CH620456A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids of the formula <IMAGE> in which R<9> is hydrogen, fluorine, chlorine or bromine; R<11> is oxo or ( alpha -H, beta -OH) when R<9> is hydrogen, or oxo, ( alpha -H, beta -OH), ( alpha -H, beta -fluoro) or ( alpha -H, beta -chloro) when R<9> is F, Cl or Br, where the atomic numbers of the substituents R<9> and R<11> in 9,11-dihalo compounds are related as R<11> </= R<9>; R<17a> is hydroxyl or acyloxy and R<20> is hydrogen, lower alkyl, halo-lower-alkyl, hydroxy-lower-alkyl, acyloxy-lower-alkyl or lower alkoxycarbonyl-lower-alkyl, and the dotted 1,2 bond is an optional C-C bond, are prepared by 6-methylation of a corresponding 6-unsubstituted compound. The 6-methylation takes place by the known multistage methods described in Claims 1-8. The compounds have an endocrine, in particular corticoid-like, activity.

Description

The invention relates to a process for the preparation of D-homosteroids of the formula coon io a_

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in which R9, R11, R17a and R20 have the meanings given above, transferred and the latter catalytically hydrogenated.

4. A process for the preparation of a compound of the formula I in which R20 is different from hydrogen, characterized in that a compound of the formula I in which R20 is hydrogen is prepared by the process according to claim 1, and this with a group other than hydrogen R20 donating agent treated.

5. A process for the preparation of an A4-D homosteroid of the formula I, characterized in that an A1'4-D homosteroid of the formula I is prepared by the process of claim 1 and the 1,2-double bond in the A1 obtained, 4-D-homosteroid of formula I hydrogenated.

6. A process for the preparation of an A14-D-homosteroid of the formula I, characterized in that a 1,2-saturated D-homosteroid of the formula I is prepared by the process of claim 1 and this is dehydrated in the 1,2-position.

7. A process for the preparation of a 1 lß-hydroxy-D-homo-steroid of the formula I, characterized in that an 11-oxo-D-homosteroid of the formula I is prepared by the process of claim 1 and then the 11-keto group under inter-

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I.

in the R9 hydrogen, fluorine, chlorine or bromine; R11 means oxo or (aH, ß-OH) if R9 is hydrogen, or oxo, (aH, ß-OH), (aH, ß-fluorine) or (aH, ß-chlorine) if R9 = F, Is Cl or Br, where for the atomic numbers of the substituents R9 and R11 of 9,11-dihalogen compounds R "= R5; R17a is hydroxy or acyloxy and R20 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, acyloxy- lower alkyl or lower alkoxycarbonyl-lower alkyl and the dotted 1,2 bond mean an optional CC bond.

An acyloxy group can be derived from a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic, araliphatic or an aromatic carboxylic acid with preferably up to 15 C atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthic acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid. C 1-4 Alkanoyloxy groups are particularly preferred. Lower alkyl groups can be straight or branched chain and contain 1 to 6 carbon atoms. Lower alkyl groups with 1-4 carbon atoms, in particular methyl and ethyl, are particularly preferred. In the same way, the terms halo-lower alkyl, hydroxy-never

620 456

to understand deralkyl, acyloxy-lower alkyl and lower alkoxy-carbonyl-never-deralkyl. The term “halo” includes, unless specifically defined, fluorine, chlorine, bromine and iodine. Examples of halo-lower alkyl radicals are fluoromethyl, chloromethyl, bromomethyl, ß-fluoroethyl, ß-chloroethyl and ß-bromoethyl. Examples of hydroxy (and acyloxy) lower alkyl are ß-hydroxyethyl and ß-acetoxy-ethyl. A lower alkoxy-carbonyl-lower alkyl radical is, for example, methoxycarbonyl-methyl.

In 9,11-dihalogen compounds of the formula I, as mentioned, the halogen atom in the 11-position should have a smaller or at most the same atomic number as the 9-position halogen atom. In contrast, in the case of compounds of the formula I where R9 = H, R11 should only be oxo or (a-H, ß-OH).

A preferred group of compounds of formula I are those in which R11 represents (a-H, β-OH). Compounds in which R9 represents hydrogen, fluorine or chlorine are also preferred. Another preferred subgroup is represented by the compounds of the formula I with a 1,2-double bond.

Examples of compounds according to the invention are 11β, 17aa-dihydroxy-6a-methyl-3-oxo-D-homoandrost-4-en-17ass-carboxylic acid and the methyl, ethyl, propyl and butyl esters of this compound, and also 17aa -Acetate-, "Propionate and -Butyrate.

The D-homosteroids of the formula I can be prepared according to the invention by methylating a D-homosteroid of the formula in the 6-position.

The 1,2-dehydrogenation of a D-homosteroid of formula I can be carried out in a manner known per se, e.g. be carried out microbiologically or by means of dehydrating agents such as iodine pentoxide, periodic acid or selenium dioxide, 2,3-dichloro-5,6-dicyanobenzochinone, chloranil or lead tetraacetate. Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the Genera Arthrobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13805 and B. sphaericus ATCC 7055; Pseudomonas, e.g. P. aeruginosa IFO 3505; Flavobacterium, e.g. F. flavenscens IFO 3058; Lactobacillus, e.g. L. brevis IFO 3345 and Nocardia, e.g. N. opaca ATCC 4276.

The methylation according to the invention can be accomplished by converting the starting compound of the formula II into a 3-enol ether (for example by treatment with an orthoformate such as ethyl orthoformate in the presence of an acid such as p-toluenesulfonic acid, optionally with the addition of the corresponding one Alcohol; or by treating the starting compound II with a di-alkoxypropane, for example 2,2-dimethoxypropane in methanol-dimethylformamide in the presence of p-toluenesulfonic acid) and the enol ether with a tetrahalomethane, for example CBr4, CCl2Br2 or CCl3Br converted to trihalomethyl A4-3 ketone. The trihalomethyl A4-3 ketone can be used with bases such as collidine to

ethylene A4-3 ketone can be dehydrohalogenated, which in turn can be catalyzed by hydrogenation under mild conditions, e.g. can be converted into the 6a-methyl-A4-3-ketone using a Pd / SrC03 catalyst.

Another methylation method consists in converting a 1,2-saturated D-homosteroid of the formula II as described above into a 3-enol ether and converting it in a manner known per se to a corresponding 6-formyl derivative, the formyl group Sodium borohydride reduced to the hydroxymethyl group and the reaction product finally dehydrated with cleavage of the enol ether, a D-homosteroid of the formula

COOR20

0

CH

in which R9, R11, R17a and R20 have the meanings given above is obtained.

Such 6-methylene intermediates can also be obtained by converting Compounds II into a 3-enamine, e.g. the 3-pyrrolidinium enamine, hydroxymethylation with formaldehyde with cleavage of the enamine and elimination of water using acids such as p-toluenesulfonic acid. The 6-methylene-D-homosteroids of formula III thus obtained can be catalytically, i.e. be hydrogenated to the corresponding 6-methyl compounds by means of the known hydrogenation catalysts.

To reduce the 11-keto group contained in a compound I, the keto group of the compound I in the 3-position and the —COOR20 group are first protected. The 3-keto group can be protected by ketalization or, if a 1,2-double bond is present, also by the formation of an enamine. A 20-carboxyl group can be reacted with ethanolamine or 2,2-dimethylaziridine [Tetrah. Letters 30, 3031 (1972)] as oxazoline. These protective groups can be removed again by acid hydrolysis. An A1.4-3 ketone can with a sec. Amine can be converted into an Au, 5-3 enamine in the presence of TiCl4. The 11-keto group of the compound protected in this way can be reduced using complex metal hydrides, such as lithium aluminum hydride, sodium borohydride or diisobutyl aluminum hydride.

For the oxidation of the 11-OH group contained in a compound I, oxidizing agents such as chromic acid, e.g. Cr03 / sulfuric acid in acetone or Cr03 / pyridine.

The acylation of a 17a-hydroxy group can be carried out in a manner known per se, e.g. by treatment with an acylating agent such as an acyl chloride or anhydride in the presence of an acid binding agent, e.g. Pyridine or triethylamine or in the presence of a strong acid catalyst, e.g. p-Toluenesulfonic acid are carried out. Non-hydroxyl-containing organi4 are used as solvents for the acylation

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see solvents, e.g. chlorinated hydrocarbons such as methylene chloride or hydrocarbons such as benzene. It is also possible to first convert a 17aa-hydroxy-17ass-carbonic acid D-homosteroid of the formula I with a corresponding carboxylic acid anhydride into a mixed anhydride of the steroid carboxylic acid and to mix this mixed anhydride acidic or basic (for example with aqueous acetic acid or aqueous Pyridine) to treat, whereby the desired 17aa-acyloxy derivative of the starting compound I is obtained.

The functional modification of the group -COOR20 can e.g. consist in an esterification of a 20-carboxyl group, a transesterification of an esterified 20-carboxyl group or an esterification of a hydroxyl group contained in the radical R20. All of these reactions can be carried out according to methods known per se. The esterification can e.g. by treating the free acid with a diazoalkane, e.g. Diazomethane in ether; or with an O-alkyl-N.N'-dicyclo-hexylisourea in an aprotic solvent; or by reacting a salt of the acid, e.g. an alkali salt, with an alkyl halide or sulfate, e.g. Methyl or ethyl iodide or dimethyl or diethyl sulfate can be achieved.

The acylation of a hydroxyl group contained in the radical R20 can be accomplished analogously to the acylation of a 17acx-hydroxyl group described above. The transesterification of an esterified carboxyl group, e.g. the exchange of an alkyl group represented by R20 for another alkyl group can be carried out by reaction with the corresponding alcohol in the presence of an acidic catalyst such as perchloric acid. Compounds in which R20 represents a halogen or hydroxy substituted alkyl group can e.g. prepared by reacting a salt of a D-homosteroid carboxylic acid of formula XII with a sulfonyloxyalkyl halide to give a sulfonyloxyalkyl ester and hydrolyzing the latter to obtain a hydroxyalkyl substituent R20; or with an alkali or alkaline earth halide, e.g. Lithium chloride in dimethylformamide, treated to obtain an R20 haloalkyl substituent. Haloalkyl esters can also be obtained by reacting the D-homosteroid carboxylic acid with a corresponding aldehyde in the presence of hydrogen halide, advantageously in the presence of a catalyst such as ZnCl2.

The hydrogenation of a 1,2-double bond in a D-homosteroid of formula I can be catalytic, e.g. with Pd or tris (triphenylphosphine) rhodium chloride.

Unless they are known or described below, the starting materials can be prepared in analogy to known methods or those described in the examples.

The D-homosteroids of formula I are endocrine, in particular anti-inflammatory. They have a good ratio of the anti-inflammatory effect to effects of mineral or glucocorticoid nature.

The process products can be used as medicinal products in the form of pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Water, gelatin, gum arabic, milk sugar, starch, magnesium

620 456

stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly etc. can be used. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffer substances.

A guideline for the composition of topical preparations can be about 0.01-1% content of a compound of formula I. In the case of systemic preparations, approximately 0.1-10 mg of active ingredient can be provided per application.

The pharmaceuticals can be prepared in a manner known per se by combining the compounds of the formula I with non-toxic, suitable for therapeutic administration, solid and / or liquid carrier materials which are customary in such preparations, e.g. the above p, mixed and optionally brought into the desired shape.

example

2.0 g of 17aa-acetoxy-11ß-hydroxy-3-oxo-D-homoandrost-4-en-17aa-carboxylic acid methyl ester were dissolved in 20 ml of methanol and, after adding 1.5 ml of pyrrolidine, heated under reflux for 10 minutes under nitrogen. The solution obtained was kept at -10 ° C. overnight. The crystalline precipitate was filtered off and dried under reduced pressure at room temperature. 2.0 g of 17aa-acetoxy-11ß-hydroxy-3-pyrrolidino-D-homoandrosta-3,5-diene-17ass-car-bonic acid methyl ester were obtained; UV: e278 = 19,500.

2.0 g of 17aa-acetoxy-1-beta-hydroxy-3-pyrrolidino-D-homo-androsta-3,5-diene-17-a-carboxylic acid methyl ester were mixed with a mixture of 11 ml of benzene, 50 ml of methanol and 4 ml of 35% strength Formaldehyde solution stirred for 45 minutes at room temperature. The crude product obtained by conventional work-up was chromatographed on silica gel with methylene chloride / acetone (9: 1) and gave 1.1 g of pure 17aa-acetoxy-1-lß-hydroxy ~ 6ß-hydroxymethyl-3-oxo-D-homoandrost-4-ene -17aa-carboxylic acid methyl ester. 1.0 g of this substance was dissolved in 50 ml of dioxane and concentrated with 1 ml of water and 1 ml. Hydrochloric acid stirred for 2 hours at room temperature. After the usual work-up and chromatography of the crude product, pure 17aa-acetoxy-11ß-hydroxy-6-methylene-3-oxo-D-homoan-drost-4-en-17 aß-carboxylic acid methyl ester was obtained.

UV: e26I = 11 200.

230 mg of 17aa-acetoxy-11ß-hydroxy-6-methylene-3-oxo-D-homoandrost-3-en-17aa-carboxylic acid methyl ester and 80 mg of 1,4-diazobicyclo [2.2.2.] Octane were dissolved in 17 ml of methoxyethanol , mixed with 30 mg of 5% palladium-carbon and shaken under hydrogen until no more hydrogen was absorbed. The catalyst was filtered off under argon and 1.3 ml of 25% hydrochloric acid were added to the filtrate.

After 1 hour it was poured onto water, extracted with methylene chloride, washed neutral with sodium bicarbonate solution and brine, dried and evaporated. Chromatography on silica gel provided 17acc-acetoxy-1-beta-hydroxy-6a-methyl-3-oxo-D-homoandrost-4-en-17ass-carboxylic acid, methyl ester. UV: e232 - 15,000.

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Claims (8)

620 456 2nd PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula in which R9 is hydrogen, fluorine, chlorine or bromine; R11 means oxo or (aH, ß-OH) when Ry is hydrogen, or oxo, tali, ß-OH), aH, ß-fluorine) or (aH, ß-chlorine) when R9 = F, Cl or Br is, where for the atomic numbers of the substituents R9 and R11 of 9,11-dihalogen compounds R "ë R9, R17a is hydroxy or acyloxy and R2U is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-nideralkyl, acyloxy-lower alkyl or lower alkoxycarbonyl-lower alkyl, characterized in that a D-homosteroid of the formula in which R9 is hydrogen, fluorine, chlorine or bromine; R11 is oxo or (aH, β-OH) if R9 is hydrogen, or oxo, (a - H, ß-OH), (aH, ß-fluorine) or (aH, ß-chlorine) means when R9 = F, Cl or Br, whereby for the atomic numbers of the substituents R9 and R11 from 9.11- Dihalogen compounds R11 R9 applies, R17a is hydroxy or acyloxy and R20 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl or lower alkoxycarbonyl-lower alkyl and the dotted one I, 2-bond mean an optional CC bond, characterized in that a D-homosteroid of the formula is methylated in the 6-position by using a 3-enol ether corresponding to the D-homosteroid 25 of the formula II 'in the 6-position for -mylated, the formyl group reduced to the hydroxymethyl group, the reaction product with cleavage of the enol ether to a D-homosteroid of the formula 30th COOR20 methylated in the 6-position by reacting a 3-enol ether corresponding to the D-homosteroid of the formula II with a tetrahalomethane to give the trihalomethyl A4-3 ketone, which is dehydrohalogenated with a base to give the dihalomethylene A4-3 ketone and the latter catalytically hydrogenated. 2. Process for the preparation of D-homosteroids of the formula in which R9, R11, R! 7a and R20 have the meanings given above, are dehydrated and the latter is catalytically hydrogenated. 3. Process for the preparation of D-homosteroids of the formula 1 20th COOR q V 3rd 620 456 in the Rl) hydrogen, fluorine, chlorine or bromine; R "means oxo or (aH, ß-OH) when R9 is hydrogen, or oxo, (aH, ß-OH), (aH, ß-chlorine) or (aH, ß-chlorine) means when R9 = F , Cl or Br, where for the atomic numbers of the substituents R9 and R "of 9,11-dihalogen compounds R" = R9, R17a is hydroxy or acyloxy and R20 is hydrogen, lower alkyl, halo-lower alkyl, hydroxy-nideralkyl, Acyloxy-lower alkyl or lower alkoxycarbonyl-lower alkyl, characterized in that a D-homosteroid of the formula 20th medial protection of the 3-oxo group and any free 17a-carboxy group present to the 1 lß-hydroxy group reduced. 8. A process for the preparation of an 11-oxo-D-homosteroid of the formula I, characterized in that an 11-hydroxy-D-homosteroid of the formula I is prepared by the process of claim 1, and then the 11-hydroxy group to the keto group oxidized. 9. A process for the preparation of a 17a-acylated D-homo-steroid of the formula I, characterized in that a 17a-hydroxy-D-homostere-roid of the formula I is prepared by the process of claim 1 and then the 17a-hydroxy group in the resulting D-homosteroid of formula I acylated. 10. The method according to claim 1, characterized in that D-homosteroids of the formula I are prepared in which R11 is (a-H, ß-OH). 11. The method according to claim 1 or 10, characterized in that D-homosteroids of the formula I are prepared in which R9 represents hydrogen, fluorine or chlorine. 12. The method according to claim 1, characterized in that 1,2-unsaturated D-homosteroids of the formula I are prepared. methylated in the 6-position by hydroxy-methylating a 3-enamine corresponding to the D-homosteroid of the formula II 'in the 6-position, the enamine being cleaved, the compound obtained by elimination of water into a D-homosteroid of the formula