NO151826B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW, THERAPEUTICALLY ACTIVE 7-CHLORINE OR BROME-3,20-DIOXO-1,4-PREGNANCY AND-4 PREGNANCY - Google Patents

Description

The present invention relates to an analogue method for the production of new steroids of the pregnane series with valuable pharmacological properties.

The invention thus relates to an analogous method for the production of therapeutically active 3,20-dioxo-7a-chloro-(or bromo)-pregnenes and -1,4-pregnadienes of the formula

wherein the dashed line in the 1,2 position indicates a 1,2-single bond or a 1,2-double bond;

W is a group (H,H), (H, lower alkyl), (H, a-OV<1>) or =CHT, where V<1> is a hydrogen atom or an acyl radical from a hydrocarbon carboxylic acid of 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 hydrocarbon carboxylic acid of up to 12 carbon atoms; or wherein Q and W together form a 16a,17o-lower alkylidenedioxy group together with a 163-hydrogen atom;

G is a hydrogen atom or a halogen atom with an atomic weight of less than 100, or a group OV 2 , in which V 2 is a hydrogen atom or an acyl radical from a hydrocarbon carboxylic acid of up to 12 carbon atoms;

X is a hydrogen atom or a halogen atom having an atomic weight less than 100;

Y is an oxygen atom or a group (H,3~0H) or, provided X is chlorine or bromine, Y may also be a group (H,3-halogen), which halogen has an atomic weight less than 100 and is at least as electronegative as X, or provided X is hydrogen, Y may also be a group (H,H);

and Z is chlorine or bromine;

wherein the lower alkyl groups have up to 6 carbon atoms.

The lower alkyl groups included within the definitions

of W and T, has up to 6 carbon atoms, and thus includes

pentyl and hexyl groups, but preferably have up to 4 carbon atoms, e.g. are these methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl or t-butyl.

The acyl radicals of the carboxylic acids with up to 12 carbon atoms included in V, V 1 and V 2 are derived from hydrocarbon carboxylic acids such as alkanoic acids exemplified by formic acid, trimethyl edoxy, isobutyric acid, isovaleric acid, enanthic acid, capric acid, cyclo-pentylpropionic acid, undecyl acid, lauryl acid and adamantane carboxylic acids , substituted alkanoic acids such as phenoxyacetic acid, trifluoroacetic acid and 3-chloropropionic acids, aromatic and substituted

aromatic acids, especially benzoic acids substituted with a halogen atom or a methoxy group, such as benzoic acid, toluene acid, p-chlorobenzoic acid, p-fluorobenzoic acid, p-methoxybenzoic acid,

and 3,5-dirnethylbenzoic acids, aromatic-heterocyclic acids, in particular isonicotinic acid, aryl-alkanoic acids such as phenylacetic acid, phenylpropionic acid, and (3-benzoylaminoisobutyric acids, unsaturated acids such as acrylic and sorbic acids, and dibasic acids such as succinic acid, tartaric acid and phthalic acids.

The preferred acyl groups are those derived from

lower alkanoic acids with up to 8 carbon atoms, in particular from acetic acid, propionic acid, butyric acid, valeric acid, caprylic acid, caproic acid and t-butylacetic acid, and from benzoic acid or the above-mentioned substituted benzoic acids, and in particular those derived from propionic acid, n-butyric acid and benzoic acid.

X is preferably a fluorine or especially a hydrogen atom.

The alkylidene or alkylidenedioxy groups represented

at =CHT, or at W and Q together, preferably has up to 4 carbon atoms and thus includes methylene, ethylidene, n-propylidene, isopropylidene, n-butylidene and secondary butylidene and their corresponding dioxy derivatives. W is preferably a methylene group or the group (H,CH3), especially (H,a-CH3).

Y is preferably an oxygen atom or the group (H,(3-OH).

A particularly preferred group is 1,4-pregnadienes which have the formula:

wherein Z is a chlorine or bromine atom, W is a methylene group or the group (H,CH3),

Y is an oxygen atom or the group (H,3-OH), and

V and V 2 , which may be the same or different, are hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12, especially up to 8, carbon atoms.

The dashed line at the 1,2-positions preferably represents a 1,2-double bond as the 1,4-pregnadienes are generally more stable and more convenient to prepare than the 4-pregnadines.

A preferred group of 3,20-dioxo-7a-chloro- or bromo-4-pregnenes can be represented by the formula:

wherein Z is a chlorine or bromine atom,

Y is an oxygen atom or the group (H,pi-OH),

W is a methylene group or the group (H,CH3) or (H,H), and

V and V 2 , which may be the same or different, are hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12 (preferably up to 8) carbon atoms. In particular, V and V 2 in formulas II and III can be any of the previously defined acyl groups.

A particularly preferred compound of this group is 7α-chloro-4-pr egnen-11(3,17α,21-triol-3,20-dione-17,21-dipropionate.

7α-Chloro- or bromo-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 and their esters such as the hemisuccinate and phosphate esters) and soluble in most organic solvents, especially in acetone, dioxane, dimethylformamide and dimethylsulfoxide, although they have limited solubility in non-polar solvents such as dialkyl ethers and alkanes.

7a-Chloro- or bromo-1,4-pregnadienes are preferably kept below room temperature (e.g. at 0 - 5° C) when stored for longer periods to slow down decomposition to the corresponding 1,4,6-pregnatrienes (from which they are usually produced). For short-term storage, the 7a-chloro derivatives are relatively stable up to 100°C, however, the 7a-bromo derivatives should be stored below 55°C.

The 7a-chloro or bromo-3,20-dioxc-4-pregnenes are preferably stored in an open vessel placed in a chamber under reduced pressure and at moderate temperatures (e.g. 0 - 40° C) to reduce decomposition into the corresponding 4,6-pregnadienes (from which they are usually prepared) with release of hydrogen halide.

In general, the 3,20-dioxo-7cx-chloro- or bromo-1,4-pregnadienes of formula I, especially those in which V is a hydrogen atom or an acyl group or in which OV and Q together are a 17a,21-alkylidenedioxy group, exhibit a corticoid Activity. The compounds which have halogen atoms at both C-9 and C-11 or an oxygen function at Oll and a halogen or hydrogen at C-9 exhibit glucocorticoid activity and are particularly valuable as anti-inflammatory agents. Preferred anti-inflammatory active compounds, especially for topical administration, are 3,20-dioxo-7a-chloro- or bromo-1,4-pregnadiene-17(x-21-diols and especially 113,17a,21-triols of formula II and their esters.

The 7a-bromo and 7a-chloro compounds of formula I with a cortical side chain at C-17 (ie compounds of formula I in which

-CH2G is CH20V~ and Q is OV) and ester derivatives thereof, in particular compounds unsubstituted at C-9, are particularly useful as topical anti-inflammatory agents, and in particular compounds substituted at C-16 with a lower alkyl group

(preferably a 16-methyl and especially a 16a-methyl group)

or with a 16-methylene group, exhibits excellent topical anti-inflammatory activity which is generally better than the topical anti-inflammatory activity of corresponding 7-unsubstituted analogues. Thus, particularly advantageous compounds are 7a-chloro-or bromo-3,20-dioxo-1,4-pregnadienes of formula II in which Y is the group (H,3~OH).

Particularly useful topical anti-inflammatory agents of formula II are those in which V and V 2 are acyl radicals of hydrocarbon carboxylic acids with up to 8 carbon atoms, in particular the 17-propionate, 17-n-butyrate and 17-benzoate derivatives which exhibit high topical anti-inflammatory activity with very low systemic corticoid effect. 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 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 17,21-diacyl derivatives of formula II are most valuable as their topical activity is generally better than the corresponding 7-unsubstituted compounds.

The superior topical activity of the preferred 3,20-dioxo-7α-chloro or bromo-1,4-pregnadienes of formula II, in particular of the 16α-methyl derivatives, can be demonstrated by pharmacological tests on animals. For example, in topical testing on mice by a modification of the croton oil induced ear edema test (G. Tonelli et al., Endocrinology 77: 625 - 634 (1965)), 7a-bromo-16a-methyl-1,4-pregnadiene-113 ,17a,21-triol-3,20-dione-17-benzoate-21-acetate approx. the double topical activity but only a fraction of the systemic effect of betamethasone dipropionate (9a-fluoro-160-methyl-1,4-prega-dien-llp,17a,21-triol-3,20-dione-17,21 -dipropionate). When tested on mice by a modification of the skin atropy test (E.G. Weirich and J. Longauer, Res. Exp. Med. 163, 229 (1974)), this 7a-bromo compound exhibited a markedly lower hydatropic potency than betamethasone dipropionate. Furthermore, 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate exhibited a good separation of local activity from systemic efficacy when injected locally in the rat, and has very low glucocorticoid activity when administered orally in both mice and rats.

The purpose of the croton oil-induced ear edema test is to determine the topical effect and the systemic effect of the steroids used. Systemic effect is usually undesirable as this indicates absorption and therefore general activity in the body, including a particularly undesirable side effect, namely adrenal suppression.

The skin atrophy test is intended to indicate another side effect, namely atrophy of the skin upon chronic administration.

In the following tables, the therapeutic activity of preferred compounds of formula I has been compared with known 7-unsubstituted compounds and well-known standard corticoids such as betamethasone-17-valerate and betamethasone-17,21-dipropionate. These equation compounds were chosen for the following reasons: - They are standard compounds that are fully recognized on the market. - Norwegian patent 122 367 concerns betamethasone and its 21-ester, but as no therapeutic data is stated in the patent document, a 17-ester and a 17,21-diester have been chosen for the sake of comparison. - Norwegian patent document 122 647 describes 16-methylene-11-oxygenated steroids of the pregnane series which are relatively closely related to betamethasone (instead of a 163-methyl group they contain a 16-methylene group).

The subsequent tables indicate the results obtained.

As can be seen from the tables, the compounds produced according to the invention exhibit good topical activity (table I), low systemic activity (table II) and relatively low activity in the skin atrophy test (table III).

In a similar manner, other 70-chloro- or bromo-1,4-pregnadienes of formula II exhibited in the above-described tests on animals, e.g. 7α-chloro- and 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate a high topical anti-inflammatory activity coupled with a low systemic action by topical application, and a low skin atropy as well as low parenteral and oral glucocorticoid activity.

Preferred compounds are the following: 7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate,

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate and

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate.

7α-chloro- or bromo-3,20-dioxD-4-pregnenes of formula III also exhibit topical anti-inflammatory activity and are thus useful in the treatment of corticosteroid-susceptible dermatoses such as contact and allergic dermatitis and psoriasis. They may also be applied topically or locally in any suitable pharmaceutical form provided it is free from acids and bases.

ON. Diassi et. al., J. Med. Chem., Vol. 10, 551

(1967) describes 7a-chloro-A-nor-progesterone and stated that the introduction of the 7-chloro atom greatly reduces the progestational activity of the 7-unsubstituted precursor. In addition, the P.A. Diassi et al. that no 7a-chloro-4-dehydro-3-one ever

has been stated to be obtained either by oxidation of a 4-dehydro-3-one with 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of hydrogen chloride (quinone is simultaneously reduced to the corresponding quinol) or by addition of hydrogen chloride to 4, 6-bis-dehydro-3-ones, and postulated that steroids with a 7a-chloro-4-dehydro-3-one structure may be present in the reaction mixture but are unstable and revert to 4,6-bis-dehydro-3-ones when attempts are made to isolate 7a-chloro-4-dehydro-3-ones and liberate these from quinone and quinol.

However, it has now been found that 7a-chloro-4-dehydro-3-ones can be isolated mainly pure and in particular free or mainly free of corresponding 6,7-dehydrohalogenated compounds, quinone and quinol. It has also been found that 7α-chloro- or bromo-4-pregnane-3,20-diones and in particular 7α-chloro- or bromo-1,4-pregnadiene-3,20-diones are generally valuable steroids with a valuable activity such as corticoid activity.

The analogy method according to the invention is characterized in that

(a) hydrogen chloride or hydrogen bromide is added to the 6,7-double bond in a compound of formula

wherein the dashed line, X, Y, W, Q and G have the above meanings, in the presence of an inert solvent; provided that (i) when hydrogen chloride is added, X is a hydrogen atom; (ii) when Y is the group (H,jB-OH) and hydrogen bromide is added, X is a hydrogen atom;

or that

(b) a compound of formula

wherein X, Y, W, Q and G are as defined above, except that G is not a hydroxy group; reacted with a chlorinating or brominating agent capable of replacing the 7j3-hydroxy group with a 7CC chlorine or bromine atom, in the presence of an inert organic solvent; or (c) for the preparation of a compound of formula I in which Y is the group (H,|3-OH), that a compound of formula I in which Y is an oxygen atom is reduced; after which the product obtained according to process alternative (a), (b) or (c) is, if desired or necessary, subjected to one or more of the following final treatments in any order, on the condition that the final (iii) cannot follow process alternative (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 17a- and/or 21-position; (iii) reduction of an 11-oxo group to a 113-hydroxy group; (iv) 9(11)-dehydration of a 9-unsubstituted-113-ol to a 4,9(11)-pregnadiene or to a 1,4,9(11)-pregnatriene, followed by addition of chlorine to 9( 11)-double bond.

Alternative a) is preferably carried out under anhydrous conditions, especially when the starting material has a 1,2-double bond, in order to reduce side reactions such as hydrolysis of possibly present ester groups. 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 this process are those in which the starting material of formula IV and the hydrogen halide are soluble. With

"non-reactive" means any organic solvent which will not react with the steroid substrate or the hydrogen halide to thus effect operative reactions. In this process, the solvent usually avoided includes water (which will cause hydrolysis of esters), alcohols (which can cause ester exchange under acidic conditions), and nitriles, e.g. acetonitrile (which will form iminoethers with steroidal alcohols).

Particularly useful solvents for use in this method are ethers such as dioxane, tetrahydrofuran and diethyl ether, chlorinated hydrocarbons such as chloroform, methylene chloride and ethylene dichloride, organic acids such as acetic and propionic acids, tertiary amides such as dimethylformamide, diethylformamide and hexamethylphosphoric triamide, and dimethylsulfoxyd. Dioxane, acetic acid and tetrahydrofuran are particularly suitable solvents, and tetrahydrofuran is preferred; by reactions with hydrogen chloride and acetic acid by reactions with hydrogen bromide or hydrogen iodide.

This reaction is preferably carried out at temperatures within the range of 0° C to 30° C or preferably up to ambient temperature (e.g. 20° C) although lower temperatures (e.g. -20° C) and temperatures as high as about. 60° C, can be used. (Temperatures above 30° C are preferably not used, except when a 7a-chloro-1,4-pregnadiene-17a,21-diol-3,20-dione or an ester thereof is prepared). The reaction time depends on the hydrogen chloride or bromide, the solvent and the concentration used. The addition of hydrogen bromide at room temperature can be completed from 20 to 60 minutes. The addition of hydrogen chloride in tetrahydrofuran is preferably carried out at 0° C instead of at room temperature, as the larger concentrations of hydrogen chloride can be achieved and enable the reaction to be completed within 1 hour instead of approx. 24 hours.

Substituents present in the 3,20-dioxo-1,4,6-pregnatriene and 3,20-dioxo-4,6-pregnadiene parent steroids generally remain unchanged under the process conditions so that it is generally preferred that the parent steroids have all the desired substituents in the 7o-chloro or bromo-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 -4,6-pregnadiene either in the solid state or in solution, to a saturated solution of dry hydrogen chloride or bromide in an anhydrous solvent, usually at 0 - 20°C, and where the molar ratio between hydrogen chloride or bromide and steroid is approx. 40 to 1. After the reaction is complete, as determined by thin layer chromatography, the reaction mixture is poured into ice water, and the resulting precipitated 7α-chloro- or bromo-3,20-dioxo-1,4-pregnadiene or -4-pregnadiene is separated by filtration or extraction and is isolated in a pure state usually by chromatography. When, in particular, the product is a 7a-chloro- or bromo-3,20-dioxo-4-pregnene, this is preferably separated at temperatures not higher than 25° C. in a state essentially free of acid and base by releasing an excess of acid and solvent without being subjected to a predominantly basic medium.

In the starting material of formula IV, X is preferably

a hydrogen atom, as the O-unsubstituted compounds of formula IV generally tend to undergo addition of hydrogen chloride or bromide more readily than their 9a-halo derivatives. It is also advantageous that X in the final product of formula I is a hydrogen atom, as the 9α-unsubstituted compounds of formula I generally have better topical anti-inflammatory activity than their 9α-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 more rapidly than the conversion of a 3,20-dioxo -1,4,6-pregnatriene to a 3,20-dioxo-7a-chloro-1,4-pregnadiene, and can therefore, if desired, be carried out in the presence of water without causing significant hydrolysis of ester groups which may be present. 1,2-dihydro-4-pregnenes of formula I, which are much less stable than the 1,4-pregnadienes, must furthermore be isolated from excess acid as quickly as possible without the use of a basic medium and must be stored in vacuum in an open vessel at temperatures not higher than 25° C.

When a 7α-chloro- or bromo-110-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 113-hydroxy group. Better overall yields of pure product are obtained if the steroid of formula IV has an 11-oxo group, and the resulting 7α-chloro- or bromo-3,11,20-trioxo-1,4-pregnadiene or -4-pregnene is then reduced at 11 - the position as specified in procedure alternative c). Suitable reducing agents include sodium, potassium or lithium borohydride, tetra-n-butylammonium borohydride or lithium-tri-t-butoxy-aluminum hydride, in an inert solvent, preferably sodium borohydride in an inert solvent comprising methanol or dimethylformamide. When the starting material of formula IV is a 3,11,20-trioxo-17α-hydroxy-1,4,6-pregnatriene-17-acylate where any 21-hydroxy group is esterified, the reaction proceeds very specifically at the 11-oxo group. However, when a 3-oxo-7a-chloro- or bromo-11(3-hydroxy-1,2-dihydroxy-4-pregnene is prepared by reduction of the corresponding 11-oxo derivative (e.g. with sodium borohydride), an accompanying reduction at the 3-keto group tends to take place so that better yields of the desired product are obtained when the resulting 7a-chloro or bromo-llo-hydroxy product is oxidized with an oxidizing agent capable of oxidizing an allyl hydroxy group to a oxo group under essentially non-basic conditions The oxidizing agent can be, for example, pyridinium chlorochromate in an inert organic solvent, eg methylene chloride, for-

step by step in the presence of a weak base such as sodium acetate,

or a carbodiimide, e.g. dicyclohexylcarbodiimide together

with dimethyl sulfoxide and a weak acid, e.g. pyridinium trifluoroacetate, but is advantageously neutral active magnesium dioxide in 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 from their 6,7-dihydro derivatives by standard methods for carrying out dehydrogenation between C-6 and C-7, for example by means of chloranil or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or by bromination at C-6 followed by dehydrobromination. As ester groups are usually present in the 6,7-dihydroderivatives, anhydrous conditions are preferably used to reduce the hydrolysis.

In process alternative b) the halogenating agent is preferably either a tertiary amine with an N-(2-chloro-1,1,2-trifluoroethyl) group in the presence of a metal chloride or bromide which is soluble in the reaction mixture for the production of a 7a-chloro- or 7a-bromsteroid, or a tertiary amine with an N-trichlorovinyl group to produce a 7a-chlorosteroid. A particularly preferred halogenating agent is N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine, also known as fluoramine, and where the reaction between the steroid and fluoramine is preferably carried out at moderately low temperatures (e.g. approx. 0° C) under an inert atmosphere (e.g.

under argon, neon or nitrogen) and under anhydrous conditions. All primary and unhindered secondary alcohol groups (i.e. wood

the 21 and 16a positions, but not at the llj3 position) must be protected, e.g. by esterification. The preferred molar ratio between fluoramine and steroid is approx. 6:1.

The preferred metal chloride and bromide are lithium chloride and bromide.

When fluoramine is used together with lithium bromide as a brominating agent, the solvent is preferably a halohydrocarbon, especially methylene chloride, and the product is a 7a-bromosteroid. When fluoramine is used together with lithium chloride as a chlorinating agent, the solvent is preferably an ether, especially tetrahydrofuran, and the product is a 7a-chlorosteroid. The molar ratio between lithium chloride or lithium bromide and steroid is preferably approx. 12:1.

The reaction of the steroid of formula V with fluoramine

in the presence of lithium chloride or bromide is preferably allowed to proceed fully, e.g. 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 form the desired 7a-chloro or bromo derivative, sometimes in mixture with the corresponding 7-unsubstituted-6-dehydro derivative. Such a mixture can be separated by converting this 6-dehydro derivative into a derivative that is easily separable from the 7a-chloro or bromo product by chromatography, in particular into a 6,7-disubstituted derivative, e.g. to the corresponding 6f},7f3-diol by reaction with osmium tetroxide in dioxane in the presence of pyridine.

7a-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 halohydrocarbon, e.g. methylene chloride,

as a solvent and preferably at moderately low temperatures, e.g. about. 0° C and under an inert atmosphere, e.g. nitrogen. The molar ratio between N,N-diethyl-1,2,2-trichlorovinylamine and steroid is preferably approx. 6:1.

The compound of formula V which in these processes reacts with the halogenating agent has a 1,2-

double bond as the resulting 1,4-pregnadienes are generally more stable, can be isolated more easily and are more active as topical anti-inflammatory agents than the corresponding 1,2-dihydro-4-pregnanes.

The steroids of formula V used as starting materials in this process are new

is produced by converting the corresponding 63,73-dihydroxy derivatives into 63,73-alkyl orthoalkanoate esters, hydrolysis at the 7-position with weak acid and then reduction of the resulting 63-acyloxy-73-hydroxy derivative, preferably with chromic acetate, sodium acetate and aqueous acetic acid in acetone.

The product of one or the other of the two main reaction steps as described above (starting from a steroid of formula IV or V) can then be subjected to one or more final steps i) to iv) as indicated above. Whether it is appropriate or not or even necessary to carry out such a final step will normally be clear to the person skilled in the art, it will often be more appropriate to carry out corresponding chemical changes during the preparation of the steroid of formula IV or V.

7a-chloro- or bromo-3,20-dioxo-1,4-pregnadines and -4-pregnanes with ester functions at C-17 and/or C-21 can be converted to 7<x-chloro- or bromo-3, 20 -dioxo-1, 4-pregnadienes and -4-pregnenes with free hydroxyl groups at C-17 and/or C-21, e.g. by the influence of acidic saponification agents, e.g. a strong inorganic acid and preferably 70% perchloric acid in methanol. By regulating the reaction time and the amount of acid, a 17,21-dihydrocarboncarboxylate can be converted into the corresponding 17-monoester or 17,21-diol. The compounds have a chlorine or bromine atom at C-7 so that basic hydrolysis agents are usually not desirable as unexpected side reactions will often take place, such as elimination of the 7a chlorine or bromine atom. However, mild basic saponification agents such as aqueous sodium bicarbonate in methanol can often be used successfully.

The hydrolysis of an esterifying group at C-21 is preferably carried out by means of diastase enzyme-of malt in aqueous ethanol. Malt diastase hydrolyzes 7α-chloro- or bromo-3,20-dioxo-pregnadiene-17,21-dihydrocarboncarboxylates only at C-21 to form 17-monohydrocarboncarboxylates, which, if desired, can be transesterified at C-21 in a known manner with a acylating agent that introduces a different acyl function from the present C-17 to form mixed 17,21-diacyl derivs.

16a,17a orthoesters and 17a-21 orthoesters can be hydrolyzed at the 16a and 21 positions to give a 17-ester.

This hydrolysis is preferably carried out under mildly acidic conditions, for example in the presence of a lower alkanoic acid (for example acetic acid or propionic acid) or a strong inorganic acid (for example hydrochloric or sulfuric acid). When no substituents are present at C-16, the hydrolysis is preferably carried out

under buffered conditions at pH in the range from 4 to 6.

The preferred compounds have ester groups

at C-17 and includes 17-mono- and 17,21-diesters,

in particular 17-propionates, 17-n-butyrates and 17-benzoates. It is usually advantageous to have these ester groups already present in the starting material of formulas IV and V. However, it may often be appropriate to introduce these groups after one of the above-described main reaction steps according to the invention has been carried out.

Thus, the 17a,21-diesters can be prepared by acylation of the corresponding 17a,21-diols or 17a-hydroxy-21-acyloxy compounds, preferably with the help of a carboxylic acid with up to 12 carbon atoms or retinoic acid together with an esterification agent or with the help of a reactive derivative of this acid. In particular, the steroid can be reacted with an appropriate acid anhydride, in the presence of a strong acid catalyst, for example toluene-p-sulfonic acid, perchloric acid or a strong acid cation exchange resin, or with trifluoroacetic anhydride and the appropriate acid, e.g. a lower alkanoic acid, and a strong acid catalyst.

Before a 17a-hydroxyl group is esterified, any 113-hydroxyl function should be protected, for example as 113-trifluoroacetate, which after esterification at C-17, can be hydrolyzed with mild base (e.g. dilute aqueous sodium benzoate) without hydrolysis of other ester groups at C -17 and/or C-21. Alternatively, the 17a-esterification can be carried out on an 11-oxo compound,

and the 1,1-oxo group can then be reduced (as described above after the discussion of the first main reaction step) to the desired 113,17a-diol-17-acylate.

17,21-diesters can also be prepared by acylation of the corresponding 21-hydroxy-17a-monoesters with the appropriate acid anhydride or acid chloride under basic conditions, preferably in the presence of a tertiary organic base, for example pyridine, quinoline, N-methylpiperidine , N-methylmorpholine, p-dimethylaminopyridine or N,N-dimethylaniline.

The 17a-monoesters can be prepared by hydrolysis of a corresponding 17,21-orthoester or 17a,21-diester as described above, the 17,21-orthoester group can be introduced by reaction of a 17a,21-diol with an alkyl orthoester either before or after the main the step according to the invention.

The reduction of an 11-oxo group to a 110-hydroxy group has already been described.

When 7a,9a,110-trihalo compounds and 7a,9a-dihalo-110-hydroxy compounds of formula I are prepared, the 9a,110-dihalo or 9a-halo atoms may be present in the molecule before introduction of the 7a-chloro or bromo atom. However, the 9α,110-dihalogen or the 9α-halogen atoms can be introduced into a 7α-chloro- or bromo-9(11)-dehydro compound (especially a 7α-chloro- or bromo-3,20-dioxo-1,4,9 (11)-pregnatriene), which may be derived from a 7a-chloro- or bromo-110-hydroxy-3,20-dioxo compound by dehydration with methanesulfonyl chloride and a tertiary amine (e.g. collidine) in a dialkylamide (e.g. eg dimethylformamide) in the presence of sulfur dioxide. For example, the reaction of a resulting 7a-chloro- or bromo-8(11)-dehydro compound with chlorine in a halogenated solvent (e.g. chloroform) in the presence of a tertiary amine (e.g. pyridine) will give the corresponding 7α-chloro- or bromo-9α,110-dichloro derivative. Alternatively, reaction of the resulting 7a-chloro- or bromo-9(11)-dehydro compound with hydrogen fluoride and an N-chloramide or N-bromamide or with hydrogen chloride and an N-bromamide in an inert solvent gives 7a,9a,110-trihalo derivatives in which the more electronegative halogen is substituted at the llfJ position.

Furthermore, reaction of the resulting 7α-chloro- or brpm-9(11)-dehydro compound with an N-chloramide or N-bromamide (preferably N-chlorosuccinimide or N-bromosuccinimide) and a strong inorganic acid (preferably perchloric acid) in an inert organic solvent (eg crude dioxane or tetrahydrofuran) an oleol with a 9a-chloro or 9a-bromo substituent.

17a-Chlorination or bromination can be carried out using an N-chloramide or N-bromamide, especially N-chlorosuccinimide or N-bromosuccinimide, in an inert organic solvent such as tetramethylene sulfone at reduced temperature and preferably in the presence of an inorganic acid such as hydrofluoric acid .

The following description shows how the starting materials of formulas IV and V can be obtained.

Manufacturing

73- hydroxy- l, 4- pregnadiene- 3, 20- diones 9 a- fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20-dione-6,7- n-butylorthopropionate-21-acetate Add to 3 g of 9a-fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20-dione-21-acetate in 15 ml of dimethylsulfoxide 5, 4 ml of tri-n-butyl orthopropionate and 0.2 25 g of toluene-p-sulfonic acid monohydrate and stir at room temperature for 3.5 hours. Pour the reaction mixture into 500 ml of water and 100 ml of saturated sodium bicarbonate. Extract the aqueous mixture with ethyl acetate, wash the combined extracts with water, dry over magnesium sulfate and evaporate to a residue comprising 9a-fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20 -dione-6,7-n-butyl orthopropionate-21-acetate.

9a-fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20-dione-6-propionate-21-acetate

Dissolve the product from the previous step in 50 ml of glacial acetic acid and 1 ml of water. Allow the reaction mixture to stand at room temperature for 1 hour, then pour into 500 ml of ice water and separate the resulting precipitate by filtration. Wash the precipitate with water and dry at room temperature to form 9a-fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20-dione-6-propionate-21-acetate.

9a-fluoro-16a-methyl-1,4-pregnadiene-73,113,17a,21-tetrol-3,20-dione-21-acetate

Add to 3 g of 9a-fluoro-16a-methyl-1,4-pregnadiene-63,73,113,17a,21-pentol-3,20-dione-6-propionate-21-acetate in 750 ml of acetone a solution of 21 g sodium acetate, 60 ml of water and 15 ml of acetic acid followed by a chromium acetate slurry (freshly prepared from 70 g of chromium chloride reduced with zinc amalgam followed by treatment with sodium acetate according to known procedures). Stir the reaction mixture at room temperature for 2.5 hours, filter and evaporate. Add water to the resulting residue, filter and evaporate. Add water to the resulting residue, extract with ethyl acetate, wash the combined organic extracts with water, dry and evaporate in vacuo to a residue comprising 9a-fluoro-16a-methyl-1,4-pregnadiene-73113,17a,21-tetrol- 3,20-dione-21-acetate. Pure by recrystallization from acetone:hexane, m.p. 181 - 185° C, [α]^<6> +48.7° (dimethylformamide).

The following examples illustrate the invention.

Example 1

7g- chloro- 16a- methyl- 1, 4- pregnadiene- 113, 17a, 21- triol-3, 20- dione- 17, 21- dipropionate

A. Add 2.0 g of 16α-methyl-1,4,6-pregnatriene,113,17α,21-triol-3,20-dione-17,21-dipropionate to 24 mL of dioxane which has been saturated with dry hydrogen chloride gas. Stir at room temperature for 16 hours, pour into ice water (600 ml), separate the resulting precipitate by filtration, wash the precipitate with water and air dry. Separate the components of this precipitate on silica gel by thin-layer chromatography using ether:hexane (2:1) as the developing solvent, and elute with ethyl acetate the band containing 7a-chloro-16a-methyl-1,4-pregnadiene-113,17a,21 -triol-3,20-dione-17,21-dipropionate as seen by ultraviolet light. Evaporate the combined ethyl acetate eluates and triturate the resulting residue with acetone:ether, filter off and dry the triturated precipitate to give 7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20- dione-17,21-dipropionate.

(For assay data, see Example 1C).

Alternatively, the compound according to this example can be prepared according to the procedures described in IB and 1C. B. 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate

Saturate dry tetrahydrofuran (137 mL) at 0°C with dry hydrogen chloride gas. Add 16α-methyl-1,4,6-pregnatriene-17α,21-diol-3,11,20-trione-17,21-dipropionate (6.85 g) and stir the reaction mixture at 0° C. for 1 hour. Then pour over ice water (1 litre) and stir for 1/2 hour. Separate the resulting precipitate by filtration, wash it with water and dry it in air to give 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21 -dipropionate. Purify by recrystallization from

2 6 methanol:acetone containing traces of propylene oxide; fa^D <+ >76.2° (dimethylformamide); [M]<+> 520, 518; sm.p. 180 - 183° C, AMeOH 238 nm (e = 15,800)m

max

C. Add to a solution of 3.2 g of 7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate in

24 ml of tetrahydrofuran and 8 ml of methanol at 0° C under nitrogen atmosphere 0.697 g of sodium borohydride and stir the reaction mixture for 15 minutes at 0° C. Pour into 1.8 liters of ice water and 250 ml of IN hydrochloric acid. Filter from the resulting precipitate and dry it in air to give 7α-chloro-16α-methyl-1,4-pregnadiene-110,17α,21-triol-3,20-dione-17,21-dipropionate. Purify by recrystallization twice from acetone:methanol:isopropylether, m.p. 212 - 216° C, [aj£<6> + 42.6° (dimethylformamide) , [M]<+> 522, 520, X ^ tks^ 01

242 nm (e 15 600), 6 J^jg 1 1743 , 1730, 1720 , 1562, 1610, 1595

cm"<1>, nmr (dmso-d6) 0.84 (Clg-CH3, d J7Hz) , 1.02 (C^-CH^ s) ,

1.42 (C10-CH3, s), 4.38 (lla-H, mult.), 4.67 (73-H, mult.),

4.80 (C21-H, s), 5.95 (C4-H, s), 6.20 (C2-H, dd J10.2HZ),

7.35 (C₂-H, d JlOHz) .

Example 2

7a- bromo- 16a- methyl- 1, 4- pregnadiene- 113, 17a, 21- triol-3, 20- dione- 17, 21- dipropionate

A. Add 0.29 g of 16a-methyl-1,4,6-pregnatriene-113,17a,21-triol-3,20-dione-17,21-dipropionate to a solution of 30%

(w/v) dry hydrogen bromide in 4 ml of acetic acid previously cooled to 0° C. Stir the reaction mixture at 0° C for 1 hour, pour it into ice water, separate the resulting solid material by filtration and wash the precipitate with water and dry it . Purify by trituration with acetone:ether, dry the triturated precipitate to give 0.19 g of 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21 -dipropionate.

(For analysis data, see Example 2C-).

Alternatively, the compound according to this example can be prepared according to the procedures described in 2B and 2C.

B. 7α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate

Add to a solution of 0.5 g of 16α-methyl-1,4,6-pregnatriene-17α,21-diol-3,11,20-trione-17,21-dipropionate in 2 ml of glacial acetic acid at 0° C. a fresh prepared solution of 3 g of dry hydrogen bromide gas in 8 ml of glacial acetic acid at 0° C. Stir the reaction mixture for 1 hour at 0° C, pour it into 400 ml of ice water, stir for 30 minutes, filter the resulting precipitate and wash it with water until the wash water is neutral. Dry it in air to give 7α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate (0.51 g), [a] ^6 +

105.1° (dimethylformamide), Δ<®>°" 238 nm (e = 15,400).

C. To 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 of sodium borohydride, under nitrogen atmosphere at 0° C added 8 ml of methanol previously cooled to 0° C and the reaction mixture was stirred for 5 minutes at 0° C. Pour the reaction mixture into 2 liters of ice water and 300 ml of 1N hydrochloric acid, filter from the resulting precipitate and wash with water. Dry in air to give 2.6 g of 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate. Purify by recrystallization from acetone:ether:hexane, 1.44 g, m.p.

> 295° C, fa]^6 +37.3° (dimethylformamide), A methano1 242 nm D max

(e 15,350); \ ^^ s, 1 1743' 1735' 1660, 1612, 1600 cm<-1>, no.

(amso-dg) 6 0.85 (C16~C<H>3, d J7Hz), 1.03 (C13"CH3, s), 1.43

(C10-CH3, s) , 4.38 (lla-H, mult.), 4.75 (7fJ-H, mult.), 4.81

(C21-H, s) , 5.86 (C4-H, s), 6.19. (Cy-H, dd J10, 2Hz), 7.31

(C^-H, d JlOHz) .

Example 3

7a- bromo- 16a- methyl- 1, 4- pregnadiene- llØ, 17a, 21- triol- 3, 20-dione- 17- benzoate- 21- acetate

A. To 0.31 g of 16α-raethyl-1,4,6-pregnatriene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate add a solution of 30% dry hydrogen bromide in 6 .2 ml of glacial acetic acid at 0° C. After 1 hour at 0° C, pour the mixture into ice water, filter the resulting precipitate, wash it with water and dry it in air. Purify by thin-layer chromatography on silica gel using ether:hexane (2:1) as developing solvent, and elute with ethyl acetate the band containing the desired product as shown by ultraviolet light. Evaporate the combined ethyl acetate eluates to a residue comprising 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate. Purify the residue further by trituration with isopropyl ether (yield 0.125 g). (For assay data, see Example 3C.).

Alternatively, the compound according to this example can be prepared according to the following procedures 3B and 3C.

B. 7α-bromo-16-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-benzoate-21-acetate

To a freshly prepared solution of dry hydrogen bromide gas (9.3 g) in 16 ml of glacial acetic acid at 0° C add dropwise a solution of 1.56 g of 16a-methyl-1,4,6-pregnatriene-17a,21-diol- 3,11,20-trione-17-benzoate-21-acetate in 5 ml of glacial acetic acid. Stir the mixture for 1 hour at 0°C, pour it into ice water, stir the aqueous mixture for 30 minutes, filter the resulting precipitate, wash it with water and dry in air to give 1.6 g of 7a-bromo-16a -methyl-1,4-pregnadiene-17a,21-diol-3,11,20-trione-17-benzoate-al-acetate. Purify further by recrystallization from acetone:hexane, m.p. 190 - 192.5° C, [α]^<6> +77.3°

(dimethylformamide), X J^<1>^<1>101 232 nm (e 27 600).

C. 7α-bromo-16α-methyl-1,4-pregnadiene-11α,17α,21-triol-3,20-dione-17-benzoate-21-acetate

(1) Add to a mixture of 1.05 g of 7α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-benzoate-21-acetate and 0, 1 g of sodium borohydride under a nitrogen atmosphere at 0° C. a pre-cooled solution of 7.5 ml tetrahydrofuran and 2.5 ml methanol and stir the reaction mixture for 25 minutes at 0 C. Pour the reaction mixture into 500 ml ice water and 100 ml IN hydrochloric acid. Filter the resulting precipitate, wash it with water and dry it in air to give 0.53 g of 7α-bromo-16α-methyl-1,4-pregnadiene-1lg,17α,21-triol-3,20-dione- 17-benzoate-21-acetate. Purify further by recrystallization from acetone: hexane:ether, m.p. 156 - 159° C, U]^<6> +21.1° (dimethylformamide) , ^-*£xan<01> 233 ^ (£ 25,800)' nmr (dmso-dg) 60.89

(<C>16-CH3, d J7Hz), 1.12 (C13-CH3, s) , 1.48 (C-^-CHy s) , 2.13 (OAc, s), 4.46 (lla- H, mult.), 4.96 (C21-H, quatr.), 4.90

(73-H, mult.), 6.00 (C4-H, s), 6.28 (C2~H, d,d J10.2Hz), 7.39 (C1-H, d, JlOHz), 7 .50 - 8.00 (phenyl, multi.).

(2) Alternatively, the compound according to this example can be prepared as follows. To a mixture of 0.65 g of 7α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-benzoate-21-acetate and 61.7 mg of sodium borohydride under nitrogen atmosphere and at room temperature, 6.2 ml of dimethylformamide and 0.3 are added

ml of water. Stir at room temperature under a nitrogen atmosphere for 1 hour and pour the reaction mixture into a mixture of 200 ml of water and 50 ml of IN hydrochloric acid. Filter from the resulting precipitate, wash it with water and dry it in air to give 7α-bromo-16α-methyl—1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate- 21-acetate. Purify further by recrystallization from ether:acetone. (Analysis data: see example 3C.(1) above).

Example 4

7a- chloro- and 7a- brorn- ll- oxo- 1, 4- pregnadiene- 17a, 21- diol- 3, 20-diones and esters thereof

The subsequent compounds were prepared as described in Example IB, 2B or 3B.

7α-chloro-1,4-pregnadiene-17α,21-diol-3,11,20-trione-21-acetate, m.p. 220 221° C, [a]<26> +113.3° (dimethylformamide), A "<®>°"

238 nm (e = 15,000).

7α-chloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-21-acetate [α]D +101.6° (dimethylformamide), ^ax 240 nm (e 15,350)'

7α-chloro-163-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-21-acetate, m.p. 175 - 178° C, [a]<26> +134.3° (dimethylformamide)

A M<e>?<H> 237 nm (e = 17,450).

max

7α-chloro-16β-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-benzoate-21-acetate, m.p. 209° C (decomposition), [a]<26>+124.7°

MeOH

(dimethylformamide), ^max 233 nm (e= 30,000).

7α-bromo-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-acetate,

sm.p. 168° C (decomposition), [α]^ +100.7° (dimethylformamide).

7α-bromo-16α-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dibenzoate, m.p. > 285° C, X 231 nm (e = 31,500),

[a]<2>^ +65.8° (dimethylformamide).

7α-bromo-163-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17-benzoate-21-acetate, m.p. 160° C (decomposition), [a]2<6> +131.9°

MeOH

(dimethylformamide), ^ax 235 ^ (e = 28 400) *

Example 5

7a-chloro- and 7a-bromo-113-hydroxy-1,4-pregnadiene-17a,21-diol-3,20-diones and their esters

The subsequent compounds were prepared directly from the 113-ol precursors by the method of Example IA, 2A or 3A, or from the corresponding 11-keto precursors by the method of Example IB, 2B or 3B, followed by reduction by the method of Example 1C, 2C or 3C: 7α-chloro-16α-methyl-1,4-pregnadiene—113,17α,21-triol-3,20-dione-21-acetate, m.p. 197 - 203° C, [a]2<6> +49.9° (dimethylformamide),

X Me°H 242 (e = 14,300).

max

7α-chloro-1,4-pregnadiene-113,17α,21-triol-3,20-dione-21-acetate,

sm.p. 230 - 233° C, [a] 26 +60.8° (dimethylformamide), xJJ|°"

243 nm (e = 11,600) .

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dibenzoate, m.p. 230 - 234° C, X 232 nm (e = 39,800),

[a]<26> +30.5° (dimethylformamide).

7α-Chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-21-benzoate, [M]<+> 514, 512.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-n-butyrate-21-propionate, m.p. 155 - 160° C, [M]<+> 536, 534.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-di-n-butyrate [M]<+> 550, 548; sm.p. 145 - 147° C,

A 240 nm (e = 16,500), [a]<26> +40.2° (dimethylformamide).

7a-chloro-16[3-methyl-1,4-pregnadiene-113,17a,21-triol-3,20-dione-17-benzoate-21-acetate, m.p. 195 - 198° C, [α]<26> +69.3°

MpOH (dimethylformamide), A 235 nm (e = 27,000).

7α-chloro-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate. sm.p. 125 - 130° C, [ct]<2>^ +31.3° (dimethylformamide) . A 240 nm (e = 16,000).

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-propionate-21-isoburyrate, [M]<+> 536, 534, nmr (dmso- dg) 6 0.84, 1.04, 1.44, 4.69, 5.99, 6.24, 7.37.

7α-chloro-163-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-propionate-21-n-butyrate nmr (dmso-dg) 6 0.92, 1, 25, 1.44, 4.62, 4.72, 4.44, 6.00, 6.25, 7.39.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-propionate-21-valerate, m.p. 134 - 137° C, [α]^ +37.5°

MeOH

(dimethylformamide), A 240 nm (fe = 13,700).

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-isobutyrate-21-acetate, [M]<+> 522, 520.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate, [M]<+> 556, 554, nmr (dmso- dg) & 0.88, 1.12, 1.46, 4.73, 6.02, 6.26, 7.40, 7.50 - 8.00.

7α-Chloro-16-methylene-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate, nmr (dmso-dg) 5 0.98, 1.44, 4.45, 4.73, 4.88, 5.50, 6.00, 6.26, 7.38.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-propionate-21-acetate; [M]<+> 508, 506, nmr (dmso-dg) 6 0.84, 1.01, 1.42, 4.84, 4.67, 4.40, 5.99, 6.24, 7 ,37.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-propionate-21-n-butyrate; [M]<+> 536, 534; nmr (dmso-dg) 6 0.85, 1.02, 1.44, 4.69, 5.99, 6.25, 7.37.

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-valerate-21-acetate; [M]<+> 536, 534.

7α-chloro-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17-n-butyrate-21-acetate; [M]<+> 522, 520.

7α-chloro-16α-methyl-1,'4-pregnadiene-11|3,17α,21-triol-3,20-dione-21-pivalate, m.p. 227 - 230° C, 243 nm (e = 13,900), [M]<+> 494, 492.

7a-chloro-160-methyl-1,4-pregnadiene-110,17a,21-triol-3,20-dione-21-acetate, m.p. 228° C (decomposition); I^ q6 +78.3° (dimethylformamide); A 241 nm (e = 15,500).

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate, m.p. 125° C (decomposition), [a]<26> +74.4°

(dimethylformamide) , A 241 nm (e = 15,200) .

7α-chloro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione, m.p. 210 - 213°C, [o]D + 55.3° (dimethylformamide).

7α-bromo-163-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-acetate, [M]<+> 600, 598, m.p. 170° C (decomposition), [a]<26> +72.8°, A 235 nm (e = 26,500).

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-n-buryrate-21-propionate, m.p. 147° C (decomposition), [cx]D2 6 + 30.8° (dimethylformamide), A ^ks 243 nm (e = 15,600).

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-trio1-3,20-dione-17,21-di-n-buryrate, m.p. 143 - 146° C, [α]<26> 31.8° (dimethyl-MeOH

formamide) , A 7. 243 nm (e = 15,600) .

rriciKs

7α-bromo-16α-methyl-1,4-pregriadiene-113,17α,21-triol-3,20-dione-17-benzoate-21-propionate, m.p. 163 - 170° C, ["Jq^ +27.1°

(dimethylformamide), A ^aks 233 nm ^£ = ^ 900).

7α-bromo-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17-benzoate-21-n-butyrate, m.p. 138 - 144° C, [a]<2>.<6> +24.2°

(dimethylformamide), A MeO" H 234 nm (e = 27,100).

7a-bromo-1,4-pregnadiene-lip,17a,21-triol-3,20-dione-17,21-dipropionate [a]<26> +29.8° (dimethylformamide), X 242 nm

(£ = 15,700) .

7α-bromo-16α-methyl-1,4-pregnadiene-110,17α,21-triol-3,20-dione-MeOH +

21-acetate X ni 3. Kr. S 244 nm (e = 13,700), [M] 496, 494.

7α-bromo-16β-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-21-acetate, m.p. 165° C (decomposition), U] 26 +64.6°, A

242 nm (e = 15,600).

7α-bromo-16β-methyl-1,4-pregnadiene-lip, 17α,21-triol-3,20-dione-17,21-dipropionate, m.p. 135 - 137° C, lo.]^ 6 +66.4° (dimethyl-MeOH

formamide), A , 242 nm (e = 15,500).

IU3.K S

7α-bromo-16α-methyl-1,4-pregnadiene-IIØ,17α,21-triol-3,20-dione-17-propionate-21-acetate [M]<+> 552, 550.

7α-bromo-16α-methyl-1,4-pregnadiene-lip ,17α,21-trio1-3,20-dione-

+ o 17-propionate-21-n-butyrate, [M] 580, 578, m.p. 153 - 155 C, [α]26 +34.7° (dimethylformamide), Δ 241 nm (e = 15,800).

7α-bromo-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17-n-butyrate-21-acetate, [α]D +27.1°, / Vmakg242 (£= 15,500).

7α-bromo-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17-valerate-21-acetate; [M]<+> 580, 578.

7α-bromo-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17-propionate-21-isobutyrate, m.p. 168 - 172° C, [M] 580,

578, [a]<26> +36.3° (dimethylformamide), A J^°" 240 nm (e = 15,500

7a-bromo-16p-methyl-1,4-pregnadiene-liP,17a,21-triol-3,20-dione-17-propionate-21-acetate, [M]<+> 552, 550, nmr (dmso- dg) 6 0.90, 1.44, 4.89, 5.96, 6.25, 7.38.

7α-Bromo-16β-methyl-1,4-pregnadiene-11β,17α,21-triol-3,20-dione-17-propionate-21-buriate. sm.p. 145° C, [M]<+> 580, 578, nmr (dmso-d6) 60.94, 1.28, 1.44, 4.90, 4.61, 4.45, 5.98, 6, 28, 7, 39.

Example 6

7a, 9a, lip- trichior- 1, 4- pregnadiene- 17a, 21- diol- 3, 20- dione-17, 21- dihydrocarboncarboxylates

A. 7α-chloro-16α-methyl-1,4,9(11)-pregnatriene-17α,21-diol-3,20-dione-17,21-dipropionate

(1) Add to 0.37 g of 7a-chloro-16a-methyl-1,4-pregnadiene-llp,17a,21-triol-3,20-dione-17,21-dipropionate in 11.1 ml of dimethylformamide and 0 .67 ml of collidine 3.5% by weight of sulfur dioxide in 0.22 ml of methanesulfonyl chloride. Stir the reaction mixture at 0° C. for 1/2 hour and then at room temperature for 1/2 hour. Add aqueous 1N hydrochloric acid, extract the reaction mixture with ethyl acetate, wash the combined organic extracts with water, dry over magnesium sulfate and evaporate in vacuo to give a residue comprising 7α-chloro-16α-methyl-1,4,9(11)-pregnatriene -17α,21-diol-3,20-dione-17,21-dipropionate. Purify the residue by trituration with ether and filtering the resulting precipitate: m.p. 198 - 201° C, [a]<26> +26.3° (dimethylformamide), , MeOH , ^ rn„, u

A , 2 39 nm (e = 16 50 0).

max

B. 7α,9α,lip-trichloro,16α-methyl-1,4-pregnadiene-17α,21-diol-3,20-dione-17,21-dipropionate

■ Jiy Add to a solution of 0.18 g of 7a-chloro-16a-methyl-1,4,9(11)-pregnatriene-17a,21-diol-3,20-dione-17,21-dipropionate in 5 ml chloroform and 0.9 mL pyridine a solution of dry chlorine gas (28 mg, 1.1 equivalents) in 4 mL chloroform and allow the mixture to stand at room temperature for 3 hours. Add 300 mL of methylene chloride, wash the reaction mixture sequentially with 10% aqueous sodium thiosulfate solution, 1N hydrochloric acid, and water, dry the mixture over magnesium sulfate, and evaporate. Purify the resulting residue on silica gel by thin layer chromatography using a developing solvent consisting of chloroform:ethyl acetate (9:1). Remove the least polar band as shown by ultraviolet light and elute with ethyl acetate. Evaporate the combined ethyl acetate eluates to a residue comprising 7α,9α,lip-trichloro-16α-methyl-1,4-pregnadiene-17α,21-diol-3,20-dione-17,21-dipropionate. Purify further by trituration with acetone and filtration of the triturated precipitate: m.p. 225 - 228° C, Δ 236 nm (e = 15,600). C. Treat 7o-chloro-1,4-pregnadiene-11,17a,2i-triol-3,20-dione-21-acetate (prepared according to Example 5) in a similar manner as described in Example 6A followed by reaction of the resulting 7a-chloro-1,4,9(11)-pregnatriene-17a,21-diol-3,20-dione-21-acetate with chlorine in the manner described in Example 6B to form 7a,9a,113- trichloro-1,4-pregnadiene-17a,21-diol-3,20-dione-21-acetate, m.p. 299 - 301°C, [a]<26> +71.1° (dimethylformamide),

*max 239 nm = 14,500>-

Example 7

7g- chloro- 9a- fluoro- 16a- methyl- 1, 4- pregnadiene- llp, 17a, 21-triol- 3, 20- dione- 21- acetate

Add to 0.5 g of 9a-fluoro-16a-methyl-1,4-pregnadiene-7fJ,113,17a, 21-tetrol-3,20-dione-21-acetate in 100 ml of methylene chloride

rid at 0° C. under a nitrogen atmosphere 1.67 ml of N,N-diethyl-1,2,2-trichlorovinylamine. Stir at 0° C. for 7 hours, evaporate in vacuo, apply the resulting residue to a silica gel column (50 g)

and elute with chloroform:ethyl acetate (3:1). Combine equal fractions containing the desired compound as determined by thin layer chromatography and evaporate. Further purify the resulting residue on thin-layer silica gel plates, develop with chloroform:ethyl acetate (3:1). Remove the band containing the desired product as determined by ultraviolet light and elute with ethyl acetate. Evaporate the eluate to a residue comprising 7α-chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-113,17α,21-trio1-3,20-dione-21-acetate. Purify further by recrystallization from acetone:hexane, [M]<+> 470, 468, NMR (dmso-dg) '6 0.82, 0.90,

1.50, 4.17, 4.55, 4.95, 6.09, 6.27, 7.32.

Example 8

7a- bromo- 9a- halo- 1, 4- pregnadiene- 3, 20- diones

A. 7α-bromo-9α-fluoro-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate

Add to a solution of 0.1 g of 73~hydroxy-9a-fluoro-• 16a-methyl-1,4-pregnadiene-113,17a,21-triol-3,20-dione-17,21-dipropionate and 0, 1 g of lithiurobromide in 100 methylene chloride cooled to 0° C

0.2 3 ml fluoramine. Stir at 0° C for 2 4 hours and evaporate there-

ter in a vacuum. 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 chloroform:ethyl acetate (2:1) as developing solvent. Remove the band containing the desired product as shown under ultraviolet light and elute with ethyl acetate. Evaporate the combine-

te ethyl acetate eluates in vacuo to a residue comprising 7α-bromo-9α-fluoro-16α-methyl-1,4-pregnadiene-lip,17α,21-triol-3,20-dione-17,21-dipropionate, m.p. 160-164°C; [α]D +17.9° (dimethylformamide).

D. By using in the method according to example 8 A

1 instead of lithium bromide, an equivalent amount of lithium chloride and using tetrahydrofuran as solvent instead of methylene chloride, the corresponding 7a-chloro compound is obtained,

i.e. 7α-chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-llp", 17α,21-triol-3,20-dione-17,21-dipropionate, which can be purified from acetone:hexane; [M]<+> 470, 468; NMR (dmso-dg) in 0.82, 0.92, 1.50, 4.17, 4.55,

4.95, 6.09, 6.27, 7.32.

Example 9

7a-chloro- oq bromo- 21- desoxy- 1, 4- pregnadiene- 3, 20- diones and certain 21- ester derivatives

A- 7a- chloro- 21- desoxy- 1, 4- pregnadiene- 3, 20-dione

(1) 7α-chloro-1,4-pregnadiene-17α-ol-3,20-dione and its 17-acetate Add to 0.5 g 17α-hydroxy-1,4,6-pregnatriene-3,20-dione 20 ml of glacial acetic acid saturated with dry hydrogen chloride gas and 2 g of lithium chloride. Stir at room temperature for 4 5 minutes,

then pour into an aqueous sodium carbonate solution and extract the aqueous mixture with ether. Wash the combined organic extracts with water, dry over magnesium sulfate and evaporate to a residue comprising 7α-chloro-1,4-pregnadien-17α-ol-3,20-dione. Purify by recrystallization from methanol, m.p.

229 - 231° C, [a]<26> +50.7° (dioxane).

7α-chloro-17α-acetoxy-1,4-p_regnadiene-3,20-dione

sm.p. 200 - 206° C, [a]^<6> +4.8° (dimethylformamide), X 242

nm (e = 16,100)) can be prepared in a similar manner from 17α-acetoxy-1,4,6-pregnatriene-3,20-dione. (2) By using the 17-propionate of 1,4-pregnadiene-110,17a-diol-3,20-dione as starting compounds in the above procedure, the corresponding 7a-chloro derivative is obtained, i.e. the 17-propionate of 7a- chloro-1,4-pregnadiene-llp", 17a-diol-3,20-dione. ^™fvo 243 nm (£ == 15,800); NMR (dmso-dc) 8 0.85, 1.43, 1 .96, ITlaKS D 4.44, 4.72, 5.99, 6.23, 7.39.

B. 7a-bromo-17a-acetoxy-1,4-pregnadiene-3,20-dione

([a]26 +5.7° (dimethylformamide), A Me?H 242 nm

u max

(£ = 14,000) can be prepared in a similar way from 17a-acetoxy-1,4,6-pregnatriene-3,20-dione by proceeding as described in Example 10A(1) from 17a-acetoxy-1,4, 6-pregnatriene-3,20-dione by using an equivalent amount of dry hydrogen bromide instead of hydrogen chloride, and lithium bromide instead of lithium chloride.

C. 7a-iodo-17a-acetoxy-1,4-pregnadiene-3,20-dione, m.p. 144°C

(cleavage), la]^ -3.5° (dimethylformamide), ^^ax 242 nm = 15 100) can be prepared from 17α-acetoxy-1,4,6-pregnatriene-3,20-dione as described in Example 8A ).

Example 10

7a, 21-dihalo-1,4-pregnadiene-3,20-diones

A. 7a-chloro-21-halo derivatives

(1) 7a,21-dichloro-16a-methyl-1,4-pregnadiene-1P,17a-diol-3,20-dione-17-propionate

is produced by reacting 16a-methyl-21-chloro-1,4,6-pregnatriene-113,17a-diol-3,20-dione-17-propionate with dry hydrogen chloride gas in dioxane by the method described in example IA, <+> 458 , 456 , 454 . (2) 7α,21-dichloro-1,4-pregnadiene-110,17α-diol-3,20-dione-17-propionate, [M]<+> 472, 470, 468, nmr (dmso-dg) 6 0.87, 0.97, 1.41, 2.32, 4.41, 4.75, 5.95, 6.36, 7.35 can be prepared in a similar manner.

B. 7a-bromo-21-halo derivatives

7α-bromo-21-chloro-1,4-pregnadiene-11(3,17α-diol-3,20-dione-17-propionate, nmr (dmso-du,) So,90, 1.00, 1.45 , 2.33, 4.43, 4.85, 5.93, 6.21, 7.36 can be produced by the method according to example 2A or B.

Example 11

A. In a similar manner as described in Example IA, treat 16α,17α-isopropylidenedioxy-1,4,6-pregnatriene-110,21-diol-3,20-dione-21-acetate with dry hydrogen chloride gas in dioxane to form 7a -chloro-16a,17a-isopropylidenedioxy-1,4-pregnadiene-113,21-diol-3,20-dione, m.p. 255-257; [a]<26> +104.9° (dimethylformamide) A"®?" 242 (E = 15,600) .

max

B. In a similar manner as described in Example 2A or B, treat 16a,17a-isopropylidenedioxy-1,4,6-pregnatriene-113,21-diol-3,20-dione-21-acetate with dry hydrogen bromide in acetic acid to form of 7α-bromo-16α,17α-isopropylidenedioxy-1,4-pregnadiene-113,21-diol-3,20-dione-21-acetate, m.p. 197 - 200°C,

[a]<26> +91.9° (dimethylformamide), *JJaks 242 (£= 15,000).

Example 12

Preparation of 17a-monoesters

A. Application of malt diastase

(1) 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate

Add to a suspension of 1.67 g of diastase enzyme from malt in 33.5 ml of ethanol and 16 7.5 ml of water 3 3.5 mg of 7a-bromo-16a-methyl-1,4-pregnadiene-113,17a,21- triol-3,20-dione-17-benzoate-21-acetate. Stir the reaction mixture at room temperature for 3 days, then evaporate in vacuo at room temperature. Dissolve the resulting residue in ethyl acetate and water and filter the solution through a Celite filter cake, washing with ethyl acetate. Separate the organic and aqueous layers and then extract the aqueous layer with ethyl acetate. Wash the combined organic extracts with water, dry over magnesium sulfate and evaporate in vacuo. Purify the resulting residue by thin layer chromatography using chloroform:ethyl acetate (3:1) as eluent. Remove the tape containing the desired product as shown under ultraviolet light. Elute with ethyl acetate and evaporate to a residue comprising 7α-bromo-16α-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17-benzoate.

Purify by trituration with ether:hexane, m.p. 144 - 155.5°C;

MeOH

*mSs 233 nm (£ = 24,700) •

B. By acid hydrolysis

7α-bromo-16α-methyl-1,4-pregnadiene-113,17α-21-triol-3,20-dione-17-benzoate

Add to 0.44 g 7α-bromo-16α-methyl-1,4-pregnadiene-lip,17α/21-triol-3,20-dione-17-benzoate-21-acetate in 69 ml methanol 1.67 ml 70 % aqueous perchloric acid and stir the reaction mixture for 4 hours. Bring the reaction mixture to neutral with saturated aqueous sodium bicarbonate and remove the methanol by evaporation in vacuo. Cool the aqueous reaction mixture and filter from the resulting precipitate comprising a mixture of 7α-bromo-1,4-pregnadiene-110,17α,21-triol-3,20-dione and the corresponding 17-monobenzoate and 21-monobenzoate esters thereof. Separate by thin-layer chromatography on silica gel, develop with ethyl acetate:chloroform (1:1), and remove the band containing the desired 17-benzoate ester as shown under ultraviolet light, elute with ethyl acetate and evaporate to a residue of 7α-bromo-16α-methyl-1 ,4-pregnadiene-113,17a,21-triol-3,20-dione-17-benzoate,

m.p. 144 - 144, 5°C, A ^ax 233 nm (£ = 24,700} *

Example 13

7a- chloro- 16g- methy 1- 1, 4- pregnadiene- ll| 3, 17a, 2l- triol- 3, 20- dione

Add to a solution of 3.5 g of 7a-chloro-16a-methyl-1,4-pregnadiene-113,17<g>,21-triol-3,20-dione-17,21-dipropionate in 300 ml of methanol 30 ml of a saturated aqueous sodium bicarbonate solution and allow the reaction mixture to stand at room temperature for 18 hours. • Pour it into water, filter the resulting precipitate, wash it with water until it is neutral and dry it in air. Recrystallize the dried precipitate from acetone/hexane to give 7a-chloro-16a-methyl-1,4-pregnadiene-11|3,17a,21-triol-3,20-dione, yield 1.3 g, m.p. . 176 - 179° C, [α]<26 >+ 47.5 (dimethylformamide), Δ n 242 nm (e = 15,500).

Example 14

7a- bromine- l, 4- pregnadiene- ll| 3,17a,21-triol-3,20-dione and its 21-acetate

To a solution of 5 g of 1,4,6-pregnatriene-113,17a,21-triol-3,20-dione-21-acetate in 62 ml of glacial acetic acid add 37.5 g of dry hydrogen bromide and allow the reaction mixture to stand at 0 - 5° C for 45 minutes. Pour the reaction mixture into water, filter the resulting precipitate, wash with water and dry in air to give 7α-bromo-1,4-pregnadiene-HP,17α,21-triol-3,20-dione-21- acetate.

Dissolve the preceding product in 525 ml of methanol, add 13.2 ml of 70% aqueous perchloric acid and stir the reaction mixture at room temperature for 18 hours. Add water, then saturated aqueous sodium bicarbonate until the solution is neutral, and evaporate the reaction mixture until the methanol is removed. Extract the aqueous reaction mixture with ethyl acetate, wash the combined ethyl acetate extracts with water, dry them over sodium sulfate and evaporate them. Recrystallize the resulting residue from acetone to give 7α-bromo-1,4-pregriadiene-113,17α,21-triol-3,20-dione, yield 0.3 g, m.p. >320°C,

[α]<26> +48.2° (dimethylformamide), X 241 nm (e = 15,100).

7a-chloro-16a-methyl-1,4-pregnadiene-llp",17a,21-triol-3,20-dione, m.p. 176 - 179° C, [a]<26> +47.5° (dimethylformamide),

MeOH

A max 2 42 nm (e = 15,500) can be produced in a similar way.

Example 15

7a- chloro- 4- pregnene- 113, 17a, 21- triol- 3, 20- dione- 17, 21- dipropionate and its 16a- methyl- and 16g- methyl derivatives

A. Dissolve at 10° C 911 mg of 4,6-pregnadiene-17a,21-diol-3,11,20-trione-17,21-dipropionate in a freshly prepared solution

of hydrogen chloride in tetrahydrofuran and in water (10 ml) comprising 38.2 wt% hydrogen chloride and 3.7 wt% water. Stir the reaction mixture for 15 minutes at - 2° C, then pour it into 100 ml of ice water. Filter from the resulting precipitate, wash it with water, and partially dry it under a blanket of nitrogen and then at room temperature in vacuo for 17 hours to form

a mixture of 7a-chloro-4-pregnene-17a,2l-diol-3,11,20-trione-17,21-dipropionate and 4,6-pregnadiene-17a,21-diol-3,11,20-trione -17,21-dipropionate. Separate the components of this mixture by thick-layer chromatography on silica gel, develop with hexane:dimethoxyethane (2:1), and elute with ethyl acetate the band containing 7a-chloro-4-pregnene-17a,21-diol-3,11,2 0- trione-17,21-dipropionate as shown by ultraviolet spectrum. Evaporate the ethyl acetate eluate at room temperature and recrystallize the resulting residue from acetone:hexane at room temperature to give 7o-chloro-4-pregnene-17a,21-diol-3,11,20-trione-17,21-dipropionate. The product must be stored in an open vessel at room temperature in a vacuum.

B. Dissolve at room temperature 3.1 g of 7a-chloro-4-pregnene-17a,21-diol-3,11,20-trione-17,21-dipropionate in 375 ml of methanol and add 30 ml of water. Add to this solution at 0 - 2° C under a nitrogen atmosphere 2.38 g of sodium borohydride. After 30 minutes, carefully add the reaction solution to 4.2 liters of water containing 80 ml of N hydrochloric acid. Filter the resulting precipitate and chromatograph it on silica gel, eluting with chloroform:ethyl acetate (3:1). Evaporate the combined eluates in vacuo. Add to 152 mg of the resulting residue a suspension of 600 mg of manganese dioxide in 7 ml of benzene, stir for 5 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 ultraviolet spectrum. Evaporate the ethyl acetate solution in vacuo to a residue comprising 7α-chloro-4-pregnene-110,17α,21-triol-3,20-dione-17,21-dipropionate. Purify further by recrystallization from ether:hexane at room temperature, X ™aks<an>°"'" 237 nn (e = 15,500) .

Example 16

7a- bromo- 9 2- fluoro- 163- methyl- 1, 4- pregnadlen- llg, 17a, 21- triol-3, 20- dione- 17, 21- dipropionate

(A) 7α-bromo-9α-fluoro-163-meth<y>l-1,4-p_regnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate

Add to a solution of 0.5 g of 7a-fluoro-163-methyl-1,4,6-pregnatriene-17a,21-diol-3,11,20-trione-17,21-dipropionate in 1 ml of glacial acetic acid a solution of dry hydrogen bromide in glacial acetic acid (48% by weight, 5 ml), stir at 5° C. for 1 hour, then pour into 300 ml of ice water. Filter from the resulting precipitate, wash it thoroughly with water and dry it in air at room temperature. Clean the precipitate on thick-layer silica gel plates, develop with ethyl acetate/chloroform (1:5). Scrape off the band containing the desired compound as shown 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-9α-fluoro-163-methyl-1,4-pregnadiene-17α,21-diol-3,11,20-trione-17,21-dipropionate, yield = 60% theoretical, sm.p. 115° C (decomposition).

(B) In a similar manner as described in Example 3C (1), reduce the product of Example 19(A) with sodium borohydride in

methanol/tetrahydrofuran to form 7α-bromo-9α-fluoro-163-methyl-1,4-pregnadiene-113,17α,21-triol-3,20-dione-17,21-dipropionate. Temp. 148 - 151°C, [α]D +45.1° (0.2% DMF);

^max 238 nm (E = 16,000] ' [M<+>] 592' 471' 45°-

Example 17

(A) 7a- bromo- 9a- fluoro- 16g- methyl- 1, 4- pregnadiene- 17a, 21-diol- 3, 11, 20- trione- 17, 21- dipropionate

is produced by reacting 9a-fluoro-16a-methyl-1,4,6-pregnatriene-17a,21-diol-3,11,20-trione-17,21-dipropionate with hydrogen bromide in glacial acetic acid in the dark by the method that is described in Example 17(A). [a]D +20.1° (0.<3%>)<;> A^aks 235 nm (£ = 15,000> *

[M+]501.

(B) 7a- bromo- 9a- fluoro- 16a- methyl- 1, 4- pregnadiene- 113, 17a, 21-triol- 3, 20- dione- 17, 21- dipropionate

is prepared by reducing the compound from part (A) with sodium borohydride by the method described in example 3C (IB). Temp. 160 - 164°C; [α] + 17.9° (0.12% DMF);

*max 238 nm 17,300}; [M<+>] 446, 432, 428, 415-

Example 18

(A) 7a- bromo- 9a- fluoro- 16a, 17a- isopropylidenedioxy- 1, 4- pregnadien- 2 l-ol- 3, 11, 20- trione- 21- acetate

is produced by reacting 9a-fluoro-16a,17a-isopropylidenedioxy-1,4,6-pregnatrien-21-ol-3,11,20-trione-21-acetate with hydrogen bromide in glacial acetic acid and in the dark by the method described in example 17 (A) . [α]Q +81.3° (0.2% DMF); A ^aks 235 (£ = 15,300)

[M+]472.

(B) 7a- bromo- 92- fluoro- 16a, 17a- isopropylidenedioxy- 1, 4- pregnadiene- 113, al- diol- 3, 20- dione- 21- acetate

is prepared by reducing the compound from part (A) with sodium borohydride by the method described in example 3C(1).

[α] +74.4° (0.25% DMF); A JJ®£jj 238 nm (£ = 14,980) ' tM<+>l 474 -

Claims (1)

Analogous process for the preparation of therapeutically active 3, 20-dioxo-70C-chloro-(or bromo)-4-pregnenes and -1, 4-pregnadienes of formula wherein the dashed line in the 1,2 position indicates a 1,2-single bond or a 1,2-double bond; W is a group (H,H), (H, lower alkyl), (H, a-OV<1>) or =CHT, where V<1> is a hydrogen atom or an acyl radical from a hydrocarbon carboxylic acid of 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 hydrocarbon carboxylic acid of up to 12 carbon atoms; or wherein Q and W together form a 16a,17a-lower alkylidenedioxy group together with a 163-hydrogen atom; G is a hydrogen atom or a halogen atom with an atomic weight of less than 100, or a group OV 2 , in which V 2 is a hydrogen atom or an acyl radical from a hydrocarbon carboxylic acid of up to 12 carbon atoms; X is a hydrogen atom or a halogen atom having an atomic weight less than 100; Y is an oxygen atom or a group (H,3-OH) or, provided that X is chlorine or bromine, Y may also be a group (H, (3-halogen) , which halogen has an atomic weight 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 or bromine; wherein the lower alkyl groups have up to 6 carbon atoms; characterized in that (a) hydrogen chloride or hydrogen bromide is added to the 6,7-double bond in a compound of formula in which the dashed line, X, Y, W, Q and G have the meanings given above, in the presence of an inert solvent; provided that -(i) when hydrogen chloride is added, X is a hydrogen atom; (ii) when Y is the group (H,J6-OH) and hydrogen bromide is added, X is a hydrogen atom; or that (b) a compound of formula wherein X, Y, W, Q and G are as defined above, except that G is not a hydroxy group; is reacted with a chlorinating or brominating agent capable of replacing the 7jB-hydroxy group with a 7CC-chloro or bromine atom, in the presence of an inert organic solvent; or (c) for the preparation of a compound of formula I wherein Y is the group (H,3-OH), that a compound of formula I wherein Y is an oxygen atom is reduced; after which the product obtained according to process alternative (a), (b) or (c) is, if desired or necessary, subjected to one or more of the following final treatments in any order, on the condition that the final (iii) cannot follow process alternative (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 17a- and/or 21-position; (iii) reduction of a 11-oxo group to a 11-hydroxy group; (iv) 9 (11)-dehydration of a 9-unsubstituted-11|3-ol to a 4,9(11)-pregnadiene or to a 1,4,9(11)-pregnatriene, followed by addition of chlorine to the 9(11) double bond.