MC1166A1 - D-HOMOSTEROIDES - Google Patents

Description

The invention relates to new chemical compounds. Within the scope of the present invention, it has been found that the D-homosteroids of the pregnane series have the formula f*3

CO

61

where R represents an atom of hydrogen, fluorine, chlorine or

91

a methyl radical; R an atom of hydrogen, fluorine, of

171a 111

chlorine or bromine; S a hydroxyl or acyloxy radical and R

a hydroxyl or acyloxy radical, a fluorine or chlorine atom,

where in the 9,11-dihalogenated compounds the atomic number of

111.A, ✓ qi

R must be less than or equal to that of R; and where the dotted 1,2 bond represents an optional C-C bond, have an inhibitory effect on inflammation.

The invention relates to pharmaceutical preparations having an anti-inflammatory effect, which contain as an active ingredient a compound of formula I', as well as a process for preparing these pharmaceutical preparations.

The following compounds of formula I' 11(3,17a-dihydroxy-D-homopregn-4-ene-3,20-dione, 11P,17a-dihydroxy-D-homopregn-1,4-diene-3,20-dione and 6a-fluoro-1,17a-dihydroxy-D-homopregn-4-ene-3,20-dione are known compounds whose preparation is described in Belgian patent no. 797 4-12.

Among the compounds of formula I', those of formula

^H3

where the dotted 1,2 bond represents a faculta- C-C bond

g tive; R an atom of hydrogen, fluorine, chlorine or a radical

15 methyl; R^ an atom of hydrogen, fluorine, chlorine or 11

"bromine; R a hydroxy, acyloxy, fluorine or chlorine radical, and E' a hydroxy or acyloxy radical, where in the

11

9511 dihalogenated compounds, the atomic number of R must be less than or equal to that of R^, and where, if in a compound 20 11 ,l7a-dihydroxy R^ represents a hydrogen or in a compound 11 ,l7a-dihydroxy-4~ene R^ represents a fluorine, R^ must be a fluorine, chlorine or bromine atom,

are novel compounds and as such also form the subject matter of the present invention.

25 The invention further relates to a method for preparing compounds of formula I.

An acyloxy radical can be derived from a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic or araliphatic carboxylic acid, or an aromatic carboxylic acid preferably having up to 15 carbon atoms. Examples of such acids include formic acid, acetic acid, trifluoroacetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, oenanthyl acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid, and benzoic acid. Alkanoyloxy groups having 1 to 7 carbon atoms are of particular interest.

0

11

We prefer the group of compounds with formula I, where E represents a hydroxyl radical. We also prefer compounds where E represents a hydrogen, fluorine, or chlorine atom. Another preferred subgroup is represented by compounds with formula I₅ and a 1,2 double bond.

Examples of compounds of formula I according to this invention include:

1ip~butyryloxy~17a-hydroxy~D~homopregna-1,4-dièn-3,20-dione, 11p-trifluoroacetoxy-17a-hydroxy-D~homopregna-1,4-dièn-3,20-dione, 10 17a-butyryloxy-11(3-trifluoroacetoxy-D-homopregna-1,4-dien-3,20-dione,

17a-butyryloxy-1ip-hydroxy-D-homopregna-1,4-dien-3,20-dione, 6a-fluoro-Hp, 17a ~ dihydroxy-D-homopregna-1,4-dien-3,20-dione, 6a-chloro-11p, 17a-dihydroxy-D-homopregna-1,4-dien-3,20-dione, 15 6a-fluoro-17a-hydroxy-1ip~trifluoroacetoxy-D-homopregna-1,4-dien-3,20-dione,

: 17a-butyryl oxy-6ct-fluor o-l 1 P-trifluorac etoxy ~ D ~ homopregna-1,4-dien-3,20-dione, . ■

17a-butyryloxy-5a-fluoro-1ip-hydroxy-D-homopregna-1,4-dien-3,20-20 dione,

17a-valeroyloxy~6a-chloro-11(3~hydroxy~D-hoEopregna~1,4-dien~ 3,20-dione,

9-fluoro-1ip,17a-dihydroxy-D-homopregna-1,4-aièn-3,20-dione, 9-chloro~11p,17a-dihydroxy-D-homopregna-1,4-dièn--3', 20-dione, 25 9-bromo-1ip,17a-dihydroxy-D-h.omopregna-1,4-dien-3,20-dione, 9-fluoro~17a-hydroxy-11p-propionyloxy-D-homopregna-1,4-dien-. 3}20-dione,

17a-butyryloxy-9-fluoro-11p-propionyloxy-D-homopregna-1,4-dien-3,20-dione,

30 9-fluoro-17a-hydroxy-11p-trifluoroacetoxy-D-hoinopregna-1,4-dien-3,20-dione,

17a-butyryloxy-9-fluoro-11p-trifluoroacetoxy-D-homopregna-1,4-di en-3,20-di one,

17a-bu tyryl oxy ~9-fluor o-l ip--hydroxy-D-homopr egna-1,4-dièn~3,20-55 dione,

9-chloro-1ip-hydroxy~17a-propionyloxy-D-homopregna-1,4-dien-3,20-dione,

4

7 - D-homosteroids of formula

<^3

where the dotted 1,2 bond represents an optional G-C bond; R^ an atom of hydrogen, fluorine, chlorine or a methyl radical; R^ an atom of hydrogen, fluorine, chlorine or i a*

bromine; R a hydroxy radical, acyloxy radical, a fluorine atom or

I A Og.

of chlorine and R- • a hydroxy or acyloxy radical, or in the

! 11

9,11-dihalogenated compounds the atomic number of R must be less than or equal to that of R^ and where, if in a 11,17a~ dihydroxy compound R represents a hydrogen or in a 11,17a~ dihydroxy-4—ene compound R^ represents a fluorine, R^ must be an atom of fluorine, chlorine or bromine.

8 - D-hoiaosteroids according to claim 7,

11

where R is a hydroxyl group.

9 - The D-homosteroids according to claim 7 or o

8, where Ry is hydrogen, fluorine, or chlorine.

10 - The D-homosteroids according to any one of claims 7 to 9, which are unsaturated at position 1,2.

5

11 - A method for preparing D-homosteroids of

formula i

R6

17a

where the dotted 1,2 bond represents an optional C-C bond; R^ an atom of hydrogen, fluorine, chlorine or a methyl radical; R^ an atom of hydrogen, fluorine, chlorine or 11

of bromine; R a hydroxy, acyloxy radical, a fluorine atom or 17a of chlorine and R a hydroxy or acyloxy radical, where in the

✓ 11

In 911-dihalogenated compounds, the atomic number of R must be less than or equal to that of R^, and where, if in a compound

11,17a-dihydroxy R^ represents a hydrogen atom in a compound

11,17a-dihydroxy-4-ene R^ represents a fluorine atom; R^ must be a fluorine, chlorine, or bromine atom.

characterized in that, in a) hydroxylating at position 11, a D-homosteroid of formula

17a

R6

6

by means of a microorganism or an enzyme derived from it, or b) by replacing iodine with hydrogen in a D-homosteroid of formula

10

15

R

ch2j

17a or c) by dehydrogenating at position 1,2 a saturated 1,2-D-homosteroid of formula I or 20d) by attaching C1P, BrJ?, BrCl or hypochlorous or hypobromous acid to the 9,11 double bond of a D-homosteroid of formula

25

30

35

or h3c k3Ç

R6

ch3 co

R

17a

IV

e) by treating a D-homosteroid of formula

7

10

R6

17a

'with hydrofluoric, hydrochloric or hydrobromic acid, or f) by saponifying an acyloxy group in a D-homosteroid of

17a 11

formula I, where at least one of the radicals R' or R is a 15-acyloxy, or g) by isomerizing a 6p-isomer of a 6-fluoro-, chloro-, or methyl-D-homosteroid of formula I to give the 6a isomer, or h) by fluorinating or chlorinating a D-homosteroid of formula

20

2-5

r11 H3Ç

ç«3

17a

30 in position 6, or i) by acylating an 11p- or 17a-hydroxy group in a D-homo-

11

steroid of formula I, where at least one of the radicals R or 17a

R' is a hydroxyl group, or j) by oxidizing into a D-homosteroid of formula

co

5 4-

the 3-bydroxy-A^ group to give the 3-keto~A group,

or by reducing the 11-keto group of a D-homosteroid of formula

^h3

CO

under the protection of the 3-keto and 20-keto groups to give a hydroxy group;

Or

1) by oxidizing the 17a(20) double bond of a D-homosteroid of general formula

9

5

10

R6

to give a hydroxyketone group or m) by methylating at position 6 a D-homosteroid of formula VT, 15 or n) by transforming the 17p-ethinyl group in a D-homosteroid of formula

20

25

R6

17a

30 or o) by dehydrogenating at position 4 a D-homosteroid of formula

10

10

r611

CH3

co

17 a q

u - 11 17a where, in the formulas above, R, R^, R, R' and the bond

6^1

dotted 1,2 have the meaning given above and where R 15 represents a hydrogen or a methyl.

12 - A process according to claim characterized in that D-homosteroids of formula I are prepared where R is a hydroxyl group.

13 - A process according to any one of claims 11 and 12, 20 characterized in that D-homosteroids of for- are prepared

mule I, where R represents hydrogen, fluorine, or chlorine.

. 14 - A process according to any one of claims 11 to 13, characterized in that 1,2-unsaturated D-homosteroids of formula I are prepared.

I

10

15

20

25

30

9-chloro-11p~fluoro-17a-hydroxy-D-homopregna-1,4-dien-3,20-dione, 17a-butyryloxy-9-chloro-1lp-fluoro-D-homopregna-1,4-dien-3,20-dione,

11p,17a-dihydroxy-6a-methyl-D-homopregn-4-en-3,20-dione, 17a-butyryloxy-1p-hydroxy-6a-methyl-D-homopregn-4-en-3,20-dione, 11p,17a-dihydroxy-6a-methyl-D-homopregn-1,4-dien-3,20-dione, 17a-butyryloxy-1p-hydroxy-6a-methyl-D-homopregn-1,4-dien-3,20-dione,

6a-methyl-1ip,17a-dipropionyloxy-D-homopregn-1,4-dien-3,20-dione, 9-fluoro-11 J3,17a-dihydroxy-6a-methyl-D-homopregn-4-en-3,20-dione, 17a-butyryloxy-9~ïlu.oro-1lp~hydroxy-6a-methyl-D-homopregn-4-en-3,20-dione,

9-fluoro-1ip,17a-dihydroxy-6a-methyl-D-honiopregna-1,4-dien-3,20-dione,

9-fluoro-1ip-hydroxy-6ct-methyl-17a-valeroyloxy-D--homopregna-1,4-dien-3,20-dione,

11p,17a-dibutyryloxy-9-chloro-6a-methyl-D-horaopregna-1,4-dien-3,20-dione,

9-chloro-6a-fluoi?o-1ip,17a-dihydroxy-D-homopregna-1,4-dien-3,20-dione,

6a,9-difluoro~1'ip,17a-dihydrcxy-B-homopregna~1,4-dien-3,20-dione, 6a,9-difluoro-11p-hydroxy-17a-propionyloxy-D-homopregna-1,4-dien-3,20-dione,

6a-chloro-9~fluoro-11p,17a-divaleroyloxy~I)-homopregna-1,4-dien-3,20-dione,

9-chloro-1ip-fluoro-17a-hydroxy-6a-methyl-D-hoin.opr egna-1,4-dien-3,20-dione,

9-chloro-1ip-fluoro-6α-methyl-17α-valeroyloxy-D-homopregna-1,4-dien-3,20-dione,

9,1ip-dichloro-6a-iaethyl-17a-propionyloxy-D-hoEiopregn-4-en-3,20-dione,

9-chloro-5a,1ip-difluoro-17a-hydroxy-D-homopregna-1,4-dien-3,20-dione,

17a-butyryloxy-9~chloro-6a,1ip-difluoro-D-homopregna-1,4-dien-3,20-dione,

6a,9,1ip~trichloro-17a~hydroxy-D-homopregna-1,4-dien-3,20-dione, 6a,9-dichloro-1ip~fluoro-l7a-valeroyloxy-D-horaopregna-1,4-dien-3,20-dione, •

r-

D-homosteroids of formula I can be prepared according to this invention, by a) hydroxylating at position 11 a D-homosteroid of formula

10

15

,pl7a

R'

.by means of a microorganism or an enzyme derived from it, or b) by replacing iodine with hydrogen in a D-homo-

Formula 20 steroid

25

30

R6

17a or c) by dehydrogenating at position 1,2 a saturated D-homosteroid 35 1j2 of formula i or d) by attaching C^, C1F, BrF, BrCl or hypochlorescent or hypobromous acid to the 9,11 double bond of a D-homosteroid of formula

-6-

10

15

20

25

or e)

17a

R6

by treating a D-homosteroid of formula

ch3

co

17a

R6

with fluorine-, chlor- or hydrobromide acid, or f) by saponifying an acyloxy group in a D-hoiaoste-

v 17a 11

30. Roid of formula I, or at least one of the radicals R' or R

is an acyloxy, or g) by isomerizing a 6[3-isomer of a 6-fluoro, chloro- or methyl-D-homosteroid of formula I to give the 6a isomer, or

35 k) by fluorinating or chlorinating a D-homosteroid of formula

~7~

<j^3

co

10

17a at position 6, or i) by acylating an 11(3-) or 17a-hydroxy group in a

15 D-homosteroid of formula I, where at least one of the radicals R 17a or B' is a hydroxy, or >.

g) by oxidizing in a D-homosteroid of formula

11

20

25

5 4

30 the 3-kydroxy-A^ group to give the 3-keto-A group,

Or

*0 by reducing the 11-keto group of a D-homosteroid of formula

-8~

10

ch3

co

17a r6 "

under the protection of the 3-keto and 20-keto groups to give a 15-hydroxy group;

Or

1) by oxidizing the 17a(20) double bond of a D-homosteroid of general formula

20

25

30

r6

to give a hydroxyketone group or m) by methylating at position 6 a D-homosteroid of liver VI5 or

35 u) by transforming the 17P- group into an acotyledon

ôthinyl in a D-homosteroid of formula

-9-

or o)

Formula 15

20

25

30

35

by dehydrogenating at position 4 a D-homosteroid of

ch3

17 a

CO

r611

where, in the formulas above, R^, R^, R^, R^a and the bond

STSL S\

dotted 1,2 have the meaning given above and where R represents a hydrogen or a methyl.

11-hydroxylation of a compound of formula II can be carried out according to variant a) of the process using a method known for the microbial 11-hydroxylation of steroids. For this purpose, microorganisms of the taxonomic group Mycetes and Schizomycetes, in particular the subgroups Ascomycetes, Phycomycetes, Basidionycetes, and Actinomycetales, should be mentioned. Mutants produced by chemical means, for example by nitrite treatment, or

-10-

by physical means, for example by irradiation, as well as cell-free enzymatic preparations obtained from microorganisms. Suitable microorganisms for 11|3-hydroxylation are in particular those of the genera Curvularia, e.g. C. lunata NRBL 2380 and NRRL 2178; ATCC 13633, 1343, 14678, IMI 770075 IPO 2811; Absidia, e.g. A. coerula IFO 44-35; Colletotrichum, e.g. C. pisi ATCC 12520; Pellicola-ria, e.g. P. filamentosa IFO 6675; Streptomyces, e.g. S. fradiae ATCC 10745; Cunninghamella, for example 10 C» bainieri ATCC 9244, C, verticellata ATCC 8983; C. elegans

EREL 1392 and ATCC 9245, C. blakesleeana ATCC 8688, 8688a, 8688b, 8983, and Co echinulata ATCC 8984; Pycnosporiun, for example sp. ATCC 12231; Verticillium, for example V. theobromae CBS 39858; Aspergillus, for example A. quadrilieatus JAIv! 2763; .15 Trichothecium, for example T. roseum ATCC 12519; and Phoma, for example sp. ATCC 13145.

One can proceed to replace an iodine atom in a compound of formula III with a hydrogen according to variant b) of the process by treating compound II with a reducing agent, such as îTaHSO-r.

The 1,2-dehydration of a 1,2-saturated D-homosteroid of formula I (variant c) of the process) can be undertaken in a conventional manner, for example by microbiological means or by means of dehydrating agents such as iodine pentoxide, periodic acid or selenic dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, or lead tetraacetate. Suitable microorganisms for 1,2-dehydration include, for example, Schizomycetes, in particular those of the genera Arthrobacter, for example A. simplex ATCC 6946; Bacillus, for example lentus ATCC 13805 and B. sphaericus ATCC 705; Pseudomonas, for example P. aeruginosa IFO 3505; Flavo-bacterium, for example F. flavenscens IFO 3058; Lactobacillus, for example L. brevis IFO 3345 and Nocaraia, for example N. opaca ATCC 4276.

35 In order to carry out variants d) and e) of the process, the starting product IV or V is dissolved in a suitable solvent, for example an ether such as tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methyl chloride.

-11-

lene or chloroform, or a ketone, such as acetone, is added, and the reagent to be inserted is allowed to act. In practice, hypochlorous or hypobromous acid is prepared in the reaction mixture itself; for example, from N-bromo- or N-chloro-arnides or -imides, such as N-chlorosuccinimide or N-bromacetamide, and a strong acid, preferably perchloric acid. Variant e) is preferably used to prepare 9-fluoro-11-hydroxy-D-homosteroids of formula I.

The saponification of an acyloxy group 10 in a steroid of formula I (variant f) of the process) can be carried out in a conventional manner, for example with an aqueous-methanolic solution of potassium carbonate or a solution of NaHCO3.

Isomerization of a 6(3) isomer of a 6-substituted compound of formula I, in particular of a 6(3-fluoro or chloro (variant g) compound of the process) can be carried out by treatment with an acid, in particular a mineral acid, such as hydrochloric acid, in a solvent, for example dioxane or glacial acetic acid.

The halogenation of a steroid of formula VI at position 20 6 (variant h) of the process) can be carried out in a conventional manner. A 6,7-saturated D-homosteroid of formula VI can be halogenated by reaction with a halogenating agent, such as an N-chloramide or -imide (for example, 1F-chlorosuccinamide) or with elemental chlorine (cf. J. Am. Chem. £2? 4-534 (1950)). Halogenation 25 at position 6 is preferably carried out by reacting a 6,7-saturated D-homosteroid of formula VI in a 3-enolester or a 3-enolether, for example, 3-enolacetate, and then with chlorine (cf. J. Am. Chem. Soc. 82, 1230 (1960)); with an N-chlorimide (cf J. Am. Chem. Soc. 82, 1230 (1960); 77, 3827 (1955)) or a 30 perchloryl fluoride (cf J. Am. Chem. Soc., 81_, 5259 (1959).; Chem. et Ind. 1959* 1317)» As a fluorinating agent, trifluoromethyl hypofluorite should also be mentioned.

Insofar as mixtures of isomers are formed in the halogenations described above, that is to say 35 mixtures of 6a- and 6p-halosteroids, these can be resolved to give the pure isomers by classical methods, such as chromatography.

The acylation of a hydroxyl group 11(3) and/or 17a(va

-12-

Step (i) of the process) can be carried out conventionally, for example by treatment with an acylizing agent such as an acyl chloride or an acyl anhydride, in the presence of an acid-binding agent, for example pyridine or triethylamine, and a suitable catalyst, such as p-dimethylaminopyridine, or in the presence of a strong acid catalyst, for example p-toluene-tissunic acid. Organic solvents without hydroxyl groups should be mentioned as solvents for acylation, for example chlorinated hydrocarbons, such as methylene chloride, or hydrocarbons such as benzene. If working in a basic medium in the presence of p-dimethylaminopyridine, the hydroxyl group 11(3) adjacent to the hydroxyl group 17(1) can be selectively acylated.

The oxidation of a compound of formula VIII (variant j)

15 of the process) can be carried out according to the Oppenauer process, for example using aluminum isopropylate, or with oxy-

.dants such as chromium trioxide (for example, the reagent of

Jones), or according to the Pfitzner-Moffatt process using dimethyl sulfoxide/dic7/clohexylcarboaiimide (operation during

5

20 which must be isomerized the Ay-3~ketone which first appeared as A^-3-ketone); or by means of pyridine/SO^.

To carry out variant k) of the process, the ketone group of compound IX at positions 3 and 20 is first protected, for example, as a semicarbazone. If there is a 25,1,2 double bond, the 5-keto group can also be protected by the formation of an enamine. The protecting groups can be separated again by acid hydrolysis. A 14-,

A ' -3-ketone with a secondary amine in the presence of TiCl,.

13 5. ' , ,

in A''-3-enamine. Reduction of the 11-keto group of the compound

30 This protection can be achieved with complex metal hydrides, such as lithium aluminium hydride, sodium borohydride or diisobutyl aluminium hydride.

The oxidation of the 17(20) double bond of the compound of formula X (variant 1) of the process) can be carried out by 35 examples with oxidants, such as a tertiary amine-N-oxide peroxide in tert-butanol/pyridine in the presence of catalytic amounts of osmium tetroxide. Examples of tertiary amine-N-oxide peroxide include N-methyl-

S

-13-

5

10

15

20

30

morpholino-H-oxids and triethylaminooxide peroxide. On the other hand, it can be oxidized with oxidants such as osmium tetroxide or permanganate to give 17,20-glycol and continue to oxidize the latter with oxidants such as chromic acid to give hydroxyketone.

Methylation according to variant m) of the process can, for example, be carried out by transforming the starting product of formula VI into a 3-enolether (for example by treatment with an ester of orthoformic acid, such as ethyl orthoformate, in the presence of an acid such as p-toluenesulfonic acid, possibly adding the corresponding alcohol; or by treatment of the starting product VI with a dialcoxypropane, for example 2,2-dimethoxypropane in methanol/dimethylformamide in the presence of p-toluenesulfonic acid) and by reacting the enolether with a tetrahalomethane, for example CBr, ,

Ll H'

CClpBr2 or CCl^Br^ to give trihalomethyl-A-3-ketone.

Trihalomethyl-A^^-ketone can be dehydrohalogenated with

4

bases such as collidine to give dihalomethylene-A-3-ketone which can in turn be transformed by catalytic hydrogenation under mild conditions, for example with a Pd/SrCO^ catalyst to give 6ct-methyl~A-3-ketone.

Another methylation method involves transforming a 1,2-saturated D-homosteroid of formula VI, as described above, into a 3-enolether and then transforming this compound conventionally to give the corresponding 6-formyl derivative, reducing the formyl group with sodium borohydride to give the hydroxymethyl group, and finally dehydrating the reaction product by separating the enolether, resulting in a D-homosteroid of formula

CH3

17a

CO

-14.-

9 11 173.

where R, R and R1' have the meanings given above.

Such 6-methyl intermediates can also be prepared by transforming 1,2-saturated compounds VI into a 3-enamine, for example, 3,5-pyrrolidinium enamine, by hydroxymethylation with formaldehyde and separation of the water using acids, such as p-toluenesulfonic acid. The 6-methylene-D-homosteroids of formula VII thus obtained can be catalyzed with hydrogenation, that is, using known hydrogenation catalysts, to give the corresponding 10 6-methyl compounds.

Hydration according to variant n) of the process can be carried out in the presence of a suitable catalyst, such as p-toluenesulfonamide-mercury or with ion exchangers made of acidic activated mercury salts.

15 A saturated D-homosteroid of formula XII can be dehydrogenated at position 4 or* at position 1,4 by bromuration followed by dehydro-bromuration.

The starting products for the process of this invention can be prepared, insofar as they are not known or are not described below, by analogy with known processes or processes described below.

Given their effectiveness in inhibiting inflammation, formula I compounds can be used, for example, in the treatment of inflammatory diseases such as eczema.²⁵ In general, preparations for internal administration may contain from 0.01 to 5.0% of a formula I D-homosteroid. The daily dose may vary between 0.5 and 10.0 mg depending on the condition of the person being treated and the desired duration of treatment. The proportion of active formula I D-homosteroid in topical preparations is generally in the range of 0.0001 to 5% by weight, preferably in the range of 0.001 to 0.5%, and preferably in the range of 0.01 to 0.25%.

The products of this process can be used as 35 medications, for example in the form of pharmaceutical preparations, which contain them mixed with an inert pharmaceutical carrier, organic or inorganic, suitable for enteral, percutaneous or parenteral administration, such as water, the

-15-

Gelatin, acacia gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. Pharmaceutical preparations can be presented, for example, as ointments or as solutions, suspensions, or emulsions. They may be sterilized and, depending on the case, contain adjuvants such as preservatives, stabilizers, wetting agents, or emulsifiers, salts to modify osmotic pressure, or buffers. They may also contain other therapeutically useful products.

In the following examples, temperatures are given in degrees Celsius.

Example 1

100 mg of 1p,17a-acetoxy-D--hoaoprogn-4-ene-20-ine-3-one and 200 mg of mercuric p-toluenesulfonamide are boiled under reflux for 20 hours in 155 ml of alcohol. The reaction mixture is poured onto dilute hydrochloric acid and extracted 3 times with methylene chloride. The organic phases are washed with a dilute solution of table salt, dried, and concentrated. Silica gel chromatography of the residue gives 1p,17a-diacetoxy-D--hon:oprogn-4-ene-3,20-dione.

UV: S 2^2 = 16250 EMIT: signals at 25 ô = 1.08 ppm (S) 3H)

18-Ke, 19-Me

-COCH, and 3

2x-00CCH7 30 5.47 "On) 1H H^eq

"(m) 1H

The starting product can be prepared in the following way:

3P,11p,17a-trihydroxy-D-homopregn-5-35-ene-20-ine is oxidized according to the Oppenauei process* to give 11p,17a-dihydroxy-D-homopregn-4-ene-20-ine-3-one, and the latter is then reacted in acetic acid anhydride and acetic acid in the presence of catalytic amounts of acid.

1.24

II

(S)

3H J

2.02

II

(S)

3H -\

2.09

tt

(S)

3 hours

2.13

L!

(S)

3H

5.47

II

On)

1 hour

5.70

II

(m)

1 hour

-16-

p-toluenesulfonic acid to give 11(3,17a-diacetoxy-I)-homo-pregn~4~ene-20~ine-3-one.

Example 2

One g of 11p-acetoxy-6α-fluoro-D-homo-5-pregna-4,17α(20)-diene-3-one, 22 mL of β-butanol, 1.5 mL of pyridine, 4.3 mg of osmium tetroxide, and 5.3 mL of a α-methylmorpholinoxide-hydrogen peroxide solution (L. Pieser, M. Pieser, Reagents for Organic Synthesis 690 (1967)) are stirred at 25°C. After 24 hours, 2.5 mg of osmium tetroxide and 3.0 mL of a α-methylmorpholinoxide-hydrogen peroxide solution are added. After another 24 hours, 20 mL of β-hydrochloric acid, 1.5 g of thiourea, and 50 mL of methylene chloride are added while stirring. The aqueous phase is separated and extracted twice more with methylene chloride. The methyl-15-lene chloride solutions are washed with water and a dilute solution of table salt, dried over sodium sulfate, and concentrated. Silica gel chromatography of the residue yields 11p-acetoxy-6α-fluoro-17α-hydroxy-D-homopregn-4-ene-3,20-dione, P^ 202-203°C. UV: S234 = 15900, [ce]jj = +98° (in dioxane, c = 0.1%). The starting material can be prepared as follows:

1-ip-hydroxy-D-homopregna-4,17α(20)-diene-3-one is reacted in ether and acetic acid anhydride in the presence of perchloric acid to give 3,11p-diacetoxy-D-homopregna-3,5α(20)-triene. Treatment with perchloryl fluoride followed by isomerization yields 1-ip-acetoxy-6α-fluoro-D-homopregna-4,17α(20)-diene-3-one.

Example 3

Four hundred mg of 1ip-17a-diacetoxy-3P-hydroxy-D-homopregn-5-ene-20-one is heated to boiling in 5 mL of cyclo-30 hexanone and 30 mL of toluene. Five mL is distilled. After adding 600 mg of aluminum tritert-butylate, the mixture is boiled under reflux for 6 hours with argon. The reaction mixture is poured onto 2N hydrochloric acid and extracted three times with toluene. The organic phases are washed to neutrality with sodium bicarbonate solution and table salt solution, dried, and concentrated. Silica gel chromatography of the residue gives 1ip,17a-diacetoxy-D-homopregn-4-ene-3,20-dione, which is identical to the product of Example 1.

-17-

The starting product can be prepared as follows:

3P,11p-dihydroxy-D-homo-anarost-5-ene-17a-one is reacted under reflux with 1-ethylmagnesium bromide in THF. By chromatographic purification of the reaction mixture, 17ap-ethinyl-3p,11(3,17acc-trihydroxy-D-homoandrost-5-ene, 232-234°G; [«.J^ = -77° (c = 0.1% in dioxane)] is obtained.

. From this, with mercury p-toluenesulfonamide • in boiling alcohol, we obtain 3(3 ,Hp ,17a-trihydroxy-D-homopregn~5~ 10 en-20-one, Pf 244-247°C [a]D = -1.01° (c = 0.1 % in dioxane).

This compound is transformed with acetic acid anhydride and a catalytic amount of perchloroic acid in ethyl acetate to give 3P,Hp,17a-triacetyl-D-15 homopregn-5-ene-20-one. Partial saponification with potassium carbonate in methanol yields 1P,17a~

di ace t oxy •~3p-hydroxy-D-hom opr egn-5-è ne-2 0-one.

Example 4

4.9 g of 9-fluoro-20-1ip,17a-dihydroxy-21-iodo-D-homopregna-1,4-diene-3,20-dione, 80 mL of ether, 80 mL of benzene, 40 mL of water, and 40 mL of a saturated sodium sulfite solution are stirred at 25°C for 30 hours. The reaction mixture is diluted with ethyl acetate. The aqueous phase is separated and extracted twice with ethyl acetate. The ethyl acetate solutions are washed twice with a salt solution, dried over sodium sulfate, and concentrated. By silica gel filtration and crystallization from acetone-hexane we obtain 9-fluoro-1ip,17a-dihydroxy-D-homcpregna-1,4-diene-3,20-dione, Pf 268-269°C 30 UY : s 229 = 15200, [a]^ = +67° (in methanol, c - 0.1 ?&).

The starting product can be prepared by transforming 9-fluoro-D-homoprednisolone, P^ 241-246°C, [a]^ = +101° (c = 0.1% in dioxane), UV: G^g = 14540, by reaction with methanesulfonyl chloride in pyridine to give 9-fluoro-1ip,17a-dihydroxy-21-mothanesulfonyloxy-B-

homopregna-1,4-diene-3,20-dione and by transforming the latter with sodium iodide in acetone to give 9-fluoro-11p,17a-dihydr oxy-21-iodo-D~homopregna-1,4-diene-3,20-

k

-18-

Or

/O

dione. 190°C (dec.) [etJ^ = +118° (in dioxane, c = 0.1%), UV; € 238 = 15750.'

Similarly, from 6a-fluoro-11p,17a-dihydroxy-21-iodo-D-homopregnan-5 1,4-dien-3,20-dione, Pf 175-177°, UV: λ = 15830,

[a]jj = +121° (c = 0.1 c/o. in dioxane) 6a-fluoro-1ip,17a-dihydroxy-D-homopregna-1,4-dien-3,20-dione, Pf 183-184°, UV: s242 = 14400, [a]D = +56° (c = 0.1 in dioxane)

10 from 6a,9-difluoro-1lp,17a-dih.yaroxy-21-iodo-D-hono-pregna-1,4-dièn~3,20-dione, P^ 189-190°, UV: S 23g "16750, [a]p = +115° (c = 0.1% in dioxane) 6a,9-â.ifluoro-1ip,17a-dihydroxy-D-h.ociopregna-1,4-dièn~3,20-dione, Mp 230-231°, UV: £23q = 16000, [a]D = +57° 15 (c = 0.1% in dioxane).

Example 5

60 mg of 9,11p-epoxy-17α-dihydroxy-D-homo-9P-pregna-1,4-diene-3,20-dione is stirred for 15 minutes at 25°C in 1.5 ml of ethyl acetate and 0.15 ml of 20-37% hydrochloric acid*. The reaction mixture is poured onto a dilute solution of sodium bicarbonate and extracted 3 times with methylene chloride. The methylene chloride solutions are washed twice with a dilute solution of kitchen salt, dried, and concentrated. From acetone, 9-chloro-11p,25α-dihydroxy-D-homo-9P-pregna-1,4-diene-3,20-dione is obtained at a boiling point of 265-270°C (dec). UV: £-240 = 15080, [a]D = +94° (DLISO, c = 0.1%).

Example 6

• 340 mg of 17a-hydroxy-D-homopregna-1,4,9(11)-triene-3,20-dione and 330 mg of 11-chloro-30 succinimide are stirred for 6 hours at 25°C in 3.5 mL of a solution of one part urea and one part hydrofluoric acid. The reaction mixture is poured onto water and extracted three times with methylene chloride. The organic phases are washed twice with a dilute solution of table salt containing 1% sodium bicarbonate and 1% sodium sulfite, then dried and concentrated. By silica gel chromatography we obtain 9-chloro-1ip-fluoro-17a~hydroxy-D-hotaopregna-1,4~diene~3,20-dione, P^ 296-297°, [a]D = +85° (dioxane, c = 0.1 %), UV :258 - 15870.

S

-19-

Exenrolment 7

100 mg of 9,11(3-epoxy-17α-hydroxy-D-homo-9P-pregna-1,4-diene-3,20-dione is stirred for one hour at 25°C in 2 mL of a solution of one part urea and 1.3 parts α-5 hydrofluoric acid. The reaction mixture is poured onto water and extracted as usual with methylene chloride. Silica gel chromatography of the crude product yields 9-fluoro-11(3,17α-dihydroxy-D-hornopregna-1,4-diene-3,20-dione with a Pf of 268-269°C, UV: α = 15200, [α] = +67°C (c = 0.1% in 10 methanol).

The starting product, 9,11p-epoxy-17a~hydroxy-D-homo~9p-pregna-1,4-diene-3,20-dione, P^ 179-180°, UV : e 248 = 16060, [ct]-g = -13° (c = 0.1% in dioxane), can be obtained from 9-bromo-1ip,17a-dihydroxy-D-homopregna-1,4-diene-3,20-15 diene and potassium acetate in alcohol after heating under reflux for several hours.

Example 8

One hundred and seventy milligrams of 17α-hydroxy-D-homopregna-1,4,9(11)-triene-3,20-dione and 130 milligrams of α-β-bromoacetamide are mixed in 8.2 mL of dioxane and 1.65 mL of water with 0.84 mL of a 10% perchloric acid solution. After 15 minutes, 435 milligrams of sodium sulfite are added, and the reaction mixture is diluted with water and a large amount of methylene chloride. The aqueous phase is extracted three times with methylene chloride, the methylene chloride solutions are washed twice with a dilute solution of table salt, dried over sodium sulfate, and concentrated. The 9-bromo-11p,17a-dihydroxy-D-homopregna-1,4-diene-3,20-dione obtained melts at 215°C by decomposing. UV: μ242 = 14050, [α]D = +91°C (DIuSO₄, c = 0.09%). 30 The starting product, 17α-hydroxy-D-

homopregna-1,4,9(11)-triene-3,20-dione, P^ 190-191°, UV : £ 230 = 15500, [a]p = -80° (c = 0.1 % in dioxane), from 1ip,17a-dihydroxy~D-homopregna-1,4-diene-3,20-dione by reaction with methanesulfonyl chloride and sulfur dioxide in pyriaine and DMP.

Example 9

Shake for 2 hours at 25°C under argon 1 g of 9-fluoro-1ip,17a-dihydroxy-D-honopregna-1,4-diènc-3,20-dione,

-20-

375 mg of 4-dimethylaminopyridine, 3 ml of triethylamine, and 5 ml of propionic acid anhydride. After adding 5 ml of water, the mixture is stirred for 10 minutes, then poured over 2 Ef hydrochloric acid and extracted 3 times with 5 methylene chloride. The methylene chloride solutions are washed with water to neutrality, dried over sodium sulfate, and concentrated. Silica gel chromatography of the residue yields 9-fluoro-17-hydroxy-11(3-propionyloxy-D-homopregna-

1,4-diene-3,20-dione, Pf 201-202°, UV : £ 2^8 = 15500, [a]D = 10 +93° (dioxane, c = 0.1 %).

Ex euro on the 10th

490 mg of 9-fluoro-17α-hydroxy-11(3-propionyloxy-D-homopregna-1,4-diene-3,20-dione is shaken for 4.5 hours at 40°C in 5 mL of butyric acid and 2 mL of tri-15-fluoroacetic anhydride. After 10 minutes, the mixture is acidified with hydrochloric acid and extracted with methylene chloride. The organic phases are washed to neutrality with a sodium bicarbonate solution and a dilute solution of table salt, then dried and concentrated. Silica gel chromatography of residue 20 yields 17α-butyryloxy-9-fluoro-11(3-propionyloxy-D-homopregna-1,4-diene-3,20-dione with a P value of 199–2000, UV: ^238 = 16550, [a]^ = +71° (dioxane, c = 0.1 °/o).

Similarly, we obtain:

from 9-chloro-11p-fluoro-17a-hydrcxy~D-homcpregna-1,4-25 dien-3,20-dione 17a-butyryloxy-(3~chloro-11 (3-f luoro-D-homopregna-1,4-dien-3,20-dione, Pf 170-1710, UV: £238 = 15750, [a]D = +43° (dioxane, c = 0.1%).

Example 11

30. The mixture is agitated under reflux for 24 hours with argon.

1 g of 6α-fluoro-1ip,17α-dihydroxy-D-homopregn-4-ene-3,20-dione and 660 mg of selenium dioxide in 50 mL of β-butanol and 0.5 mL of glacial acetic acid. The reaction mixture is filtered and concentrated. The residue is dissolved in β-ethyl acetate and washed successively with sodium bicarbonate solution, water, ice-cold ammonium sulfide solution, dilute ammonia, water, dilute hydrochloric acid, and water. The β-ethyl acetate solution is dried.

-21-

ethyl with sodium sulfate and concentrated under vacuum. By silica gel chromatography we obtain 6a~fluoro-1ip, 17a-dihydroxy~D-homopregna-1,4-diene-3,20-dione, P^ 183-184-°C, UV : S 242 = 14-4-00, [a]^ +56° (in dioxane, c = 0.1%).

5 Example 12

The mixture is stirred for 2 hours at 25°C under argon with 4 mg of 11p-15-butyryloxy-17α-hydroxy-D-homopregna-1,4-diene-3,20-dione, 15 mg of 4-(dimethylanino)-pyridine, 0.2 mL of triethylamine, and 0.2 mL of butyric acid anhydride. After adding 0.2 mL of water, the mixture is stirred for 10 minutes, then poured over 2H hydrochloric acid and extracted three times with Cl₂G₂O. The methylene chloride solutions are washed to neutrality with water, dried over sodium sulfate, and concentrated. Non-crystalline 11p-15-butyryloxy-17α-hydroxy-D-homopregna-1,4-diene-3,20-dione is obtained by preparative thin-layer chromatography.

UV: £242 ~ 14,000.

El® 1.21 ppm S, 3H | 18 19 1.37 " S 3H J Me > Ke '20 5.50 " m 1ÏÏ 11cxH.

Example ^ 3

One g of 1ip,17a-diacetoxy-D-hcmopregn-4-ene-3,20-dione is dissolved in 10 mL of orthofomic acid ethyl ester and 10 mL of absolute alcohol and mixed with 10 mg of p-25 toluenesulfonic acid in 1 mL of alcohol. After 10 minutes, two drops of pyridine are added to the reaction mixture, and this mixture is poured onto a dilute sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate, and concentrated to dryness. Perchloryl fluoride is bubbled through crude 3-ethoxy-1ip,17a-dihydroxy-D-homo-pregna-3,5-diene-20-one in 4-0 ml of DMF and 4- ml of water until no enolether is detectable on thin-layer chromatography. The reaction mixture is concentrated under vacuum and allowed to stand for 30 minutes at 25°C in 100 ml of glacial acetic acid and 1 ml of hydrobromic acid. A mixture of the two isomers of 11p,17a-diac.ethoxy-6-fluoro-I)-honopregn-4-enc-3,20-dione is then prepared.

S

Having added 5 cil of pyridine, the mixture is concentrated under vacuum. By chromatography of the residue on silica gel, we obtain 11{3,17a-diacetoxy-6a-fluoro-D-homopregn-4-ene-3,20-dione, P*. 236-237°C, [ajp = +25° (c = 0.1% in dioxane), UV: £, ^32 = 16100.

5 Example 14-

1.1 g of 11(3,17a-dihydroxy-D-homo-pregna-1,4-diene-3,20-dione) is dissolved at -10°C in 6.2 mL of pyridine and 0.4 mL of trifluoroacetic anhydride and stirred for 30 minutes at 0°C under argon. The reaction mixture is poured onto dilute hydrochloric acid and extracted 3 times with methylene chloride. The methylene chloride solutions are washed to neutrality with sodium bicarbonate solution and sodium chloride solution, dried, and concentrated. Silica gel chromatography yields 13(17a-hydroxy-11p-trifluoroacetoxy-D-homo-pregna-1,4-diene-3,20-dione). UV: g 230 = 142C0, [cx]D = 84° (c = 0.1% in dioxane).

Example 15

One 1.2 g of 17α-hydroxy-11p-trifluoroacetoxy-D-20 homopregna-1,4-diene-3,20-dione is dissolved in a mixture of 12 mL of butyric acid and 4.8 mL of trifluoroacetic anhydride and stirred for 4 hours at 50°C. The reaction mixture is poured onto aqueous pyridine, stirred for 10 minutes, acidified with 2N hydrochloric acid, and extracted 25 times with methylene chloride. The methylene chloride solutions are washed to neutrality with sodium bicarbonate solution and table salt solution, dried over sodium sulfate, and concentrated. Silica gel chromatography of the residue yields pure 17a-butyryloxy-11p-trifluoro-30 acetoxy-D-homopregna-1,4-diene-3,20-dione in foam form. UV: 240 ~ 13900, [ct]D = +41° (dioxane, c = 0.1%).

Example 16

One 1.1 g of 17a-butyryloxy-11p-trifluoroacetoxy-D-homopregna-1,4-diene-3,20-dione is mixed in 35 mL of methanol and 4.2 mL of water with a saturated sodium bicarbonate solution. The methanol is evaporated, and the residue is absorbed into methylene chloride and water. The methylene chloride solution is washed with a dilute solution of table salt.

?

~23~

The mixture is dried and concentrated. 17α-Butyryloxy-11p-hydroxy-β-homopregna-1,4-diene-3,20-dione is obtained as a pure foam by thin-layer chromatography. UV: α = 13940, α = +22° (dioxane, c = 0.1%).

5 Example 17

' »

By analogy with examples 14-16, we obtain from 9-fluoro-11p,17a-dihydroxy-D-homopregna-1,4-dien-3,20-dione the 17a-butyryloxy-9-fluoro-11p-hydroxy-D-homopregna-1,4-dien-3,20-dione, Pf 187-188°, UV: e24Q - 14000, [a]D =

+13° (dioxane, c = 0.1%).

from 6a,9-difluoro-11 (3,i7a-dihydroxy--D-homopregna-1,4-dièn-3,20-di one la 17a-butyryloxy-6a,9-difluoro-11 (3-h.ydroxy-D-homopregna--~1,4-15 dien-3,20-dione, Pf 224-225°; UV: S 2^g = 16400,

[a]p = +14° (c = 0.1% dioxane).

Example 18

By analogy with examples 14-16 we obtain from 6a~fluoro-11p,17a-dihydroxy-D-homopregna-1,4-20 dien-3,20-dione the 17a-butyryloxy~6a-fluoro-11 j3-hydroxy-D~homopregna-1,4-dien-3,20-dione, Pf 168-169°, UV : e 2^2 = 16600, [a]D = +13° (Dioxane, c = 0.1 c/o).

Example 19

25 If we use instead of the butyric acid used

In example 15, with acetic acid, propionic acid, or valerianic acid, we obtain, in a manner analogous to examples 14-16,

from 9-fluoro-lip,17a™ dihydroxy-D-homopregna-1,4-dien-30 3,20-dione,

17α-acetoxy-8-fluoro-11p-hydroxy-D-homopregna-1,4-dien-3,20-dione, Pf 232-233°, UV: Σ 2$9 = 13900, [α]D = +29° (c = 0.1% in dioxane) 9-fluoro-11p-hydroxy-17α-propionyloxy-D-homopregna-1,4-dien-3,20-dione, Pf 204-205°, UV: Σ 23Q = 15100, [c]D =

+23° (c = 0.1% in dioxane)

or 9-fluoro-1ip-hydroxy-17a-valeroyloxy-D-homopregna-1,4-dien-3,20-dione, P.j> 144-146°, UV : S 2^^ = 154 00, [a]]) = +17° (c = 0.1 °,o in dioxane).

b

-24-

Example 20

300 mg of 11(3,17α-dihydroxy-6α-methylene-D-homopregn-4-ene-3,20-dione), 150 mL of palladium/carbon (5%), 1.5 mL of cyclohexene, and 15 mL of ethanol are boiled under reflux for 8.5 hours under argon. The mixture is cooled to 25°C, mixed with 0.75 mL of 25% hydrochloric acid, and stirred for 1 hour. The catalyst is filtered, and the filtrate is concentrated. Silica gel chromatography yields 11(3,17α-dihydroxy-6α-methyl-D-homopregn-4-ene-5,20-dione, 10 Pf 223-225°, UV: s 242 = 14100'> Wd = +46° (c = ^ in the dioxane)«

The starting product can be prepared as follows:

11p,17a-dihydroxy-D-homopregn-4-ene-3,20-dione is reacted in boiling methanol with pyrrolidine 15 to give 11(3,17a-dihydroxy-3-(1-pyrrolidinyl)-D-homo-

pregna-3,5-diene-20-one. From this, 11p,17a-dihydroxy-6p-hydroxyniethyl-D-homopregn-4-ene-3,20-dione is obtained by reaction with formalin in benzene and methanol. Treatment with hydrochloric acid in dioxane yields 11(3,17a-dihydroxy-6-methylene-D-homopregn-4-ene-3,20-dione.

Example 21

A 2-liter Erlenmeyer flask containing 500 ml of a nutrient solution sterilized for 50 minutes at 25-120°C in an autoclave and composed of 1% corn steep liquor, 1% soybean powder, and 0.005% soybean oil, brought to pH 6.2, is inoculated with a freeze-dried culture of Curvularia lunata (KRRL 2380) and shaken for 72 hours at 30°C on a rotary shaker. This preculture is then inoculated into a 20-liter stainless steel fermenter containing 15 ml of a medium sterilized at 121°C and 1.1 atm and composed of 1% corn steep liquor, 0.5% glucose, and 0.005% soybean oil, brought to pH 6.2. Adding silicone oil (Silicon SH) as an antifoam, the culture is inoculated for 24 hours at 29°C with aeration (10 L/min), under a pressure of 0.7 atra and with agitation (220 U/min). One volume of the culture broth is transferred under sterile conditions into 14 liters of a sterilized medium as described above, composed of 1 L of corn steep liquor, 1.25% soy powder, and 0.005% oil.

r~

of soybeans and it is cultivated under the same conditions. After 12 hours, a solution of 4 g of 17α-acetoxy-D-homo-4-pregn-3,20-dione in 100 ml of dimethylformamide is added. After 52 hours of contact, the contents of the fermenter are shaken twice, each time with 10 L of methyl isobutyl ketone, and the extract is concentrated under vacuum at a bath temperature of 50°C. The residue is washed several times with hexane to remove the silicone oil and separated from the unreacted starting product by chromatography on a 10-silica gel column (gradient elution: hexane + hexane/ethyl acetate 1 + (1/1)). 17aa-acetoxy-11(3-hydroxy-D~homo-4--pregnene-3,20-dione is recrystallized from isopropyl ether;

234-/235-237°, 6 24-2 = 16700.

Example 22

15. A 2-liter Erlenmeyer flask containing

500 ml of a nutrient solution sterilized for 30 minutes at 120° in an autoclave and composed of 1.5% peptone, 1.2% Corn steep and 0.2% MgSOZ1, brought to pH 6.5 with a lyophilized culture of Bacillus lentus (ATCC 13805) and shaken for 24 hours at 30°. With this preculture, a 20-litre stainless steel fermenter is then inoculated, which contains 15 litres of a medium sterilized at 121° and 1.1 atm, composed of 0.2% yeast extracts, 1% Corn steep liquor and 0.1% glucose, brought to pH 7.0. Adding silicone oil 25 (Silicon Si) as an antifoam, inoculate at 29°C while aerating and agitating. After a 6-hour growth phase, add a solution of 1.6 g of 17ao:-acetoxy-1ip-hydroxy-D-homo-4-pregnene-3,20-dione in 50 ml of dimethylformamide.

After 15 hours of contact, the contents of fermenter 30 are extracted twice, each time with 10 ml of methylisobutyl ketone, and the extract is concentrated under vacuum. The residue is washed with hexane to remove silicone oil and recrystallized from acetone-diisopropyl ether in the presence of activated carbon, yielding 17α-acetoxy-11p-hydroxy-D-homo-1,4-pregnaaiene-3,20-35 dione with a Pf of 218/219-220° and a G = 15100.

Example 25

D-homosteroids of formula I1 can be formulated, for example, as ointments, as follows:

8

-p o-

D-homosteroic acid 0.01-1% by weight

Liquid paraffin 10.0% in peas

White soft paraffin to make up to 100 parts by weight

5. The steroid is ground with some of the liquid paraffin in a ball mill until a grain size of less than 5 µm is achieved. The paste is diluted, and the mill is washed with the remaining liquid paraffin wax. The suspension is added to melted colorless soft paraffin (10–50°C) and stirred until the mass is cool, resulting in a homogeneous ointment.

Claims (1)

-27- ~ EITVSI-IDICATIONS -1 - A process for preparing D-homosteroids of formula 25 ^H3 co 10 17a r6 15 where the dotted 1,2 bond represents an optional C-C bond; R^ an atom of hydrogen, fluorine, chlorine or a ra- o methyl dicalcium; R"1 an atom of hydrogen, fluorine, chlorine or 11 of "bromine; R a hydroxy radical, acyloxy, a fluorine atom or 17a 20 of chlorine and R' a hydroxy or acyloxy radical, where in the 11 In 9,11-dihalogenated compounds, the atomic number of R must be less than or equal to that of R^, and where, if in a compound 11,17a-dihydroxy R^ represents a hydrogen atom in a compound 6 o 11,17a-dihydroxy-4-ene R represents a fluorine atom, Ry must be a fluorine, chlorine, or bromine atom. characterized in that in a) hydroxylating at position 11 a D-homosteroid of formula 30 35 17a r6 -28- by means of a microorganism or an enzyme derived from it, or b) by replacing iodine with hydrogen in a D-homosteroid of formula 10 15 r6 ch2j 17a or c) by dehydrogenating at position 1,2 a saturated 1,2-D-homosteroid of formula I or 20d) by attaching Cl₂O₁F, BrF, BrCl₂ or hypochlorous or hypobromous acid to the 9,11 double bond of a D-homosteroid of formula 25 30 35 Or 17a r6 e) by treating a D-homosteroid of formula 29- 10 r6 ch3 co 17 a with hydrofluoric, chlor- or hydrobromic acid, or f) by saponifying an acyloxy group in a D-homosteroid of 17a 11 formula I, where at least one of the radicals R' or R is a 15-acyloxy, or g) by isomerizing a 6p-isomer of a 6-fluoro-, chloro-, or methyl-D-homosteroid of formula I to give the 6a isomer, or h) by fluorinating or chlorinating a D-homosteroid of formula 20 25 Chapter 3 CO R11 hSÇ 17 a 30 in position 6, or i) 'by acylating a 1lp- or 17a-hydroxy group in a D-hono~ 11 steroid of formula I, where at least one of the radicals R or 17a r' is a hydroxyl group, or j) by oxidizing to a D-homosteroid of formula g -28- by means of a microorganism or an enzyme derived from it, or b) by replacing iodine with hydrogen in a D-homosteroid of formula or c) by dehydrogenating at the 1,2 position of a saturated 1,2-D-homosteroid of formula I or d) by attaching Cl₂O₁₂F, BrF, BrCl₂ or hypochlorous or hypobromous acid to the 9,11 double bond of a D-homosteroid of formula CH2 J CO r11 x--r17a 10 15 25 ch3 co R17a h3c 30 IV 35 or e) by treating a D-homosteroid of formula 29- 10 R6 9*3 co 17 a with hydrofluoric, chlor- or hydrobromic acid, or f) by saponifying an acyloxy group in a D-homosteroid of 17a 11 formula I, or at least one of the radicals R' or R is a 15-acyloxy, or g) by isomerizing a 6p-isomer of a 6-fluoro, chloro-, or methyl-D-homosteroid of formula I to give the 6a isomer, or h) by fluorinating or chlorinating a D-homosteroid of formula 20 25 CH3 CO R11 H3Ç 17 a 30 in position 6, or i) 'by acylating a 1lp- or 17a-hydroxy group in a D-homo~ 11 steroid of formula I, where at least one of the radicals R or 17a R' is a hydroxyl group, or j) by oxidizing to a D-homosteroid of formula g -30- 10 ?H3 co 17a 5 ^ the 3-hydroxy group "A^" to give the 3-keto~Ar group, Or 15k) by reducing the 11-keto group of a D-homosteroid of formula ^h3 CO H3C ,17 a 20 25 R6 under the protection of the 3-keto and 20-keto groups to give a hydroxy group: 30 or 1) by oxidizing the 17a(20) double bond of a D-homosteroid of general formula sf -31- 10 R6 to give a hydroxyketone group or m) by methylating at position 6 a D-homosteroid of formula VI, 15 or n) by transforming the 17P-ethinyl group into an acetyl group in a D-homosteroid of formula 20 R6 17a 30 or o) by dehydrogenating at position 4- a D-homosteroid of formula If r611 ?h3 co 17a 20 where, in the formulas above, R^, R^, R^, R^^ and link 611 25- dotted 1,2 have the meaning given above and where R represents a hydrogen or a methyl. 2 - A method according to claim 1, characterized in 11 what is being prepared are D-homosteroids of formula I where R is a hydroxyl group. 3 - A process according to any one of claims 1 and 2, characterized in that D-homosteroids of formula I are prepared, where R^ represents a hydrogen, a fluorine or a chlorine 4- A process according to any one of claims 1 to 3, characterized in that it prepares 1,2-unsaturated D-homosteroids of formula I* 5 - A process for preparing pharmaceutical preparations with an anti-inflammatory effect, characterized in that a compound of formula is used 30 35 fH3 co 111 ^Hs9 1 r171 a r 61 S -33- 61 where R represents an atom of hydrogen, fluorine, chlorine or 91 a methyl radical; R an atom of hydrogen, fluorine, of 171a chlorine or bromine; R a hydroxy or acyloxy radical and 111 R a hydroxy or acyloxy radical, a fluorine atom or of 5 chlorine, where in the 9,11-dihalogenated compounds the atom number- 111 " 91 the inequality of R must be less than or equal to that of R; and where The dotted link 1,2 represents an optional C-C link, with a support that can be used in pharmacies. 6. A method according to claim 5 for preparing 10 "pharmaceutical preparations with an anti-inflammatory effect, characterized in that a compound of formula is mixed 15 20 17a R 25 30 35 where the dotted 1,2 bond represents an optional C-C bond; R^ an atom of hydrogen, fluorine, chlorine or a methyl radical; R^ an atom of hydrogen, fluorine, chlorine or 11 of bromine; R a hydroxy, acyloxy, fluorine or chlorine radical, and R' a hydroxy or acyloxy radical, where in the 11 In 9,11-dihalogenated compounds, the atomic number of R must be less than or equal to that of Ry, and where, if in a compound 11,17a-dihydroxy R^ represents a hydrogen atom in a compound 6 9 11,17a-dihydroxy-4-ene R represents a fluorine atom; R must be a fluorine, chlorine, or bromine atom. with a support that can be used in pharmacies. 7 - A process according to claim 5 for preparing pharmaceutical preparations with an inflammation-inhibiting effect, characterized in that the 1ip,17a~ is mixed dihydroxy-D-b.omopregïi-/-l—ene-3,20-dione > the 11(3,17a-dihydroxy D-homopregn-1,4-dien-3,20-dione or the 6a-fluoro-11p, 17a-dihydroxy-D-homopregn--2}—ene-3,20-dione with a support usable in pharmacy. OR* N A L in P®9®* Route containing O&ù^References word added Xit-word José CURAU Industrial Property Consultant 26 •»' », Princess Charlotte Blvd. MONTE-ca^LO By proxy* =Y'. S.oeiête- ÇViOSvjme.