CH626098A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids with hormonal activity and the formula <IMAGE> in which the dotted lines in the A ring are optional C-C bonds; R<3> is oxo if ring A is saturated or is oxo, ( alpha -H, beta -OH) or ( alpha -H, beta -O-acyl) if ring A is unsaturated; R<17a beta > is hydrogen, C1-10-alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl are prepared in a manner known per se starting from corresponding 17a-keto- or 3,17a-diketo-D-homosteroids.

Description

The invention relates to a process for the preparation of new D-homosteroids of the formula

I '

wherein the dotted lines in the A-ring designate optional C-C bonds and R31 and R171afi have the same meanings as R3 and R17ass in claim 1, however

55

60

65

17 on

3,626,098

wherein the dotted lines in the A-ring are optional C-C buffers metal hydrides, e.g. Designate fertilize di (lower alkoxy) aluminum hydrides; R3, if the ring A is saturated, oxo or, such as di-isobutoxyaluminum hydride, tri- (lower alkoxy) -aluminum-if the ring A is unsaturated, oxo, (aH, β-OH) or (aH, nium, such as Triisopropoxy aluminum; lithium aluminum hydride; β-O-acyl); R17aP is hydrogen, C] _10-alkyl, benzyl, cyclo-sodium aluminum hydride or sodium borohydride; or tri

hexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; be 5 methoxy or tributoxylithium aluminum hydride carried out, with at least one hydroxyl group in 3ß- or. Suitable solvents for this are hydro-

17ass position is present. fabrics, e.g. Cyclohexane, benzene, toluene; or ether, e.g. Di-

The term “acyl” is intended to mean, in particular, organic acid ethyl ether or tetrahydrofuran. If a 17a-keto group designates residues, for example residues of up to 11C atoms in the presence of a 3-keto group alone, containing alkane carboxylic acids, in particular residues of never-10, the 3-keto group is protected as an intermediate. A 3-ketogrup alkane carboxylic acid (containing up to 7 C atoms), such as pe, can be protected in the presence of a 4,5-double bond in the form of acetic acid, propionic acid, caproic acid, valeric acid, Ön- an enamine or enol ether. A non-acidic, undecylic acid; or oxalic acid, succinic acid, zi-conjugated 3-keto group can be protected as a ketal. Tronic acid; or residues of aromatic carboxylic acids such as introduction and the removal of such protective groups can be benzoic acid, phenylacetic acid, or phenoxyacetic acid; or 15 according to known working methods.

heterocyclic carboxylic acid such as nicotinic acid; or cycloali- The acylation of a 3- or 17-degree free hydr

phatic carboxylic acid such as cyclopentylpropionic acid. oxy group in a D-homosteroid of formula I can by

Lower alkyl residues can contain up to 7 carbon atoms and treatment with a reactive acid derivative, e.g. a straight-chained or branched chain. Examples include methyl, rehalogenide or acid anhydride in the presence of a base such as ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred pyridine or collidine.

Lower alkyl radicals are methyl and ethyl. An alkyl residue R17af! A 1,2-dehydrogenation can contain up to 10 carbon atoms in a manner known per se. Examples of such residues dehydrogenating agents such as selenium dioxide, 2,3-dichloro-5,6-are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and dicyanobenzoquinone, thallium triacetate or lead tetraacetate decyl. be made. 1,2-dehydrogenation can also be

Cycloalkenyl radicals preferably contain 5-8 carbon atoms. At 25 microbiologically, for example by means of Schizomycetes, in particular games for this are Cyclopenten-1 -yl and Cyclohexen-l-yl. those of Genera Arthrobacter, e.g. A. simplex ATCC

A preferred linking group within Formula I 6946; Bacillus, e.g. B. lentus ATCC 13805 and B. sphaericus are the compounds in which R3 represents oxo and the ring ATCC 7055; Pseudomonas, e.g. P. aeruginosa IFO 3505, Fla-A contains a double bond. Furthermore, such compound bacteria, e.g. flavenscens IFO 3058; Lactobacillis, e.g. L. fertilize of formula I preferred, in which R17 is hydrogen 30 brevis IFO 3345 and Nocardia, e.g. N. opaca ATCC 4276 or lower alkanoyl. consequences.

The D-homosteroids of the formula I can, according to the invention, double bonds in the 1,2 and 4,5-positions can simultaneously

can be obtained by using bromination to give 2,4-dibromo-3-ketone and dehydro-

Bromination of the latter using lithium carbonate and lithium 35-bromide in dimethylformamide are introduced. A 4,5-double bond can also be introduced by brominating a 3-keto-steroid saturated in the A-ring in glacial acetic acid to give the 2a, 4a-dibromo derivative and reducing this with chromium-II-chloride to the 4a-bromo compound. The latter compound 40 can then be dehydrobrominated via the semicarbazone by treatment with succinic acid to form the A4-3 ketone.

The etherification of a 17ass hydroxy group can e.g. by treatment with dihydropyran (to produce the tetrahydropyranyl ether) or by treatment with a cycloalkanone ketal in the presence of a catalytic amount of acid such as p-toluenesulfonic acid (to produce a cycloalkenyl ether). A 3-oxo group is expediently protected in order to prepare a 17a-Ci_io-alkyl, benzyl or cyclohexylmethyl ether. The protection of the meaning of the 3-oxo group in the R3 and the dotted lines is preferably accomplished by ketalization and Z represents oxo or (OR17ap, H) if Z provides oxo, e.g. represents with ethylene glycol in the presence of a catalytic, the 17a-keto group with intermediate protection of a lot of acid, such as p-toluenesulfonic acid. The etherification of the 3-keto group to the hydroxy group is reduced or, if R3 is oxo 17ass hydroxy group can be converted into an alkali and the A-ring is simply unsaturated, the 3-keto metal salt, e.g. the sodium salt, with a strong base, e.g. grappe and any 17a keto group present to the hydroxy 55 sodium hydride, and reaction with a Q.jo alkyl, ben group reduced. cyl- or cyclohexylmethyl halide, such as pentyl iodide, ben-

A 3- or cyl chloride or cyclohexylmethyl iodide obtained by this process can be produced in a solvent such as 17ass-hydroxy- or 3.17ass-dihydroxy-D-homosteroid such as dimethyl sulfoxide or benzene. Formula I mono- or diacylate, a 17ass-hydroxy-D-homo- The saponification of 17a-acyloxy groups or the cleavage

Steroid of the formula I to a 17a (C1-10 alkyl, benzyl, Cy-60 of 17a ether groups can be clohexymethyl, cycloalkenyl or tetrahydropyranyl) ether in a manner known per se. Acyloxy groups can e.g. etherify with aqueous-alcoholic of formula I, a saturated or simple base in the A-ring, such as aqueous-methanolic potassium carbonate saponified unsaturated D-homosteroid of formula I into an in the A-ring, ether groups can be mono- or double-unsaturated with aqueous-alcoholic D-dehydrate D-homosteroid of the formula mineral acids or organic acids such as oxalic acid or I or one in a D-homosteroid of the formula I 65 p-toluenesulfonic acid are cleaved.

saponify present 17ass acyloxy group. The starting materials for the inventive

The reduction of a 3- or 17a-keto group in accordance with the above position of the compounds of the formula I can, provided that they cannot be carried out in a conventional manner by means of complex known or their preparation is described here, according to an roid of the formula z

626 098

4th

known methods or in analogy to the methods described below.

The compounds of formula I are hormonal, in particular androgenic / anabolic.

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

The process products can be used as healing agents e.g. in the form of pharmaceutical preparations which are used in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

example 1

15.0 g of D-homo-androsta-4,16-diene-3,17a-dione was dissolved in 150 ml of methanol and refluxed for 10 minutes with 8.1 ml of pyrrolidine in the absence of air. The reaction solution was cooled to -10 °. The crystallized enamine was sucked and dried at 20 ° in a high vacuum. 16.1 g of pure 3- (l-pyrrolidinyl) -D-homo-an-drosta3,5,16-trien-17a-one were obtained, mp. 207-210 °.

UV: e279 = 19,500; s227 = 13,000. [a5 ° = - 295 °.

16.1 g of this enamine were abs in 750 ml. Tetrahydro-furan dissolved and inert for 15 minutes to a well-stirred solution of 8.0 g of lithium aluminum hydride in 750 ml abs. Ether added dropwise at 0 °. The mixture was then stirred at 0 ° for 1 hour. The reaction solution was initially worked up with

300 ml of moist ether carefully added. Then 40 ml of saturated Na2SO4 solution were added, the mixture was stirred for a further 10 minutes and the precipitate was filtered off. The filtrate was evaporated in vacuo. 15.8 g of substance were obtained, which were heated to 50 ° with a mixture of 1,000 ml of methanol and 200 ml of 2N sodium hydroxide solution with stirring and gassing with argon for 45 minutes. The reaction solution was then poured onto 61 ice water and 200 ml of acetic acid and extracted three times with methylene chloride. The organic extract was washed with water, dried with Na2S04 and evaporated in vacuo. The residue was chromatographed on 650 g of silica gel. With acetone-hexane 1: 1, 13.0 gray 17ass-hydroxy-D-homo-an-drosta-4,16-dien-3-one could be eluted. M.p. 183-185 °.

UV: e241 = 16,200. [A5 "= +76 °.

Example 2

A solution of 6.3 g of 17ass-hydroxy-D-homo-androsta-4,16-dien-3-one in 60 ml of pyridine and 60 ml of acetic anhydride was kept at room temperature overnight. The solvent was then removed in vacuo and the residue removed

Acetone-hexane recrystallized. 6.0 g of pure 17ass acetoxy-D-homo-androsta-4,16-dien-3-one were obtained, mp. 165-167 °.

UV: e240 = 17,000. [A5 ° = +91 ° (c = 0.1 in dioxane).

5

According to the same method, using the appropriate acid anhydride, were made:

17ass-propionoxy-D-homo-androsta-4,16-dien-3-one, mp. 139-140 °,

io 17aß-Butyroxy-D-homo-androsta-4,16-dien-3-one, mp. 117-118 °.

Example 3

2.0 ml of phenylacetyl chloride were added dropwise to a solution of 2.0 g of 17ass-hydroxy-D-homo-andro-15 sta-4,16-dien-3-one in 20 ml of pyridine within 15 minutes and the mixture was left open for 5 hours Heated to 60 °. For working up, the mixture was poured onto water and extracted with methylene chloride. The organic extract was washed neutral with dilute hydrochloric acid, NaHC03 solution and 20 water, dried with Na2S04 and evaporated in vacuo. The residue was chromatographed on silica gel. With hexane-acetone 9: 1, 1.7 g of pure 17ass-phenylacetoxy-D-homo-androsta-4,16-dien-3-one was eluted, mp 135-136 ° (acetone-hexane).

25th

UV: 8240 = 17,200. [A5 "= +108 ° (c = 0.1 in dioxane).

The following method, using the appropriate acid chloride, was used to prepare: 30 17ass-undecanoyloxy-D-homo-androsta-4,16-dien-3-one; amorphous; [a5 ° = +80 ° (c = 0.1 in dioxane), e240 = 17 100,

17ass-heptanoyloxy-D-homo-androsta-4,16-dien-3-one; oily, [a5 ° = +88 ° (c = 0.1 in dioxane),

17 a-phenoxyacetoxy-D-homo-androsta-4,16-dien-3-one, 35 mp 174-176

Example 4

1.0 g 17ass-hydroxy-D-homo-androsta-4,16-dien-3-one was in 40 ml abs. Dissolved benzene and then distilled off 10 ml of Ben-40 zol. 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 at room temperature for 30 minutes. For working up, the reaction solution was successively washed neutral with NaHC03 solution and water 45, dried with Na2S04 and evaporated in vacuo. The residue was recrystallized from ether-hexane and gave pure 17a-tetrahydropyranyloxy-D-homo-androsta-4,16-dien-3-one, mp. 137-138 °. UV: e240 = 16,650, [a5 ° = +64 0 (c = 0.1 in dioxane).

50

Example 5

A solution of 2.0 g of 17ass-hydroxy-D-homo-androsta-4,16-dien-3-one in 40 ml of cyclopentanone-diethyl ketal was heated to 120 ° C. for 6 hours. The reaction solution was evaporated to dryness in a vacuum and the residue was chromatographed through 40 g of aluminum oxide act. II. With benzene, 1,2-greine 17ass-cyclopentenyloxy-D-homo-androsta-4,16-dien-3-one could be isolated. Mp 135-137 ° (methanol), [a5 '= +100 ° (c = 0.1 in dioxane). UV spectrum:

6o c24 (, = 17 200.

Example 6

A solution of 342 mg 17ass-acetoxy-D-homo-andro-sta-4,16-dien-3-one and 328 mg 2,3-dichloro-5,6-dicyano-ben-65 zoquinone (DDQ) in 30 ml of benzene was heated under reflux for 24 hours. The solution was cooled and filtered through a column of 10 g of Act. II alumina. The column was finally completely eluted with 200 ml of ethyl acetate. The Ver-

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626 098

united eluates provided 270 mg of crystalline material which recrystallized from acetone-hexane to give pure 17a-acetoxy-D-homo-androsta-l, 4,16-trien-3-one. Mp 222-224 °, UV: e244 = 14,800, [a] £> 5 ° = +53 °.

Example 7

• The following method is used as in Example 4:

17ass-pentyloxy-D-homo-androsta-4,16-dien-3-one, mp 58-59 ° (from methanol-water), [<x] d ° = +112 ° (c = 0.1 in Dioxane), e24o = 16 700,

17 aß-n-decyloxy-D-homo-androsta-4,16-dien-3-one, oily, barrel 5 ° = +94 ° (c = 0.1 in dioxane) 8240 = 16 650,

17ass-benzyloxy-D-homo-androsta-4,16-dien-3-one; Mp 139-141 ° (from acetone-hexane) [a] ^ 5 ° = +130 °;

£ ■ 240 = 16,600;

17ass-CyclohexyImethyIoxy-D-homo-androsta-4,16-dien-3-one; mp. 98-99 °; [a5 "= + 112 °; e241 = 16,700.

Example 8

To a solution of 3.0 g of lithium aluminum hydride in 400 ml abs. Ether was added dropwise with stirring and cooling to 0 °, a solution of 6.0 g of D-homo-androsta-4,16-diene-3,17a-dione in 100 ml of tetrahydrofuran and 100 ml of ether, and the mixture was then stirred for a further 1 hour at 0-5 °. For working up, 300 ml of moist ether and then 10 ml of saturated Na2SO4 solution were carefully added. The reaction mixture was stirred for a further 15 minutes, then the precipitate was filtered off and washed thoroughly with methylene chloride. The combined filtrates were evaporated in vacuo. The residue was chromatographed on 330 g of silica gel and gave 4.1 g of pure 3β, 17ass-dihydroxy-D-homo-andro-sta-4,16-diene, mp. 158-162 ° (acetone-hexane).

[o] d ° = +23 ° (c = 0.1 in dioxane).

A solution of 3.0 g3ß, 17aß-Dihydroxy-D-homo-an

drosta-4,16-diene in 50 ml pyridine and 50 ml acetic anhydride was kept at room temperature for 18 hours. The solution was then evaporated in vacuo and the residue recrystallized from methanol. Pure 3ß, 17ass-diacet-5 oxy-D-homo-androsta-4,16-diene was obtained, mp 115-116 °.

wr = + i2 °.

Example 9

The following is prepared in a manner analogous to Example 1: io 17ass-hydroxy-D-homo-5a-androst-16-en-3-one, mp. 203-205 ° (acetone-hexane), [<x] d ° = + 1 ° (c = 0.1 in dioxane).

Example 10

2.0 g 17ass-hydroxy-D-homo-5a-androst-16-en-3-one i5 were acetylated with 50 ml pyridine and 50 ml acetic anhydride at room temperature. The 17a acetate obtained by conventional workup was dissolved in 20 ml of dioxane and, after adding 3 drops of 40% HBr glacial acetic acid solution, a solution of 0.36 ml bromine and 570 mg sodium acetate 20 in 37 ml glacial acetic acid was added within 30 minutes. 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 were obtained, which was dissolved in 20 ml of dimethyl acetamide and added to a boiling mixture of 5.1 g of calcium carbonate and 45 ml of dimethylacetamide within 20 minutes. The mixture was then refluxed for a further 30 minutes, then cooled to 60 ° and the calcium salts were filtered off. The filtrate was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, dried with Na2SO4 and evaporated in vacuo. 2.2 g of crude product were obtained, which was chromatographed on 50 times the amount of silica gel. With methylene chloride, 1.2 gray 17ass acetoxy-D-homo-andro-stal, 16-dien-3-oneluated. M.p. 133-135 °.

35 [a 5 ° = + 55 °. UV spectrum: e229 = ll 100.

C.

Claims (7)

626 098 PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula , 17 ate at least one acyloxy group is present in the 3ß or 17ass position, characterized in that a D-homosteroid of the formula I is prepared by the process of claim 1 and a free hydroxyl group is esterified in the 3ß and / or 17ass position. 3. Process for the preparation of a D-homosteroid of the formula 17 2ass where the dotted lines in the A-ring denote optional C-C bonds; R3, if ring A is saturated, oxo or, if ring A is unsaturated, oxo, (a-H, ß-OH) or (a-H, ß-O-acyl); R17aP is hydrogen, Ci_10-alkyl, benzyl, cyclohexylmethyl, acyl, tetrahydropyranyl or cycloalkenyl; mean, wherein at least one hydroxyl group is in the 3ß- or 17ass position, characterized in that in a D-homosteroid of the formula n in which R3 and the dotted lines have the meaning given and Z represents oxo or (OR17afî, H), if Z represents oxo, the 17a-keto group is reduced to the hydroxy group with intermediate protection of a 3-keto group or, if R3 represents oxo and the A Ring is monounsaturated, the 3-keto group and any 17a-keto group present are reduced to the hydroxy group. 2. A process for the preparation of a D-homosteroid in which the dotted lines in the A ring and R3 have the meanings given in claim 1 and R172ass C] _10-alkyl, benzyl, cyclohexylmethyl, tetrahydropyranyl or cycloalkenyl, characterized in that one 17aß-Hydroxy-D-homosteroid of formula I according to the method of claim 1 and etherified. 4. The method according to claim 1, characterized in that starting from a D-homosteroid of the formula II obtained in the A-ring saturated or monounsaturated D-homosteroid of the formula I to a mono- or doubly unsaturated D-homosteroid in the A-ring of formula I dehydrated. 3s 5. The method according to claim 1, characterized in that the 17ass acyloxy group is saponified in a D-homosteroid of the formula I obtained from a D-homosteroid of the formula II. 6. The method according to claim 1, characterized in that 40 compounds of formula I are prepared in which R17afi Is hydrogen, lower alkanoyl, tetrahydropyranyl or cycloalkenyl. 7. The method according to claim 1, characterized in that compounds of formula I are prepared in which R3 is oxo and the ring A contains a double bond. 8. The method according to claim 1, characterized in that compounds of formula I are prepared in which R17ap represents hydrogen or lower alkanoyl. 45 50 17 let