CS197245B2 - Method of producing novel 2-brom-6-beta,9alpha-difluor-pregna-1,4-diene-3,20 diones or 17,21-esters,17-21-alkylorthoesters or 17,21-cyclic acetals or ketals thereof - Google Patents

Description

THE CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE PATENT 197245 (11) (B2) (22) Registered 24 02 75 (21) (PV 1199-75) (51) Int. Cl.3 C 07 J 5/00 // A 61 K 31/57 (32) (31) (33) Priority from 27 02 74 (8928/74) United Kingdom (40) Published 31 07 79 INVENTORY OFFICE DISCOVERIES (45) Published 15 05 83 (72)

The inventor of RIVA MARIO, MONZA (Milan) and TOSCANO LUCIANO, MILAN (Italy) (73)

Patent proprietor PIERREL SpA, MILAN (Italy) (54) Method for the production of new 2-bromo-6 / 3,9a-difluoro-pregna-1,4-diene-3,20-dione or 17,21-ester thereof, 17 , 21-alkylorthoesters or 17,21-cyclic acetals or ketals 1

The present invention relates to a process for the preparation of new 2-bromo-6β, 9α-difluoro-pregna-1,4-diene-3,20-diones or their 17,21-esters, 17,21-alkyl-orthoesters or 17, 21-cyclic acetals or ketals, which have significant anti-inflammatory activity.

Many steroids are known which exhibit pro-inflammatory activity when administered topically and / or systemically, and some of them have very good anti-inflammatory activity. Unfortunately, all of them cause undesirable side effects. For example, they may break the balance of minerals, such as lowering potassium and / or sodium levels, and may adversely affect kidney function. You need to be careful with them. SUMMARY OF THE INVENTION It is an object of the present invention to provide novel steroids having significant anti-inflammatory activity, i.e., greater than that of most of the known steroids, and which have very little or no side-effects in absolute terms. in particular, when expressed in the form of a thiotherapeutic insex, i.e., an effective dose ratio that is required to achieve the desired anti-inflammatory effect, to a minimum dose that produces undesirable side effects.

It has been found that 2-bromo-6,3,9a-difluoro-pregene-1,4-diene-3,20-diones have high anti-inflammatory activity and have no or only minimal side effects of known steroid compounds .

The present invention provides a process for the preparation of said novel 2-bromo-6 / 3,9a-difluoro-pregna-1,4-diene-3,20-dione or its 17, 21-ester, 17,21-alkylorthoester or 17,21 - cyclic acetals or ketals, general formula A

CH.OGL

AND

wherein Q is either a hydrogen atom or an acyl radical having 2 to 12 carbon atoms, or both OQ groups are taken together to form a cyclic ketal of 2 to 12 carbon atoms, an acetal to 2 to 12 carbon atoms, or an alkylorthoester. up to 12 carbon atoms, R represents a hydrogen atom or a-197245 197245 -OQ wherein Q is as defined above, and pharmaceutically acceptable salts or esters of compounds of formula A wherein Q is a carboxylic acid residue of 2 to 12 carbon atoms or organic acids.

Suitable pharmaceutically acceptable salts are, in particular, water-soluble salts, preferably alkali metal salts such as sodium or potassium. Preferred esters are esters containing an aliphatic, aryl, arylaliphatic or cycloaliphatic group.

Typical representatives of the aliphatic groups useful in the present invention for esterifying the di-carboxylic acyl group are alkyls, especially those having from 1 to 7 carbon atoms, and alkenyls. Particularly preferred are alkyl groups containing up to 4 carbon atoms, especially methyl, ethyl and propyl. Suitable cycloaliphatic groups are those having from 5 to 8 carbon atoms, for example cyclopentyl cyclohexyl. Typical arylaliphatic groups are phenylalkyl groups whose alkyl moiety is as defined above, for example benzyl. Typical aryl groups include phenyl, for example unsubstituted phenyl.

When Q in the above general formula (A) is acyl, OQ is an ester residue in which Q may be an inorganic acid residue, for example sulfuric or phosphoric acid, or an organic acid residue, for example sulfonic acid or carboxylic acid, including aliphatic. , alicyclic, aromatic, arylaliphatic and heterocyclic carboxylic acids, including thiocarboxylic acids and aminocarboxylic acids. Suitable carboxylic acids include, for example, formic acid, acetic acid, chloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, trimethylacetic acid, diethylacetic acid, caproic acid, crotonic acid, acid enanthic, caprylic, caproic, palmitic, un-decanoic, undecylenic, oxalic, succinic, glucaric, pimelic, tartaric, maleic, lactic, carbamic, glycine, alkoxycarboxylic, acids, hexahydrobenzoic acid, cyclopentylpropionic acid, cyclohexylacetic acid, cycloihexylbutyric acid, benzoic acid, phthalic acid, phenylacetic acid, phenylpropionic acid, furan-2-carboxylic acid, nicotinic acid and isonicotinic acid. Preferred sulfonic acids are methanesulfonic acid and toluenesulfonic acid.

Particularly preferred acyl radicals are those derived from acetic acid, trimethylacetic acid, propynoic acid, (3-phenylpropionic acid, α-phenylpropionic acid, valeric acid and from dicarboxylic acids, e.g. when at position 21 the group Q is the aforementioned acyl group, especially the preferred carboxylic acid mentioned above, since the 21-esters have a particularly good biological activity, in the 16,17 or 17,21 positions of the steroid of formula A, Any conventional cyclic ketal or cyclic acetal, preferably acetonide or 17,21-methyl-dioxy derivative, is formed, for example, 17,21-methylorthoacetate, 17,21-methylorthoacetate, may be suitable cyclic ortho-esters. , 21-ethylorthopropionate, 17,21-methylorthobenzoate and 17,21-methylorthovalerate The preferred group of compounds of the present invention are those compounds of formula (A) wherein R is hydrogen or a-OQ.

The general method for producing pregna-1,4-diene-3, 20-dione is well known. Also known is a process for the production of some 2-bromosteroids and a process for producing 6-α-fluorsteroids. Several methods for the preparation of 6, 3-fluorsteroids are described in the literature, but it is generally believed that from the pharmaceutical point of view 6- / 3-fluorsteroids are less effective than 6-a-fluorsteroids. The combination of 2-bromo- and Q-β-fluoro substituent in pregna-1,4-diene-3,20-dioethane is novel and leads to substances with significant anti-inflammatory activity which, as noted above, have little or negligible effects.

The novel steroids of formula A have significant anti-inflammatory activity. This activity manifests itself in the conventional method of application, for example, by local or systemic application. Some compounds give better results for topical application and others for systetic administration, especially when administered orally. Due to the very high potency of the preferred compounds of the invention, they can be used at lower doses than usual for known anti-inflammatory active steroids; however, even with the usual dosage, the compounds of the invention have a much lower, and usually no, side-effect to the known anti-inflammatory-active steroids.

The novel steroids of the present invention can be used to treat a variety of inflammatory diseases, for example, to treat inflammatory conditions of the skin, eyes and ears in humans and pets, to contact dermatitis and other allergic reactions, and also to be effective against rheumatoid arthritis.

The therapeutic compositions of the present invention contain a steroid of formula A and a pharmaceutically acceptable liquid or solid carrier as active ingredient. Any of the therapeutically appropriate and effective concentrations of the compound of the invention can be used in said formulations. Depending on the method of administration chosen, any suitable formulation can be made. For oral administration, all forms of therapeutic agents are, for example, capsules, tablets, capsules, solutions, syrups or elixirs, for injecting liquid form analogous to known injectable preparations of natural and synthetic cortico-steroid hormones, and topical application, for example ointments, creams and lotions. The medicaments may also contain co-acting antibiotics, germicides, and other substances that form preferred combinations with the compounds of the invention.

The local anti-inflammatory activity of the compounds of the invention was tested on rats with a sgranuloma-induced paper pellet, where the test compounds were administered directly in the pellet. All new steroids of formula (A) showed significant anti-inflammatory activity without undesirable side effects of the buff and weight gains, in very high concentrations (40 micrograms / pellet).

The most potent compounds of formula (A) inhibit the paper-induced granuloma already at a dose of 0.002 to 0.1 microgram / pellet, while Fluocinolone-16,17-acetonide produces the same effect at a dose of 0.5 to 2 micrograms / pellet. Other compounds of the present invention are effective at dosages ranging from 0.1 to 2 micrograms / pellet, while Tamamethasone 17-valerate is effective at 5 to 20 micrograms / pellet. Some other compounds of the present invention are effective at doses greater than 2 micrograms / pellet, and Iydrocortisone acetate exhibits the same activity at a dose of about 100 to 200 micrograms / pellet.

Systemic anti-inflammatory effects were evaluated in rats with granuloma-induced paper pellets, the test compounds administered orally for 8 days. The most effective compounds of formula (I) were effective at doses ranging from 0.01 to 0.1 mg / kg body weight. rats. Under the same experimental conditions, Bepetethazone (alcohol or phosphate) showed efficacy at doses of about 0.05 to 0.1 mg / kg, while Hydrocortisone acetate and Methylprednisolone were effective at doses ranging from 10 to 50 mg / kg. The invention has no kidney weight inhibitory effect in this test, and their thymolytic activity, or their body weight reduction effect, was less than the effects of the most effective steroids already suggested.

The principle of producing new 2-bromo-6 (3,9a-difluoropregna-1,4-diene-3,20-dione or its 17, 21-esters, 17,21-alkylorthoesters or 17,21-cyclic acetals) or ketals of the present invention in that 2-bromo-6H-fluoro-17,21-dihydroxy-pregna-1,4,9 (11) -trien-3,20-dione-17, 21-diester, 17,21-alkyl-thoester or 17,21-cyclic acetal or ketal of formula B

With CMOGL · I *

in which

Q and R are as defined above, reacting with bromine acid to give 2,9-dibromo-6S-fluoro-11,17,21-trihydroxy-preg-na-1,4-dlen-3,20-dione -17,21-diester, 17,21-alkylorthoester or 17,21-cyclic acetal or ketal of formula C CHJJQ,

I Z

in which

Q and R are as defined above, whereby a compound of formula C wherein Q is a carboxylic acid residue of 2 to 12 carbon atoms or an inorganic acid residue, optionally converted to pharmaceutically acceptable salts or esters, is then treated with a carbonate solution alkali metal to give 9,11-epoxide 2-bromo-6 H -fluoro-9,3,11 S-oxide-17,21-dihydroxy-pregna-1,4-diene-3,20-dione and its 17,21-di-ester, 17,21-alkylorthoester or 17,21-cyclic acetal or ketal, general formula D

wherein Q and R are as defined above, whereupon the compound of formula D is reacted with hydrogen fluoride to give 2-bromo-6,3,3-difluorophenyl, 17,21-trihydroxy-pregna-1, 4-diene-3,2-dione and its 17,21-diester, 17, 21- 197245

an alkylorthoester or a 17,21-cyclic acetal or ketal of formula F

wherein Q and R are as defined above, optionally converting the compound of formula F wherein Q is a carboxylic acid residue of 2 to 12 carbon atoms or an inorganic acid residue into a pharmaceutically acceptable salt or ester thereof.

The 16,17-unsaturated compound required as starting material for the preparation of the 16,17-dihydroxy compound can be produced by dehydrating the corresponding 17-hydroxy compound of the formula XI below, wherein R 3 is a hydrogen atom such that all the aforementioned methods 1 to 7 can be carried out using a 9,11-unsaturated compound of the general formula VIII (see below) wherein R 3 represents a hydrogen atom or a methyl group as starting material. Scheme 1 lists the reactions suitable for the preparation of compounds of formula VIII using the known starting compound of formula I.

Scheme 1

Hereinafter, a suitable method for carrying out the individual reaction steps shown in Scheme 1 is described. Known starting material, 11a, 17a, 21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (Ij, or its known 16 " - or the 16/2-analogue is first converted to the 3-ketal (preferably as the ketalizing agent, ethylene glycol is preferably used in the presence of p-toluenesulfonic acid or pyridine hydrochloride). double bonds from position 4.5 to position 5.6.

Epoxidation of 5 (6-double bond IIperic acid with acid (perbenzoic acid, mono-acetal acid or other known epoxidizing agent) affords the appropriate 5a, 6'-epoxide (III). For the next reaction step, α-epoxide III is used, in which step 11a, 17a, 21-trihydroxy-3,3-ethylenedioxy-5a, 6a-oxidase is used. pregnan-20-on-21-acetate (III) is not reacted with hydrofluoric acid, whereby the epoxide ring opens to give the corresponding 6 / M-fluoro-5a, 11a, 17a, 21-tetrahydroxy- pregnane-3,20-dione-21-acetate (IV) followed by buffered bromination of compound IV, which is stopped on 2α-bromo-6 (3'-fluoro-5α) IIIa, 17α, 21-tetrahydroxypregnane-3,20-dione -21-acetate (V).

Addition of methanesulfonyl chloride to compound V gives 2a-bromo-6H-fluoro-5α, 11β, 17β-21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI) . Treatment of the mesylate VI with acetic anhydride and hydrochloric acid gave 2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17, 21-triacetate (VII), which is converted to 2,2-dibromo-6 (3-fluoro-11a, 17'-21-trihydroxy-pregn-4) by bromination in acetic acid in the presence of potassium acetate or sodium acetate. -en-3,20-dione-11-methyl-17,21-diacetate (VII bis). Treatment of some metal halides, especially lithium chloride and lithium bromide in dimethylformamide with heating, dehydrobromines the corresponding VII-trienvIII, 2- bromo-6/1-fluoro-17α, 21-dihydroxy-pregna-1,4,9 (11) -trien-3,20-dione-17,21-diacetate. amidic solvents such as dimethylacetamide or N-formylpiperidine The modified method involves the use of excess lithium carbonate in dimethylformamide.

A particularly important step in the above reaction scheme is the preparation of the compound of formula V. The corresponding 2a-compounds are prepared according to the invention by bromination of the compounds of the formula IV as well as by bromination of the corresponding 11 and / or 17-esters and / or 21-hydroxy derivatives. By introducing bromine into the 2-position at this stage, it appears that 6β-fluorochinase is fixed so that the steroid molecule is stable during subsequent reactions.

Compounds of formula V, as well as 11 and / or 17-esters and / or 21-hydroxy derivatives are novel compounds; the novel compounds are also all compounds of formulas II to VIII inclusive.

Suitable methods for carrying out the above-mentioned processes 1 to 7 according to the invention are shown in Reaction Scheme 2. 197245

Scheme 2 CH.OAo CH.OAc, CHO Oa and l ** i * - | - * ·

CO CO. CO

197245 11

By reacting compound VIII with bromine acid, the appropriate 9a-bromo compound IX is prepared. When this 9a-bromo compound is reacted with potassium carbonate in acetone, 9 / 11,11-3-oxo compound X is formed. Reaction of the title compound with fluoro-hydrogen to give 2-bromo-6 (3,9a-difluoro) - 11 (3, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI, R 1 = R 2 OCOCH 3), which by hydrolysis is converted to the corresponding free alcohol of XIa (XI, R 1 = R 2 = OH) In a similar manner, by reacting Compound X with hydrochloric acid, 11-hydro-oxy-9a-chloroalogene is prepared, which is particularly useful when R 3 is methyl.

The stable configuration of the fluorine atom in 6 / Ϊ of compound XI (R1 = R2 = OCOCH3) results from the following observations. In attempts to isomerize 2-bromo-6 (3,9a-fluoro-11w, 17ia, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI, R1 = R2 = - OCOCH3) with anhydrous hydrogen chloride in chloroform at 0 ° C for 2 hours did not change the curve of the optical rotational dispersion of the crude product, and after recrystallization of this product a pure substance was obtained which was identical in all respects to the starting pattern XI (R t = R 2 = OCOCH 3).

Treatment of compound X with hydrochloric acid yields 2-bromo-6β-fluoro-9α-chloro-11 (3,17α, 21-trihydro-pregna-1,4-diene-3,20-dione). 17,21-diacetate (XIII).

Triene VIII is reacted with N-chlorosuccinimide to give 2-bromo-6 (3'-fluoro-9α, -11 / 3-dichloro-17α, 21-dihydroxy-pregna-1,4-diene) -3,20-dione-17,21-diacetate (XII, R 1 = R 2 = OCOCH 3), which by hydrolysis yields the corresponding free alcohol XIIa (XII, R 1 = R 2 - = OH).

Similarly, by reacting triene VIII with N-bromosuccinide, the corresponding 9a, 11β-dibromo-compound XII is formed, especially when R 3 is ethyl.

When compound XI (wherein R 1 = R 2 = OCOCH 3 and R 3 = H) is reacted with potassium acetate in hot dimethylformamide, 2-bromo-6,3,9a-difluoro-11 (3,21-dihydro- xy-pregna-1, 4,16-triene-21-acetate (XI, bis, R 1 = OCOCH 3) Oxidation of compound XI bis (R 1 = O'COCH 3) with potassium permanganate affords 2-bromo-6 (3,9a-difluoro- 11 (3,16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII, R 1 = OCOCH 3), which gives the corresponding free alcoholXVIIa (XVII, R t = OH).

Suitably, the esterification of the hydroxyl function at position 21 is carried out with a lower fatty acid anhydride, for example acetic anhydride, or preferably a lower aliphatic acid chloride, for example acetyl chloride, in the presence of pyridine, which simultaneously serves as a solvent; The 17α-esters are prepared by reacting the corresponding 17α, 21-diols with lower aliphatic oresters in the presence of an acid catalyst followed by acid hydrolysis of the resulting 17α, 21-orthoester (a mixture of two epimeric orthoesters).

Esterification of the hydroxyl function at position 21 can also be accomplished by transesterification of the appropriate 17α-esters.

Reaction of 17α, 21-diols with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid yields 17,21-acetonides.

Reaction of XVII with acetone and perchloric acid affords 16,17-acetonitrile XIX.

Esterification of the hydroxyl group at position 16 of compound XVII is carried out with the anhydride of the lower fatty acid in the presence of pyridine, which simultaneously serves as a solvent. The following is a particularly preferred compound of the invention and, for clarity, the following compound, corresponding to the general formula number in Schemes 1 and 2, given the large number of descriptive data required for the compounds of Formula XI. . Compounds in which R 3 represents a hydrogen atom or a hydroxyl group are numbered identically to the numbering of the formulas given in Schemes 1 and 2. Compounds in which R 3 denotes α- or β-methyl have a different numbering method in which the number 10 is general formula IX, number 11 corresponds to formula X and number 12 of formulas XI, XII and XIII. Preferred Compounds of the Invention: 2,9-dibromo-61d-fluoro-11'-17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (IX) , 2-bromo-613,9a-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI), 2-bromo-6,33 9a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa), 2-bromo-6 (3,9a-difluoro-11 (3 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (X1b), 2-bromo-6 (3,9a-difluoro-11 (3, r7a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate [XIc), 2-bromo-6 (3,9a-difluoro-11, 17K, 21-trihydrogen) -roxy-pregna-1,4-diene-3,20-dione-21-propionate (Xldt), 2-bromo-6,3,9a-difluoro-11 (3,11a, 21-trihydroxy-pregna-1) , 4-diene-3,20-dione-21-valerate (Xle), 2-bromo-6 / 3,9a-difluoro-1113 ', 17a, 21-trihydroxy-pregna-1,4-diene- 3,20-dione -21-pivalate (X1f), 2-bromo-6,3,9a-difluoro-11 (3,17a, 21-trihydroxy-1 97 245 13 roxy-pregna-1,4-diene-3 , 20-dione-21-tert-butyl acetate (1g), 2-bromo-6-i, 9'-difluoro-11 / S, 17a, 21-trihydroxy-pregna-1,4-diene-3,20- dione-21-enanthate (X1h), 2-bromo-61d, 9 α-difluoro-11 H, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (Xi1, 2-bromo-6β, 9α-difluoro-11) , 17 · α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XII), 2-bromo-6 / 3,9a-difluoro-11/1, 17a , 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate-21-acetate (X1m), 2-bromo-6, 9a-difluoro-11'1, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (Xln), 2-bromo-6 / 3,9a-difluoro-11, 17a, 21-trihydric roxy-pregna-1,4-diene-3,20-dione-17-acetate-21-valerate (XIo), 2-bromo-6,3,9a-difluoro-11j, 17a, 21-trihydroxy-pregna- 1,4-diene-3,20-dione-17-propionate (XIp), 2-bromo-6R, 9a-difluoro-11/3 ', 17', 21-trihydroxy-pregna-1, 4-diene-3,20-dione-17-benzoate (X1q), 2-bromo-6'-fluoro-9a, 11'-dichloro-17a, 21-dihydroxy-pregna-1,4-diene-3 20-dione-17,21-diacetate (XIII) 2-bromo-6? -Fluoro-9?, 11? -Dichloro-17?, 21-dihydroxy-pregna-1,4-diene-3,20- - dione (XIIa), 2-bromo-6 (1-fluoro-9a, 11'-dichloro-17,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (XHb ), 2-bromo-6-chloro-9a, 11 '-dichloro-17,21-dih' ydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XIIc), 2-bromo-6β, 9a-difluoro-11 / 3,16a, 17a, 21 - tetrahydroxy-pregna 1,4-diene-3,20-dione-21-acetate (XVII), 2-bromo-6R, 9a-difluoro-11H, 16a, 17a, 21-tetrahydroxy-pregna-1, 4-diene-3,20-dione (XVIIa), 14 2-bromo-6H, 9a-difluoro-11 / S, 1 & a, r7a, 21-tetrahydroxy-pregna-1,4-diene 3,20-dione-16,17-acetonide (X1aa), 2-bromo-6'-fluoro-9a-chloro-11jS, 17f1f, 21-trihydroxy-pregna-1,4-diene-3,20 -dione-17,21-diacetate (XIII), 16α-methyl-2,9α-dibromo-6β-fluoro-11β (3,17α, 21-trithydroxy-pregna-1,4-dien-3) 20-dione-17,21-diacetate (10a), 16β-methyl-2,9w-dibromo-6 H -fluoro-11 (3,17,21-trihydroxy-pregna-1,4-diene) -3,20-dione-17,21-diacetate (10b), 16α-methyl-2-bromo-B (S, 9α-difluoro-II (5,17β, 21-trihydroxy-pregna-1,4-) diene-3,20-dione-17,21-diacetate (12a), 16α-methyl-2-bromo-6β ', 9α-dlfluoro-11β, 17α, 21-trilhydroxy-pregna-1, 4 -dien-3,20-dione-17,21-diacetate (12b), 16α-methyl-2-bromo-6β-fluoro-9α-chloro-11β, 17α, 21-tritiydroxy-pregna-1 , 4- dien-3,20-dione-17,21 ' acetate (12c), 16β-methyl-2-bromo-6β-fluoro-9α-chloro-11 (3,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17) , 21-diacetate (12d), 16α-methyl-2-bromo-6 (α-fluoro-9α, 16β-dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione) 17,21-diacetate (12e), 16 (S-methyl-2-bromo-6β-fluoro-9α, 11β-di-chloro-17α, 21-dihydroxy-pregna-1,4-diene-3 , 20-dione-17,21-diacetate (12f), 16α-methyl-2-bromo-6,9,9a, -difluoro-11β, 17β, 21-trihydroxy-pregna-1,4- diene-3,20-dione (12g), 16β-methyl-2-bromo-6β, 9α-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20 -dione (124i), 1α-methyl-4-bromo-Oj-fluoro-gce.l, N-di-chloro-17,21-dihydroxy-pregna-1,4-diene-3,20-dione (121 ), 16-methyl-2-bromo-8,3-fluoro-9a ', 11S-di-chloro-17,21-dihydroxy-pregna-1,4-diene-3,20-dione (12)) , 16α-methyl-2-bromo-6 H, 9α-difluoro-11 (3.17w, 21-trihydroxy-pregna-1,4-dene-3,20-dione-21-acetate (12k), 16'-methyl-2-bromo-6'9a-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (121), 16α-methyl-2-bromo-6,3,9,9-diflu or - 11 / 3,17of, 21-trihydroxy-pregna-1,4-diene-3,20'-dione-21-propionate (12m), 2-bromo-6 (1,9a-difluoro-11) J, 16, 17, 21 - tetrahydroxy-pregna-1,4-diene-3,20-dione-16,21-diacetate (XVIII), 2-bromo-6β, 9a-difluoro-11,1 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide-21-acetate (XIX) 197245 15 16/2-methyl-2-bromo- 60,9-difluoro-11,17,17, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (12n), 16a-methyl-2-bromo-6 / 3- fluoro-9a, 11 3-di-chloro-17,10 ', 21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12o), 1b-methyl-4-bromo N, N -fluorobenzo [d] -di-chloro-17,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12p), 16a-methyl-2-bromo-6β , 9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q), 16α-methyl-2-bromo-6β , 9a-difluoro-11 / 3,17ia, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12r), 16/3-methyl-2-bromo-6 / 3,9a-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12s), 16/3-methyl-2-bromo-6,9,9a -difluoro-11,17a, 21-trihydr oxy-pregna-1,4-diene-3,20-dione-17-acetate (121), 16'-methyl-2-bromo-6 (3-fluoro-9a, 11'-di-chloro-17-ene, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12u), tert-S-methyl-Z-bromo-B / S-fluoro-tert-1-di-chloro- 17,21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12v), 16a-methyl-2-bromo-6 / 3,9a-difluoro-11/3, 17: α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12w), 16β-methyl-2-bromo-60,9a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12z), 16a-methyl-2-bromo-b (3,9a-difluoro-- 11,17w, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12aa), 16-methyl-2-bromo-6 / 3,9a-difluoro-11 3,17, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12ab), 16a-methyl-2-bromo-6,3,9a-difluoro-11/3 , 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12ac), 16/3-methyl-2-bromo-6 / 3,9a-difluoro-11 ( 3,17, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12ad), 16a-methyl-2-bromo-6,3,9a-difluoro-11/3 ' , 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12ae, 16/3-methyl-2-bromo-6 (3,9a-difluoro-11S, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12af), 16 16a-methyl-2-bromo-6,3,9a-difluoro-11j, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate (12ag) and 16α-methyl-2-bromo-6,3,9a-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-benzoate (12ah).

Particularly suitable for topical application are the compounds of formulas XI and Xd1, Xle, Xlf, Xl1, Xlm, X1p and Xlq and compounds 12k, 12i and 12o. Particularly preferred for systemic administration, as well as prosystemic and topical application, are those of Formulas XIa, XIc, XIII, XIX, 12g and 12k; a compound of the general formula X n1 is also very suitable for systemic application. Particularly preferred compounds of the invention are compounds of formula XI and XIa.

The process according to the invention is explained in more detail below. In the examples, the sales designations refer to products of the following composition: CELITE is a diatomaceous earth product, FLORISIL is a magnesium silicate based product (100: 200 mesh), POLYSORBATE 60 is a polyoxyethylene-20-sorbitan monostearate, POLYSORBATE 8.0 and TWEEN 80 are polyoxyethylene-20-sorbate monooleate, CARBOPOL 934 is carboxyvinyl polymer-soluble water-soluble resins, having a number average molecular weight of 2 to 3. 106, EMULGIN C-700 is cetostearyl alcohol condensed with 10 ml of ethylene oxide. Example 1

A mixture of 8 g of 11a, 17a, 21-trihydroxy-preg-4-ene - 3,20-dione-21-acetate (I), 200 ml of benzene, 80 ml of ethylene glycol and 4.8 g of pyridine hydrochloride is heated with stirring 8 hours boiling to distill off and separate the resulting water in the separator. Upon completion of the reaction, 200 mL of 5% aqueous sodium bicarbonate solution is added and the mixture is concentrated to form crystals and then poured into cold water. The precipitate formed is filtered off, washed with water into a neutral reaction and dried. After recrystallization of the product from chloroform / ethyl ether, 6 g of 11a, 17a, 21-trihydroxy-3,3-ethylenedioxy-pregn-5-en-20-one-21-acetate (II) are obtained. IR (KBr) (infrared spectrum in KBr table): 3565, 3540, 3450 (broad), 1755, 1730, 1220 cm -1. 17 197245

Analysis: for C25H36O7 calculated: 66.94% C, 8.09% H, found: 67.07% C, 8.15% H. Example 2 To a solution of 6 g of 11a, 17a, 21-trihydroxy-3,3- -ethylenedioxy-pregn-5-en-20-one-21-acetate (II) in chloroform (200 ml) was added dropwise at -30 ° C over 1.5 hours to a solution of monoperphthalic acid (8 g) in ether (60 ml) ). The reaction mixture was maintained at -30 ° C for 3 hours and then washed with 5% aqueous sodium bicarbonate solution to lose the acidic reaction. The organic phase was washed with water, dried and the solvent was distilled off. The residue obtained after recrystallization from methanol was 4.5 g of 11a, 17of, 21-trihydroxy-3,3-ethylenedioxy-5a, 6a-oxido-pregan-20-one-21-acetate (III). IR (KBr): 3585, 3540, 3485 (broad), 1760, 1732, 1230 cm @ -1.

Analysis: for C 25 H 36 O 8: Calculated: 64.63% C, 7.81% H, found: 64.78% C, 7.82% H. Example 3 4.5 g lla, 17a, 21- trihydroxy-3,3-ethylenedioxy-5α, 6α-oxido-pregnan-20-one-21-acetate (III) is added to 45 ° C with stirring and cooling at 6565 ° C. ml of 70% aqueous hydrofluoric acid. After addition of the solution, the solution was stirred at -60 ° C for 0.5 h and then poured into water (650 mL). The precipitate was dissolved in ethyl acetate (400 mL), washed with aqueous sodium bicarbonate until the acidic reaction was lost, then washed with water until neutral and dried over sodium sulfate. After distilling off the solvent, a crude product was obtained, m.p. 198-101 ° C.

After one crystallization from acetone with spetrol ether, 3 g of 6β-fluoro-5α, 11α, 17α, 21-tetrahydroxypregnane-3,20-dione-21-acetate (IV) are obtained, m.p. 205-207 ° C.

Optical rotation: [α] D = + 36 ° (c = 1.0, dioxane), UF (ultraviolet spectrum): λ max (methanol) = 290 nm (ε 104), IR (KBr): 3640, 3440 (broad) 1745, 1730, 1705, 1230 cm @ -1. 18

Analysis: for C 23 H 33 FO 7 calculated: 62.71% C, 7.55% H, 4.31% F, found: 62.83% C, 7.52% H, 4.45% F.

After purification of the crude product by silica gel column chromatography (FLORI-SIL), the ratio of product to silica gel was 1: 50 using chloroform-methanol (99: 1) as eluent to give 6β-fluoro-5a, 11a, 17a, 21-tetrahydroxy-pregan-3,20-dlon-21-acetate (IV) mp 223-224 ° C. UF: linax (methanol) 290 nm (ε 97), optical rotation: [α] 02θ = + 51 ° (c = 1.0, chloroform) Example 4 To a solution of 2 g of sodium acetate and 10 g of 6 S-fluorine 5a, 11a, 17a, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IV) in 100 ml of dioxane with stirring, at 25 to 30 ° C, over 2 to 3 minutes, dropwise a solution of 4 g of bromine in 50 ml of dioxane. After addition of chromium, the reaction mixture was poured into 1500 ml of 5% aqueous sodium chloride solution.

The mixture was stirred at room temperature for 1 hour and then the precipitated white crystalline product was filtered off, washed with water and dried (8.5 g).

Recrystallization from a mixture of acetone, methanol and chloroform (1:10:20) gave 6 g of 2'-bromo-6,3-fluoro-5α, 11α, 17α, 21-tetra-hydroxy-pregnane-3,20 -dione-21-acetate (V) mp 139-140 ° C (dec.).

Optical rotation: [α] D = + 49 ° (c = 1.0, dioxane), UF:

Imax (methanol) = 288 nm (ε124),

Analysis: for C23H32BrFO7 calculated: 53.18% C, 6.20% H, 15.38% Br, 3.65% F, found: 52.93% C, 6.36% H, 15.59% Br, 3 EXAMPLE 5 To a solution of 10 g of 2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (V) in 50 mL of pyridine was added. with stirring, at a temperature of -5 ° C, 8 g of methanesulfonyl chloride are added in about 15 minutes. After the addition of chloride, the reaction mixture was stirred at about 0 ° C for 1.5 hours and then poured into a mixture of 400 ml of cold water and 200 ml of dichloroethane. The mixture was acidified with 4 N sulfuric acid pH 3.5 and stirred for 1 hour. The product is filtered, washed with water and dried; 9 g of 2α-bromo-6β-fluoro-5α, 11α, 17β, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (VI) are obtained.

Recrystallization from benzene gave a colorless solid, m.p. 122-123 ° C (dec.).

Optical rotation: [.alpha.] D @ 20 = -47 DEG (c = 1.0, dioxane); UF: .lambda.max (m @ +; thinol) 288 cm @ -1; IR (KBr): 3560, 3520 (broad); ), 1730 (broad), 1330, 1230, 1170 cm -1.

Analysis: for C21H34BrFO9S calculated: 48.24% C, 5.73% II, 13.37% Br, 3.17% F, 5.36% S, found: 48.44% C, 5.60% H, 13 52% Br, 3.06% F, 5.45% S. Example 6 10 g of 2a-bromo-6,3-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20 The dione-11-mesylate-21-acetate (VI) was added to a solution of 75 ml of α-cetyl anhydride and 0.5 ml of 70% chloroacetic acid in 450 ml of ethyl acetate. The reaction mixture was heated to 30 ° C for 0.5 h and then extracted several times with 5% aqueous sodium bicarbonate. The ethyl acetate portion was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Recrystallization of the residue from methanol yields 9 g of 2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate - 5,17,21- of triacetate (VII), m.p. 131-132 ° C (dec.).

Optical rotation: [α] D = -11.7a (c = 1.0, chloroform), UF:

Λmax (λi), nm (ε 104), IR (KBr): 1740 (broad), 1370, 1230 (broad), 1170 cm -1, NMR spectrum (CDCl 3 - TMS),

Hz at 60 mHz: 304-290 (m, 2, C-2H and C-11H), 300, 284, 278, 262 (doublet of doublets, 2, -CH 2 OAc), 224, 210 (d, 1, C- 4 Ha), 184 (S, 3, OSO 2 CH 5), 124 (S, 8, 2 OAc), 120 (S, 3, OAc), 94, 90 (d, 3, 19 CH 3 cleaved 6.3/3F), 48 (S, 3, 18 CH 3).

Analysis: calculated for C28H38BTFO11S: 49.34% C, 5.62% H, 11.72% Br, 2.79% F, 4.70% S, found: 49.13% C, 5.43% H, 12% , 03% Br, 2.65% F, 4.57% S. Example 7 6.8 g 2-bromo-6,3-fluoro-5α, 11α, 17α, 21-tetra-hydroxy-pregnane -3,20-dione-11-mesylate-5,17,21-triacetate (VII) is dissolved in 330 ml of anhydrous acetic acid on a water bath at 90 ° C. A solution of sodium acetate (15.3 g, dried at 110 ° C) in acetic acid (60 ml) was added to the solution at 90 ° C, and then a solution of 1.75 gbromic acid in acetic acid (25 ml) was added in one portion. The reaction mixture was heated to 90 ° C until discolouration (about 3 minutes total), then cooled rapidly to room temperature and poured cold water if possible. The precipitated material is filtered off, washed thoroughly with water and dried to a constant weight. Approximately 6.5 g of 2,2-dibromo-6 (3-fluoro-11a, 17a, 21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-di) is obtained. acetate (VII bis) which, after recrystallization from methanol, forms a colorless substance, m.p. 140-142 ° C (decomp.).

Λmax (MeOH) = 242 to 243 nm (ε 10,000) .delta. (KBr): 1745, 1730, 1697, 1625, 1340, 1230, 1170 cm @ -1.

Optical rotation: [α] D = -18 ° (c = 1.0, chloroform). NMR (CDCl 3 - TMS),

Hz at 60 mHz: 362, 358 (d, 1, C-4 H), 328, 278 (doublet of triplets, 1, C-6 H), 320-290 (m, 1, C-11 H), 302, 286, 280, 264 (doublet of doublets, 2, -CH 2 OAc), 228, 212, 204, 188 (doublet of doublets, 2, Cl

Ha and HjS), 190 (S, 3, -OSO2CH3), 130 (S, 3, OAc), 128 (S, 3, OAc), 108, 104 (d, 3, 19 CH3 cleaved 6 / 3F), 52 (S, 3, 18 CH 3). 355, 307 (doublet of triplets, 1, C-6 H), 197245 21

Analysis calculated for C26H33Br2FO9S:% C, 44.58;% H, 4.75; F, 2.71;% F, 4.58; Found: C, 44.63; H, 4.81; Br, 2.84% F, 4.38% S. EXAMPLE 8 7 g 2,2-Dibromo-6S-fluoro-11a, 17a, 21-trihydroxy-pregn-4-ene-3,20-dione 11-mesylate-17,21-diacetate (VII bis) is added to a mixture of 70 ml of dimethylformamide, 14 g of lithium carbonate and 7 g of lithium bromide in one portion while stirring at 100 ° C. The reaction mixture was heated to 130 ° C for 0.5 hour under nitrogen, then cooled and poured into cold water. The precipitate formed is filtered off, washed with water and dried.

After recrystallization of the crude product from acetone, 4.8 g of 2-bromo-6H-fluoro-17α, -21-dihydroxy-pregna-1,4,9 (11) -trien-3,20-dione-17,21- is obtained. diacetate (VIII), m.p. 270 DEG-271 DEG C. (dec.).

Optical rotation: [α] D = -88.5 ° (c = 1.0, chloroform), UF:

Λmax (methanol) = 246-247 ηΐΒ (ε12,750), IR (KBr): 1740 (broad), 1765, 1645, 1600, 1230 cm @ -1. NMR (CDCl 3 - TMS)

Hz at 60 mHz: 452 (S, 1, Cl Hj, 376, 372 (d, 1, C-4 H), 342-332 (m, 1, C-11 H), 334, 286 (doublet of triplets, 1 , C-6 H), 302, 284, 280, 262 (doublet of doublets, 2, CH 2 OAC), 130 (S, 3, OAc), 123 (S, 3, OAc), 94, 92 (d, 3, 19 CH3 cleaved 6 / 3F), 45 (S, 3, 18 CH3).

Analysis: for C25H28BrO2c: 57.37% C, 5.39% H, 15.27% Br, 3.63% F, found: 57.53% C, 5.61% H, 15.03% Br, 3.71% EXAMPLE 9 To a suspension of 10 g of 2-bromo-6,8-fluoro-17α, 21-dihydroxypregna-1,4,9 (11) -trien-3,20-dione-17,21-diacetate (VIII) in a mixture of 200 ml of tetrahydrofuran with 1 g of 70% perchloric acid and 10 ml of water at room temperature, for 22 hours, 7.1 g, 3-dibromo-5,5- dimethylhydantoin. During the addition of the dibromohydantoin, the suspension is gradually thinned and after 45 minutes all the substance is in solution. The reaction mixture was stirred for a further 2 hours, then a 10% aqueous solution of sodium sulfite was added with stirring (until a positive reaction to iodine starch was lost) and the solution was poured into 1000 ml of cold water. The precipitated product IX is filtered off and still used in the next reaction.

Analytically pure 2,9a-dibromo-6'-fluoro, r-11'S, 17or, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (IX) was obtained by recrystallization of the crude product from the acetone-hexane mixture. After drying in vacuo at room temperature, mp 208-210 ° C (dec.).

Optical rotation: [α] D = -18.2 ° (c = 1.0, chloroform), UF: λ max (methanol) 248 ΠΙΠ (ε 10,250). IR (KBr): 3520, 1755, 1740, 1710, 1675, 1640, 1605, 1230 cm @ -1.

Analysis: for C25H29Br2FO7: C, 48.41; H, 4.71; Br, 25.76; F, 3.06; Found: C, 48.74; H, 4.65; 3.31% F. Example 10 To a wet solution of 2,9a-dibromo-6/3-fluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dion-17 Of 21-diacetate (IX) (obtained according to Example 9 from 10 g of product VIII) in 200 ml of acetone at 20 ° C, with stirring, over 20 minutes, add 40 ml of 14% aqueous potassium carbonate solution and mix with 4 hours.

The reaction mixture is diluted with ice-water while stirring to rapidly precipitate 2-bromo-6,3-fluoro-17α, 21-dihydroxy-9,3,11 (S-oxido-pregna-1,4-diene-3, 20-dione-17,21-diaicetate (X), filtered off, washed with water and dried, m.p. 241-242 ° C. After recrystallization from benzene-cyclohexane, the melting point was increased to 248-249 ° C (dec.). Optical rotation: [α] D = -88.4 ° (c = 0.5, chloroform) IR (KBr): 1755, 1740 (broad), 1670, 1640, 1600, 1230 (broad) cm -1. 23

Anal. Calcd. For C25H2BrFO7: 30.07; C, 3.23; H, 14.81;% Br, 3.52; F, Found: C, 55.80; H, 5.15; 14.72% Br, 3.45% F. Example 11

The polyethylene bottle, equipped with an electro-magnetic stirrer, was charged with 100 ml of 70% defective hydrofluoric acid, cooled to -10%, and 10 g of 2-bromo- was added with stirring. 6d-fluoro-17α, 21-dihydroxy-9 (3,11β-oxido-pregna-1'-dione-1-yl acetate (X)) After 0.5 hours the reaction mixture is precipitated by pouring into a mixture of water The precipitated material is filtered off, washed with water and dried to constant weight to give about 9.5 g of 2-bromo-8S, 9a-difluoro-11S, 17ef, 21-trihydroxy-pregna-1,4. diene-3,2'-diion-17,21-diacetate (XI, R1 = R2 = OCOCH3). After recrystallization from benzene, 7 g of pure compound is obtained which is uniform in the thin layer chromatography on silica gel (chloroform-acetone-cyclohexane: 3: 2: 2: 3). Mp 290-292 ° C (dec.).

Optical rotation: [α] D = -36 ° (c = 1.0, chloroform), UF:

Imax (methanol) 246 UH1 (ε12,500). IR (KBr): 3520, 1758, 1733, 1705, 1680, 1650, 1610, 1235 cm @ -1. NMR (dimethyl-D 6 -sulfoxide - TMS)

Hz at 60 mHz: 471 (S, 1, Cl H), 393, 389 (d, 1, C-4 H), 350, 300 '(doublet of triplets, 1, 06 H), 341, 335 (d, 1 , Oll OH), 289 (S, 2, CH2 OAC), 270-240 (m, 1, H11H), 127 (S, 3, OAc), 122 (S, 3, OAc), 99, 96 (d, 19 CH 3 cleaved 6 / SF), 56 (S, 3, 18 CHS).

Mass spectrum (70 ev, source temperature 210 ° C, direct sample introduction): ions at m / e 558/560 (M +, C 25 H 29 BrF 2 O 7), 540/542, 538/540, 518/520, 498/500, 483 / 485,478 / 480, 458/460, 397/399, 377/379, 359/361, 357/359, 339/341, 317/319, 315/317, 299 / 301,278, 217/219, 212/214, 199/201 , 165, 147, 139, 121, 109, 91, 79, 73 (baseline), 89, 60.55.

Analysis: for C25H28BrF2O7 24 calculated: 53.67% C, 5.22% H, 14.28% Br, 6.79% F, found: 53.27% C, 5.22% H, 14.32% Br, 6.80 % F. Example 12

A suspension of 10 g of 2-bromo-8 S, 9 H -difluoro-11β, 17α and 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21 diacetate (XI, R 1 = R 2 = C) COCH 3) in 200 mL of a methanolic solution of potassium hydroxide is stirred at 0 ° C for 3 hours in a nitrogen atmosphere. Cold water is then added to the reaction mixture, the methanol is distilled off in a vacuum, the concentrated solution is acidified with acetic acid and the precipitate is filtered off to give 7 g of 2-bromo-6,9,9a-difluoro-17a, 21-- three hydroxy-progna-1,4 diene-3,20-dione (Xla j (XI, R 1 = R 2 = OH) with a melting point of 223 to 227 degrees Celsius (decomposition). mp 228-230 ° C.

Optical rotation: [α] D = -5.6 ° (c = 1.0, dioxane.

Imax (methanol) 246 ηΐΠ (ε 11700). IR (KBr): 3430 (broad), 1715, 1670, 1645, 1600 cm @ -1. NMR (dimethyl-D 6 -sulfoxide - TMS)

Hz at 60 mHz: 470 (S, 1, Cl H), 392, 388 (d, 1, C-4 H), 348, 298 (doublet of triplets, 1, C-6 H), 327, 322 (d, 1, C-11 OH), 316 (S, 1, C-17 OH), 280, 276, 270, 266, 261, 257, 250, 246 (eye-to-quartet after de-exchange, 2 , COCH 2 OH), 99, 96 (d, 3, 19 CH 3 cleaved 6 / 3F), 48 (S, 3, 18 CH 3).

Mass spectrum (70 ev, source temperature 210 ° C, direct sample introduction): ions at m / e 447/448 (M +, (I21H25BCF2O5), 456/458, 444/446, 427/429, 414/416, 394 / 396, 379/381, 359/361, 317/319, 315/317, 219/221, 217/219 (baseline), 212/214, 199/201, 139, 109, 95, 67, 55.

Analysis for C 21 H 25 BrF 2 O 5 calculated: 53.06% C, 5.30% H, 16.81% Br, 7.99% F, found: 53.15% C, 5.30% H, 16.73% Br, 8, Example F. To a solution of 10 g of 2-bromo-6β-fluoro-17α, 21-di-hydroxy-pregna-1,4,9 (11) -trien-3,20-dione - 17 Of 21-diacetate (VIII) and 40 g of lithium chloride in 200 ml of glacial acetic acid at 20 ° C, add 5 g of N-chlorosuccinimide with stirring, then mix for about 10 minutes at 20 ° C with stirring 10 ml of a 12% solution of hydrogen chloride in tetrahydrofuran are added dropwise, the reaction mixture is stirred for 3.5 hours and then poured into cold water, the precipitated product is filtered off, washed with water and dried, yielding 6 g of pure 2-bromo-6-ol. fluoro-9a, 11β-di-chloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII, R1 = R2 = -OCOCH3) at a temperature of mp 244-246 ° C (background).

Optical rotation: [.alpha.] D = -2.5 DEG (c = 1.0, chloroform), IR (KBr): 1753, 1740, 1672, 1645, 1602, 1230 cm @ -1, NMR (dimethyl-D6-sulfoxide - TMS)

Hz at 60 mHz: 465 (S, 1, Cl H), 394, 390 (d, 1, C-4 H), 350, 300 (doublet of triplets, 1, C-6 H), 320-305 (m, 1, C-11 H), 289 (S, 2 CH 2 OAC), 127 (S, 3, OAc), 110, 106 (d, 3, 19 GH 3 resolved 6 F), 61 (S, 3, 18 CH 3) .

Analysis: for C25H21BrCl2O2: 50.27% C, 4.72% H, 3.18% F, 11.87% Cl, 13.38% Br, found: 50.55% C, 4.81% H, 3 CI, 12.05% Cl, 13.67% Br. UF:

Imax (methanoi) 245-246 nm (ε 12,280). Example 14

By the method described in Example 12, 2-bromo-6 H -fluoro-9a, 11 + dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XII, R1 = R2 = OCOCH3) converts to 2-bromo-6/3-fluoro-9a, 11,3-dichloro-17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione (IIIa) ( XII, R 1 = R 2 = OH) m.p. 185-187 ° C (dec.). UF: λ max (methanol) = 245 nm (ε 12,000),

Optical rotation: [α] D = -j-34 ° (c = 0.7, chloroform). IR (KBr): 3450 (broad), 1715, 1675, 1645, 1605 cm-1, 26

Analysis for C 21 H 24 BrCl 2 FO 4 calculated: 49.43% C, 4.74% H, 3.72% F, 13.90% Cl, 15.66% Br, found: 49.78% C, 4.76% H, 3 F, 14.07% Cl, 15.75 Br. Example 15

A mixture of 7 g of 2-bromo-6H, 9α-difluoro-11,11a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (XI, Ri =! R2 = OCOCH3), 70 billion dimethylformamide and 3.5 g anhydrous potassium acetate were heated at 120 degrees Celsius for 0.5 hour under a nitrogen atmosphere. The reaction mixture is then cooled, poured into cold water and the precipitate formed is filtered off, washed with water and dried. Recrystallization of the crude product from acetone-hexane gave 5 g of 2-bromo-6,9,9-difluoro-11,21-dihydroxy-pregna-1,1,16-triene-3,20-dione-21-acetate (XI bis) (R 1 = R 2 = OCOCH 3) with a melting point of 257 to 258 ° C (decomposition).

Optical rotation: [ice] D = - (- 24 0 (C = 1.0, chloroform), IR (KBr): 3520, 1730, 1680, 1640, 1600, 1588, 1220cm -1. Analysis: Calculated: C, 55.32; H, 5.04; H, 16.00; C, 61.9; F: 55.21; % H, 16.25% Br, 7.49% F. Example 16 To a solution of gg 2-bromo-6R, 9a-difluoro-11S, 21-dihydroxy-pregna-1, 4,16-triene-3 20-dione-21-acetate (VI bis, R 1 = OCOCH 3) in a mixture of acetone (150 ml) with formic acid (1.7 ml) was added at once to a solution of potassium manganate (3.5 ml) at -5 ° C. g) in a mixture of acetone (75 ml) with water (25 ml), the reaction mixture was stirred at -15 ° C for 5 minutes and then a 10% solution of sodium sulfite was added and the mixture was filtered through diatomaceous earth (light yellow filtrate). it is concentrated under reduced pressure and the concentrated solution is poured into cold water.

After filtration and recrystallization from the acetone / hexane mixture, 4.5 g of 2-bromo-6 (3 ', 9 ' -difluoro-1 ', 16 ', 17a, 21-tetrahydroxy-pregna-1) are obtained. , 4-diene-3,20,

19724S2728-dione-21-acetate (XVII, Rt = OC0CH3), m.p. 225-227 ° C (dec.).

Optical rotation: [w] n = -16 [deg.] (C = 1.0, dioxane), UF: [lambda] nax ([lambda], [lambda], [lambda] 1) = ^ 45-246 nm ([lambda] 12,000), IR (KBr): 3440 (broad), 1745, 1732, 1672, 1645, 1605, 1230 cm -1, NMR (dimethyl-Dc-sulfoxide - TMS),

Hz at 60 mHz: 472 (S, 1, C-H), 392, 388 (d, 1, C-4 H), 348, 298 (doublet of triplets, 1, C-6 H), 337, 332 (d , 1, C-11 OH), 328, 323 (d, 1, C-16 OH), 312, 296, 292, 276 (doublet of doublets, 2, CH 2 O), 290 (S, 1 C-17 OH), 290-280 (m, 1, C-16 H), 265-240 (m, 1, C-11 H), 126 (S, 3, OAc), 98, 95 (d, 3, 19 CH 3 split 6 / 3F), 52 (S, 3, 18 Cl13).

Analysis: for C 23 H 27 BrF 2 O 7 calculated: 51.79% C, 5.10% / H, 7.12% F, 14.98% Br, found: 52.05% C, 5.02% H, 7.25% Br, 16.18%. Example 17

By the method described in Example 12, 2-bromo-6- (9a-difluoro-11,13,16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20, dion-21-acetate (XVII , R 1 = OCOCH 3) is converted to 2-bromo-6 (S, 9α-difluoro-11β, 16α, 17α, 21-tetrathihydroxy-pregna-1,4-diene-3,20-dione (XVIIa) (XVII, R 1 = OH) m.p. 208-210 ° C (decomp.) IR (KBr): 3460 (broad), 1715, 1670, 1645, 1605 cm -1.

Analysis: for C 21 H 28 BrF 2 O 6 calculated: 51.33% C, 5.13% H, 16.26% Br, 7.37% F, found: 51.51% C, 5.10% H, 16.15% Br, 7.81% F.

Optical rotation: [α] n = ~ 30 ° (C = 1.0, dioxane), UF:

Anmx (.011, .DELTA.) = 246-247 nm (ε 11,400). Example 18 To a solution of 5 g of 2-bromo-6β, 9α-difluoro-11β-17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, R1 = R2 = OH) in 10 ml of dimethylformamide is added 37 ml of 2,2-dimethoxypropane and 0.025 g of p-toluenesulfonic acid and the mixture is heated at 115 degrees Celsius for 6 hours.

The reaction mixture was cooled, poured into a 10% aqueous solution of bicarbonate and chloroform, the chloroform was separated, washed with water, dried and the solvent was evaporated. Recrystallization of the residue from acetone yields 4 g of 2-bromo-6S, 9a-di-fluoro-11,6-dihydro-3-hydroxy-pregna-1-diene-3,20-dione-17,21-acetonide ( Xlb) with a melting point of 230 to 231 ° C (decomposition).

Optical rotation: [α] D = -1 ° (c = 1.0, chloroform), UF:

Ainax (meLhanoi) = 245 already 246 nm (ε 12,100), IR (KBr): 3440 (broad), 1720, 1670, 1645, 1600 cm -1. Calculated: 55.93% C, 5.67 % Η, 15.50% Br, 7.37% F, found: 56.07% C, 5.72% H, 15.37% Br, 7.50% F. Example 19 To a suspension of 10 g 2-bromo -6 / S, 9a-difluoro-11 $ -16, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate (XVII, R 1 = OCOCH 3) in 400 ml acetone is 2.5 ml of 70% perchloric acid are added at 15 ° C with stirring. The mixture is stirred at 15 ° C for 50 minutes, then 5 g of sodium bicarbonate is added and after 10 minutes of stirring the suspension is filtered off. The solvent was evaporated from the acetone solution under reduced pressure at 60 ° C and the evaporation was recrystallized from ethyl acetate / petroleum ether; obtaining 6 g of pure 2-bromo-6 $ 9a-difluoro-11 $ 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dictn-21-acetate-16,17-- acetonide (XIX, R 1 -OCOCH 3, R 4 = R 5 = CH 3) 1 H (KBr): 3560, 3480, 3430, 1755, 1730, 1670, 1645, 1600, 1225 cm -1.

Analysis: for C26H31BrF2O7 calculated: 54.46% C, 5.45% H, 13.93% Br, 6.62% F,

Found: C, 54.65; H, 5.57; Br, 13.85; F, 6.47.

Optical rotation: [α] D = + 8 ° (c = 1.0, chloroform). UF: (πίηχ (methanoi) 246 ΠΕΠ (ε 11550).

To a mixture of 50 ml of pyridine and 10 g of 2-bromo-6,3,9a-difluoro-11 (1H, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-acetate ( XVII, R1 = OCOCH3) was added dropwise to 5 ml of acetic anhydride, the mixture was allowed to stand at room temperature for 1.5 hours and then poured into 500 ml of cold water under intensive stirring. filtered, washed well with cold water and dried to dryness to give 9.5 g of 2-bromo-6 / 1,9a'-difluoro-11 / S, 16a, 17a, 21-tetrahydroxy-pregna-1 , 4-diene-3,20-dione-16,21-diacetate (XVIII, R 1 = R 3 = OCOCH 3 O, which, after recrystallization from methanol / water, has a melting point of 238-240 ° C (decomposition). [α] D = -49.4 ° (c = 1.0, chloroform) UF: d-max (methanoi) 246 ΠΙΠ (s 11900), IC (KBr): 3570, 3500 (broad), 1760, 1735 (broad), 1670, 1645, 1.605, 1240 (broad) cm @ -1: Analysis: for C25 H29 BrF2 O8 calculated: 52.18% C, 5.08% H, 13.39% Br, 6.60% F, found: 52 % H, 5.10; Br, 14.07; Example 21 5 g of 2-bromo-6,3,9a-difluoro-11 / S, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Ri = R2) = OH) was added to a mixture of 50 ml of pyridine and 25 ml of acetic anhydride and the solution was allowed to stand at room temperature for 12 hours. Ice water is added to the reaction mixture, the product is extracted into chloroform, the chloroform extract is washed with water, 2 N hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried (Na2SO4) and the solvent is distilled off in a vacuum. The residue is recrystallized from acetone-hexane to give pure 2-bromo-6 (S, 9a-difluoro-11 (d, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione). 21-acetate (XIc) (XI, R1-OCGCH3, R2 = OH) with a melting point of 194 DEG-196 DEG C. (decomposition).

Optical rotation: [α] D = + 12 ° (c = 1.0, chloroform). UF: (meihanol) - 246 ΗΗ1 (ε 11800). TLC (CHCl 3): 3620, 3500 (broad), 1745, 1730, 1672, 1645, 1605, 1230 (broad) cm -1.

Analysis: for C23H27BrF2O6 calculated: 53.39% C, 5.20% H, 15.44% Br, 7.34% F, found: 53.51% C, 5.21% H, 15.70% Br, 7.28% F. Example 22

By the method described in Example 21, 2-bromo-6 / 3,9a-difluoro-11H, 17a, 21-trihydroxy-pregna-1,4-diene-3,2Q-dlQn (XIa) (XI, Ri = Ra = OH) to 2-bromo-6,9,9a-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate ( Xld) (XI, Rt = OCOCH 2 CH 3, R 2 = OH) by reaction with propionic anhydride.

Melting point 180 DEG-183 DEG C. (decomposition) Optical rotation: [.alpha.] D = + 22 DEG (c = 22 DEG (c = 1.0, chloroform), UF: .lambda.max (methanoi). alcohol (ε 10,900) IC (CHGls): 3610, 3500 (broad), 1740, 1728, 1672, 1645, 1605, 1220 cm -1: 1.Analysa: for C 21 H 16 BrF 3 O 2 calculated: 54.25% C, 5.50% H Br, 7.15% F, found: 54.09% C, 5.60% H, 14.92% Br, 7.05% F. Example 2 3

By the method described in Example 21, 2-bromo-6 / 1,9a-difluoro-11'-17a, 21-trihydroxy-pregna-1,4-diene-3,2-dione (XIa) (XI, Ri = R2 = OH) by reaction with valeric anhydride to convert 2-bromo-6 (3,9a-difluoro-11,17a, 21-trihydroxy-pregna-1,4-dlen-3,20-dione) -21-valerate (Xle) (XI, R 1 = OCO (CH 2) 3 CH 3, R 2 = OH).

Mp 155-157 ° C (dec.). 197243 31 32

Optical rotation: [α] D = + 27 ° (c = 1.0, chloroform), UF: λ max (methanol) 246 ΠΓΠ (ε 11,600). IC (KBr): 3500 (broad), 1740, 1720, 1670, 1640, 1600, 1230 (broad) cm -1.

Analysis: for C26H38BrF2O6 calculated: 55.82% C, 5.94% H, 14.28% Br, 6.79% F, found: 55.70% C, 5.91% H, 14.35% Br, 6.87% F. Example 24

By the method described in Example 21, 2-bromo-6,9,9-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Ri = R2 = OH) by reaction with pivalic anhydride to convert 2-bromo-6 / S, 9a-difluoro-11 (S, 17α, 21-trihydroxy-pregna-1,4-dieine-3,2O) -dione-21-pivalate (X1f) (XI, R1 = OCOC (CH3) 3, R2 = 'OH).

Melting point 224 DEG-226 DEG C. (decomposition) Optical rotation: [.alpha.] D @ 20 = - 22 DEG (c = 1.0, chloroform). UF: λ, ηπχ (n, branoi) = 245-246 nm (ε 10,900). IC (KBr): 3470 (broad), 1740, 1730, 1665, 1640, 1600, 1220 cm < -1 >, calculated: 55.82 o / c, 5.94% H, 14.28% Br, 6 % H, 79.9%; 55.75%; C, 5.88; H, 14.07; Br, 6.65%. EXAMPLE 25 3 g of 2-bromo-6 (3,9a-difluoro-11 ( 17a, 21-trihydroxy-pregna-1,4-diene-3,20-diou (XIa) (XI, R1 = R2 -OH) are added to a mixture of 30 ml of pyridine with 1 ml of tert-butyl chloride. The reaction mixture was diluted with ice water, the product was extracted with chloroform, the chloroform extract was washed with 5% sodium bicarbonate solution and water, dried (Na2SO4) and concentrated to dryness. the solvent is distilled off under reduced pressure, and after recrystallization from a mixture of acetone and hexane, the solvent is 2-bromo-6β, 9'-difluoro-11,1,17a, 21-trihydroxy-pregna-1,4,4. diene-3,20-dione-21-tert-butyl acetate (X1g) (XI, R1 = O 'OCOCH2C (CH3) 3, R2 = OH).

Mp 198-200 ° C (dec.)

Optical rotation: [α] D = + 25 ° (c = 1.0, chloroform). UF: λ max (methanol) 245-246 nm (ε 10,900). IC (KBr): 3490 (broad), 1735 (broad), 1670, 1640, 1600, 1230 cm @ -1.

Analysis: for C27H35BrF2O6 calculated: 56.55% C, 6.15% H, 13.93% Br, 6.62% F, found: 53.71% C, 6.02% H, 13.85% Br, 6.75% F. Example 26

By the method described in Example 25, 2-bromo-6 (S, 9a-difluoro-11 (5,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, R 1 = = R2 = OH) is converted with 2-bromo-6 / 3,9-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione by reaction with enanthium chloride. -21-enanthate (X1h) (X1, R1 = O 'OCO (CH2) 5CH3, R2 = OH).

Mp 173-175 ° C (dec.)

Optical rotation: [α] D = + 28 ° (c = 1.0, chloroform), UF: λmax (methanol) 245-246 nm (ε 11,500) IR (KBr): 3500 (broad), 1735 (broad) ), 1670, 1640, 1600, 1230 (broad) cm -1.

Analysis: for C 23 H 37 BrF 2 O 6 calculated: 57.24% C, 6.35% H, 13.60% Br, 6.47% F, found: 57.31% C, 6.30% H, 13.72% Br, 6.29% F. Example 27

By the method described in Example 21, 2-bromo-6 (31,9a-difluoro-11,1 (S, 17a, 21-trihydroxy-prregna-1,4-diene-3,20-dione (XIa) (XI, Ri = R 2 = OH) by reaction with benzoic anhydride converts to δ-bromo-ε-difluoro-11/1, 33 197245 34 17α, 21-trihydroxy-pregna-1,4-diene-3,20- dione-21-benzoate (Xi1) (XI, R1 = OCO6H5, R2 = OH).

Melting point 209 DEG-210 DEG C. (with decomposition) Optical rotation: [.alpha.] D = -93 DEG (c = 1.0, chloroform). UF:

Amax (methanol) -233 ΆΪ 234 IM1 (ε 22,000) Č (KBr): 3Θ00, 3420 (wide), 1725, 1710, 1670, 1640, 1600 cm cm1.

Analysis: for C28H29BrF2O6 calculated: 58.04% C, 5.04% H, 13.79% Br, 6.56% F, found: 58.21% C, 4.93% H, 13.68% Br, 6 , 39% F. Example 28

A mixture of 5 g of 2-bromo-6,3 ', 9a-difluoro-1 S, 17, 21, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, R 1 = R 2 = OH) 5 ml of methyl orthovalerate, 0.020 g of p-toluenesulfonic acid and 15 ml of dimethylformamide are heated at 115 ° C for 4 hours under nitrogen. The reaction mixture was neutralized with pyridine, evaporated in vacuo to dryness, and the residue was purified by silica gel column chromatography (1: 30 ratio of product adsorbate) using a 8: 2 mixture of benzene with chloroform as eluent. 3.5 g of 2-bromo-6,3 ', 9a-difluoro-11,6,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione - 17,21- (1 1-methoxy-n-pentylidenedioxyderiate which is further suspended in a mixture of 25 ml of methainol with 3 ml of 1 N hydrochloric acid without further purification and the mixture is heated to 40-50 ° C with a water bath. After the starting material has completely dissolved, the solution is concentrated under reduced pressure, the precipitated product is filtered off, washed with water and dried. The obtained crude 2-bromo-6R, 9a-difluoro-1-ol, 17,21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XII) (XI, R 1 = OH, R 2 = CO 2 (CH 2) 3 CH 3) is recrystallized from acetone-hexane, melting point 201-203 ° C (decomposition) .Optical rotation: d = -74 ° (c = 1.0, chloroform). UF: λ max (methanol) - 246 ΠΙΏ (ε 12,600). IR (KBr): 3500 (broad), 1730, 1715, 1670, 1645, 1600 cm @ -1.

Analysis: for C26H33BrF2O6 calculated: 55.82% C, 5.94% H, 14.28% Br, 6.79% F, found: 55.91% C, 6.07% H, 14.27% Br, 6.72% F. Ex. 2 9

In the method described in Example 21, 2-bromo-6,31,9'-difluoro-11,13,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (XII) (XI) , R 1 = OH, R 2 = 'OCO (CH 2) 3 HH 3) is converted to 2-bromo-6,3,9,9-di-fluoro-11,17,17,21-trihydroxy-pregna-1,4-diol with acetic anhydride by reaction en-3,20-dione-17-valerate-21-acetate (X1m) (XI, R1 = OCOCH3, R2 = OCO (CH2) sCH3). The product was recrystallized from acetone-hexane. The crystals obtained were converted to the starting form I at 125 ° C of form II by melting point 173-175 ° C (decomposition). Optical rotation: [α] D = -25 ° (c = 1.0, chloroform). UF: λmax (methanol) 245 already 246 nm (ε 11,400). IR (KBr): 3500 (broad), 1735 (broad), 1672, 1645, 1605, 1230 (broad) cm -1. Calculated: C, 55.91; H, 5.86; H, 13.28%. F, 6.32% F, found: 56.03% C, 5.91% H, 13.07% Br, 6.28% F. Example 30

In the manner described in Example 28, 2-bromo-6,9a-difluoro-11,1 (S, 17o, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI) , R 1 = R 2 = OH) is converted into the corresponding 17,21-oirthoacetate by reaction with ethyl orthoacetate to give the 2-bromo-6 / 3,9a-difluoro-11,17a, 21-trihydroxy-pregna-1 by acid hydrolysis 4-diene-3,20-dione-17-acetate (ΧΙη) (XI, R 1 = OH, R 2 = IOOCCH 3) The product is crystallized from a mixture of acetone and hexane.

Mp 230-232 ° C (dec.) Optical rotation: [α] D = -75.8 ° (c = 1.0, chloroform). UF: λ max (methanol) 245 nm (ε 11700). IR (KBr): 3500, 3420, 1730, 1720, 1675, 1640, 1610, 1220 cm @ -1.

Anal. Calcd for C23H27BrF2O6: C, 53.40; H, 5.26; H, 15.44; F, 7.34; Found: C, 53.52; H, 5.32; Br, 7.27 O / F F. Example 31

In the method described in Example 21, 2-bromo-6,9a-difluoro-11,1,17a, 21-trihydroxy-preglio-1,4-diene-3,20-dione-17-acetate (Xln) ) (XI, R 1 = OH, R 2 = OCOCH 3) converts the reaction with valeric anhydride to 2-bromo-6 $ 9a-difluoro-110,17a, 21-trihydroxy-pregna - 1,4-diene-3,20- dione-17-acetate-21-valerate (XIo) (XI, R 1 = OCO (CH 2) 3 CH 3, R 2 = OCOCH 3). The product is crystallized from acetone / hexane.

Melting point 159 DEG-160 DEG C. (decomposition) Optical rotation: (.alpha.) D -37 DEG (c = 1.0, chloroform).

Amax (iiimiianoi) - 246-247 nm (ε 11,750). IR (KBr): 3660, 3520, 3380, 1730 (broad), 1675, 1640, 1600, 1240 cm @ -1.

Analysis: for C28H35BrF2O7: 55.91% C, 5.86% II, 13.28% Br, 6.32% F, found: 56.07% C, 5.73% H, 13.21% Br, 6 , 55% F. Example 32

In the method described in Example 28, 2-bromo-6H, 9α-difluoro-11H, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Ri Ra-OH) by reaction with ethylorthopropionate into the corresponding 17,21-orthopropionate, which by acid hydrolysis yields 2-bromo-6 (3 ', 9a-difluoro-11, 17w, 21-trihydroxy-pregna-- 1,4-diene-3,20-dione-17-propioinate (ρρ) (XI, R1 = OH, R2 = OCOCH2'CH3) The product is recrystallized from acetone-hexane.

Melting point 215 DEG-217 DEG C. (dec.). UF:

Ammix (nicihnnoi) 245 to 246 nm (ε 12 300).

Optical rotation: [α] D = -75 ° (c-1.0, chloroform). IR (KBr): 3500, 3420, 1730, 1712, 1675, 1640, 1605, 1200 cm @ -1.

Analysis: for C24H29BrF2O6 calculated: 54.24% C, 5.50% H, 15.04% Br, 7.15% F, found: 54.20% C, 5.52% H, 14.79% Br, 6.97% F. Example 33

In the manner described in Example 28, 2-bromo-6R, 9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (XIa) (XI, Ri R 2 -OH is converted to the corresponding 17,21-ortho-benzoate by reaction with ethylorthobenate to give the 2-bromo-6/3 ', 9a-difluoro-11,17a, 21-trihydroxy-preg by acid hydrolysis -na-1,4-diene-3,20-dione-17-benzoate (X1q) (XI, R1 = OFI, R2 = OCOC6H5. The product is recrystallized from acetone-hexane).

Melting point 241 DEG-243 DEG C. (decomposition) Optical rotation: [.alpha.] D = -103 DEG (c = 1.0, chloroform), UF: .lambda.max (methano) 234-235 nm (.delta. 23,500). IC (KBr): 3520, 3430, 1730, 1700, 1680, 1645, 1610 cm @ -1.

Analysis: for C28H29BrF2O6 calculated: 58.04% C, 5.04% o H, 13.79% Br, 6.56% F, found: 58.12% C, 4.95% H, 13.62%. Br, 6.50% F. Example 34

In the manner described in Example 28, 2-bromo-6 / 3'-fluoro-9α, 11β-dichloro-17α, 21-dihydro-10'-pregna-1,4-diene-3,20-dione ( XIIa) (XII, R 1 - R a = OH) is converted into the corresponding 17,21-orthoacetate by reaction with ethyl chloroacetate to give 2-bromo-6 / S-fluoro-9a, 11 (3-di-chloro-17o-2, 21) by acid hydrolysis. -diihydroxyprege-1,4-diene-3,20-dione-17-acetate (XIIb) (XII, R 1 -OH, R 2 = OCOCH 3) The product was recrystallized from acetone-hexane.

Melting point 193 DEG-194 DEG C. (decomposition) Optical rotation: [.alpha.] D = -32 DEG (c = 1.0, chloroform). UF: λ max (methanol) 245 nm (ε 11,700). 37 197243 IC (KBr): 3500, 1730 (broad), 1705, 1680, 1650, 1605, 1240 (broad) cm-1. Analysa: for C23H26BrCl2FOs, calculated: 50.02% C, 4.74% H, 14.47 % Br, 12.84% CI, 3.44% F, found: 50.11% C, 4.82% H, 14.35% Br, 13.03% Cl, 3.32% F. Example 35

In the manner described in Example 21, 2-bromo-6β-fluoro-9α, 11β-dichloro-17α, 21'-dihydroxy-pregna-1,4-diem-3,20-dione (XIIa) (XII, R 1 = R 2 = OH) is converted to 2-bromo-6, d-fluoro-9or, 11β-dichloro-17α, -21-dihydroxy-pregna-1,4-diene-3,20 by reaction with acetic anhydride -dione-21-acetate (XIIc) (XII, R 1 = OCOCH 3, R 2 = OH). The product is recrystallized from benzene-petroleum ether.

Melting point 202 DEG-204 DEG C. (decomposition) Optical rotation: [.alpha.] D = + 49 DEG (c = 1.0, chloroform). UF:

IniaK (methanol) 245 ηΐΠ (ε 11,800). IR (KBr): 3470, 1750, 1730, 1668, 1640, 1600, 1230 cm @ -1.

Analysis: for C23H26FCl2BrO5 calculated: 50.02% C, 4.74% H, 14.47% Br, 12.84% Cl, 3.44% F, found *: 50.21% C, 4.63% H Br, 14.41% Cl, 3.38% F. Example 36

By the method described in Example 19, 2-bromo-ω-difluoro-11-thiophenyl-1α-tetrahydro-pregna-1,4-diene-3,20-dione (XVIIa) (XVII, Ri = OH) is converted to 2-bromo-6S, 9a; -di-fluoro-11β, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione-16,17-acetonide ( XXa) (XIX, R 1 = OH, R 4 = R 5 —CH 3), which is recrystallized from acetone-hexane.

Melting point 221 to 223 ° C (decomposition) .Optical rotation: [α] η20 = - (- 9ο (c -1.0, chloroform) .UF: λ max (methanol) = 246 nm (ε 11,950). IR (KBr): 3500, 3280, 1730, 1670, 1645, 1605 cm @ -1

Analysis: for C24H29BrF2O6 calculated: 54.25% C, 5.50% H, 15.04% Br, 7.15% F, found: 54.37% C, 5.42% H, 14.95% Br, 7, 10% F. Example 37 To a suspension of 5 g of 2-bromo-6H-fluoro-17α, 21-di-hydroxy-OjSiIll ^ -oxido-pregna-1 H -dien-S OO-dione-17.2 acetate (X) in 30 ml of acetone at 0 ° C, 50 ml of hydrochloric acid are added over 30 minutes. The mixture was stirred at 0 ° C for 6 h, then 2-bromo-8,3-fluoro-9α-chloro-11,17α, 21-trihydroxy-preg-na-1,4-diene-3 was precipitated. 20-dione-17,21-diacetate (XXIII) is filtered off, washed repeatedly with water, dried and recrystallized from acetone-hexane.

Melting point 258 DEG-260 DEG C. (decomposition) .Optical rotation: [.alpha.] D @ 20 = -22 DEG (c ~ 1.0, chloroform). UF: λ max (methanol) = 246 ΠΠ1 (ε 11,100), IR (KBr): 3440 (broad), 3350, 1753, 1740, 1705, 1675, 1645, 1600, 1230 cm -1.

Analysis calculated for C25H29BrClFO7: C, 52.14; H, 5.08; Br, 6.18; Cl, 3.30; C, 52.34; H, 5.02; 72% Br, 6.22% Cl, 3.25% F. Example 38

A mixture of 4.1 g of 16α-methyl-11β, 17α, 21-trihydroxy-pregn-4-ene-3,20-dione-21-acetate (Ia) (R3 = aCH3), 110 ml of benzene, 41 ml ethylene glycol and 2.45 g of pyridine hydrochloride are heated to boiling with stirring for 8 hours and the resulting water is separated in a separator. After completion of the reaction, 100 ml of 5% aqueous sodium bicarbonate solution was added, the mixture was concentrated until crystals began to precipitate and then poured into cold water. The precipitate is filtered off, washed with neutral water and dried. After recrystallization of the crude product, 3.7 g of 16α-methyl-11α, 17α, 21-trihydroxy-3,3-ethylenedioxy-pregn-5-εa-20-one-21-acetate (2a) is obtained (R 1 = β 2 CH 3). .

Mp 214-216 ° C. 197245 39 UF:% iax (methanol) = 292 Mil (ε 110).

Optical rotation: [α] η 0 = + 1 ° (c = 1.0, chloroform). IC (KBr): 3480 (broad), 1755, 1730, 1230 cm @ -1.

Analysis: for C26H38O7 Calculated: 67.51% C, 8.28% H, Found: 67.68% C, 8.35% H. Example 3 9

By the method described in Example 38, 160-methyl-11a, 17a, 21-trihydroxy-pregn-4-ein-3,20-dione-21-acetate (1b) (R 3 = / CH 3) was converted to 16 ( β-methyl-11,17α, 21-trihydroxy-3,3-ethylenedioxy-pregn-5-en-20-one-21-acetate (IIb) (R 3 =, / JCH 3).

Mp 214-216 ° C. UF:

Irnax (melhanol) = 292 η! Ώ (ε 130).

Optical rotation: [α] D 20 = + 36 ° (c-1.0, chloroform). IC (KBr): 3525 (broad), 1755, 1730, 1230 cm @ -1.

Analysis: for C28H38O7 calculated: 67.51% C, 8.28% H, found: 67.57% C, 8.15% H. Example 40 To a solution of 15 g of 16a-methyl-11, 17a, 21-tri -hydroxy-3,3-ethylenedioxy-pregn-5-en-20-one-21-acetate (IIa) and (R 3 = aCH 3) in chloroform (500 ml) at -30 ° C, during 1 hour 5 hours, a solution of mono-phthalic acid (21 g) in ether (120 ml) was added. The reaction mixture was kept at -30 ° C for 3 hours, then the acid from the organic phase was taken up in 5% aqueous sodium bicarbonate solution, the organic layer was washed with water, dried and the solvent was evaporated. The residue was recrystallized from methanol (12 g) of 16or-methyl-11a, 17a, 21-trihydroxy-3,3-ethylenedioxy-5a, 6'a-oxido-pregnan-20-one-21-acetate (IIIa). (R 3 = from CH 3). IC (KBr): 3600, 3520, 1755, 1725, 1235 cm @ -1. 40

Analysis: for C26H38O8 calculated: 65.25% C, 8.00% H, found: 65.20% C, 7.92% H. Example 41

By the method described in Example 40, 1Θ (3-methyl-11, 17, 21-trihydroxy-3,3-ethylenedioxy-pregn-5-en-20-one-21-acetate (IIb) (Rs = = / 3CH3) is converted to 16/3-methyl-11a, 17a, 21-trihydroxy-3,3-ethylenedioxy-5a, 6a-oxido-pregnan-20-one-21-acetate (IIIb) (R 3 = ( 3CH3) .IC (KBr): 3550, 3450 (broad), 1740, 1728, 1235 cm @ -1.

Analysis: for C26H38O8 Calculated: 65.25% C, 8.00% H, found: 65.37% C, 8.08% H. Example 42 4.5 g 16cf-methyl-11a, 17a, 21-trihydroxy- 3,3-ethylenedioxy-5a, 6a-oxido-pregfnan-20-one-21-acetate (IIIa) (R3 = CH3) is added to 45 ml of 70% aqueous hydrofluoric acid cooled with stirring over 1.5 hours to -65 ° C. After the introduction of compound IIIa, the solution was stirred at -60 ° C for 0.5 h and then poured into water (650 mL). The solid was dissolved in ethyl acetate (400 mL), the ethyl acetate solution washed with aqueous sodium bicarbonate until all the acid was removed, then water was neutralized, dried over sodium sulfate and the solvent was distilled off. The crude residue was crystallized from 3.2 g of 16of-methyl-6 (1-fluoro-5a, 11a, 17o, 21-tetrahydroxy-pregnane-3,20-dion-21-ace) from acetone-hexane. (IVa) (R 3 = or CH 3).

Mp 218-220 ° C. UF:

Imax (melhanol) ~ 290 nffi (ε 90),

Optical rotation: [α] D 20 = -j-21 ° (c = 1.0, chloroform), IR (KBr): 3640, 3560, 3450 (broad), 1740, 1730, 1710, 1230 cm -1.

Analysis: C21 H35 FO7 requires: 63.42% O / C, 7.76% H, 4.18% F, found: 63.50% C, 7.65% H, 4.15% F. 197245 41 42 Example 43

In the procedure described in Example 42, 16 (1-methyl-11a, 17a, 21-trihydroxy-3,3-ethylenedioxy-5a, 6'-oxido-pregnan-20-one-21-acetate (IIIb) (R 3 = : SCH3) is converted to 16β-methyl-6,1-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregan-3,20-dione-21-acetate (IVb) (R 3 = CH 3) .

Melting point 220-222 ° C.

Optical rotation: [α] η 2θ = + 54 ° (c = 1.0, chloroform). UF: ^ max (methanol) = 292 UH1 (ε 98). IR (KBr): 3640, 3460, (broad), 1750, 1730, 1705, 1235 cm -1.

Analysis: for C 24 H 35 FO 7 calculated: 63.42% C, 7.76% H, 4.18% F, found: 63.31% C, 7.62% H, 4.02% F. Example 44

To a mixture of 2 g of sodium acetate, 10 g of 16 a-methyl-6, 6-fluoro-5a, 11a, 17a, 21-tetrahydropyrano-3,20-dione-21-acetate (IVa) (Rs) CH3) and a solution of 4 g of bromine in 50 ml of dioxane are added dropwise with stirring at 25 to 30 DEG C. with stirring at a temperature of 25 to 30 DEG C. After the addition of bromine, the reaction mixture is poured into 1500 ml of cold 5% aqueous solution. The mixture is stirred for 1 hour and the white crystalline product formed is filtered, washed with water and dried. Recrystallization of the crude product from mixture of acetone and hexane yields 7 g of 16α-methyl-2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate in the form of colorless crystals (Va) (R 3 = 1aCH 3).

Melting point 137 DEG-138 DEG C. (decomposition) .Optical rotation: [.alpha.] D @ 20 = + 27 DEG (c = 1.0, dioxain). UF: λ max (methanol) = 288 1Π1 (ε 112). IR (KBr): 3640, 3560, 3470 (broad), 1730 (broad), 1230 (broad) cm @ -1.

Analysis calculated for C24H34BrFO7: 54.04% c, 6.42% H, 14.98% Br, 3.56% F, found: 54.23% C, 6.46% H, 14.81% Br, 3.57% F. Example 45

By the method described in Example 44, 16β-methyl-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (IVb) (R 3 == / 3CH3) is converted to 16 ' -methyl-2a-bromo-6S-fluoro-5a, 11w, 17a, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) (R3 = 'SCH3) ).

Optical rotation: [A] d 20 = + 68 ° (c = 1.0, dioxa-n), UF: max (methanol) 292 -1 (ε 123). IR (KBr):. 3640, 3460, 3420, 1745, 1735 (broad), 1230 cm @ -1.

Analysis: Calculated for C24H34BrFO7: 54.04% C, 6.42% H, 14.98% Br, 3.56% F, found: 54.25% c, 6.48% H, 14.75% Br, 3.48% F. Example 46

To a solution of 10 g of 16-methyl-2a-bromo-6-fluoro-5a, 11a, 17a, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Va) (R 3 = laCH 3) in 50 g of pyridine are added dropwise with 8 g of methanesulfonyl chloride with stirring at 55 ° C over about 15 minutes. After addition of the sulfonyl chloride, the reaction mixture is stirred for 1.5 hours at about 0 ° C, then poured into a mixture of 400 ml of cold water with 200 ml of dichloroethane, acidified with 4 N sulfuric acid to pH 3.5 and stirred. 1 hour. The dichloroethane layer was separated, the crop was extracted with 200 ml of dichloroethane, the combined organic phases were washed with water to neutral reaction, dried and the solvent was distilled off under reduced pressure at 60 ° C. The yellow oily residue gave, after recrystallization of benzene / hexane, 16α-methyl-2a-bromo-6id-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-21-acetate (Via ) (R 3 = | CH 3).

Optical rotation: [α] D 20 = -) - 30 ° (c = 1.0, dioxane). UF:

Anax (methanol) 288 nm (ε 110). IR (KBr): 3520 (broad), 1730 (broad), 1330, 1230, 1170 cm -1.

Analysis: for C25H36BrFO9S 43

H, 5.93;% H, 13.07;% F, 3.11; Found: C, 48.85; H, 5.81; C, 13.23; 20% F. Example 47

By the method described in Example 46, 16β-methyl-2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-21-acetate (Vb) { R 3 = (CH 3) converts to 16 (3-methyl-2α-bromo-6/3-fluoro-5α, 11β, 17α, 21-tetrahydroxy-pregan-3,20-diOn-11-mesylate) 21-acetate (VIb) (R 3 = R 3 CH 3).

Melting point: 148 DEG-150 DEG C. (decomposition) Optical rotation: [.alpha.] D @ 20 = -60 DEG (c = 1.0, dioxane). UF: ληιπχ (μiiciiianui) 292 nm (ε 99). IC (KBr): 3660, 3520 (broad), 3370 (broad), 1740, 1725, 1330, 1230, 1170 cm-1. Analysa: for C25H36BrFO9S: C, 49.10; H, 5.93; % Br, 3.11% F, found: 49.23% C, 5.89% H, 13.25% Br, 2.98% F. Example 48 10 g 16a-methyl-2a-bromo-6/3 -fluoro-5a, 11a, -17a, 21-tetrahydroxy-pregnane-3,20-dioin-11-mesylate-21-acetate (VIa) (R3 = aCH3) is introduced into a solution of 75 ml of acetic anhydride and 0, 5 ml of 70% perchloric acid in 450 ml of ethyl acetate. The mixture was heated to 30 ° C for 0.5 h, then shaken several times with 5% aqueous sodium bicarbonate solution, the ethyl acetate portion was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol (about 9 g). -bromo-6/3-fluoro-5a, 11a, 17a, 21-tetrahydroxy-pregnane-3,20-dione-11-mesylate-5,17,21-triacetate (VIIIa) (R 3 = CH 3).

Melting point 136 DEG-138 DEG C. (decomposition) .Optical rotation: [.alpha.] D @ 20 = -30 DEG (o = 1.0, chloroform). IC (KBr): 1745 (broad), 1365, 1220 (broad, 1170 cm -1).

Analysis: for C29H40BrFOnS calculated: 50.07% C, 5.80% H, 11.49% Br, 2.73% F, found: 50.25% C, 5.92% H, 11.35% Br, 2.63% F. Example 49

By the method described in Example 48, 16β-methyl-2α-bromo-6β-fluoro-5α, 11α, 21-tetrahydroxy-pregnane-3,20-dione-11-lunesylate-21-acetate (VIb) (R 3 = P 1 CH 3) is converted to 16 3-methyl-2α-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxypregnane-3,20-dione. 11-mesylate-5,17,21-triacetate (VIIb) (R 5 = 1 / CH 3).

Melting point 131 DEG-132 DEG C. (decomposition) Optical rotation: [.alpha.] D @ 20 = -27 DEG (c = 1.0, chloroform). IR (KBr): 1750 (broad), 1370, 1220 (broad), 1170 cm -1.

Analysis: for C29H40BrFOuS calculated: 50.07% C, 5.80% H, 11.49% Br, 2.73% F, found: 50.15% C, 5 (72% H, 11.55% Br, 2.82% F. Example 50 6.9 g 16α-methyl-2 2-bromo-6β-fluoro-5α, 11α, 17α, 21-tetrahydroxy-pregnane-3,20-dione-11- -mesylate-5,17,21-triacetate (VIIa) (R3 = aCH3) is dissolved at 90 DEG C. (in a water bath) in 320 ml of anhydrous acetic acid, a solution of sodium acetate (15 g) is added at 90 DEG C. 100 [deg.] C.) in glacial acetic acid (60 ml), then a solution of 1.80 g of bromine in acetic acid (25 ml) is added to the reaction mixture and the reaction mixture is heated to 90 [deg.] C. until the bromine color disappears (about 5 minutes in total) ), then the solution is cooled to room temperature as quickly as possible and poured into cold water, the precipitated material is filtered off, washed thoroughly with water and dried to constant weight: about 7 g of 16α-methyl-2 is obtained, 2-dibromo-6 / S-fluoro-11a, 17a, 21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-17,21-diacetate (VIIIbis a) (R 3 = ia) CH3).

Melting point 135 DEG-137 DEG C. (decomposition) Optical rotation: [.alpha.] D @ 20 = -20 DEG (c = 1.0, chloroform). UF:

Amax (methanoi) = 242 to 243 nm (ε 10,700). 45 197245 46 IR (KBr): 1745, 1730, 1698, 1620, 1330, 1220, 1170cm.

Analysis: for C27H35Br2FO9S calculated: 45.39% C, 4.94% H, 22.37% Br, 2.66% F, found: 45.62% C, 5.05% H, 22.23% Br, 2.55% F. Example 51

By the method described in Example 50, 16β-methyl-2α-bromo-6β-fluoro-11α, 17α, 21-trihydroxy-pregnane-3,20-dione-11-mesylate-5,17, - 21-triacetate (VIIb) (R3 = 1 / 3CH3) converts to 16/3-methyl-2,2-dibromo-6/3-fluoro-11a, 17a, 21-trihydroxy-pregn-4- &amp; n-3 20-dione-11-methyl-17,21-diacetate (VIIIbis b) (R 3 = CH 3). Melting point 141-142 ° C (decomposition) Optical rotation: (<= 20-12 ° C) (c = 1.0, chloroform) UF: rcinx (methanol) 243 ΠΠ1 (ε 10,600) IR KBr: 1745, 1730, 1696, 1625, 1330, 1220, 1170 cm -1.

Analysis: for C27H55Br2FO9S: C, 45.39; H, 4.94; Br, 22.37; F, 2.66; Found: C, 45.51; H, 4.88; 2.52% F. EXAMPLE 52 6 g of 16α-methyl-2,2-dibromo-6β-fluoro-l, 17α, 21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate The 17,21-diacetate (VIIb a) (R 3 = 1aCH 3) is added to a mixture of 60 ml of dimethylformamide, 12 g of lithium carbonate and 6 g of lithium bromide in one portion, with stirring. The reaction mixture was heated to 130 ° C under nitrogen for 0.5 hour, then cooled and poured into cold water. The precipitated product was filtered off, washed with water and dried. Recrystallization of the crude product from copper acetone-hexane gave 3.5 g of 16α-methyl-2-bromo-6β-fluoro-17α, 21-dihydroxy-pregna-1,4,9 (11) -trien-3, 20-dione-17,21-diacetate (VIIIa) (R3 = 16CH3) .Optical rotation: [.alpha.] D @ 20 = -84 DEG (c = 1.0, chloroform). UF:

Λmax (methanol) = 246-247 nm (ε12,900) µB KBr): 1745, 1730, 1680, 1605, 1230 cm -1.

Analysis: for C26H30BrF6O: 58.11% C, 5.63% H, 14.87% Br, 3.53% F, found: 58.07% C, 5.69% H, 14.79% Br , 3.47% F. Example 53

By the method described in Example 52, 16β-methyl-2,2-dibromo-6 ^-fluoro-11α, 17α, 21-trihydroxy-pregn-4-ene-3,20-dione-11-mesylate-- 17,21-diacetate (VIIIbis b) (R 3 = / GH 3) is converted to 16β-methyl-2-bromo-6/3-fluoro-17α, 21-dihydro-pregna-1,4,9 (11 ) -trien-3,20-dione-17,21-diacetate (VIII b) (R 3 = I / CH 3).

Optical rotation: [α] D 20 = -66 ° (c = 1.0, chloroform), UF: λ max (methanol) 246 nm (ε 12,430), IR KBr): 1760, 1740 (broad), 1670, 1600, 1235 cm -1, NMR (CDCl 3 - TMS)

Hz at 60 mHz: 454 (C, 1, Cl H), 376, 372 (d, 1, C-4 H), 342, 288 (doublet of triplets, 1, C-6 H), 340-330 (m, 1, C-11 H), 298, 282, 266, 250 (doublet of doublets, 2, CHOAc), 130 (S, 3, OAc), 96, 94 (d, 3, 19 CH 3 cleaved 6 / 3F), 85 , 78 (d, 3, C-16 / SCH 3), 46 (S, 3, 18 CH 3).

Analysis: Calculated for C26H30BrF6O: 58.11% C, 5.63% H, 14.87% Br, 3.53% F, found: 58.20% C, 5.71% H, 14.92% Br Example 54. To a suspension of 11 g (16-methyl-2-bromo-6,3'-fluoro-17α, 21-dihydroxy-pregna-1,4,9 (11) -trien) -3,20-dioin-17,21-diacetate (VIIIa) (R3 = aCH3) in a mixture of 250 ml of tetrahydrofuran with a solution of 1.1 g of 70% perchloric acid in 11 ml of water in the dark, with stirring, at the heartbeat At 15 ° C, in about 0.5 hours, 8.5 g of 197245 47 1,3-dibromo-5,5-dimethylthydantoin are added, and during the addition of dibromohydantoin, the suspension is reduced to a solution after a reaction time of 45 minutes. 10% aqueous sodium sulfite solution was added thereto, with stirring, until the starch iodine was dyed blue, the solution was slowly poured into 1000 ml of cold water, the precipitated product was filtered off and still wetted into other reactions.

Analytically pure 16α-methyl-2,9α-dibromo-6β-fluoro-11α, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 a) ) (R 5 = = CH 3) is obtained by recrystallization to yield the crude material from acetone / hexane.

Mp 205-207 ° C (dec.), IR KBr) 3470, 1760, 1730, 1670, 1640, 1610, 1230 cm -1.

Analysis: for C26H31Br2FO7 calculated: 49.23% C, 4.93% H, 25.19% Br, 2.99% F, found: 49.31% C, 5.05% H, 25.35% Br, 3.10% F. Example 55

By the method described in Example 54, 16/5-methyl-2-bromo-6/5-fluoro-17α, 21-dihydroxy-pregna-1,4,9 (11) -trien-3,20-dione 17,21-diacetate (VIIIb) (R3 = / 5CH3) converts to 16/5-methyl-2,9os-dibromo-8/5-fluoro-11 / 5,17of, 21-trihydroxy-pregna- 1,4-diene-3,20-dione-17,21-diacetate (10b) (R 3 = i / 5CH 3).

Melting point 207 DEG-209 DEG C. (decomposition), IR (KBr): 3500 (broad), 1740, 1725, 1675, 1645, 1600, 1235 cm @ -1.

Analysis: for C26H31Br2FO7: 49.23% C, 4.93% H, 25.19% Br, 2.99% F, found: 49.37% C, 5.10% H, 24.95% Br , 2.91% F.

However, for the next reaction, a crude, still moist product 10b is used, which is obtained by filtration of the water-diluted reaction mixture. Example 56

Wet 16α-methyl-2,9α-dibromo-6β-fluoro-48 -11 / 5,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (10 a) (R 3 = CH 3), obtained by the method of Example 54 from 11 g of the product VIIIa (R 3 = aCH 3), is dissolved in 200 ml of acetone and, with stirring, at 20 ° C, 20 ml is added over 20 minutes. % aqueous potassium carbonate solution. The reaction mixture is stirred for 3.5 hours, then ice water and the precipitated 16α-methyl-2-bromo-6β-fluoro-17α, 21-dihydroxy-O / II / 1-oxide-pregna are added with stirring. The N-diene-3,20-dione-17,21-diacetate (11a) (R 5a and CH 3) is filtered off, washed with water and dried. Melting point 232-234 ° C (dec.), Optical rotation: [α] D 20 - —96 ° (c = 1.0, chloroform), IR (KBr): 1755, 1735, 1675, 1645, 1610, 1235 cm -1, Anal .: C26H30BrFO7: 56.43%, 5.46% H, 14.44% Br, 3.43% F, found: 56.61% C, 5.32% H, 14.27% Br, 3 52% F. Example 57

By the method described in Example 56, 16β-methyl-2,9α-dibromo-6/3-fluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione- 17,21-diacetate (10b) (R 3 - / SCH 5) converts to 16 R -methyl-2-bromo-6 R -fluoro-17α, 21-dihydro-oxy-9β, 11β? -oxid-pregna-1,4-diene-3,20-dione-17,21-diacetate (11b) (R 3 = R 3 CH 3).

Mp 234-235 ° C (dec.), Optical rotation: [α] 20 D = -530 (c = 1.0, chloroform), IR (KBr): 1755, 1730, 1675, 1645, 1610, 1240 cm -1 % Calculated: 56.43% C, 5.46% H, 14.44% Br, 3.43% F. Found: 56.29% C, 5.32% H, 14.57% Br, 3.37%. % F. Example 58

50 ml of 70% aqueous hydrofluoric acid are introduced into a polyethylene bottle equipped with an electromagnetic stirrer, cooled to -10 DEG C., and 3.7 g of 16% is added to it during stirring for about 15 minutes. 50-methyl-2-bromo-6β-fluoro-17α, 21-dihydroxy-9β, 11'-oxido-pregna-1,4-diene-3,20-diion-17,21-diacetate (11 a) R 3 = aCH 3). The reaction mixture is stirred for 1.5 hours and then the product is precipitated by pouring the mixture into aqueous ammonia. The precipitate is filtered off, washed with water and dried to constant weight. 3.5 g of crude product are obtained which, after recrystallization from a benzene-n-hexane mixture, yields 3 g of pure 16a-methyl-2-bromo-6 / 3,9a-difluoro-11 / 3,17a, 21. -trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 a) (X = OH, Y = F, R 1 = R 2 = OGOCH 3, R 5 =? t CH 3).

Mp 288-289 ° C (dec.), Optical rotation: [α] D 20 = -47 ° (c = 1.0, chloroform), UF: 1max (methanol) 246 nm (ε 12,100), IR ( KBr): 3500, 1760, 1730, 1710, 1680, 1640, 1610, 1230 cm -1.

Analysis: for C26H31BrF2O7 calculated: 54.46% C, 5.45% H, 13.93% Br, 6.63% F, found: 54.58% C, 5.37% H, 13.80% Br, 6.75% F. Example 59

By the method described in Example 58, 16β-methyl-2-bromo-6β-fluoro-17α, 21-idihydroxy-9,3,11β-oxido-pregna-1,4-diene-3, 20-dione-17,21-diacetate (11b) (R 3 - (CH 3)) was converted into 16β-methyl-2-bromo-6,3,3,9a-difluoro-11,17w, -21-trihydroxy-pregna 1,4-diene-3,20-dione-17,21-diacetate (12b) (X = OH, Y = F, R 1 = R 2 = OCOCH 3, R 3 => 3CH 3).

Optical Rotation: [.alpha.] D @ 20 = -13 DEG (c = 1.0, chloroform), .lambda.max (methanol) = 246 .delta. , 1645, 1600, 1235 cm -1.

Analysis: for C26H31BrF2O2: C, 54.46; H, 5.45; Br, 13.93; F, 54.65; Example 60 To a solution of 5 g of 16-methyl-2-bromo-6/3-fluoro-17-a, 21-dihydroxy-9/3, 11/3-oxido-pregna-1 , 4-diene-3,20-dione-17,21-diacetate (11a) (R3 = 1, aCH3) in 30 ml of acetone is added at 0 DEG C. over 40 minutes, 50 ml of hydrochloric acid are added. The mixture was stirred at 0 ° C for about 2.5 hours, and then 16α-methyl-2-bromo-61S-fluoro-9α-chloro-11 (3,17α, 21-trihydroxy-pregna-1,4,4) was precipitated. diene-3,20-dione-17,21-diacetate (12 c) (X = OH, Y = Cl, R 3 = R *, CH 3, R 1 = R 2 = OCOCH 3) is filtered, washed repeatedly and dried (4.9) g) The crude product is recrystallized from acetone-hexane. Melting point: 245-246 ° C (dec.), UF: max max (methanol) 246 nm (ε 12,000),

Optical rotation: [.alpha.] D @ 20 = -34 DEG (c = 1.0, chloroform), IR (KBr): 3460, 1757, 1730, 1710, 1678, 1645, 1608, 1230 cm @ -1.

Analysis: for C26H31BrClFO7 calculated: 52.94% C, 5.30% H, 13.54% Br, 6.01% Cl, 3.22% F, found: 53.12% / c, 5.37% H, 13 , 71% Br, 6.12% Cl, 3.14% F. Example 61

By the method described in Example 60, 16β-methyl-2-bromo-6β-fluoro-17α, 21-dihydroxy-9,3,11-oxido-1,4-diene-3,20-dione -17,21-di-acetate (11b) (R 3 = R 1 CH 3) converts to 16/3-methyl-2-bromo-6/3-fluoro-9a-chloro-11 / 3,17a, 21- -trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate (12 d) (X = OH, Y = C1, R 1 = "R 2 ==" OCOCH 3, R 3 = / SiH 3) .

M.p. 250-251 ° C (dec.), UF: (methanol) = 246 nm (ε 12,150),

Optical rotation: [α] D 20 - + 2 ° (c = 1.0, chloroform), IR (KBr): 3480, 1740 (broad), 1723, 1675, 1645, 1600, 135 cm -1.

Analysis: for C26H31BrClFO7 calculated: 52.94% C, 5.30% H, 13.54% Br, 6.01% Cl, 3.22% F, 197245 31 found: 52.73% C, 5.32% H, 13.60% Br, 6.15% Cl, 3.31% F. Example 62 To a solution of 10 g of 16α-methyl-2-bromo-6β-fluoro-17α, 21-dihydroxy-pregna-1,4 , 9 (11j-triene-3,20-dione-17,21-diacetate (9a) (R 1 = aCH 3) and 40 g lithium chloride in 200 ml of glacial acetic acid at 20 ° C under stirring, 5 g of N-chlorosuccinimide are added, and the mixture is stirred at 20 DEG C., with stirring, for about 10 minutes, with dropwise addition of 10 ml of a 12% solution of hydrochloric acid in tetrahydrofuran, after 3.5 hours the reaction mixture is poured into cold water. 7.5 g of pure 16α-methyl-2-bromo-6 (3-fluoro-9α, 11 (3-dichloro-17α, 21-dihydroxy-pregna) were obtained. 1,4-diene-3,20-dioin-17,21-diacetate (12 e) (X = Y = Cl, R 1 = R 1 = R 2 = OCOCH 3, R 5 - "CI-I3") with melting point 253 to 255 ° C (decomp.).

Optical rotation: (α] υ20 = -100 (c = 1.0, Chloroform), -UF: d.inix (median)) 245 ΙΠΙΠ (t 12,350), IR (KBr): 1745, 1730, 1670, 1645 , 1605, 1235 cm -1, MMR (dimethyl-D-sulfoxide - TMS),

Hz at 60 mHz: 464 (S, 1, Cl H), 393, 398 (d, 1 C-4 H), 346, 396 (doublet of triplets, 1, C-6 H), 318-304 (m, 1 , C-11H), 309, 293, 288, 272 (doublet of doublets, 2, Cl-OAc), 125 (S, 1, OAc), 123 (S, 1, OAc), 108, 104 (d, 3, 19) CH3 cleaved 6/3F), 65 (S, 3, 12CH3), 58.51 (d, 3.16CH3).

Analysis: for C26H30BrCl2F06: 51.33% C, 4.97% H, 13.14% Br, 11.66% Cl, 3.12% F, found: 45% C, 5.07% H, 13.04% Br, 11.81% Cl, 3.19% F. Example 63

By the method described in Example 62, 16 R -methyl-2-bromo-6 R -fluoro-17α, 21-dihydroxy-pregna-1,4,9 (11) -trien-3,20-dione-17 21-diacetate (9b) (R3 = 1CH3) is converted to 16: (3-methyl-2-bromo-6H-fluoro-9a, 11-J-dichloro-17a, 21-dihydroxy) -pregna-1,4-diene-3,20-dton-17,21-diacetate (12 f (R 1 = R 2 = OCOCH 3, R 3 = C 1 -C 13, X = Y = C 1).

Melting point 224 to 226 ° C (decomposition), Optical rotation: [α] η 20 = - (- 21 ° (c = 1.0, chloroform), IR (KBr): 1750, 1730, 1675, 1645, 1605, 1230 cm -1, NMR (dimethyl-D 6 -sulfoxide - TMS),

Hz at 60 mHz: 465 (S, 1, Cl, H), 394, 390 (d, 1, C-4 H), 348,298 (doublet of triplets, 1, C-6H), 320-305 (m , 1, C-11H), 295, 279, 270, 254 (doublet of doublets, 2, CHAOAc), 126 (S, 6, 2X OAc), 109, 105 (d, 3, 19 CH 3 cleaved 6 / 31F) , 78, 72 (d, 3, 16 / 3CH 3).

Analysis: for C26H30BrCl2F6O calculated: 51.33% C, 4.97% H, 13.14% Br, 11.66% Cl, 3.12% F, found: 51.55% C, 4.82% H, 12.98% Br, 11.65% Cl, 3.12% F. Example 64

A suspension of 5.2 g of 16α-methyl-2-bromo-6α, 9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20β-dione-17,21- diacetate (12 a) (X = OH, Y = F, R 3 = and CH 3, R 1 = R 2 - OCOCH 3) in 120 mL of a 1% methanolic potassium hydroxide solution was stirred at 0 ° C for 3 hours under nitrogen. The reaction mixture is then diluted with water, the methanol is distilled off under reduced pressure, the concentrated solution is acidified with acetic acid and the precipitate is filtered off; 4 g of 16α-methyl-2-bromo-6,3,9-difluoro-11β, 17β, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) are obtained ( X = OH, Y = F, R 1 = R 2 = OH, R 3 = CH 3).

Optical rotation: [α] D 20 = -24 ° (c = 1.0, chloroform), UF: α max (methanol) = 245 to 246 lim (ε 12,250), IR (KBr): 3460 (broad), 1710, 1665, 1640, 1603 cm -1, NMR (dimethyl-D 6 -sulfoxide - TMS)

Hz at 60 mHz: 466 (S, 1, Cl H), 388, 384, (d, 1, C-4 H), 345,295 (doublet of triplets, 1, C-6 H), 318-314 (d , 1, C-11 OH), 296 (S, 1, C-17 OH), 280-225 (multiplet, which passes after the change by deuterium, 2, COCH 2 OH), 96, 94 (d, 3, 19 CH 3 cleaved 6 (SF), 54 (S, 3, 18 CH3), 54, 44 (d, 3, C-16 &quot; CH3).

Analysis: for C22H27BrF2O5 calculated: 53.99% C, 5.56% H, 16.33% Br, 7.76% F, 'ΠΉ1ΘΖ θ ΠΌ * 54.10% C, 5.70% H, 16.41 % Br, 7.85% F. Example 65

By the method described in Example 64, 16β-methyl-2-bromo-6β, 9α-difluoro-11 / 3,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione- 17,21-diacetate (12 b) (X = OH, Y = F, R 1 = R 2 == 'OCOCH 3, R 3 = R 3 CH 3) is converted to 16 3-methyl-2-bromo-6 / 3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12h) (X = OH, Y = F, R 1 = R 2 = '= m.p. 216 DEG-217 DEG C. (dec.), Optical rotation: [.alpha.] D @ 20 = + 11 DEG (c = 1.0, chloroform), UF: .lambda. '246 ΠΠ1 (£ 11,900), IR (KBr): 3440 (sieve), 1715, 1665, 1640, 1600 cnr1, NMR (dimethyl-D6-sulfoxide - TMS),

Hz at 60 mHz: 472 (S, 1, Cl H), 388, 384 (d, 1, C-4 H), 346, 296 (doublet of tritets, 1, C-6 H), 339-334 (m, 1, C-11 OH), 315 (S, 1, C-17 OH), 280-240 (multiplet, which passes after the change by deuterium, 2, COCH 2 OH), 96, 94 (d, 3, 19 CH 3 split 6 (3'F), 65.58 (d, 3, C-16 / SCH3), 58 (S, 3, 18 CH3).

Analysis: for C22H27BrF2O5: 53.99% C, 5.56% H, 16.33% Br, 7.76% F, found: 53.75% C, 5.45% H, 16.41% Br, 7% , 87% F. Example 66

By the method described in Example 64, 16α-methyl-2-bromo-6β-fluoro-9α, 11β-dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione -17,21-diacetate (12 e) (R 1 = R 2 = OCOCH 3, R 3 = iaCH 3, X-Y = Cl) converts to 16α-methyl-2-bromo-6/3-fluoro-9α, 11β - dichloro-17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione (12 i) (R 1 = R 2 = 'OH, R 3 = 1 H 3, X = Y = C 1). The product 54 was recrystallized from acetone-hexane.

Melting point 216-218 ° C

Optical rotation: [α] D 20 = - 21 ° (c = 1.0, chloroform), IR (KBr): 3640, 3500, 3400, 1705, 1665, 1642, 1605 cm -1.

Analysis: for C 22 H 21 BrCl 2 FO 4 calculated: 50.40% C, 4.99% Η, 15.24% Br, 13.52% Cl, 3.62% F. found: 50, 63% C, 5.12% Br, 13.38% Cl, 3.61% F. Example 67

By the method described in Example 66, 16β-methyl-2-bromo-6β-fluoro-9α, 11β-dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3, 20-dione-17,21-diacetate (12 d) (R 1 = R 2 = OCOCH 3, R 5 = (3CH 3, X = Y = C 1) converted to 16/3-methyl-2-bromo-6) - fluoro-9a, 11/3-dichloro-17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione (12] ') (R 1 = R 2 = OH, R 5 = 1 / SCH 3, X = Y = C1).

Optical rotation: [α] η 2θ = + 51 ° (c = 1.0, chloroform), UF: t-max (methanol ·) ~ 345 U 246 MU (ε 11,500), IR (KBr): 3600, 3480 , 3360, 1710, 1665, 1645, 1610 cm -1.

Anal. Calcd for C22H26BrCl2FO4: C, 50.40; H, 4.99; Br, 15.24; Cl, 13.52. Found: C, 50.35; 15.20% Br, 13.31% Cl, 3.68% F. Example 68 7g 16a-Methyl-2-bromo-6 / 3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna- 1,4-diene-3,20-dione (12 g) (R t = R 2 = OH, R 3 = 1a CH 3, X = OH, Y = F) is added to a mixture of 70 ml of pyridine with 35 ml of acetic anhydride and the reaction mixture. The mixture is then diluted with ice water, the precipitate is taken up in chloroform, the chloroform solution is washed with water, 2 N hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, dried. (Na 2 SO 4) and the solvent was distilled off under reduced pressure. Recrystallization from acetone-hexane 6.7 g of 16-methyl-2-nitro-6,3,3-aza-fluoro-1,2,3,4-trihydroxy-pregna-1,4 -dien-21-acetate (12 k) (R 1 = OCOCH 3, R 2 = OH, X = OH, Y = F, R 3 = * CH 3).

Melting point 229-231 ° C

Optical Rotation: [α] D 20 = -6 ° (c = 1.0, chloroform), UF: ω (inctanol) 24b MU (ε 11,300), IR (KBr): 3520 (broad), 1740, 1720, 1665, 1640, 1605, 1230 cm -1.

Analysis: for C24H29BrF2O6 calculated: 54.25% C, 5.50% H, 15.04% Br, 7.15% F, found: 54.41% C, 5.60% H, 14.95% Br, 7.12% F. Example 69

By the method described in Example 68, 16β-methyl-2-bromo-6,3 ', 9α-difluoro-11,1,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 h) ) (R 1 = R 2 = OH, R 3 =: / CH 3, X = OH, Y = F) converted to 16/3-πιβί) 1 ^ 1-2-ΒΓ0ΐη-6 / ϊ, 9α-difluoro-11 ( 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 L) (R 1 = OCOCH 3, R 2 = OH, X = OH, Y = F, R 3 == , / CH3).

Melting point 216-218 ° C

Optical rotation: [α] D 20 = + 25 ° (c = 1.0, chloroform), UF: linax (methanol) 245 3Z 246 Mil (ε 11,500), IC (KBr): 3500 (broad), 1745, 1720, 1675, 1645, 1610, 1230 cm -1.

Analysis: for C24H2BrF2O6 calculated: 54.25% C, 5.50% H, 15.04% Br, 7.15% F, found: 54.45% C, 5.38% H, 15.11% Br, 7.08% F. Example 70

By the method described in Example 68, 16 α-56-methyl-2-bromo-6β, 9'-difluoro-11 ', 3', 17α, 21-trihydroxy-pregna-1,4-diene-3,20- dione (12 g) (R1 = R2 = OH, R3-kCH3, X = OH, Y = F) by reaction with propionic anhydride at 16a-methyl-2-bromo-6/3, 9'-difluoro-11 ', 3', 17w, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (12m) (R 1 = OCOCH 2 CH 3, R 2 = IOH, R 3 = « CH 3, X = OH, Y = F).

Optical rotation: [α] θ 2θ = + 4 ° (c = 1.0 chloroform), UF: λ max (inctanol) 246 ΜΠ (ε 10,800), IC (KBr): 3520 (broad), 1740, 1728, 1672, 1645, 1605, 1225 cm -1 '.

Analysis: for C25H31BrF2O6 calculated: 55.05% C, 5.73% H, 14.65% Br, 6.97% F, found: 55.25% C, 5.62% H, 14.55% Br , 7.07% F. Example 71

By the method described in Example 68, 16 H -methyl-2-bromo-6 H, 9α-difluoro-11,1,17,21-trihydroxy-pregna-1,4-dieine-3,20-dione ( 12 h) (R 1 = R 2 = OH, R 3 =. 3 CH 3, X = OH, Y = F)) is reacted with 16-β-methyl-2-bromo-6 / J by reaction with propionic anhydride, 9α-difluoro-11 / 3,17,21-trihydroxy-pregna-1,4-diene-3,20-dione-21-propionate (12 n) (R 1 = OCOCH 2 CH 3, R 2 = OH, R 3 = '-) CH 3, X = OH, Y = F).

Optical rotation: [α] ϋ20 = - 2727 ° (c = 1.0, chloroform), UF: λ max (methanol) = 246 ΜΠ (ε 11000), IR (KBr): 3500 (broad), 1745, 1730, 1670, 1645, 1605, 1220 cm -1.

Analysis: for C 25 H 31 BrF 2 O 6 Calculated: C, 55.05; H, 5.73; Br, 14.65; F, 6.97; Found: C, 55.10; H, 5.72; 7.08% F. Example 72

By the method described in Example 68, 16α-methyl-2-bromo-6 / 3'-fluoro-9α, 11β-dihydro-17β, 21-dihydroxy-pregna-1,4-diene-3,20- dion (12 i) (R 1 = R 2 = OH, R 3 = R 3, X = Y = "C1) 197245 57 converts to 16 α-methyl-2-bromo-6/3-fluoro-9a, 11/3 -dichloro-17a, 21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12o) (R 1 -OCOCH 3, R 2 = OH, R 5 = i and CH 3, X = Y = Cl). The product is recrystallized from methanol. The crystals are passed at 158 ° C from mold II to yield Form I with a melting point of 237-238 ° C (decomposition).

Optical rotation: [α] η 2θ = + 32 ° (c = 1.0, chloroform), UF: λ max (methanol) 246 nm (s 11 550), IR (KBr): 3550, 3460, 3340, 1755, 1730 , 1673, 1635, 1605, 1230 cm -1.

Analysis: for C28H21BrClO2S: 50.90% C, 4.98% H, 14.11% Br, 12.52% Cl, 3.35% F, found: 51.12% C, 5.05% H, 13 98% Br, 12.40% Cl, 3.28% F. Example 73

By the method described in Example 68, 16β-methyl-2-bromo-6β-fluoro-9α, 11β-dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione ( 12 j) (R 1 = R 2 = OH, R 3 = / CH 3, X = Y = 'Cl) converts to 16/3-methyl-2-bromo-6/3-fluoro-9a, 11/3-dichloro-17a 21-dihydroxy-pregna-1,4-diene-3,20-dione-21-acetate (12 p) (R 1 = OCOCH 3, R 2 = OH, R 3 = / 3 CH 3, X = Y = C 1).

Optical rotation: [α] D 20 = +61 ° (c = 1.0, chloroform), UF:

Λ max (methanol) = 245-246 nm (ε 11,000), IR (KBr): 3500 (broad), 1750, 1730, 1675, 1645, 1605, 1230 cm -1.

Analysis: for C 13 H 15 BrCl 2 O 2 S calculated: 50.90% C, 4.98% H, 14.11% Br, 12.52% Cl, 3.35% F, found: 51.12% C, 4.88% H, 13 95% Br, 12.41% Cl, 3.28% F. Example 74

A mixture of 5 g of 16w-methyl-2-bromo-6,3,9-difluoro-11H, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (R 1 5 ml of methylorthovalerate, 0.020 of 58 grams of p-toluenesulfonic acid and 15 ml of dimethylformamide are heated at 115 ° C for 4 hours under a nitrogen atmosphere. Reaction mixture. neutralized with pyridine, evaporated in vacuo to dryness, and the residue purified by column chromatography on silica gel (1: 150) to give 1: 1 benzene / chloroform as eluent. 4 g of 16α-methyl-2-bromo-6 / 3,9α-difluoro-11 / 3,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21- are obtained. (1'-methoxy) -n-pentylidene dioxy derivative, which is suspended in a mixture of 25 ml of methanol with 3 ml of 1 N hydrochloric acid without further purification and heated in a water bath at 40-50 ° C. the solution is concentrated under reduced pressure, the precipitated product is filtered off, washed with water and dried; to give 16α-methyl-2-bromo-6,3,9a-difluoro-11,1,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valerate (12 q ) (Z = H, R 1 = 'OH, R 2 == OCO (CH 2) 5 CH 3, R 3 =' CH 3, X = OH, Y = F) .Optical rotation: [a] [) 20 = - 92 ° (c = 1.0, chloroform), UF:

246 nm (ε 12,300), IR (KBr): 3500 (broad), 1730, 1715, 1672, 1640, 1605 cm -1.

Analysis: for C27H35BrF2O6 calculated: 56.55% C, 6.15% H, 13.93% Br, 6.63% F, found: 56.67% C, 6.05% H, 14.12% Br, 6.75% F. Example 75

By the method described in Example 74, 16α-methyl-2-bromo-6,3,9α-difluoro-11 / 3,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) ( R 1 = R 2 = OH, R 3 -CH 3, X = OH, Y = F) to 16α-methyl-2-bromo-6 / 3,9a-difluoro-11 / 3,17α, 21-trihydroxy-pregna 1,4-diene-3,20-dione-17-acetate (12r) (R1 = OH, R2-OCOCH3, R3 = CH3, X = OH, Y = Z).

Melting point 212 DEG-214 DEG C. (decomposition) Optical rotation: [.alpha.] D @ 20 = -91 DEG (c = 1.0, chloroform). UF: methanol (methanol) = 246 nm (12 12,000), IR (KBr): 3450 (broad), 1725, 1710, 1680, 1640, 1610, 1250 cm -1. 197245 59 60

Analysis: for C24H29BrF2O6 calculated: 54.25% C, 5.50% H, 15.04% Br, 7.15% F, found: 54.48% C, 5.57% H, 15.18% Br, 7.20% F. Example 76

By the method described in Example 74, 16/3-methyl-2-bromo-6,9,9a-difluoroT-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12h) (R 1 = R 2 = OH, R 3 =; / 51CH 3, X = OH, Y = F) to 16/3-methyl-2-bromo-6 / 3,9a-difluoro-11/3 , 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-valorate (12s) (R 1 = OH, R 2 = 'OCO (CH 2) 3 CH 3, R 3 = CH 3, X = OH, Y = Z) Optical rotation: [α] 20 D = -60 ° (c = 1.0, chloroform). UF:

Ainax (nietliniiol) 246 lim (ε 12,000). IC (KBr): 3480 (broad), 1730, 1710, 1675, 1640, 1610 cm @ -1.

Analysis: for C 27 H 35 BrF 2 O 6 calculated: 56.55% C, 6.15% H, 13.93% Br, 6.63% F, found: 56.80% C, 6.08% H, 13.83% Br, 6% , 75% F. Example 78

By the method described in Example 74, 16β-methyl-2-bromo-6β, 9α-difluoro-11β, 17,21-tri-hydroxy-pregna-1,4-diene-3, 20-dione (R 1 = R 2 = OH, R 3 = 3 CH 3, X = OH, Y = F) to 16 (R-methyl-2-bromo-6 (3,9a-difluoro-11) 3-17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12t) (R 1 = OH, R 2 = OCOCH 3, R 3 =? CH 3, X = OH, Y = FROM).

Melting point 227-228 ° (decomposition). UF: linax (melhanol) 246 ΜΠ (ε 11,100), IR (KBr): 3500 (broad), 1670, 1642, 1605, 1230 cm -1.

Analysis: for C 24 H 29 BrF 2 O: calculated: 54.25% C, 5.50% H, 1.5.04% Br, 7.15% F, found: 53.97% C, 5.61% H, 15.24% Br, 7 , 27% F. P rin g 7 9

By the method described in Example 74, 16α-methyl-2-bromo-6 / 3'-fluoro-9α, 11 (3-dichloro-17α, -21-dihydroxy-pregna-1,4-diene-3,20-dione) (12i) (R 1 = R 2 = OH, R 3 = 1aCH 3, X = Y = Cl) converted 16α-methyl-2-bromo-6β-fluoro-9α, 11β-di-chloro-17α, 21-dihydroxy -pregna-1,4-diene-3,20-dione-17-acetate (12u) (R1 = OH, R2 = OCOCH3, R3 = CH3, X = Y = C1).

Melting point 245 DEG-247 DEG C. (decomposition) .Optical rotation: [.alpha.] D @ 20 = -43 DEG (c = 1.0, chloroform). UF: λ max (methanol) 245 ΙΪ1 (c 11,750). IC (KBr): 3500, 1720, 1710, 1675, 1640, 1607 cm-1. Calculated: C, 50.90; H, 4.98; H, 14.11; Cl, 12.52. Found: 51.12% C, 5.07% H, 13.97% Br, 12.30% Cl, 3.27% F. Example 80

By the method described in Example 74, 16β-methyl-2-bromo-6α-3-fluoro-9α, 11β-dihydroxy-17α, -21-dihydroxy-pregna-1,4-diene-3, 20-dione (12h) (R 1 = OH, R 2 = OCOCH 3, R 3 = / 3CH 3, X = Y = Cl) converts to 16/3-methyl-2-bromo-6/3-fluoro-9 ', 11 / 3-dichloro-17α, 21-dihydroxy-pregna-1,4-diene-3,20-dione-17-acetate (12v) (R1 -OH, R2 = OCOCH3, R3 = / 3CH3, X = Y = C1 ).

Optical rotation: [α] D 20 = -12 ° (c = 1.0, chloroform). UF: kmax (methanol) 246 lim (ε 11,600). IC (KBr): 3500 (broad), 1720, 1710, 1670, 1645, 1605 cm -1.

Analysis: for C24H28BrCl2FOs calculated: 50.90% C, 4.98% H, 14.11% Br, 12.52% Cl, 3.35% F, found: 51.15% C, 5.19% H, 1.4 Br, 12.47% Cl, 3.28% F. 197245 61 62 Example 81 To a solution of 6 g of 16α-methyl-2-bromo-6,9,9a-di-fluoro-11β, 17a, 21- trihydroxy-pregna-1,4-diene-3,20-dione (12g) (R 1 = R 2 = OH, R 3 =) and CH 3) in 12 ml of dimethylformamide and 40 ml of 2,2-dimethoxypropane are added with 0.030 g of acid p-toluenesulfonic acid and the mixture was heated at 115 ° C for 5 hours. The reaction mixture was cooled, poured into a 10% aqueous bicarbonate / chloroform mixture, washed with water, dried and evaporated to dryness. The residue is recrystallized from acetone-hexane (5 g) with 16α-methyl-2-bromo-6β, 9α-difluoro-11β, 17α, -21-trihydroxy-pregna-1,4-diene-3,20-dione. -17,21-acetonide (12w).

Optical Rotation: [α] ιι 2θ = -18 ° (c = 1.0, chloroform). UF:

Λ max (methanol) 246 nm (c 11,950). IC (KBr): 3480 (broad), 1725, 1678, 1645, 1605 cm @ -1.

Analysis: calculated for C25H31BrF2O5: 56.72% C, 5.90% H, 15.09% Br, 7.18% F, found: 56.90% C, 6.08% H, 15.25% O / Br Br. , 27% F. Example 82

By the method described in Example 81, 16 R -methyl-2-bromo-6,3,9a-difluoro-11 (17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12h)) (R 1 = R 2 = OH, R 3 = / SCH 3, X = OH, Y = F) is converted to 16β-methyl-2-bromo-6,3,9a-difluoro-11β, 17a, 21- trihydroxy-pregna-1,4-diene-3,20-dione-17,21-acetonide (12z).

Optical rotation: [α] D 20 = - (1414 ° (c = 1.0, chloroform) .UF: λ max (methanol) 246 nm (ε 12,000) IC (KBr): 3475 (broad), 1720, 1675 , 1640, 1605 cm -1.

Analysis: for C 25 H 31 BrF 2 O 5 calculated: 56.72% C, 5.90% H, 15.09% Br, 7.18% F, found: 56.91 ° / o C, 5.73% H, 14.89% Br, 7 , 12% F, Example 83

By the method described in Example 68, 16α-methyl-2-bromo-6α, 9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) was converted by reaction with hydrochloric anhydride to 16α-methyl-2-bromo-6 / 3,9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dion-21 -valerate (12aa) (R 1 = OCO (CH 2) 3 CH 3, R 2 = <tf CH 3, X = OH, Y = F).

Optical rotation: [α] D 2 () = + 10 ° (c = 1.0, chloroform). UF: linox (methanol) 246 lim (ε 11700). IC (KBr): 3500 (broad), 1740, 1725, 1670, 1640, 1605, 1230 cm &lt; -1 &gt;.Analysa: for C27H35BrF2O6, calculated: 56.55 o / c, 6.15% H, 13.93% Br, 6.62 O / F, found: 56.48% C, 6.21% H, 14.05% Br, 6.55% F. Example 84

By the method described in Example 68, 16β-methyl-2-bromo-6β, 9α-difluoro-11β, 17α, 21-trihydroxy-pregna-1,4-diene-3,20-dioin ( 12ih) (R 1 = R 2 = OH, R 3 = CH 3, X = OH, Y = F) is reacted with valeric anhydride with 16 R -methyl-2-bromo-6,3,9a-difluoro-11 (I). 17a, -21-trihydroxy-pregna-1,4-diene-3,20-dione-21-valerate (12ab) (R 1 = OCO (CH 2) 3 CH 3, R 2 = OH, R 3 =? CH 3, X = OH, Y = F).

Optical rotation: [α] D 20 = - (-39 ° (c = 1.0, chloroform).

Imax (methanol) 246 ΠΠ1 (ε 11800). IC (KBr): 3520 (broad), 1745, 1730, 1670, 1645, 1605, 1230 cm -1 calculated: 56.55% C, H 6.15%, 13.93% Br, 6.62% F, found 56.61 ° C, 6.05% H, 13.89% Br, 6.70% F. Example 85

By the method described in Example 68, 16α-methyl-2-bromo-6 (S ', 9α-difluoro-11β, 17α, 21-83)

19724S 84-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) (R1 = R2 = OH, R3 = 'CH3, X = OH, Y = F) is reacted with acid anhydride pivalic acid 16α-methyl-2-bromo-6 / 5,9α-difluoro-11 / 3,17α, -21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12ac) ( R 1 = OCOC (CH 3) 3, R 2 = OH, R 3 = i 'CH 3, X = OH, Y = F).

Optical rotation: [Ια] π 2θ = + 5 ° (c = 1.0, chloroform). UF: A, nax (n.ethanoi) = 245-246 nm (ε 10,850). IC (KBr): 3480 (broad), 1740, 1730, 1670, 1645, 1605, 1225 cm @ -1. Calculated: C, 56.55; H, 6.15; Br, 13.93; F, found: 56.60% C, 6.12% H, 13.95% Br, 6.55% F. Example 86

By the method described in Example 68, 16, 3-methyl-2-bromo-6,3,9a-difluoro-11β, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12h) (R1 = R2 = OH, R3 = 3CH3, X = OH, Y = F) is reacted with pivalic anhydride by reaction with 16/3-methyl-2-bromo-6 / 3,9a-difluoro-11/3 , 17a, -21-trihydroxy-pregna-1,4-diene-3,20-dione-21-pivalate (12ad) (R 1 = OCOC (CH 3) 3, R 2 = OH, R 3 = (3CH 3, X = OH, Y = F).

Optical rotation: [α] 20 D = 36 ° (c = 1.0, chloroform). UF:

Xntax (methanol) 245 UŽ 246 ηΐΏ (ε 11,000). IC (KBr): 3490 (broad), 1740, 1730, 1670, 1640, 1600, 1230 cm -1 calculated: 56.55% C, H 6.15%, 13.93% Br, 6.62% F, found: 56.70% C, 6.23% H, 14.08% Br, 6.75% F. Example 87

By the method described in Example 68, 16α-methyl-2-bromo-6,3,9α-difluoro-11,1,17α, 21-trihydroxy-pregna-1,4-diene-3,20-dione (12 g) ) (r 1 = r 2 = OH, R 3 = «CH 3, X = OH, Y = F) is converted to 16? -methyl-2-bromo-6 (3,9a-difluoro-11/3, by reaction with benzoic anhydride) 17a, -21-trihydroxy-pregna-1,4-diene-3,20-dione-21-benzoate (12ae) (R 1 = OCOC 6 H 5, R 2 = t H CH 3, X = OH, Y = F).

Optical rotation: [α] D 20 = + 75 ° (c = 1.0, chloroform). UF:

Xmax (methanol) 234 nUl (ε 22,500). IC (KBr): 3600, 3430 (broad), 1730, 1710, 1670, 1645, 1605 cm -1 calculated: 58.69% C, 5.26% H, 13.46% Br, 6, 40% F, TI 316 Z Π O * 58.85% C, 5.35% H, 13.37% / Br, 6.30% F. Example 88

By the method described in Example 68, 16/3-methyl-2-bromo-6,9,9a-difluoro-11 / 3,17a, 21-trihydroxy-ipregna-1,4-diene-3,20-dione ( 12h) (R1 = R2 = OH, R3 = 1 / 3CH3, X = OH, Y = F) is reacted with benzoic anhydride with 16/3-methyl-2-bromo-6 / 3,9a-difluoro-11 (3,17a, -21-trihydroxy-pregina-1,4-diene-3,20-dione-21-benzoate (12af) (R 1 = OCOC 6 H 5, R 2 = OH, R 5 == '/ 3 CH 3, X = OH) , Y = F).

Optical rotation: [α] D 20 = + 106 ° (c = 1.0, chloroform). UF:

Zniax (methanol) 234 nill (ε 22,700). IR (KBr): 3580, 3420 (broad), 1725, 1710, 1670, 1640, 1600 cm -1, Analysa: for C 29 H 31 BrF 2 O calculated: 58.69% C, 5.26% H, 13.46% Br, 6.40% F, found: 58.78% C, 5.15% H, 13.27% Br, 6.25% F. Example 89

By the method described in Example 74, 16α-methyl-2-bromo-6,9,9a-difluoro-11,1,17,21, 21-trihydroxy-pregna-1,4-diene-3,20-dione ( 12g) (R1 = R (f = OH, R3 = aCH3, X = OH, Y = F) is converted to 16a-methyl-2-bromo-6 / 3,9a-difluoro-11p, 17a, 21- trihydroxy-pregna-1,4-diene-3,20-dione-17-propionate (12ag) (R 1 = OH, R 2 = OCOCH 2 CH 3, R 3 = CH 3, X = OH, Y = F). 65 197245 66

Optical rotation: [α] D 20 = -92 ° (c = 1.0, chloroform). UF: λ max (methanol) 246 ΠΠ1 (ε 12,100). IR (KBr): 3500, 3430, 1730, 1710, 1675, 1645, 1605 cm -1.

Anal. Calcd for CPHPiBrFzOe: 55.05% C, 5.73% H, 14.65% Br, 6.97% F, found: 55.15% C, 5.68% H, 14.47%. Br, 7.02% F. Example 90

By the method described in Example 74, 16-methyl-2-bromo-6H, 9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dioin (12 g) (R 1 = R 2 = OH, R 3 = «CH 3, X = OH, Y = F) transfer to 16α-methyl-2-bromo-6,3,9a-difluoro-11 / 3,17a, 21-trihydroxy -pregna-1,4-diene-3,20-dione-17-benzoate (12ah) (R 1 = OH, R 2 = OCOC 6 H 5, R 3 = CH 3, X = OH, Y = F).

Optical rotation: [α] η 2 θ = -120 ° (c = 1.0, chloroform). UF:

Imax (methanol) 234 ΙΏΙΏ (&amp; 23,000). IC (KBr): 3490, 3420, 1730, 1710, 1678, 1645, 1605 cm @ -1.

Analysis: for C29H31BrF2O6 calculated: 58.69% C, 5.26% H, 13.46% Br, 6.40% F, found: 58.75% C, 5.18% H, 13.35% Br, 6.30% F. Example 91 Example of a process for the preparation of topical creams containing varying amounts of 2-bromo-6,9,9a-difluoro-11,17a, 21-trihydroxy-pregna-1,4-diene-3 , 20-dione-17,21-diacetate (XI).

Cream Ingredients Content in% (weight / weight)

Polysorbate 60Polysorbate 80isopropylmyristate glycerylmonosteate solution sorbitolsuccinating agent distilled water 1 - 51— 55—151— 51—10 0.2— 0.5q.s.ad 100

The ingredients of the cream are mixed and processed in the manner customary for the preparation of pharmaceutical creams for topical application.

Optionally, an antibacterial component such as neomycin may be added to the cream in an amount of from 0.1 to 3%. Example 92 Example of a process for the preparation of ointments containing varying amounts of 2-bromo-6 / 3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dion-17 21-acetate (XI) (intended for local administration).

Ointment Ingredients% (w / w) 2-bromo-6 / 3,9-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dion-17 , 21-diacetate 0.005-0.5 white vaseline qs ad 100

The components are mixed and processed in a manner customary for the preparation of colorless formulations for topical application.

An antibacterial component such as neomycin may optionally be added to the ointment in an amount of from 0.1 to 3%. Example 93 Example of a process for the preparation of jelly for topical application, containing various amounts of 2-bromo-6,3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17, 21-diacetate (XI).

Jelly Ingredients% in% (m / m) 2-bromo-6 (3,9a-difluoro-11,6,17a, 21-trihydroxy-pregna-1,4-diene-3,20- dion-17,21-diacetateCarpobol 934di-isopropanolamine propylene glycolPolysorbate 80sorbate potassiumDistilled water 0,005—0,50,5 — i 2,50,2— 1 5—500,5—5 0,05— 0,25q.s ad 100 2-bromo-6,3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21-diacetate 0,005— 0,5 cetostearyl alcohol 5— 20

The components are mixed and processed in a manner customary for the preparation of pharmaceutical jellies for topical application. Example 197 Example of a method of preparing lotions (topical lotions) for topical application, containing varying amounts of 2-bromo-6./3,9a-difluoro-ll/3,17a,21-trihydroxy-pregna- 1,4-diene-3,20-diol-17,21-acetate (XI).

Folders

Content in% (w / w) 2-bromo-6 / 3,9a-difluoro-17α, 21-trihydroxy-pregna-1,4-d, ien-3,20-dione-17,21-diacetate 0.005 - 0.5 propylene glycol 5 - 35 cetostearyl alcohol 0.5 - 2 isopropyl myristate 0.5 - 2

Emulgin C-700 0.25 - 1 potassium sorbate 0.05 - 0.25 distilled water q.s. ad 100

The individual components are mixed and worked in a manner customary for the preparation of lotions for topical application.

Optionally, an antibacterial component, such as neomycin, in an amount of from 0.1 to 3% can be added to the lotion. Example 95 Example of a process for the preparation of ophthalmic ointments containing various amounts of 2-bromo-8i (3,9-difluoro-11 / 3,17a ', 21-trihydroxy-pregna-1,4-diene-3, 20-dione-17,21-diacetate (XI) The active ingredient, starch and lactose are mixed, blended and the kernels are granulated, talc is added to the granular mixture and magnesium stearate is added and the mixture is bleached to tablets of 200 g. the tablet contains 1 to 50 mg of active substance Example 97 Example of a process for the preparation of oral suspensions containing various amounts of 2-bromo-6,3,3-a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene) -3,20-dione-21-acetate [XIc J.

Ingredients Suspension 100 ml suspension (w / v 2-bromo-6 (3,9a-difluoro-11 (6, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dion-21-) tragacanth acetate glycerol

Tween 80 sucrose

Methylparaben

Propylparaben flavoring and dye distilled water 0.010 0 0.53 3 0.1 50 0.15 0.05 9.5 q.s. ad 100

Ointment ingredients

% (W / w) 2-bromo-6 (3,9a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-17,21- - diacetate 0,005 - 0,5 mineral oil 1 - 10 white vaseline qs ad 100

The components are mixed and processed in a manner customary for the preparation of ocular ointments.

An antibacterial component may be optionally added to the ointment, for example, neomycin in the form of a micronized sulfate salt. Example 96

Process for preparing tablets containing varying amounts of 2-bromo-6 (3,9a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dioin [Xla])

The individual components are mixed and processed in a manner customary for the preparation of flavoring agents. Example 98 Example of a process for preparing a suspension for injection comprising various amounts of 2-bromo-8,9a-difluoro-11 (3,17a, 21-trihydroxy-1,4-diene-3,20-dion-21- acetate (XIc).

Suspension components

100 ml suspension (w / v 2-bromo-6: (3,9a-difluoro-11 (3,17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione-21-) acetate sodium carboxymethylcellulose (CMC) sodium chloride polysorbate 80benzylalcohol distilled water 0,5—10 qs 0,75 0,65 0,04 0,9ad 100

Tablet Ingredients

Amount in mg per200 mg tablet

The individual ingredients are mixed and processed in a manner customary for the preparation of sterile suspensions containing the active ingredient in finely divided particles.

The pharmaceutical compositions containing the other compounds of the present invention can be prepared in the same manner as described in Examples 91 to 98 using any of the above-mentioned specific compounds of Formula A instead of the active compounds exemplified herein. 2-bromo-6 (3,9a-difluoro-11 / 3,17a, 21-trihydroxy-pregna-1,4-dien-3,20-dione 1 - 50 starch 99-75 lactose 90-65 talc 8 magnesium stearate 2

Claims (1)

69 197245 70 EMBODIMENT A process for the preparation of new 2-bromo-6,3,9a-difluoro-pregna-1,4-diene-3,20-dione or 17, 21-esters, 17,21-alkylorthoesters or 17 thereof. , 21-cyclic acetals or ketals of formula A in CH 2 OQ-1 wherein Q and R are as defined above, wherein the compound of formula C wherein Q is a carboxylic acid residue of 2 to 12 carbon atoms or a residue of an inorganic acid, optionally converted to pharmaceutically acceptable salts or esters, to the compound of formula C is then treating with a carbonate-alkali metal solution to form 2-bromo-6,3-fluoro-9,3,11-oxide-17,21-dihydroxy-pregna-1,4-diene-3,20-dton 9,11-epoxide; its 17,21-dt-ester, 17,21-alkylorthoester or 17,21-Q are each a hydrogen atom or an alkyl radical of 2 to 12 carbon atoms, or both OQ groups together form a cyclic ketal of 2 to 12 atoms carbon, acetal of 2 to 12 carbon atoms or alkyl chloroester of 2 to 12 carbon atoms, R is hydrogen or w-OQ wherein Q is as defined above, and the pharmaceutically acceptable salts or esters of compounds of formula A wherein Q is a carboxylic acid residue of 2 to 12 carbon atoms or an inorganic acid, characterized in that 2-bromo- &lt; 3 &gt; -fluoro-17,2-dihydroxy-pregna-1,4,9 [11] -trien-3,20-dione-17,21- diester, 17,21-alkylorthoester or 17,21-cyclic acetal or ketal of general-cyclic acetal or D ketal of general formula CH and I-J-OGL O F (D) wherein Q and R are as defined above whereupon formula B is reacted with hydrogen fluoride to give 2-bromo-6le, 9a-difluoro-11,3,17,21-trihydroxy-pregna-1,4-diene-3,20- dione and its 17,21-diester, 17, 21-alkylorthoester or 17,21-cyclic acetal or ketal of formula F CtyOGL wherein Q and R are as defined above, reacting with bromine acid to give 2,9-dibromo-6S-fluoro-11,3,17,21-trihydroxy-preg-na-1,4-diene-3,20- dione-17,21-diester, 17,21-alkylorthoester or 17,21-cyclic acetyl or ketal of formula C CWOQ. I K wherein Q and R are as defined above, wherein the compound of formula F wherein Q is the remaining carboxylic acid having 2 to 12 carbon atoms or an inorganic acid moiety is optionally converted into pharmaceutically acceptable salts or esters. Severografla, p., Race 7, Most