SE429865B - PROCEDURE FOR PREPARING 3,20-DIOXO-7ALFA-HALOGEN-DELTA? 724-PREGNANCES AND -1,4-PREGNANCY - Google Patents

Description

The acyl group of retinoic acid or of a carbonic acid having up to 12 carbon atoms and T is hydrogen, fluorine, chlorine or lower alkyl; Q is chlorine or bromine or a group OV, wherein V is a hydrogen atom or an acyl group of a carbonic acid having up to 12 carbon atoms or, provided that W is a group (H, H) or (H, lower alkyl), Q may also be a hydrogen atom; or wherein Q and W together form 16a, 17a- (lower alkylidene) -dioxy, -cycloalkylidenedioxy or -aralkylidenedioxy together with a 166- hydrogen atom or a group --- s \\\ Ö šššc-al r __0 ”// or __o R 1 wherein R is lower alkyl and R; is lower alkyl or phenyl; B is a hydrogen atom or together with Q forms a 14m, 17a-lower alkylidene dioxy group; M is a group -GHO or such a group in the form of an acetal, hemiacetal or aoylal, -CH 3, -COOR 3, -CH 2 Hal or CH 2 O 2, wherein R 3 is a hydrocarbon group having up to 12 carbon atoms, Hal is a halogen atom having a lower atomic weight than 100 and V2 is a hydrogen atom or an acyl group of retinoic acid, of a carbonic acid having up to 12 carbon atoms or of phosphoric acid, which may be in the form of a mono- or dialkali or alkaline earth metal salt; or wherein OV 2 together with Q forms one of the groups alkylidene dioxy, cycloalkylidene dioxy, aralkylidene dioxy, alkyl orthoalkanoate or alkyl orthoaryl carboxylate; or, provided that Q is an O-acyl group, M may also be any group -OR 2, wherein R 2 is lower alkyl or halogen- (lower alkyl); X is a hydrogen atom or a halogen atom having an atomic weight of less than 100; Y is an oxygen atom or a group (H, B-OH) or (H, B-OCOH), or, provided that X is chlorine or bromine, Y may also be a group (H, B-halogen), which halogen has an atomic weight lower than 100 and is at least as electronegative as X or, provided that X is hydrogen, Y may also be a group (H, H); A, which is present in the α-position of the 4-pregnenes, is a hydrogen atom or, provided that Y is (H, ß-OH), A may also be a chlorine or fluorine atom or a methyl group; and Z is chlorine, bromine or iodine; and, when W is (H, H), Dehomo analogues thereof. The hydrocarbon groups in the substituent R 3 may be, for example, aliphatic groups having up to 12 carbon atoms, incl. straight or branched alkyl groups, in particular lower alkyl groups and cycloaliphatic groups, which may be saturated or unsaturated or substituted or unsubstituted, and aryl, aralkyl and alkaryl. However, alkyl groups having up to 4 carbon atoms are most suitable. Typical unsaturated aliphatic groups are vinyl, propenyl, propynyl and butenyl; typical cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and pedicyclohexyl; typical aryl groups are phenyl, α-naphthyl and p-diphenyl; typical alkaryl groups are tolyl, xylyl and sym-diethylphenyl; and typical aralkyl groups are benzyl and phenethyl.

The lower alkyl groups included in the definitions of W, T, R, E1, R2 and R3 contain up to 6 carbon atoms and thus comprise pentyl and hexyl, but preferably contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl.

The acyl groups of carboxylic acids having up to 12 carbon atoms included in the definitions of V, V1 and V2 may be saturated, unsaturated, straight or branched, aliphatic, ocyclic, cycloaliphatic, aromatic, aromatic-heterocyclic, arylaliphatic or alkylaromatic, substituent with one or more hydroxy groups or of alkoxy groups containing 1 to 5 carbon atoms or of halogen atoms. Typical ester groups of the 7-halo-3,20-dioxo-1,4-pregnadienes of the invention are thus derived from hydrocarbon carboxylic acids, such as alkanoic acids exemplified by formic acid, trimethyl acetic acid, isobutyric acid, isovaleric acid, oenoic acid, capric acid, eiclopentylpuryl acid - tank carbonic acid; substituted alkanoic acids such as phenoxyacetic acid, trifluoroacetic acid and 9-chloropropionic acid; aromatic and substituted aromatic acids, especially benzoic acids, substituted by a halogen atom or a methoxy group, such as benzoic acid, toluic acid, p-chlorobenzoic acid, p-fluorobenzoic acid, p-metoribenzoic acid and 3,5-dimethylbenzoic acid; aromatic-heterocyclic acids, especially isonicotinic acid; arylalkanoic acids such as phenylacetic acid, phenylpropionic acid and β-benzoylaminoisobutyric acid; unsaturated acids such as acrylic acid and sorbic acid; and dibasic acids, such as succinic acid, tartaric acid and phthalic acid.

The most suitable acyl groups are those derived from lower alkanoic acids having up to 8 carbon atoms, especially from acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, caproic acid and t-butyl acetic acid, and from benzoic acid or the substituted benzoic acids mentioned, in particular those derived from propionic acid, n-butyric acid and benzoic acid.

X is preferably fluorine or especially hydrogen and Z is preferably chlorine or bromine. The alkylidene or alkylidene dioxy groups represent of = CHT, of W and W together, of B and Q together or of OVZ and Q together, preferably contain up to 4 carbon atoms and thus include methylene, ethylidene, n-propylidene, isopropylidene , n-butylidene and sec-butylidene and their corresponding dioxide derivatives.

W is preferably a methylene group or a group (H, CH 3), especially (H, a-C 3). Y is preferably an oxygen atom or a group (H, B-OH).

A particularly suitable group of the 1,4-pregnadienes according to the invention has the formula (II) wherein Z is a chlorine or bromine atom, W is a methylene group or the group (H, CH 3), Y is an oxygen atom or the group (H, 6-OH ) and V and V2, which may be the same or different, are hydrogen atoms or acyl groups of hydrocarbon carboxylic acids having up to 12, especially up to 8 carbon atoms.

The dashed line at the 1,2-positions preferably represents a 1,2 = double bond, since the 1,4-pregnadienes are generally much more stable and easier to produce than the 4-pregnenes.

A particularly suitable group of the 3,20-dioxo-7m-halogen-4-impregnates according to the invention may be represented by the formula (III) wherein Z is an iodine atom or preferably a chlorine or bromine atom, Y is an oxygen atom or the group (H, ß-OH), W is a methylene group or the group (H, CH 3) or (H, H) and V and V 2, which may be the same or different, are hydrogen atoms or acyl groups of hydrocarbon carboxylic acids having up to 12, preferably up to 8 carbon atoms. V and V2 in formulas II and III may in particular be any of the aoyl groups defined above.

A particularly suitable compound within this group is 7α-chloro-4 -pregnene-11β, 17α, 21-triol-3,20-dione-17,2-dipropionate. The 7d-halogen-3,20-dioxo-4-pregnenes and -1,4-pregnadienes of formula I are usually white to off-white crystalline solids which are insoluble in water (with the exception of alkali metal salts of their esters such as hemisuccinate). and the phosphate esters) and are soluble in most organic solvents, especially in acetone, dioxane, dimethylformamide and dimethyl sulfoxide, although they exhibit limited solubility in non-polar solvents such as dialkyl ethers and alkanes. The 7α-halo-1,4-pregnadienes are preferably maintained at room temperature, such as 0-5 ° C, when stored for long periods to reduce the decomposition to the corresponding 1,4,6-pregnatrienes (from which they can usually be prepared). For short-term storage, the 7d chlorine derivatives are relatively resistant up to 100 ° C, but the 7a-bromine derivatives should be stored below 55 ° C. The 7d-halo-3,20-dioxo-4-pregnenes are preferably stored in an open vessel, placed in a chamber under reduced pressure and at moderate temperatures, such as 0-40 ° C, to reduce the decomposition to the corresponding 4.6 -pregnadienes (from which they are usually produced) during the release of hydrogen halide. The 3,20-dioxo-7d-halogen-1,4-pregnadienes of formula I, especially those in which V is hydrogen or acyl or in which OV and Q together are a 17d, 2,1-alkylidene dioxy group, usually show corticoid activity.

Those exhibiting halogens in both C-9 and C-II or an oxygen function at C-11 and a halogen or hydrogen atom at C-9 exhibit glucocorticoid activity and are particularly valuable as anti-inflammatory agents.

Particularly suitable anti-inflammatory agents, especially for topical administration, are the 3,20-dioxo-7a-halogen-1,4-pregnadiene-17a, 21-diols and especially the -11B, 17a, 21l triols of formula II and their esters . The 7a-breme and 7a-chloro compounds of formula I have a cortical side chain at C-17 (ie compounds of formula I wherein n is cnaovz and Q ar ov) and eseefaerivae aarev, especially compounds which are unsubstituted at C-2, C-9 and C-14, are particularly valuable as topical anti-inflammatory agents; and especially compounds substituted at C-16 with a lower alkyl group (preferably a 16-methyl or especially a 16d-methyl group) or with a 16-methylene group exhibit an excellent topical anti-inflammatory activity which is generally superior to the of the topical anti-inflammatory activity of the corresponding 7-unsubstituted analogs. Particularly valuable compounds of the invention thus comprise 7α-halo-3,20-dioxo-1,4-pregnadienes of formula II, wherein Y is the group (H, B-OH).

The compounds of formula II wherein Y is the group (H, β-OH) and V is a hydrogen atom and especially wherein V 2 is also a hydrogen atom are essentially valuable as intermediates in the preparation of the particularly suitable 17-mono- and 17,21 -diester derivatives. The 17,21-deoxy-, 17-hydroxy-21-deoxy- and 17-acyloxy-21-deoxy-derivatives of the formula I show anti-inflammatory activity, but are more valuable as progestational agents. Particularly valuable topical anti-inflammatory agents of formula II are those in which V and V2 are acyl groups of hydrocarbon carboxylic acids having up to 8 carbon atoms, especially 17-propionate, 17-n-butyrate and 17-benzoate derivatives, which exhibit high topical anti-inflammatory activity. with very low systemic corticosteroid effects. It has been found that when the compounds of formula II are administered topically or systemically, the topical anti-inflammatory effect of the compounds depends much more on the nature of the ester group at C-17 than on the ester group at C-21 and in particular that the topical anti-inflammatory The inflammatory activity of a 17-propionate-21 ester of formula II is largely independent of the nature of the C-21 ester group. The 16α-methyl- 17-mono- and 17,2,1-diacyl derivatives of the formula II are the most valuable because their topical activity is greatly improved over the corresponding 7-unsubstituted compounds.

Bones superior to the topical activity of the most suitable 3,20-dioxo-7a-halogen-1,4-pregnanediens of formula II, especially the solder methyl derivatives, can be illustrated by pharmacological tests on animals.

For example, in topical testing on animals according to a modification of the test with croton oil-induced ear edema (G. Tonelli et al., Endocrinology.ï1: 625-634 (1965)), Thus, 7d-bromo-16d-methyl-1, 4-pregnadiene-11B, 17d, 21-triol-3,20-dione-17-benzoate-21-acetate an approximately twice as high topical activity, but only a fraction of the systemic effect of betamethasone dipropionate (9a-fluorine). 166-methyl-1,4-pregnadiene-11β, 17d, 21-triol-3,20-dione-17,21-dipropionate). When testing on mice according to a modification of the skin atrophy test (E.G. Weirioh and J.

Longauer, Res. Exp. With. låå, 229 (1974)) further said 7a-bromine compound of the invention further exhibits a markedly lower skin atropia activity than betamethasone dipropionate. 7α-bromo-solder-methyl-1,4-pregnadiene-116,17q, 21_-triol-3,20-dione-17-benzoate-21-acetate exhibits high separation of local from systemic effects upon local injection into rats and has a very low glycorticoid activity when administered orally to both mouse and rat.

When tested according to any of the above methods on animals, other 7α-halo-1,4-pregnadienes of formula II, such as 7d-chloro- and 7α-bromo-16u-methyl-1,4-pregnadiene-11β, 17α, 21l ~ triol-3,20- -dione-17,21-dipropionate, high topical anti-inflammatory activity coupled with low systemic effects after topical application and low skin atopy as well as low parenteral and oral glycorticidal activity.

Particularly suitable compounds of formula II include: 21-acetate, 21-propionate, 21-n-butyrate, 21-isobutyrate and 21-valerate of 7d-chloro- and 7a-bromo-10α-methyl-1,4-pregnadiene-11B, 17d , 21-triol-3,20-dione-17-propionate; The 21-acetate, 21-propionate and 21-n-butyrate of 7α-chloro- and 7α-bromo-1,6-methyl-1,4-pregnadienphyllos, 17α, 21-triol-3,20-dione-17β-n butyrate and 21-acetate, 21-propionate, 21-n-butyrate and 21-benzoate of 7α-chloro- and 7α-bromofluoromethyl-1,4-pregnadiene-11B, 17α, 21β-triol-3,20- dion-17-benzoate. 7d-chloro- and 7a-bromo-16α-methyl-1,4-pregnadiene-11β, 17α, 211-triol-3,20-dione-17,21-dipropionate and 7d-bromo-16α-methyl-1,1 4-Pregnancy-11B, 17d, 21-triol-3,20-dione-17-benzoate-21-acetate are especially valuable because they exhibit high topical anti-inflammatory activity coupled with low systemic effects after topical application. and low skin atrophy activity as well as low parenteral and oral glucocorticoid activity; Other valuable compounds of formula II include: 7α-chloro- and 7α-bromo-16α-methyl-1,4-pregnadiene-1B, 17d, 211-triol-3,20-dione-17-valerate-21-acetate; 14-chloro- and 7α-bromo-16α-methyl-1,4-pregnadiene-116,17α, 211-triol-3,20-dione-17-isohutyrate-21-acetate; 7d-chloro- and 7a-bromo-solder-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione and their 21-acetate, 21-benzoate, 21-pivalate, 17-propionate and 17-valerate; The 16B-methylpimers of these 16α-methyl derivatives, such as the 21-acetate, the 17,21-dipropionate, the 17-propionate-21-n-butyrate, the 17-propionate-21l-acetate and the 17-benzoate-21-acetate of the 7d-methyl chloro »and 7α-bromo-166-methyl--1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione; 7714538-48 and 16-methylene derivatives, such as 7d-chloro-16-methylene-1,4-pregnadiene-11B, 17a, 21-triol-3,20-dione-17,21-dipropionate.

The invention also relates to 7α-halo-3,20-dioxo-1,4-pregnadienes of the formula I as 9α-halogen derivatives of the compounds of the formula II, in particular their 9α-fluorine and 9-chloro derivatives; 9a, 11β-dihalogen-pregnadienes of the formula I, such as 7α, 9α, 11β-trichloro-1,4-pregnadiene-17d, 21-diol-3,20-dione [21] acetate, in particular 7α, 9α, 11β- trichloro-1a-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione »17,2l-dipropionate; 21-halo-21-deoxy-pregnadienes, such as 7α, 211-dichloro-16α- and 166-methyl-1,4-pregnadienyl, 17α-diol-3,20-dione [17] -propionate and 7α, 21-dichloro- 1,4-pregnadiene-11β, 17α-diol-3,20-dione-17-propionate and its Yo-bromo analog; 21-deoxy-pregnadienes, such as 7α-chloro- and 7α-bromo-1,4-pregnadiene-11β, 17d-diol-3,20-dione-17-propionate and 7α-chloro-, 7α-bromo- and 7α- iodo-1,4 -pregnadiene-17α-ol-3,20-dione and its 17-acetate and 17-propionate; 16d-hydroxy-pregnadienes and their ester derivatives, such as 7α-chloro- and 7α-bromofil, 4-pregnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione and their 17-propionates, 16,21-diacetate- 17-propionates, 17-benzoates, 17-benzoate-21-acetates and 16a, 17a-methyl orthobenzoate-21-acetates; 16a, 17a-lower alkylidene dioxy compounds, especially 7a-bromo-16a, 17a- -isopropylideneioxy-1,4-pregnadiene-11B, 211-diol = 3,20-dione-21-acetate; and IX-iodine derivatives; 1α-iodo-loafmethyl-1,4-pregnadiene-11β, 17M, 21-triol-3,20-dione, its 21-acetate and its 17,21-dipropionate, their β-β-methylpimers, and all of their 9-fluorine derivatives.

Another particularly suitable group of compounds of the invention comprises the II-oxo derivatives of formula I, which exhibit anti-inflammatory activity, but are more often used as intermediates in the preparation of the corresponding III-hydroxide derivatives according to the methods described below. Particularly valuable are II-oxo derivatives are the compounds of formula II defined above, wherein Y is an oxygen atom.

Particularly suitable compounds of formula III include: the zl acetate, 21-propionate, 21-n-butyrate, 21-isobutyrate and 21-valerate of 7α-chloro-16α-methyl-4-pregnene-11β, 17α, 21-triol-3,20- dione »-17-propionate and 21-acetate, 21-propionate, 21-n-butyrate and 21-isobutyrate of 7α-bromofluoromethyl-4-pregnene-11B, 17u, 21-triol-3,20--dione- 17-propionate; 21-acetate, 21-propionate and 21-n-butyrate of 7α-chloro- and 7α-bromofluoromethyl-4-pregnene-116,17a, 211-triol-3,20-dione-17-n-butyrate; In 7914538-19 and 21-acetate, 21-propionate. The 21-n-butyrate and the 21-benzoate of 7α-chloro- and 7α-bromo-16α-methyl-4-pregnene-11β, 17β, 2,1-triol-3,20-dione-17-benzoate.

Other compounds of formula III include: 7α-chloro- and 7α-bromo-16α-methyl-4-pregnene-11β, 17α, 21-triol--3,20-dione, their 17-valerate-21-acetate, 17- isobutyrate-21-acetate, 21-acetate, 21-benzoate, 21-pivalate, 17-propionate and 17-valerate; their 16B-methylpimers, such as the 21-acetate, the 17,2l-dipropionate, the 17-propionate-21-n-butyrate, the 17-propionate-21l-acetate and the 17-benzoate-21l-acetate of 7α-chloro- and 7α-bromo -166-methyl-4-pregnene-116, 17α, 211-triol-3,20-dione; 16-methylene derivatives such as 7α-chloro-16-methylene-4-pregnene-11β, 17α, 21β-triol-3,20-dione-17,21-dipropionate; and 16-unsubstituted analogs of said 16-substituted derivatives, for example 7α-chloro-4-pregnene-11β, 17α, 21-triol-3,20-dione-17,21-dipropionate. The 7α-halo-3,20-dioxo-4-pregnenes of formula III also exhibit topical anti-inflammatory activity and are thus useful for the treatment of corticosteroid-sensitive dermatoses, such as contact and allergic dermatitis and psoriasis. They can be applied topically or topically in any conventional pharmaceutical form, provided it is free from acids and bases.

P.A. Diassi et al., J. hed. Chem., Vol. 10, 551 (1957) describes 7α-chloro-A-nor-progesterone and reveals that the introduction of the 7-chlorine atom greatly reduces the progestational activity of the 7-unsubstituted precursor. Furthermore, P.A. Diassi et al. revealed that no 7α-chloro-4-dehydro-3-one has ever been reported as obtained either by oxidation of a 4-dehydro-3-one with 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of hydrogen chloride (whereby the quinone simultaneously reduced to the corresponding quinol) or by adding hydrogen chloride to 4,6-bis-dehydro-3-ions; they assume that steroids having a 7α-chloro-4-dehydro-3-one structure may exist in the reaction mixture, but are volatile and change to 4,6-bis-dehydro-3-one in attempts to isolate the 7a-chloro-4-dehydro-3-ones and free them from the quinone and quinol.

However, it has now been found that 7α-chloro-4-dehydro-3-ones can be isolated in substantially pure form and free or substantially free of the corresponding 6,7-dehydrohalogenated compounds, quinone and quinol.

It has also been found quite unexpectedly that 7α-halo-4-pregnene-3,20-diones and especially 7α-halogen-1,4-pregnadiene-3,20-diones are generally valuable steroids with valuable activity, such as corticoid activity. According to the invention there is therefore provided a process for the preparation of a compound of formula I as defined above, wherein Z is a chlorine, bromine or iodine atom, with the proviso that Z is not chlorine when X is a halogen atom, wherein as the main reaction step, a hydrogen halide, namely hydrogen chloride, hydrogen bromide or iodine hydrogen, adds to the 6,7-double bond in a compound of formula IV wherein the dashed line, ßA, B, X and Y have the meaning given and W ", Q 'and M' have the same meaning as W, Q and M, or wherein W "and Q" together form a 10a, 17a-alkylortoalkanoate or 16a, 17a-alkylortoarylcarboxylate group together with a 163 hydrogen atom, or M 'is the group -CHéOV3 and OV3 and Q 'together with the oxygen atom in the C20 carbonyl group form a 17a, 20; 20.2l = bis-methylenedioxy group, in the presence of an inert solvent, with the proviso that (I) when the hydrogen halide is hydrogen chloride, X is a hydrogen atom; (II) when Y is the group (H, B-OH) and the hydrogen halide is hydrogen bromide, then X is a hydrogen atom; and (III) when Y is the group (H, B-OH) and the hydrogen halide is iodine hydrogen, then X is a hydrogen-9 chlorine or flun atom.

The halogenated hydrogen should be used in an amount which is at least equimolar relative to the steroid and preferably in an at least 5 molar excess, such as 10-50 molar excess.

To obtain a compound of formula I, this step may be accompanied by at least one of the following steps: when W 'and Q' together form a 16a, 17a-alkyl orthoalkanoate or loa, 17a-alkylortoaryl carboxylate group together with a 166 hydrogen atom, hydrolyzed the product to form a compound wherein Q is a hydroxy group and W is the group (H, a-OH); Or when OV3 and Q 'together with the oxygen atom at the C20 carbonyl group is a 17a, 20; 20,21-bis-methylenedioxy group, the product is hydrolyzed to form a compound wherein OV3 and Q are hydroxy groups; and / or when Y is an oxygen atom and either (i) Z is a bromine atom and X is a halogen atom, or (ii) Z is an iodine atom and X is a bromine atom, and a compound wherein Y is the group (H, B- OH) is desired, this compound is prepared by reduction of a corresponding product, wherein Eiär is an oxygen atom; and / or when X is a hydrogen atom, Y is the group (H, ß-OH) and Z is a chlorine atom, a 9 (11) double bond is introduced by dehydration and the product is subjected to the addition of halogen to the 9 (11) double bond or of a 9a-chlorine or bromine atom and of a 11α-hydroxy group to the 9 (11) -aubbeibin ring; then finally isolating a compound of formula I.

The immediate product of this step and / or the compound of formula I may be subjected to a number of final steps in any order, which may be more generally defined as follows: a) Hydrolysis of an esterified group resp. groups at the 16a, 17a ~ and / or 21 positions to hydroxy; b) Hydrolye of a 17a, 20; 20,21-bis-methylenedioxy group to 20-oxo-17a, 21-dihydroxy groups or of a Z1-ethylene ketal to 21-oxo, or of a 17a, 21-alkylidenedioxy group to 17u, 211- dihydroxy-åFuPP® Tš c) Esterification of a hydroxy group at the lóa, 17d and / or 21 positions; d) Reduction of an 11-oxo group to a 11β-hydroxy group; e) 9 (11) -dehydration of a 9-unsubstituted 11β-ol to a 4,9 (11) -pregnancy or to a 1,4,9 (11) -pregnated sodium, except when Z is an iodine atom , followed by the addition of halogen to the 9 (II) double bond; or subsequent addition of a chlorine or bromine atom and a hydroxy group to the 9 (11) double bond to form a 9a-chloro or 9a-bromo-11β hydroxysteroid; f) l7a ~ chlorination or ~ bromination; after which a compound of formula I is isolated. The main step is preferably carried out under anhydrous conditions, especially when the starting material has a 1,2-double bond, to reduce the side reactions such as hydrolysis of any ester groups present. Saturated solutions of hydrogen halide in an anhydrous solvent are preferably used to reduce the reaction time. Non-reactive organic solvents suitable for use in the present process are those in which the starting material of formula IV and the hydrogen halide are soluble. By "non-reactive" is meant any organic solvent which does not react with the steroid substrate or the hydrogen halide to give rise to competing side reactions. Thus, in the present process, solvents such as water (may cause hydrolysis of the esters), alcohols (may cause ester exchange) under acidic conditions) and nitriles, such as acetonitrile (which would form iminoethers with steroidal alcohols).

Particularly suitable solvents for use in the process are ethers such as dioxane, tetrahydrofuran and diethyl ether; chlorine-containing hydrocarbons such as chloroform, methylene chloride and ethylene dichloride; organic acids such as acetic acid, propionic acid; tertiary amides such as dimethylformamide, diethylformamide and hexamethylphosphoric triamide; and dimethyl sulfoxide Dioxane, acetic acid and tetrahydrofuran are particularly suitable solvents, tetrahydrofuran being particularly suitable for reactions with hydrogen chloride, and acetic acid for reactions with hydrobromic hydrogen or iodine hydrogen. This reaction is preferably carried out at temperatures in the range 0 to 30 ° C, or preferably up to room temperature, such as 2000, although lower temperatures, for example -20 ° C, and temperatures such as up to 6000 can be used. (Temperatures above 30 ° C are suitably not used except when a 7α-chloro-1,4-pregnadiene-17α, 211-diol-3,20-dione or ester thereof is prepared.) The reaction times depend on the hydrogen halide, the solvent and the concentration used. .

Thus, for example, at the reaction time in acetic acid, the addition of hydrogen iodine is usually completed within one or two minutes, while the addition of hydrogen bromide at room temperature can be completed within 20-60 minutes. The addition of hydrogen chloride in tetrahydrofuran is preferably carried out at 0 ° C, instead of at room temperature, since the higher concentrations of hydrogen chloride thereby obtained enable the reaction to be completed within one hour instead of about 24 hours.

Substituents present in the 3,20-dioxo-1,4,6-pregnatriene and 3,20-dioxo-4,6-pregnadiene starting steroids usually remain unchanged under the conditions of this process, so it is usually advantageous for the starting steroids to carry all the desired substituents in the Ta-halogen-3,20-dioxo-1,4-pregnadiene and -4-pregnene products.

This process is preferably carried out by adding the starting 3,20-dioxo-1,4,6-pregnatriene or 44,6-pregnadiene, either in solid state or in solution, to the saturated solution of dry halogenated hydrogen in an anhydrous solvent. , usually at 0-2000, the molar ratio of hydrogen halide to steroid being about 40 to 1. After completion of the reaction, as determined by thin layer chromatography, the reaction mixture is poured into ice water and the precipitate formed of 7d-halophosphate, 20-dioxo-1 , 4-pregnadiene or -4-pregnene are separated by filtration or extraction and isolated in the pure state, usually by chromatography. The product. especially when it is a 7a-halogen-3,20-dioxo-4-pregnene, is preferably separated at temperatures of not more than about 25 ° C in a state which is substantially free of acid and base by liberating it from excess acid and solvent without subjecting it to a more strongly basic medium.

In the starting material of formula IV, X is preferably a hydrogen atom, since the 9-unsubstituted compounds of formula IV generally tend to undergo addition of halogenate more readily than their Qd-halogen derivatives. It is really advantageous even for X in the final product of formula ï to be a hydrogen atom, since the 9d-unsubstituted compounds of formula I generally give a better topical anti-inflammatory activity than their 9d-halogen derivatives.

When the starting compound is a 1,2-dihydro-3,20-dioxo-4,6-pregnadiene, its conversion to a 3,20-dioxo-7a-chloro-4-pregnene proceeds faster than the conversion of a 3,20-dioxo -1,4,6-pregnatriene to a 3,20-dioxo-7α-chloro-1,4-pregnadiene and can therefore optionally be carried out in the presence of water without involving any significant hydrolysis of ester groups which may be present. Furthermore, the 1,2-dihydro-4-pregnenes of formula I, which are considerably less resistant than the 1,4-pregnadienes, must be isolated from the excess acid as quickly as possible without the use of a basic medium and should therefore be stored in vacuum in an open vessel at temperatures not exceeding approximately 25 ° C.

When a 7α-analog-11β-hydroxy-3,20-dioxo + 1,4-pregnadiene or -4-pregnene of formula I is prepared from a steroid of formula IV, relatively low yields of pure product are obtained, if the steroid of formula IV contains a llß-hydroxy group. Better overall yields of pure product are obtained if the steroid of formula IV has an 11-oxo group and the resulting 7d-halogen-3,11,20 = trioxo-1,4-pregnadiene or -4-pregnene is then reduced at the ll position. Suitable reducing agents include sodium, potassium or lithium borohydride, tetra-n-butylammonium borohydride or lithium tri-t-butoxyaluminum hydride, in an inert organic solvent, preferably sodium borohydride in an inert organic solvent, comprising methanol or dimethylformamide. When the starting material of formula IV is a 3,11,20-trioxo-17α-hydroxy-1,4,6-pregnatrien-13-acylate, in which an optional 21-hydroxy group is esterified, reduction takes place very specifically at the 11-oxo group. However, when a 3-oxo-7α-halo-11β-hydroxy-1,2-dihydro-4-pregnene is prepared by reduction of the corresponding 11-oxo derivative (for example with sodium borohydride), simultaneous reduction at the 3-keto group tends to why better yields of the desired product are obtained when the formed 7d-halo-11B-hydroxy product is oxidized with oxidizing agent capable of oxidizing an allylic hydroxy group to an oxo group under substantially non-basic conditions. Oxidizing agents may be, for example, pyridinium chlorochromate in an inert organic solvent such as methylene chloride, preferably in the presence of a weak base such as sodium acetate, or a carbodiimide such as dicyclohexylcarbodiimide together with dimethylsulfoxide and a weak acid such as pyridinium dioxide. an inert organic solvent at room temperature. The 3,20 = dioxo-1,4,6-pregnatriene and 3,20-dioxo-4,6-pregnadiene starting compounds of formula IV are either known compounds or can be readily prepared according to known methods from their 6,7-dihydro derivatives for efficient dehydrogenation between C ~ 6 and C ~ 7, such as with the aid of chloranil or 2,3-dichloro = 5,6-dicyanobenzoquinone (DDQ) or by bromination at C ~ 6 and subsequent dehydrobromerins. Since ester groups are usually present in the 6,7 = dihydro derivatives, anhydrous conditions are preferably used to avoid hydrolysis.

The invention further relates to a process for the preparation of a compound of formula I defined above, wherein Z is a fluorine, chlorine or bromine atom, with the proviso that Z is a fluorine atom, when a 1,2-single bond is present, wherein as the main reaction step, a compound of formula 7714-538-1 / fi 4 NQ is reacted in which the dashed line, Q ', A and B have the specified meaning, M "and! W" have the same meaning as B' and W 'defined above, with the proviso that species M "is not a hydroxymethyl group and W" is not the group (H, a-OH), and the group .f H \ C / Y \ / f * ill represents ll or É I 'w C "wherein Y and X have the indicated meaning, with a halogenating agent capable of replacing the YB hydroxy group with a 7a-halogen atom, namely fluorine, chlorine or bromine, in the presence of an inert organic solvent, with the proviso that a 7a «chloro- or 7a The bromine atom is introduced only when a 1,2-double bond is present.

To obtain a compound of formula 1, this main step may be accompanied by at least one of the following steps: when W "ech Q" together form a 16a, 17a-alkylortoalkanoeth or 10a, 17a «alkylortearylcarboxylate group together with a 168- hydrogen hydrogen, the product is hydrolyzed to form a compound wherein Q is a hydroxy group and W is a group (H, a-GH), or, when OV 3 and Q 'together with the oxygen atom in the C 20 carboxy group are a 17a, 20; 20, 21-bis-methylenedioxy group, the product is hydrolyzed to form a compound in which OV3 and Q are hydroxy groups; C1 / H2, U11 .. \ P and / or when the group's Ü is added to the analog XC9 To the 9,11-double bond or a chlorine or bromine atom and a hydroxy group is added to the 9,11 double bond to form a Qa-kior or Qm-bromo-nitroaroxyl radical. .

The immediate product of this main step and / or the compound of formula I may optionally be subjected to a number of final steps in any order, which are more generally defined as follows: I 'a) Hydrolysis of an esterified group resp. groups at the löa, 17m and / or 21 positions to hydroxy; b) hydrolysis of a 17α, 20,20,21-bis-methylenedioxy group to 20 = oxo-17α, 21-dihydroxy groups or of a 21-ethylene ketal to 21-oxo or of a 17α, 211-alkylidene dioxy group to 17d, 21-dihydroxy groups ; c) esterification of a hydroxy group at the loa, 17a and / or 21 positions; s d) reduction of a ll-oxo group to a llß-hydroxy group; e) addition to the aii-aubibebinaning of halogen or of a 9a-chlorine or bromine atom and of a l1ß-hydroxy group, either when the group gíšï is H \\ C ,, / or after such a 9 (ll) -dubble 1 n Zcgeg / C 2 bond has been introduced by 9 (11) -dehydration of a 9-unsubstituted 11c-cl; i f) l7a ~ chlorination or = bnomering.

The halogenating agent is preferably either a tertiary amine having an N- (2-chloro-1,2,2-trifluoroethyl) group, which amine is used separately to prepare a 7u = fluorsteroid, but in the presence of a metal chloride or = bromide, which is soluble in the reaction mixture, for the preparation of a 7d = chlorine resp. 7a-bromine steroid, or a tertiary amine with a Hetrichlorvinyl group for the preparation of a 7a-chlorine steroid. A particularly suitable halogenating agent is N # (2-chloro-1,1,2,2-trifluoroethyl) = diethylamine ° also known as fluoramine; the reaction between the steroid and the fluoramine is preferably carried out at moderately low temperatures, such as at about 0 ° C, under an inert atmosphere, for example under argon neon or nitrogen, and under water-free conditions. All primary and unblocked secondary alcohol groups, ie. at the 2l ~ and l6d = positions, but not at the llB ~ position, should be protected, for example by esterification. The most suitable molar ratio of fluoramine to steroid is about 6: 1. 7714538-1 17 When the fluoramine separately, i.e. in the absence of metal chloride and bromide, used as fluorinating agent, the solvent is preferably a halogenated hydrocarbon, especially methylene chloride, and the product is a 7a-fluorosteroid. The most suitable metal chloride and bromide are lithium chloride and bromide. When the fluoramine is used together with lithium bromide as brominating agent, the solvent is preferably a halogen-containing hydrocarbon, especially methylene chloride, and the product is a 7α-bromine steroid. When the fluoramine is used together with lithium chloride as the chlorinating agent, the solvent is preferably an ether, especially tetrahydrofuran, and the product is a 7α-chlorine steroid. The molar ratio of lithium chloride or lithium bromide to steroid is preferably about 12 to 1.

The reaction between the steroid of formula V and the fluoramine, optionally in the presence of lithium chloride or bromide, is preferably allowed to proceed to completion, for example until thin layer chromatography shows that the starting steroid is no longer present. The product can then be isolated by evaporation of the reaction mixture and purified by chromatography to give the desired 7α-halogen derivative, in some cases in admixture with the corresponding 7-unsubstituted 6-dehydro derivatives, especially when the fluoramine is used separately as halogenating agent. Such a mixture can be separated by transferring this 6-dehydro derivative to a derivative which can be easily separated from the 7d-halogen "rhododene by chromatography, in particular to a 6,7-μL disubstituted derivative, for example to the corresponding o5,7B -diol by reaction with osmium tetroxide in dioxane in the presence of pyridine.

The tea chloro compounds of formula I can also be prepared from a steroid of formula V by reaction with N, N-diethyl-1,2,2-trichlorovinylamine in a halogenated hydrocarbon, such as methylene chloride, as solvent and preferably at moderately low temperatures, such as at about 900, and under an inert atmosphere, such as nitrogen. The molar ratio of N, Nsdiethyl-1,2,2-trichlorovinylamine to steroid is preferably about 6 to 1.

The compound of formula Y which in this process reacts with the halogenating agent preferably exhibits a 1,2-double bond, since the formed 1pregnadienes are generally more durable, can be more easily isolated and are more active as topical anti-inflammatory agents than the corresponding 1 , 2-dihydro-4-pregnenes. The steroids of the formula V, necessary as starting materials in the process, are new compounds and can be prepared by converting the corresponding 6β, 7β-dihydroxy derivatives to 6B, 7β-alkyl orthoalkanoate esters, hydrolysis at the 7-position with weak acid and subsequent reduction of the obtained 65-acyloxy-7B-hydroxide derivative, preferably with chromium (II) acetate, sodium acetate and aqueous acetic acid in acetone. The product of either of the two main reaction steps described above (starting from a steroid of formula IV or V) may then be subjected to one or more final steps a) to f), which are described above. If appropriate or not or t.o.m. essential to perform such final steps is normally quite clear to an experienced steroid chemist; it may often be more convenient to make corresponding chemical changes during the preparation of the steroid of formula IV or V, 7m-halogen3,20 = dioxo-1,4-pregnadienes and -4-pregnenes exhibiting ester functions at C = 16, C-17 and / or C-21, can be converted to 7d-halogen-3,20-dioxo = 1,4-pregnadienes and -4-pregnenes having free hydroxy groups at Jelly, C-17 and / or C-21, for example by the action of acidic saponifying agents, for example a strong mineral acid and preferably 70% = perchloric acid in methanol® By regulating the reaction time and the amount of acid, one can transfer a 17,2l = dicarbonate, carboxylate to the corresponding 17 = monoester or 17,21-diol. The compounds of the invention exhibit a halogen atom at 0 '7, so basic hydrolyzing agents are usually undesirable, since undesirable side reactions can often take place, such as elimination of the 7d halogen atom; Mild basic saponifying agents such as sodium bicarbonate in aqueous methanol can often be used to advantage. The hydrolysis of an esterifying group at C = 21 or at C166 is preferably carried out by means of diastase enzyme of malt in aqueous ethanol. Malt diastase hydrolyzes 7α-halo-3. 20-dioxo-pregnadiene-17,21--dicolhydrocarboxylate only at G = 21, obtaining 17 = monohydrocarbonecarboxylates, which may be transesterified at C-21 in a known manner with acylating agents which introduce a different ayl function compared to that which is present at C-17 to give mixed 1,7,2l-diacyl derivatives. Laloid orthoesters and 17a, 2l ~ orthoesters can be hydrolyzed at the l6a ~ and 2l = positions to form a 17-ester. This hydrolysis is preferably carried out under mildly acidic conditions, such as in the presence of a lower alkanoic acid, for example acetic acid or propionic acid, or a strong mineral acid, such as hydrochloric acid or sulfuric acid. When no substituent is present in C-16, the hydrolysis is preferably carried out under buffered conditions at a pH in the range 4-6.

The hydrolysis of 17d, 211-alkylidenexy-, ε-cycloalkylidenedioxy or aralkylidenedioxy group to 17d, 211-dihydroxy groups is normally carried out under mildly acidic conditions, such as with 50% acetic acid in water, preferably under an inert atmosphere, such as nitrogen. 21-ethylene petals and 17α, 2β; 20,21-bis-methylenedioxy groups can also be hydrolyzed under mildly acidic conditions; 17a, 20; 20,21-bis-methylenedioxy groups can hydrolyze under substantially neutral conditions with the aid of triphenylcarbenium tetrafluorohorate.

The most suitable compounds of the present invention have ester groups at C-17 and include 17-mono-eeh 17,21-diesters, especially 17-propionates, 17-n-butyrates and 17-benzoates.

It is usually advantageous to have these ester groups already present in the starting materials of formulas IV and V. However, it is sometimes convenient to introduce these ether groups after said main reaction step according to the invention has been carried out. Thus, the diethyl ethers can be prepared by aylation of the corresponding 17α, 21l-di- or 1,1'-hydroxy-21-alkyl radicals, preferably by means of a carbonic acid having up to 12 carbon atoms or retinoic acid together with an esterifying agent or by means of a reaction-prone agent. derivatives of said acid. In particular, the steroid may be reacted with a suitable acid anhydride in the presence of a strong acid catalyst, such as teluenepsuephenic acid, perchloric acid or a strongly acidic catenary exchange agent or with trifluoroacetic anhydride and the acid in question, such as a lower alkanoic acid, and a hydrocarbon catalyst. Before esterifying a hydroxy group, any possible hydroxy function, such as the trifluoroacetate, should be protected after esterification with Gel. can be hydrolyzed with a mild base, such as a dilute aqueous solution of sodium eneeate, without the addition of ester groups at the C-17 and / or F-21 hydrelycerated 17α precursor ring, alternatively it can be carried out on a as described above after the discussion of the first major reaction step of the β1β-17α-diol-177-aylate. to form 17, the corresponding anhydride or in the presence of a tertiary organic base, such as pyridine, quinoline, N-methylpiperidine, N-methylmorpholine, p-dimethylaminopyridine or N, N-dimethylaniline. The 17α-monoesters of the invention can be prepared by hydrolysis of a corresponding 17,21-orthoester or 17α, 21-diester as above; The 17,21-orthoester group can be introduced by reacting a 17α, 21-diol with an alkyl orthoester, either before or after carrying out the main reaction step of the invention.

A 21-dihydrogen phosphate ester is preferably prepared in a final step after reaction of the corresponding 21-hydroxy compound with pyrophosphoryl chloride. The mono- and dialkali metal salts and the alkaline earth metal salts of dihydrogen phosphate stone can be obtained by partial or complete neutralization with an alkali metal methoxide or alkaline earth metal methoxide.

The reduction of an II-oxo group to a III-hydroxy group has already been described.

When the 7a, 9a, 11β-trihalogen compounds and the 7α, 9α-dihalogen-11B-hydroxy compounds of formula I are prepared, the 9α, 11β-dihalogen or 9m-halogen atoms may be present in the molecule prior to the introduction of the 7α-halogen atom 9a However, the 11β-dihalogen or 9α-halogen atoms may be introduced into the 7α-halo-9 (11) -dehydro compound (especially a 7α-halo-3,20-dioxo-1,4,9 (11) -pregnatriene), which may have been obtained from a Td-halogen-11β-hydroxy-3,20-dioxo compound by dehydration with methanesulfonyl chloride and a tertiary amine, such as collidine, in a dialkylamide, such as dimethylformamide, in the presence of sulfur dioxide. an obtained 7α-halo- -9 (11) -dehydro compound with chlorine in a halogenated hydrocarbon, such as chloroform, in the presence of a tertiary amine, such as pyridine, corresponding to 7α-halo-9α, 11β-dichloro derivative. Alternatively, reaction of the obtained? the α-halo-9 (11) -dehydro compound with hydrogen fluoride and an N-chloroamide or N-bromoamide or with hydrogen chloride and an Nb romamide in an inert organic solvent 7a, 9a, llß-trihalogen derivative, wherein the more electronegative halogen substitutes the llß position. Furthermore, reaction of the resulting 7d-halo-¶ (II) -dehydro compound with an N-chloro-amide or N-bromo-amide (preferably N-chloro-succinimide or N-bromo-suoinimide) and a strong mineral acid, preferably per chloroacid, in an inert organic solvent, such as moist dioxane or tetrahydrofuran, a 11β-ol with a 9α-chloro or 9α-bromo substituent. 17α-chlorination or bromination can be carried out with the aid of an N-chloro-amide or N-bromo-amide, especially N-chloro-succinimide or N-bromo-succinimide, in an inert organic solvent, such as tetramethylene sulfone, at reduced temperatures and preferably in the presence of a mineral acid, such as hydrofluoric acid. 7714538-1 The following Tables I, II and III show the high anti-inflammatory topical activity and the low side effects of the preferred compounds of formula I compared to previously known 7-unsubstituted compounds Amumwnmumv OH n umHwHm> |> H | mommuwEmuwn H fifl u no al microns al wu H muxoænuuø nwwnwuo f wm fifi uämm .vmwunouælmw al ocououxnmøå w f> ma flfi wsum umn al ommm 22 7171453â ~ ¶ .J UMC, wH | 0fi monm fl @ | H ~.> H commnmšmumn ^ mumvnøHmv OH umHwHm> 1ßH commumåmumn \ AEO fi @ | o ~ .m | Ho fl H »| H ~ .x> H.¶wH »cw fl ø am: | m: mmHm | w_H | fl wuwE | Q6H \ ~ .H | o fi @ onm fl ø | fi N.> H co fl om fl nww fl mn fl æpmszww fi nmuwom mN ~ .H oH x fl mnumomnmnn ~ åfpmco fi wmw fi wwww .Ao fifi u fifl .Kßßw fifi v fi wvmwwï fi mm. am: | m: mmHm | w ~ H | HæuwEL fi w fi N oH mH @_H mo | o fi mou @ «ø | H ~.> H øoHomHnwwum | H>» @ s; x @ H hJK> Hmzïß Huxäß mLKw Hwwmm Eømww vc fi nwnwunwøøo> : oo co fi vøu fl nmnømyïß mc fl nwnmh nvwnv fi xw fifl v fi ß ÜAHÛUÜHQHOÄ MMHQOQ. .MQ COHUU.U=HU.WQUWH@UOHMSIVQF> ß UMNMMW H H fl wßmü 7714538-1 .CO fi umuomnm GMU al xumm Hmumm umuxwwmm mxm al ëwuwwm: www: mvxmmmw mxm fi mou muxmu f w mmm> m cwco al vmhmmwm um wnnßum Oßmmw Hm cw fifl wnmu H pm fi mu onnmum sh .0.H> mw @Hm> wumw: MVW uum m »fl> al UXM In flfifl u Eom." MHW ~ m> 1ßH commuwämumn fififi u Qo al wm fi wu al etc. wßom microns «Ewuwæm \ m wuom Mwwmøß nm fifl WS wwmm fifi ws: hmm uxw fl u al mmmumu Eomwm wmxuænuwu Go f umnownm cmuøxuwm .uzmmmw mxm flfi mumæm msmw fi øuwøw> m mc f nwmä mmm uumncm mw al ocououx fi am fi nm umuw mnwnm www uum www um fl o .uxmmmm mxm fi mou mcmw fi ouwwm METS ußm mmm mmm ßuw mm mw FLOW al ouonx al mc Fi CMSS f m mwøummmm CMW al ouwvw .wmww: onm | mm fi0 couOHMlmøE U fl> m fifi manw al wumu al dmom m ~ o UMNO al monm al wu al mhß fi nowmuwämvwß fi wumwcmumv o. al vmHmHm> | SSH aomßuwämuwn mwo fi wnowäm | Ho fl u »| H ~ .x> H.wAH | øm fl w | m fl mmHm | wH | HwmwE | @@ fi \ _ w_ fl umcO fi mowm fi U | HN.ßH cOM0m fi øwmum | H>» mE | @@ H .ZJ 2, m @ mum | H ~! pmom: @n | ßH: Ho fl MM | H ~ ä ¥>% wm% wmmwww mH> .m «mn> u: Q: HNnvmmo fl m0um: ßH Imnmmumuwä fi l fi wuwñlw fifi w N_m Ow mO @ mmO @ & Oum. > fi mOHomH fl wmHm | fi æumELKwH ummïß Humöß mnäë mwumm Eommm ws fi ummmmuwwoä ¥ ®MH> HQMM E00 GOHM5H al ¥ wQ5WLKP ÜGHÉÜHÛW HOWHÛMHHMU MMHQOU HÜHMÜ HÅÜMMÜWGÛMQQHÛWQM CM # fl ¥ M0 @ MQ al OH # 5HHUmQ5m al Ü @ OH flfl! ¥ P> M MÄÜMMN HH H fi mßmå 77145å% ~ ¶ .uämmmw fifl wwmxm al w QMOH MC FL et al uw MUW flfl ä oumwu Hw umUHm> mamma Sh .wnmwcmum Eommm w fi coawomno fl o flfi uëm fi uv H flfi u Qo fi um fl wu H WÜÅUMHQPÜ .N fl HÜm fl ÜUOnA .HÜUGWUHOÜNr CWHW UHÜMHTHOQ fHOvmOÜkv. Hwmu fifi .Hwmv fi Ou fifi uw fi Ov fi »ÉW MÜUCHGMDH ICÖPUUM .mvUE .ÛMHUGÜÃÜQ UÜSMÜE> d MÜHMUOWM. .HHÜM PM .m fififi nwwš MMHHNUEOPWHS mu al xr .NQHHWSHÜ UMQHSMÜM w \ H umG0 al m0nm al w1Hm ~> H Gowmumämumn> ~ O #mHwHm> | SSH nommuwšøumn + UHMW al mumv O. fl w fl noumum fl o f o flfi VSSS fi now Mw n0 «w | Ow ~ m @ .o pmpwumf fi wlpmomnwnuß fl | Ho fl up | H ~ @ <> H_Q »H1 = WHW WO m O nwnæu fl an access mlumno al moumnß fl | sscm @ um | wH | HmnmEmSwH \ N _ o N ~ o» É f Moum f W Na _ S no access if access hwwama fi æpwešw fi Hmlxš Hunäw mßïß Hwuwm Eommm mc al cmummuwøoä »wßH> fi UXM Soc Co. al uou fi pmßsmbßß mc al cmuwm fi uugpmwøm mm ao fl ps» f » wQ§m = @ mø fi m; ma>> m uxwuwm HHH H fl w fl mß 7714538-1 For the preparation of starting materials, reference is made to British Patent Specification 1,474,436, in particular the compounds therein of formulas V and IIA.

The following examples illustrate the process of the invention.

The stated temperatures refer to degrees Celsius.

Example Gel 1. 7d-Chloro-16a-methylyl, 4-oregnadiene-11β, 1,7'-triol-3,2G-dione-17,2l-digrogionate A. Add 2.0 g of 16d-methyl-1,4 , 6-pregnatrien-11β, 17α, 211-triol-3,20-dione-17,21-dipropionate to 24 ml of dioxane, which is saturated with dry hydrogen chloride gas. Stir the mixture for 16 hours at room temperature, pour it into 600 ml of ice water, separate the resulting precipitate by filtration, wash the precipitate with water and dry in air. Separate the components of this precipitate on silica gel by thin layer chromatography using ether / hexane (2: 1) as developing solvent and eluting with ethyl acetate the band containing 7α-chloro-la-methyl-1,4-pregnadiene-11 fi, 17-, Z1 -triol ~ 3,20-dione-17,21-dipropionate, as determined by ultraviolet light. Evaporate the combined ethyl acetate eluates and triturate the resulting residue with acetone / ether, filter and dry the triturated precipitate to give 7α-chloro-16α-methyl-1,4-pregnadiene-11β, 1,4-triol-triol. 3,20-dione-17,21-dipropionate.

(For analysis data, see Example 1C below.) The compound of this example may alternatively be prepared according to the following procedures 1B and 1C.

B. 7d-chloro-solder-methyl-Ig4-nreanadiene-17α, 21-diol-3,11,20-trione-17,2-di-dinrogionate Saturate 137 ml of dry tetrahydrofuran at 0 DEG C. with dry hydrogen chloride gas. Add 5.55 g of 16α-methyl-1,4,6-pregnatrien-17d, 21-diol-3,11,20? trion-17,21-dipropionate and stir the reaction mixture at CQ for one hour. Pour this mixture into 1 liter of ice water and stir for 1/2 hour.

Separate the precipitate formed by filtration, wash it with water and dry it in air to give 7a-chloro-16a «methyl-1,1-pregnadiene-17d, 21-diol-3,11.2% -trione-17 , 2l-dipropionate. Purify by recrystallization from methanol / acetone, containing a trace of propylene oxide; [a] â6. ,.> ~, _ _ »... g ~, "-0 + 76,2 ° (d1methylformam1u); [h] + 520, 518; melting point iöG-lo3 °; j & m ° I _ _ max 230 nm ($ .l.1.öOC). '7ïï45šd ~ l 26 C. Add a solution of 3.2 g of 7α-chloro-16α-methyl-1,4-pregnane-17α, 211-diol-3,11,20-trione-17,21-dipropionate in 24 ml of tetrahydrofuran and 8 ml of methanol at 0 DEG C. under a nitrogen atmosphere with 0.697 g of sodium borohydride and stir the reaction mixture for 15 minutes at 0 DEG C. Pour the mixture into 1.8 liters of ice water and 250 ml of 1N hydrochloric acid, filter off the precipitate formed and dry it in air to give 7α-chloroform. loa-methyl-11β, 17α, 21-triol-3,20-dione-1,7,21-dipropionate Purify it by recrystallization twice from acetone / methanol / isopropyl ether; mp 212-216 °; 26 [KID 9 * 42'6 (aimety1formam1a); [M] * 522, -52o ;; {::: an ° 1 242 nm 1 (g 1s.eøo); \> §§§ ° 1 1743, 1730, 1720, 1652, 1610 , 1595 cm -1; mm (amso-a6) δ 0.84 (C16-GH3, a J7Hz), 1.02 4013-CH3, S), 1.42 (010-cH3, S), 4.38 (11a -H, mu1t.), 4.67 (75-H, mu1t.), 4.80 (C21-H, S), 5.95 (c4_H, S), 6.20 (c2-H, aa J10, 2Hz), 7.35 (cl-H, and J10Hz ).

Example 2. 2.-bromo-16α-methyl-Ig-5-nregadiene-11β, 17α, 21-triol-3,2O-dione-17,2-digronionate A. Add 0.29 g of la-methyl-1,4,6- pregnatrien-11β, 17Q, 211-triol--3,20 = dione-17,21-dipropionate to a solution of 30% (w / v) dry hydrogen bromide in 4 ml of acetic acid, which has been pre-cooled to 0 DEG. Stir the reaction mixture for one hour at 0 DEG C., pour it into ice water, separate the solids formed by filtration, wash the precipitate with water and dry it. Purify by trituration with acetyl / ether and dry the triturated precipitate to give 7α-bromo-16α-methyl-1,4-pregnadiene-116,17d, 21l-triol-3,20-dion-17,2l = dipropionate (0.19 g).

(For analysis data, see Example ZC below.) The compound of this example is alternatively prepared according to the following procedures 2B and 20.

B.? A-bromo-1β-methyl-1,4 = nregnadiene-17α; 2lfdiol-3,1,20-trione-1,7,2l-dinrogionate 1 Add a solution of 0.5 g of solder-methyl-1,4 , 6-pregnatrien-17α, 21- -a101 ~ 3,11,20-trione-17,21 = a1prop10nate 1 2 ml of glacial acetic acid at 0 ° with a HY-prepared solution of 3 g of dry bromine hydrogen gas in 8 ml of acetic acid at C ° .

Stir the reaction mixture for one hour at 0 °, pour it into 400 ml of ice water, stir for 30 minutes, filter off the precipitate formed and wash it with water until the water-washing liquids are neutral. Dry it in air to give 7α-bromo-solder-methyl-1,4-pregnadiene-17d, 2,1-diol-3,11,20-trion-17,21-dipropionate (0.51 g); fa} å + l05, l ° (dimethylformamiâ),; ¿ï: gH 238 nm gg = 15,400). 7714538-127 C. Add a mixture of 2.84 g of 7α-bromo-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate and 0.573 g sodium borohydride under a nitrogen atmosphere at 0 DEG C. with 8 ml of methanol, which is pre-cooled to 1111 m, mm, stir the mixture for 5 minutes at 0 DEG. Heli the reaction mixture in 2 liters of ice water and 300 ml of 1N hydrochloric acid, filter off the precipitate formed and wash it with water and dry it in air to give 7d-bromofluoride-methyl-1,4-pregnadiene-11β, 17α, 211-triol-3,20-dione-17,21-dipropionate (2.6 g). Pure by recrystallization from acetone / ether / hexene; 1.44 g; melting point §> 295 ° C [a] open + 37.3 ° (dimethylformamideh: anol 242 nm (¿l5,350); Qšnvåâol 1743, 1735, 1660, 1612, 1600 mfl; mvm (amsø-aöwoßö (ClKGHB, <1 J7Hz), 1.03 (clg-CHB, s), 1.43 (ClO-CHBA, s), 4.325 (im-H, mura), 4.75 (fm-H, ore,: mn (c2l '"Hs 3): 5986 (C4" H¶ 5): 6119 (C9 "Hs ad Jlos QHZ), 7.31 (C1-H, ISLAND.

J10Hz). Example 3.

Ye-bromofluoromethyl-1,4-nreaanadiene 1,16,17a, 211-triol-3,20-dione-17-benzoate-2,2-acetate Acetate Add 1.31 g of solder-methyl-1,6,6 Pregnatrien-11β, 17d, 211-triol-3,2C-dione-17-benzoate-21-acetate with 6.2 ml of 30% hydrobromic hydrogen reading in glacial acetic acid at 0O. After one hour at Oo, pour the mixture into ice water, filter off the precipitate formed, wash it with water and dry it in air. Purify it by thin layer chromatography on silica gel using ether / hexane (2: 1) developing solvent and elute with ethyl acetate the band containing the desired product, as determined by ultraviolet light. Evaporate the combined ethyl acetate eluates to a residue, comprising 7d-bromo-10-methyl-1,4-pregnadiene-116,17m, 21-triol-3,20-dione-17-beneoate-21-acetate. Further purify the residue by trituration with isopropyl ether (yield 0.125 g). (For analysis data, see Example 3G below.) The compound of this example may alternatively be prepared according to the following procedures 3B and 30.

B. 7d-Bromo-solder-methyl-1,4-n-enenadiene-17a, 21-diol-3,11,20-trione-17-benzoate-21-acetate Add a freshly prepared solution of 9.3 g of dry bromine hydrogen gas in 16 ml of vinegar at UC dropwise with a solution of 1.56 g of 16α-methyl-1,4,6--pregnatriene-17α, 21β-diol-3-ol, 20-trione-17-benzoate-21-acetate in 5 ml ice vinegar. Stir the mixture for one hour at 0 DEG C., pour it into ice water, stir the aqueous mixture for 30 minutes, filter off the precipitate formed, wash it with water and dry it in air to give 7α-bromo-16α-methyl-1,4- pregnadiene-17α, 21-diol-3,11,20-trione-17-benzoate-21-acetate (1.6 g).

Purify further by recrystallization from acetone / hexane; mp 19 ° -192.5 °; [α] D + 77.3 ° (methylformemia) ;, 1 ::: an ° 1 232 mn (e 27,609), C. Yaebrom-solder-methyl-1,4-nregnadiene-l1§.l7a, 21-triol-3 , 20-dione-17-benzoate-21-acetate (1) Add a mixture of 0.05 g of 7α-bromo-16α-methyl-1,4-pregnenediene-17α, 211-diol-3,11,20 -trion-17-benzoate-21-acetate and 0.1 g of sodium-borne-aria under quavate atmosphere at 0 ° with a pre-cooled solution of 7.5 ml of tetrahydrofuran and 2.5 ml of methanol and stir the reaction mixture for 25 minutes at 0 °. Pour the mixture into 500 ml of ice water and add 10 ml of 1N hydrochloric acid. Filter the precipitate formed, wash it with water and dry it in air to give 7α-bromofluoromethyl-1,4-pregnadienellis, 17α, 21l-triol-3,20-dione-17-benzoate-21L-acetate ( 0.53 g).

Purify further by recrystallization from acetone / hexane / ether; emaitpmmf 1ss-159 °; fl åö + 21.1 ° (aimetyiformamiang fi âfcafml 233 nm (¿26.8oo); Nmn (ameo-a6) 5o, 89 (016-0113, a J7Hz), 1.12 (ol3-cH3, s), 1.48 ( cm-any s), 2.13 (one, e), 4.46 (lim-H, mura), 4.96 (ozl-H, mill), 4.90 (wa-H, mura), 6, 00 (c4-H, s), 6.28 (oz-H, a, <1 Jicnznz), 7.39 (cl-H, a, Jio fi z), 7.50-8, oo (phenyl, ore). (2) The compound of this example may alternatively be prepared as follows: Add a mixture of 0.65 g of 7α-bromo-16α- -methyl-1,4-pregnadiene-17β, 21-diol-3,11, 20-Trion-17-benzoate-21L-acetate and 61.7 g of sodium borohydride under nitrogen at room temperature with 6.2 ml of dimethylformamide and 0.3 ml of water Stir the mixture at room temperature under a nitrogen atmosphere for one hour and pour it into a mixture of 200 ml of water and 50 ml of 1N hydrochloric acid, filter off the precipitate formed, wash it with water and dry it in air to give 7m-bromo-166-methyl-1,4-pregnadienell, 17m, 21l = triol-3, 20-dione-17-benzoate-21-acetate.

Purify further by recrystallization from ether / acetone.

(For analysis data, see Example 3C (1) above.) Exeggel 4.

Zgloro- and 7d-bromo-11-oxo-1,4-nregnadiene-17a, 21-digl-3,20-dicn and esters thereof A. 7a-chlorine derivatives Repeat the experiment according to Example 1B by treating each of the following 11 Oxo-1,4,6-pregnatrienes with dry hydrogen chloride in tetrahydrofuran: -21-acetate-, 21-n-butyrate-, 21-isobutyrate-, 21-valerate-, 21-caprylate-, 21- (1'- adamantyl) -carboxylate-, 21- (1'-adamantyl) -acetate-, 21-benzoate-, 29 and 21-p-methoxybenzoate esters of the solder-methyl-1,4,6-pregnatrien-17a, 21- -diol-3,11,20-trione-17-propionate; 21-acetate-, 21-n-butyrate-, 21-isobutyrate-, 21-valerate-, 21-caprylate-, 21- (1'-adamantyl) -carboxylate-, 21- (1'-adamantyl) -acetate-, 2l the benzoate and 21-p-methoxybenzoate esters of 16α-methyl-1,4,6-pregnatrien-17α, 2,1-diol-3,11,20-trione-17-n-butyrate; 21-acetate, 21-n-butyrate, 21-isobutyrate, 21-valerate, 21-caprylate, 21- (1'-adamantyl) -carboxylate, 21- (1'-adamantyl) -acetate- , The 211-benzoate and 21-p-methoxybenzoate esters of solder-methyl-1,4,6-pregnatrien-17q, 21; -diol-3,11,20-trione-17-benzoate; 16α-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-1,7,21-diacetate; The 21-acetate, 21-propionate and 21-valerate esters of 16α-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-17-valerate; solder-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-17-isobutyrate-21-acetate; and loa-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-tricine-17-dodecanoate-2,1-propionate; and the 166-epimer and the 16-unsubstituted analogs of said substances and the 16-methylene derivatives corresponding to said substances.

Isolate and purify each of the resulting products in the same manner as described in Example 1B to give the following: 21-acetate, 21-n-butyrate, 21-isobutyrate, 21-valerate, 21-caprylate, The 21- (1'-adamantyl) -carboxylate, 21- (1'-adamantyl) -acetate, 2,1-benzoate and 21-p-methoxybenzoate esters of Ta-chloro-16a-methyl-1,4-pregnadiene- 17α, 21-diol-3,11,20-trione-17-propionate; Z1-acetam-, 21-n-butyrate-, 21-isobuylate-, 21-valerate-, 21-caprylate-, 21- (1'-adamantyl) -carboxylate-, 21- (1'-adamantyl) -aceta- , The 21-benzoate and 21-p-methoxybenzoate esters of 7α-chloro-16d-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-erion-17-n-buirate; 21-Acetyl, 21-n-butyric, 21-isobutyrate, 21-valerate, 21-caprylyl-, 21- (1'-adamantyl) -carboxynate-, 21- (1'-adamantyl) -acetate The 21, benzoate and 21-p-methoxybenzoate esters of 7α-chloro-salary-methyl-1,4-pregnadiene-1,17a, 2,1-diol-3,11,20-trione-17-benzoate; 7α-chloro-solder-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-diacotate; The 21-aceto-, 21-propionate and 21-valerate esters of 7α-chloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-valerate; 7α-chloro-solder-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-iso-buvyrate-2,1-acetyl; 77 145,318 * 1 50 and 7q-chloro-solder-methyl-1,4-pregnadiene-17α, 21-diol-2,11,20-trione-17-dodecanoate-21-propionate; and the 16B epimers and the 16-unsubstituted analogs of said substances and the 16-methylene derivatives corresponding to said substances. B. 7d Bromine Derivatives Repeat the experiment of Examples 2B and 3B by treating each of the starting compounds listed in Example 4A with dry hydrobromic hydrogen in glacial acetic acid. Isolate and purify each of the obtained products in the same manner as described in Examples 2B and 3B to give the respective 7d bromo derivatives corresponding to the 7d chlorine products of Example 4A.

Thus, the following compounds can be particularly obtained according to the method of Example 4A or 4B. 7α-chloro-1,4-pregnadiene fl7a, 21-diol-3,11,20-trione-21-acetate; melting point 22 ° -221 °; .fujšö + 113.3 ° (aimetyifomamiah zšfâff 238 mn (g = '15 ~ 000). 7d-chloro-l6d ~ methyl-1,4-pregnadien-l7a, 21-diol-3,11,20-trion-2l Acetate [α] D + 110 ° (methylformaminangia fl 240 mn (ν = 15,350) 7d-chloro-166-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-211- acetate, melting point 175-178 °; [α] D + 134.3 ° (methylformylamine 237 mn (2 = 17,450). 7d-chloro-166-methyl-1,4-pregnadiene-17a, 21-diol-3,1,11,2G -trion-17-benzoate--21-acetate, m.p. 2090 (decomposition); [.alpha.] D @ 20 + 1224.7 DEG (dimethyl-formamian / IÅIÃQH 233 mn (e = 30,000), 7α-bromomel, 4-pregnadiene-17α). , 21-diol-3,11,20-trione-17-acetate, melting point 168 ° (decomposition); [α] D 6 + 10.0 ° (dimethylformamide) 7α-bromo-solder-methyl-1,4-pregnadiene -17a, 21-diol-3,11,20-trione-17,2l-di-tens-eat, melting point> 285 °;, 1fš: íH 231 mn (¿= 31.500 »[oqff + a5, s ° (dimethylformamide ).

Td-bromo-16B-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17-benzoate-2-zi-acetate, melting point 160 ° (sonar unit [ajff +131.9) ° (eimety-formamidhaïšâgæí 235 nm (5 = 28,400).

Example 5. 7α-Chloro- and 7α-bromo-118-hydroxy-1,4-pregnadiene-17β2-dicl-3,20-diones and esters thereof A. By reduction of II-ketanoalogs Repeat the experiments according to Example 10 , 2C and 30 by treating each of the 7α-chloro- and 7u-bromo-11-oxo-1,4-pregnadienes prepared according to Example 4 with sodium borohydride in tetrahydrofuran and methanol at 0 ° C under a nitrogen atmosphere, then isolating the products and pure each of these in the same manner as described therein: the 7α-chloro and 7α-bromo derivatives of each of 21-acetate, 21-n-butyrate-, 21-isobutyrate-, 21-valerate , 21-caprylate, 21- (1'-adamantyl) -carboxylate-, 21- (1'-adamantyl) -acetate-, 21-benzoate- and 21-p-methoxybenzoate esters of the loa-methyl-1,4-pregnadiene 11b, 17a, 21-triol-3,20-dione-17-propionate, of loam-methyl-1,4-pregnadiene-11β, 17a, 21-triol-3,20-dione-17-n-butyrate and of looc- methyl 1,4-pregnadiene-11β, 170 m, Z1-triol-B, ZO-di On-1Y-benzate; The 7α-chloro and 7α-bromo derivatives of the 16α-methyl-1,4-pregnadiene-118, 17α, 211-triol-3,20-dione-17,21-diacetate, the 7α-chloro and 7α-bromo derivatives of each and one of the 21-acetate, 21-propionate and 21-valerate esters of 16α-methyl-1,4-pregnadienphilis, 17a, 211-triol-3,20-dione-17-valerate; The 7α-chloro and 7α-bromo derivatives of 16α-methyl-1,4-pregnadiene-11β, 17α, 211-triol-3,20-dione-17-isobutyrate-21-acetate; The 7m-chloro and 7a-bromo derivatives of 10α-methyl-1,4-pregnadiene-11β, 17α, 211-triol-3,20-dione-17-dodecanoate-21-propionate; and the 166-epimers and the 16-unsubstituted analogs of said substances and the 16-methylene derivatives corresponding to these substances.

The compounds of this example are alternatively prepared by treating the corresponding 11β-hydroxy-7-unsubstituted 1,4,6-pregnatriene, i.e. The 21-acetate, 21-pivalate and 21-benzoate of the 10-methyl-1,4-pregnadiene-11β, 17m, 21-triol-3,20-dione, with hydrogen chloride or hydrogen bromide described in Examples 1A, 1B and 1C and isolates and purifies each of the products formed in the manner described therein to form the corresponding 7a-chloro and 7a-bromo-1,4-pregnadiene.

Thus, the following compounds can be specially prepared according to the method of Example 5A or 5B. 7α-chloro-1α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-21-acetate, m.p. 197-2035; [α] D 6 + 49.9 ° (α-methylformamide); Ta-chloro-1,4-pregnaäien-llß, 17a, 21l-triol-3,20-dione-21-acetate, melting point 23o-233 °; m? + 6o, 8 ° (aimefyifomamianz fi âg fi 243 mn (g = 11,600 7m = bromo-loa-methyl-1,4-pregnadienphyll, 17a, 21l-triol-3,20-dione-1,7,2l-dibenzoate, m.p. 230-234 °; H1: 3H 232 nm (¿, = 39,506); [a] šF + 30,5 ° (emeticformemia). L Ta-chloro-16a-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-21-benzoate, [MF 514, 512. 7α-chloro-10α-methyl-1,1α-pregnadiene-11β, 17α, 211-triol-3,20-dione-17-n-butyrate-21-propionate, m.p. 155-160 °; [M] + 536, 534. 7α-chloro-16α-methyl-1,4-pregnadienphyllis, 17α, 21-triol-3,20-dione-17,2l-di-n-butylate, [MF 550, 548; melted powder 145-147 °; iMSOH 240 mn (a = 16.5oo); .a IBEX m1? +40, 2 ° (aimefyiformamia). 7? 14š38-4 _ 32 7a-chloro-166-methyl-1 , 4-pregnadienphylls, α7a, 21-triol-3,20-dione-17-benzoate-2, O-21-acetate, m.p. 195-198 °; [α] D + 69.3 ° (dimethylformamide) ;; 1fi§ xH 235 nm (¿= 27,000).

Ta-chloro-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17,21-dipropionate, m.p. 125-130 °; [«] Š6 + 3l, 3 ° (dimethylformamide}; R 1 :: H 240 Hm (5: 16,000). '7a-chloro-16a-methyl-1,4-pregnadiene-11β, 17a, 21- triol-3,20-dione-17-propionate-21-isobumyrate; [M] + 536, 534; NNE (ÖMSO-α) 50:84, 1.94, 1.44, 4.59, 5, 99, 6,24, 7,37, 7a-clear-166-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17-propiolate-21-n-buryrate, Nm (amso-a6) δ "0.92, 1.25, 1.44, 4.62, 4.72, 4.44, 6.0, 6.25, 7.39. methyl 1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17-propionate-21-valerate, m.p. 134-137 °; [α] D 25 + 37.5 ° (dimethylformamide) ΛMeOX-I 240 nm (g: 13,700), max 7α-chloro-16α-methyl-1,4 = pregnadiene-11β, 17α, 211-triol-3,20-dione-17-isoburyrate-21-acetate ; [m] * 522, 520. 7α-chloro-loa-methyl-1,4-pregnadiene / B1, 17a, 21-trial-3,20-dione-17-benzoate-21-acetate, [M] * 556, 554; NMR (amso-a6) δ, 88, 1.12, 1.46, 4.73, e, o2, 6.26, 7.40, 7.50-8.00. 16-methylene-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17,21-aipropionate; NM (amso-a6> $ 0.98; 1.44, 4.45, 4 73, 4,88,45,50, 6,00, 6,26, 7,38 7a-chloro-16a-methyl-1,4-pregnadi en-11ß, 17u, 21-triol-3,20-dione-17-propiona: -21-acetate; 5 [M] + 508, 506; Nma (amso-a6) g 0.84, 1.01, 1.42, 4.64, 4.67, 4.40, 5.99, 6.24, 7.37.

Ta-chloro-16m-methyl-1,4-pregnadiene-116,17a, 211-triol-3,20-dione-17-propionate-21-butyrate; [M] + 536, 534; Nma (amso446) g'o, 85, 1.02, 1.44, 4.69, 5.99, 5.25, 7.37, 7a-chloro-16a-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17-valerate-21-acetate; [M] + 536, 534, 7α-chloro-loa-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-17-n-buryl-21-acetate; [M] * 522, 520. 7α-Clot-10α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-21-pivalate; m.p. 227 DEG-23 DEG C.; DEG-23 DEG C. Hg 243 nm (β = 13,900), [m] * 494, 492. 7α-chloro-16β-methyl-1,4-pregnadiene-β1, 17α, 21-triol-3,20 -dione-21-acerate, melting point 228 ° (decomposition); [α] D f +8; 3 ° (dimethylformamide) ;, εE: gH 241 nm (¿= 15,500). 7u-chloro-168-methyl-1,4-pregnadienphilis, 17a, 21-triol-3,20-dione-17,2l-dipropionate; melting point 125 ° (decomposition); [α] D + 74.4 ° (dimethyl- Me ° H 241 nm (¿= 15,200). formamide); ÅnmX 7714552-1 55 7oL- løro-lö fl- mefzyl-1,1-pregnadien-llß, 1704 ,, Z1-triol-B, ZO-dione, m.p. 210-213 ° C; ¿K] D + 55.3 ° (methylformamia). 7α-bromo-166-methyl-1,4-pregnadiene-116,17a, 21-triol-3,20-dione-174 benzoate-21-acetate; [M] + 600, 598; melting point 1700 (decomposition); [aff + 72, s °; ¿§f: §fï 235 m (g = zsßoo). 7α-bromo-16α-methyl-1,4-pregnadiene-116,17a, 21-trio1-3,20-dione-17-n-butyrate-21-propionate, m.p. 147 ° (dec.); [α] D 6 + 30.8 ° (α-methylformamiah fifi âg fl 243 m (g = 15,600). 7a-bromo-166-methyl-1,4-pregnadiene-116 17α, 21-uriol-, 20-dione ~ 17,2l-di - -n-butyrate, melting point: 143.-146 °; [α] D + 31.8 ° (methylformamide 243 nm (α = 120). 2 "7α-bromo-16α-methyl-1,4-pregnadiene-118.17a , 21-triol-3,20-dione-17-benzoate--21-propionate, m.p. 136.7 DEG C.; [.alpha.] D @ 20. @ 6 .10 (dimethylformamide); c. 233 .mu.m (e = 27,900). bromo-loa-methyl-1,4-pregnadiene-11β, 17α, 211-trial-3,20-dione-17-benzoate-21-n-butyrate, m.p. 138-1440; [α] D 6 + 2β, 2 ° (dimethylformamide); Agâg fi 234 mn (g = 27,100) .7a-bromo-1,4-pregnaäien-116,17a, 21-triol-3,20-dione-17,21-dipronionate; [@] â6 +29 δ ° (dimethylformamide); δ% δ H 242 nm (δ = 15,700) - 7α-bromo-16m-methyl-1,4-pregnadiene-11β, 17α, Zlftriol-3,20-dione-21-acetate, δ 244 mn (2 = 13,700 »[MT 496, 494. 7a ~ bromo-l6ß ~ methyl-1,4-pregnadien-llß, l7a, 21-trioà; åâ20-dione-21-acetate, Smäl fi punkæ 1s5 ° (sönae-faelnirlgh [α] 25 D + ε4,6 °; λmax 242 nm (δ = 15.502 Tambrom-165-methyl-1,4-pregnadiene aipz-opionate, melting point: 135-137 °; [α] D + + 6,4 ° (α-methylformene) -Magg 242 mn (a = 15,500). 7a-bromine-loa-methyl-1,4-pregnadiene »11b, 17a, 21 ~ triol-3,20-dione-17 -propionate-21-acetate; [M] + 552, 550. 7α, bromo-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,2O-dione-17-propionate 21l-n-butyrate; [α] 25 D = 578; mp 153-1550; [α] D + 34.7 ° (methylmormamide); λ max: 244 nm (C = 15,800). methyl 1,4-pregnadiene-11β, 17α, 21-uriol-3,20-ion-17-n-butyrate-21-acetate, 7α-bromine-16α-methyl-1,4-pregnadiene-116,17a , 21-triol-3,20-dione-17-valerate-_g1_aCetate; [M] + 580; 573; ß2] D + 27, 10 (dimethylformamide] Rnmx 242 (2 = 15,500) 7 7a-bromo «16a« methyl-1,4-pregnadiene-l1ß, 17a, 211-triol-, 20-dione-17-propio-.nafw-zl-isobu yrava, m.p. 168-172 °; [mf 580, 578; m? + 36.3 ° MEOH 240 mn (δ = 115 m). (Dimethylformamide);} \ maX 'precipitate; 7711 4538-1 34 7a-bromo-166-methyl-1,4epregnadiene-116, 17a, 21-triol-3, 20-dione-17-propionate-21-acetate; [M] + 552, 550; NHR (dmso-d6) § 0.90, 1.44, 4.89, 5.96, 6.25, 7 38. 7a-bromo-166-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3 , 20-dione-17-pr0pi0_ nat-zi-bufyrae, smäi fi point 145% [mf sso, 578; Nm (msn-döp: 0.94, 1.28 »1344, 4.90» 4:51, 4145 »5.98, 5.28» 7; 39- Exemgel 6. 7a, 9a, 1l6-trihaloaen-1 , 4-nregnadiene-17d, 21-diol-3,20-dione-17,21-diclo- -hydrocarbols A., 7 «-41 ~: 1or ~ 16« -methyl-1, 4, 9 (11) -pregnatrien-17m , 21-eio1-3, ao-aion-lv, 21 .. digrogionate in Fox method 0.37 g w-kior-isa-methyl-i, 4-pregnaaien-11ß, 17a, 21-triol-3, 20-Dione-17,21-dipropionate in 11.1 ml of dimethylformamide and 0.67 ml of collidine with 0.22 ml of 3.5% (w / w) solution of sulfur dioxide in methanesulfonyl chloride Stir the reaction mixture for 30 minutes at 0 ° and then 30 minutes at room temperature Add 1N hydrochloric acid, extract the reaction mixture with ethyl acetate, wash the combined organic extracts with water, dry them over magnesium sulphate and evaporate in vacuo to a residue, comprising 7α-chloro-16α-methyl-1, 4.9 (11) -Pregnatriene-17D, 211-diol-3,20-dione-17,21-dipropionate Purify the residue by trituration with ether and filter the precipitate formed, m.p. 198-220 °; + 26.3 ° (aimefyiformamidh Råå? 238 nm (ε = 16,500).

B. Ta, 9a, 116-triglor-16a-methyl-1,4-nreanadiene-17u, 21-diol-3,20-dione-1,7,1-dirogionate Add a solution of 0.18 g of 7d-chloro-16a- methyl 1,4,9 (11) -pregnatrien-17a, 21-diol-3,20-dione-17,21-dipropionate in 5 ml of chloroform and 0.9 ml of pyridine with a solution of 28 mg (1, 1 equivalents) of dry chlorine gas in 4 ml of chloroform and allow the mixture to store for three hours at room temperature. Add 300 ml of methylene chloride, wash the reaction mixture successively with 10% sodium thiosulphate solution in water, 1N hydrochloric acid and water, dry it over magnesium sulphate and evaporate it. Purify the resulting precipitate on silica gel by thin layer chromatography using as a developing solvent of chloroform ethyl acetate (9: 1). Remove the least polar band, as determined by ultraviolet light, and elute with ethyl acetate. Evaporate the combined ethyl acetate, then add 7-ethyl acetate. , 9a, 11B-tricloro ~ 16d- -methyl = 1,4-pregnadiene = 17a, 21-diol-3,20-dione-17,21-dipropionate, Purify by trituration with acetone and filter off the triturated melting point 225 ~ 228 ° 236 nm (δ = 15.600), further 7714538-155 ° C. Treat 7x-chloro-1,4-pregnadiene-16,6x, 21-triol-3,20-dione-21-acetate ( prepared according to Example 5) in a manner similar to that described in Example 6A followed by reaction of the resulting 7-chloro-1,4,9 (11) -pregnatriene-17K, 21-diol-3,20-dione-21-acetate with chlorine in the manner described in Example 6B to give 7α, 9K, 11β-trichloro-1,4-pregnadiene-1β, 21-diol-3,20-dione-21-acetate, mp 299-31 ° C; ÄRJÉ6 + 71.1c (dimethylformamide): } Lä :: H 239 nm (¿= 14,500).

Example 7. 7a-chloro-9a-halo-gla4-nreenadiene-17α, 21-di9l-, 20-dione A. 7α-chloro-9α-fluoro-16α-methyl; 1β-Qreggadiene-11β, 17α, 21-triol -§, 20 ~ -dione-2l-acetate Add 0.5 g of 9m-fluoro-16a-methyl-1,4-pregnadiene-75,11§, 17a, 21_-tetrol-3,20-dione-2l-acetate in 100 ml of methylene chloride at 0 DEG under a nitrogen atmosphere with 1.67 ml of N, N-diethyl-1,2,2-trichlorovinylamine. Stir for 7 hours at 0 DEG C., evaporate in vacuo, transfer the resulting residue to a column of 50 g of silica gel, eluting with chloroform-ethyl acetate (3: 1). Combine equal fractions. containing the desired compound, as determined by thin layer chromatography, and evaporating. Further purify the resulting residue on thin layer silica gel plates and develop with chloroform: ethyl acetate (3: 1). Remove the band containing the desired product, as determined under ultraviolet light, and elute with the ethyl acetate. Evaporate the eluate to a residue, comprising 7m-chloro-9-d-fluoro-16a-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-2I-acetate.

Purify further by recrystallization from acetone-hexane; [M] + 470, 466; une (afnsø-aóäë 0.82, 0.90, 1.50, 4.17, 4.55, 4.95, 6.09, 6.27, 7.32- B. Repeat the experiment according to Example 7A by as starting material, each of the 9a-chloro and 9a-bromine analogues of the 9u-ileuro-73-hydroxy-1,4-pregnadiene starting compound is used to give the corresponding 7a-chlorine derivatives, i.e. 7m, 9a- dichloro-10α-methyl-1,4-pregnadiene-11B, 17α, 21-triol-3,20-dione-21-acetate and 7α-chloro-9α-bromo-16α-methyl-1,4-pregnadiene- 116, 17a, 21-triol-3,20-dione-21-acetate.

C. Similarly, using the 7β-hydroxy derivatives prepared in Preparation II as starting material in the experiment of Example 7A, 7α-chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-11β, 17d, 21 -trial-3,20-dione-17,2l-dipropionate, 7d-chloro-9a-fluor-16a-methyl-1,4-pregnadiene-l1B, 17x, 2l-triol-3,20-dione-l7 Benzoate-21-propio-771 4538-21 36 nat, 7d-chloro-9a-fluoro-16a-methyl-1,4-pregnadionin-11β, 17α, 21-triol-3,20--dione-17α-n -butyrate-21-propionate, their 9α-bromo and 9α-chlorine analogs, their solvent-methylpimers and 16-unsubstituted analogues and the corresponding 16-methylene derivatives.

Example 3. 7q-Iodo-9d-unsubstituted-1,4-presnadiene-3,20-aion @ P A. 7α-iodine-16α-methyl-1,4-nreanadiene-11β, 17α, 21-triol-3,20 -dione-21-acetate add 0.1 g of 161-methyl-1,4,6-pregnatrien-11β, 17α, 211-triol-3,2O-dione-2,1-acetate to a solution of 0.512 g of dry hydrogen iodide in 2 ml of glacial acetic acid and stir the reaction mixture for 50 minutes at room temperature. Pour the mixture into ice water, filter the precipitate and dry it; triturate it with ether, filter the solid, dissolve it in methylene chloride, wash the methylene chloride solution with a 0.1N aqueous solution of sodium thiosulphate and with water, dry it over magnesium sulphate and evaporate in vacuo. Triturate the resulting residue with hexane and filter to give 7m-iodo-16α-methyl-1,4-pregnadienphyllis, 17m, 21l-triol-3,20-dione-z-acetate (8 microns; [iaf 542)).

B. The following compounds can be prepared in a similar manner: 7α-iodo-9-unsubstituted-1,4-pregnadiene-3,20-dione, such as 7α-iodine-16α-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-1,7,21-dipropionate, melting point lä0 ° (decomposition), [α] δ + 22.0 ° (dimethylformamiahaïfâg fi 241 nm (g = 14.5 ° C); , [fi šß + 52, o ° (amphylformemia fl a lífâgH 241 mn (e = 14.5oo); and w-joa-isa-methyl- = 1,4-pregnadiene = l1B, l7a, 2l-triol-3,20-dione- 17-benzoate-21-aeetate, [a] â6 + 34.3 ° (aime-: yiformamiangf fi âí fi 233 mn (e = 24,400).

Example g fl å 7a = bromo-9a-halo§en = 1,4 = nregnadien-3,20-dioner A »4- rnill. -dione-17,21-dipropionate Add a solution of 0.1 g of 7B-hydroxy-9a-fluoro-16d-methyl-1,4-pregnadiene-11β, 17m, 211-triol-3,20-dione-17 , 2l fl dqmoprmmn; ochcLl glit v mv bromide in 100 ml methylene chloride, cooled to 0o, with 0.23 ml fluoramine.

Stir for 24 hours at 0 DEG C. and then evaporate in vacuo. Dissolve the resulting residue in chloroform, wash the chloroform solution with water, dry it over magnesium sulfate and evaporate, purify by thin layer chromatography using as chloroform / ethyl acetate (2: 1) developing solvent. Remove the band containing the desired product, such as determined under ultraviolet light, eluting with ethyl acetate. Evaporate the combined ethyl acetate eluates in vacuo to a residue, comprising 7α-bromo-Qaefluoro-16α-methyl-1,4-pregnadiene-11B, 17α, 21l-triol-, 3,3-zaion-1-methyl-propionae; melting point 1eo-164 ° C; [27 D + 17.9 ° (methyl-7714538-1 57 formamide).

B. Repeat the experiment of Example 9A by using instead of lithium bromide an equivalent amount of lithium chloride and by using tetrahydron as solvent instead of methylene chloride to give the corresponding Wu chlorine compound, i.e. Wx-chloro-9 '- fluoro-leaf methyl-1,4-pregnadiene-11β, 17', 2,1-triol-3,20-dione-17,2l-dipropionate; it can be purified by recrystallization from acetone / hexane; ZMY * 470, 468; NMR (dm 50 -do) δ 0.82, 0.90, 1.50, 4.17, 4.55, 4.95, 6.09, 6.27, 7.32.

Example 10. 7α-Halogen-21-deoxyflux-nreenadiene-3,20-diones and certain 21-enter derivatives A. 7α-chloro-21-deoxy-1,4-nre: nadien-, 20-dione (1) 7α-chloro-1,4-preanadiene-17α-01-3,20-dione and its 17-acetate Add 0.5 g of 17α-hydroxy-1,4,6-pregnatrien-3,20-dione with 20 ml of glacial acetic acid , saturated with dry hydrogen chloride gas, and 2 g of lithium chloride.

Stir the mixture for 45 minutes at room temperature, then pour it into an aqueous solution of sodium carbonate and extract the hydrogen mixture with ether. Wash the combined organic extracts with water, dry over magnesium sulfate and evaporate to a residue comprising 7α-chloro-1,4-pregnenediene. l7a-ol ~ 3,20-dione. Purify by recrystallization from methanol; mp 229-2310; [α] D 6 + 5O, 70 (aioxane). 7a-chloro ~ l7a ~ acetozi ~ ¿, fi ~ nregneQ¿en-3,20 ~ dion melting point 200-2060; fa fi šb + 4.5 ° (dimethylformamide); P \ E: gH 242 nm (α = 16,100) can be prepared in a similar manner from 17α-acetoxy-1,4,6--pregnatriene-3,20-dione. (2) By using as starting material in the above experiments 1,4-pregnadiene-11β, 17β-diol-3,20-dione-17-propionate, the corresponding 1m-chloro derivatives are obtained, i.e. 7α & chloro-1,4-pregnadiene-11β7-diol-3,20-aion-17-prepionate, λ max δ 243 nm (β = 15,800), NMR (dm 50 -do) δm, 1.43, 1.96 , 4.44, 4.72, 5.99, 6.23, 7.39.

B. 7-Bromo-17-acetoxy-1,4-pregnadiene-3,20-dione (fw + + s, 7 ° (methylformanamide) / λ 242 nm (¿= 14,000)) can be prepared according to Example 10A (l) of 17 racetoxy-1,4,6-pregnatriene-3,20-dione by using an equivalent amount of dry hydrogen bromide instead of hydrogen chloride and an equivalent amount of lithium bromide instead of lithium chloride 737145-38-1 50 7a-bromo-17a- acetoxy-1,4-nregnadiene-3,20-dione, [α] D 6 + 5.7 ° (dimethylformamide); 24 H 242 nm (5 = 14,000) can be prepared in a similar manner from 17α-acetoxy- 1,4,6-pregnatrien ~ 3,20-dione. (2) Treat each of the starting compounds of Example 11A (2) with dry hydrogen bromide and lithium bromide in glacial acetic acid in the manner described in Example 11B (1) to give resp. The IT propionate, the 17-n-butyrate, the 17-valerate and the 17-benzoate of 7α-bromomel, 4-pregnadiene-116, 17α-diol1-3,20 dione.

C.--Iodo-17-hydrocetoxy-1,4-pregnadiene-3,20-dione (m.p. 144 ° C (dec.); Åsjß -3.50 (dimethylformamide); (MeOH 242 nm (Ef. 15.110)) can be prepared Example 8A starting at max from 17Mracetoxy-1,4,6-pregnatrien ~ 3,20-dione.

Example 11 7%, 21-dihalo-1,4-pregnadiene-3,20-diones A.% K-chloro-21-halogen derivative (1,7M, 21-dichloro-16-methyl) 1,4-pregnadiene-11β, lysine -diol-3,20-dione-17-Brogionate is prepared by reacting 1β-methyl-21-chloro-1,4,6-pregnatrien-11β, lixardiol-3,20-dione-17-propionate with dry hydrogen chloride gas in dioxane according to Example 1A; Fi7 + 458, 456, 454. (2) 7M, 2,1-dichloro-1,4-pregnadiene-11β, 17β & diol-3,20-dione-17-propionate (β / J * 472, 470, 468; NMR (d d fi) 50.87, 0.97, 1.41, 2.32, 4.41, 4.75, 5.95, 6.36, 7.35) can be prepared in a similar manner.

B. 7% -bromo-21-halo derivative fi-bromo-21-chloro-1,4-pregnadiene-11β, 17m & diol1,20-dione-17-propionate (mm (amso-dβ) 50.90, 1, 00, 1.45, 2.33, 4.43, 4.85, 5.93, 6.21, 7.36) can be prepared according to Example 2A or B.

Example 12 Other 7d} halo-9-unsubstituted 1,4-pregnadiene-3,20-diones A. In a manner similar to that of Example 1A, treat 16M, 17M: isopropylidenedioxy-1,4,6-pregnatrienes. 10,21-diol-3,20-dione-21-acetate with dry hydrogen chloride in dioxane to give 7-chloro-1609,17 fl: isopropylidene-oxy-1, zi-pregnaaien-liß, 21-a101-3, zo-aion; melting point 255-2s7 ° c; 5 5556 + 104.9 ° (αmethylformamide / ï fi âg fl 242 (¿~ _ = 15,600). 77414538-1 59 * B. In a manner similar to that in Example 2A or B treat 16 u., 1voc-disopropylideneioxy-1,4 , e-pregnatrien-in 1/1, zl-aiol-s, zo-aion-21-acetate with dry hydrogen bromide in acetic acid to obtain W brbromo- -1602,17-drisopropylidene dioxy-1,4-pregnadiene-llß, 21-diol-3, 20-dione-zl-aeetate; mp 197-2oo ° c; [åäö + 91.9 ° (aimethylformamia), fl flâfç fl 242 (a = 15, ooo).

Example 13

Preparation of 17α-monoesters A. Using malt diastase (1) 7α-bromo-10α-methyl-1,4-preanadiene-11β, 17α, 21β-triol-3,2O-dione-17β-benzoate Continue a suspension of 1.67 g of diastase enzyme from malt in 33.5 ml of ethanol and 167.5 ml of water with 33.5 g of 7α-bromo-solder-methyl-1,4-pregnadiene-11B, 17d, 21-triol-3,20- dion-17-be fl S0at-21 ~ acetate. Stir the reaction mixture for three days at room temperature and then evaporate in vacuo at room temperature. Dissolve the resulting residue in ethyl acetate and water and filter the solution through a pad of Celite and wash with ethyl acetate. Separate the organic water layers and then extract the water layers with ethyl acetate. Wash the combined organic extracts with water, dry them over magnesium sulphate and evaporate in vacuo.

Purify the residue obtained by thin layer chromatography using the chloroform-ethyl acetate (3:) developing solvent.

Remove the tape containing the desired product, as determined under ultraviolet light. Elute with ethyl acetate and evaporate to a residue, comprising 7α-bromo-16α-methyl-1,4-pregnadiene-11B, 17α, 21-triol-3,20-dione-17-valerate. Purify by trituration with ether hexane; emit point .im-isafcwlââg fl 233 mn (g = 24,700).

B. By acid hydrolysis 7-bromo-16-dimethyl-1,4-pregnadiene-11β, 1,7-q21-triol-3,20-dione-17-benzoate Add Q, 44 g of 7d: bromo-16-k-methyl-1,4-pregnadiene-11β 17 ', 21-triol-3,2O-dione-17-benzoate-21-acetate in 69 ml of methanol with 1.76 ml of 70% perchloric acid in water and stir the reaction mixture for four hours. Set the reaction mixture to neutral reaction with a saturated aqueous solution of sodium hydrogencarbonate and remove the methanol by evaporation in vacuo.

Cool the aqueous reaction mixture and filter the precipitate formed, comprising a mixture of 7α-bromo-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione and the 17-monobenzoate and 2,1-monobenzoate esters thereof. Separate by thin layer chromatography on silica gel, eluting with ethyl acetate: chloroform (1: 1), removing the band containing the desired 17-benzoate ester, as prepared under ultraviolet light, eluting with ethyl acetate and evaporating to a residue of W -loxyl methyl-1,4-pregnadiene-1hs, 17α, 2,1-triol-3,20-dione-17-benzoate, m.p. 144 DEG-144 DEG, 233 nm (λ = 24,700).

C. 7α-halo-9α-fluoro-1,4-oregnadiene-116.16 ml, 17α, 211-tetrol-3,10-dione-17-hydrocarbon carboxylates (1) 7α-chloro- and 7α-bromo-9α -fluoro-1,4-pregnadiene-11β, 16a, 17α, 2,1-tetetrol-3,20-dione-17-nropionate and 17-nebutyrate (a) glycylene-1,4,6-pregnatrien-16α, 17α, 21- triol-3,11,12G-trione-16,21-; Qiacetate-17-propionate and 17-nebutyrate are prepared by reacting 9d-fluoro-1,4,6-pregnatrien-16a, 17m, 21-triol-3, 11,20-trione-16,21-diacetate with trifluoroacetic anhydride, toluene-p-sulfonic acid monohydrate and either propionic acid or n-butyric acid according to preparation 5D. (b) Qa-fluoro-1,4-pregnadiene-76,16a.17a, 211-tetrol-β, 11,20-trione-1,6,2-diacetate-17-propionate and 17-n-butyrate are prepared by Qa-fluoro-1,4,6-pregnafrien-16a, 17a, 21-triol-3,11,20-trione-16,21-diacetate-17-propionate and -17-n-butyrate are subjected to a reaction series similar to that described in Preparation 11A (1-4). (c) 1α-β-difluoro-1,4-preenadiene-16α, 17α, 21-triol-3,11,20-trione-16,2,1-diacetate-17-pronionic acid and -17-n-butyrate is prepared by reacting 7α, 9α-fluoro-1,4-pregnaalene-16q, 17e, 21-triol-3,11,20-ionrion-16,21-'-diacetate-17-propionate and -17-n-butyrate with fluoramine in methylene chloride according to Example 8A. The 17-propionate and 17-n-butyrate of 7m-bromo-9a-flucr-1,4-pregnadiene-16a, 17a, 21-triol-3,11,20-trione-16,21-diacetate and of Ta- -chloro- 9α-fluoro-1,4-pregnadiene-16a, 17a, 21-triol-3,11.2G-trione-16,21--diacetate can be obtained according to examples 10A and 10C by reacting the 76-hydroxypregnadienes from example 16C (16a). ) (b) with lithium bromide and flucramine or with lithium chloride and fluoroamine in methylene chloride. (d) Ta-halczen-9α-fluoro; β-nregnadiene-116,16a, 17a, 211-tetrol-3,2C-dione-16,21-diacctate-17-propionates and -17-n-butyrates. Examples 1C and 20 are repeated by treating all six products of Example 16C (16) (c) with sodium borohydride in tetrahydrofuran and methanol under a nitrogen atmosphere and isolating each of the obtained products in the manner described therein to give the respective 17-propionate and a 17-n-butyrate text of the 7c, 9a-difluoro-1,4-pregnadiene-11β, 16a, 17a, 211-tetrol-3,26-dione-16,21-diacetate, 177-7714538-14 propionate and 17 the n-butyrate of the 7α-chloro-9α-fluoro-1,4-preginol-11β, solder, 17α, 21-tetrol-3,20-dione-16,2] -diacetate and the 17-propionate and 17-n-butyrate of 7α-bromo-9α-fluoro-1,4-prcagnadiene-11β, 16α, 17α, 21-tetrol-3,20-dione-1,6,2-diaoetate. (e) 7a-haloene-9a-fluoro-1,4-nregnedien-llß, l6d, l7a, 2l ~ tetrcl ~ 312 (~ -dione-17-oronionates ooh ~ l7-n-butyrates Repeat the experiment according to example 16A by treating all six products of Example 16C (16) (d) with diastase enzyme from malt in aqueous ethanol and isolating and purifying each of the products obtained in the manner described therein to give the respective 17-propionate and 17-n-butyrate of 7d , 9d-difluoro-1,4-pregnadiene-11β, solder, 17α, 21-tetrol-3,20-dione, 17-propionate and 17-n-butyrate of 7α-chloro-9α-fluoro-1,4-pregnenediene -11ß, 16a, 17a, 21-tetrol-3,20-dione and the 17-propionate and 17-n-butyrate of 7a-bromo-9a-fluoro-1,4-pregnadiene- -11ß, 16a, 17d, 21- tetrol-3,20-dione. (2) 7d-chloro- and 7d-bromo-9a-fluoro-1,4-pregnadienrines, 16a, 17d, 21l-tetrol-3,23-dione-17-beneoate e ( a) Ba-fluoro-1,4,6-pregnatrienrrilß.l6a, 17d, 211-tetrol-3,20-dione-1,1'-methyl orthobenzoate-2I-acetate is prepared by reacting 9d-fluoro-1,4 6-pregnatrien-11β, 16d, 17α, 21-tetrol-3,20-dione-21-acetate with trimethyl orthobenzoate o and pyridinium toluene-p-sulfonate in dioxane and benzene according to Preparation 2G (1). (b) 7α-Chloro- and 7α-bromo-Cgifluoro-1,4-nregnadiene-11β, 16α, 17α, 211-tetrol-3,20-dione-16β-methylgretobenzoate-21-acetate are prepared from 1,4,6-pregnatrien-11β, 16α, 17d, 21-tetrol-3,20-dione-16,17-methyl-orthobeneoate-21-acetate by reaction with hydrogen chloride in tetrahydrofuran resp. with hydrogen bromide in glacial acetic acid according to the methods of Examples 1B and 2B. (c) 7d-Chloro- and 7a-bromo-9a-fluoro-1,4-pregggdienrellis, 16a, 1,1'-2,2-tetrcl-3,20-dione-17-benzcate-21-acetate are prepared from 7a-chloro- resp. 7d-Bromo-9α-fluoro-1,4-pregnadiene-11β, 16α, Yα, 21-tetrol-3,20-dione-16,17-methyl-orthobenzoeth-21-acetate by hydrolysis with aqueous acetic acid according to Preparation 2A (2). (d) 7α-chloro- and 7α-bromo-9α-fluoro-1,4-nregnadiene-11β, 16α, 17α, 211-tetrcl-3,20-dione-17-benzoate are prepared from 7d-chloro- and. 7a-bromof9a-fluoro-1,4-pregnadiene-11β, 16d, 17α, 21-tetrol-3,20-dione-17-benzoate-21-acetate by hydrolysis with diastase enzyme from malt in aqueous ethanol according to Example 10A. 77145384 42 Example 14. 7α-Chloro-16α-methyl-1,4-nreggadiene-11β.17d.21-triol-3,20-dione Add a solution of 3.5 g of 7α-chloro-16α-methyl-1,4- pregnadi @ n- -llß, 17a, 21-triol-3,20-dione-17,21-dipropionate in 300 ml of methanol with 30 ml of saturated aqueous solution of sodium hydrogencarbonate and store the mixture for 18 hours at room temperature. Pour the mixture into water, filter off the precipitate formed, wash it with water until neutral and then dry in air. Recrystallize the dried precipitate from acetine / hexane to give 7α-chloro-16α-methyl-1,4-pregnadiene-11β, 17d, 21-triol-3,20-dione, yield 1.3 g, melting point 176-1790, [ajâs + 47.5 ° (aimefyiformamian A fi âg fi 242 mn (5 = 15,500).

Exemnel gg. 7d-bromo-1,4-preanadiene-116, 17d, 21-triol-3,20-dione and its 21-acetate Add a solution of 5 g of 1,4,6-pregnatrien-11B, 17a, 21-triol- -3,20-dione-21-acetate in 62 ml of glacial acetic acid with 37.5 g of dry bromine and store the reaction mixture for 45 minutes at 0-50. Pour the reaction mixture into water, filter the precipitate formed, wash it with water and dry it in air to give 7α-bromo-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione-21 -aoetat.

Dissolve said product in 525 ml of methanol, add 13.2 ml of 70%; aqueous solution of downchloric acid and stir the reaction mixture for 10 hours at room temperature. Add water, then saturated aqueous sodium bicarbonate solution until the solution is neutral and evaporate the reaction mixture until the methanol has been removed. Extract the aqueous reaction mixture with ethyl acetate, wash the combined ethyl acetate layers with water, dry them over sodium sulfate and evaporate. Recrystallize the resulting residue from acetone to give 7α-bromo-1,4-pregnadiene-11β, 17α, 21-triol-3,% Q-dione, yield 0.3 g, melting point j> 32 ° C; [α] D 25 + 4S, 2 (dimethylformamide); δ 2 H 24l nm (E = 1.5.10). 7d-chloro-16a-methyl-1,4-pregnadiene-11β, 17α, 21-triol-3,20-dione, m.p. 176-179 °; [o fl šó + 47.5 ° (dimethylformi 242 nn (¿; l5,500) can be prepared in a similar manner.

Example 16. 7Ta-Chloro-4-nrenene-11β, 17β, 211-triol-3,20-dione-17,21-dipropionate and its 16α-methyl- and β-β-methyl derivatives A. Dissolve at 10 ° 911 mg 4 , 6-pregnadiene-17α, 2,1-diol-3,11,12u-trione-17,21-dipronionate in 10 ml of freshly prepared solution of hydrogen chloride in tetrahydrofuran and water, containing 38.2% by weight of hydrogen chloride and 3.7% by weight of water . Stir the reaction mixture for 15 minutes at G-20 and then pour it into 100 ml of ice water. Filter the resulting precipitate, wash it with water and partially dry it under a nitrogen blanket and then at room temperature in vacuo for 17 hours to give a mixture of 7α-chloro-4-pregnene-17α, 21 diol-3,1,11,2G-trione-17,17-zipropionate and 4,5-preglifadiene-17α, 21-diOl-3,1,11,20-1,1-1,1-2,7,21-dipropionate. Separate the components of this mixture EGHÛW by chromatography on silica gel, develop with hexane dimethoxyethane (2: 1) and elute with ethyl acetate the band containing 7α-chloro-4-pregnen 21-dipropionate as determined by the ultraviolet spectrum. Evaporate the ethyl acetate eluate at room temperature and recrystallize the residual acetone: hexane at room temperature to give 7d ~ k10r-4-PT @ ê fl @ fl “17fl» 21 “@ i ° 1“ 3: l1v20 * -trion-17, 21-dipropionate. Store the product in an open container at room temperature in a vacuum.

B. Dissolve at room temperature 3.1 g of 7α-chloro-4-pregnene-17α, 21- -diol-3,11,2C-trione-17,21-dipropionate in 375 ml of methanol and add 30 ml of water. Add this solution at 0 ~ 2 ° under a nitrogen atmosphere with 2.38 g of sodium borohydride. After 30 minutes, carefully add the reaction mixture to 4.2 liters of water, containing 50 ml of 1N hydrochloric acid. Filter the precipitate formed and chromatograph it on silica gel, eluting with chloroform: ethyl acetate (3: 1). Evaporate the combined eluate in vacuo. Add 152 mg of the residue obtained with a suspension of 60 DEG C. of manganese dioxide in 7 ml of benzene, stir for five hours, filter and chromatograph the filtrate on silica gel by thin layer chromatography, develop with chloroform: ethyl acetate (3: 1) and elute with ethyl acetate. the band containing the desired product, as determined by the ultraviolet spectrum. Evaporate the ethyl acetate solution in vacuo to a residue, comprising 7α-chloro-4-pregnene-11β, 17α, 21-triol-J, 20--dione-17,21-dipropionate. Purify further by recrystallization from ether: hexane at room temperature: λ max 237 nm (E, = 15,500).

Example 17. 17-Iodo-Qo-fluoro-16B-methyl-1,4-oreanadiene-11β, 17α, 21β-triol-2β-dione-1,7,2I-dinronicate (A) Add a solution of 0. 4 g of dry iodine hydrogen in 1.5 ml of glacial acetic acid at room temperature, protected from light, with a solution of C050 g of fluoro-16β-methyl-1,6,6-pregnatrien-16,6d, 21-triol -3,2C-dione-17,2l-dipropionate in 0.5 ml of glacial acetic acid. Stir the reaction mixture (protected from light) at room temperature for 30 minutes and then add 2 ml of 5% sodium thiosulfate solution. Extract the mixture with twice SQ ml of methylene chloride, wash the combined organic extracts twice with water, dry them over anhydrous sodium sulfate and evaporate to room temperature in vacuo Clean the resulting residue on silica gel by thick layer chromatography and develop with ethyl acetate: chloroform (1: 9) Scrape off the more polar band as determined under ultraviolet light, wash the silica gel with , evaporate the combined ethyl acetate washings in vacuo and recrystallize the resulting residue from ether to give 7α-iodo-9α-fluoro-166-methyl-1,4-pregnadienphilβ, 17d, 21-triol-3,2G-dione -17.21-dipropionate, yield 16 mf, (39%); mp 1450 (dec.); NMR (dmso-d 6) δ 0.95, 1.2o, 1.55, 4.20, 4.59, 4 , 70, 5.99, 6.20, 7.25.

The compound from this example is alternatively prepared according to Example 17 (B) OCh (C) - (B) Ta-iodo-9α-fluoro-16β-methyl-1,4-nregnadiene-17α, 2,1-diol-3,11, 20- trion-17,21-dipropionate is prepared according to Example 24 (A) from 10C mg of 9α-fluoro-166-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-17,2l -dipropionate and 0.8 g dry hydrogen iodine in 4 ml glacial acetic acid; yield 80 mg (64%). It is further purified by recrystallization from ether, m.p. 1050 (dec.).

(C) 70: - iodo-Qcx-fluoro-solvent-methyl-1,1'-pregnadiene-11β, 1Tc. .Gamma.-triol-Z., 2G- -dione-1,7,2-dininionionate is prepared according to Example 3C (1) from 7α-iodo-9α-fluoro-166-methyl-1,4-pregnadiene-17α, 21-diol -3,11,20-trione-17,21-dipropionate by reduction with sodium borohydride at 0 ° in tetrahydropurane and methanol under nitrogen; (aa above) - Exemoel 18. 7a-iodine-9a-chloro-solvent-1,4-pregnaeienfllß, 17a, 21l-triol-3,20-dione- -17,21-digrogionate (A) 7a-iodod- 9a-chloro-16B-methyl-1,4-preanatrien-11β, 17e, 211-triol-3,20--dione-1,7,2-digrogionate is prepared according to Example 17 (A) from 9d-chloro-16B-methyl -1,4,6-pregnatrien-116,17a, 21-triol-3,20-dione-17,21-dipropionate and joavate 1 isavilza; yield 15 * mp melting point 121-129 ° C, 'MeOH _ 2, max z 40 nm (g - 15,131).

(B) The compound of this example is alternatively prepared by treating 9α-chloro-166-methyl-1,4,6-pregnatriene δ 17m, 211-diol-3,11,20-trione-17,21-dipropionate with iodine hydrogen in acetic acid according to Example 17 (A) and then the formed 7a-iodine-9d-chloro-16--methyl-1,4-pregnadiene-17a, 21-diol-3,1,11,20-trionph17,21-dipropionate with sodium borohydride in methanol / tetrahydrofuran according to Example 3C (1). 7714538-1 45 Exemgel 19. 7α-bromo-9d-fluoro-166-methylssl, 4-preanadien-11β, 17α-butriol-3,20-dione- -17,21-digrogionate (A) 7a-bromo-9d ~ fluoro-16B-methyl-1,4-preenadiene-17a, 211-diol-3,11,2C--trione-17.21-dipronionate Add a solution of 0.5 g of α-fluoro-163-methyl-1,4, 6-Pregnantriene-17α, 211-diol-3,11,20-trione-17,21-dipropionate in ml of glacial acetic acid with 5 ml of 48% (w / w) solution of dry hydrogen bromide in glacial acetic acid. Stir the mixture for one hour at 5 ° and then pour it into 300 ml of ice water. Filter out the precipitate formed, wash it thoroughly with water and dry it in air at room temperature. Clean the precipitate on two-layer silica gel plates and develop with ethyl acetate-chloroform (1: 5). Scrape off the tape containing the desired compound, as determined under ultraviolet light, and extract the compound from the silica gel with ethyl acetate. Evaporate the ethyl acetate solution to a residue comprising 7α-bromo-9d-fluoro-166-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-mipropicnate, yield 60%, emission point 115 ° (unit).

(B) Repeat the experiment of Example 3C (1) by reducing the product of Example 19 (A) with sodium borohydride in methanol / tetrahydrofuran to give 7-bromo-9-fluoro-10-methyl-1,4-pregnadiene-11-crude 17 2,1-triol-3,20-dione-1,7,21-dipropionate; mp 148-115 ° C; [Α] D = + 4s, 1 ° (0.2 e; methylformamidnàïâg fl 238 nm (g = 16.ooo); 11117 502, 471, 450.

Example 20 (A) 7-Diodo-9-fluoro-soldermethyl-1,4-pregnadiene-17%, 21-diol-3,11,20-trione-1,7,2l-digrogionate is prepared by reacting 9Kfluoro-1,6-methyl-1,4 .6-pregnatrien-17dq21-diol-3,11,20-trione-17,2l-dipropionate with hydrogen iodine in glacial acetic acid in the dark according to Example 17 (A). Melting point ll0 ° C (sönaeraeiningn [ødD -o, 9 ° (aimethylformamian Råå? 235 nm (¿= 12.eoo)) [MÜ soo, 413.

(B) 7m-Iodo-fluorofluoromethyl-1,4-pregnadiene-11β, 170921-triol-3,20--dione-17,21-dipropionate is prepared by reducing the compound from step (A) with sodium borohydride according to Example 3C (l). Melting point 155-160 ° C (after turning yellow at 115%); [MID + z1.4 ° (amethynform- amianñfêg fi zss (e_ = 1s.soo>. 7714558-1 A 46 Example 21 (A) 7 “bromof9d-fluoro-16utmethyl-1,4-pregnadiene-17K, 21-diol -3,1l, 20- -trione-1,7,2l-dipropionate is prepared by reacting Qaefluoro-16-dimethyl-1,4,6-pregnatrien-17m, 21-diol-3,1,11,20-trione-1,7,2l- dipropionate with hydrogen bromide in glacial acetic acid in the dark according to Example 17 (A); ßfjn + 2o, 1 ° (0.3 5): Raw? 235 mn (¿= 15,000), [MV 501.

(B) 7-Bromo-9arfluoro-1-dimethyl-1,4-pregnadiene-11β, 17β, 2,1-triol-3,20--dione-1,7,2-dipropionate is prepared by reduction of the compound from torque (A with sodium borohydride according to Example 3C (l); mp 160-164 ° C; [α] D + 17.9 ° (0.12 δ, α, β, λ max) (g = 17.30 ° C); t [M +] 446, 432, 428, 415.

Example 22 (A) Hydroiodine-9d-fluoro-16M, 17d & isopropylidenedioxy-1,4-pregnadien-21-ol--3,11,2-trion-21-acetate is prepared by reacting 9M-fluoro-16%, 17m-isopropylidenedioxy 1,4,6-pregnatrien-21-ol-3,11,20-trione-21-acetate with hydrogen iodide in glacial acetic acid in the dark according to Example 17 (A); melting point 130 ° C (sonar eel) Q 235 nm (¿= 14,300); 54+] 472, 457.

(B) E-iodo-9-fluoro-1609,17-drisopronylidene dioxy-1,4-pregnadiene-11 / α1l-diol-3,20-dione-21-acetate is prepared by reduction of the compound from step (A) with sodium borohydride according to Example 3C (1); mp 192-197 ° C; [_4513 + 53.1 ° (o, 27 2, aimethylformamian fi äâï fi 237 (a = 14.530); m? 474.

Example 23 (A) 7-Debromo-Hydrofluoro-1609,17-Chrisoproylidenedioxy-1,4-pregnadien-21-ol--3,11,20-trione-21-acetate is prepared by reacting Sdefluoro-16%, 11xrisopropylidenedioxy-1,4,6- pregnatrien-21-ol-3,11,20-trione-21-acetate with hydrogen bromide in glacial acetic acid in the dark according to Example 17 (A); Ljejb + 8l, 3 ° (0,2 94, aimetylførmamiangïâg fi 235 (5 = 15,300), [MÜ 472.

(B) 7d = bromo-9d = fluoro-10-cell isopropylidene dioxy-1,4-pregnadiene-11β, 2,1-diol-3,20-dione-21-acetate is prepared by reducing the compound from step (A) with sodium borohydride according to Example 3C ( l); [Α] D + 74.4 ° (0.25 <4, α, orm = 14,980), [MAY] 474 ° C

Claims (5)

771453-8-1 47 PATENT REQUIREMENTS A process for the preparation of 3,20-dioxo-7α-halo--4-pregnenes and -1,4-pregnadienes having the formula (I) wherein the dashed line II, 2-position indicates a 1,2- - single bond or a 1,2-double bond; w is a group 01,11), (H, lower alkyl), (n, a-ovl) or = CHT, wherein V 1 is a hydrogen atom or an acyl radical from a carboxylic acid having up to 12 carbon atoms, and T is a hydrogen atom or a lower alkyl group; Q is a group OV, wherein V is a hydrogen atom or an acyl radical of a carboxylic acid having up to 12 carbon atoms; or wherein Q and W together form a 16d, 17d-lower alkylidene dioxy group together with a 16ß hydrogen atom; G is a hydrogen atom or a halogen atom having an atomic weight of less than 100, or a group OV2, wherein V2 is a hydrogen atom or an acyl radical from a carboxylic acid having up to 12 carbon atoms; X is a hydrogen atom or a halogen atom having an atomic weight of less than 100; Y is an oxygen atom or a group (H, ß-OH) or, provided that X is chlorine or bromine, Y may also be a group (H, ß-halogen), which halogen has an atomic weight of less than 100 and is at least as electronegative as X, or, provided that X is hydrogen, Y may also be a group (H, H); and Z is chlorine, bromine or iodine; wherein the lower alkyl groups have up to 6 carbon atoms; characterized in that (a) a hydrogen halide selected from hydrogen chloride, hydrogen bromide and hydrogen iodide is added to the 6,7-double bond in a compound having the formula (IV) wherein the dashed line, X, Y, W, Q and G are as defined above, in the presence of an inert solvent; provided that, (i) when the hydrogen halide is hydrogen chloride, X is a hydrogen atom; (ii) when Y is the group (H, ß-OH) and the hydrogen halide is hydrogen bromide, X is a hydrogen atom; and (iii) when Y is the group (H, ß-OH) and the hydrogen halide is hydrogen iodide, X is hydrogen, chlorine or fluorine; or bringing (b) a compound having the formula CH 2 G C = O (v) OH wherein X, Y, W, Q and G are as defined above except that G is not a hydroxy group; reacting with a halogenating agent which can replace the Z0- hydroxy group with a 7m-halogen atom selected from chlorine and bromine, in the presence of an inert organic solvent; or that (c) to prepare a compound of formula I, wherein Y is the group (H, ß-OH), a compound of formula I, wherein Y is an oxygen atom, is reduced; after which the product obtained in processes (a), (b) or (c) is, if desired or necessary, subjected to one or more of the following final treatments in any order, provided that the final step (iii) cannot follow the process; (c): (i) hydrolysis of an esterified group or groups at the 17a- and / or 21-position to hydroxy; (ii) esterification of a hydroxy group in the 17u and / or 21- position; (iii) reduction of an 11-oxo group to a 11β-hydroxy group; (iv) 9 (11) -dehydration of a 9-unsubstituted-11β-ol to a 4.9 (11) -pregnantiene or to a 1,4,9 (11) -pregnantriene, except when Z is an iodine atom , followed by the addition of chlorine to the 9 (II) double bond. 2. A process according to claim 1, characterized in that the compound of formula IV is reacted with hydrogen chloride in tetrahydrofuran. 3. A process according to claim 1, characterized in that the compound of formula IV is reacted with hydrogen bromide or hydrogen iodide in glacial acetic acid. 4. A process according to any one of claims 1-3, characterized in that a steroid of formula I, wherein Y is the group (H, ß-OH), is prepared from a steroid of formula IV as defined in claim 1, wherein Y is an oxygen atom, by reaction with hydrogen chloride, hydrogen bromide or hydrogen iodide in an inert organic solvent, followed by reduction at the II position. 5. A process according to claim 1 (b), characterized in that the halogenating agent is either a tertiary 77 G 5 amine having an N- (2-chloro-1,1,2-trifluoroethyl) group, which amine was used in the presence of a metal chloride or bromide, which is soluble in the reaction mixture, to prepare a 7a-chloro- or 7mf bromosteroid, or a tertiary amine having an N-trichlorovinyl group to produce a 7d-chloro-steroid.