CH637406A5 - Novel steroids of the pregnane series, process for their preparation and pharmaceutical products containing them - Google Patents

Abstract

The invention relates to novel 7 alpha -halogen-substituted steroids of the pregnane series and their preparation, and to pharmaceutical products which contain the novel steroids. The novel steroids are 7 alpha -halo-3,20-dioxo-4-pregnenes and -1,4-pregnadienes which can be substituted in the 2-, 9 alpha -, 11-, 14 alpha -, 16-, 17 alpha - and 21-positions, preferably by a 11 beta -hydroxyl group, a 17 alpha -hydroxyl or -acyloxy group, a 21-acyloxy group and a 16-methylene or -methyl group. The novel 7 alpha -halosteroids have useful pharmacological properties, in particular local antiinflammatory action.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 
EMI2. 1
 wherein Z is a chlorine atom, bromine atom or iodine atom, Y is an oxygen atom or the group (H, ss-OH), Wein methylene radical or the group (H, CH3) or (H, H) and V and V2, which are the same or different can, are hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12 carbon atoms, in particular 7a-Chlorffipregnen-l 1113.1 l ss, 17a, 21-triol-3,20-dione-17,21-dipropionate. 



   5.  A process for the preparation of compounds according to Claim 1, in which Z is a chlorine atom, bromine atom or iodine atom, with the proviso that Z is not a chlorine atom in cases where X is a halogen atom, characterized in that a hydrogen halide is obtained from that from hydrogen chloride, Hydrogen bromide and hydrogen iodide group to the 6,7 double bond of a compound of the formula
EMI2. 2nd
 in which the dashed line A, B, M, Q, W, X and Y have the meanings given in claim 1, in the presence of an inert solvent with the proviso that
I) in cases where the hydrogen halide is hydrogen chloride, X is a hydrogen atom,
II) in cases where Y is the group (H, ss-OH) and the hydrogen halide is hydrogen, X is a hydrogen atom and
III) in cases

   in which Y is the group (H, B-OH) and the hydrogen halide is hydrogen iodide, X is a hydrogen atom, chlorine atom or fluorine atom, and isolates a compound according to claim 1. 



   6.  A method according to claim 5, characterized in that a compound of formula (IV) containing a 1,2-double bond and an anhydrous inert organic solvent is used. 



   7.  Process according to Claim 6, characterized in that the compound of the formula (IV) is reacted with hydrogen chloride in tetrahydrofuran or with hydrogen bromide or hydrogen iodide in glacial acetic acid. 



   8th.  Method according to one of claims 5 to 7, characterized in that one carries out the reaction at a temperature in the range of 0 "C to room temperature. 



   9.  Pharmaceutical preparation containing as an active ingredient at least one compound according to claim 1 together with a pharmaceutical carrier or excipient. 



   10th  Medicament preparation according to Claim 9, comprising as active ingredient at least one compound according to one of Claims 2 to 4. 



   The invention relates to new steroids of the Pregnan series with valuable pharmacological properties, processes for their preparation and pharmaceutical preparations containing them. 



   The invention relates to 3,20-dioxo-7a-halogen-4 pregnene and 1,4-pregnadienes of the formula
EMI2. 3rd
 in which the dashed line in the 1,2 positions indicates a 1,2 single bond or a 1,2 double bond,
W is a group of the formula (H, H), (H, lower alkyl), (H, a-0V ') or = CHT, where V' is a hydrogen atom or an acyl radical of vitamin A acid or a carboxylic acid with bis to 12 C atoms and T is a hydrogen, fluorine or chlorine atom or a lower alkyl radical,
Q represents a chlorine atom or bromine atom or a group of the formula OV, in which V is a hydrogen atom or an acyl radical of a carboxylic acid having up to 12 C atoms, or Q in cases in which W is a group of the formula (H, H) or (H, lower alkyl), can also be a hydrogen atom,

   or Q and W together form a 16a, 1 7a-lower alkylidene dioxy, cycloalkylidendioxy or aralkylidendioxy group together with a 16ss hydrogen atom or a group of the formula
EMI2. 4th
 form in which R is a lower alkyl radical and R 'is a lower alkyl radical or phenyl radical,
B is a hydrogen atom or together with Q forms a 1 4a, 1 7a-lower alkylidenedioxy group,
M is a group of the formula -CHO or such a group in the form of an acetal, hemiacetal or acylal, a group



  of the formula -CH3, -COOR3, -CH2Hal or -CH2OV2, wherein R3 is a hydrocarbon radical with up to 12 C atoms, Hal is a halogen atom with an atomic weight of less than 100 and V2 is a hydrogen atom or an acyl radical of vitamin A acid , a carboxylic acid with up to 12 carbon atoms or phosphoric acid, which may be in the form of a mono- or dialkali or alkaline earth metal salt, or OV2 together with Q is an alkylidendioxy, cycloalkylidendioxy or aralkylidendioxy group or an alkyl o-alkanoate or alkyl-o-arylcarboxylate group of the formula
EMI3. 1
 in which R and R 'have the meanings given above, or M in cases in which Q is an O-acyl radical also a group of the formula -OR2 in which R2 is a lower alkyl radical or lower haloalkyl radical,

   can be,
X is a hydrogen atom or a halogen atom with an atomic weight of less than 100,
Y is an oxygen atom or a group of the formula (H, ss-OH) or (H, ss-OCOH) or, if X is a chlorine or bromine atom, also a group of the formula (H, 13-halogen), in which the Halogen atom has an atomic weight of less than 100 and is at least as electronegative as X, or, if X is hydrogen, can also be a group of the formula (H, H),
A, which is in the a position in the QPregnenen, is a hydrogen atom or, if Y is (H, ss-OH), can also be a chlorine atom or fluorine atom or a methyl radical and
Z is a fluorine atom, chlorine atom, bromine atom or iodine atom, and, if W stands for (H, H), their D-homo analogues. 



   The hydrocarbon radicals in the substituent R3 can be, for example, aliphatic radicals having up to 12 carbon atoms, including straight-chain and branched alkyl radicals, in particular lower alkyl radicals, and cycloaliphatic radicals, which can be saturated or unsaturated or substituted or unsubstituted, and aryl radicals, aralkyl radicals and alkaryl radicals . 



  However, alkyl radicals having up to 4 carbon atoms are preferred. 



  Typical unsaturated aliphatic residues are vinyl residues, propenyl residues, propynyl residues and butenyl residues.  Typical cycloalkyl radicals are cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and p-dicyclohexyl.  Examples of typical aryl radicals are phenyl, a-naphthyl and p-diphenyl.  Examples of typical alkaryl residues are tolyl, xylyl and sym-diethylphenyl, and typical aralkyl residues are benzyl and phenethyl. 



   The lower alkyl radicals which fall under the definitions of W, T, R, R ', R2 and R3 contain up to 6 carbon atoms and thus comprise pentyl and hexyl radicals, but they preferably contain and are up to 4 carbon atoms for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -Butyl or t-butyl. 



   The acyl radicals of the carboxylic acids with up to 12 carbon atoms, for which V, V 'and V2 stand, can be saturated, unsaturated, straight-chain or branched, aliphatic, cyclic, cyclic-aliphatic, aroamtic, aromatic-heterocyclic, arylaliphatic or alkylaromatic and with one or more hydroxyl groups or with alkoxy radicals having 1 to 5 carbon atoms or with halogen atoms.  Typical ester groups of the 7-halo gene-3.20dioxo-l, 4pregnadienes according to the invention are thus of hydrocarbon carboxylic acids, for example alkanoic acids, for. B.  Formic acid, trimethyl acetic acid, isobutyric acid, isovaleric acid, enanthic acid, capric acid, cyclopentylpropionic acid, undecylic acid, lauric acid and adamantane carboxylic acid, substituted alkanoic acids, e.g. B. 

  Phenoxyacetic acid, trifluoroacetic acid and ss-chloropropionic acid, aromatic and substituted aromatic acids, in particular benzoic acids, which are substituted by a halogen atom or a methoxy radical, e.g. B.  Benzoic acid, toluic acid, p-chlorobenzoic acid, p-fluorobenzoic acid, p-methoxybenzoic acid and 3,5-dimethylbenzoic acid, aromatic-heterocyclic acids, especially isonicotinic acid, arylalkanoic acids such as phenylacetic acid, phenylpropionic acid and ss-benzoylaminoisobutyric acid, unsaturated acids. B.  Acrylic acid and sorbic acid, and dibasic acids, e.g. B.  Succinic acid, tartaric acid and phthalic acid. 



   Acyl radicals are preferred which are derived from lower alkanoic acids having 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 abovementioned substituted benzoic acids, in particular propionic acid, n- Butyric acid and benzoic acid are derived. 



   X is preferably a fluorine atom or in particular a hydrogen atom, and Z is preferably a chlorine atom or bromine atom. 



   The alkylidene or alkylidenedioxy groups for which = CHT, W and Q together or Bund Q together or OV2 and Q together preferably contain up to 4 carbon atoms and are thus, for example, methylene, ethylidene, n-propylidene, isopropylidene, n- Butylidene and sec. -Butylidene and their corresponding dioxy derivatives.  A methylene radical or the group (H, CH3), in particular (H, cc-CH3), is particularly preferred for W.    



   An oxygen atom or the group (H, ss-OH) is particularly preferred for Y.    

 

   A particularly preferred group of 1,4-pregnadienes according to the invention has the formula
EMI3. 2nd
 wherein Z is a chlorine or bromine atom, W is a methylene radical or the group (H, CHi), Y is an oxygen atom or the group (H, ss-OH) and V and V2, which may be the same or different, for hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12, in particular up to 8, carbon atoms. 



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



   A preferred group of 3,20-dioxo-7a-halogenated according to the invention can by the formula
EMI4. 1
 being represented.  Z is an iodine atom or (preferably) a chlorine or bromine atom, Y an oxygen atom or the group (H, ss-OH), crying methylene radical or the group (H, CH3) or (H, H) and V and V2, which can be the same or different, hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12 (preferably up to 8) carbon atoms.  In particular, V and V2 in formulas (II) and (III) can be any acyl radicals which have been defined above. 



   A particularly preferred compound of this group is 7a-chloro-4-pregnen-11 113.1 ss, 1-triol-3.20-dione-17.2 l-dipropionate. 



   The 7a-halogen-3,20-dioxo-4-pregnene and 1,4-pregnadienes of the formula (I) are usually white to off-white crystalline solids which are insoluble in water (with the exception of alkali salts of their esters, e.g. B.  the hemisuccinate and phosphate esters) and in most organic solvents, especially in acetone, dioxane, dimethylformamide and dimethyl sulfoxide, but are soluble in non-polar solvents, e.g. B.  Dialkyl ethers and alkanes have limited solubility. 



   The 7a-halogen-1,4-pregnadienes are preferably at a temperature below room temperature (e.g. B.  kept at 0 to 5 "C) when stored for a long time to largely eliminate decomposition to the corresponding 1,4,6-Pregnatrienes (from which they can usually be produced).  For short-term storage, the 7a-chloro derivatives are relatively stable up to 100 C, but the 7a-bromo derivatives should be stored at temperatures below 55 C. 



   The 7a-halogen-3,20-dioxoXpregnene are preferably in open vessels in a chamber under reduced pressures and at moderate temperatures (e.g. B.    0 to 40 "C) to minimize decomposition to the corresponding Pregnadienes (from which they can usually be produced) with the development of hydrogen halide. 



   The 3,20-dioxo-7a-halogen-1,4-pregnadienes of the formula (I), in particular those in which V is a hydrogen atom or an acyl radical or in which OV and Q together form a 1 7a, 21-alkylidenedioxy group, generally have corticoid activity.  Those of them that contain halogen atoms in both C-9 and C-11 or an oxygen function in C-11 and a halogen atom or hydrogen atom in C-9 have glucocorticoid activity and are particularly valuable as anti-inflammatory agents. 



  Preferred as anti-inflammatory agents, especially for topical use, are 3,20-dioxo-7a-halogen-1,4-pregnadien-17a, 21-diols, especially the 3,20-dioxo-7a-halo gen-l, 4pregnadien -l 113, 17a, 21-triols of the above formula (II) and their esters. 



   The 7a-bromo and 7a-chloro compounds of formula (I) with a cortical side chain at C-17 (i.e. H.  Compounds of formula (I) in which M is CH2OV2 and Q are OV) and their ester derivatives, especially compounds which are unsubstituted at C-2, C-9 and C-14, are particularly valuable as topical anti-inflammatory agents.  In particular, compounds substituted at C-16 by a lower alkyl group (preferably a 1 6-methyl group, especially a 1 6a-methyl group) or a 1 6-methylene group have excellent local anti-inflammatory effects, generally of local anti-inflammatory activity is superior to the corresponding 7-unsubstituted analogues. 

  The particularly valuable compounds according to the invention thus include the 7a halogen. 3,20-dioxo-1,4-pregnadienes of the formula (II) defined above, in which Y is the group (H, ss-OH). 



   The compounds of formula (II) in which Y is the group (H, ss-OH) and V is a hydrogen atom and in particular V2 is also a hydrogen atom are mainly useful as intermediates for the preparation of the preferred 17-mono and 17,21-diester derivatives . 



   The 17,21-deoxy, 17-hydroxy-21-deoxy and 17-acyloxy21-deoxy derivatives of the formula (I) have anti-inflammatory activity, but are more valuable than progestagenic agents. 



   Particularly valuable as local anti-inflammatory agents are the compounds of formula (II) in which V and V2 are acyl radicals of hydrocarbon carboxylic acids with up to 8 C atoms, in particular the 17-propionate, 17-n-butyrate and 17-benzoate derivatives, which are one have very strong local anti-inflammatory effects with very low systemic corticoid activity.  It has been found that when the compounds of the formula (II) are used locally or systemically, the topical anti-inflammatory activity of the compounds depends much more on the type of the ester group at C-17 than on the ester group on C-21, and in particular the topical anti-inflammatory effect Effect of a 17-Propio nat-2l ester of the formula (II) is largely independent of the nature of the C-21 ester group. 

  The 16a-methyl-17-mono- and -17,21-diadyl derivatives of formula (II) are most valuable because their topical activity is significantly higher than that of the corresponding 7-unsubstituted compounds. 



   The superior topical activity of the preferred 3.20 dioxo-7a-halogen-1,4-pregnadienes of the formula (II), in particular the 16a-methyl derivatives, can be demonstrated by animal pharmacological tests.  For example, 7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate shows in topical tests on mice after modification of the experiment of ear edema caused by croton oil (G.  Tonelli et al., Endocrinology 77 (1965) 625-634) about twice the topical effect, but only a fraction of the systemic effect of betamethasondipropionate (9α-fluor-16ss-methyl-1,4-pregnadiene11 17a, 2 l-triol -3.20-dione-l 7.21-dipropionate). 

  In addition, this 7a-bromine compound according to the invention shows in a test on mice after a modification of the skin atrophy test (E. G.  Weirich and J.  Longauer, Res.  Exp.  Med.  163 (1974) 229) a significantly lower skin atrophy-inducing effect than betamethasone dipropionate.    7a-bromo-16a-methyl-1,4-pregnadiene-llss, 17Q, 2 l-triol-3,20-dione-l 7-benzoate-2 l-acetate also shows a sharp separation of the local from the systemic effects when injected topically into rats and shows very low glucocorticoid activity when administered orally to both mice and rats. 

 

   Similarly, other 7a-halo-1,4-pregnaadienes of formula (II), e.g. B.    7a-chloro- and 7a-bromo-16a-methyl 1,4-pregnadiene-l 113.1 7a, 2 l-triol-3,20-dione-17,21-dipropionate, in animal experiments according to the methods described above, high topical anti-inflammatory effect with simultaneous low systemic effects according to local
Use and low skin atrophy as well as low parental and oral glucocorticoid effectiveness. 



   Examples of preferred compounds of the formula (II) are:
The 21-acetate, 21-propionate, 21-n-butyrate, 21-isobutyrate and 21-valerate of 7a-chloro and 7a-bromo-16a-methyl-1,4-pregnadiene-11ss, 17α, 21-triol -3,20-dione-17-propionate, the 2 liter acetate, 21-propionate and 21-n-butyrate of 7a-chloro and 7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α; , 21-triol-3,20-dione-17-n-butyrate and the 21-acetate, 21-propionate, 21-n-butyrate and 21-benzoate of 7? -Fluoro, 7? -Chloro and 7? -Brom-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate.    



   In particular, 7a-chloro and 7a-bromo-16a-methyl-1,4-pregnadiene-11 IS, 17a, 21-triol-3,20-dione-17,21-dipropionate and
7α-Bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate is particularly valuable because it is associated with high local anti-inflammatory activity show with low systemic effects after topical application and cause skin atrophy to a small extent and have low parenteral and oral glucoocorticoid activity. 



   Examples of other valuable compounds of formula (II) are
7α-chloro and 7α-bromo-16α-methyl-1,4-pregnadiene
11ss, 17α, 21-triol-3,20-dione-17-valerate-21-acetate,
7α-chloro and 7α-bromo-16α-methyl-1,4-pregnadiene
11ss, 17α, 21-triol-3,20-dione-17-isobutyrate-21-acetate,
7a-chloro and 7a-bromo-16a-methyl-1,4-pregnadiene-11 1ss, 17α, 21-triol-3,20-dione and its 2l acetate, 21-benzoate,
21-pivalate, 17-propionate and 17-valerate, the 16ss-methyl epimers of these 16a-methyl derivatives, e.g. B.  the
21-acetate, 17,21-dipropionate, 17-propionate-21-n-butyrate,
17-propionate-21-acetate and the 17-benzoate-21-acetate of 7α-chloro and 7α-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α;

  ;, 21-triol-3,20-dione and
16-methylene derivatives, e.g. B.    7α-Chloro-16-methylene-1; 4-pregnadiene-1ss, 17a, 21-triol-3,20-dione-17,21-dipropionate
The invention further comprises 7α-halo-3,20-dioxo-1,4-pregnadienes of the formula (I), e.g. B. 



   9a-halogen derivatives of the compounds of the formula (II), in particular their 9a-fluoro and 9a-chloro derivatives, 9a, 11 lss-dihalopregnadienes of the formula (I), for. B. 



     7a, 9a, 11 ss-trichloro-1,4-pregnadiene-17a, 21-diol-3,20-dione-21 acetate, particularly 7α, 9α, 11ss-trichloro-16α-methyl-1,4- pregnadiene-17α, 21-diol-3,20-dione-17,21-dipropionate,
21-halogen-21-deoxy-pregnadienes, e.g. B.    7a, 21-dichloro-16a and 16ss-methyl-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate and 7α, 21-dichloro-1,4- pregnadien-11ss, 17α-diol-3,20-dione-17-propionate and its 7a-bromo analogue,
21-deoxy-pregnadienes, e.g. B.  7a-chloro and 7a-bromine. 1.4 pregnadiene-1 1ss, 17?

  ; -diol-3,20-dione-17-propionate and 7a-chloro,
7a-bromo- and 7a-iodo-1,4-pregnadien-17a-ol-3,20-dione and be
17-acetate and 1 7-propionate,
16a-Hydroxy-pregnadienes and their ester derivatives, e.g. B. 



   7a-chloro- and 7-briim-l, 4-pregnadiene-llss, 16a, 17a, 2 I-tetrol-
3,20-dione and its 1 7-propionate, 16,21-diacetate-17-propionate, 17-benzoate, 17-benzoate-21-acetate and 16α, 17α-methyl-o-benzoate-21-acetate , 16α, 17α-lower alkylidenedioxy compounds, in particular 7a-bromo-16a, 17a-isopropylidenedioxy-1,4-pregnadiene-11 1113.21-diol-3.20-dione-21 acetate,
Compounds in which Q and W together form a group of the formula
EMI5. 1
 form, namely Pregnadieno [l7, 16a-d] -1 ', 3' -oxathiolane or 



     5 ssH-Pregnadieno [17,16-d] oxazole, wherein R and R 'are preferably methyl radicals as in 7a-chloro and 7α-bromo-11ss-hydroxy-2', 2'-dimethyl-1,4-pregnadieno [17,16α-d] -1 ', 3'-oxathiolan-3,20-dione and their 9a-chloro derivatives, and 7a-chloro and 7a-bromo-1 1ss, 21-dihydroxy-2' -methyl- S'PH-1,4-pregnadieno [17,16α-d] oxazol-3,20-dione-21-acctate,
20-carboxylate pregnadienes, e.g. B.    n-butyl-7α-chloro-11ss-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-oate, propyl 2,7α-dichloro-11ss-hydroxy-3,20- dioxo-16?

  ; -methyl-1,4-pregna- -dien-21-oat and its 7a-bromo analogues,
20-alkoxy and 20-haloalkoxy-21-nor-pregnadienes (which can also be referred to as alkylaudrostadiene-17ss-carboxylates), e.g. B.    7α-chloro-16ss-methyl-20-chloro-methoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate, 7α-chloro-16-methylene-20 -fluoromethoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate, 7α-chloro-16ss-methyl-20-methoxy-21-nor-1,4 -pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate and their corresponding 7a-bromo derivatives,
21-oxopregnadienes and their derivatives, e.g. B.  their acetals, hemiacetals and acylals, e.g. B.  2,7a-dichloro-9a-fluoro-16a-methyl-1,4-pregnadiene-11ss, 17?

  ; -diol-3,20,21-trione and its 21-methylhemiacetal, 7α-chloro-9α-fluoro-16α-methyl-21,21-diacetoxy-1,4-pregnadiene-11ss, 17α-diol -3,20-dione-17-propionate, 7α-chlorine 9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α-diol-3,20,21-trione and its 21-ethylene ketal and 2l, 2l-dimethylacetal and the corresponding 7a-bromo derivatives of these compounds,
D-homo-pregnadienes, e.g. B.  7α-chloro and 7a-bromo-D homo-l, 4-pregnadiene-ll P, 17cL, 21-triol-3, 20-dione-17,21-di-n-butyrate and
7a-fluorine and 7a-iodine derivatives, e.g. B.    7a, 9a-difluoro-16a-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate and its 17-benzoate, 7α-fluoro-1,4 -pregnadiene-11ss, 17?

  ;, 21-triol-3,20-dione-21-acetate and its 17-n-butyrate and 17-benzoate and their 16α-methyl derivatives, 7α-iodine-16α-methyl-1,4-pregnadiene-11ss , 17α, 21-triol-3,20-dione, its 21-acetate and its 17,21-dipropionate, their 16ss methyl epimers and also their 9a-fluorine derivatives. 



   A further preferred group of compounds according to the invention are the 1 1-oxo derivatives of the formula (I) which have an anti-inflammatory effect, but are more frequently used as intermediates for the preparation of the corresponding 11ss-hydroxy derivatives by the processes described below.  Particularly valuable 1 1-oxo derivatives are the compounds of the formula (II) defined above, in which Y is an oxygen atom. 



   Examples of preferred compounds of the formula (III) are: 21-acetate, 21-propionate, 21-n-butyrate, 21-isobutyrate and 21-valerate of 7a-chloro-16a-methylffipregnen-11ss, 17α, 21 -triol-3,20-dione-17-propionate and the 21-acetate, 21-propionate, 21-n-butyrate and 21-isobutyrate of 7a-bromo 1 6a-methyl4pre. gnen- Ip, 17a, 21-triol-3,20-dione-17-propionate, the 2l acetate, 21-propionate and 21-n-butyrate of 7a-chloro and 7α-bromo-16α-methyl-4- pregnen-11ss, 17α, 21-triol-3,20-dione-17-n-butyrate and the 21-acetate, 21-propionate, 21-n-butyrate and 21-benzoate of 7a-chloro and 7a-bromo -16a-methyl4pregnen-1 1ss, 17a, 21-triol-3,20-dione-1 7-benzoate.    

 

   The following may be mentioned as examples of further compounds of the formula (III):
7a-chloro and 7a-bromo-l 6a-methyl-4pregnen-l 1P, 17a, 21-triol-3,20-dione, their 17-valerate-21-acetate, 17-isobutyrate-21-acetate 2l-acetate , 21-benzoate, 21-pivalate, 17-propionate and 17-valerate, their 16ss-methyl-epimers, e.g. B. 

   the 2l acetate, the 17.21 dipropionate, the 17-propionate-21-n-butyrate, the 17-propionate-21acetate and the 17-benzoate-2l-acetate of 7a-chloro- and 7a-bromo-16ss-methylffipregnen- 11 1113.1 7a, 2 1 4riol-3.20-dione,
16-methylene derivatives, e.g. B.    7a-chloro-16-methylene-4-pregnen-11 ss, 17a, 21-triol-3,20-dione-17,21-dipropionate and the 1 6-unsubstituted analogues of the above-mentioned 1 6-substituted derivatives, e.g. B.  7a-chloro-4-pregnen 1 l ss, 17a, 21-triol-3,20-dione-17,21-dipropionate.    



   The 7a-halogen-3,20-dioxo-4-pregnene of formula (III) also have local anti-inflammatory effects and are therefore valuable for the treatment of dermatoses caused by corticosteorides, e.g. B.  Contact dermatitis and allergic dermatitis and psoriasis.  They can be applied topically or topically in any conventional pharmaceutical form, provided that they are free of acids and bases. 



   P. A.  Diassi and co-workers describe in J.  Med.  Chem. 



  10 (1967) 551 a 7a-chloro-A-nor-progesterone and find that the introduction of the 7-chlorine atom greatly reduces the progestagenic effect of the 7-unsubstituted precursor. 



  In addition, the authors note that it has never been reported that a 7a-chlorofidehydro-3-one by oxidizing a 4-dehydro-3-one with 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of hydrogen chloride (the Quinone is simultaneously reduced to the corresponding quinol) or by adding hydrogen chloride to 4,6-bis-dehydro-3-one.  The authors assume that steroids with 7a-chloro vI dehydro-3-one structure may be present in the reaction mixture, but are unstable and can be converted back to 4,6-bis-dehydro 39ne if an attempt is made to use the 7a-chloro 4dehydro Isolate -3-one and get rid of quinone and quinol. 



   According to the invention, however, it was found that 7a-chloro-xdehydro-3-one can be isolated essentially pure and completely or essentially free of the corresponding 6,7-dehydrohalogenated compounds, the quinone and quinol.  It was also surprisingly found that 7a-halogen4pregnen-3,20-diones, in particular 7a-halogen 1, 4-pregnadiene-3,20-dione, generally valuable steroids with valuable activity, e.g. B.  Corticoid effectiveness, are. 



   The invention further relates to a process for the preparation of compounds of the formula (I) defined above, in which Z is a chlorine, bromine or iodine atom, with the proviso that Z is not a chlorine atom in cases in which X is a halogen atom .  As a main reaction step, the process comprises the addition of a hydrogen halide from the group consisting of hydrogen chloride, hydrogen bromide or hydrogen iodide to the 6,7 double bond of compounds of the formula
EMI6. 1
 in the dashed line, A, B, X and Y the above
Have meanings and W ', Q' and M 'are W, Q and M with the abovementioned meaning or W' and Q 'together are a 16a, 17a-alkyl-o-alkanoate or 16a,

   Form 1 7a-alkyl-o-arylcarboxylate group together with a lop hydrogen atom or M 'is the group -CH20V3 and OV3 and Q' together with the oxygen atom of the clo-carbonyl group
1 7a, 20; Form 20.21-bis-methylenedioxy group, in the presence of an inert solvent with the proviso that
I.  in cases where the hydrogen halide is hydrogen chloride, X is a hydrogen atom,
II.  in cases where Y is the group (H, j8-OH) and the
Is hydrogen halide, X is a hydrogen atom and
III.  in cases where Y is the group (H, ss-OH) and the
Hydrogen halide is hydrogen iodine, X is a hydrogen atom,
Is chlorine atom or fluorine atom. 



   The hydrogen halide should be present in an amount at least equimolar to the steroid, preferably at least
5 molar excess, e.g. B.  be used in a 10- to 50-molar excess. 



   To prepare a compound of formula (I), this main stage can be followed by at least one of the following stages:
If W 'and Q' together form a 16a, 17a-alkyl-o-alkanoate group or 1 6a, 1 7a-alkyl-o-arylcarboxylate group together with a 16ss hydrogen atom, the product is hydrolyzed, a compound in which Q is a hydroxyl group and W is the group (H, a-OH). 



   If OV3 and Q 'together with the oxygen atom on the C20-carbonly group form a 17a, 20; 20,21-bis-methylenedioxy group, the product is hydrolyzed to give a compound in which OV3 and Q are hydroxyl groups, and finally isolating a compound of formula (I). 



   The main reaction step is preferably carried out under anhydrous conditions, in particular when the starting material contains a 1,2-double bond, in order to avoid side reactions, e.g. B.  Hydrolysis of any ester groups present, largely switched off.  Saturated solutions of the hydrogen halide in an anhydrous solvent are preferably used to minimize the reaction time. 



   Non-reactive organic solvents in which the starting material of the formula (IV) and the hydrogen halide are soluble are suitable for this process.  Non-reactive organic solvents are understood to mean any organic solvent that does not react with the steroid substrate or the hydrogen halide in such a way that competing side reactions are caused. 



  Solvents that are generally better avoided in this process include water (which causes hydrolysis of esters), alcohols (which could cause ester exchange under acidic conditions) and nitriles, e.g. B.  Acetonitrile (which would form imino ethers with steroid alcohols). 

 

   Particularly suitable solvents for this process are the ethers, e.g. B.  Dioxane, tetrahydrofuran and diethyl ether, chlorinated hydrocarbons, e.g. B.  Chloroform, methylene chloride and ethylene dichloride, organic acids, e.g. B.  Acetic acid and propionic acid, tertiary amides, e.g. B.  Dimethylformamide, diethylformamide and hexamethylphosphoric triamide, and dimethyl sulfoxide.  Dioxane, acetic acid and tetrahydrofuran are particularly suitable solvents, with tetrahydrofuran being preferred for reactions with hydrogen chloride and acetic acid for reactions with hydrogen bromide or hydrogen iodide.   



   The reaction is preferably carried out at temperatures in the range of about 0 "to 30" C or preferably to ambient temperature (e.g. B.  20 "C) performed, but can also at lower temperatures (z. B.  -20 "C) and temperatures up to about 60" C can be worked.  (Temperatures above 30 ° C. are preferably not used unless a 7a-chloro-1,4-pregnadiene-l 7a, 2-diol-3,20-dione or its ester is produced. ) The reaction time depends on the hydrogen halide, the solvent and the concentration used. 

  For example, in acetic acid, the addition of hydrogen iodine usually ends in one or two minutes, while the addition of hydrogen bromide can be completed in 20 to 60 minutes at room temperature.  The addition of hydrogen chloride in tetrahydrofuran is preferably carried out at 0.degree. C. instead of at room temperature, since the higher hydrogen chloride concentrations which can be achieved in this way enable the reaction to be completed within one hour instead of in 24 hours. 



   Substituents present in the steroids used as starting materials, i.e. H.  3,20-dioxo-1,4,6-pregnatriene and 3,20-dioxo4,6-pregnadiene are usually unchanged under the conditions of this process, so that usually the starting steroids are preferably all in the 7a-halogen-3, Contain 20-dioxo-l, 4pregnadiene and 4-pregnen products desired substituents. 



   This process is preferably carried out as follows: The starting material 3,20-dioxo-1,4,6-pregnatriene or 4,6-pregnadiene is added either in the solid state or in solution to a saturated solution of the dry hydrogen halide in any one anhydrous solvent, usually carried out at 0 "to 20" C and the molar ratio of hydrogen halide to steroid is about 40: 1.  After completion of the reaction determined by thin layer chromatography, the reaction mixture is poured into ice water.  The precipitated 7a-halogen-3,20-dioxo-1,4-pregnadiene or 4-pregnen is separated off by filtration or extraction and is usually isolated in pure form by chromatography. 

  Specifically, especially when it is a 7a-halo-3,20-dioxo4pregnen, the product is preferably isolated at a temperature of no more than about 25 ° C in a substantially acid-free and base-free state by removing excess acid and is freed from the solvent without exposing it to a very basic medium. 



   In the starting material of the formula (IV), X is preferably a hydrogen atom, since the addition of hydrogen halide to the 9-unsubstituted compounds of the formula (IV) is generally easier than to their 9a-halogen derivatives.  Indeed, it is advantageous if X in the final product of formula (I) is also a hydrogen atom since the 9a-unsubstituted compounds of formula (I) generally have better topical anti-inflammatory activity than their 9a-halogen derivatives. 



   If the starting compound is a 1,2-dihydro-3,20-dioxo-4,6-pregnadiene, its conversion to a 3.20 dioxo-7a-chloro-4-pregnen is faster than the conversion of a 3,20-dioxo-1 , 4,6-pregnatriens in a 3,20-dioxo-7a-chloro-1,4-pregnadiene.  It is therefore possible, if desired, to work in the presence of water without substantial hydrolysis of
To cause ester groups that may be present.    Fer.    



  The 1,2-dihydro-4-pregnenes of the formula (I), which are much more volatile than the 1,4-pregnadienes, have to be isolated from the excess acid as quickly as possible without using a basic medium, and they should be vacuumed in stored in an open container at temperatures not exceeding about 25 "C. 



   If a 7a-halogen-1 B-hydroxy-3,20-dioxo-1, 4-pregnadiene or 4-pregnene of formula (I) is prepared from a steroid of formula (IV), the pure product falls into yields are quite low when the steroid of formula (IV) contains an 11 ss-hydroxy group.  Better overall yields of pure product are obtained if the steroid of the formula (IV) contains a 1 1-oxo group and the 7a-halogen formed 3.1 1,20-trioxo-l, 4-pregnadiene or 4-pregain on the 11th Position is reduced. 

  Suitable reducing agents are, for example, sodium, potassium or lithium borohydride, tetra-n-butylammonium borohydride or lithium tri-t-butoxyaluminium hydride in an inert organic solvent, preferably sodium borohydride in an inert organic solvent such as methanol or dimethylformamide.  If the starting material of formula (IV) is a 3,11,20-trioxo-17a-hydroxy-1,4,6-pregnatrien-17-acylate in which any 2l-hydroxyl group is esterified, the reaction takes place very specifically the 1 1-oxo group instead. 

  However, if a 3-oxo-7a halogen-1 lss-hydroxy-1,2-dihydro4-pregnen by reducing the corresponding 1 l-oxo derivative (e.g. B.  with sodium borohydride), simultaneous reduction on the 3-keto group tends to take place, so that better yields of the desired product are obtained if the 7a-halogeno-13-hydroxy product formed with an oxidizing agent which is capable of oxidizing an allylic hydroxyl group to an oxo group , is oxidized under essentially non-basic conditions.  Suitable oxidizing agents are, for example, pyridinium chlorochromate in an inert organic solvent, e.g. B.  Methylene chloride, preferably in the presence of a weak base, e.g. B.  Sodium acetate, or a carbodiimide, e.g. B. 

  Dicyclohexylcarbodiimide, together with dimethyl sulfoxide and a weak acid, e.g. B.  Pyridinium trifluoroacetate, however neutral active manganese dioxide in an inert organic solvent is preferably used at room temperature. 



   The starting compounds of formula (in), i.e. H.  the 3.20 dioxo-1,4,6-pregnatriene and 3,20-dioxo4,6-pregnadiene are either known compounds or are expediently derived from their 6,7-dihydro derivatives by customary methods for carrying out the dehydrogenation between C-6 and C-7 is produced, for example, with the aid of chloranil or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or by bromination at C-6 and subsequent dehydrobromination.  Since ester groups are usually present in the 6,7-dihydro derivatives, work is preferably carried out under anhydrous conditions in order to largely prevent hydrolysis. 

 

   Compounds of formula (I) defined above, in which Z is a fluorine atom, chlorine atom or bromine atom, with the proviso that Z is a fluorine atom when a 1,2-single bond is present can also be prepared by a process which is characterized in that is that in a main reaction stage you have a compound of the formula
EMI7. 1
 in which the dashed line, Q ', A and B have the meanings given above, M "for M' and W" for W 'with the meaning given above with the proviso that M "no hydroxymethyl radical and W" not the group (H, a-OH) and the group
EMI8. 1
 in which Y and X have the meanings given above, with a halogenating agent which is able to replace the 7ss-hydroxyl group with a 7a-halogen atom from the group consisting of fluorine, chlorine and bromine,

   in the presence of an inert organic solvent with the proviso that a 7a-chloro or 7a-bromine atom is only introduced if a 1,2-double bond is present. 



   To prepare a compound of formula (I), this main reaction step can be followed by at least one of the following steps:
If W "and Q 'together form a 16a, 17a-alkyl-o-alkanoate group or 16a, 17a-alkyl-o-arylcarboxylate group together with a 16ss hydrogen atom, the product is hydrolyzed, a compound in which Q is a hydroxyl group and W is the group (H, a-OH) is obtained, or when OV3 and Q 'together with the oxygen atom of the C20 carboxyl group form a 17a, 20 20,21-bis-methylene-dioxy group the product hydrolyzes to give a compound in which OV3 and Q are hydroxyl groups and / or when the group is a group of the formula
EMI8. 2nd
 is

   halogen is attached to the 9.11 double bond, or a chlorine atom or bromine atom and a hydroxyl group are attached to the 9.1 1 double bond, whereby a 9a-chloro or 9a-bromo-l-lss-hydroxysteroid is obtained. 



   The immediate product of this main reaction stage and / or the compound of formula (I) can optionally be subjected to a number of final reaction stages in any suitable order.  The following reaction stages are generally suitable: a) hydrolysis of one or more esterification groups at the 1 6aO, 1 7a and / or 21 position to the hydroxyl group; b) hydrolysis of a 17a, 20; 20,21-bis-methylenedioxy group to 20-oxo-17a, 21-dihydroxy groups or a 21-ethylene ketal to 21-oxo group or a 17a, 21-alkylidenedioxy group to 17a, 21-dihydroxy groups, c) Esterification on a hydroxyl group at the 1 6a, 1 7a and / or 21 position; d) reduction of a 1 l-oxo group to an 11 13-hydroxyl group;

  e) Addition of halogen or a 9a chlorine atom or 9a bromine atom and a 1113 hydroxyl group to the 9.11 double bond, either if the group is a group of the formula
EMI8. 3rd
 or after this 9 (11) double bond has been introduced by 9 (11) dehydration of a 9-unsubstituted 11 13 as; f) 17a chlorination or 17a bromination.    



   The halogenating agent used is preferably either a tertiary amine which contains an N- (2-chloro-1,1,2-trifluoroethyl) group and for the preparation of a 7a-fluorsteroid alone, but for the preparation of a 7a-chloro steroid or 7a Bromsteroids are used in the presence of a metal chloride or metal bromide which is soluble in the reaction mixture, or a tertiary amine containing an N-trichlorovinyl group for the preparation of a 7a-chlorsteroid.  N- (2-chloro 1,1, 2-trifluoroethyl) diethylamine, also known as fluoramine, is a particularly preferred halogenating agent. 

  The reaction between the steroid and the fluoramine is preferably carried out at moderately low temperatures (e.g. B.  at about 0 "C) under an inert atmosphere (e.g. B.  under argon, neon or nitrogen) and under anhydrous conditions. 



  All primary and non-sterically hindered secondary alcohol groups (i.e. H.  at the 21 and 16a position, but not at the 1113 position), they must be protected, for example, by esterification.  The molar ratio of fluoramine to steroid is preferably about 6: 1. 



   If fluoramine alone (i.e. H.  Without metal chloride and metal bromide) is used as the fluorinating agent, a halogenated hydrocarbon, in particular methylene chloride, is preferably used as the solvent, a 7a-fluorosteroid being obtained as the product.  Lithium chloride and lithium bromide are preferably used as the metal chloride and metal bromide.  If the fluoramine is used together with lithium bromide as the brominating agent, a halogenated hydrocarbon, in particular methylene chloride, is preferably used as the solvent, a 7a-bromsteroid being obtained as the product.  If the fluoramine is used together with lithium chloride as the chlorinating agent, an ether, in particular tetrahydrofuran, is preferably used as the solvent, a 7a-chloro steroid being obtained as the product. 

  The molar ratio of lithium chloride or lithium bromide to steroid is preferably about 12: 1. 



   The reaction of the steroid of formula (V) with fluoramine (optionally in the presence of lithium chloride or lithium bromide) is preferably allowed to proceed to completion until, for example, thin layer chromatography shows that there is no longer any starting steroid.  The product can then be isolated by evaporation of the reaction mixture and purified by chromatography, the desired 7a-halogen derivative sometimes being obtained in a mixture with the corresponding 7-unsubstituted 6-dehydro derivative (especially when fluoramine is used alone as the halogenating agent). 

  Such a mixture can be separated by converting this 6-dehydro derivative into a derivative which can be easily separated from the 7a-halogen product by chromatography, in particular into a 6,7-disubstituted derivative, e.g. B.  is converted into the corresponding 6ss, 7ss-diol by reaction with osmium tetroxide in dioxane in the presence of pyridine. 

 

   7a-chlorine compounds of the formula (I) can also be obtained from steroids of the formula (V) by reaction with N, N-diethyl-1,2,2-trichlorovinylamine in a halogenated hydrocarbon, e.g. B.  Methylene chloride, as a solvent and preferably at moderately low temperatures, for example at about 0 "C, and under an inert atmosphere, e.g. B.  Nitrogen.  The molar ratio of N, N-diethyl-1,2,2-trichlorovinylamine to steroid is preferably about 6: 1. 



   The compound of formula (V) which reacts with the halogenating agent in these processes preferably contains a 1,2-double bond, since the 1,4-pragadienes obtained in this way are generally more stable, easier to isolate and more active as topical anti-inflammatory agents than the corresponding 1,2-dihydro4-pregnene.    



   The steroids of the formula (V) required as starting materials for this process are new compounds and can be converted to the 7-position with a weak acid by converting the corresponding 6ss, 7ss-dihydroxy derivatives into 6B, 7B-alkyl-o-alkanoate esters and then reducing the 6ss-acyloxy-7a-hydroxy derivative obtained, preferably using chromium (II) acetate, sodium acetate and aqueous acetic acid in acetone. 



   The product of the two main reaction stages described above (starting from a steroid of the formula IV or V) can then be subjected to one or more of the above-mentioned final reaction stages (a) to (f).  It is normally obvious to the steroid chemist whether carrying out such a final reaction step is expedient or not or even essential.  It is often more appropriate to make the appropriate chemical changes during the manufacture of the steroid of formula (IV) or (V). 



     7a-Halogen-3,20-dioxo-1,4-pregnadienes and -4pregnene with ester functions at C-16, C-17 and / or C-21 can be found in 7o-Halogen-3,20-dioxo-l, 4pregnadienes and -4-pregnene with free hydroxyl groups at C-16, C-17 and / or C-21 for example by the action of acidic saponifiers, e.g. B. 



  a strong mineral acid, preferably 70% perchloric acid in methanol.  By controlling the reaction time and the amount of acid, a 17.21-hydrocarbon carboxylate can be converted into the corresponding 17-monoester or the corresponding 17.21-diol.  The compounds according to the invention contain a halogen atom at C-7, so that basic hydrolyzing agents are usually not desirable since undesirable side reactions, e.g. B.  Elimination of the 7a halogen atom take place, however, mild basic saponifiers, e.g. B.  aqueous sodium bicarbonate in methanol, often used successfully. 



   The hydrolysis of an esterification group at C-21 or G16 is preferably carried out with the aid of the malt enzyme diastase in aqueous methanol.  Malt diastase hydrolyzed 7a-halo-3,20-dioxo-pregnadiene-l 7.21 -dicarbon carboxylates only at C-21 to form 17-monohydrocarbon carboxylates, optionally at C-21 in a known manner with an acylating agent that has an acyl function which is different from that present at C-17 can be esterified again, so that mixed 17,21-diacyl derivatives are formed. 



     16a, 17a orthoesters and 17a, 21 orthoesters can be hydrolyzed at the 16a and 21 positions to form a 17 ester.  This hydrolysis is preferably carried out under slightly acidic conditions, for example in the presence of a lower alkanoic acid (e.g. B.  Acetic acid or propionic acid) or a strong mineral acid (e.g. B.  Hydrochloric acid or sulfuric acid).  If there is no substituent on C-16, the hydrolysis is preferably carried out with buffering at a pH in the range from 4 to 6. 



   The hydrolysis of a 17a, 21-alkylidenedioxy group, a 17a, 21-cycloalkylidenedioxy group or 17a, 21-aralkylidenedioxy group to 17a, 21-dihydroxy groups is normally carried out under mild acidic conditions (e.g. B.  50% aqueous acetic acid) preferably under an inert atmosphere (e.g. B.  Nitrogen).  21-ethylene-ketals and 17a, 20; 20,21-bis-methylenedioxy groups can also be hydrolyzed under mild acidic conditions, and 17a, 20; 20,21-bis-methylenedioxy groups can be hydrolyzed under essentially neutral conditions using triphenylcarbenium tetrafluoroborate be hydrolyzed. 



   The preferred compounds according to the invention contain ester groups at C-17.  These include 17-monoesters and 17.21-diesters, in particular 17-propionates, 17-n-butyrates and 17-benzoates.  E is generally advantageous if this
Ester groups are already present in the starting materials of the formulas (IV) and (V).  Sometimes, however, it may be appropriate to introduce these ester groups after one of the main reaction steps described above according to the
Invention has been carried out. 



   For example, the 17a, 21-diesters by acylation of the corresponding 17a, 21-diols or 17a-hydroxy-21-acyloxy compounds preferably with a carboxylic acid with up to
12 carbon atoms or vitamin A acid (retinoic acid) together with an esterifying agent or with the help of a reactive derivative of this acid.  In particular, the steroid can be mixed with a suitable acid anhydride
Presence of a strongly acidic catalyst, e.g. B.  Toluene-p-sulphonic acid, perchloric acid or a strongly acidic cation exchange resin, or with trifluoroacetic anhydride and the appropriate acid, e.g. B.  a lower aliphatic carboxylic acid, and a strong acid catalyst. 



   Before a 17a-hydroxyl group is esterified, any 11 lss-hydroxyl function that is present should be protected, for example as 11B-trifluoroacetate, which after esterification at C-17 with a mild base (e.g. B.  dilute aqueous sodium benzoate) can be hydrolyzed without other ester groups at C-17 and / or C-21 being hydrolyzed.  It is also possible to carry out the 17a esterification on a 1 1-oxo compound and the 1 1-oxo group can then (in the manner described after the description of the first main reaction stage) reduced to the required 1 lss, 17a-diol-17-acylate will. 



   17,21-diesters can also 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, e.g. B. 



  Pyridine, quinoline, N-methylpiperidine, N-methylmorpholine, p-dimethylaminopyridine or N, N-dimethylaniline. 



   The 17a monoesters according to the invention can be prepared by hydrolysis of a corresponding 17.21 orthoester or 17a, 21 diester in the manner described above. 



  The 17.21 orthoester group can be introduced by reacting a 17a, 21 diol with an alkyl orthoester before or after a main process step according to the invention. 



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



   The reduction of a 1 l-oxo group to a 1 lss-hydroxy group has already been described. 



   If 7a, 9a, 11 ss-trihalogen compounds and 7a, 9a-dihalogen-1 ss-hydroxy compounds of formula (I) are prepared, the 9a, 11B-dihalogen atoms or 9a-halogen atoms may be present in the molecule before the introduction of the 7a-halogen atom .  However, the 9a, 11 13-dihalo or 9a-halogen atoms can be converted into a 7o-halogen-9 (l 1) -dehydro compound (in particular a 7a-halogen-3,20-dioxo-1,4,9 (11) -pregna - Triene) are introduced, which consist of a 7a-halogen-1 1ss-hydroxy-3,20-dioxo compound by dehydration with methanesulfonyl chloride and a tertiary amine (e.g. B.  Collidine) in a dialkylamide (e.g. B.  Dimethylformamide) may have been prepared in the presence of sulfur dioxide.  

  For example, by reacting a 7a-halo gene-9 (11) -dehydro compound obtained with chlorine in a halogenated solvent (e.g. B.  Chloroform) in the presence of a tertiary amine (e.g. B.  Pyridine) the corresponding 7a-halogen 9a '11 13-dichloro derivative.  As another possibility, by reacting the 7a-halogen-9 (11) -dehydro compound obtained with hydrogen fluoride and an N-chloramide or N-bromamide or with hydrogen chloride and an N-bromamide in an inert organic solvent 7a, 9a, 1 lss - Trihalogen derivatives in which the more electronegative halogen substitutes the 11ss position. 

  Furthermore, the reaction of the 7a-halo-9 (l 1) -dehydro compound obtained with an N-chloramide or N-bromamide (preferably N-chlorosuccinimide or N-bromosuccinimide) and a strong mineral acid (preferably perchloric acid) results in an inert organic Solvents (e.g. B.  damp dioxane or tetrahydrofuran) an 11ss-oil with a 9a-chloro or 9a-bromine substituent. 



   The 1 7a chlorination or 1 7a bromination can be carried out with the aid of an N-chloramide or N-bromamide, in particular with N-chlorosuccinimide or N-bromosuccinimide in an inert organic solvent, e.g. B.  Tetramethylene sulfone, at reduced temperature, preferably in the presence of a mineral acid, e.g. B.  Hydrofluoric acid. 



   The preparation of the starting materials of the formulas (IV) and (V) is illustrated by the following preparation examples and the invention by the subsequent examples. 



  Preparation 1 16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione and its 21-ester A. 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-21-acetate
To a solution of 22 g of dry hydrogen chloride gas in 660 ml of dioxane are added 10 g of 16a-methyl-1,4-pregnadiene 1113,1 7a, 2 1 -triol-3,20-dione-2 1 -acetate and then 6.55 g 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and the mixture is stirred for 24 hours at room temperature.  The reaction mixture is filtered and the filtrate is evaporated at 40 ° C. under reduced pressure.  The residue obtained is dissolved in chloroform: ethyl acetate (1: 1) and the solution is filtered through a column of neutral aluminum oxide, the column being washed with the same solvent mixture. 

  The eluates are evaporated and the residue obtained is recrystallized from methanol: hexane, giving the desired acetate. 



     B.  16a-methyl-1,4,6-pregnatriene-11 113,1 7a, 2 14 riol-3,20-dione
40 ml of saturated aqueous sodium bicarbonate solution are added to a solution of 1.5 g of 16a-methyl-1,4,6-pregnatriene lss, 17a, 21-triol-3,20-dione-21-acetate in 360 ml of methanol.  The mixture is stirred at room temperature for 2 hours, then filtered and evaporated under reduced pressure.  The residue obtained is dissolved in ethyl acetate, the ethyl acetate solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, giving 16a-methyl-1,4,6-pregnatriene-113,1 7a, 2 l-triol Receives -3.20-dione. 



      C.  1 6a-methyl-1, 4,6-pregnatriene-l ip, 17a, 21-triol-3,20-dione-21-benzoate
1.  To 0.68 g of 16a-methyl-1,4,6-pregnatriene-1 11ss, 17α, 21-triol-3,20-dione in 6.12 ml of pyridine are added 1.36 ml of benzoyl chloride.  The mixture is stirred at room temperature for 30 minutes and then poured into 550 ml of 0.1N hydrochloric acid solution.     The aqueous mixture is extracted with ethyl acetate, the organic extracts are washed with saturated aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and evaporated under reduced pressure to give the desired compound as a residue. 



   2nd  In the experiment described above, if the benzoyl chloride is replaced by equivalent amounts of a substituted benzoyl chloride, e.g. B.  p-toluyl chloride, p-fluorobenzoyl chloride and 3 ', 5'-dimethylbenzoyl chloride, is replaced, the corresponding 21-substituted benzoate ester, e.g. B.  the 21-p-toluate, 21-p-fluorobenzoate and 21- (3,5'-dimethylbenzoate) of 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20- dion, received. 



      D. 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-21-hydrocarbon carboxylate 1. 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-21-trimethyl acetate
A solution of 0.4 ml of trimethylacetyl chloride is added dropwise at 0 ° C. to 0.4 g of 1 6a-methyl-1, 4,6-pregnatriene-SS, 17a, 21-triol-3,20-dione in 3 ml of pyridine in 1 ml of pyridine.  The reaction mixture is left to warm to room temperature and is kept at room temperature for 30 minutes.  The reaction mixture is poured into 250 ml of water, the aqueous mixture is extracted with ethyl acetate and the organic extracts are then washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate and water. 

  The organic phase is dried over magnesium sulfate and evaporated under reduced pressure, the desired compound being obtained as residue. 



   2nd  If, in the experiment described above, the trimethylacetyl chloride is replaced by equivalent amounts of other hydrocarbon carboxylic acid chlorides, e.g. B.  Propionyl chloride, dodecanoyl chloride, valeryl chloride, n-butyryl chloride, cyclopentylpropionyl chloride, cyclohexylcarbonyl chloride, 1-adamantylacetyl chloride and l-adamantyl carboxylic acid chloride, the corresponding 21-hydrocarbon carboxylates, e.g. B.  the 21-propionate, 21-dodecanoate, 21-valerate, 21-n-butyrate, 21-cyclopentyl propionate, 21-cyclohexane carboxylate, 21- (1'-adamantyl acetate) and 21- (1'-adamantyl carboxylate) of 16α-methyl- 1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione was obtained. 



  Preparation 2 1 6a-methyl-1, 4,6-pregnatrien-l lp, 17a, 21-triol-3,20-dione-17-lower alkanoates and -17,21-alkylorthoalkanoates A.  16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17-propionate 1. 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17,21-ethyl-o-propionate
3.8 ml of triethyl orthopropionate and 0.142 g of toluene are added to 1.9 g of 16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione in 9.5 ml of dimethyl sulfoxide. p-sulfonic acid monohydrate.  The mixture is stirred for 2 hours at room temperature, poured into 250 ml of water, 150 ml of saturated aqueous sodium bicarbonate are added and the mixture is extracted with ethyl acetate. 

  The ethyl acetate extracts are combined and washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the desired compound as a residue. 

 

   2nd  The product of preparation 2A (1) is dissolved in 15 ml of glacial acetic acid and 0.3 ml of water.  The mixture is left to stand at room temperature for one hour, then poured into 300 ml of water and 50 ml of 8% aqueous sodium hydroxide solution are added.  The precipitate formed is separated off by filtration, washed with water and dried at room temperature, using 1 6a-methyl-1,4,6-pregnatrien-l Ip, 17c1,21-triol-3,20-dione-17 -propionate receives.  The compound is further purified by recrystallization from acetone-hexane. 



      B.  16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17-lower alkanoate 1.  16a-methyl-l, 4,6-pregnatriene-l 113.1 ss, 17α21-triol-3,20-dione-
17,21-alkyl orthoalkanoates
In the manufacturing process 2A (1), the triethyl orthopropionate is replaced by the following trialkyl orthoalkanoates: triethyl orthoacetate, triethyl ortho-n-butyrate, triethyl orthoisobutyrate and tri-n-butyl orthovalerate, whereby the corresponding 17,21-alkyl orthoalkanoates are obtained: the 17.21 ethyl-o acetate, 17.21-ethyl-butyrate, 17.21-ethyl-o-isobutyrate or  the 17,21-n-butyl-o-valerate of 16a-methyl-1,4,6-pregnatriene-1 1s, 17a, 21-triol-3,20-dione.    



  2nd    16α-methyl-1,4,6-pregnatriene-11ss, 17α-21-triol-3,20-dione-17-lower alkanoates
The 17.21-alkyl orthoalkanoates prepared in preparation process 2B (1) are treated with aqueous acetic acid in the manner described in preparation 2A (2), the 1 7-acetate, 17-n-butyrate, 17-isobutyrate or  1 7-valerate of 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione is obtained. 



  C.    16α-methyl-1,4,6-pregnatrien-11ss, 17α-21-triol-3,20-dione-17-benzoate 1. 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-
17.21 methyl orthobenzoate
To a solution of 1 g of 16a-methyl-1,4,6-pregnatriene 1113,1 7a, 2 1 -triol-3,20-dione in 56 ml of dioxane and 84 ml of benzene are added 0.25 g of pyridinium toluene-p- sulfonate and 1.5 1 trimetyl-o-benzo &.     The reaction mixture is heated under reflux for 2 days and then a further 0.1 g of pyridinium toluene p-sulfonate and 1 ml of trimethyl o-benzoate are added.  The mixture is heated under reflux for a further 3 days and then a further 0.1 g of pyridinium toluene p-sulfoant and 1 ml of trimethyl o-benzoate are added. 



  The mixture is heated under reflux for a further 3 days, cooled, 0.45 ml of pyridine is added and the mixture is evaporated under reduced pressure.  The residue obtained is dissolved in ethyl acetate, the ethyl acetate solution is washed with water, dried over magnesium sulfate and evaporated, the residue being 16α-methyl-1,4,6-pregnatrien- ss, 17a, 21-triol-3, 20-dione-17,21-methyl-o-benzoate obtained. 



   In the experiment described above, if the trimethyl-o-benzoate is replaced by an equivalent amount of trimethyl-o (p-fluorobenzoate), 16a-methyl-1,4,6 pregnatrien-11ss, 17α, 21-triol-3 is obtained , 20-dione-17,21-methyl-o- (p-fluorobenzoate). 



   2nd    16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-17-benzoate and 16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-17-p-fluorobenzoate are obtained by hydrolysis of 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17a, 21 methyl o-benzoate or    16α-methyl-1,43,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-17α, 21-methyl-o- (p-fluorobenzoate) with aqueous acetic acid according to production process 2A ( 2) received. 



  Preparation 3 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17,21-hydrocarbon carboxylic acid ester A.    16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17-propionate-2 l-alkanoate 1.  1 oa-methyl-l, 4,6-pregnatriene-11 11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate
4.6 ml of propionic anhydride are added to 2.8 g of 16a-methyl-l, 4,6-pregnatriene-1 1ss, 17α, 21-triol-3,20-dione-17-propionate in 23 ml of pyridine and left to do so Stand mixture for 3.5 hours at room temperature.  It is poured into 250 ml of water containing 50 ml of 1N hydrochloric acid.  It is extracted with 100 ml of ethyl acetate, the combined organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure. 



  The residue obtained is chromatographed on a silica gel column, eluting with chloroform: ethyl acetate (4: 1).  The combined eluates are evaporated, the desired compound being obtained as residue. 



   2nd  If in the manufacturing process 3A (I) the propionic anhydride is replaced by equivalent amounts of other alkanoic anhydrides, e.g. B.  Acetic anhydride, n-butyric anhydride, isobutyric anhydride, caprylic anhydride and valeric anhydride, the corresponding are obtained
17-propionate-21 alkanoates, e.g. B.  the 17-propionate-21-acetate, 17-propionate-21-n-butyrate, 17-propionate-21-isobutyrate, 17-propionate-21-caprylate and 17-propionate-21-valerate of 16α-methyl 1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione.    



   3rd    16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-
17-propionate-21-benzoate is prepared from 16a-methyl-1,4,6-pregnatriene-l 1ss, 17α, 21-triol-3,20-dione-17-propionate and benzoyl chloride by the manufacturing method 1C (1) .  17-propionate-21 substituted benzoate esters, e.g. B.  the 17-propionate-21-p-toluate, 17-propionate-21-p-fluorobenzoate and the 17-propionate 21 - (3 ', 5' -dimethylbenzoate) of 16a-methyl-1,4,6-pregnatriene
1 1ss, 17α, 21-triol-3,20-dione can be prepared in a similar manner using the corresponding substituted benzoyl chloride. 



  B.    16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-
17.21 hydrocarbon carboxylates
1.  The 17-acetate, 17-n-butyrate, the 17-isobutyrate, the 17-valerate and the 17-benzoate of 16α-methyl-1,4,6- are treated in a similar manner to that of Preparation 3A (1). pregnatriene-1 1ss, 17α, 21-triol-3,20-dione in pyridine each with the following alkanoic anhydrides: acetic anhydride, propionic anhydride, n-butyric anhydride, isobutyric anhydride and valeric anhydride. 

  The products obtained are isolated and purified in the manner described, the corresponding 17-hydrocarbon-carboxylate-21 alkanoates of 16a-methyl-1,4,6-pregnatriene-11 11ss, 17α, 21-triol-3,20-dione being isolated receives, namely its 17,21-diacetate, 17-acetate-21-propionate, 17-acetate-21-n-butyrate, 17-acetate-21-isobutyrate, 17-acetate-21-valerate, 17-n-butyrate- 21-acetate, 17-n-butyrate-21-propionate, 17,21-di-n-butyrate, 17-n-butyrate-21-isobutyrate, 17-n-butyrate-21-valerate, 17-isobutyrate-2l acetate, 17-isobutyrate-2l-propionate, 17-isobutyrate-21-n-butyrate, 17.21-diisobutyrate, 17-isoburyate-21-valerate, 17-benzoate-21-acetate, 1 7-benzoate -2 1 -propionate, 1 7-benzoate-2 l-butyrate, 1 7-benzoate-2 1 -isobutyrate, 1 7-benzoate 21-valerate,

   17-valerate-21-acetate, 17-valerate-21-propionate, 17-valerate-21-n-butyrate, 1 7-valerate-2l-isobutyrate and 17.21 divalerate. 



   2nd  In a manner similar to that of Manufacturing Process 1C, the starting compounds of Manufacturing Process 3B (1), i.e. H.  the 16a-methyl-l, 4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-17-monoester in pyridine each with benzoyl chloride, p-toluyl chloride, p-fluorobenzoyl chloride and 3 ', 5' -Dimethylbenzoyl chloride, the corresponding 21-benzoates or  substituted benzoates, i.e. H.  the 21-benzoate, 21-p-toluate, 21-p-fluorobenzoate and 21- (3 ', 5'-dimethylbenzoate) the 16α-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol -3.20- dione-17-monoester starting compounds. 

 

  Preparation 4 The 17-esters, 21-esters and 17.21-diesters of 16ss-methyl-1,4,6 pregnatrien-11ss, 17α, 21-triol-3,20-dione and of 16α-methyl-1 , 4,6-pregnatrien-17,21-diol-3, 11,20-trione and their 16ss methyl epimers
1.    16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-2 l-acetate is made from 16ss-methyl-1,4-pregnadiene-l 113,1 7a, 2 1-triol-3,20-dione-21-acetate prepared according to the production process 1A and subjected to the sequence of the reactions of the production processes 1 to 3, whereby the 16ss-methyl epimers of the 16a-methyl compounds described here are obtained.   



   2nd  In a similar manner, 16a-methyl-1,4,6-pregratien-17α, 21-diol-3,11,20-trione-21-acetate is prepared from 16α-methyl-1,4-pregnadiene-17a , 21 -diol3, 11, 20-trione-21-acetate according to the preparation process 1A and leads it through the reactions described under preparation 1 to preparation 3, whereby the 11-oxo-16α-methylpregnatriene derivatives are obtained, those mentioned there 11 correspond to 1ss-hydroxy-16α-methylpregnatriene compounds. 



   3rd    16ss-methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-21-acetate is obtained from lop-methyl-1,4-pregnadiene-1,7a, 21-diol-3 , 11,20-trione-21-acetate prepared according to production process 1A and passed through the reaction sequence of production processes 1 to 3, the 11-oxo-16ss-methylpregnutrienderivate, the 1 11S-hydroxy-1 6a mentioned there correspond to methyl pregnatrien products can be obtained. 



  Production 5 Alternative process for the production of 1,4,6-Pregnatrien
17a, 21-diol-3,11,20-trions and their 17,21-diesters A.    oss-bromo-l ocr-methyl-l, 4-pregnadiene-17a, 2 1-dio13,11,20-trione-21-acetate
7 g of N are added to a solution of 11 g of 16a-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-21-acetate in 110 ml of carbon tetrachloride and 110 ml of chlorobenzene at the reflux temperature -Bromosuccinimid and then 530 mg Azobis isobutyronitrile.  The mixture is heated under reflux for 30 minutes, cooled and 300 ml of 10% aqueous sodium bisulfite solution are added with stirring.  150 ml of chloroform are added, the organic layer is separated off, washed with water and dried over anhydrous magnesium sulfate. 

  It is evaporated under reduced pressure, the desired compound being obtained as residue. 



   B.    16α-methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione acetate
To a solution of 6ss-bromo-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-21-acetate (from production method 5A) in 125 ml of dimethylacetamide is added 4.4 g
Lithium bromide and 7.75 g calcium carbonate.  You heat it
Reaction mixture for one hour at 120 C under a nitrogen atmosphere.  The mixture is cooled, filtered and the filtrate is diluted with
500 ml chloroform.  The chloroform solution is washed with
Water, dry them over magnesium sulfate and evaporate them, the residue being obtained as the desired compound. 



  C.    16α-Methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione is made from 16α-methyl-1,4,6-pregntriene-17α, 21-diol-3 , 11,20-trion-21-acetate by hydrolysis with aqueous sodium bicarbonate according to the production process 1B. 



     D. 16α-methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-
17.21 dialkanoate
1.  A solution of 8 ml of trifluoroacetic anhydride, 200 ml of propionic acid and 200 mg of toluene-p-sulfonic acid monohydrate is stirred for one hour at room temperature and then 2 g of 16α-methyl-1,4,6-pregnatrien-17α, 21-diol-3 are added , 11.20-trion. 



  The reaction mixture is stirred for 17 hours and then a further 6 ml of trifluoroacetic anhydride are added.  After another
Stirring for 5 hours is poured into 400 ml of 0.5N sodium hydroxide.  The aqueous mixture is extracted with chloroform, the combined chloroform extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure
Pressure.  The residue obtained is dissolved in methanol and the solution is subjected to steam distillation in order to remove volatile impurities.  The water is decanted from the distillation residue and the residue is dried, 16α-methyl-1,4,6-pregnatriene-17α, 21-diol-
3,11,20-trione-17,21-dipropionate. 



   2nd  By using equivalent amounts of others
Alkanoic acids, e.g. B.  Acetic acid, valeric acid and n-butyric acid, instead of propionic acid, the corresponding 17.21
Dialkanoates, e.g. B.  the 17,21-diacetate, 17,21-divalerate and 17,21
Dibutyrate of 16α-methyl-1,4,6-pregnatriene-17α, 21-diol-
3,11,20-trione obtained. 



   Preparation 6 16α, 17α-isopropylidenedioxy-1,4,6-pregnatrien-11ss, 21-diol-3,20-dione 1. 16α, 17α-isopropylidenedioxy-1,4-pregnadien-11ss, 21-diol-
3,20-dione-21-acetate is made from 16a, 1,7a-isopropylidenedioxy-l, 4 pregnadiene-11ss, 21-diol-3,20-dione and acetic anhydride in
Pyridine produced by manufacturing process 3A. 



      2nd 16a, 17a-isopropylidenedioxy-1,4,6-pregnatriene-11 ss, 21-diol-3,20-dione-21 -acetate is converted from 1 6a, 1,7a-isopropylidenedioxy-l, pregnadiene-lss, 21-diol -3,20-dione-21-acetate, DDQ and dry hydrochloric acid in dioxane according to the manufacturing process 1A. 



   Preparation 7 21-Halogen-1,4,6-pregnatrien-11ss, 17α-diol-3. 20-dione-17-hydrocarbon carboxylates A.  21-Halogen-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-hydrocarbon carboxylates
1.    16α-methyl-21-chloro-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-
17-propionate
To a solution of 0.87 g of 16a-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-n-butyl-o-propionate in 87 ml
Chloroform is added 1.15 ml of trimethylsilyl chloride and heated for 24 hours on a reflux condenser.  The reaction mixture is evaporated under reduced pressure and the result is obtained
Residue on a silica gel column (80 g), eluting with chloroform: ethyl acetate (2: 1). 

  The combined eluates are evaporated, the desired compound being obtained as residue. 



      2nd  1 6a-methyl-21-bromo-l, 4-pregnadiene-l 1113.1 7a-diol-3.20-dione-
17-propionate
When using trisilyl bromide as a reagent in the process described above, the corresponding 21-bromo derivative, i.e. H.  16a-methyl-21-bromo-l, 4pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate was obtained. 



   3rd  The following compounds are treated with trimethylsilyl chloride in the manner described in preparation 7A (1): loa-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-ethyl- o-acetate, 16α-methyl-1,4-pregnadiene-l 1113,1 7a, 2 17a, 21-triol-3,20-dione-l 7,21-ethyl ortho-n-butylate, 16α-methyl- 1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-n-butylorthovalerate and 1,6a-methyl-l, 4-pregnadiene-11ss, 17α, 21-triol-3 , 20-dione-17,21-methylorthobenzoate, The products obtained are isolated and purified as described, using 16α-methyl-21-chloro-1,4-pregnadiene-11ss, 17α-diol-3.20 -dione-17-acetate, 16?

  ; -Methyl-21-chloro-1,4-pregnadiene-llp, 17a-diol-3,20-dione-17-n-butyrate, 16c-methyl-21-chloro-l, 4-pregnadiene-11P, 17a diol-3.20-dione-1 7-valerate or 

 

     16α-methyl-21-chloro-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-benzoate. 



   In the experiment described above, by using trimethylsilyl bromide as the reagent, the 21-bromo derivatives are obtained, each of which corresponds to the 21-chloro derivatives. 



   4th  In the production processes 7A (1) to 7A (3), the corresponding 16ss methyl epimers of the 21-halogenopregnadiene products mentioned are obtained by using the 16ss methyl epimers of the 16 α-methyl compounds mentioned there as starting steroids.  Likewise, when using derivatives that have a 1 1-oxo function instead of a
11 ss-hydroxyl function contain, as starting materials, the corresponding 21-halogen derivatives containing an 11-oxo function. 



     
B.  1 6a-methyl-2 1 -halogen-1,4,6-pregnatriene-1 1113.1 ss, 17a-diol-3,20-dione-17-alkanoate
1.    16α-methyl-21-halogen-1,4,6-pregnatriene-11ss, 17α-diol-3,20-dione-17-propionate
16α-methyl-21-chloro-1,4,6-pregnatriene-11ss, 17α-diol-3,20-dione-17-propionate and 16α-methyl-21-bromo-1,4,6-pregnatriene - 11ss, 17α-diol-3,20-dione-17-propionate are made from 16α-methyl-21-chloro-1,4-pregnadiene-Ip, 17-diol-3,20-dione-17-propionate or    16cl-methyl-21-bromo-11B, 17a-diol-3,20-dione-l'l-propionate
DDQ and dry hydrogen chloride in dioxane after the
Manufacturing process 1A. 



   2nd  The 21-halogeno-1,4-pregnadienes of preparation processes 7A (3) and 7A (4) are treated in the same way
DDQ and dry hydrogen chloride in dioxane to give the corresponding 21-halogeno-1,4,6-pregnatrienes. 



   3rd    16a-methyl-21-fluoro-1,4,6-pregnatrien-11ss, 17a-diol-3,20-dione-17-propionate 16α-methyl-1,4,6-pregnatrien-11ss, 17α- diol-3,20-dione-17-propionate-21-methanesulfonate is made from 16α-methyl-1,4,6-pregatratrien-l 1 B, 7a, 2 1 -triol-3,20-dione-l 7-propionate and methanesulfonyl chloride in pyridine were prepared by the production process 1C and then reacted with silver fluoride in acetonitrile by known processes, 16a-methyl-21-fluoro-1,4,6-pregnatrien-11ss, 17α-diol-3, 20-dione-17-propionate is obtained. 



  Manufacturing 8
1,4,6-Pregnatrien-l 1113,1 17a-diol-3,20-dione-17-hydrocarbon carboxylate A.  1,4-Pregnadien-11ss, 17α-diol-3,20-dione-17-hydrocarbon carboxylates 1.  3.68 ml of trimethylsilyl iodide are added to 4 g of 1,4-pregnadiene-1 113.1 ss, 17α, 21-triol-3,20-dione-17,21-ethyl orthopropionate in 100 ml of methylene chloride under a nitrogen atmosphere at 0 ° C. . 

  After one minute, the reaction mixture is poured into 300 ml of 1N sodium thiosulfate solution with vigorous stirring.     The reaction mixture is extracted with methylene chloride, washed with water, dried over magnesium sulfate and evaporated to a residue which is then purified on a silica gel column (300 g) by elution with chloroform: ethyl acetate (4: 1), 1 , 4Pregnadien-l 1ss, 17α-diol-3,20-dione-17-propionate. 



   2nd  In the same way, 1, 4Pregnadien-11ss, 17α, 21-triol-3,20-dione-17,21-ethylortho-n-butyrate, 1,4-Pregnadien-11ss, 17α, 21 are treated in each case -triol-3,20-dione-17,21-n-butyl ortho-valerate, 1,4-pregnadiene-1113,1 7a, 2 l-triol-3,20-dione-17,21-ethyl-orthoacetate and 1,4 -Pregnadien-1 11ss, 17α, 21-triol-3,20-dione- 17.2 l-methyl-o-benzoate with trimethylsilyl iodide and then immediately isolate the product which has been formed, the 17-n-butyrate, the 1st 7-valerate, the 1 7-acetate or  contains the 17-benzoate of 1, 4Pregnadien-1113.1 ss, 17α-diol-3,20-dione.    



  B.    1,4,6-Pregnatrien-11ss, 17α-diol-3,20-dione-17-hydrocarbon carboxylates
In the manner described in preparation 1A #, the 1,4-pregnadiene-17-esters prepared by the production process 8A are treated with DDQ and hydrogen chloride in dioxane, 1,4,6-pregnatriene-11 ss, 17a-diol-3 20-dione-17-propionate, 1,4,6-pregnatriene-11ss, 17α-diol-3,20-dione-17-n-butyrate, 1,4,6-pregernatriene-l 18,17a- diol-3,20-dione-17-valerate, 1,4,6 Pregnatrien-1 1ss, 17α-diol-3,20-dione-17-acetate and 1, 4,6-Pregnatien-1 1B, 17a-diol-3,20-dione-17-benzoate is obtained.    



   Preparation 9 16-methylene-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-21-hydrocarbon carboxylates and -17,21-hydrocarbon carboxylates A.    16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21 hydrocarbon carboxylates
1.    16-methylene-1,4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione-
21-propionate is made from 16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione (5 g) and propionic anhydride (10 ml) in pyridine (100 ml) according to production process 3A ( 1) manufactured. 



   2nd  In the method described above, when using other alkanoic anhydrides instead of propionic anhydride, e.g. B.  Acetic anhydride, n-butyric anhydride and valeric anhydride, the corresponding lower 21-alkanoates, e.g. B.  the 2l acetate, 21-n-butyrate and 21-valerate obtained from 16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione. 



   3rd    16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-benzoate becomes 16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3 , 20-dione and benzoyl chloride in pyridine obtained by the 1 C preparation process. 



  B.    16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-2 1-propionate
1.  To a solution of 1 g of 16-methylene-1,4-pregnadiene 1113, 17a, 21 -triol-3,20-dione-21-propionate in 10 ml of pyridine is added at -23 C 1 ml of trifluoroacetic anhydride, which is based on -23 C has been pre-cooled.  The reaction mixture is left to stand at -23 C for 40 minutes and then poured into 200 ml of ice water which contains 8.8 ml of concentrated hydrochloric acid.  The precipitate formed is isolated by filtration, washed with water and dried to give the desired compound. 



   2nd  The 21-hydrocarbon carboxylates obtained by the production processes 9A (2) and (3) can be converted into their 1 l-trifluoroacetates in the same way. 



  C.    16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-17,21-hydrocarbon carboxylates
To a solution of 1.07 g of 16-methylene-l, 4pregnadiene-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-21-propionate in 10 ml of propionic acid containing 0.1 g of toluene- contains p-sulfonic acid monohydrate at 0 C, dropwise 4 ml of trifluoroacetic anhydride are added.  The reaction mixture is left to stand at 0 C for 5 minutes, then left to warm to room temperature and held at room temperature for 3 hours. 

  The reaction mixture is poured into water, the aqueous mixture is extracted with ethyl acetate, the combined organic extracts are washed with 5% sodium hydroxide and then with water, dried over magnesium sulfate and evaporated, the residue being 16-methylene-1,4- pregnadien-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-17,21-dipropionate. 



   2nd  The 1 l-trifluoroacetate esters obtained by preparation process 9B (2) are treated in the manner described above, the corresponding 17-propionate esters, namely the 17-propionate-21-acetate, the 17-propionate-21n-butyrate, the 17th -Propionate-21-valerate and the 17-propionate-21-benzoate of 16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-l l-trifluoroacetate. 

 

   3rd  In the manufacturing process 9C (1), by replacing the propionic acid with other hydrocarbon carboxylic acids, e.g. B.  n-butyric acid and acetic acid, 16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-17-n-butyrate-21-propionate or    16-methylene-1, pregnadiene-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-17-acetate-21-propionate. 



   4th  The products obtained in manufacturing process 9B (2) can be made into their products by manufacturing process 9C (3)
17-n-butyrates and 17-acetates are converted. 



     
D. 16-methylene-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione
11 -trifluoroacetate-17,21-hydrocarbon carboxylates
1. 16-methylene-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-l l-trifluoroacetate-17,21-dipropionate is made from 16-methylene-1,4-pregnadiene-11 ss , 17a, 21-triol-3,20-dione-11-trifluoroacetate
17,21-dipropionate, dry hydrogen chloride and DDQ in
Dioxane produced by manufacturing process 1A. 



   2nd  The products are treated in the same way
Manufacturing process 9C (2) to (4) with DDQ and dry
Hydrogen chloride in dioxane to give their corresponding 6-dehydro derivatives. 



     
E.  1 6-methylene-1, 4,6-pregnatriene-1 ss, 17a, 21 -triol-3,20-dione-
17,21-dipropionate
1.  To a solution of 0.52 g of 1 6-methylene-1, 4,6-pregratien-11ss, 17α, 21-triol-3,20-dione-11-trifluoroacetate-17,21-dipropionate in 26 ml of methanol are given 1.5 g of sodium benzoate and stirred for 2.5 hours at room temperature.  The solution is evaporated under reduced pressure at room temperature and the residue obtained is washed well with water.  The solids are filtered off and dried, giving 16-methylene
1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate. 

  Additional product is obtained by extracting the combined aqueous washes and the filtrate with ethyl acetate, washing the organic extract with water, drying over magnesium sulfate and evaporation. 



  The desired compound is obtained as a residue. 



   2nd  In the same way, the 1 l-trifluoroacetates obtained as products in the production process 9D (2) are treated in methanol with sodium benzoate, the corresponding 1 lss-hydroxy derivatives being obtained. 



  Manufacturing 10
16-methylene-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-17,21-hydrocarbon carboxylates A.    1 o-methylene-l, 4-pregnadiene-l 7a, 21-dio13,11, 20-trion-17,21-alkyl orthocarbon carboxylates
1.  1 o-methylene-1,4-pregnadiene-1,7a, 21-dio13,11, 20-trione-17,21-methyl-o-benzoate is made from 1 6-methylene-1,4-pregnadiene-17α, 21 -diol-3,11,20-trione and trimethyl-o-benzoate with pyridinium toluene-p-sulfonate in dioxane and benzene obtained by the preparation process 2C (1). 



   2nd  In the manner described in preparation 2A (2), 16-methylene-1,4, -pregnadiene-17α, 21-diol-3,1 1,20-trione in dimethyl sulfoxide in the presence of toluene-psulfonic acid is treated with triethyl o-propionate, triethyl-on-butyrate and tri-n-butyl-o-valerate, the corresponding 17.21-alkyl-o-alkanoate, namely 17.21-ethyl-o-propionate, 17.21-ethyl -on-butyrate or  17,21-n-butyl-o-valerate of lo-methylene-l, 4-pregnadiene-17a, 2 I-diold, ll, 20-trione. 



  B.    16-methylene-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-hydrocarbon carboxylate
1.  2 g of 16-methylene-1,4-pregnadiene-17α, 21-diol-3.1, 1.20-trione-17.21-methyl-o-benzoate are dissolved in 15 ml of glacial acetic acid and 0.3 ml of water.  The mixture is left to stand at room temperature for 20 minutes, then poured into 300 ml of water and 50 ml of 8% sodium hydroxide solution are added.  The precipitate formed is filtered off, washed with water and dried at room temperature.  The desired compound is isolated by preparative thin layer chromatography on silica gel using ethyl acetate: chloroform (1: 1) as developer solvent.  The band with the strongest polarity, which can be seen in UV light, is removed and eluted with ethyl acetate. 

  It is evaporated to give 16-methylene-1,4-pregna diene 17a, 21-diol-3,11,20-trione-17-benzoate as residue. 



   2nd  The 17.21-alkyl-o-alkanoates obtained in production process 10A (2) are treated with acetic acid in the manner described above, the 17-propionate, the 17-n butyrate or  the 17-valerate of 16-methylene-1,4-pregnadiene 17a, 2l-diol-3, 1 1,20-trione. 



      C. 16-methylene-1,4-pregnadiend-17α, 21-diol-3,11,20-trione-17,21-hydrocarbon carboxylates
1.  The 16-methylene-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-1 7-hydrocarbon carboxylates obtained by preparation 10B are treated with benzoyl chloride in pyridine according to preparation 1 C, whereby the 17a, 21-dibenzoate, the 17-propionate-21-benzoate, the 1 7-n-butyrate-21-benzoate and  the 17-valerate-21-benzoate of 16-methyl-1,4-pregnadiene-17a, 21-dio13, 11, 20-trione. 



   2nd  In the manner described in preparation 3A (I), the 17-hydrocarbon carboxylates of 1 6-methylene-1,4-pregnadiene-17a, 21 -diol-3,11,20-trione in pyridine obtained by the preparation process 10B are treated with propionic anhydride, whereby the 17-benzoate-21-propionate, the 17,21-dipropionate, the 1 7-n-butyrate-2 1-propionate and the 1 7-valerate-2 1-propionate of 16-methylene-1,4- pregnadien17a, 21 -diol-3,11,20-trione. 



  D.    1 o-methylene-1,4, o-pregnatriene-l 7a, 21-dio13,11, 20-trione-17,21-hydrocarbon carboxylates
In the manner described in Preparation 1A, the 16-methylene-1,4-pregnadienes prepared according to Preparation 10C are treated with dry hydrogen chloride and DDQ in dioxane and the products formed in each case are isolated and purified, the corresponding 1,4,6- Pregnatriene, namely the 17-benzoate-21-propionate, 17-benzoate-2 ln-butyrate, 17-benzoate-21-valerate, 17-propionate-21-butyrate, 17,21-dipropionate, 17-n-butyrate-21 -propionate and 17-valerate-21 -propionate. 



  Preparation 11 7P-Hydroxy-1,4-pregnadiene-3,20-dione A, 9α-fluoro-16α-methyl-1,4-pregnadiene-7ss, 11ss, 17α, 21-tetrol-3,20- dion-21 acetate 1. 9α-Fluoro-16α-methyl-1,4, -pregnadiene-6ss, 7ss, 11ss, 17α, 21-pentol-3,20-dione-21-acetate
4.9 g of 8.3 g of 9α, - fluoro-16α-methyl-1,4,6-pregnatriene-1113,1 7a, 2 1-triol-21-acetate in 350 ml of dioxane and 5 ml of pyridine are added g osmium tetroxide.  The reaction mixture is stirred for 5 days at room temperature, then the solution is saturated with hydrogen sulfide and the reaction solution is filtered through Celite. 

  The filtrate is evaporated under reduced pressure at room temperature, the residue obtained is triturated with chloroform: methanol and the precipitate formed is filtered off, giving the desired compound. 



      2nd  9a-fluoro-l oa-methyl-l, 4-pregnadiene-6ss, 7ss, ss, 17a, 21-pentol-3,20-dione-6,7-n-butyl-o-propionate-2 1 - acetate
To 3 g of 9α-fluoro-16α-methyl-1,4-pregnadiene-613,713,1113,1 7α, 21-pentol-3,20-dione-21-acetate in 15 ml of dimethyl sulfoxide is added 5.4 ml Tri-n-butyl-o-propionate and 0.225 g of toluene-p-sulfonic acid monohydrate and the mixture is stirred for 3.5 hours at room temperature.  The reaction mixture is poured into 500 ml of water and 100 ml of saturated aqueous sodium bicarbonate.  The aqueous mixture is extracted with ethyl acetate, the combined extracts are washed with water, dried over magnesium sulfate and evaporated to give the desired compound as a residue. 

 

      3rd 9α-Fluoro-16α-methyl-1,4-pregnadiene-6ss, 7ss, 11ss, 17α, 21-pentol-3,20-dione-6-propionate-21-acetate
The product obtained according to the manufacturing process 1 IA (2) is dissolved in 50 ml glacial acetic acid and 1 ml water.  The reaction mixture is left to stand at room temperature for one hour, then poured into 500 ml of ice water and the precipitate formed is separated off by filtration.  The precipitate is washed with water and dried at room temperature to give the desired compound. 



      4th 9α-Fluoro-16α-methyl-1,4-pregnadiene 7ss, 11ss, 17α, 21-tetrol3,20-dione-21-acetate
To 3 g of 9a-fluoro-16a-methyl-l, 4-pregnadiene-6ss, 7ss, 11ss, 17α, 21-pentol-3,20-dione-6-propionate-21-acetate in 750 ml of acetone is added Solution of 21 g sodium acetate in 60 ml water and 15 ml acetic acid, then a chromium (II) acetate slurry (freshly prepared by reduction of 70 g chromium (III) chloride with zinc amalgam and subsequent treatment with sodium acetate according to known methods).  The reaction mixture is stirred for 2.5 hours at room temperature, filtered and evaporated. 

  Water is added to the residue obtained, extracted with ethyl acetate, the combined organic extracts are washed with water, dried and evaporated under reduced pressure, the desired compound being obtained as residue.  It is purified by recrystallization from acetone: hexane; Melting point 181 to
185 C; [a] D6 +48.7 (dimethylformamide). 



   B.  In each case 9α-chloro-16α-methyl-1,4,6-pregatratrien-11ss, 17α, 21-triol-3,20-dione-21-acetate, 9α-bromo-16α - are treated methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-21-acetate and 16-methyl-1,4,6-pregnatriene-1 1B, 17a, 21-triol- 3,20-dione-21acetate in the manner described in Preparation I IA, whereby 9a-chloro-16a-methyl-1,4-pregnadiene-7P, 1113,17o, 2 1-tetrol-3,20-dione- 21-acetate, 9a-bromo-1 6a-methyl-1,4-pregnadiene-7ss, 1 lp, 17a, 21-tetrol-3,20-dione-21-acetate and 16a-methyl-1,4-pregnadiene-7ss, 11ss , 17α, 21-tetrol-3,20-dione-21-acetate.    



   C.  1.  In the same way, the corresponding 7ss-hydroxy-1,4-pregnadienes are obtained by treating the pregnatrienes prepared according to production processes 1 to 8 according to production process 1 1A. 



   2nd  In the same way, treatment of the corresponding 9a-fluorine, 9a-chloro and 9a-bromo derivatives gives the 9-unsubstituted 1,4,6-pregnatrienes obtained according to the preparation processes 1 to 8 by the preparation process
1A shows the corresponding 7ss-hydroxy-9α, fluoro-1,4-pregnadienes.    



   D. 7ss-hydroxy-16-methylene-1,4-pregnadiene 1. 16ss-methyl-16α, 17α-oxido-1,4-pregnadiene-6ss, 7ss, 11ss, 21-tetrol-3,20-dione-2 1 -acetate is made from lop-methyl-16a, 17a-oxido- 1, 4,6-pregnatrien-l ss, 21 -diol-3,20-dione-21-acetate and osmium tetroxide in dioxane and pyridine obtained by the production process 1 lA. 



      2nd 16-methylene-1,4-pregnadiene-6ss, 7ss, 11ss, 17α, 21-pentol-3,20-dione-21-acetate
To a solution of 100 mg 16ss-methyl-16a, 17a-oxido-1,4 pregnadien-6ss, 7ss, 1 1113.2 1-tetrol-2 l-acetate and 10 mg toluene-p-sulfonic acid in 1 ml acetic acid one at 5 C 0.1 ml trifluoroacetic anhydride.  The reaction mixture is left to stand at room temperature for 25 minutes, then poured into water and the desired compound is filtered off. 



      3rd 16-methylene-1,4-pregnadiene-7ss, 11ss, 17α, 21-tetrol-3,20-dione-2 1 acetate is made from 16-methylene-1,4-pregnadiene-6ss, 7ss, 11ss, 17α ;, 21-pentol-3,20-dione-21-acetate according to the manufacturing process 1 1A (2), (3) and (4). 



   4th  In a similar manner, 1613-methyl-16α, 17α-oxido-1,4,6-pregnatrien-21-ol-3,11,20-trione-21-acetate, its 9a-fluoro- and 9a- Chlorine derivatives, 9a-fluoro-16P-methyl-16α, 17α-oxido-1,4,6-pregnatrien-11ss, 21-diol-3,20-dione-21-acetate and 16ss-methyl-16α , 17α-oxido-9α-chloro-1,4,6-pregnatriene-1 lss, 21-diol-3,20-dione-21-acetate as described in preparation 1 ID (1) to (3), where 16-methylene-1,4-pregnadiene-7ss, 17?

  ;, 21-triol-3,11,20-trione-21-acetate, its 9n-fluoro and 9a-chloro derivatives, 9a-fluoro-16-methylene-1,4-pregnadiene-7ss, 11ss, 17α, 21 -tetrol-3,20-dione-21-acetate and 9α-chloro-16-methylene-1,4-pregnadiene-7ss, 11ss, 17α, 21-tetrol-3,20-dione-21-acetate receives. 



  Production 12 1 l-Oxygenated 4,6-Pregnadien-17a, 21-diol-3,20-dione and their esters
According to production processes 1 and 4, 1,2-dihydro-4,6-pregnadienes are obtained as starting materials using the 1,2-dihydro derivatives of the 1,4-pregnadienes mentioned there as starting materials, the 1,4-obtained according to production processes 1 and 4 , 6-Pregnatriene correspond and, if they are treated according to the manufacturing processes 2, 3 and 9, give 4,6-Pregnadiene, which correspond to the 1,4,6-Pregnatriene mentioned there. 



  Example 1 7α-Chloro-16α-methyl-1,4, -pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate
A.  2.0 g of 16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate are added to 24 ml of dioxane, which saturates medium-dry hydrogen chloride gas has been.  The mixture is stirred at room temperature for 16 hours, poured into 600 ml of ice water, the precipitate formed is filtered off, the precipitate is washed with water and dried in air. 

  The components in this precipitation are separated by thin layer chromatography on silica gel using ether: hexane (2: 1) as the developing solvent and the band is eluted with ethyl acetate, which, as can be seen by UV light, 7α-chloro-16α-methyl - 1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate.  The combined ethyl acetate eluates are evaporated and the residue obtained is triturated with acetone: ether, then filtered off and the triturated precipitate is dried, giving the desired compound. 



   The compound of this example can also be prepared by methods 1B and 1C described below. 



      B.  7a-chloro-10-methyl-1, 4-pregnadiene-17a, 2 1-dio13,11,20-trione-17,21-dipropionate
137 ml of dry tetrahydrofuran are saturated at 0 ° C. with dry hydrogen chloride gas.  6.85 g of 16a-methyl-1,4,6-pregnatriene-17a, 21-diol-3.1, 1.20-trione-17,21-dipropionate are added and the reaction mixture is stirred at 0 C for one hour.  It is poured into 11 ice water and stirred for 30 minutes.  The precipitate formed is filtered off, washed with water and air-dried to obtain the desired compound. 

  It is purified by recrystallization from methanol acetone, which contains a trace of propylene oxide.    [a] D6 +76.2 (dimethylformamide); [M] + 520, 518; Melting point 180 to 183 C; #maxMeOH 238 nm (± = 15. 800). 



   C.  To a solution of 3.2 g of 7α-chloro-16α-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17,21-dipropionate in 24 ml of tetrahydrofuran and 8 ml of methanol are added at 0 C under a nitrogen atmosphere, 0.697 g of sodium borohydride and the reaction mixture is stirred for 15 minutes at 0 C.  You pour in
1.8 l ice water and 250 ml ln hydrochloric acid.  The precipitate formed is filtered off and air dried to give 7α-chloro-16α-methyl-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate.  The compound is purified by recrystallization twice from acetone / methanol isopropyl ether.    

 

  Melting point 212-216 C.    [α] D26 + 42.6 (dimethylformamide); [M] + 522, 520; #maxMethanol 242 nm (# 15. 600); vNnuaixol 1743, 1730, 1720,
1652, 1610, 1595 cm '; NMR (DMSO-d6) 8 0.84 (C, 6-CH3, d J 7 Hz), 1.02 (C13-CH3, s), 1.42 (Clo-CH3, s), 4.38 ( 1 la-H, mult. ), 4.67 (7ss-H, mult), 4.80 (C21-H, s), 5.95 (C4-H, s), 6.20 (C2-H, dd J10, 2 Hz), 7.35 (C1-H, d J 10 Hz).   



  Example 2 7a-bromo-1 6a-methyl-1, 4-pregnadiene-11ss, 17α, 21-triol-3,20dione-17,21-dipropionate
A.    0.29 g of l6a-methyl-l, 4,6-pregnatriene
11ss, 1 7a, 2 1 -triol-3,20-dione-17,2 1-dipropionate to a 30% solution previously cooled to 0 C (wt. / Vol. ) dry hydrogen bromide in acetic acid (4 ml).  The reaction mixture is stirred for 1 hour.  at 0 C, pouring into ice water, filtering off the solids formed and washing the precipitate by trituration with acetone: ether, drying the triturated precipitate and receiving 0.19 g of the desired compound. 



   The connection of this example can also be made by the following methods 2B and 2C: B.    7a-bromo-1 6a-methyl-1, 4-pregnadiene-1 7α, 21-diol-3,11,20-trione-17,21-dipropionate
To a solution of 0.5 g l6a-methyl-l, 4,6-pregnatriene
1 7a, 2 1 -diol-3, 11.20-trione-17.2 1-dipropionate in 2 ml of glacial acetic acid are added at 0 C to a freshly prepared solution of 3 g of dry hydrogen bromide gas in 8 ml of glacial acetic acid.  The reaction mixture is stirred for 1 hour.  at 0 C, pour it into 400 ml of ice water, stir for 30 minutes, filter the precipitate formed and wash it with water until the wash water is neutral. 

  The precipitate is dried in air, giving 0.51 g of the desired compound.    [a] 26 + 105.10 (dimethylformamide), #maxMeOH 238 nm (c = 15. 400).    



   C.  To a mixture of 2.84 g of 7o-bromo-16a-methyl-l, 4-pregnadiene-1 7a, 2 1 -diol-3, 1 1, 20-trione-17,2 1-dipropionate and 0.573 g of sodium borohydride 8 ml of methanol, which has been precooled to 0 ° C., under a nitrogen atmosphere at 0 ° C., and the reaction mixture is stirred for 5 minutes.  at 0 C The reaction mixture is poured into 21 ice water and 300 ml of 1N hydrochloric acid, the precipitate formed is filtered off and washed with water.  It is dried in air, giving 2.6 g of 7a-bromo-1 6a-methyl-1, 4-pregnadiene-11ss, 1 7a, 2 1 -triol-3.20 dione-17,21-dipropionate. 

  It is purified by recrystallization from acetone ether hexane.  1.44 g; Melting point> 295 C; [α] D26 + 37.3 (dimethylformamide); # maxMethanol 242 nm (# 15. 350); vNnuixol 1743, 1735, 1660, 1612, 16OOcm - '; NMR (DMSO-d6) 6 0.85 (C16-CH3, d J 7 Hz), 1.03 (Cs3-CH3, s), 1, 43 (CIo-CH3, s), 4.38 (1 lo-H, Mult. ), 4.75 (7ss-H), mult. ), 4.81 (C21-H, s), 5.86 (C4-H, s), 6.19 (Cs-H, ddJ 10.2 Hz7), 7.31 (C, -H, dJ 10Hz ). 



  Example 3 7α-Bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-1 7-benzoate-2 1 -acetate
A. To 0.31 g of 16α-methyl-1,4,6-pregnatriene-11ss, 17α, 21-triol-3,20-dione-1 7-benzoate-2 1 -acetate is added a solution of 30% dry Hydrogen bromide in glacial acetic acid (6.2 ml) at 0 C.  After 1 hour at 0 C, the mixture is poured into ice water, the precipitate formed is filtered off, washed with water and dried in air.  It is purified by thin layer chromatography on silica gel using ether: hexane (2: 1) as the developing solvent, the band recognizable by UV light, which contains the desired product, being eluted with ethyl acetate.  The combined ethyl acetate eluates are evaporated, the desired compound being obtained as a residue. 

  The residue is further purified by trituration with isopropyl ether (yield 0.125 g). 



   The connection of this example can also be made by the following methods 3B and 3C. 



  B.  7a-bromo-1 6a-methyl-1, 4-pregnadiene-l 7α, 21-diol-3,11,20-trione-1 7-benzoate-2 1 -acetate
To a freshly prepared solution of 9.3 g of dry hydrogen bromide gas in 16 ml of glacial acetic acid, a solution of 1.56 g of l6a-methyl-l, 4,6-pregnatriene-17a, 21 -diol-3,11, is added dropwise at 0 ° C. 20-trione-17-benzoate-21 acetate in 5 ml of glacial acetic acid. 



  The mixture is stirred for 1 hour at 0 ° C., poured into ice water, the aqueous mixture is stirred for 30 minutes, the precipitate formed is filtered off, washed with water and dried in air, 1.6 g of 7α-bromine being 16? -Methyl-1,4-pregnadiene-17a, 21-diol-3, 11,20-trion-l 7-benzoate-21-acetate.  It is further purified by recrystallization from acetone: hexane. 



  Melting point 190-192.5 ° C; [a] 26 + 77.3 (dimethylforma mid); # maxMethanol 232 nm (s 27. 600). 



     C.  7a-bromo-1 oa-methyl-l, 4-pregnadien-1113.1 7α, 21-triol-3,20-dione-17-benzoate-21-acetate
1.  To a mixture of 1.05 g of 7a-bromo-1 6a-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17-benzoate-21 acetate and 0.1 g of sodium borohydride a previously cooled solution of 7.5 ml of tetrahydrofuran and 2.5 ml of methanol is added under a nitrogen atmosphere at 0 ° C. and the reaction mixture is stirred at 0 ° C. for 25 minutes. It is poured into 500 ml of ice water and 100 ml of 1N hydrochloric acid.  The precipitate formed is filtered off, washed with water and dried in air, giving 0.53 g of the desired compound.  It is further purified by recrystallization from acetone: hexane: ether. 

  Melting point 156-159 C; [α] D26 + 21.1 (dimethylformamide; #maxMethanol 233 nm (± 26. 800); NMR (DMSO-d6) 80.89 (Cl6-CH3, d J 7 Hz), 1.12 (CI3-CH3, s), 1.48 (Clo-CH3, s) 2.13 (OAc, s), 4.46 (11α-H, mult. ), 4.96 (C21-H, quart. ), 4.90 (7ss-H, Mult. ), 6.00 (C4-H, s), 6.28 (C2-H, d, d J 10.2 Hz), 7.39 (C, -H, d, J 10 Hz), 7.50 -8.00 (phenyl, mult. ). 



   2nd  The compound of this example can also be prepared as follows: To a mixture of 0.65 g of 7a-bromo-16a methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-benzoate -21- Acetate and 61.7 mg of sodium borohydride are added at room temperature under nitrogen to 6.2 ml of dimethylformamide and 0.3 ml of water.  Stir for 1 hour  at room temperature under nitrogen and poured into a mixture of 200 ml of water and 50 ml of hydrochloric acid.     The precipitate formed is filtered off, washed with water and air-dried to obtain the desired compound.  It is further purified by recrystallization from ether: acetone. 



  Example 4 7α-chloro and 7α-bromo-11-oxo-1,4-pregnadiene-17α, 21-diol-3,20-diones and their esters A. 7a chlorine derivatives
The following 1 1-oxo-1,4,6-pregnatrienes are treated with dry hydrogen chloride in tetrahydrofuran in the manner described in Example 1B:

  :
The 21-acetate, 21-n-butyrate, 21-isobutyrate, 21-valerate, 21-caprylate, 21- (l'-adamantyl) carboxylate, 21- (1'-adamantyl) - acetate, 21-benzoate and 21-p-methoxybenzoate esters of 16α-methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-17-propionate, the 21st Acetate, 21-n-butyrate, 21-isobutyrate, 21-valerate, 2 l-caprylate, 2 l- (1'-adamantyl) carboxylate, 21- (l'-adamantyl) acetate, 21 benzoate and 21 p-methoxybenzoate esters of 1 oa-methyl-l, 4,6-pregnatriene-l 7a, 21-dio13,11, 20-trione-l 7-n-butyrate, the 21st 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 1 Ga-methyl-l, 4,6-pregnatriene-l 7a, 21-dio13,11, 20-trion-l 7-benzoate, 16a-methyl-1, 4,6-pregnatriene-l 7a, 21-diol-3,1 1,20-trione-17,21-diacetate, the 21-acetate, 21 21-propionate and 23 1-valerate esters of 16α-methyl 1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-17-valerate;
16α-methyl-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-17-isobutyrate-21-acetate and 16α-methyl-1,4,6-pregnatriene-17α ;

  ;, 21-diol-3,11,20-trione-17dodecanoate-21-propionate and the 16ss epimers and 1 6-unsubstituted analogues of the above-mentioned compounds and the 16-methylene derivatives corresponding to the above-mentioned compounds
The products obtained are each isolated and purified in the manner described in Example 1B, the following compounds being obtained:

   21-acetate, 21-n-butyrate, 21-isobutyrate, 21-valerate, 2 l-caprylate, 2 l- (l'-adamantyl) carboxylate, 21- (1'-adamantyl) ) acetate, 21-benzoate and 21-p-methoxybenzoate esters of 7α-chloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-propionate , the 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 7α-chloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-n- butyrate, the 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 7?

  ; Chloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-benzoate, 7a-chloro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17,21-diacetate, the 2 liter acetate, 21-propionate and 21-valerate esters of 7α-chloro-16α-methyl-1,4-pregnadiene-17α ;, 21-diol-3,11,20-trion1 7-valerate,
7α-chloro-16α-methyl-1,4, -pregnadiene-17α, 21-diol-3,11,20-trione-17-isobutyrate-21-acetate and 7α-chloro-16α-methyl- 1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-dodecanoate-21-propionate and the 16ss epimers and 1 6-unsubstituted analogues of the above-mentioned compounds and the corresponding 1 6 Methylene derivatives. 



  B.  7a bromo derivatives
In a similar manner to that described in Examples 2B and 3B, the starting compounds mentioned in Example 4A are treated with dry hydrogen bromide in glacial acetic acid.  The products obtained in each case are isolated and purified in the manner described in Examples 2B and 3B, the 7a-bromo derivatives corresponding to the 7a-chlorine products of Example 4A being obtained in each case. 



   For example, the following compounds in particular can be obtained by the process described in Example 4 (A) or 4 (B): 7-chloro-1,4-pregnadiene-17a, 21-diol-3,1 1,20-trione-21 -ace- tat, melting point 220-221 C; [a] D6 + 113.3 (dimethylforma mid); XmMaexOH238 nm (r = 15. 000). 



   7a-chloro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20 trione-21-acetate; [α] D26 + 101.6 (dimethylformamide); # maxMeOH 240 nm (# = 15. 350). 



      7a-chloro-16ss-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-21-acetate, melting point 175-178 C; [α] D26 + 134.3 (dimethylformamide) #maxMeOH 237 nm (± = 17. 450). 



      7a-chloro-16ss-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17-benzoate-21-acetate, melting point 209 C (dec. ); [α] D26 + 124.7 (dimethylformamide); #maxMeOH 233 nm (± = 30. 000). 



      7cl-bromo-1, ppregnadiene-17a, 21-diol-3.1, 1.20-trione-17-acetate; Melting point 168 C (decomp. ); [a] D6 + 100.70 (dimethylformamide). 



      7a-bromo-l 6a-methyl-1,4-pregnadiene-17a, 21-diol-3, 11,20-trione-17,21-dibenzoate, melting point> 285 C; #maxMeOH 231 nm (± = 31. 500); [α] D26 + 65.80 (dimethylformamide). 



   7α-bromo-16ss-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17-benzoate-21-acetate, melting point 160 C (dec. ); [α] D26 + 131.9 (dimethylformamide); #maxMeOH 235nm (c = 28. 400).    



   Example 5
7a-chloro- and 7a-bromo-l 1 1P-hydroxy-l, 4-pregnadiene-l 7a, 21-diol-3,20-dione and their esters A.  By reducing the 1 1-keto analogues
In a similar manner to that described in Examples 1C, 2C and 3C, the products prepared in Example 4 are treated
7a-chloro and 7α-bromo-11-oxo-1,4-pregnadienes with sodium borohydride in tetrahydrofuran and methanol at 0 C under a nitrogen atmosphere and isolate and purify the products obtained in the manner described above, taking the following Connections receives:

  :
The 7a-chloro and 7a-bromo derivatives of the 21-acetate, 21-n-
Butyrate, 21-isobutyrate, 21-valerate, 21-caprylate, 21- (l'-adamantyl) carboxylate, 21- (l'-adamantyl) acetate, 21-benzoate and 21-p -Methoxybenzoate ester of 16α-methyl-1,4-pregadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate, 16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-n-butyrate and
16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate, the 7a-chloro and 7a-bromo derivatives of 16a-methyl-1,4-pregnadiene-l 113.1 1 P, 17a, 21-triol-3, 20aion-l 7,21-diacetate, the 7a-chloro and 7a-bromo derivatives of the 21-acetate, 21-propionate and 21-valerate esters of 16a -Methyl-l, 4-pregnadiene-11ss, 17?

  ;, 21-triol-3,20-dione-17-valerate, the 7a-chloro and 7a-bromo derivatives of 16a-methyl-1,4-pregnadien-11ss. 17α, 21-triol-3,20-dione-17-isobutyrate-21-acetate, the 7a-chloro and 7a-bromo derivatives of l6a-methyl-l, 4-pregnadiene-11ss, 17α, 21-triol- 3,20-dione-17-dodecanoate-21-propionate and the 16ss epimers and 16-unsubstituted analogues of the above-mentioned compounds and those corresponding to the 16-methylene derivatives. 



   B.  Alternatively, the compounds of this example are treated by treating the corresponding 11 ss-hydroxy-7-unsubstituted. 1,4,6-Pregnatrien, e.g. B.  of 21-acetate, 21-pivalate and 21-benzoate of 16a-methyl-1,4-pregnadiene-l 11ss, 17α, 21-trio13, 20-dione, with hydrogen chloride or hydrogen bromide to those in Examples 1A, 1B and 1C and isolation and purification of the products obtained in each case were prepared in the manner described, the corresponding 7a-chloro and 7α-bromo-1,4-pregnadienes being obtained. 

  For example, the following compounds in particular can be prepared by the method of Example 5 (A) or 5 (B): 7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3, 20-dione-21-acetate, melting point 197-203 C; [a] 26 +49.9 (dimethylformamide); ÄmMax0OH 242 (± = 14. 300). 



      7α-Chloro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate, melting point 230-233 C; [α] D26 +60.8 (dimethyl formamide ; #maxMeOH 243 nm (± = 11. 600). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α-triol-3,20-dione-17,21-dibenzoate, melting point 230-234 C; #maxMeOH 232 nm (± = 39. 800; [α] D26 + 30, So (dimethylformamide). 



   7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-benzoate, [M] +514, 512. 



      7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-n-butyrate-21-propionate; Melting point 155-160 C; [M] +536, 534. 



      7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-di-n-butyrate [M] + 550, 548; Melting point 145-147 C; #maxMeOH 240nm (# = 16. 500); [α] D26 + 40.2 (dimethylformamide). 

 

      7α-chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate, melting point 195-198 C; [a] 26 + 69.3 (dimethylformamide); # maxMeOH 235nm (# = 27. 000). 



      7α-chloro-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate, melting point 125-130 C; [a] 26 +31.3 (dimethylformamide); #maxMeOH 240 nm (± = 16. 000).   



      7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-isobutyrate; [M] + 536, 534; NMR (DMSO-d6) Ï 0.84, 1.04, 1.44, 4.69, 5.99, 6.24, 7.37. 



      7α-chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-n-butyrate; NMR (DMSO-d6) # 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-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-valerate; melting point 134-137 C; [α] D26 +37.5 (dimethylformamide); # maxMeOH 240nm (# = 13. 700). 



     
7a-chloro-16α-methyl-1,4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione-17-isobutyrate-21-acetate; [M] + 522,520. 



     
7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate; [M] + 556, 554; NMR (DMSO-d6) Ï 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-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate; NMR (DMSO-d6) 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-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-acetate; [M] + 508, 506; NMR (DMSO-d6) Ï 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-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-n-butyrate; [M] + 536, 534; NMR (DMSO-d6) Ï 0.85, 1.02, 1.44, 4.69, 5.99, 6.25, 7.37. 



     
7α-Chloro-16α-methyl-1,4-pregandien-11ss, 17α, 21-triol-3,20-dione-17-valerate-21-acetate; [M] + 536,534. 



     
7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17n-butyrate-21-acetate; [M] + 522, 520. 



     
7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-pivalate; melting point 227-230 C; #maxMeOH 243nm (# = 13. 900); [M] + 494,492. 



     
7α-Chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate, melting point 228 C (dec. ); [α] D26 + 78.3 (dimethylformamide); #maxMeOH 241 nm (± = 15. 500). 



     
7α-chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate;    125 C (dec. ); [α] D26 + 74.4 (dimethylformamide); # maxMeOH 241 nm (# = 15. 200). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate; [M] + 600,598; Melting p.  170 C (dec. ); [α] D26 + 72.8; #maxMeOH 235 nm (# = 26. 500). 



     
7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-n-butyrate-21-propionate, melting p.  147 C (dec. ); [α] D26 +30.8 (dimethylformamide); # maxMeOH 243 nm (# = 15. 600). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-di-n-butyrate;    143-146 C; [α] D26 + 31.8 (dimethylformamide); # maxMeOH 243 nm (# = 15. 600). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-propionate, melting p.    163-170 C; [α] D26 +27.1 (dimethylformamide); # maxMeOH 233 nm (# = 27. 900). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-n-butyrate, melting point 138-144 C; [α; ] D26 +24.2 (dimethylformamide); # maxMeOH 234 nm (# = 27. 100). 



      7α-bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate [α] D26 + 29.8 (dimethylformamide); # maxMeOH 242 nm (( ± = 15. 700). 



     
7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate; #maxMeOH 244nm (# = 13. 700); [M] + 496.494. 



      7α-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate;  165 C (dec. ); [α] D26 + 64.6; #maxMeOH 242 nm (± = 15. 600). 



      7α-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate;    135-137 C; [α] D26 + 66.4 (dimethylformamide); # maxMeOH 242 nm (# = 15. 500). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-acetate [M] + 552,550. 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-n-butyrate; [M] + 580,578; melting point 153- 155 C; [α] D26 + 34.7 (dimethylformamide); # maxMeOH 241 nm (± = 15. 800).    



      7a-bromo @ 6α-methyl-1,4-pregnadiene-11 11 ss, 17a, 21-triol-3,20-dione-17-n-butyrate-21-acetate. 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-valerate-21-acetate; [M] + 580,578. 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-valerate. 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-isobutyrate, melting point 168-172 C; [M] + 580,578; [α] D26 + 36.3 (dimethylformamide); # maxMeOH 240 nm (# = 15. 500). 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, triol-3,20dione-17-propionate-21-acetate; [M] + 552,550; NMR (DMSO-d6) # 0, 90, 1.44, 4.89, 5.96, 6.25, 7.38. 



      7α-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate-21-butyrate, melting point 145 C; [M] + 580, 578; NMR (DMSO-d6) Ï 0.94, 1.28, 1.44, 4.90, 4.61, 4.45, 5.98, 6.28, 7.39. 



  Example 6 7a, 9a, 11 ss-trihalogen-1,4-pregnadiene-17a, 21-diol-3,20-dione-17,21-hydrocarbon carboxylates A.    7α-Chloro-16α-methyl-1,4,9 (11) pregnatrien-17α, 21-diol, 3,20-dione-17,21-dipropionate
1.  To 0.37 g of 7α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate in 11.1 ml of dimethylformamide and 0, 67 ml of collidine are added to 0.22 ml of a 3.5% solution of sulfur dioxide in methanesulfonyl chloride.  The reaction mixture is stirred at 0 C for 30 minutes and then at room temperature for 30 minutes. 

  Aqueous 1N hydrochloric acid is added, the reaction mixture is extracted with ethyl acetate, the combined organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the desired compound as a residue.  The residue is purified by trituration with ether and filtration of the precipitate formed.  Melting point 198-201 C.    [α] D26 + 26.3 (dimethyl formamide); # maxMeOH 238 nm (# = 16. 500). 



   2nd  7a-Bromo-16a-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate and 7α-bromo-16α-methyl- are treated in a similar manner. 1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate in dimethylformamide and collidine with a 5. 5% solution of sulfur dioxide in methanesulfonyl chloride, whereby 7a-bromo-16a-methyl-1,4,9 (11) -pregnatrien-17α, 21-diol-3,20dione-17,21-dipropionate or    7α-bromo-16α-methyl-1,4,9 (11) -pregnatrien-17α, 21-diol-3,20-dione-17-benzoate-21-acetate. 



  B.    7a, 9a, 11 11ss-trichloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione-17,21-dipropionate
1.  To a solution of 0.18 g of 7α-chloro-16α-methyl-1,4,9- (11) -pregnatrien-17α, 21-diol-3,20-dione-17,21-dipropionate in 5 ml of chloroform and 0.9 ml of pyridine are added to a solution of 28 mg (1.1 equivalent) of dry chlorine gas in 4 ml of chloroform and the mixture is left to stand at room temperature for 3 hours. 



  300 ml of methylene chloride are added, the reaction mixture is washed successively with 10% aqueous sodium thiosulfate solution, in hydrochloric acid and water, and is dried over magnesium sulfate and evaporated.  The residue obtained is purified on silica gel by thick layer chromatography, using chloroform; ethyl acetate (9: 1) as the developing solvent.  The smallest polar band visible in UV light is removed and eluted with ethyl acetate.  The combined ethyl acetate eluates are evaporated, the desired compound being obtained as a residue.  It is further cleaned by triturating with acetone and filtering off the triturated precipitate.  Melting point 225-228 C.    #maxMeOH 236 nm (# = 15. 600). 

 

   2nd  In the same way, the 7α-bromo-1,4,9 (11) -pregnatrienes prepared according to Example 6A (2) are treated with chlorine, 7α-bromo-9α, 11ss-dichloro-16α-methyl being used -1,4-pregnadiene-17a, 21 -diol-3,20-dione-17,21 -dipropionate or  7a-bromo 9α, 11ss-dichloro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione-17-benzoate-21-acetate. 



  C.  7a, 9a-dichloro-11 ss-fluoro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3. 20-dione-17,21-dipropionate
1.  To a solution of 0.5 g of 7a-chloro-16a-methyl-1,4,9 (1 1) pregnatrien-17α, 21-diol-3,20-dione-17,21-dipropionate in 10 ml of chloroform and 1 ml of pyridine is given a solution of 5 g of hydrogen fluoride in 5 ml of tetrahydrofuran and then
128 mg of N-chlorosuccinimide.  The reaction mixture is diluted with enough methylene chloride to form a solution and the reaction mixture is stirred for 48 hours at room temperature.  The reaction mixture is poured into aqueous sodium carbonate, the aqueous mixture is extracted with methylene chloride, the combined organic extracts are washed successively with water, diluted with hydrochloric acid and then with water. 

  It is dried over magnesium sulfate, filtered and evaporated to give the desired compound as a residue. 



   The residue is purified by trituration with ether, filtration and recrystallization from acetone: hexane. 



   2nd  The 7a-bromo-1,4,9 (11) -pregnatrienes prepared according to Example 6A (2) in chloroform are treated in the same way with hydrogen fluoride and N-chlorosuccinimide in the presence of pyridine and the products formed are isolated, 7a -Brom-9a-chloro-1 P-fluoro-l aa-methyl-l, 4-pregnadiene-17α, 21-diol-3,20-dione-17,21-dipropionate or    7α-bromo-9α-chloro-11ss-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,20-dione-17-benzoate-21-acetate. 



  D.    7α-Chloro-9α-bromo-11ss-fluoro-16α-methyl-1,4-pregnadiene-17a. 21-diol-3,20-dione-17,21-dipropionate
1. To a solution of 0. 5g of 7α-chloro-16α-methyl-1,4,9- (11) -pregnatriene-17α, 21-diol-3,20-dione-17,21-dipropionate in 10 ml of chloroform and 1 ml of pyridine a solution of 5 g of hydrogen fluoride in 5 ml of tetrahydrofuran and then 130 mg of N-bromoacetamide.  Dilute the reaction mixture with enough methylene chloride to form a solution and stir for 48 hours at room temperature.  The reaction mixture is poured into aqueous sodium carbonate, the aqueous mixture is extracted with methylene chloride and the combined organic extracts are washed successively with water, dilute hydrochloric acid and water. 

  The solution is dried over magnesium sulfate, filtered and evaporated.  The residue obtained is dissolved in acetone: ether and filtered through a column of Florisil and eluted with water.  The eluates are combined and evaporated under reduced pressure, the desired compound being obtained as a residue. 



   2nd  By using the 7α-bromo-1,4,9 (11) -regnatrienes prepared according to Example 6A (2) as starting compounds in the process described above, 7α, 9α-dibromo-11ss-fluoro-16α-methyl is obtained -1,4-pregnadiene-17α, 21-diol-3,20-dione-17,21-dipropionate or    7α, 9α, - dibromo-11ss-fluoro-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-17-benzoate-21-acetate.    



  E.    7a, 11 ss-dichloro-9a-bromo-16a-methyl-1,4-pregnadiene-17a, 21-diol-3,20-dione-17,21-dipropionate
1.  To a solution of 0.5 g of 7α-chloro-16α-methyl-1,4,9 (11) pregnatrien-17α, 21-diol-3,20-dione-l 7,21-dipropionate in 10 ml of chloroform and 1 ml of pyridine are added with stirring at -20 C 130 mg of N-bromoacetamide and a solution of 100 mg of hydrogen chloride in 5 ml of tetrahydrofuran.  The mixture is stirred for a further 15 minutes at -20 ° C., the reaction mixture is allowed to warm to room temperature and is left to stand for a further 15 minutes at room temperature. 

  Additional methylene chloride is added to the reaction mixture and it is washed with thiosulfate solution, water, 10% aqueous sodium bicarbonate and finally with water.  It is dried over magnesium sulfate, filtered and evaporated under reduced pressure.  The residue obtained is recrystallized from acetone: hexane, giving the desired compound. 



   2nd  In the process described above, 7α-bromo-1,4,9 (11) -pregnatrienes prepared according to Example 6A (2) are obtained as starting compounds 7α, 9α-dibromo-11ss-chloro-16α-methyl -1,4-pregnadiene-17α, 21-diol-3,20-dione-l 7,21-dipropionate or    7a, 9a-dibromo-l 13-chloro-16a-methyl-1,4-pregnadiene-17a, 21 -diol-3,20-dione- 17-benzoate-
21 acetate. 



   F.  The products prepared according to Example 5 are treated
7a-chloro and 7a-bromo-1 1 lss-hydroxy-1,4-pregnadiene-17a, 21 diol-3,2O-dione in the manner described in Example 6A and then sets the 7a-chloro and 7a Bromine 1,4,9 (11) -pregnatrien-17α, 21-diol-3,20-dione with chlorine in the manner described in Example 6B or with a mixture of
Halogenating agents to that described in Example 6C-6E
Way, whereby the corresponding 7a-chloro and 7o-bromo-9x, 11 ss-dihalogen-1,4-pregnadiene-17a, 21-diol-3,20-dione, e.g. B.    7a, 9a, Ilss-Trichlor-l, 4-pregnadien-17a, 2 1-diol-3,20-dione-2 l-acetate of melting point 299-301 C, is obtained.    [a] 26 +71.1 "(dimethylformamide);

  ; ÄmMae2H 239 nm (e = 14. 500). 



   Example 7 7α-Chloro-9α-halo-1,4-pregnadiene-17α, 21-diol-3,20-dione A.    7α-Chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss-17α, 21-triol-3,20-dione-21-acetate
To 0.5 g of 9α-fluoro-16α-methyl-1,4-pregnadiene-7ss, 1 lp, 17a, 21-tetrol-3,20-dione-2 l-acetate in 100 ml of methylene chloride is added at 0 C under a nitrogen atmosphere 1.67 ml of N, N-diethyl-1,2,2-trichlorovinylamine.     The mixture is stirred at 0 C for 7 hours, evaporated under reduced pressure, the residue obtained is applied to a column of 50 g of silica gel and eluted with chloroform: ethyl acetate (3:

  :1).     The same fractions are combined which contain the desired compound, determined by thin layer chromatography, and the mixture is evaporated. 



  The residue obtained is further purified on thin-layer silica gel plates, developing with chloroform: ethyl acetate (3: 1).  Remove the band visible in UV light, which contains the desired product, and elute with ethyl acetate.  The eluate is evaporated, the desired compound being obtained as a residue.  It is further purified by recrystallization from acetone: hexane.  [M] + 470, 468; NMR (DMSO-d6) 0.82, 0.90, 1.50, 4.17, 4.55, 4.95, 6.09, 6.27, 7.32. 



   B.  According to the method described in Example 7A, but using the 9a-chloro and 9a-bromo analogues of the 9α-fluor-7ss-hydroxy-1,4-pregnadiene compound used, the corresponding 7a-chloro derivatives, namely 7α, are obtained ;, 9α, - dichloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate or    7α-Chloro-9α-bromo-16α-methyl-1,4-pregnadiene-1113,1 7a, 2 l-triol-3,2O-dione-2 l-acetate.    

 

   C.  In the same manner, but using the 7ss-hydroxy derivatives produced according to production process 11, 7α-chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α is obtained in the process described in Example 7A ;, 21-triol-3,20-dione-17,21-dipropionate, 7α-chloro-9αfluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3.20 -dione-17-benzoate-21-propionate, 7α-chloro-9α-fluro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione17-n -butyrate-21-propionate, its 9a-bromo and 9a-chloro analogues, its 16ss methyl epimers and 1 6-unsubstituted analogs and the 16-methylene derivatives corresponding to these compounds.   



  Example 8 7a-Fluoro-1,4-pregnadiene-3,20-dione A.    7a-fluoro-la a-methyl-l, 4-pregnadiene-llss, l 7a, 21-triol-3,20-dione-2 1 -acetate To 0.13 g of 16a-methyl-1,4-pregnadiene-7ss , 11 ss, 17a, 21 -tetrol-3,20-dione-21-acetate in 15 ml methylene chloride are added at 0 C under a nitrogen atmosphere 0.286 ml N- (2-chloro-1,1,2-trifluoroethyl) -diethylamine (Fluoramine).  The mixture is stirred at 0 C for 18 hours, then evaporated under reduced pressure and the residue obtained is purified by thin layer chromatography, eluting with chloroform: ethyl acetate (5: 2) and a mixture of 7a-fluoro-16a-methyl-1,4- pregnadia
1113.1 ss, 17a, 21-triol-3,20-dione-21-acetate and 16α-methyl-1,4,6-pregatratrien-11ss, 17α, 21-triol-3,20-dione -21-acetate is obtained. 

  This mixture (55 mg) in 0.58 ml of dioxane and 3 drops of pyridine is treated with 10 mg of osmium tetroxide for 5 days at room temperature.  The reaction mixture is saturated with hydrogen sulfide, the reaction mixture is filtered, the filtrate is evaporated under reduced pressure at room temperature and the residue obtained is purified by thin layer chromatography on silica gel, developing with chloroform: ethyl acetate (2: 1).  The combined eluates containing the desired product are evaporated and the residue obtained is triturated with ether: hexane, giving 7α-fluoro-16α-methyl-1,4-pregnadiene-l 113.1 7a, 2 14riol-3,2O-dione-2 1 acetate is obtained.  [M] + 434; NMR (DMSO-d6) 0.80, 0.91, 1.42, 4.36, 4.89, 4.92, 5.99, 6.21, 7.37. 



  B.    7α, 9α-difluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate
To 0.35 g of 9a-fluoro-16a-methyl-l, 4-pregnadiene-713.1 1ss. 17α, 21-tetrol-3,20-dione-21-acetate in 350 ml of methylene chloride is added at 0 C under a nitrogen atmosphere to 0.76 ml of fluoramine.  The mixture is stirred at 0 C for 24 hours and the reaction mixture is evaporated under reduced pressure.  The residue obtained is subjected to thin layer chromatography on silica gel, developing with chloroform: ethyl acetate (2: 1) and eluting the band which can be seen in UV light and which contains the desired product with ethyl acetate.  The combined eluates are evaporated, the desired compound being obtained as residue. 

  It is further purified by recrystallization from acetone, methanol: hexane.  Melting point 234 to 237 C; [a] 26 +45.4 "(dimethylformamide).    



   C.  In the same way, by treating the 7ss-hydroxy1,4-pregnadienes obtained according to production process 11 with fluoramine in the manner described in Examples 8A and 8B, the corresponding 7a-fluoro-1,4pregnadienes, e.g. B.       7a-fluoro-l, 4-pregnadiene-l 113.1 7a, 2 1-triol-3.20-dione-21-acetate of melting point 243-246 C.    [a] D6 +62.7. 



   Example 9 7a-iodine-9a-unsubst. - 1,4-pregnadien-3,20-dione A.    7α-iodo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-2 1 -acetate 0.1 g of 16a-methyl-1,4,6 is added -pregnatrien-l 1ss, 17α, 21-triol-3,20-dione-21 acetate to a solution of 0.512 g of dry hydrogen iodide in 2 ml of glacial acetic acid and the reaction mixture is stirred for 50 minutes at room temperature.  It is poured into ice water, the precipitate is filtered off and dried, it is triturated with ether, the solid is filtered off, dissolved in methylene chloride, the methylene chloride solution is washed with aqueous 0.1N sodium thiosulfate solution and with water, dried over magnesium sulfate and evaporated under reduced pressure. 

  The residue obtained is triturated with hexane and filtered to give the desired compound (8 mg); [M] + 542. 



  B.  In the same way, the 9-unsubstituted 1,4,6-pregnatrien-3,20-diones prepared according to production processes 1 to 10 are treated with hydrogen iodide in acetic acid in the manner described in Example 9A, the corresponding 7α - Iodine-9-unsubst. -1,4-pregnadiene-3,20-dione, e.g. B.    



      7α-iodine-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate, melting point 150 C (dec. ), [a] D6 +22.0 (dimethylformamide), #maxMeOH 241 nm (# = 14. 500), its 16ss analog [α] D26 + 52.0 (dimethylformamide), #maxMeOH 241 nm (# = 14. 500) and 7α-iodo-16α-methyl-1,4, -pregnadiene
11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate [α] D26 + 34.3 (dimethylformamide); #maxMeOH 233 nm (± = 24. 400) receives. 



   Example 10 7a-bromo-9a-halogen-1,4-pregnadiene-3,20-dione A.    7α-bromo-9α-fluoro-16α-methyl-1,4-pregnadiene-11 ss, 17a, 21 - triol-3,20-dione-21-acetate
To a solution of 0.1 g of 7ss-hydroxy 9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21α, 21-triol-3,20-dione-21-acetate and cooled to 0 C and 0.1 g of lithium bromide in 100 ml of methylene chloride is added to 0.23 ml of fluoramine.  The mixture is stirred at 0 C for 24 hours and then evaporated under reduced pressure.  The residue obtained is dissolved in chloroform, the chloroform solution is washed with water, dried over magnesium sulfate and evaporated. 

  Purify by thin layer chromatography using chloroform: ethyl acetate (2: 1) as the developing solvent.  Remove the band visible in UV light, which contains the desired product, and elute with ethyl acetate.  The combined ethyl acetate eluates are evaporated under reduced pressure, the desired compound being obtained as a residue. 



   B.  In the manner described in Example 10A, but using the 9a-chloro and 9a-bromo analogs of the 9α-fluoro-7ss-hydroxy-1,4-pregnadienes used, the corresponding 7a-bromo derivatives, namely 7a-bromo 9a-chloro-16a methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-21-acetate and 7a, 9a-dibromo-16a-methyl-1,4-pregnadiene-l 113 , 1 7a, 2 1 -triol-3,20-dione-21-acetate. 



   C.  In the same way, the 7ss-hydroxy obtained in accordance with the production process 11 is obtained by treatment
1,4-pregnadienes with fluoramine and lithium bromide in the manner described in Example 10A the corresponding 7a-bromine
1,4-pregnadiene derivatives. 



   D.  In the process described in Example 10A, using an equivalent amount of lithium chloride instead of lithium bromide and using tetrahydrofuran instead of methylene chloride as solvent, the corresponding 7a-chloro compound, i.e. H.  7a-chloro 9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione21 acetate.    



  Example 11 7a-Halogen-21-deoxy-1,4-pregnadiene-3,20-diones and certain 21-ester derivatives A.    7a-chloro-21-deoxy-1,4-pregnadiene-3,20-dione 1.    7a-chloro-l, 4-pregnadiene-l 7a-ol-3,20-dione and its 17-acetate
To 0.5 g of 17a-hydroxy-l, 4,6-pregnatrien-3,20-dione are added 20 ml of glacial acetic acid, which is saturated with dry hydrogen chloride gas, and 2 g of lithium chloride.  The mixture is stirred for 45 minutes at room temperature and then the mixture is poured into an aqueous sodium carbonate solution and the aqueous mixture is extracted with ether.  The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated to give 7α-chloro-1,4-pregnadiene-17α-ol-3,20-dione as a residue.  It is purified by recrystallization from methanol. 

 

  Melting point 229-231 C.    [a] D6 +50.7 (dioxane). 



     7a-chloro-l 7a-acetoxy-l, 4-pregnadiene-3,20-dione (melting point 200-206 C; [α] D26 +4.8 (dimethylforma mid); # maxMeOH 242 nm (# = 16. 100)) can be prepared in the same way from 17α-acetoxy-1,4,6-pregnatrien-3,20-dione. 



   2nd  In the process described above, if the starting compounds used are 17-propionate, 17-n butyrate, 17-valerate and 17-benzoate of 1,4-pregnadiene-11 ss, 17a-diol-3,20-dione, the corresponding 7a-chloro derivatives, namely the 17-propionate, 17-n-butyrate, 17-valerate and 17-benzoate of 7α-chloro-1,4-pregnadiene-11 ss, 17a-diol-3,20-dione.    



  B.    7α-Bromo-21-deoxy-1,4-pregnadiene-3,20-dione I.     In the process described in Example 11A (I), but using an equivalent amount of dry hydrogen bromide instead of dry hydrogen chloride and an equivalent amount of lithium bromide instead of lithium chloride as reagents, the corresponding 7a-bromo derivative is obtained. H.    7α-bromo-1,4-pregnadiene-17α-ol-3,20-dione. 



     7α-Bromo-17α-acetoxy-1,4-pregnadiene-3,20-dione ([α] D26 + 5.7 (dimethylformamide); # maxMeOH 242 nm (# = 14. 000)) can be prepared in the same way from 17a-acetoxy-1,4,6 pregnatrien-3,20-dione. 



   2nd  The starting compounds of Example I IA (2) are each treated with dry hydrogen bromide and lithium bromide in glacial acetic acid in the manner described in Example 11 B (I), the 17-propionate, 17-n-butyrate, 17-valerate and    17-benzoate of 7α-bromo-1,4-pregnadiene-1 Iss, 17a-diol-3. 20-dione receives. 



  C.    7? -Fluoro-21-deoxy-1,4-pregnadiene-3,20-diones and certain 21-ester derivatives
1,4-Pregnadien-7ss, 17α-diol-3,20-dione and the 17-propionate, 17-n-butyrate, 17-valerate and 17-benzoate of 1 are each treated in the manner described in Example 8A. 4-pregnadiene-7ss, 11 ss, 17a-triol-3,20-dione with fluoramine in methylene chloride under a nitrogen atmosphere.  The products obtained are isolated and purified in the manner described, 7α-fluoro-1,4-pregnadiene-17α-ol-3,20-dione or  17-propionate, 17-n-butyrate, 17-valerate and 17-benzoate of 7α-fluoro-1 1,4-pregnadiene-11 ss, 17a-diol-3,20-dione.    



     7α-fluoro-17α-acetoxy-1,4-pregnadiene-3,20-dione (melting point 262-265 C) and 7α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate (melting point 157-161 C; [α] D26 + 32.9 (dimethylformamide); # maxMeOH 240nm (± '= 15. 900)) can be prepared in the same way from 1,4-pregnadiene-7ss, 17α-diol-3,20-dione-17-acetate and 16α-methyl-1,4-pregnadiene-7ss, 11ss, 17α ;, 21-tetrol-3,20-dione-17,21-dipropionate. 



  D.    7α-iodine-21-deoxy-1,4-pregnadiene-3,20-dione
In the manner described in Example 9A, the Pregnatrienverbindungen used in Examples 11A (1) and 11A (2) are treated with hydrogen iodide in glacial acetic acid and the products obtained in each case are isolated in the manner described, 7a-iodo-1,4-pregnadiene -17a-ol-3.20-dione or  the 17-propionate, 17-n-butyrate, 17-valerate and 17-benzoate of 7α-iodo-1,4-pregnadiene-11ss, 17α-diol-3,20-dione. 



     7α-iodine-17α-acetoxy-1,4-pregnadiene-3,20-dione (melting point 144 C (dec. ); [α] D26-3.5 (dimethylformamide); # maxMeOH 242 nm (g = 15. 100)) can be prepared in the same way from 17a-aceto-toxy-1,4,6-pregnatrien-3,20-dione. 



  Example 12 7α, 21-Dihalogen-1,4-pregnadiene-3,20-dione A.    7? -Chloro-21-halogen derivatives I.  oa-methyl-l, 4-pregnadiene-ll ss, 17a-diol-3,20-dione-17-propionate is obtained by reacting 16a-methyl-21-chloro-1,4,6-pregnatrien-11ss, 17α, diol-3,20-dione-17-propionate prepared with dry hydrogen chloride gas in dioxane in the manner described in Example IA.    [M] + 458, 456, 454. 



   2nd  Using the 21-fluoro and 21-bromo analogues of the 21-chloro compound used as the starting compound in the process of Example 12A (I) gives the corresponding 21-fluoro and 21-bromo derivatives, namely 7α - Chloro-21-fluoro-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-1 7-propionate and 7α-chloro-21-bromo-1,4-pregnadiene 11ss, 17-alpha-diol -3,20-dione-17-propionate.    



   3rd  In the process described in Example 1 2A, using starting compounds with various esters at C-17, e.g. B.  of the 1 7-n-butyrate and 1 7-benzoate corresponding to the 17-propionate ester mentioned there are the corresponding 7α-chloro-21-halogen derivatives, namely the 17-n-butyrate and 17-benzoate of 7α, 21-dichloro-16α; -methyl-1,4-pregnadiene-11ss, 17α-diol-3,20-dione, from 7α-chloro-21-fluoro-1,4-pregnadiene-l @ ss, 17α-diol-3,20 -dione and 7a-chloro-21-bromo 1,4-pregnadiene-11ss, 17α-diol-3,20-dione.    



   4th  If the 16ss-methyl epimers or 16-unsubstituted or 16-methylene derivatives of the 16a-methyl compounds used in Examples 12A (I) to (3) are used as starting compounds, the corresponding 16ss-methyl-, 16-unsubst. - or 16-methylene derivatives of the 7α, 21-dihalogen products mentioned therein, for example 7a, 21 dichloro-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate; [M] + 472, 470, 468; NMR (DMSO-d6) Ï 0.87, 0.97, 1.41, 2.32, 4.41, 4.75, 5.95, 6.36, 7 , 35. 



  B.  7a-bromo and 7α-iodine-21-halogen derivatives
The 1,4,6-pregnatrienes used as starting materials for Examples 12A (1) to (4) are each treated with dry hydrogen bromide in the manner described in Examples 2A and 2B or with dry hydrogen iodide in acetic acid in the manner described in Example 9A to obtain the 7a-bromo and 7a-iodine analogs corresponding to the 7a-chloro derivatives of Example 12A, e.g. B.    7a-bromo-21-chloride, 4-pregnadiene-1 I ss, 17a-diol-3,20-dione-17-propionate, NMR (DMSO-d6) Ï 0.90, 1.00, 1.45, 2 , 33, 4.43, 4.85, 5.93, 6.21, 7.36. 



  C.    7? -Fluoro-21-halogen derivatives I.  7a-fluoro-2 1-chloro-1 6a-methyl-1, 4-pregnadiene-1 lss, 1 7a-diol-3,20-dione-17-propionate is obtained by reacting 16α-methyl-21-chloro 1,4-pregnadien-7ss, 11 ss, 17α-triol-3,20-dione-17-propionate with fluoramine in methylene chloride under a nitrogen atmosphere in the manner described in Example 8A. 



   2nd  If the starting compounds used are the 21-fluorine and 21-bromo analogues of the 2 I-chloro compound used as starting compounds in Example 12C (1), the corresponding 2 1-fluorine and 21-bromo derivatives, namely 7a-fluoro-2, are obtained 1-bromo-16α-methyl-1,4-pregnadiene-I Iss, 17a-diol-3,20-dione-17-propionate and 7a, 21-difluoro-16a methyl-1,4-pregnadiene-11ss, 17α ; -diol-3,20-dione-17-propionate.    

 

   3rd  When using the 9a-fluoro and 9a-chloro derivatives of the starting materials used in the process of Examples 12C (1) and 12C (2), the corresponding 9a-fluoro and 9a-chloro derivatives of the 7a-fluoro- 1,4-pregnadiene.    



  Example 13 Other 7? -Halogen-9-unsubst. -1,4-pregnadien-3,20-dione A.  1,4,6-Pregnatrien-3,20-dione I unsubstituted in the 9a position.     In the same manner as described in Preparation 1A, the following 1,4-pregnadiene-3,20diones are treated with dry hydrogen chloride gas in dioxane and DDQ: 1.  .  16α, 17α-isopropylidenedioxy-1,4-pregnadiene-11 113.21 -diol-3.20-dione-21-acetate. 



      2,14α, 17α-butylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



   3rd    2 ', 2'-Dimethyl-1,4-pregnadiene17, 16a-d] -1', 3'-oxathiolan-3,11,20-trione. 



   4th    11ss-hydroxy-2 ', 2'-dimethyl-1,4-pregnadiene [17,16α-d] -
1 ', 3'-oxathiolan-3,20-dione. 



   5.    D-Homo-l, 4-pregnadiene-l 7a, 2 I-diol3, 11, 20-trione-17,21-dipropionate. 



   6.    D-homo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-di-n-butyrate. 



   7.    n-butyl-11ss-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadiene-2 1 -oate.    



   8th.  Propyl-2-chloro-11 ss-hydroxy-3,20-dioxo-1 6a-methyl-1,4-pregnadiene-21-oat 9.  1 6ss-methyl-20-chloromethoxy-2 1 -nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate.    



   10th  16ss-methyl-20-fluoromethoxy-21-nor-1,4-pregnadiene 11ss, 17α-diol-3,20-dione-17-propionate.    



   11.  16-methylene-20-chloromethoxy-21-nor-1,4-pregnadiene 11ss, 17α-diol-3,20-dione-17-propionate.    



   12.  16-methylene-20-fluoromethoxy-21-nor-1,4-pregnadiene 11ss, 17α-diol-3,20-dione-17-propionate.    



   13.    16-fluoromethylene-1,4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione-17,21-dipropionate. 



   14.    16-chloromethylene-1,4-pregnadiene-17a, 21-diol-3,11 -20-trione-17-benzoate-21-propionate. 



   15.    1 o-butylidene-1,4-pregnadiene-1,7a-ol-3,20-dione-1 17-propionate. 



   16.    16-ethylidene-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate. 



   17th    16α, 17α-cyclopentylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate.    



   18th    16ss-methyl-20-methoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate. 



   19th    16α-methyl-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-pivalate. 



   The products obtained in each case are isolated and purified in the manner described in Preparation 1A, the 6-dehydro derivative of the starting compounds being obtained in each case. 



   2nd  The following compounds are treated with dry hydrogen chloride in dioxane and then with DDQ in the manner described in Preparation 1A:
1.    14α, 17α- (2'-butenylidenedioxy) -1,4-pregnadien-11ss, 21-diol-3,20-dione-21-isonicotinate and
2nd  11ss, 21-dihydroxy-2'-methyl-5'ssH-1,4-pregnadieno [17,16α-d] oxazole-3,20-dione-21-acetate.    



   The reaction mixture is stirred for 24 hours at room temperature, filtered and the filtrate is evaporated at 40 ° C. under reduced pressure.  The residue obtained is dissolved in water, neutralized with sodium hydroxide and extracted with chloroform.  The organic solution is washed with water, dried over magnesium sulfate and filtered through a column of neutral aluminum oxide and the column is washed with chloroform: ethyl acetate.     The eluates are evaporated individually, the 6-dehydro derivative of the starting compounds mentioned being obtained in each case as a residue. 



     B.  7? -Chlor-9-unsubst. -1,4-Pregnadiene
1.  In the manner described in Example 1 (A), the 1,4,6-pragnatien-3,20-dione prepared according to Example 13A (I) is treated with dry hydrogen chloride in dioxane and the products obtained in each case are isolated and purified described manner, whereby the 7a-chloro derivatives of the starting compounds of Example 13A (1) are obtained, for. B.    7α-chloro-16α, 17α-isopropylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione, melting point 255-257 C; [a] 26 + 104.9 (dimethylformamide); #maxMeOH 242 (r = 15. 600). 



   2nd  Treat 14α, 17α- (2'-butenylidenedioxy) -1,4,6-pregnatrien-11ss, 21-diol-3,20-dione-21-isonicotinate with hydrogen chloride gas in dioxane for 16 hours at room temperature to the in Example 1A described manner.  The reaction mixture is poured into ice water, the aqueous solution is neutralized with sodium hydroxide, the precipitate formed is filtered off, washed with water and dried in air.  The components of the abovementioned precipitation are separated in the manner described in Example 1 and 7α-chloro-14α, 17α - (2'-butenylidendioxy) -1,4-pregnadiene-11ss, 21-diol-3.20 is obtained -dion-21 isonicotinate. 

  In the same way, 1113.2 1-dihydroxy-2'-methyl-5's SH-1,4,6-pregnatrieno [17,16α-d] -oxazole-3,20-dione-21-acetate in 7a -Chlor-1. 1P, 21-di hydroxy-2 'methyl - i' SH-1. 4-pregnadieno [7,16a-d] oxazole-3,20-dione-21-acetate.    



  C.    7a-bromo-9-unsubst. -l, 4-pregnadiene
1.  In the manner described in Example 2, the 1,4,6-Pregnatrien3,20-dione prepared according to Example 1 3A (1) is treated individually with dry hydrogen bromide in acetic acid.  The products obtained are isolated and purified, and the corresponding 7a-bromo derivative of the starting compounds from Example 13A (1), for. B.  7a-bromo 16α, 17α-isopropylidene-dioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate; melting point 197-200 C; [α] D26 + 91.9 (Dimethylformamide); # maxMeOH 242 (e = 15. 000). 



   2nd  The 1,4,6-pregnatriene-3,20-dione derivatives prepared according to Example 13A (2) are each treated with dry hydrogen bromide in acetic acid in the manner described in Example 2A.  The reaction mixture is stirred for one hour at 0 ° C., poured into water, neutralized with sodium hydroxide, the precipitate formed is filtered off, washed with water, dried and purified in the manner described in Example 2A.  The 7a-bromo derivatives of the starting compounds from Example 13A (2) are obtained.    



     D. 7α-iodine-9-unsubst, -1,4-pregnadiene
1.  In the manner described in Example 9A, the 1,4,6-Pregnatrien3,20-dione derivatives prepared according to Example 13A (1) are treated with dry hydrogen iodide in glacial acetic acid. 



  The products obtained in each case are isolated and purified in the manner described, giving the 7α-iodo derivative of the 1,4-pregnadiene-3,20-dione starting compounds from Example 13A (1).    



   2nd  The 1,4,6-Pregnatrien-3,20-dione compounds of Example 13A (2) are treated with dry hydrogen iodide in acetic acid in the manner described in Example 9A.  The reaction mixture is stirred for 15 minutes at room temperature, poured into ice water, neutralized with sodium hydroxide, the precipitate formed is filtered off and purified in the manner described in Example 9A.  The 7a-iodine derivatives of the 1,4-pregnadiene-3,20-dione starting compounds from Example 13A (2) are obtained. 

 

   E.  7a-fluoro-9-unsubst. - 1,4-pregnadienes
1.  7ss-hydroxy-1,4-pregnadiene-3,20-dione
The following 1,4,6-pregnatriene-3,20-diones are subjected to a reaction sequence similar to that described for preparation 1 1A (1) - (4):
1.    16α, 17α, - isopropylidenedioxy-1,4,6-pregnatrien-11ss, 21-diol-3,20-dione-21-acetate. 



   2nd    14a, 1 7a-n-butylidenedioxy-1, 4,6-pregnatriene-ll 1113,21 -diol-3,20-dione-21 -acetate. 



   3rd    D-homo-1,4,6-pregnatriene-17α, 21-diol-3,11,20-trione-
17,21-dipropionate. 



      4th  D-homo-l, 4,6-pregnatriene-l 1ss, 17α, 21-triol-3,20-dione-di-n-butyrate.   



   5.    1 6B-methyl-20-chloromethoxy-2 I-nor-l, 4,6-pregnatriene-11ss, 17α-diol-3,20-dione-17-propionate.    



   6.  16ss-methyl-20-fluoromethoxy-21-nor-1,4,6-pregnatriene 11ss, 17α-diol-3,20-dione-17-propionate and
7.    16α, 17α-cyclopentylidenedioxy-1,4,6-pregnatrien-11ss, 21.    



  dion-3,20-dione-21 acetate. 



   The products obtained in each case are isolated and purified in the manner described in Preparation 11A (4), giving the following compounds:
1.    16α, 17α-isopropylidenedioxy-1,4-pregnadiene-7α, 11ss, 21-triol-3,20-dione-21 acetate. 



      2nd  1 4a '1 7a-n-butylidenedioxy-1,4-pregnadiene-713' 11ss, 21-triol-3,20-dione-21-acetate. 



   3rd    D-Homo-l, 4-pregnadiene-7a, 17a, 21-trio13, 11, 20-trione-17,21-dipropionate. 



   4th    D-Homo-l, 4-pregnadiene-7a '11 13'2l-tetrol-3,2O-dione-17,21-di-n-butyrate. 



   5.  16ss-methyl-20-chloromethoxy-21-nor-1,4-pregnadiene 11ss, 17α-diol-3,20-dione-17-propionate.    



   6.    16ss-methyl-20-fluoromethoxy-21-nor-1,4-pregnadiene-7ss, 11ss, 17α-triol-3,20-dione-17-propionate.    



   7.    16α, 17α-cyclopentylidenedioxy-1,4-pregnadiene-7ss, 11ss, 21-triol-3,2O-dione-2 1 -acetate.    



   2nd  In the manner described in Example 8A, the 7ss-hydroxy derivatives of Example 13E (1) are treated with fluoramine in methylene chloride at 0 C under a nitrogen atmosphere. 



  The products obtained in each case are isolated and purified in the manner described, giving the following compounds: 1. 7α-Fluoro-16α, 17α-isopropylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



      2nd 7α-Fluoro-14α, 17α-n-butylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



      3rd 7α-Fluoro-D-homo-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate. 



      4th 7α-Fluoro-D-homo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-di-n-butyrate 5. 7α-Fluoro-16ss-methyl-20-chloromethoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate. 



   6. 7α-Fluoro-16ss-methyl-20-fluoromethoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate. 



   7. 7α-Fluoro-16α, 17α-cyclopentylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



  Example 14 Other 7α, 9α-dihalogen-11ss-hydroxy-1,4-pregnadiene-3,20-dione A.    7ss-hydroxy-9α-halo-1,4-pregnadiene-3,20-dione
1.  The 6,7-unsubstituted 9a-halo-1,4-pregnadiene-3,20-diones mentioned below are treated with dry hydrogen chloride gas and DDQ in dioxane in the manner described in Preparation 1A and the 9a-halogeno-1 obtained in this way is subjected to 4,6-pregnatrien-3,2O-diones of a reaction sequence similar to that described in Preparation 1 1A (1) - (4): 1. 9α-Fluoro-11ss, 21-dihydroxy-2'-methyl-5'ssH-1,4-pregnadiene [17,16α-d] oxazole-3,20-dione-21-acetate. 



   2nd 9α-Fluoro-16α, 17α-cyclopentylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



   3rd    9n-fluoro-l 1 P-hydroxy-2 ', 2' -dimethyl-l, 4-pr. egnadien- [17,16a-d] l ', 3'-oxathiolan-3,20-dione. 



      4th 9α-Chloro-11ss-hydroxy-21,21-dimethyl-1,4-pregnadiene [17,16α-d] -1 ', 3'-oxathiolan-3,20-dione.    



   5.    9a-fluoro-16a-methyl-2 ', 2'-diacetoxy-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate. 



   6. 9α-Fluoro-16α-methyl-1,4-pregnadien-11ss-ol-3,20,21-trione-21,21-dimethylacetal. 



      7. 9α-fluoro-16α-methyl-1,4-pregnadien-11ss-ol-3,20,21-trione-
21-ethylene ketal. 



   8th.    2-chloro-9a-fluoro-16a-methyl-1,4-pregnadiene-11 ss, 17a-diol-3,20,21-trione. 



   9. 2-chloro-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α-diol-3,20,21-trione-21-methylhemiacetal. 



   10th    9a-fluoro-1 6P-methyl-20-f luormethoxy-21-nor-1, Cpregnadien-11ss, 17α-diol-3,20-dione-17-propionate. 



   11.  9α-Fluoro-16α-methyl-20-chloromethoxy-21-nor-1,4-pregnadiene-l 113, 1 7a-diol-3,20-dione-1 7-propionate.    



      12. 9α-Fluoro-16α-methyl-1,4-pregnadiene-11ss, 21-diol-3.20 dione-2L acetate.    



   The products obtained in each case are isolated and purified in the manner described in Preparation 1A (4), the corresponding 7ss-hydroxy derivatives of the above-mentioned starting compounds being obtained. 



   2nd  In a similar manner to that described in Example 1A, the following 6,7-unsubstituted 9a-fluoro-1,4 pregnadiene-3,20-diones are treated with dry hydrogen chloride and
DDQ in dioxane and then treats the 9a-fluoro-1,4,6-pregnatrien-3,20-dione thus obtained in the manner described in preparation I 1 D:
1.  9a-fluoro-16-methylene-20-fluoromethoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate,
2nd 9α-fluoro-16-methylene-20-chloromethoxy-21-nor-1,4-pregnadiene-11ss, 17α-diol-3,20-dione-17-propionate and 3. 9α-Fluoro-16-fluoromethylene-1,4-pregnadiene-11ss, 17α, 21triol-3,20-dione-2L acetate.    



   The products obtained are isolated and purified in the manner described in Preparation 1 ID (3), giving the corresponding 7ss-hydroxy derivatives, namely 1.  9a-fluoro-1 6-methylene-20-fluoromethoxy-2-nor-1,4-pregnadiene-713, 11ss, 1 7a-triol-3,20-dione-1 7-propionate,
2nd    9a-fluoro-16-methylene-20-chloromethoxy-21-nor-1,4-pregnadiene-7ss, 11ss, 17α-triol-3,20-dione-17-propionate and
3rd    9a-fluoro-16-fluoromethylene-1,4-pregnadiene 7ss, 11ss, 17α, 21-tetrol-3,20-dione-21-acetate.    



   3rd  (a) Treat n-butyl-9α-fluoro-11 13-hydroxy-16α, 17α-isopropylidenedioxy-3.20-dioxo-1,4-pregnadien-21-oate with dry hydrogen chloride and DDQ in dioxane the manner described in Example 1A and treats the 1,4,6-Pregnatrien obtained in a similar manner.  as described in Preparation 11A (1), (2) and (3), using n-butyl 6ss-propionyloxy-7ss, 11ss-dihydroxy-9α-fluoro-16α, 17α-isopropylidenedioxy-3.20 -dioxo- 1,4-pregnadien-21-oat. 



   3rd  (b) Treat 1 g of n-butyl-6ss-propionyloxy-7ss, 11 ss-dihydroxy-9α-fluoro-16α, 17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadien-21-oat one hour at room temperature with 1 g zinc and 10 ml acetic acid.  The reaction mixture is filtered, the filtrate is poured into water, the precipitate formed is filtered off and dried in air, whereby n-butyl-7ss, 11ss dihydroxy-9α-fluoro-16α, 17α-isopropylidenedioxy-3, 20-dioxo-1,4-pregnadien-21-oat is obtained. 

 

  B.    7α-Fluoro-9α-halo-1,4-pregnadiene-3,20-dione
In the manner described in Example 8A, the 7ss-hydroxy-1,4-pregnadienes prepared according to Example 14A are treated with fluoramine in methylene chloride at 0 C under a nitrogen atmosphere.  The products obtained in each case are isolated and purified in the manner described, the 7a-fluorine derivative of the starting compounds from Examples 14A (1), 14A (2) and 14A (3) being obtained in each case. 



  C.    7α-bromo-9α-halo-1,4-pregnadiene-3,20-dione
In the manner described in Example 10A, the 7ss-hydroxy-1,4-pregnadiene-3,20-dione prepared according to Example 14A is treated with fluoramine and lithium bromide in methylene chloride and the products obtained are isolated and purified in the manner described , whereby the 7a-bromo derivative of the starting compounds mentioned in Examples 14A (1), 14A (2) and 14A (3) is obtained. 



   D.    7α-Chloro-9α-halo-1,4-pregnadiene-3,20-dione
In the manner described in Example 10D, the 7ss-hydroxy-1,4-pregnadiene-3,20-dione prepared according to Example 14A is treated with fluoramine and lithium chloride in methylene chloride and the products obtained in each case are isolated and purified in the manner described Manner to obtain the 7α-chloro derivative of the starting compounds mentioned in Examples 14A (1), 14A (2) and 14A (3). 



   E.    7α, 9α, 17α-trihalogen-1,4-pregnadiene-3,20-dione 1. 7α, 9α-difluoro-17α-chloro-16α-methyl-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate and the corresponding 17a-bromo derivative
At - 78 C, 15 ml of anhydrous hydrogen fluoride are added to a mixture of 5 g of 7a, 9a-difluoro-16a-methyl-1,4-pregnadiene 1ss, 21-diol-3,20-dione-21-acetate and 2 g N-chlorosuccinimide in 5 ml tetramethylene sulfone.  The reaction mixture is left to stand at 3 C for 7 days and then poured into 300 ml of a mixture of equal parts of water, ice and 25% aqueous ammonium hydroxide with stirring. 

  The precipitate formed is filtered off, washed with water and dissolved in methyl chloride.  The organic solution is washed with
10% aqueous sodium sulfite and water, dry them over sodium sulfate and evaporate them under reduced pressure.  The residue obtained is chromatographed on silica gel, eluting with chloroform: ethyl acetate (2: 1). 



  The same eluates which contain the desired compound, determined by thin layer chromatography, are combined and evaporated under reduced pressure, leaving 7α, 9α-difluoro-17α-chloro-16α-methyl-1,4-residue as residue. pregnadiene-11ss, 21-diol-3,20-dione-21-acetate. 



   In the experiment described above, when the N-chlorosuccinimide is replaced with an equivalent amount of N-bromosuccinimide, the corresponding 17a-bromine compound, i. H.  7a, 9a-difluoro-17α-bromo-1 16a-methyl-l, 4-pregnadiene-l l -diol-3,20-dione-21 -acetate. 



   2nd  In the same way, 7a, 9a-difluoro-16a-methyl-1,4-pregnadiene-11s-ol-3,20,21-trione-21-ethylene ketal is treated with N-chlorosuccinimide or  N-bromosuccinimide and hydrogen fluoride in tetramethylene sulfone in the manner described in Example 14E (1), giving 7α, 9α-difluoro-17α-chloro-16α. methyl-1,4-pregnadiene-11 lss-ol-3,20,21-trione or  7a, 9a-difluoro-17α-bromo-1 16a-methyl-1,4-pregnadien-11 ss-ol-3,20,21-trione. 



   3rd  According to the procedure of Examples 14E (1) and 14E (2), but starting from the 7a-chlorine and  7a-bromo analogues which correspond to the 7a-fluoro-1,4-pregnadiene starting compounds mentioned therein give the 7α-chloro-17a-halogen compounds corresponding to the 7α-fluorine-17α-halogen compounds mentioned there respectively.    7α-Bromo-17α-halogen derivatives, namely 7α, 17α-dichloro-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate , 7α-bromo-9α-fluoro-17α-chloro-16α-methyl-1,4-pregnadiene-11 ss, 21-diol-3,20-dione-21-acetate, 7a-chloro9? -fluoro-17?

  ; -bromo-16α-methyl-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate, 7α, 17α-dibromo-9α-fluoro-16α-methyl-1 , 4-pregnadiene-11 ss, 21-diol-3,20-dione-21-acetate, 7a, 17a-dichloro-9a-fluoro-16α-methyl-1,4-pregnadien-11ss-ol-3.20 , 21-trione, 7α-chloro-9α-fluoro-17α-bromo-16α-methyl-1,4-pregnadien-11ss ol-3,20,21-trione, 7α-bromo-9α - fluoro-17α-chloro-16α-methyl-1,4-pregnadien-11 ss-ol-3,20,21-trione and 7α, 17α-dibromo-9α-fluoro-16α-methyl-1 , 4-pregnadien-11ss-ol-3,20,21-trione.    



  Example 15 Other 7α, 9α, 11ss-trihalogen-1,4-pregnadiene-3,20-dione A.    7α, 7α, 11ss-trichloro-21-fluoro-16-methylene-1,4-pregnadiene-17α, ol-3,20-dione-17-propionate 1. 7α-Chloro-21-fluoro-16-methylene-1,4,9 (11) -pregnatrien-17α-ol 3,20-dione-17-propionate is obtained by reacting 7a-chloro-21-fluoro-16 -methylene-1,4-pregnadiene-l lss, 17a-diol-3,20-dione-17-propionate with methanesulfonyl chloride and sulfur dioxide in dimethylformamide and collidine in the manner described in Example 6A (1). 



      2nd  7a, 9a, 11 ss-trichloro-21-fluoro-1 16-methylene-1,4-pregnadiene-17α-ol-3,20-dione-17-propionate is obtained by reacting the 7α mentioned in Example 15A (1) Chlorine-21-fluoro-1,4,9 (11) -pregnatrien with chlorine in chloroform and pyridine in the manner described in Example 6B (1). 



      B. 7α, 9α-trichloro-11ss-fluoro-16α-methyl-1,4-pregnadien-21-ol-3,20-dione-21-pivalate 1. 7α-Chloro-16α-methyl-1,4,9 (11) -pregnatrien-21-ol-3,20-dione-21-pivalate is obtained by reacting 7α-chloro-16α-methyl-1, 4-pregnadiene-11ss, 21-diol-3,20-dione-21-pivalate with methanesulfonyl chloride and sulfur dioxide in dimethylformamide and collidine in the manner described in Example 6A (1). 



      2nd  7a, 9a, 17a-trichloro-11 ss-fluoro-16a-methyl-1,4-pregnadiene-21 ol-3,20-dione-21-pivalate is obtained by reacting 7α-chloro-16α-methyl-1 , 4.9 (11) - pregnatrien-21-ol-3,20-dione-21-pivalate with anhydrous hydrogen fluoride and N-chlorosuccinimide in tetramethylene sulfone in the manner described in Example 14E (1). 



   C.  The 7-unsubstituted 1,4-pregnadiene-3,20-diones mentioned below are treated with DDQ and hydrogen chloride in the manner described in preparation 1A, and the 1,4,6-pregnatrien-3,20-dione obtained are then prepared according to process described in Preparation 11A and then treats the 7ss-hydroxy derivatives thus obtained with fluoramine in the manner described in Example 8A or with fluoramine together with lithium chloride in the manner described in Example 10D or with fluoramine together with lithium bromide in the manner described in Example 10A Way, the corresponding 7α-fluorine or  7a chlorine or 7a-bromo derivatives of the following starting compounds:

  : n-Butyl-9α-chloro-11ss-fluoro-14α, 17α-ethylenedioxy-3.20dioxo-1,4-pregnadiene-21-oate, methyl-9a, 11s-dichloro-16a-methyl-17α ; -acetoxy-3,20-dioxo-1,4-pregnadien-21-oat, n-butyl 11ss-fluoro-9α-chloro-14α, 17α-ethylidene-dioxy-3,20-dioxo-1, 4-pregnadiene-21-oat, n-butyl-9a-chloro-11 ss-fluoro-14a, 17a-ethylidendioxy-3,20-dioxo-1,4-pregnadiene-21-oat, n-butyl-9α ; -chloro-11ss-fluoro-14α, 17α-ethylenedioxy-3.20-dioxo-1,4-pregnadiene-21-oate, methyl-9α, 11ss-dichloro-16α-methyl-17α;

  ; -acetoxy-3,20-dioxo-1,4-pregnadien-21-oat, methyl-9a, 11 ss-dichloro-16a-methyl-17α-acetoxy-3,20-dioxo-1,4- pregnadien-21-oat and methyl 9α, 11ss-dichloro-16α-methyl-17α-acetoxy-3,20-dioxo-1,4-pregnadiene-21-oat. 



   Example 16 Preparation of 17a Monoesters A.  Using malt diastase
I.  7a-bromo-16a-methyl-1,4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione-17-valerate
To a suspension of 1.67 g of the enzyme diastase from
Malt in 33.5 ml ethanol and 167.5 ml water are added 33.5 mg 7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione- 17-valerate-21-acetate.  The reaction mixture is stirred for 3 days at room temperature and then evaporated under reduced pressure at room temperature.  The residue obtained is dissolved in ethyl acetate and water and the solution is filtered through a pad of Celite, washing with ethyl acetate.  The organic layer is separated from the aqueous layer and the aqueous layer is extracted with ethyl acetate. 



  The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated under reduced pressure.  The residue obtained is purified by thin layer chromatography using chloroform: ethyl acetate (3: 1) as a developing solvent. 



  Remove the band visible under UV light, which contains the desired product.  It is eluted with ethyl acetate and evaporated to give the desired compound as a residue.  You clean by rubbing with ether: hexane. 



   2nd  In the same way, 7a-chloro 16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-valerate-21-acetate and 7a-chloro-1 are treated in each case 6a-methyl-1, 4-pregnadiene 11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate with the enzyme diastase from malt in aqueous ethanol in the manner described in Example 1 6A (1), where 7a-chloro-16a-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-l 7-valerate or 



     7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate. 



   3rd  In the manner described in Example 16A (1), the corresponding 21-hydroxy derivatives are obtained by treating the 7α-halo-21-acyloxy-1,4-pregnadienes mentioned in Examples 1 to I5 with the enzyme diastase of malt in aqueous ethanol . 



  B.  By acidic hydrolysis 7α-bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate and its 16a-methyl derivative
To 0.44 g of 7α-bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate-21-acetate in 69 ml of methanol are added 1.76 ml of 70% aqueous perchloric acid and the reaction mixture is stirred for 4 hours.  The reaction mixture is neutralized with saturated aqueous sodium bicarbonate and the methanol is evaporated off under reduced pressure.  The aqueous is cooled
Reaction mixture and the resulting precipitate is filtered off, which consists of a mixture of 7a-bromo-1,4-pregnadiene 11ss, 17α, 21-triol-3,20-dione and its 17-monobenzoate and 21-monobenzoate esters. 

  The mixture is separated by thin layer chromatography on silica gel, developing with chloroform (1: 1) using ethyl acetate, removing the band visible under UV light, which contains the desired 17-benzoate ester, eluting with ethyl acetate and evaporating, leaving 7α- as the residue. Bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate. 



      7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-benzoate, melting point 144-144.5 C, #maxMeOH 233nm (# = 24 . 700) can be similarly prepared by hydrolysis of 7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dibenzoate. 



   C.    7α-Halogen-9α-fluoro-1,4-pregnadiene-11ss, 16α, 17α, 21-tetrol-3,20-dione-17-hydrocarbon carboxylates
1.  7a-chloro and 7a-bromo-9a-fluoro-1,4-pregnadiene 11ss, 16α, 17α, 21-tetrol-3,20-dione-17-propionate and 17-n-butyrate a) 9α - Fluoro-1,4,6-pregnatrien-16α, 17α, 21-triol-3,11,20-trion-
16,21-diacetate-17-propionate and -17-n-butyrate are obtained by reacting 8-fluoro-l, 4,6-pregnatriene-1,6a, 17a, 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 prepared according to the 5D manufacturing process. 



   b) 9α-Fluoro-1,4-pregnadiene-7α, 16α, 17α, 21-tetrol-3,11,20-trione-l 6,21-diacetate-l 7-propionate and -17-n -Butyrate are prepared by using 9a-fluoro-l, 4o-pregnatriene-l 6a, 17a, 21-triol-3,11,20-trione-16,21-diacetate-17-propionate and -17-n-butyrate Follow a sequence of reactions similar to that described in Preparation 1A (1-4). 



   c) 7a, 9a-difluoro-l, tpregnadiene-16a, 17a, 21-trio13,11, 20-trione-16,21-diacetate-17-propionate and - 1 7-n-butyrate are reacted by reacting 7α, 9α-difluoro-1,4-pregnadiene-16α, 17α, 21-triol-3,11,20-trione-16,21-diacetate-17-propionate and -17-n-butyrate with fluoramine in methylene chloride the method of Example 8A. 



   The 17-propionate and 17-n-butyrate of 7α-bromo-9α-fluoro-1,4-pregnadiene-16a, 17a, 21-trio13,11, 20-trione-16,21-diacetate and of 7- Chloro-9a-fluoro-l, 4-pregnadiene-16a, 17a, 21-triol-3,11,20-trione-16,21-diacetate can be prepared according to the examples
10A and 10C described processes by reacting the 7ss-hydroxypregnadienes mentioned in Example 16C (1) (b) with lithium bromide and fluoramine or with lithium chloride and fluoramine in methylene chloride. 



  d) 7α-halo-9α-fluoro-1,4-pregnadiene-11ss, 16α, 17α, 21-tetrol-3,20-dione-16,21-diacetate-1 7-propionate and - 1 7 -n-butyrate
In the manner treated in Examples 1C and 2C, all six products from Example 16C (1) (c) are treated with sodium borohydride in tetrahydrofuran and methanol under a nitrogen atmosphere and the products obtained are each isolated in the manner described, the 17-propionate and
17-n-butyrate of 7α, 9α-difluoro-1,4-pregnadiene
11ss, 1 16a, 17a, 21-tetrol-3,20-dione-l 6,21-diacetate, the 17-propionate and the 17-n-butyrate of 7a-chloro-9a-fluoro-1,4-pregna diene -11ss, 16?, 17?

  ;, 21-tetrol-3,20-dione-16,21-diacetate and that
1 7-propionate and 17-n-butyrate of 7a-bromo-9a4luoro-1 4-pregnadien-11ss, 16α, 17α, 21-tetrol-3,20-dione-16,21-diacetate. 



  e) 7α-halo-9α-fluoro-1,4-pregnadiene-11ss, 16α, 17α, 21-tetrol-3,20-dione-17-propionate and-17-n-butyrate
In the manner described in Example 16A, all six products from Example 16C (1) (d) are treated with the enzyme diastase from malt in aqueous ethanol and the products obtained are isolated and purified in the manner described, using the 17-propionate and the 17-n-butyrate of 7a, 9a-difluoro-1,4-pregnadiene-11ss, 16α, 17α, 21-tetrol-03,20-dione, the 17-propionate and 17-n-butyrate of 7α-chlorine -9α-fluoro-1,4-pregnadiene-11 ss, 16a, 17a, 21-tetrol-3,20-dione and the 17-propionate and 17-n-butyrate of 7α-bromo-9α-fluoro- 1,4-pregnadien-11ss, 16α, 17α, 21-tetrol-3,20-dione. 



  2nd  7a-chloro- and 7a-bromo-9a-fluoro-1,4-pregnadiene 11ss, 16α, 17α, 21-tetrol-3,20-dione-17-benzoate a) 9α-fluoro-1,4, 6-pregnatriene-11ss, 16α, 17α, 21-tetrol-3,20-dione-16, 17-methyl-o-benzoate-21-acetate is obtained by reacting 9α-fluoro-1,4,6- pregnatrien-11ss, 16α, 17α, 21-tetrol-3,20-dione-21-acetate with trimethyl-o-benzoate and pyridinium toluene-p-sulfonate in dioxane and benzene according to manufacturing method 2C (1). 

 

  b) 7a-chloro and 7a-bromo-9a-fluoro-1,4-pregnadiene 11ss, 16α, 17α, 21-tetrol-3,20-dione-16,17-methyl-o-benzoate-21- Acetate from 9a-fluoro-1,4,6-pregnatriene-1 11ss, 16α, 17α, 21-tetrol-3,20-dione-16,17-methyl-o-benzoate-21-acetate Reaction with hydrogen chloride in tetrahydrofuran with hydrogen bromide in glacial acetic acid according to the method described in Examples 1B and 2B. 



  c) 7a-chloro and 7α-bromo-9α-fluoro-1,5-pregnadiene-11ss, 16α, 17α, 21-tetrol-3,20-dione-17-benzoate-21-acetate are made from 7a-chloro and 7α-bromo-9α-fluoro-1,4-pregnadiene-11ss, 16α, 17α, 21-tetrol-3,20-dione-16,17-methyl-o-benzoate-21 -ace- tat by hydrolysis with aqueous acetic acid according to the manufacturing process 2A (2). 



   d) 7a-chloro and 7a-bromo-9a-fluoro-l, 4-pregnadiene 11ss, 16α, 17α-21-tetrol-3,20-dione-17-benzoate are made from 7a-chloro and 7a-bromo -9a-fluoro-l, 4-pregnadiene 1113.1 ss, 16a, 17a, 21 -tetrol-3.20-dione-l 7-benzoate-21-acetate
Hydrolysis with the enzyme diastase of malt in aqueous ethanol prepared according to the procedure described in Example 16A. 



   Example 17
7a-halogen-1, 4-pregnadiene-l 7a, 2 1-diol-3,20-dione-17-carbon hydrogen carboxylate-2 1 -retinoate A.    7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-1 7-propionate-2 1 -retinoate
To a suspension of 464 mg (1 mmol) 7a-chloro-1 6-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17-propionate in 50 ml of methylene chloride is added Nitrogen in the dark 300 mg (1 mmol) vitamin A acid and 424 mg (1 mmol)
1-Cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate.  The mixture is stirred at room temperature for 17 hours, then a further mmol of retinonic acid and a further mmol of the diimide are added and the reaction mixture is stirred for a further 24 hours. 

  The reaction mixture is extracted successively with 2% hydrochloric acid, water, 5% aqueous sodium bicarbonate and again with water.  It is dried over sodium sulfate and evaporated under reduced pressure.  The residue obtained is chromatographed on thick-layer plates made of silica gel GF, eluting with ethyl acetate: chloroform (1: 2).  The band of steroid retinoate is removed from the thick-layer plate, extracted with ethyl acetate and evaporated under reduced pressure, the desired compound being obtained as residue.  One cleans further by recrystallization from ether: petroleum ether. 



   B.  In the same way, by treating any 21-hydroxy-7a-halogen-1,4-pregnadiene-3,20-dione according to the invention, its 21-retinoates are obtained by the method described in Example 17A. 



  Example 18 7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α21-triol-3,20-dione
To a solution of 3.5 g of 7α-chloro-16α-methyl-1,4-pregnadiene-l 113.1 7a, 2 l-triol-3'20-dione-17,21-dipropionate in 300 ml of methanol is added to 30 ml of saturated aqueous sodium bicarbonate solution and left to stand for 18 hours at room temperature. 



  It is poured into water, the precipitate formed is filtered off, washed neutral with water and then air-dried.  The dried precipitate is recrystallized from acetone / hexane, the desired compound being obtained in a yield of 1.3 g.  Melting point 176-179 C.    [oi26 +47.5 (dimethylformamide); SMex H 242 nm (e 15. 500). 



  Example 19 7α-Bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione and its 21-acetate
37.5 g of dry hydrogen bromide are added to a solution of 5 g of 1,4,6-Pregnatrien-1 lss, 17a, 21-triol-3,20-dione-21-acetate in 62 ml of glacial acetic acid and the reaction mixture is left for 45 minutes stand at 0 to 5 C.  The reaction mixture is poured into water, the precipitate formed is filtered off, washed with water and dried in air, 7a-bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3.20- receives dion-21-acetate. 



   This product is dissolved in 525 ml of methanol, 13.2 ml of 70% aqueous perchloric acid are added and the reaction mixture is stirred at room temperature for 18 hours.  Water and then saturated aqueous sodium bicarbonate are added until the solution is neutral, and the methanol is evaporated from the reaction mixture.  The aqueous reaction mixture is extracted with ethyl acetate, the combined ethyl acetate extracts are washed with water, dried over sodium sulfate and evaporated. 



   The residue thus obtained is recrystallized from acetone to give 7a-bromo-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione in a yield of 0.3 g.  Melting point> 320 C; [a] E2.6 +48.2 (dimethylformamide); #maxMeOH 242 nm (± =
15. 500) 7α-Chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione, melting point 176-179 C; [α] D26 + 47.5 (dimethyl formamide), XMax H 242 nm (± = 15. 500) can be made in the same way. 



   Example 20
7α-Chloro-4-pregnen-17α, 21-diol-3,11,20-trione-17,21-dipropionate and its 16a-methyl and 16ss-methyl derivatives
A.  At 10 0C, 911 mg of 4,6-Pregnadien-17α, 21-diol-
3,11,20-trion-17,21-dipropionate in in 10 ml of a freshly prepared solution of hydrogen chloride in tetrahydrofuran and water, the 38.2 wt. -% hydrogen chloride and 3.7 wt. -% contains water.  The reaction mixture is stirred at 0 to 2 C for 15 minutes and then poured into 100 ml of ice water. 

  The precipitate formed is filtered off, washed with water and partially dried under nitrogen and then at room temperature under reduced pressure for 17 hours, taking one
Mixture of 7a-chloro-4-pregen-17a, 21 -diol-3,11,20-trione 17,21 -dipropionate and 4,6-pregnadiene-17a, 21 -diol-3,11,20-trione-17,21 -dipropionate receives.  The components of this mixture are separated by thick layer chromatography on silica gel, developing with hexane: dimethoxyethane (2: 1) and eluting with ethyl acetate the band recognizable in the UV spectrum, the 7a-chloro-4-pregnen- 17a, 21 -diol- 3,11,20-trione-17,21-dipropionate contains. 

  The ethyl acetate eluate is evaporated at room temperature and the residue obtained is recrystallized from acetone: hexane at room temperature, giving a-chloro-Cpregnen-l 7a, 21-dio13.11, 20-trione-l 7.21-dipropio- nat receives.  The compound is stored in an open vessel at room temperature under reduced pressure. 



      B.  7α-chloro-16α-methyl-4-pregnen-17α, 21-diol-3,11,20-trione-
17,21-dipropionate and 7α-chloro-16ss-methyl-4-pregnen-17α, 21-diol-3,11,20-trione-17,21-dipropionate are obtained by reaction of 16a-methyl-4,6 -pregnadiene 17a, 21-dio13,11, 20-trion-l 7,21-dipropionate and 16ss-methyl 4,6-pregnadien-17α, 21-diol-3,11,20-trione-17,21-dipropionate prepared with hydrogen chloride in aqueous tetrahydrofuran according to the procedure described in Example 20A. 



  Example 21 7a-Brom4-pregnen-l 7a, 21-dio13,11, 20-trion-l 17,21-dipropionate and its 16a-methyl and 16ss-methyl derivatives
A.  235 mg of 4,6-Pregnadien 17a, 21-dio13,11, 20-trion-l 7,21-dipropionate are dissolved in 2.5 ml of a freshly prepared solution of 44% hydrogen bromide in acetic acid at room temperature.  The mixture is stirred at room temperature for 30 minutes, then poured into 100 ml of water, the precipitate formed is filtered off, washed with water and dried under nitrogen, giving a mixture of 7a-bromo-4-preg nen-17a, 21 -diol-3,11,20-trione-17,21-dipropionate and 4,6-pregnadiene-17a, 21 -diol-3,11,20-trione-17,21-dipropionate.  

  The 7α-bromo-4-pregnen-17α, 21-diol-3,11,20-trione-17,21-dipropionate is isolated from this mixture in the manner described in Example 20A and stored in an open vessel Room temperature under reduced pressure. 



      B.  7a-bromo-l oa-methyl4-pregnen-17a, 21-dio13,11, 20-trione-17,21-dipropionate and 7α-bromo-16ss-methyl-4-pregnen-17α, 21-diol-3 , 11,20-trione-17,21-dipropionate are obtained by reacting 16α-methyl-4,6-pregnadiene-17cr, 21-dio13,1 1,20-trione-17,2 i-dipropionate and 16ss-methyl 4,6-pregnadiene-l 7a, 21-dio13,11, 20-trione-l 7,21-dipropionate with hydrogen bromide in acetic acid according to the method described in Example 21A. 



  Example 22 7a-Halogen-4-pregnen-11 11P, 17a, 21 -triol-3,20-dione-l 7,21-dipropionate and its l6o-methyl and 16ss-methyl derivatives A.  7a-chloro-4-pregnen-113,17a, 21-triol-3,20-dione-l 7,21-dipropionate and its 16a-methyl and 16ss-methyl derivatives
1.  At room temperature, 3.1 g of 7a-chloro-4-pregnene 17α, 21-diol-3,11,20-trione-17,21-dipropionate are dissolved in 375 ml of methanol and 30 ml of water are added.  2.38 g of sodium borohydride are added to this solution at 0 to 2 ° C. under a nitrogen atmosphere.  After 30 minutes, the reaction solution is carefully added to 4.2 l of water containing 80 ml of n-hydrochloric acid. 

  The precipitate formed is filtered off and chromatographed on silica gel, eluting with chloroform: ethyl acetate (3: 1). 



  The combined eluates are evaporated under reduced pressure.  A suspension of 600 mg of manganese dioxide in 7 ml of benzene is added to 152 mg of the residue obtained, the mixture is stirred for 5 hours, and the filtrate is filtered and chromatographed on silica gel by thin layer chromatography, eluting with chloroform: ethyl acetate (3: 1) and by UV - Spectrum determined band, which contains the desired product, eluted with ethyl acetate.  The ethyl acetate solution is evaporated under reduced pressure to a residue which contains 7α-chloro-4-pregnen-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate.  It is further purified by recrystallization from ether: hexane at room temperature.    #maxMethanol 237 nm (± = 15. 500). 



   2nd 7α-chloro-16α-methyl-4-pregnen-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate and 7a-chloro-16ss-methyl-4-pregnen-11ss, 17α ;, 21-triol-3,20-dione-17,21-dipropionate by reacting 7a-chloro-1 6a-methyl-4-pregnen-17a, 21-diol 3,11,20-trione-17,21 dipropionate and 7a-chloro-16ss-methyl-4-pregnen-l 7a, 21-dio13.1 1,20-trione-17,21 -dipropionate with sodium borohydride in aqueous methanol and reaction of the product obtained with manganese dioxide in benzene the method described in Example 22A (1). 



      B. 7a-bromo-4-pregnen-11 11P, 17a, 21 -triol-3,20-dione-l, 7,21-dipropionate and its 16a-methyl and 16ss-methyl derivatives are obtained by the method described in Example 22A the 7a-bromo analogues of the 7a-chlorine compounds mentioned there used as starting materials. 



  Example 23 Other 7a-halogeno-11-oxygenated-4-pregnen-17α21-diol-3,20-diones and their ester derivatives
Esters of 4,6-pregnadiene-3,1, 1,20-trione-17a, 21 -diols (produced by production process 12) can be used in the same way as starting materials for the experiments described in Examples 20 and 21.  The resulting esters of 7a-chloro- and 7a-bromo-4-pregnen-3.1, 1.20-trione-17a, 21-diols can be treated in the manner described in Example 22, esters of 7a-chloro- and 7a-bromo-4 pregnen-3,20-dione-1113,1 7a, 2 1 4riolen can be obtained.    



  Example 24 7α-iodo-9α-fluoro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate
A.  To a solution of 0.4 g of dry hydrogen iodide in
1.5 ml of glacial acetic acid are added at room temperature with exclusion from light, a solution of 0.05 g of 9α-fluoro-16ss-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20- dion-17,21-dipropionate in 0.5 ml glacial acetic acid.  The reaction mixture (protected from light) is stirred for 30 minutes at room temperature and then 20 ml of 5% sodium thiosulfate solution are added. 

  You extract that
Mix twice with 50 ml of methylene chloride, wash the combined organic extracts twice with water, dry them over anhydrous sodium sulfate and evaporate them at room temperature under reduced pressure.  The residue obtained is purified on silica gel by thick layer chromatography, developing with ethyl acetate: chloroform (1: 9).  The more polar band, which can be seen under UV light, is scraped off, the silica gel is washed with ethyl acetate, the combined ethyl acetate washing liquids are evaporated under reduced pressure and the residue obtained is recrystallized from ether, the desired compound being obtained in a yield of 16 mg ( 39%) receives.  Melting point 145 C (dec. ).    



  NMR (DMSO-d6) 0.95, 1.28, 1.55, 4.20, 4.59, 4.70, 5.99, 6.20, 7.25. 



   Alternatively, the compound of this example is prepared according to the following Examples 24 (B) and 24 (C). 



  B.    7a-iodo-9a-fluoro-16ss-methyl-1,4-pregnadiene-17a, 21-diol-3,11,20-trione-17,21-dipropionate becomes 100 in the manner described in Example 24 (A) mg 9α-fluoro-16ss-methyl-1,4,6-pregnatrien-17α, 21-diol-3,11,20-trione-17,21-dipropionate and 0.8 g dry hydrogen iodide in 4 ml glacial acetic acid .  Yield 80 mg (64% of theory Th. ). 



   The compound is further purified by recrystallization from ether.  Melting point 106 C (dec. ). 



  C.    7α-iodo-9α-fluoro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate is described in Example 3C (1) Manner from 7a-iodine 9α-fluoro-16ss-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate by reduction with sodium borohydride at 0 C in tetrahydrofuran and Methanol made under nitrogen. 



  Example 25 7α-iodo-9α-chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol3,2O-dione-17,21-dipropionate A.  7a-iodo-9a-chloro-16ss-methyl-1,4,6-pregnatrien-1 113,1 7a, 2 1 - triol-3,20-dione-17,21-dipropionate is based on the method described in Example 24 (A ) described from 9α-chloro-16ss-methyl-1,4,6-pregnatrien-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate and hydrogen iodide in glacial acetic acid.  Yield 15%. 



   B.  Alternatively, the compound of this example is prepared by treating 9α-chloro-16ss-methyl-1,4,6-pregnatriene-17a, 21-diol-3.1, 1.20-trione-17.2 I-dipropionate with hydrogen iodide in acetic acid in the manner described in Example 24 (A) and then reducing the 7a-iodo-9a-chloro-16ss-methyl-l, 4-pregnadiene-l 7a, 2 l-diol3,1 1,20-trione- 17.21 dipropionate with sodium borohydride in methanol / tetrahydrofuran in the manner described in Example 3C (1). 

 

  Example 26 7α-iodo-9α-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate
9α-Bromo-16ss-methyl-1,4,6-pregnatrien-17α-21-diol-3,11,20-trione-17,21-dipropionate is treated with hydrogen iodide in glacial acetic acid, based on that described in Example 24 (B ) described and then reduces the 7a-iodo-9a-bromo-16ss-methyl-1,4-pregnadiene-17a, 2l-diol-3.1, 1,20-trione-17,21-dipropionate obtained with sodium borohydride in methanol / Tetrahydrofuran in the manner described in Example 24 (C), whereby 7a-iodo-9a-bromo-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17, 21-dipropionate.   



  Example 27 7α-bromo-9α-fluoro-16ss-methyl-1,4, -pregnadiene-11ss, 17α, 21-triol3,20-dione-17,21-dipropionate A.    7α-bromo-9α-fluoro-16ss-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate
To a solution of 0.5 g of 8α-fluoro-16ss-methyl-1,4,6-pregatratrien-l 7a, 21-dio13,11, LO-trion-17,21-dipropionate in 1 ml of glacial acetic acid 5 ml of a solution of dry hydrogen bromide in glacial acetic acid (48% by weight / Wt. ).  The mixture is stirred at 5 C for one hour and then poured into 300 ml of ice water.  The precipitate formed is filtered off, washed well with water and dried in air at room temperature. 

  The precipitate is cleaned on thick-layer silica gel plates, developing with ethyl acetate: chloroform (1: 5).  The band visible under UV light, which contains the desired compound, is scraped off and the compound is extracted from the silica gel with ethyl acetate.  The ethyl acetate solution is evaporated to a residue which contains the desired compound.  Yield 60% of theory.  Melting point 115 C (dec. ). 



   B.  In the manner described in Example 3C (I), the product of Example 27 (A) is reduced with sodium borohydride in methanol / tetrahydrofuran, whereby 7a-bromo-9a-fluoro-16ss-methyl-l, 4-pregnadiene-17a, 21 -diol-3, 11.20-trione-l 7.21-dipropionate. 



  Example 28 7α-Bromo-9α-chloro-16ss-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate
9a-chloro-l 6ss-methyl-l, 4,6-pregnatriene-17a, 21-dio13,11, 20-trione-l 7,21-dipropionate is treated with hydrogen bromide in acetic acid to that described in Example 27 (A) Way and then reduced the 7a-bromo-9a-chloro 16B-methyl-1,4-pregnadiene-17a, 21-diol-3, 11,20-trione-17,21-dipropionate obtained with sodium borohydride in methanol and tetrahydrofuran to the manner described in Example 3C (1) to obtain the desired compound. 



  Example 29 A.    7α-iodo-9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate is obtained by reacting 9a-fluoro-16a -methyl-l, 4,6-pregnatrien-17a, 21-diuol-3,11,20-trion-17,21 -dipropionate with hydrogen iodide in glacial acetic acid in the dark in the manner described in Example 24 (A). 



  B.    7α-iodo-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate is obtained by reducing the compound of part (A ) with sodium borohydride according to the method described in Example 3C (1). 



  Example 30
A.    7α-Bromo-9α-fluoro-16α-methyl-1,4-pregnadiene-17α, 21-diol-3,11,20-trione-17,21-dipropionate is obtained by reacting 9α-fluoro- 16α-methyl-1,4,6-pragnatien-17a, 21-diol-3,1 1,20-trione-17,21-dipropionate with hydrogen bromide fin glacial acetic acid in the dark to that described in Example 24 (A) Manufactured way. 



  B.    7α-Bromo-9α-fluoro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate is obtained by reducing the compound of part (A ) with sodium borohydride in the manner described in Example 3C (1). 



  Example 31 A.  7a-iodo-9a-chloro-16a-methyl-1,4-pregnadiene-17a, 21-diol3,11,20-trione-17,21-dipropionate is obtained by reacting 9a-chloro-16a-methyl-1,4 , 6-pregnatrien-1 7a, 2 -diol-3,11,20-trion-17,21 -dipropionate with hydrogen iodide in glacial acetic acid in the dark in the manner described in Example 24 (A). 



      B.  7α-iodo-9α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol3,20-dione-17,21-dipropionate is obtained by reducing the compound of part (A) with Sodium borohydride prepared in the manner described in Example 3C (1). 



  Example 32 A.  7a-bromo-9a-chloro-laa-methyl-1,4-pregnadiene-1 7a, 2 1 -diol- 3.1 1,20-trione-17,21-dipropionate is obtained by reacting 9α-chlorine- 16α-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 in the manner described in Example 24 (A) produced. 



      B.  7α-Bromo-9α-chloro-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-17,21-dipropionate is obtained by reducing the compound of part (A ) with sodium borohydride in the manner described in Example 3C (I). 



  Example 33 A.  7α-iodo-9α-fluoro-16α, 17α-isopropylidenedioxy-1,4-pregnadien-21-ol-3,11,20-trione-21-acetate is obtained by reacting 9a-fluoro-16a, 17a -isopropylidene-dioxy-1,4,6-pregnatrien-21-ol-3,11,20-trione-21-acetate with hydrogen iodide in glacial acetic acid in the dark in the manner described in Example 24 (A). 



  B.  7a-iodo-9a-fluoro-1 6a, 1 7a-isopropilidendioxy-1,4-pregnadien11ss, 21-diol-3,20-dione-21-acetate is obtained by reducing the compound of part (A) with sodium borohydride to the in Example 3C (I) prepared. 



  Example 34 A.  7α-bromo-9α-fluoro-16α, 17α-isopropylidenedioxy-1,4-pregnadien-21-ol-3,11,20-trione-21-acetate is obtained by reacting 9α-fluorine- 16α, 17α-isopropylidene-dioxy-1,4,6-pregnatrien-21-ol-3,11,20-trione-21-acetate with with hydrogen bromide in glacial acetic acid in the dark on the in Example 24 (A) described manner produced. 



      B. 7a-bromo-9a-fluoro-16a, 17a-isopropylidenedioxy-1,4-pregnadiene-11ss, 21-diol-3,20-dione-21-acetate is reduced by reducing the compound of part (A) with sodium borohydride prepared in the manner described in Example 3C (1). 



   The invention further comprises pharmaceutical preparations which are particularly suitable for the treatment of inflammation in animals and humans and contain at least one compound of the formula (1), preferably with a compatible pharmaceutical carrier or auxiliary. 

 

   The preparations can be in the form of dosage units, e.g. B.  Tablets, granules, capsules, dragees, suppositories or injectables are formulated in ampoules.  The dosage units preferably contain 0.05 to 10 mg of active ingredient.  The preparations can also be formulated as a spray, powder, drops, aerosols, retention enemas, suspensions, syrups, elixirs, emulsions, ointments, lotions or creams.  These preparations preferably contain 0.0001 to 5% by weight. -%, preferably 0.001 to 0.5 wt. -%, in particular 0.01 to 0.25 wt. -% of the active ingredient of formula (I).   



   The pharmaceutical preparations can be administered orally for the treatment of inflammation, in particular arthritis and rheumatism, intravenously in aqueous solution as 21-hemisuccinate or 21-phosphate ester for the treatment of shock, intramuscularly for achieving a systemic long-term effect or intra-articularly for achieving a local long-term effect with little systemic effects for the treatment of primary chronic rheumatoid arthritis, tennis elbow, bursitis, gout and similar diseases by administration in aqueous suspension as 17.21 -dicarbon carboxylates, e.g. B. 

   17,21-dipropionate, 17,21-dibutyrate and 17-benzoate-21 acetate, locally in creams, lotions or ointments as 17-mono-lower alkanoate or benzoate for the treatment of contact dermatitis and allergic dermatitis and psoriasis and of diseases such as Alopezia areata and alopezia totalis can be administered as a result of corticosteoride hypersensitivity, in the form of eye suspensions or nasal sprays or as inhalation aerosols for the treatment of asthma and allergic rhinitis.  These pharmaceutical forms are manufactured by known methods and can contain other active ingredients such as antibacterial agents, e.g. B.  Neomycin sulfate contained in creams for topical use. 



   The following examples illustrate pharmaceutical preparations according to the invention for topical use. 



  Each preparation contains 7a-chloro-1 6o-methyl-1, 4-pregnadiene-1 ss, 17a, 21-triol-3,20-dione-17,21-dipropionate as the preferred active ingredient, but this compound can also be produced by equivalents Amounts of other active compounds according to the invention, e.g. B.  by the 17,21-dipropionate or the 17-benzoate-21-propionate of 7a-bromo-16a-methyl-l, 4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione.  The pharmaceutical preparations are produced by customary methods. 



   Examples of drug preparations 1.  Ointment mg / g active ingredient 0.1-5.0 mineral oil 20.0 white petrolatum ad 1.00 g 2.  Glycol ointment active ingredient 0.1-0.5 hexylene glycol 100.0 propylene glycol monostearate 20.0 white wax 60.0 white petrolatum ad 1.00 g 3.  Active ingredient lotion 0.1-5.0 ethyl alcohol 400.0 polyethylene glycol 400 300.0 hydroxypropyl cellulose 5.0 propylene glycol ad 1.0 g 4.  Gel mg / g active ingredient 0.1-5.0 ethyl alcohol 400.0 polyethylene glycol 400 300.0 Carbopol 940 (Goodrich Chemical Co. ) 15.0 potassium hydroxide 5.0 propylene glycol ad 1.00 g 5.  Active ingredient cream 0.1-5.0 isopropyl palmitate 100.0 glycerol stearate 80.0 Promulgen type D (Robinson, Wagner Co. ) 50.0 white wax 50.0 propylene glycol 100.0 purified water ad 1.00 g 6. 

  Aerosol for topical use mg / can of active ingredient 6.4 mineral oil 1 250.0 caprylic acid capric acid glyceride Neobee M-5 (PVO International, Inc. ) 3 743.6 dichlorodifluoromethane 17 200.0 trichloromonofluoromethane 68 800.0
91,000.0 7.  Aerosol for inhalation active ingredient 12.60 oleic acid 1.26 trichloromonofluoromethane 5 686.14 dichlorodifluoromethane 14 700.00
20 400.00 8.  Intra-articular injection mg / ml active ingredient 0.1-5.0 sodium phosphate, dibasic, anhydrous R 2.0 sodium chloride, USP 5.0 disodium edetate, USP 0.10 polysorbate 80, USP 0.50 benzyl alcohol, R 9.00 methyl p-hydroxybenzoate, USP 1.80 propyl p-hydroxybenzoate, USP 0.20 sodium carboxymethyl cellulose 5.00 polyethylene glycol 4000, USP 20.00 lN-HCl, q. s.  pH 7.1 water for injection ad 1.00 ml 9.  

  Solution active ingredient 0.1-5.0 N-methylpyrrolidone 20 isopropyl myristate 50 isopropyl alcohol ad 1.0 ml


    

Claims (10)

 PATENT CLAIMS 1. 3,20-dioxo-7a-halogen4-pregnene and -l, pregnadienes of the formula EMI1.1  in which the dashed line in the 1,2 positions indicates a 1, 2 single bond or a 1,2 double bond, W is a group of the formula (H, H), (H, lower alkyl), (H, a-OV1) or = CHT, where V1 is a hydrogen atom or an acyl radical of vitamin A acid or a carboxylic acid with up to 12 C atoms and T is a hydrogen, fluorine or chlorine atom or a lower alkyl radical, Q represents a chlorine atom or bromine atom or a group of the formula OV, in which V is a hydrogen atom or an acyl radical of a carboxylic acid having up to 12 C atoms, or Q in cases in which W is a group of the formula (H, H) or (H, lower alkyl) is  can also be a hydrogen atom, or Q and W together represent a 1 6a, 1 7a-lower alkylidenedioxy, cycloalkylidenedioxy or aralkylidenedioxy group together with a 1 6p hydrogen atom or a group of the formula EMI1.2  form in which R is a lower alkyl radical and Rl is a lower alkyl radical or phenyl radical, B is a hydrogen atom or together with Q forms a 1 4a, 1 7a-lower alkylidenedioxy group, M is a group of the formula -CHO or such a group in the form of an acetal, hemiacetal or acylal, a group of the formula -CH3, -COOR3, -CH2Hal or -CH2OV2, in which R3 is a hydrocarbon radical having up to 12 C atoms, Hal is a halogen atom with an atomic weight of less than 100 and V2 is a hydrogen atom or an acyl residue of vitamin A acid, a carboxylic acid with up to 12 C atoms or of phosphoric acid,  which may be in the form of a mono- or dialkali or alkaline earth metal salt, or OV2 together with Q an alkylidendioxy, cycloalkylidendioxy, aralkylidendioxy group or an alkyl-o-alkanoate or alkyl-o-arylcarboxylate group of the formula EMI1.3  in which R and Rl have the meanings given above, or M in cases in which Q is an O-acyl radical can also be a group of the formula -OR2 in which R2 is a lower alkyl radical or lower haloalkyl radical, X is a hydrogen atom or a halogen atom with an atomic weight of less than 100, Y is an oxygen atom or a group of the formula (H, ss-OH) or (H, -OCOH) or, if X is a chlorine or bromine atom,  also a group of the formula (H, -halogen) in which the halogen atom has an atomic weight of less than 100 and is at least as electronegative as X, or, if X is hydrogen, can also be a group of the formula (H, H) , A, which is in the a-position in the SPregnenes, is a hydrogen atom or, if Y is (H, p-OH), can also be a chlorine atom or fluorine atom or a methyl radical and Z is a fluorine atom, chlorine atom, bromine atom or iodine atom, and, if W stands for (H, H), their D-homo analogues.  2. Compounds according to claim 1, characterized in that Z is a chlorine atom or bromine atom and / or X is a hydrogen atom and / or W is a methylene radical or the group (H, CH3) and / or Y is an oxygen atom or the group (H , 13-OH) and / or the dashed line in the 1,2 positions indicates a 1,2 double bond.  3. Compounds according to claim 1 or 2 with the formula EMI1.4  where Z is a chlorine atom or bromine atom, W is a methylene radical or the group (H, CH3), preferably the group (H, α-CH3), Y is an oxygen atom or preferably the group (H, ss-OH) and V and V2, which may be the same or different, are hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids having up to 12 C atoms, preferably having up to 8 C atoms, in particular those compounds in which V eirre n-butyryl or preferably a propionyl or benzoyl group, Y are the group (H, B-OH) and V2 are a lower alkanoyl radical with up to 8 C atoms,  how 7a-chloro-16a-methyl-1,4-pregnadiene-11 ss, 17a, 21-triol-3,20-dione-17,21-dipropionate, 7a-bromo-16a-methyl-1,4-pregnadiene-1 lss, 17a, 21-triol-3,20-dione-l 7.21 dipropionate, 7α-bromo-16α-methyl-1,4-pregnadiene-11ss, 17α, 21-triol-3,20-dione-1 7-benzoate-2 l-acetate and 7α-Chloro-16-methylene-1,4-pregnadiene-11ss, 17α, 21-triol3,20-dione-l 7.2 1-dipropionate.    4. 3,20-dioxo-7a-halogen-4-pregnene according to claim 1 of the formula EMI2.1  wherein Z is a chlorine atom, bromine atom or iodine atom, Y is an oxygen atom or the group (H, ss-OH), Wein methylene radical or the group (H, CH3) or (H, H) and V and V2, which are the same or different can, are hydrogen atoms or acyl radicals of hydrocarbon carboxylic acids with up to 12 carbon atoms, in particular 7a-Chlorffipregnen-l 1113.1 l ss, 17a, 21-triol-3,20-dione-17,21-dipropionate.  5. A process for the preparation of compounds according to claim 1, wherein Z is a chlorine atom, bromine atom or iodine atom, with the proviso that Z in cases where X is a halogen atom is not a chlorine atom, characterized in that a hydrogen halide is obtained from the Group consisting of hydrogen chloride, hydrogen bromide and hydrogen iodine to the 6,7 double bond of a compound of the formula EMI2.2  in which the dashed line A, B, M, Q, W, X and Y have the meanings given in claim 1, in the presence of an inert solvent with the proviso that I) in cases where the hydrogen halide is hydrogen chloride, X is a hydrogen atom, II) in cases where Y is the group (H, ss-OH) and the hydrogen halide is hydrogen bromide, X is a hydrogen atom and III) in cases  in which Y is the group (H, B-OH) and the hydrogen halide is hydrogen iodide, X is a hydrogen atom, chlorine atom or fluorine atom, and isolates a compound according to claim 1.  6. The method according to claim 5, characterized in that one uses a compound of formula (IV) containing a 1,2-double bond, and an anhydrous inert organic solvent.  7. The method according to claim 6, characterized in that reacting the compound of formula (IV) with hydrogen chloride in tetrahydrofuran or with hydrogen bromide or hydrogen iodide in glacial acetic acid.  8. The method according to any one of claims 5 to 7, characterized in that one carries out the reaction at a temperature in the range from 0 "C to room temperature.  9. A pharmaceutical preparation containing as an active ingredient at least one compound according to claim 1 together with a pharmaceutical carrier or excipient.  10. Pharmaceutical preparation according to claim 9, containing as active ingredient at least one compound according to one of claims 2 to 4.  The invention relates to new steroids of the Pregnan series with valuable pharmacological properties, processes for their preparation and pharmaceutical preparations which contain them.  The invention relates to 3,20-dioxo-7a-halogen-4 pregnene and 1,4-pregnadienes of the formula EMI2.3  in which the dashed line in the 1,2 positions indicates a 1,2 single bond or a 1,2 double bond, W is a group of the formula (H, H), (H, lower alkyl), (H, a-0V ') or = CHT, where V' is a hydrogen atom or an acyl radical of vitamin A acid or a carboxylic acid with bis to 12 C atoms and T is a hydrogen, fluorine or chlorine atom or a lower alkyl radical, Q represents a chlorine atom or bromine atom or a group of the formula OV, in which V is a hydrogen atom or an acyl radical of a carboxylic acid having up to 12 C atoms, or Q in cases in which W is a group of the formula (H, H) or (H, lower alkyl), can also be a hydrogen atom,  or Q and W together form a 16a, 17a-lower alkylidene dioxy, cycloalkylidenedioxy or aralkylidenedioxy group together with a 16ss hydrogen atom or a group of the formula EMI2.4  form in which R is a lower alkyl radical and R 'is a lower alkyl radical or phenyl radical, B is a hydrogen atom or together with Q forms a 1 4a, 1 7a-lower alkylidenedioxy group, M is a group of the formula -CHO or such a group in the form of an acetal, hemiacetal or acylal, a group ** WARNING ** End of CLMS field could overlap beginning of DESC **.