CH621804A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids with endocrine activity of the formula <IMAGE> in which R<6> is hydrogen, fluorine, chlorine or methyl; R<9> is hydrogen, fluorine, chlorine or bromine; R<17a> is hydrogen, hydroxyl or acyloxy and R<21> is hydrogen, halogen or a sulphate or phosphate radical, where appropriate in the form of a water-soluble salt, are prepared by 1,2-dehydrogenation of corresponding 1,2-saturated D-homosteroids and optional 21-halogenation, 17a alpha -acylation or 17a alpha -hydrolysis.

Description

The present invention relates to new D-homosteroids of the formula

CHa-R21

c = o

Rm

R8

wherein R6 is hydrogen, fluorine, chlorine or methyl; R9 is hydrogen, fluorine, chlorine or bromine; R17a is hydrogen, hydroxy or acyloxy and R21 is hydrogen, halogen or a sulfate or phosphate residue, optionally in the form of a water-soluble salt.

The term halogen includes fluorine, chlorine, bromine and iodine. An acyloxy group can be derived from a saturated or unsaturated aliphatic monocarboxylic acid, a cycloaliphatic, araliphatic or an aromatic monocarboxylic acid with preferably up to 15 C atoms. Examples of such acids are formic, acetic, piva lin, propion, butter, capron, oenanth, undecylene, oleic, cyclopentylpropionic, cyclohexylpropionic, phenylacetic and benzoic acid. Ci-7-alkanoyl groups are particularly preferred. A residue of a di- or tricarboxylic acid can e.g. B. derived from oxalic, malonic, succinic, fumaric, malic, tartaric or citric acid, preferably from succinic acid. Particularly suitable water-soluble salts of such acid residues are the alkali salts, such as Na, K or ammonium salts.

A preferred group of compounds of the formula I are those in which R6 is hydrogen or methyl, R8 is hydrogen or fluorine, R17a is hydroxy or Ci-7-alkanoyloxy and R21 is halogen.

Examples of compounds of the formula I are the 21-phosphates and 21-sulfates of the following compounds: 6a-chloro-17a, 21-dihydroxy-D-homopregna-l, 4-diene-3,11,20-trione,

6a-fluoro-17a, 21-dihydroxy-D-homopregna-l, 4-diene-3,11,20-trione,

17a, 21-dihydroxy-6a-methyl-D-homopregna-l, 4-diene-3,11,20-trione,

6a-chloro-9-fluoro-17a, 21-dihydroxy-D-homopregna-l, 4-

diene-3,11,20-trione, 6a, 9-difluoro-17a, 21-dihydroxy-D-homopregna-l, 4-diene-3,11,20-trione,

9-FIuoro-17a, 21-dihydroxy-6a-methyl-D-homopregna-l, 4-

diene-3,11,20-trione, 9-chloro-17a, 21-dihydroxy-D-homopregna-l, 4-diene

3,11,20-trione, 9-bromo-17a, 21-dihydroxy-D-homopregna-l, 4-diene-3,11,20-trione,

9-chloro-17a, 21-dihydroxy-6a-methyl-D-homopregna-l, 4-

diene-3,11,20-trione, 9-bromo-17a, 21-dihydroxy-6a-methyl-D-homopregna-l, 4-

dien-3,11,20-trion,

9-chloro-6a-fluoro-17a, 21-dihydroxy-D-homopregna-l, 4-diene-3, ll, 20-trione,

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621804

9-Bromo-6a-fluoro-17a, 21-dihydroxy-D-homopregna-l, 4-

diene-3, ll, 20-trione, 21-hydroxy-D-homopregna-l, 4-diene-3, ll, 20-trione, 9-fluoro-21-hydroxy-D-homopregna-l, 4-diene 3, ll, 20-trion, 6a-fluoro-21-hydroxy-D-homopregna-l, 4-diene-3, ll, 20-trion, 21-hydroxy-6a-methyl-D-homopregna-l, 4- diene-3, ll, 20-trione, 6a, 9-difluoro-21-hydroxy-D-homopregna-l, 4-diene-3,11,20-trione,

9-fluoro-21-hydroxy-6a-methyl-D-homopregna-l, 4-diene-3,11,20-trione,

and their 17a esters of acetic acid, propionic acid, butyric acid, valeric acid and succinic acid. Further examples of compounds of the formula I are:

21-chloro-17a-hydroxy-D-homopregna-l, 4-diene-3, ll, 20-trione, 21-chloro-6a-fluoro-17a-hydroxy-D-homopregna-l, 4-diene-3, 11.20-trion,

21-chloro-17a-hydroxy-6a-methyl-D-homopregna-l, 4-diene-3,11,20-trione,

21-chloro-9-fluoro-17a-hydroxy-2-homopregna-l, 4-diene

3,11,20-trion,

D-homoprednisone-21-sulfate,

D-homoprednisone-21-phosphate, sodium-D-homoprednisone-21-sulfate, potassium-D-homoprednisone-21-phosphate, 9-fluoro-D-homoprednisone-21-sulfate, 9-fluoro-D-homoprednisone-21- phosphate,

Ammonium 9-fluoro-D-homoprednisone-21-sulfate,

Potassium 9-fluoro-D-homoprednisone-21-phosphate.

The compounds of the formula I can be prepared according to the invention by using a D-homosteroid of the formula in a manner known per se

CHa-R21

c = o

R9

wherein R6, R9, R17a and R21 have the meanings given above, dehydrated in the 1,2-position.

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

The halogenation of a D-homosteroid of the formula I in the 21-position can take place by reacting such a compound in which R21 is hydrogen, if desired while protecting a 3-keto-A4 or a 3-keto-AM system, for example in the form of a 3-enaminium salt such as a 3-pyrrolidinium enamine, in acidic solution with elemental chlorine, bromine or iodine.

The acylation of a free hydroxy group in the 17a position of a D-homosteroid of the formula I can be carried out in a manner known per se by treatment with an acylating agent, such as an acyl chloride or anhydride, e.g. B. acetyl chloride or succinic anhydride, preferably in the presence of an acid-binding agent such as pyridine. The acylation of a 17a-hydroxy group is expediently carried out in the presence of an acid catalyst, such as p-toluenesulfonic acid, HCIO4 or HCl.

The saponification of a 17ad-acyloxy group in a steroid of the formula I can be carried out in a manner known per se, for. B. be accomplished with aqueous methanolic potassium carbonate solution.

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

Compounds of the formula II can be prepared from corresponding, known compounds having an 11-hydroxy group by oxidation of the latter.

The compounds of formula I are endocrine, in particular anti-inflammatory, very effective. The high effectiveness appears surprising after it was known that the D-homocortisone acetate only has Vs to V2 the hormone activity of the cortisone acetate (J. Am. Chem. Soc. 80, 3398).

The process products can be used as remedies, e.g. B. in the form of pharmaceutical preparations, which they use in a mixture with an enteral, percutaneous or parenteral application suitable organic or inorganic inert carrier material, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, dragees, supplements, capsules; in semi-solid form, e.g. B. as ointments; or in liquid form, e.g. B. 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 buffers. They can also contain other therapeutically valuable substances.

A guideline for the dose range of topical preparations can be about 0.01-1%, for systemic preparations about 0.1 to 10 mg per application unit.

The pharmaceuticals can be prepared in a manner known per se by the compounds of the formula I being used with therapeutic, non-toxic, solid and / or liquid carrier materials which are customary in such preparations, such as, for. B. the above, mixed and optionally brings into the desired shape.

example 1

500 mg of 21-chloro-17a-hydroxy ~ D-homopregn-4-en-3,11,20-trione and 350 mg of selenium dioxide were refluxed in argon for 25 hours in 25 ml of t-butanol and 0.25 ml of acetic acid. The reaction mixture was filtered and evaporated. The oil obtained was taken up in ethyl acetate and washed successively with sodium hydrogen carbonate solution, water, ice-cold ammonium sulfide solution, dilute ammonia, water, dilute hydrochloric acid and water. The ethyl acetate solution was dried and evaporated in vacuo. Chromatography on silica gel

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621 804 4

21-chloro-17a-hydroxy-D-homopregna-l, 4-diene-3, ll, 20-trione, example 2

Mp 233-234 ° C, ["] D = + 175 ° (c = 0.103 ° / o in dioxane), in a manner analogous to Example 1, D-homoprednisone UV: = 14950. 21-phosphate, UV: eää9 = 13,000.

M

Claims (5)

621804 1 wherein R6, R9, R17a and R21 have the meanings given above, dehydrated in the 1,2-position. 1 2. The method according to claim 1, characterized in that D-homosteroids of the formula I are prepared in which R6 is hydrogen or methyl, R9 is hydrogen or fluorine, Ri7a hydroxy or Ci-7-alkanoyloxy and R21 is halogen. 2nd PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula CH2-R21 : = o o wherein R6 is hydrogen, fluorine, chlorine or methyl; R9 is hydrogen, fluorine, chlorine or bromine; R17a is hydrogen, hydroxy or acyloxy and R21 is hydrogen, halogen or a sulfate or phosphate residue, optionally in the form of a water-soluble salt, characterized in that a D-homosteroid of the formula ! = 0 .R17a R » 3. The method according to claim 1 for the preparation of a compound of the formula I in which R21 is halogen, characterized in that a D-homosteroid of the formula I obtained in which R21 is hydrogen is halogenated in the 21-position. 4. The method according to claim 1 for the preparation of a 17aa-acyloxy-D-homosteroids of the formula I, characterized in that acylated 17aa-hydroxy-D-homosteroid of the formula I obtained. 5. The method according to claim 1 for the preparation of a 17aa-hydroxy-D-homosteroids of the formula I, characterized in that one saponifies a 17aa-acyloxy-D-homosteroid of the formula I obtained.