3'H-cyclopropa 6cc.17cx .7 5cc-^a2-drostano/7· 3~d_7fisoxazole in the form of colored crystals with M.p₀ 144 - 145.5°8. The analytical preparation melted

0 2 9 8 4

- 23 at 142.5 - 143.5°C. /ά_7^⁵ +76.2° (chloroform, c = 1.02).

Example XXXI

A hot solution of 1 g of hydroxylamine hydrochloride in 6 cnJ of water was added to a hot solution of 2 g of the solution described in Example 3.

XXVIII prepared hydroxymethylenesteroid in 30 cnr pyridine added. The solution was refluxed for 3 hours and then cooled overnight. The solvents were removed under reduced pressure and the residue was washed with dichloromethane. than diluted. The solution was washed twice with water, dried and concentrated. The residue was stirred at room temperature for 30 minutes with 30 ml of tetrahydrofuran and Q.76 g of sodium methoxide. The solvent was evaporated and the residue was mixed with water and extracted with dichloromethane. The extracts were dried and concentrated. The residue was dissolved in henzene and adsorbed on silica gel. Solvent elution of 5% dichloromethane in benzene to 10% ether in dichloromethane yielded crystalline fractions which recrystallized from dichloromethane ether 1.55 g (7θ%) 17P-methoxy 3'H-cyclopropa/10a.YlttJ 5a-androstano/3·. gave 2~cJ7isoxazole in the form of colorless crystals of m.p. 166.5 - 168°C. The analytical preparation had m.p. 167.5 168.5°C. +71.4° (chloroform, c = 1.08).

Example XXXII

A mixture of 100 g isoandrosterone acetate, 500 ml absolute x methanol and 100 ml triethyl ester of orthoformic acid was heated on a steam bath until dissolved. After that, 2.5 x

ml of concentrated sulfuric acid was added and the mixture was heated for a further 3 minutes. Then it was cooled to room temperature, lp x

Cnr pyridine was added and the whole was cooled in an ice bath. The 17-diethyl ketal was filtered off and partially dried in a vacuum oven. The melting point was about 90°C. A mixture of dm2 toluene and 2.5 dm2 of a 2 mole aqueous solution of py3 ; ridinium tosylate was heated and 250 ml of liquid was distilled off. The solution was then allowed to cool slightly and the crude 17-diethyl ketal obtained above was added. Then again ver5 hit and 3²O cnr solvent was distilled off over 50 minutes7202984

The residual solvent was then removed under reduced pressure and to the residue, a yellow oil of crude 17-ethoxy-androst 3,16-ene-3-ol-acetate, 250 ml of dichloromethane and 150 ml of diiodomethane were added. This mixture was added to a zinc-copper pair prepared from 160 g of granulated zinc and covered with 100 ml of ether. The mixture was refluxed overnight. The cooled solution was then poured onto a little ice and shaken. The lower aqueous layer was discarded, the organic layer was washed with water, dried and evaporated. A yellow oil was obtained, which was dissolved in about 1/3 hr of hexane and absorbed onto 200 g of silica gel. Elution with slightly polar solvents afforded a number of by-products, elution with ether afforded the desired crude product, 17p-ethoxy 3'Ecyclopropa/Ï6a.17a-7 5a-^ahdrostan 17^-(l) acetate, which after recrystallization from dichloromethane-ether in a yield of 8.72 g (25%) in the form of colorless crystals with m.p. 150.5 - 152°C 23° was obtained. /ZJ-q⁺¹5.1° (chloroform, c = 0.976).

Example XXXIII

A mixture of 8.54 g of v&amp;n. the cyclopropasteroid prepared in Example XXXII, 8.54 g of potassium bicarbonate, 400 ml of methanol and 100 ml of water was refluxed for 1 g·hour. Hot water was then added, most of the methanol was removed under reduced pressure, the residue was diluted with water, and filtered after cooling. The residue obtained after filtering was dissolved in dichloromethane, the solution was dried and evaporated. A colorless, crystalline residue of

173-Ethoxy 3'H-cyclopropa/Ï6a.17a-7 5cc·androstan 3β-θ1· This crude product was dissolved in 330 ml of dichloromethane and over 5 minutes. to a. solution obtained by adding 14.7 g of chromium trioxide to 1 dm/methylene chloride and 35.4 cr of pyridine. After stirring for 20 minutes, the dichloromethane was decanted, washed with water, dried, filtered through Florisil and evaporated. Recrystallization of the residue from dichloromethane ether-hexane afforded 6.245 g (77%) of 17P-ethoxy 3'H-cyclopropa/6a.

17cc_/ 5ct.androstan 5-oh as colorless crystals of m.p. 146.5 7202984

148°C. füj'd* +5θ?2° (chloroform, 'c ~ 0.973) '5

d

Example XXXIV

A sodium methoxide solution prepared from 1.56 g of sodium and 14.5 ml of methanol was added in one shot with stirring to a solution 3 of 5.573 g of the 3-ketone prepared in Example XXXIII in 110 ml of pyridine and 18.5 ml ethyl ester of formic acid. added. The reaction mixture solidified almost immediately and was allowed to stand for 45 minutes. It is then diluted with water, acidified with acetic acid and extracted with dichloromethane. The extract was dried and evaporated to leave a light yellow solid. This was dissolved in benzene and passed over a silica gel column. With benzene, 3.75 g of 2-hydroxymethylene 17P-ethoxy 3'H-cyclopropa/10a.17a-7

5a-androstan 3-cn eluted.

To this material was added 115 ml of hot acetic acid and the reaction mixture was placed in an oil bath heated to 160 °C. 3 minutes later, a solution of 1.67 g of hydroxylamine hydrochloride and 1.88 g of sodium acetate in 21 ml of water was added. After 2 minutes the reaction mixture started to boil. Heating was then continued for a further 5 minutes. The solution was immediately cooled in an ice bath and poured onto 2 dm of ice water. The precipitate was filtered off and dissolved in dichloromethane. The solution was dried and concentrated. The residue was dissolved in benzene and adsorbed on 38 g of silica gel. Elution with benzene, mixtures of dichloromethane-benzene and dichloromethane alone gave colorless crystal fractions, which were recrystallized from dichloromethane-ether._y/2.3-d_/isoxazole with M.p. 160.5 - 162°C.

+68.3° (chloroform, o = 0.965).

Example XXXV

Analogously to Example XXIX, wepd using the product 17p-ethoxy 3'H-cyclopropa] prepared in Example XXXIII. 17a_f 5a-androstano/3[2-c_/pyrazole prepared.

Example XXXVI ;

In analogy to Example XXXI, using the product obtained in Example XXXIII, 17P-ethoxy 3'H-cycloproh

- 26 10 pa/Ï6cc.l7a__7 óc-androstano/J. 2-c_7isoxazole prepared»

Example XXXV11

A solution of 40 mg of the cyclopropa-diacetate prepared in Example 1 in 0.5 ml of dichloromethane and 0.5 ml of ether was mixed with 0.87 ml of a 2.3 mole solution of tert-butylmagnesium chloride in ether. mixed. The solution was stirred overnight at room temperature and the reaction mixture was further processed analogously to the procedure in Example II. This gave 3'H-cyclopropa/Ï6a„17a-7 5K-^aal^°s^^aa 3β 47β“^&lt;3Η°ΐ°

Example XXXVIII

A solution of 2 g of the compound prepared in Example II was left

3 3 diol and 15 cnr p-toluenesulfonic acid in 5.5 cm propionic acid and 13 cm propionic anhydride Stand at room temperature for 7 days and then poured into ice water. The precipitate was filtered off and dissolved in dichloromethane. The solution was washed with water, dried and evaporated. The residue after crystallization from dichloromethane-ether-pentane gave 3^!H-cyclopropa_y[6a»17a__7 5h-androstan 3p17P-diol dipropionate, m.p. 150 - 155°C.

Example XXXIX

A mixture of 134 g of isoandrosterone benzoate and 600 ml of iso3 propenyl acetate was added to a solution of 0.6 ml of concentrated sulfuric acid in 3.5 ml of isopropenyl acetate. The reaction mixture was heated and distilled gradually over 21 hours, giving 1100 ml of isopropenyl acetate.⁹ isopropenyl acetate and 2.4 cnr concentrated sulfuric acid in 120 cnl isopropenyl acetate was gradually added »

A total of 825 cm of distillate was collected. The solution was allowed to stand at room temperature for 3 days, the precipitate was filtered off and washed with hexane. Ken obtained 117 g of crude 17,S-acetoxy-androst 16-ene 3P-ol-henzoate. This material was dissolved in benzene and applied to a silica gel column. Sludging with benzene yielded 14.1 g of pure enol acetate »

10.12 g of granulated zinc (20 mesh) was added to a 100°C solution of only 0.152 g of copper(II) acetate monohydrate in 15 ml of acetic acid. The dispersion was stirred at 100°C for 4 minutes. The liquid was removed and the residue was washed with 15 ccl.

0 2 SB 4 acetic acid at 100°C and washed three times with room temperature ether. The resulting zinc-copper pair was covered with 15 cm of ether, then a_X dispersion of 14.1 g of the above-prepared enol acetate in 30 ml of dichloromethane and 8.5 ml of diiodomethane. The reaction mixture was refluxed overnight, cooled to room temperature and then shaken with ice and 1 N hydrochloric acid. The organic phase and two dichloromethane extracts of the aqueous phase were combined, washed with water, dried and evaporated. Recrystallization of the residue from dichloromethane-ether afforded 6.62 g of 3'H-cyclopropa/Toct. W_7 5a-androstan 3β·17β“8ΰο1 17-acetate 3-Henzoate with m.p. 211 213°C. +10.0° (chloroform, c = 0.948) «

Example XL

To a solution of 30 mg of copper(II) acetate monohydrate in 3.0 ml of acetic acid was added 2 g of granulated zinc at 100°C.

The dispersion was stirred for 3 minutes at 100°C, the liquid was decanted and the residue was washed with hexacetic acid and room temperature ether. The resulting zinc-copper pair was covered with 3 ml of ether and 2 drops of diiodomethane were added thereto. After the initiation of the reaction, a solution of 2.5 g of androsta 5.16-diene 3P 17-8.iol diacetate, 0.86 cn 7 diiodomethane and 6 cn dichloromethane was added over 10 minutes. The reaction mixture was refluxed with stirring overnight. The organic layer and several dichloromethane washing solutions, with which the metal had been washed, were combined and shaken out with a mixture of 1 and 1 N hydrochloric acid. The organic phase was further processed to yield 2.8 g of colorless oil, which was rubbed with hexane. Recrystallization of the resulting solid from ether-hexane afforded 0.48 g (18%)¹ 3'H&gt;cyclopropa/Ï6a.17a_7 androst 5-ene 3β,·1·7β-^1ο1-άίαοθΐηαΐ with m.p. 154 - 158°C. An analytical preparation had m.p. 1^9 16l°C. /a_7p^ -64.96° (chloroform, c = 1.056).

Example XLI

A mixture of 150 g isoandrosterone acetate, 75 cc n-propanol and 230 ml orthoformic acid tripropyl ether was heated on a steam bath until dissolution had taken place. Then 3.5°m concentrated sulfuric acid was added. The reaction mixture was heated for a further 10 minutes and the reaction mixture was allowed to stand at room temperature for 20 minutes, 22.5 en/pyridine was added and the volatiles were removed under reduced pressure. In addition, one. residue obtained from 259 g crude

17.17-dipropoxy 5a*androstan 3p-el^acetate.

3

An. mixture of 3.9 ml of toluene and 3.75 ml of a 2 mol 3 aqueous solution of pyridinium tosylate was heated and 750 ml of liquid was distilled off. It was then allowed to cool slightly and the above obtained 259 g of 17.17'-dipropoxy 5a-androstane was added.

33vol acetate. It was then heated again and 750 ml of solvent was distilled off over 50 minutes. The residual solvent was then removed under reduced pressure to give oily crude 17-propoxy-5-androstan 16-ene 3p-ol-acetate.

3

This material was mixed with 350 ml dichloromethane and 225 ml diiodomethane and added to a zinc-copper pair (prepared from 240 g granulated zinc) and 150 ml ether. The mixture was refluxed with stirring overnight. The cooled solution was shaken out with a little ice. The aqueous phase was removed, the organic layer was washed with water, dried and concentrated. 213 g of a yellow oil were obtained. This oil was taken up in hexane and adsorbed onto 500 g of silica gel. Elution with 10-70% benzene in hexane yielded 125 g of a crystalline crude product, which after recrystallization from dichloromethane-hexane 24.7 g (14%) 17Pnopoxy 3'H-cyclopropa/6a.17a/5ag. ndrostan 3P-ol-^aceyielded with M.p. 139-144°C. Sen analytical preparation had M.p. 144 - . (chloroform, c = 0.980).

Example XIII

A mixture of 17.8 g of the cyclopropasteroid prepared in Example XLI, 17.8 g sodium bicarbonate, 1 dn/methanol and 250 3 ml water was refluxed for 1 g·hour. The methanol was evaporated under reduced pressure and the residue diluted with water and filtered. The solid was dissolved in dichloromethane, the t

solution was dried and evaporated to a small volume. The obtained72 0 2 9 8 4

-29 µg crystals were filtered off and washed with ether. 11.48 g (72%) of 17P-propoxy J'H-cyclopropa/10a.WjZ 5a-androstan 3β-ο1 were obtained in the form of colorless crystals of m.p. 198 - 199j5°^c* The analytical preparation had m.p. 199.5 - 200.5°Co +28.5° (chloroform, c = 1.08)o

Example XLIII

To a solution of 46.7 grams of pyridine in 1.5 grams of dichloromethane was gradually added 19.3 grams of chromium trioxide and then a solution of 9.59 grams of the 3-d prepared in Example XLII in 450 ml of dichloromethane. The mixture was stirred for 30 minutes. The chromium salts were separated and washed with dichloromethane.

The solution and the dichloromethane washing solutions were combined, washed with water, dried and passed through a Florisil column. fed and evaporated. A colorless crystalline residue was obtained which after recrystallization from dichloromethane-methanol 8.19 g (88%). 17P-propoxy 3'H-cyclopropa/Ï6cc.17ct-5n-androstan gave 5°n with iMp. 113 - 115 °C0 /a_7 +48.6° (chloroform, c = 0.916).

Example. XLIV

A sodium methoxide solution prepared from 1.13 g of sodium and 10.3 gm of methanol was added in one shot to a stirred solution of 3 . 4 g of the 3-one prepared in Example XLIII in 80 cm of pyridine and 3

13.3 cm. ethyl ester of formic acid was added. The reaction mixture solidified almost immediately and was allowed to stand for 45 minutes. It was then diluted with water, neutralized with acetic acid and extracted with dichloromethane. The extract was dried and concentrated to afford crude 2-hydroxymethylene 17p-propoxy 3'H-cyclopropa/Ï6{X.17a-5tt-androstan-3-one as a light yellow solid. To half of this material was added 65 ml hst acetic acid and the reaction mixture was immediately placed in an oil bath heated to 170°C. 2 minutes later, a solution of 0.96 g of hydroxylamine ne 2 hydrochloride and 1.08 g of sodium acetate in 12.2 g of water was added. The reaction mixture started boiling after 1 minute and was then refluxed for 5 minutes. The solution was immediately cooled in an ice bath and poured into 1 dm water. The precipitate was filtered off, washed well with water and dried,

- 30 µa of dichloromethane dissolved and applied to a column of 40 g of silica gel. Elution with dichloromethane and 5/ether in dichloromethane afforded an ot product which, after recrystallization from dichloroethane-nethanol, 435 g (20/) -propoxy 3'H-cyclopropa/Ï6a.17a-7

gave 5a-androstano/2,3-d-17isoxazole in the form of colorless crystals with m.p. 111-112°C. /aj⁷^ +70.3° (chloroform, c = 0.788).

Example XLY

In analogy to Example XXIX, starting from the 2-hydro10 xymethylene compound of Example XLIV, 17P-propoxy-3'H-cyclopropa

2Ϊ6α.17α_7 5a-androstano23.2-c_7pyrazole.

Example XLVI

In analogy to Example XXXI, from the 2-hydroxymethylene sheroid prepared in Example XLIV, there is obtained 17P-propoxy 3'H-cyclo15 propa2,6a.17a_7 5&amp;-androstano._J/3&lt;2-c_/isoxazole.

Example XLVII

3

A mixture of 10 cc dichloromethane, 1.5 cc dimethylformamide and 0.0 ciP phosphorus oxychloride was stirred at room temperature for 20 minutes. The Vilsneier's reagent thus prepared was added to a solution of 1 g of 3'H-cyclopropa/lea. Yl&amp;J 5K-^androstan 17§-ol 3-°n acetate 3.5-ethylene keial (cf. Example XVI) in 5 cm'⁵ dichloromethane added. The reaction mixture was stirred at room temperature for 75 minutes, washed with water, dried over sodium sulfate 3 and evaporated the remaining yellow oil was added with 15 ml of methanol.

3 and 30 cnr of tetrahydrofuran were mixed and thereto was added 2.5 cnr 3 H hydrochloric acid. The reaction mixture was stirred at room temperature for 90 ml, diluted with 150 ml of water and stored at 4°C overnight. The solid was filtered off and recrystallized from dichloromethane-ethanol. 2-hydroxymethylene was obtained

3'E-cyclopropa/Ï6(X. 17cc_7 5K-^androstan 17β-θ1 3-one acetate with m.p.

189.5 - 191°C. +47.0° (chloroform, c = 0.869).

Example XLVIII

In analogy to Example XXX, from the 2-hydroxymethylene steroid prepared in Example XLVII, the 17p-acetoxy 3'H-cyclo35 propa/Ï6a.17ci_75a-^an^|inostano_J/2.5-d_7 isoxazole obtained.

- 31 Example XLIX

In analogy to Example XXXI, from the 2-hydroxymethylene steroid prepared in Example XLVII, the 17P-acetoxy 3^,H-cyclopropa/Ï6a.17a_7 5a-androstano/3*2-c_7isoxazole obtained®

Example L

Each of the test compounds listed below was administered orally in sesame oil at the indicated dose once daily for 7 consecutive days to groups of 10 castrated rats. On the 8th day, the seminal vesicle, ventral prostate and levator ani were removed in the usual manner in preparation ( German: herausprSpariert) and weighed using a torsion balance. The weight ratio (mg organ per 100 g body weight) was calculated for each rat and the group averaged therefrom. The indicated values ​​represent the percentage deviation of this value from that of the comparison group.

3'H-cyclopropa/Ï6ci.17a_7 5a-^aflhrostan 17βνθ1 3-one acetate

<td rowspan="2"></td><td rowspan="2">Dose mg/day</td><td rowspan="2">Number rats</td><td colspan="3">Percentage deviation</td>

<td>seminal vesicle</td><td>ventral prostate</td><td>levator ani</td>

<td> 20</td><td> 0,5</td><td> 9</td><td> 105</td><td> 228</td><td> 12</td>

<td></td><td> 1</td><td> 9</td><td> 222</td><td> 321</td><td> 29</td>

<td></td><td> 2</td><td> 10</td><td>27Ο</td><td> 391</td><td> 34</td>

<td></td><td> 4</td><td> 10</td><td> 487</td><td> 626</td><td> 70</td>

<td></td><td></td><td>17P~hydroxy</td><td colspan="3">3'H-cyclopropa/Ï6a.17a_7 5a-andros</td>

<td> 25</td><td></td><td>3-on-acetate</td><td></td><td></td><td></td>

<td></td><td>Dose mg/day</td><td>Number rats</td><td colspan="2">Percent deviation Seminal Bladder Venterale •prostate</td><td>levator ani</td>

<td></td><td> 0,5</td><td> 10</td><td> 80</td><td> 117</td><td> 15</td>

<td> 30</td><td> 1</td><td> 9</td><td> 163</td><td> 166</td><td> 38</td>

<td></td><td> 2</td><td> 10</td><td> 239</td><td> 319</td><td> 74</td>

<td></td><td> 4</td><td> 10</td><td> 476</td><td> 565</td><td> 113</td>

- 32 Dose mg/day

JOSiS ig/day o.5

Dose mg/day

170-hydroxy 3 ^!H-cyclopropa/Ï6ct.l7a/7androst 4-®^en

<td colspan="4">3-on-acetate</td>

<td>Number</td><td colspan="2">Percentage deviation</td><td></td>

<td>rats</td><td>seminal vesicle</td><td>ventral</td><td>levator</td>

<td></td><td></td><td>prostate</td><td>ani</td>

<td> 9</td><td> 197</td><td> 283</td><td> 35</td>

<td>170-methoxy</td><td colspan="3">3 &lt;H-cyclopropa/ϊβα.17a_7 5a-androstano</td>

<td colspan="2">/2.3-d/isoxazole</td><td></td><td></td>

<td>Number</td><td>Per cent</td><td>ual deviation</td><td></td>

<td>rats</td><td>seminal vesicle</td><td>ventral</td><td>levator</td>

<td></td><td></td><td>prostate</td><td>ani</td>

<td> 10</td><td> 44</td><td> 30</td><td> 34</td>

<td> 9 .</td><td> 82</td><td> 76</td><td> 57</td>

<td> 10</td><td> 156</td><td> 225 _X</td><td> 80</td>

<td>Q z</td><td>29Ο</td><td> 257</td><td> 86</td>

<td colspan="2">3'H-cyclopropa/ΐβα. 17°l7</td><td colspan="2">5a-androstan 3β·&gt;17β-&amp;ϊο1</td>

<td>17-acetate 3</td><td>-benzoate</td><td></td><td></td>

<td>Number</td><td colspan="2">Percentage deviation</td><td></td>

<td>rats</td><td>seminal vesicle</td><td>ventral</td><td>levator</td>

<td></td><td></td><td>prostate</td><td>ani</td>

<td> 9</td><td> 147</td><td> 387 '</td><td> 34</td>

17P-ethoxy 3'H"^cyclopropa/Ï6a.l7a_7 5a-androstano /2.3-d_/isoxazole

Dose mg/day

Number of rats

seminal vesicle

Percentage deviation

Venteral prostate

164

Levator anic

17P-methoxy 3'H-cyclopropa/ΐβα. 17&lt;x_7 5cc-^aadrostan 3-on

Dose mg/day

Number of rats

seminal vesicle

Percentage deviation

173 .Venteral prostate

289

Levator anic

IA

- 33 3'H-cyclopropa/Ï6a_O17a_7 5a-^aadrostan 17β-ο1 3-one propionate__ .. . .

<td>losis</td><td>Number</td><td>Pro</td>

<td>mg/day</td><td>rats</td><td>seminal vesicle</td>

<td> 1.</td><td> 9</td><td> 226</td>

<td></td><td></td><td>conc</td>

any deviation

<td>ventral</td><td>levator</td>

<td>prostate</td><td>ani</td>

<td> 389</td><td> 5</td>

<td>1 usions :</td><td></td>

1» Process for the preparation of steroids of formula 1, wherein:

X-, and X

R

R,

R,

Rr and R

R.

with the ₂ independently represent hydrogen, fluorine, chlorine or bromine;

hydrogen, lower alkyl, cycloalkyl or acyl; hydrogen;

c hydroxyl or 3-hydroxy /y and acyl, (lower alkyl), aryl(lower alkyl) and cycloalkyl derivatives thereof, 3-keto, 3keto A¹» 3-keto⁴&gt; 3-keto¹’⁴? 3-keto⁴’^{6 and} 3-keto 2^1 4°6 _pros-calls;

, together with the carbon atom 2 of the steroid ring a membered heteroaromatic ring, in which one heteroatom bonded to the carbon atom 3 ie, and Δ⁴- and⁴” propose their dehydroderivatives;

hydrogen and, when R^3-keto Δ⁴ or 3-keto /\~*⁴ represents hydrogen, acylthio, lower alkylthio or mercapto, characterized in that these steroids are prepared by methods known per se.

2. Process for preparing steroids of formula 1, wherein

X1 and Xg independently represent hydrogen, fluorine, chlorine or bromine;

- 34 ^Βιγ

R.

R' is hydrogen, lower alkyl, cycloalkyl or acyl; hydrogen;

R 1 HycLroxyl or 3-hydroxy A 0 and acyl, (lower alkyl), aryl(lower alkyl) and cycloalkyl derivatives thereof, 3-keto, 3keto A, 3-keto A⁴, 3-keto A^*⁴? 3-keto A⁴°^ θ*¹ 3-keto A^1,4°° represents;

R_ and R, together with carbon 2 of the steroid ring a 5 2 3 membered heteroaromatic ring, in which one heteroatom is bonded to carbon 3, and Δ⁴- and _Δ4. « propose their dehydroderivatives:

hydrogen and, when R 3-keto A⁴ or 3-keto A^”⁴ represents hydrogen, acylthio, lower alkylthio or mercapto, characterized in that *

a) a methylene or halomethylene group on the 16'17-(dnhbele bond) of a steroid of formula 2, wherein R_O

3-hydroxyl, 3-hydroxy A^ ^ea acyl, (lower alkyl), aryl(lower alkyl) and cycloalkyl derivatives thereof;

R ¹

R ₁₇adds.

R 1 and R 1 , together with the carbon atom 2 of the steroid ring, represent a 25-membered heteroaromatic ring, wherein one heteroatom is bonded to the carbon atom 3, and represents acyl, lower alkyl or cycloalkyl, or . b) a steroid of formula 3, wherein R' „, Χ_Ί and X_O have the above meaning and R₇ 3-keto, 3-keto⁴ or 3-keto A⁴° represents with hydrazine or hydroxylamine conversion, or

c) an ether or. ester bond at the 3- and/or 17-position of a steroid of formula la, wherein '

R₂, R , B.']_7' ^eil a ^4th have the meaning above, splits, or

d) the 3-hydroxyl group of a steroid of formula Ib, wherein X-, Χ^ and R^₇ have the above meaning

0 2 9 8 4

- 35 oxidizes to a 3-keto group, or

e) a hydroxyl group in one. steroid of formula 1c, where

X^, Χ^, R^j S.3 θη Rjj The above meaning and at least one hydroxyl group is located on the 3- or 17-pl^aats, acylates or alkylates, or

f) a steroid of formula ld, wherein ^E17’ ^X1 ^{and X}2 have the above meaning in at least one of the positions l(2), 4(5) θη 6(7) dehydrogenates, or

g) a steroid of formula le, wherein

X^, X^ ^and Εργ The above meaning and the 1,2-(double bond) is optional, reacting with hydrogen sulfide, a lower alkylthiol or an S-metal salt of a monothiocarboxylic acid, oï ⁷ &lt;

h) the acyl thio group in a steroid of formula If, where

X^, Χ^ and R^^ have the above meaning and the 1,2-(double bond) is optional, hydrolyzes, or

i) the 1,2-(double bond) in a steroid of formula Ig, where

X_1? X₂ and have the above meaning and one or both of the double bonds represented by dashed lines are present selectively hydrogenates.

Process according to Claim 2, characterized in that a methylene or difluoromethylene group is added to the 16.17-(double bond) of a steroid of formula II, wherein R 9 is hydrogen, R 1 -j acetyl, propionyl, represents methyl, ethyl or propyl and Rg and Rj together with the carbon 2 of the steroid ring represent an isoxazole moiety.

4. Process according to Claim 2, characterized in that the starting material is a compound of the formula III, in which the two radicals X, and Xg are hydrogen or fluorine, R'-, acetyl, propionyl, methyl, ethyl or propyl, and R'. ^ 3-keto suggests.

Process according to Claim 4, characterized in that 2-hydroxymethylene 3'H-cyclopropa/Ï6a.17c(/750&gt;androstan-3-one with hydroxyl 0 2 9 8 4 xylamine is reacted.₀ » Method according to claim 4? characterized in that 2-hydroxymethylene 17p-ethoxy 3'E-cyclopropa/6a. 17cc_7 5cc-androstan 3on with hydroxylamine conversion_O

7. Process according to Claim 4, characterized in that 2-hydroxynethylene 170-propoxy 3'H-cyclopropa/Ï6a«,ΊΊΰ-J 5a-^an&lt;lrostan 3on with hydroxylamine conversion_O

8. Process for preparing preparations having a hormonal action, characterized in that a steroid of the formula 1 according to the description of claim 1 is used as active ingredient which is suitable for therapeutic administration, non-toxic, inert, solid and liquid which are customary in such preparations per se. mixing carriers and/or excipients,

9» Molded medicinal product, manufactured according to the method of