CH620458A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids of the formula <IMAGE> in which R<6> is hydrogen, fluorine, chlorine or methyl; R<9> is fluorine, chlorine or bromine, 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 treatment of the corresponding 9 beta ,11 beta -epoxy-D-homosteroid with hydrogen fluoride, chloride or bromide. The compounds have an endocrine, in particular corticoid-like action.

Description

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

COOR20

i i in the R6 hydrogen, fluorine, chlorine or methyl; R9 fluorine, chlorine or bromine; R! 7a 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 means an optional C-C 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 1-7 alkanoyloxy groups are particularly preferred. Lower alkyl groups can be straight or branched chain and contain carbon atoms. Lower alkyl groups with 1-4 carbon atoms, in particular methyl and ethyl, are particularly preferred. The terms halo-lower alkyl, hydroxy-lower alkyl are to be understood in the same way. The term “halo” includes, unless specifically defined, fluorine, chlorine, bromine and iodine. Examples of halo-lower alkyl radicals are fiormethyl, chloromethyl, bromomethyl, β-fluoroethyl, β-chloroethyl and β-bromoethyl. Examples of hydroxy (and acyloxy) lower alkyl

5

10th

15

20th

25th

30th

35

40

45

50

55

60

fi5

3rd

620 458

are ß-hydroxyethyl and ß-acetoxy-ethyl. A lower alkoxy-carbonyl-lower alkyl radical is, for example, methoxycarbonyl-methyl.

A preferred group of compounds of formula I are those in which R9 represents fluorine or chlorine. 5

Another preferred subgroup are the compounds of the formula I with a 1,2-double bond.

Examples of compounds according to the invention are: 9cx-fluor-lß, 17aa-dihydroxy-3-oxo-D-homoandrost-4-en-17ass-carboxylic acid, 111

9a-fluoro-11β, 17aa-dihydroxy-3-oxo-D-homoandrosta-l, 4-diene-17ass-carboxylic acid,

6ct, 9a-difluoro-lß, l 7aa-dihydroxy-3-oxo-D-homoan-drost-4-en-l 7ass-carboxylic acid,

6a, 9a-difluor-lß, 17aa-dihydroxy-3-oxo-D-homoan-15 drosta-1,4-diene-17 aß-carboxylic acid,

6a-chloro-9a-f luor-11 ß, 17 aa-dihydroxy-3-oxo-D-homoan-drost-4-en-17ass-carboxylic acid,

6a-chloro-9a-fluoro-11β, 17aa-dihydroxy-3-oxo-D-homoan-drosta-1,4-diene-17ass-carboxylic acid, 20

the methyl, ethyl, propyl and butyl esters of these compounds as well as the 17aa acetates, propionates and butyrates, e.g. 17aa-acetoxy-9a-fluoro-lß-hydroxy-3-oxo-D-homoan-drosta-1,4-diene-17ass-carboxylic acid methyl ester.

According to the invention, the D-homosteroids of the formula I can be prepared by using a D-homosteroid of the formula

R6

11

35

40

45

treated with hydrogen fluoride, chlorine or bromine.

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-dicyanobenzochin 50 non, chloranil or lead tetraacetate. Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the Genera Arthobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B.

lentus ATCC 13805 and B. sphaericus ATCC 7055; Pseudo-55 monas, 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 halogenation of a steroid of formula I in the 6-position can be carried out in a manner known per se. A 6.7-60 saturated D-homosteroid of formula I can be halogenated by reaction with a halogenating agent, such as an N-chloramide or imide (e.g. N-chlorosuccinimide) or with elemental chlorine [cf. J. Am. Chem. 72, 4534 (1950)]. The halogenation in the 6-position is preferably carried out by converting a 6,7-saturated D-homosteroid of the formula I into a 3-enol ester or 3-enol ether, e.g. the 3-enol acetate, transferred and then with chlorimide [cf. J. At the. Chem. Soc.

82, 1230 (I960)]; with an N-chloroimide [cf. J. Am. Chem. Soc. 82, 1230 (I960)]: 77, 3827 (1955)] or perchloryl fluoride [cf. J. Am. Chem. Soc. 81, 5259 (19597; Chem. And Ind. 1959, 1317]. Tri-fluoromethyl hypofluorite can also be used as the fluorinating agent.

If isomer mixtures, i.e. Mixtures of 6a- and 6ß-halogen-steroids are formed, these can be separated into the pure isomers by known methods, such as chromatography.

The isomerization of a 6β-halogen-D-homo-steroid obtained, i.e. a 6β-fluorine or chlorine compound can be treated by treatment with an acid, especially a mineral acid such as hydrochloric acid, or hydrobromic acid in a solvent, e.g. Dioxane or glacial acetic acid can be made.

To carry out the process according to the invention, the starting material II is expediently dissolved in a suitable solvent, e.g. an ether, such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a ketone, such as acetone, and allows the reagent to be added to act.

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. Organic solvents which contain non-hydroxyl groups, 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 To treat pyridine), 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 0-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 17acc 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. are prepared by reacting a salt of a D-homosteroid carboxylic acid of the formula I 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 metal halide, e.g. Lithium chloride in dimethylformamide, treated to obtain an R20 haloalkyl substituent. Haloalkyl esters can also be obtained by corresponding the D-homosteroid carboxylic acid with one

620 45b the aldehyde in the presence of hydrogen halide, expediently in the presence of a catalyst such as ZnCU.

The hydrogenation of a 1,2-double bond in a D-homosteroid of formula I can be catalytic, e.g. with Pd or tris (triphenyiphosphine) 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 the effects of mineral or glucocorticoid nature. The following table summarizes the effectiveness of the compound class. The tests carried out can be described as follows:

1. Vasoconstriction test

The anti-inflammatory effect on the experimentally hyperemized skin is demonstrated (Brit. J. Derm. 69, 11 (1957)). The degree of vasoconstriction as a function of time (after 4 and 8 hours) is assessed visually. The color value of the hyperaemic, untreated skin is rated O, that of the non-hyperemic skin 100. The compounds were used in a concentration of 0.1%.

2. Same ear test

The test substances, dissolved in croton oil, were applied to male mice (25-30 g) with a pressure of 600 g for 15 seconds on the right ear. The left ear served as a control. 4 hours later the animals were sacrificed and the treated

Connection test

17aa-acetoxy-9afluoro-1 lß-hydroxy-3-oxo-D-homoandrosta-1,4-diene-17ass-carboxylic acid methyl ester

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 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, mixed and optionally brought into the desired shape.

ten untreated. Ear is removed from the ear at the same location with a punch and weighed. The EC3U was determined. i.e. the concentration at which there was 50% inhibition of edema compared to a control group.

5 3> .FHzpellei-Tesi

Female rats <90-110 g) were implanted under the skin (scapular region) under ether anesthesia with 2 felt pellets. The test substances were administered orally on 4 consecutive days, starting on the day of the implantation. On the 5th

The animals were sacrificed for 10 days, the granuloma formed was removed, dried and weighed. The ED40, i.e. the dose at which a 40% inhibition of the granulation weight occurred. In addition, the thymus and adrenal fresh weight and the weight changes were determined.

4. Thymolysis test

The rats used in the felt pellet test were used. The ED5U was determined, i.e. the dose that caused a 50% reduction in thymus weight.

5 adjuvant paw edema

The experiments were carried out on female Lewis rats (130-150 g). The edema was triggered by subplantar injection of Mycobacterium butyricum into the right hind paw (0.5 mg M. butyricum / 0.1 ml viscous paraffin). The test substances (suspended in 0.5% tragacanth / 0.9% NaCl) were administered immediately before and 24 hours after the edema was set. The paw diameter was measured before and 48 hours after the edema was set. The ED5U, i.e. the dose at which 50% edema inhibition occurs was determined graphically.

example 1

2.5 g of 17aa-acetoxy-3-oxo-D-homoandrosta-l, 4.9 (l 1) -45 trien-17ass-carboxylic acid methyl ester were in 100 ml of dioxane and 10 ml of water with 1.73 g of N-bromoacetamide and 11.1 ml of 1 above perchloric acid were added and the mixture was stirred at room temperature for 10 minutes. Then 9 g of sodium sulfite in 90 ml of water were added. After stirring briefly, the mixture was extracted with methylene chloride 50, washed with water, dried and evaporated. The crude 17aa-acetoxy-9-bromo-1-beta-hydroxy-3-oxo-D-homo-androsta-1, 4-diene-17ass-carboxylic acid methyl ester and 1.5 g of dry potassium acetate were refluxed in 150 ml of Alkonol for 24 hours cooked. The reaction mixture was concentrated, poured onto water and extracted with CH2C12. The organic solution was washed, dried and evaporated. The resulting crude 17aa-acetoxy-9ß, 1 lß-epoxy-3-oxo-D-homoandrosta-1, 4-diene-17ass-carboxylic acid methyl ester was dissolved in 30 ml of a solution of 1.25 parts of hydrogen fluoride 60 in 1 part of urea for 20 minutes stirred at room temperature. The reaction mixture was poured onto ice water and washed with CH2CI; extracted. The organic extract was washed with dilute saline, dried and evaporated. Chromatography on silica gel gave 17aa-acetoxy-9-fluoro-lß-b 'hydroxy-3-oxo-D-homoandrosta-l, 4-diene-17ass-carboxylic acid methyl ester, mp 244-245 "C.

(1) (2) (3) (4) (5)

Vasoconstriction mouse ear pellet thymolysis adjuvant edema 4 hrs / 8 hrs ED5U (mg / kg) ED4U (mg / kg) ED50 (mg / kg) ED5u (mg / kg)

63/67 1 9 0.9 1.3

20th

25th

5

620 458

Example 2

In a manner analogous to Example 1, the 9a-fluorine-lß, 17aa-dihydroxy-3-oxo-D-homoandro-sta-l, 4-diene-17ass-carboxylic acid of mp 273-274 ° C. was obtained;

UV: e235 = 14,900; [a] D = + 32 ° (c = 0.1% in dioxane);

17aa-acetoxy-9cc-fluoro-1ß-hydroxy-3-oxo-D-homo-androsta-1,4, dien-17ass-carboxylic acid, mp. 232-234 ° C; UV: e24u = 15 200; [a] D = + 6 ° (c = 0.108% in dioxane); the 9a-fluoro-1ß-hydroxy-3-oxo-17aa-propionyloxy-D-

homoandrosta-l, 4-diene-17ass carboxylic acid, mp. 221 ° C, UV: e24 |] = 14 500, [a] D = 4-11 ° (c = 0.1% in dioxane).

6a, 9-difluoro-11ß, 17aa-dihydroxy-3-oxo-D-homan-drosta-l, 4-diene-17ass-carboxylic acid, UV: e238 = 164 50,

the 17aa-acetoxy-6a-9-difluoro-11β-hydroxy-3-oxo-D-homoandrosta-1,4-diene-17ass-carboxylic acid methyl ester was prepared: mp 291-292 °; UV: e238 = 16600; [<x] D = + 13 ° (c = 0.1% in dioxane).

C.

Claims (10)

620 458 2nd PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula COOR20 Uö 0 I. I. in the R6 hydrogen, fluorine, chlorine or methyl; R9 fluorine, chlorine or bromine; R! 7a is hydroxy or acyloxy and R20 is hydrogen, lower alkyl, holo-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl or lower alkoxycarbonyl-lower alkyl and the dotted 1,2 bond is an optional CC bond, characterized in that to get a D homosteroid of the formula COOR20 0 f I treated with hydrogen fluoride, chlorine or bromine. 2. 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 of claim 1, and this with a group other than hydrogen Treating R20 donors. 3. A process for the preparation of an A4-D homosteroid of the formula I, characterized in that an A '^ - D-homosteroid of the formula I is prepared by the process of claim 1 and the 1,2-double bond is then hydrogenated. 4. A process for the preparation of an AU4-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 then dehydrated in the 1,2-position. 5. A process for the preparation of a D-homosteroid of the formula I in which R6 is fluorine or chlorine, characterized in that a compound of the formula I in which R6 is hydrogen is prepared by the process of claim 1, and this with a fluorination or Chlorinating agents treated. 5. A process for the preparation of a 6a-halogenated D-homosteroids of the formula I, characterized in that a 6-unsubstituted D-homosteroid of the formula I is prepared by the process of claim 1, this is then fluorinated or chlorinated in the 6-position and that 6a isomers isolated from a mixture of isomers. 7. A process for the preparation of a 6a-halogenated D-homosteroids of the formula I, characterized in that a 6-unsubstituted D-homosteroid of the formula I is prepared by the process of claim 1, this is then fluorinated or chlorinated in the 6-position and a 6ß-substituted D-homosteroid of the formula I obtained isomerized to the 6a isomer by means of an acid. 8. A process for the preparation of a 17a-acylated D-homosteroid of the formula I, characterized in that a 17a-hydroxy-D-homostereoid of the formula I is prepared by the process of claim 1 and then the 17a-hydroxy group is acylated. 9. The method according to claim 1, characterized in that D-homosteroids of the formula I are prepared in which R9 is fluorine or chlorine. 10. The method according to claim 1, characterized in that 1,2-unsaturated D-homosteroids of the formula I are prepared.