IT9048031A1 - 6 FLUORO 6 METHYLPREGN-4-ENE-3, 20 DIONI AND 6-FLUORO-6-METHYLPREGNA-L, 4-DIENE-3, 20-DIONI, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS FOR ANTI-INFLAMMATORY ACTIVITIES CONTAIN - Google Patents

Description

in which: In positions 1, 2 the bond can be simple or double;

X is hydroxy and V is hydrogen, fluorine, chlorine or bromine; or X and V are both chlorine;

R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms;

R2 is hydroxy or acyloxy having from 2 to 12 carbon atoms;

R, is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl;

and their cyclic 16.17- and 17.21-acetals and ketals, particularly 16, 17-acetonides exhibit high anti-inflammatory activity, but with fewer unwanted side effects than known steroids.

The present invention relates to a new class of steroids (6-fluoro-6-methylcorticosteroids) having powerful anti-inflammatory activity, a process for producing them and the pharmaceutical compositions containing them.

Many steroids are known having anti-inflammatory activity for tonic and / or systemic administration and some of them have rather satisfactory anti-inflammatory activity. Unfortunately, they all tend to give unwanted side effects, such as the alteration of the mineral balance of the subject to whom they are administered. For example, they can upset the potassium and / or sodium balance, and adversely affect adrenal function. Consequently, they must be used with caution.

The object of the present invention is to produce new steroids which have good anti-inflammatory activity, preferably higher than that of most known steroids, and which have negligible or no side effects if measured preferably in absolute terms but, in particular, when expressed. as a therapeutic relationship.

By therapeutic ratio is meant the ratio between the effective dose that is required to achieve the desired anti-inflammatory activity and the minimum dose that causes unwanted side effects.

We have now found some 6-fluoro-6-methylpregn-4-ene-3.20-diones and 6-fluoro-6-methylpregna- 1, 4-diene-3.20-dions, endowed with high anti-inflammatory activity and which, at the same time, they are completely or at least substantially free of the unwanted side effects of known steroids.

The new compounds of the invention are the compounds of the general formula:

m where X is hydroxy and V and hydrogen, fluorine, chlorine or bromine: or X and V are both chlorine;

R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms;

R2 is hydroxy or acloxy having from 2 to 12 carbon atoms;

R3 is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl;

and their 16, 17- and 17.21-acetals and cyclic ketals, particularly the 16, 17-acetonides

When R1 and / or R2 are acyloxy, the acyl group is preferably that of acetic, trimethylacetic, propionic, alpha-phenyl propionic, beta-phenylpropionic, butyric and valenco acids.

It is obviously already known to prepare steroids belonging to the 6-methyl- or 6-fluoropregn-4-ene-3,20-dion class. Also known are 6-methyls - or 5-fluoropregna- 1, 4-diene-3,20-dions.

The combination of the 6-fluorine and 5-methyl substitutions in pregn-4-ene-3.20-dions and in pregn-1, 4-diene-3.20-diones, which characterizes the steroids of the present invention, is instead new. and confers excellent anti-inflammatory activity accompanied by negligible or no secondary effects. Two suitable reaction screens for the preparation of compounds according to the invention are given in the following graphs, diagram A and diagram B, in which Ac is acetyl, R1, R2, and R3 are defined as previously indicated.

An operating mode is shown below to make the products reported in the reaction scheme A in practice.

The known 6β-methyl--dihydroxyregna-4,9 (1 1) -diene-3,20-dione 21-acetate (), obtained from hydrocortisone through

according to Synthesis 1982. 34 and references cited, is treated with acetic anhydride and perchloric acid in ethyl acetate at room temperature to give the corresponding triacetate IV This, dissolved in anhydrous pyridine-dioxane-methanol a is converted into 6β-fluorine-

-methyl- -dihydroxyregna-4,9 (1 1) -diene-3,20-dione 17,21 -diacetate

and in its epimer -fluoro-6β-methyl

Treatment of the epimer with 2,3-dichloro-5,6-dicyanobenzoquinone (DDO) produces the triene The latter is transformed into bromidine IX by treatment with 1,3-dibromo-5,5-dimethylhydantoin in tetrahydrofuran in the presence of perchloric acid. Bromhydrin IX

it is transformed into the corresponding epoxide XI by means of acetone bases. The subsequent opening of the epoxide with aqueous hydrofluoric acid leads to the formation of 6β, 9-difluoro- -methyl--triohydroxy pregna- 1,4-diene-3,20-dione 17,21 -diacetate

Similarly, the -fluoro-6β-methyl VI epimer (R3 = H) is transformed into

, 9-difluoro-6β-methyl-, 21-trihydroxyregna-1,4-diene-3,20-dione 17,21 -diacetate (XIV, R3 = H) through the intermediates V

Basic hydrolysis leads to alcohols e

respectively.

These, dissolved in anhydrous pyridine, in the presence of an acetylating agent, such as for example acetic anhydride, are converted into 21-acetates

When the compounds are not converted to the trienes VII

with DDO but treated with 1,3-dibromo-5,5-dimethylhydantoin in tetrahydrofuran in the presence of perchloric acid, bromhydrins XIX are obtained, respectively.

The latter by subsequent treatment with base and hydrofluoric acid give 6β-9-difluoro- -methyl--trihydroxypregn-4-ene-3,20-dione 17,21 -diacetate (XXIII, R3 = H) and -difluoro- 6β-methyl- 1 1β,, 2ltrihydroxypregn-4-ene-3,20-dione 17,21 -diacetate

The basic hydrolysis of XXIII leads to alcohols

These, dissolved in anhydrous pyridine, in the presence of an acetylating agent, such as for example acetic anhydride, are converted into 21-acetates XXVII respectively.

An operative way is shown below to realize the products reported in the reaction scheme B in practice.

The known 6β-methyl-trihydroxypregn-4-ene-3,20-dione 21-acetate and 17,21 -di acetate

obtained from Hydrocortisone (1, R3 = H) according to Synthesis 1982. 34 and references cited through the compounds

= are converted into the respective 3-enolethers

for treatment with triethylorthoformate in dimethylformamideethanol in the presence of 4-methylbenzenesulfonic acid. The enoletere 5a (R1 =

dissolved in pyridine andra-dioxane-methanol

is converted by perchlorylfluoride to 68-fluoro-methyl-

21-trihydroxypregn-4-ene-3,20-dione 21-acetate and in the epimer -fluoro-6β-methyl Similarly the enol ether is converted by perchlorylfluoride in the epimers

For treatment of

with DDO the compounds 6β-fluoro-trihydroxyregna-1,4-diene-3,20-dione 21-acetate 68-fluoro-methyl- are obtained

diacetate -fìuoro-68-methyl--trihydroxyregna-1,4-diene-3,20-dione 21-acetate and

-fluoro-68-methyl-trihydroxyregna- 1,4-diene-3,20-dione 17, 21 -diacetate The basic hydrolysis of 21-acetate

E S E M P I O 1

PREPARATION OF 6-METHYL-TRIHYDROXYPREGNA-3,5,9

(1 1) -TRIENE-20-ONE 3, 17,2 1 -TRIACETATE (IV, R3 = H)

10 g of 6β-methyl-dihydroxyregna-4,9 (1 1) -diene-3,20-dione (III, R3

= H) were added to a solution of 90 ml of acetic anhydride and 0.5 ml of perchloric acid (70% in water) in 400 ml of ethyl acetate and the reaction mixture was stirred at 20 ° C for 0.5 hours.

The solution was carefully poured into 500 ml of ice containing 160 g of sodium bicarbonate and stirred for 3 hours.

The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried with sodium sulfate and evaporated to dryness. The crude obtained was purified by silica gel chromatography and 10 g of 6-methyl-trihydroxyregna-3,5,9 (1 1) triene-20-one 3,17,21-triacetate (IV, R3 = H).

E S E M P I O 2

PREPARATION OF 6β-FLUORO- -METHYL- -DIHYDROXYPRE

GNA-4,9 (11) -DIENE-3,20-DI0NE 17,21 -DI ACETATE (V, R3 = H) E

-FLUOR0-6B-METHYL -DIHYDROXIPREGNA-4,9 (1 1) DIENE-3,

20-DIONE 17,21 -DI ACETATE (VI, R3 = H)

In a solution of 10 g of 6-methyl--trihydroxyregna-3,5,9 (1 1) -triene-20-one 3.17,21-triacetaio (IV, R 3 = H) in 100 ml of methanol, 100 ml of dioxane and 30 ml of pyridine cooled to -20 ° C 8.5 g of perchlorylfluoride were bubbled in 1 hour.

After 20 hours at 0 ° C nitrogen is bubbled for 0.5 hours, the solution was poured into 1 liter of water and ice containing 50 ml of 36% HC1 and stirred for 2 hours. The suspension was extracted with chloroform.

The organic phase dried and evaporated to dryness gave 9.32 g of a crude mixture which was chromatographed on silica gel to separate the two epimers obtaining, after crystallization from chloroform / hexane, 1.8 g of 6β-fluoro methyl-dihydroxyregna-4.9 ( 1 1) -diene-3,20-dione 17, 21 -diacetate (V, R3 = H) and 2.2 g of fluoro-6β-methyl- 21-dihydroxy-

pregna-4,9 (1 1) -diene-3,20-dione 17,21 -diacetate (VI, R3 = H).

E S E M P I O 3

PREPARATION OF 6β-FLUORO- -METHYL- -DI HYDROXYPRE GNA- 1, 4,9 (1 1) -THIENE-3,20-DIONE 17,2 1 -DI ACETATE

(VII, R3 = H)

10 g of 6β-fluoro- -methyl - -dihydroxyregna-4,9 (1 1) - diene-3,20-dione 17,21 -diacetate (V, R3 = H) were suspended in 700 ml of anhydrous dioxane. After the addition of 6.53 g of benzoic acid and 6.07 g of 2,3-dichloro-5,6-dicyanobenzoquinone, the reaction was refluxed under stirring for 24 hours.

After the addition of another 1.5 g of 2,3-dichloro-5,6-dicyanobenzoquinone and another 24 hours of reaction, the solvent was distilled under vacuum to obtain a solid crude which was treated with 500 ml of chloroform, stirred for 10 min. and filtered; the solid was washed with 100 ml of CHCl3.

The organic phases, gathered in a separating funnel, washed with 500 ml of saturated bicarbonate, 500 ml of 1N sodium hydroxide and then with water until neutral, were anhydrated and evaporated to dryness.

The solid crude was purified by chromatography on silica gel and recrystallized from chloroform / ethyl ether to obtain 7.3 g of 6β-fluoro- -methyl-, -dihydroxyregna- 1, 4,9 (11) -trene-3,20-dione 17 , 21-of acetate (VII, R3 = H).

E S E M P I O 4

PREPARATION OF -FLUOR0-6β-METHYL- -DIHYDROXYPRE GNA- 1,4,9 (1 1) -TRIENE-3,20-DIONE 17,2 1 -DI ACETATE

(VIII, R3 = H)

Operating as in example 3, starting from 10 g of -fluoro-6β-methyl -

21 -dihydroxyregna-4,9 (1 1) -diene-3,20-dione 17,21-diacetate (VI, R3 = H), 5.9 g of -fluoro-6β-methyl -dihydroxyregna- 1, 4 were obtained, 9 (1 1) -trene-3,20-dione 17,21 -diacetate (VIII, R3 = H).

E S E M P I O 5

PREPARATION OF 9-BROMINE -6β-FLUORO- -METHYL-

TRIHYDROXYPREGNA- 1, 4-DIENE-3.20-DIONE 17,2 1 -DIACETATE (IX, R3 = H)

50 g of 1,3-dibromo-5, 5-dimethylhydantoin were added in the dark at 10 ° C, stirring for 30 min, to a solution of 6β -fluoro- -methyl-

dihydroxyregna- 1, 4,9 (1 1} -trene-3,20-dione 17,21 -diacetate (VII, R3 = H)

in 100 ml of tetrahydrofuran and 1 ml of 70% perchloric acid in 10 ml of water.

The solution was kept at room temperature for 4 hours, then an aqueous solution of 103 sodium sulphite was added, stirring, until the starch-iodinated paper no longer turned blue.

The solution was then slowly poured onto ice (2000 g).

The product 9-bromo-6β -fluoro- -methyl- - trihydroxyregna -1, 4-diene-3,20-dione 17,21 -diacetate (IX, R3 = H) was collected for

filtration, washed with water and used wet in the subsequent reaction. A small part of the wet product was dissolved in chloroform made anhydrous with sodium sulfate and evaporated to dryness, chromatographed and crystallized from chloroform / ethyl ether giving an analytical sample.

E S E M P I O 6

PREPARATION OF 9-BROMINE- -FLUORO-6β-METHYL-

TRI HYDROXIPREGNA- 1, 4-DIENE-3.20-DIONE 17,2 1 -DI ACETATE (X, R3 = H) (AF-213)

Operating as in example 5 starting from 10 g of -fluoro-6β - methyl -

-dihyroxyregna- 1, 4,9 (1 1) -triene-3,20-dione 17,2 1 -di acetate (VI I I,

R3 = H). a wet crude was obtained which was anhydrified, purified on a silica gel chromatographic column and crystallized from chloroform / ethyl ether, giving 7 1 g of 9-bromo-fluorine-6β-methyl - - tri-hydroxyregna- 1, 4- diene-3.20-dione 17,21 -diacetate (X, R3 = H).

This compound is marked AF-213 in drug tests.

E S E M P I O 7

PREPARATION OF 6β-FLUORO- -METHYL - - DIHYDROXY-9β, 1 1 β-OXIDOPREGNA- 1, 4-DIENE-3,20-DIONE 17,2 1 -DIACETATE (XI, R3 = H)

35 ml of an 18% aqueous solution of potassium carbonate were added during a period of 20 min, at 20 ° C, under stirring, and a solution of the wet product 9-bromo-6β-fluoro-methyl-trihydroxyregna- 1, 4-diene-3,20-dione 17,21-diacetate (IX, R3 = H) in 200 ml of acetone. The reaction mixture was stirred for 5 hours.

The mixture was then extracted with chloroform (3 x 1000 ml). The collected organic phases were washed with water, dried over sodium sulphate and evaporated to dryness.

A crude solid was obtained which was crystallized from acetone / hexane with a yield of 8.8 g of 6β-fluoro- -methyl- - dihydroxy -9β, 1 1 β-oxydoprene- 1 .4-diene-3,20-dione 17.21 - diacetate (XI, R3 = H)

EXAMPLE 8

PREPARATION OF -FLUOR0-6β-METHYL - - DIHYDROXY-9β, 11 β-OXIDOPREGNA- 1, 4-DIENE-3,20-DIONE 17,2 1 -DI ACETATE (XII, R3 = H)

Operands: as in example 7, starting from 10 g of 9-bromine-

fluoro-6β-methyl trihydroxyregna- 1,4-diene-3,20-dione 17, 2 1 -diacetate (X, R3 = H) 91 g of -fluoro-6β-methyl- were obtained

2 1-dihydroxy -9β. 11 β-oxidopregna- 1, 4-diene - 3.20-dione 17.21 -diacetate (XII, R3 = H).

E S E M P I O 9

PREPARATION OF 6β, 9-DIFLUORO- -METHYL--TRI-HYDROXYPREGNA- 1, 4-DIENE-3.20-DIONE 17.2 1 -DIACETATE

(XIII. R3 = H) (AF-21 1)

100 ml of a 70% aqueous solution of hydrofluoric acid were cooled to -10 ° C in a polyethylene flask equipped with an electromagnetic stirrer.

10 g of 6β-fluoro-methyl-dihydroxy-9β, 1 1 β-oxydopregna- 1,4-diene-3,20-dione 17,21 -diacetate (XI, R3 = H) were added with stirring in 15 min.

The purple solution was stirred at -10 ° C for 4 hours, then poured into ice (2000 g) containing 380 ml of a 30% ammonia solution in water.

The solid collected by filtration was washed several times in water and dehydrated.

Purification with a silica gel chromatographic column and crystallization with chloroform / diethyl ether yielded 4.1 g of 6β, 9-difluoro- -methyl--trihydroxyregna- 1,4-diene-3,20-dione 17,21 -diacetate (XIII, R3 = H)

This compound is designated AF-211 in drug testing.

E S E M P I O 10

PREPARATION OF -DIFLUORO-6β-METHYL- -TRI-

HYDROXYPRENE - 1, 4-DIENE-3,20-DIONE 17,2 1 -DI ACETATE

(XIV, R3 = H)

Operating as in example 9 from 10 g of -fluoro-6β -methyl-

2 1 -dihydroxy -9β, 11 β-oxydopregna- 1, 4-diene-3,20-dione 17,2 1 -diacetate (XII, R3 - H) 3.7 g of -difluoro-6β-methyl- were obtained

21-trihydroxyregna-1,4-diene-3.20-dione 17,21 -diacetate (XIV. R3 = H).

E S E M P I O 11

PREPARATION OF -DIFLUORO- -METHYL- -TRl-HYDROXYPREGN- 1, 4-DIENE-3,20-DIONE (XV, R3 = H) (AF-212)

10 g of 6β, 9-difluoro- -methyl-trihydroxyregna- 1,4-diene-3,20-dione 17,2 1 -diacetTO (XIII, R3 = H) (AF-21 1) were suspended in 200

rnl of a 1% methanolic solution of potassium hydroxide and stirred at 0 ° C for 3 hours in a nitrogen atmosphere

Addition of cold acacia, vacuum elimination of methyl alcohol, acidification with acetic acid and filtration yielded a crude which crystallized from 1,2-dichloroethane yields 4 g of 6β .9-difluoro- -methyl- - trihydroxyregna- 1,4-diene-3,20-dione (XV, R3 = H).

This compound is designated AF-21 2 in drug testing.

EXAMPLE 12

PREPARATION OF -DIFLUORO-6β-METHYL- -TRI-HYDROXYPREGNA- 1, 4-DIENE-3,20-DIONE (XVI, R3 = H)

Operating as in example 11 from 10 g of -dinuoro-6B-mstil-

21-tnhydroxyregna-1,4-diene-3,2Q-dione 17,21 -di acetate (XIV, R3 = H) 3.7 g of -difluoro-6β-methyl-trihydroxyregna-1,4-diene-3.20 were obtained -dione (XVI. = H).

EXAMPLE 13

PREPARATION OF 6β, 9-DIFLUORO- -METHYL--TRI-HYDROXYPREGNA- 1, 4-DIENE-3,20-DIONE 21 -ACETATE

(XVII, R3 = H)

10 g of 6β, 9-difluoro-methyl--trihydroxyregna-1,4-diene -3,20-dione (XV, R3 = H) were suspended in 35 ml of pyridine at 5 ° C.

To this vigorously stirred suspension 4-5 ml of acetic anhydride were added.

After 4.5 hours of reaction at room temperature, 2.5 ml of H2O were added and after 0.5 h the solution was poured into 250 ml of ice containing

37 ml of 37% hydrochloric acid and stirred at 10 ° C for 3 h.

The product collected by filtration on paper, washed with water until neutral was anhydrified giving 7.8 g of 6β, 9-difluoro-methyl -1 1β, -tryhydroxyregna- 1,4-diene-3,20-dione 21 -acetate (XVII , R3 = H)

EXAMPLE 14

PREPARATION OF -DIFLUORO-63-METHYL- -TRI-HYDROXYPREGNA- 1, 4-DIENE-3,20-DIONE 2 1 -ACETATE

(XVIII, R3 = H)

Operating as in example 13 from 10 g of -difluoro-6β-methyl-

21-trihydroxyregna-1,4-diene-3,20-dione (XIV, - H) 7.1 g of

-difluoro-6β-methyl --trihydroxyregna- 1,4-diene-3,20-dione 21 -acetate (XVIII R3 = H).

EXAMPLE 15

PREPARATION OF 9-BROMO-6β-FLUORO- -METHYL- -TRIHYDROXYPREGN-4-ENE-3,20-DIONE 17,2 1 -DI ACETATE

(XIX, R3 = H)

Operating as in Example 5 from 10 g of 6β -fluoro- -methyl- -dihydroxyregna-4,9 (1 1) -diene-3,20-dione 17,2 1 -diacetate (V, P, = H) we obtained a wet crude of 9-bromo-6β-fuoro- -methyl-1

trihydroxypregn-4-ene-3.20-dione 17,2 1 -diaceteto (XIX, R3 = H) which was used as such for the subsequent reaction (example 17).

A small part of the wet product was dissolved in chloroform made anhydrous with sodium sulfate and evaporated to dryness, chromatographed and crystallized from chloroform / ether giving an analytical sample.

E S E M P I O 16

PREPARATION OF 9-BROMINE- -FLUORO-6β-METHYL-

TRIHYDROXIPREGN-4-ENE-3,20-DIONE 17,2 1 -DIACETATE

(XX, R3 = H)

Operating as in example 5 from 10 g of -fluoro-6β-methyl-

-dihydroxyregna-4,9 (1 1) -diene-3,20-dione 17,2 1 -di acetate (VI, R3 = H) a wet crude of 9-bromine - -fluoro-6β-methyl- was obtained

trihydroxypregn-4-ene-3,20-dione 17,21 -diacetate (XX, R3 - H) which was

used as it is for the subsequent reaction (example 18).

A small part of the wet product was dissolved in chloroform made anhydrous with sodium sulfate and evaporated to dryness, chromatographed and crystallized from chloroform / ether giving an analytical sample.

ES EMPI O 17

PREPARATION OF 6β-FLUORO- -METHYL- -DI HYDROXY-9β, 1 1β-OXIDOPREGN-4-ENE-3,20-DIONE 17,2 1 -DI ACETATE

(XXI, R3 = H)

Operating as in Example 7 from 9-bromo-6β-fluoro- -methyl-

21-trihydroxypregn-4-ene-3,20-dione 17,21 -diacetate (XIX, R3 = H) obtained wet from example 15 8.6 p of 6β-fluoro- -methyl-17 -21-dihydroxy-9β were isolated . 11β-oxidopregn-4-ene-3.20-dione 17,21- diacetate (XXI, R3 = H)

E S EMPIO 18

PREPARATION OF -FLUORO-6β-METHYL- -DIHYDROXY-9β, 11 β-OXIDOPREGN-4-ENE-3,20-DIONE- 17,2 1 -DI ACETATE

(XXII, R3 = H)

Operating as in example 7 from 9-bromo- -fluoro-6β-methyl-, 21-trihydroxypregn-4-ene-3,20-dione 17,21 -di acetate (XX, R3 = H) obtained

wet from example 15 8.4 g of -fluoro-6β -methyl - were obtained

2 1 -dihydroxy -9β, 11β-oxydopregn-4-ene-3,20-dione 17,21 diacetate (XXII, R3 = H) '

EXAMPLE 19

PREPARATION OF 6β, 9-DIFLUORO- -METIL- -TRI-HYDROXYPREGN-4-ENE-3,20-DIONE 17,21-DIACETATE

(XXIII, R3 = H)

Operating as in example 9 from 10 g of 6β-fluoro- -methyl-

dihydroxy-9β, 11β-oxidopregn-4-ene-3,20-dione 17,21 -diacetate (XXI, R3 = H) 6.9 g of 6β, 9-difluoro- -methyl- -trìhydroxypregn-4- were obtained ene-3,20-dione 17,21-diacetate (XXIII, R3 = H)

EXAMPLE 20

PREPARATION OF -DIFLUORO-6β-METHYL--TRI-HYDROXIPREGN-4-ENE-3,20-DIONE 17,2 1 -DIACETATE

(XXIV, R3 = H)

Operating as in example 9 from 10 g of -fluoro-6β -methyl -

hydroxy-9β, 1 1β-oxidopregn-4-ene-3,20-dione 17,2 1 -diacetate (XXII, R3 =

H) 6.9 g of 9-difluoro-6β-methyl--trihydroxypregn-4-ene-3,20-dione 17,21 -diacetate were obtained (XXIV, R3 = H)

E S E M P I O 21

PREPARATION OF 6β, 9-DIFLUORO- -METIL- -TRI-HYDROXYPREGN-4-ENE-3,20-DIONE (XXV, R3 = H)

Operating as in the example 1 1 of 10 g of 60,9-difluoro- --methyl-, 2 1-trihydroxypregn-4-ene-3,20-dione 17,2 1 -diacetate (XXI I I, R3 = H) 6.1 g of 6β, 9-difluoro- -methyl--trihydroxypregn-4-ene-3,20-dione were obtained (XXV, R3 = H)

ES EMPIO 22

PREPARATION OF -DIFLUORO-6B-METHYL- -TRI-HYDROXYPREGN-4-ENE-3.20-DIONE (XXVI, R3 = H)

Operating as in Example 11 from 10 g of 9-difluoro-6β-methyl-trihydroxypregn-4-ene-3,20-dione 17,21 -di acetate (XXIV, R3 = H) 6.1 g of - difluoro-6β-methyl--trihydroxypreqn-4-ene-3,20-dione (XXVI, R3 = H)

EXAMPLE 23

PREPARATION OF -DIFLUORO- -METHYL - -TRI-

HYDROXYPREGN-4-ENE-3,20-DIONE 21-ACETATE (XXVII, R3 = H)

Operating as in example 13 from 10 g of 6β, 9-difluoro-methyl -

-triohydroxypregn-4-ene-3,20-dione (XXV, R3 = H) 6.2

g of 6 β, 9 -difluoro methyl-trihydroxypregn-4-ene-3.20-dione 2) -acetate (XXVI I, R3 = H).

EXAMPLE 24

PREPARATION OF -DIFLUORO-68-METHYL- -TRI-

HYDROXYPREGN-4-ENE-3,20-DI0NE 21-ACETATE (XXVIII, R3 = H)

Operating as in example 13 from 10 g of 9-difluoro-68-methyl-11β, -triohydroxypregn-4-ene-3,20-dione (XXVI, R3 = H) 6.2 g of -difluoro-68- were obtained methyl--trihydroxypregn-4-ene-3.20- dione 21 -acetate (XXVIII, R3 = H)

EXAMPLE 25

PREPARATION OF 3-ETHYLOXY-6-METHYL-

PREGNA-3,5-DIENE-20-ONE 21 -ACETATE

10 g of 6β-methyl-, 21-trihydroxypregn-4-ene-3,20-dione 21-acetate in 9 ml of dimethylformamide and 15 ml of anhydrous ethanol were added, under stirring, at 25 ° C and, in ambient of nitrogen, 8.7 ml of triethylorthoformate and in 5 minutes 108 mg of 4-methylbenzenesulphonic acid monohydrate dissolved in 2.5 ml of anhydrous ethanol.

After 1 hour the worm solution evaporated to half volume, slowly poured into 500 g of ice and stirred for 1 hour.

The product was extracted with methylene chloride and the organic solution was washed with a solution of sodium bicarbonate at 208 and with water. Evaporation of the solvent yielded a crude which was crystallized from ethanol to give 6.2 g of 3-ethyloxy-6-methyl-1-trihydroxyregna-3,5-diene-20-one 21 acetate

EXAMPLE 26

PREPARATION OF 6β-FLUORO -METHYL-,, -TRIHYDROXY-

PREGN-4-ENE-3,20-DIONE 21-ACETATE

-FLUORO- 6β-METHYL- 2 1 -TRIHYDROXY-PREGN-4-ENE-3, 20-DIONE 21 ACETATE

Operating as in Example 2 from 10 g of 3-ethyloxy-6-methyl-,, trihydroxyregna-3,5-diene-20-one 17-acetate, 9.4 g of a crude were obtained which was chromatographed on silica gel to separate the epimers obtaining, after crystallization from methylene chloride / n-hexane, 1.2 g of 6β-fluoro- -methyl - -triohydroxypregn-4-ene-3.20-dione 21 -acetate and 4.7 g of

-fuoro-6β-methyl -,, 2 1-trihydroxypregn-4-ene-3,20-dione 17 aceta

E S E M P I O 27

PREPARATION OF 6β-FLUORO-METHYL-, -TRIHYDROXY-PREGNA-1, 4-DIENE-3,20-DIONE 21 -ACETATE

= H)

Operating as in Example 3 from 10 g of 6β-fluoro- -methyl-

21-trihydroxypregn-4-ene-3,20-dione 21 -acetate

reacted with 10.1 g of 2,3-dichloro-5, 6-dicyanobenzoquinone and 7.4 g of benzoic acid in 900 ml of dioxane. The crude obtained was purified by chromatography on silica gel and crystallized from methylene chloride / ethyl ether, giving 2.1 g of 6β-fluoro-methyl--trihydroxyregna-1,4-diene-3,20-dione 21-acetate

E SE M P I O 28

PREPARATION OF -FLUORO-6β-METHYL-TRIHYDROSSl-PREGNA- 1, 4-DIENE-3,20-DIONE 21 -ACETATE

= H)

Operating as in example 3 from 10 g of -fluoro -

21-trihydroxypregn-4-ene-3,20-dione 21 -acetate

reacted with 7.47 g of 2,3-dichloro-5,6 -dicianobenzoquinone and 6.47 g of benzoic acid in 900 ml of dioxane. The crude obtained was purified by chromatography on silica gel and crystallized from acetone / n-hexane, giving 3.1 g of -fluoro-6β -methyl--trihydroxyregna- 1,4-diene-3,20-dione 2 1 -acetate

EXAMPLE 29

PREPARATION OF 6β-FLUORO- -METHYL- -TRIHYDROXY-PREGNA- 1, 4-DIENE-3,20-DIONE

10 g of 6β -fluoro- -methyl - -triohydroxyregna- 1, 4-diene-3, 20-dione 21 -acetate and 6.6 g of potassium carbonate

were suspended in 580 ml of methanol. The reaction mixture was stirred at 0 ° C for 1 hour and then poured into 765 ml of water. After evaporation of the methanol under vacuum at 35 ° C, the precipitate formed was filtered and dried at room temperature. 6.3 g of 6β-fluorine were obtained

-methyl- 1-trihydroxyregna-1,4-diene-3,20-dione

= H).

EXAMPLE 30

PREPARATION OF -FLUORO-6β-METHYL- -TRIHYDROXY-

PREGNA-1,4-DIENE-3,20-DIONE)

Operating as in Example 29 from 10 g of -fluoro-6β-methyl-

21-trihydroxyregna-1,4-diene-3,20-dione 21 -acetate (

H) 5.6 g of -fluoro-6β-methyl--trihydroxy -pregna- 1,4-diene were obtained

E SE M P I O 31

PREPARATION OF 3-ETHYLOXY-6-METHYL- -THRI HYDROXY-

PREGNA-3,5-DIENE-20-ONE 17,2 1 -DI ACETATE

R3 = H).

Operating as in example 25 from 10 g of 60-methyl-

trihydroxypregn-4-ene-3,20-dione 17,2 1 -diacetate

10.18 g of 3-ethyloxy-6-methyl-trihydroxyregna-3,5-diene-20-one 17,2 1 -diacetate were obtained

EXAMPLE 32

PREPARATION OF 6β-FLUOR0- -METHYL -,, -TRIHYDROXY-PREGN-4-ENE-3.20-DIONE 17,2 1 -DI ACETATE

=

H) E -FLUORO-6β-METHYL-,, -TRIIDROXIPREGN-4-

ENE-3,20-DIONE 17,2 1 -DI ACETATE

Operating as in example 2 from 10 g of 3-ethyloxy-6-methyl -

trihydroxyregna-3,5-diene-20-one 17,21 -diacetate (

H) 8.9 g of a crude were obtained which was chromatographed on silica gel to separate the epimers obtaining, after crystallization from methylene chloride / n-hexane, 1.2 g of 6β-fluoro- -methyl - -triohydroxypregn-4-ene- 3,20-dione 17, 21 -diacetate e

5.7 g d -fluoro-6β-methyl--trihydroxypregn-4-ene-3,20-dione 17,21 -diacetate

EXAMPLE 33

PREPARATION OF 6β-FLUORO- -METHYL- -TRIHYDROSSl-PREGNA- 1, 4-DIENE-3,20-DIONE 17,2 1 -DIACETATE (8b, R1 = R2 =

Ac, R3 = H)

Operating as in Example 3 from 10 g of 6β-fluoro-methyl -

21-trihydroxypregn-4-ene-3,20-dione 17,2 1 -diacetate

= H) reacted with 12.25 g of 2,3-dichloro-5,6-dicyanobenzoquinone and 6.04 g of benzoic acid in 90.0 ml of dioxane. The crude obtained was purified by chromatography on silica gel and crystallized from ethanol, giving 2.9 g of 6β-fluoro- -methyl- trihydroxyregna- 1,4-diene-3,20-dione 17,21 -diacetate

EXAMPLE 34

PREPARATION OF -FLUORO-6β-METHYL - TRIHYDROXY-PREGNA- 1, 4-DIENE-3,20-DIONE 17,2 1 -DIACETATE

Operating as in Example 3 from 10 g of -fluoro-6β-methyl-

2 1 -trhydroxypregn-4-ene-3,20-day- 17,2 1 -diacetate

= H) reacted with 12.35 g of 2,3-dichloro-5,6-dicyanobenzoquinone and .6.04 g of benzoic acid in 900 ml of dioxane. The crude obtained was purified by silica gel chromatography and crystallized from ethanol, giving 2.8 g of

-fluoro-6β-methyl- -trhydroxyregna-1,4-diene -3,20-dione

17, 21 -diacetate

PHARMACOLOGICAL DATA

Local anti-inflammatory activity was assessed in mice with the rattlesnake oil test.

The procedure for this test involves applying croton oil (20 μl of a 30% solution) topically to the anterior and posterior surfaces of the right ear of 5 mice. After 30 min the compound or excipient is applied. Ear swelling is assessed 2 hours after treatment with a micrometer. An inhibition greater than 50% compared to controls indicates an intense topical anti-inflammatory activity. Systemic anti-inflammatory activity was evaluated in rats with the carrageenan test. Four rats were treated p.o. one hour before the intra-implant injection in the right hind leg of càrragenina (0.1 ml; 1% suspension). An inhibition of paw edema greater than 50% (> 30) three hours after administration of carrageenan indicates an intense anti-inflammatory activity.

TOPICAL ANTI-INFLAMMATORY ACTIVITY TEST

TEST ON ORAL ΑΝΤI-ΙΝFLAMMATORY ACTIVITY

The new compound AF-213 exhibits topical anti-inflammatory activity, superior to that of the well-known anti-inflammatory agent Medrol diacetate. In contrast, AF-213 exhibits no oral anti-inflammatory activity and, consequently, undesirable side effects.

the new compounds AF-21 1 and AF-212 show both topical anti-inflammatory activity and oral anti-inflammatory activity superior to that of the corresponding Medrol diacetate and Medrol, respectively.

Claims (1)

CLAIMS 1. 6β-Fluoro-methylpregn-4-ene-3,20-dioni of general formyl (A): where: X is hydroxy and V is hydrogen, fluorine, chlorine or bromine; or X and Y are both chlorine; R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms; is hydroxy or acyloxy having from 2 to 12 carbon atoms; R3 is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl; 2. 16, 17- and 17.21 -acetals and cyclic -ketals of the compounds of general formula (A). 3. 16, 17-acetonides of the compounds of general formula (A). 4. Compounds of general formula (A) wherein R1 and / or R2 are acyloxy whose acyl group is that of acetic, trimethylacetic, propionic, alpha-phenylpropionic, beta-phenylpropionic, butyric and valeric acids. 5. -Fluoro-6B-methylpregn-4-ene-3,20-diones of general formula (6): where: X is hydroxy and V is hydrogen, fluorine, chlorine or bromine; or X and Y are both chlorine; R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R2 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R3 is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl; 6. 16, 17- and 17.21 -acetals and cyclic -ketals of the compounds of general formula (B). 7. 16, 17-acetones of compounds of general formula (B). 3. Compounds of general formula (B) in which R1 and / or R2 are acyloxy whose acyl group is that of acetic, trimethylacetic, propionic, alpha-phenylpropionic, beta-phenylpropionic, butyric and valeric acids. 9. 6β -Fluoro-methylpregna-1,4-diene-3,20-diones of general formyl (C) where: X is hydroxy and Y is hydrogen, fluorine, chlorine or bromine; or X and Y are both chlorine; R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R2 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R3 is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl; 10. 16, 17- and 17.2 1 -acetali and cyclic ketals of the compounds of general formula (C). 1 1. 16,17-acetonides of the compounds of general formula (C). 12. Compounds of general formula (C) wherein R1 and / or R2 are acyloxy whose acyl group is that of acetic, trimethylacetic, propionic, alpha-phenylpropionic, beta-phenylpropionic, butyric and valeric acids. 13. 6β, 9-difluoro-methyl--trihydroxyregna- 1,4-diene-3,20-dione. 14. 6β, 9-difluoro methyl-trihydroxyregna-1,4-diene-3,20-dione 17,21-diacetate. 15. floro-6β-methylpreg -1, 4-diene-3,20-dioni general formula (D): m which: X is hydroxy and V is hydrogen, fluorine, chlorine or bromine; or X and Y are both chlorine; R1 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R2 is hydroxy or acyloxy having from 2 to 12 carbon atoms; R3 is hydrogen, alpha-hydroxy, alpha-methyl or beta-methyl; 16. 16, 17- and 17.21 -acetals and cyclic -ketals of the compounds of general formula (D). 16, 17-acetonides of the compounds of general formula (D). 18. Compounds of general formula (D) in which R1 and / or R2 are acyloxy whose aryl group is that of acetic, trimethylacetic, propionic, alpha-phenylpropionic, beta-phenylpropionic, butyric and valeric acids. 19. 9-bromine fuoro-6β-methyl- trihydroxyregna- 1,4- diene -3,20-dione. 20. 9-bromo -fluoro-6β -methyl 21-trihydroxyregna- 1,4-diene -3,20-dione 17,2 1 -di acetate