FI57600C - REFERENCE TO A FRAME PROTECTION AGENT ANTI-INFLAMMATOR D-HOMOSTEROIDER - Google Patents

Description

___, -, ANNOUNCEMENT _ _. Λ ^ (11) UTLÄGGNINGSSKRIFT 5 7600 C (45) Fr.v. '"- - - ^ (51) Kv.lk3 / lnt.CI.3 c 07 J 65/00 FINLAND —FINLAND (21) Ptwnttlhakemut —P * t» »<ttn» 6knlnf 772599 (22) H »k * ml * ptlvl - An »öknlnpd« f 01.09 · 77 (23) Alkupilvt — Gittlfhttsdag 01.09.77 (41) Tullutlulkttak ·) - BllvltofTmellg 0 ^ +. 03.78

National Board of Patents and Registration (44) Date of NihtivUulptnon and the month of publication. -

Patani · och registerstyrelsen Anaekan utlagd och utUkrlftan publtm-ad 30.05.80 ^ (32) (33) (31) pyrdeccar «uolkau * -Begird prlorltet 03.09 * 76

Austria-Austria (AT) A 6560/76 (71) F. Hoffmann-La Roche & Co Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) v- (72) Leo Alig, Kaiseraugst, Andor Fiirst, Basel, Marcel Miiller, Frenkendorf , Switzerland-Schweiz (CH), Ulrich Kerb, Berlin, Klaus Kieslich, Berlin, Rudolf Wiechert, Berlin, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (7 * +) Oy Kolster Ab (5 ^) Method for the preparation of new anti-inflammatory D-homosteroids -For use of anti-inflammatory drugs other than D-homosteroids

The invention relates to a process for the treatment of anti-inflammatory formula I

“3 yen? "17 *

H3C J I

t for the preparation of D-homosteroids according to R6, wherein the dotted 1,2-bond represents a possible C-C bond; R 1 represents a hydrogen, fluorine or chlorine atom or a methyl group; R represents a hydrogen, fluorine or chlorine atom; and R represents a hydroxy group or an acyloxy group having up to 15 carbon atoms, wherein in the β 11,17α-dihydroxy compound, R represents a hydrogen atom, or in the 11,17α-dihydroxy-69 * -ene compound, R represents fluorine, R'rn be a fluorine or chlorine atom.

2 57600

The corticosteroids of formula I are highly effective anti-inflammatory agents. FI patent publications 52,099 and 5k 6oU disclose D-homopregnane derivatives having a hydroxy or chlorine substituent at the 21-position, while the 21-position of the D-homopregnane derivatives of the formula I is unsubstituted. In particular, the compounds of the formula I have anti-inflammatory activity when applied topically and are clearly more potent in this respect than the known compounds substituted at the 21-position.

The acyloxy group can be derived from a saturated aliphatic carboxylic acid having up to 15 carbon atoms. Examples of such acids are formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, n-heptylic acid and undecylenic acid. Particularly preferred are C 1-6 alkanoyloxy groups.

Preferred compounds of formula I are those having a 1,2-double bond.

According to the invention, the D-homosteroids of the formula I can be prepared in such a way that

(a) formula II

The D-homosteroid according to H3 H C C ° -ν n i6 is hydroxylated at the 11-position by microorganisms or enzymes derived therefrom, for example by the species Curvularia Lunata, or

(b) formula III

CV

H C CO

in a D-homosteroid of more than T J m s6 3 57600, iodine is replaced by hydrogen, suitably treated with a reducing agent, or c) the 1,2-saturated D-homosteroid of formula I is dehydrated in the 1,2-position, or

d) CH of formula IV

L3

H I

The D-homosteroid of R 6 is conveniently reacted with the alichloroacid produced in the reaction mixture, or e) CH 2 of formula V

C/O

H.C N

the f-D-homosteroid of formula I is treated with hydrogen fluoride or hydrogen chloride, or f) the 6- (3-isomer) of the 6-fluoro, chloro or methyl-D-homosteroid of formula I is suitably isomerized by treatment with an acid to the 6-isomer, or

(g) formula VI

"57600 CH_ I3 H3c 1 ° H0 ^ χ ··" R1Ta

* Q

the D-homosteroid of formula I is fluorinated or chlorinated in the 6-position by appropriate treatment with a fluorinating or chlorinating agent such as N-chlorosuccinimide, or h) the R 1α-hydroxy group of the D-homosteroid of formula I is acylated, or

(i) formula IX

T3

C/O

The 11-keto group of the D-homosteroid of formula R'T * · - ^ \, j I * is reduced to the hydroxy group by appropriate treatment of the metal hydride with a complex, the 3- and 20-keto groups being optionally protected, or j) the D-homosteroid of formula VI is modified to include a 6-methyl group suitably to 3-enamine, which is converted, for example, by hydroxymethylation with formaldehyde and cleavage of the hydrogen with an acid to give the 3-methylene compound, which is hydrogenated in the presence of a hydrogenation catalyst to give the 3-methyl compound.

The hydroxylation of a compound of the formula II according to process variant a) can be carried out by microbiological 11-hydroxylation of steroids in a manner known per se. In particular, the 5 57600 fungal and fungal families Ascomycetes, Phycomycetes, Basidiomycetes and Actinomycetales, as well as cell-free enzyme preparations derived from microorganisms, are considered. Suitable microorganisms for 11-hydroxylation are in particular microorganisms of the genus Curvularia, e.g. C. Lunata NRRL 23Ö0.

The replacement of iodine in the compound of formula III with hydrogen according to process variant b) can take place by treating the compound II with reducing agents such as NaHSO 4.

The 1,2-dehydrogenation of the 1,2-saturated D-homosteroid of the formula I (process variant c) can take place in a manner known per se, e.g. by a microbiological route or by means of dehydrating agents such as selenium dioxide. A suitable microorganism for 1,2-dehydrogenation is, for example, a Bacillus strain such as B. lentus ATCC 13805-

To carry out process options d) and e), the starting material IV or V is suitably dissolved in a suitable solvent, e.g. an ether such as tetrahydrofuran or dioxane, a chlorinated hydrogen chloride such as methylene—

57600 6 e.g. in the presence of pyridine or triethylamine and in the presence of a suitable catalyst such as p-dimethylaminopyridine, or a strong acid catalyst. , e.g. in the presence of p-toluenesulfonic acid. Suitable solvents are organic solvents which do not contain hydroxyl groups, e.g. chlorinated hydrocarbons, such as methylene chloride, or hydrocarbons, such as benzene. When working in a basic environment in the presence of p-dimethylaminopyridine, the 11β-hydroxy group can be selectively acylated adjacent to the 17α-hydroxy group.

To carry out process variant i), the keto group of compound IX is first protected at the 3- and 20-positions, e.g. as semicarbazone. The 3-keto group can also be protected by the formation of an enamine if 1,2-double

λ1 U

binding. The protecting groups can be removed with an acidic hydroxyl. ^ * -3-keto-m can also be converted to -Δ * '-3-enamine in the presence of TiCl 4. The reduction of the 11-keto group of the compound of formula IX (process variant i) can be carried out with a complex metal hydride such as sodium borohydride.

The methylation according to process variant j) can be carried out, for example, by converting the starting compound of formula VI into a 3-enol ether (e.g. -propane, e.g. 2,2-dimethoxypropane in methanol-dimethylformamide in the presence of p-toluenesulfonic acid) and the enol ether is reacted with tetrahalomethane, e.g. CBr>, CClBr_ or CCl_Br, trihalo-1. d. . k to the gene methyl Δ -3-ketone. The trihalomethyl Δ-3-ketone can be dehydrohalogenated with bases such as collidine to the dihalomethylene-Δ-3-ketone, which can again be converted by catalytic hydrogenation under mild conditions, e.g. using Pd / SrCO 2 as a catalyst, 6'-methyl-N-3 ketone.

In another methylation process, a 1,2-saturated D-homosteroid of formula VI is converted to a 3-enol ether and reacted in a manner known per se to the corresponding 6-formyl derivative, the formyl group is reduced with sodium borohydride to give the hydroxymethyl group and finally dehydrated.

157600H3 B3C? ° R17a

vT 1 I

CH

D-homosteroid according to Fig. 2, 9. 17a wherein R and R have the same meaning as above.

Such 6-methylene intermediates can also be prepared by converting β-1,2-saturated compounds of formula VI to 3-enamines, e.g. 3-pyrrolidinamine, by hydroxymethylation with formaldehyde and cleavage of water with acids such as p-toluenesulfonic acid. The 6-methylene-D-homosteroids of the formula VII thus obtained can be catalytically prepared in a manner known per se, i. using known hydrogenation catalysts to hydrogenate to the corresponding 6-methyl compounds.

Due to their anti-inflammatory effect, the compounds of the formula I can be used, for example, in the treatment of inflammatory diseases, such as rashes.

To compare the compounds of formula I with the known compounds, the following pharmacological experiments were performed:

Felt granuloma balloon test (systemic anti-inflammatory effect)

Felt balls were placed under the skin (shoulder-bone area) of ether-anesthetized female rats (weight 90-110 g). 5 rats were always used per dose. The test compound was administered orally and intraperitoneally twice a day for four days, starting on the day the felt ball was placed under the skin.

After four days, the rats were sacrificed and the resulting granuloma was removed, dried and weighed. The thymus and adrenal gland were weighed.

The ED 2 value given in the table indicates the amount of test compound in mg per 8,576 kg of test animal, which gives a! +0 - # granuloma inhibition.

Mouse ear swelling test (local anti-inflammatory effect) Test compounds dissolved in croton oil were used to treat the right ear of male mice (weight 25 ~ 30 g) for 15 seconds at a weight of 600 g. The left ear was as a control. After four hours, the mice were sacrificed, and a piece of tissue was taken from the treated and untreated ear with a perforated iron at the same site.

The EC ^ q shown in the table indicates the concentration of test compound at which the inhibition of edema compared to the control was 50 - #.

Compound ED, ED 2 / EC - EC 50 p.o. p.m. po p.m.

17α-butyryloxy-9-fluoro-11β-hydroxy-D-homopregna-1,10-dienene-3,20-dione 19,9 7> 3 0,003 6600 2,00 (according to the invention) 17α-butyryloxy-11 N-hydroxy iD-homopregna-1,1'-diene-3,20-dione 18, U 18,8 0,008 2300 2350 (According to the invention) ---- 1-- 9-fluoro-1β, 17α, 21-trihydroxy- D-homopregna-1,1-diene-3,20-dione-0.05 0.25 0.2 (FI patent 52,099) 11 (i, 17a, 21-trihydroxy-D-homopregna--1 1,1'-diene-3,20-dione 0.6 0.06 10 (FI patent 52,099) 21-chloro-9-fluoro-11β, 17α-dihydroxy-D-homopregna-1,1-diene- 1,1,3,16,6,8 -3,20-dione (FI patent 5,6,6θΜ-21-chloro-11β, 17α-dihydroxy-D- and homopregna-1,1'-diene-3,20-dione 3 j 0> 3 '10 | (FI patent 51 * 60U) I 1!! Li i 9 57600

A low EC ^ value indicates high local activity and a low ED ^ Q value indicates high systemic activity.

Compounds with high activity when applied topically, such as compounds of formula I, are not desirable to have high systemic activity. It can be seen from the table that the compounds of formula I in which the 21-position is unsubstituted have a significantly higher ED 1 / EC 2 value than the reference compounds in the FI patents 52,099 and 5 *> 60 2 in which the compounds have a 21-position as a substituent. hydroxy or chlorine.

In general, when administered internally, the preparations may contain 0.01 to 5.0% of a D-homosteroid of formula I. The daily dose may vary from 0.05 to 10.0 mg depending on the condition to be treated and the duration of treatment desired. The proportion of active D-homosteroid of the formula I in topical preparations is generally in the range from 0.0001 to 5% by weight, preferably in the range from 0.001 to 0.5% and most preferably in the range from 0.01 to 0.2%.

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

Example 1 k, 9 g of 9-fluoro-11β, 17α-dihydroxy-21-iodo-D-homopregna-1,1-diene-3,20-dione, 80 ml of ether, 80 ml of benzene, U0 ml of water and + 0 ml of saturated sodium hydrogen sulfite solution was stirred at 25 ° C for 30 hours.

The reaction mixture was diluted with ethyl acetate. The aqueous phase was separated and extracted twice with ethyl acetate. The ethyl acetate solutions were washed twice with brine, dried over sodium sulfate and evaporated.

Filtration through silica gel and crystallization from acetone-hexane afforded 9-fluoro-11β, 17α-dihydroxy-D-homopregna-1,1'-diene-3,20-dione, m.p. 268-269 ° C, UV = ^ 29 ~ 15200, 1 ° ^] - Q - + 67 ° (in methanol, c = 0.1%).

The starting material can be prepared by converting 9-fluoro-D-homoprednisolone, w m.p. 2 ^ 1-2U6 ° C, = + 101 ° (c = 0.1% in dioxane), UV: ^ 238 = ^ 5 ^ 0, by reacting it with methanesulfonyl chloride in pyridine 9-fluoro-11 ($ -17a-dihydroxy- 21-methanesulfonyloxy-D-homopregna-1,1-diene -—-3,20-dione and reacting it with sodium iodide in acetone 9-fluoro-11β, 17α-dihydroxy-21-iodo-D-homopregna-1, 4-diene-3,20-dione.

Sp. 190 ° C (decomposes), λ max = + 118 ° (in dioxane, c = 0.1%), UV: λg = 15750.

In an analogous manner, 6β-fluoro-11β, 17α-dihydroxy-21-iodo-D-homopregna-1,1'-diene-3,20-, 0 57600 dione, m.p. 175-177 °, UV: = 15830, / <X / D = + 121 ° (c = 0.1 N in dioxane) 6'-fluoro-11β, 17α-dihydroxy-D-homopregna-1, ii-diene-3,20-dione, m.p.

183-18 °, UV: ^ 21 + 2 = 1 00, = + 56 ° (c = 0.1% in dioxane) 60, 9-difluoro-11,13,17a-dihydroxy-21-iodo-D -homopregna-1,1 *-diene-3,20-dione, m.p. 189-190 °, UV: & 23q = 16750, / <* 7 = + 115 ° (c = 0.1% in dioxane) δ N-difluoro-11β, 3,17α-dihydroxy-D-homopregna-1,1 +-diene-3,20-dione, m.p. 23Ο-231, UV: ^ 238 = 1600, λ max = 57 ° (c = 0.1% in dioxane).

Example 2 w, 60 mg of 9,11β-epoxy-17α-hydroxy-D-homopregna-1,1-diene-3,20-dione were stirred in 1.5 ml of glacial acetic acid and 0.15 ml of 37% hydrochloric acid For 15 minutes at 25 °. The reaction mixture was poured into dilute sodium hydrogen carbonate solution and extracted three times with methylene chloride. The methylene chloride solutions were washed twice with dilute brine, dried and evaporated. Acetone gave 9-chloro-11β, 17α-dihydroxy-D-homopregna-1,1'-diene-3,20-dione, m.p. 265-270 ° (dec.); UV: = 15080, = +9> + (DMSO, c = 0.1%).

Example 3 100 mg of 9,11 (3-epoxy-17α-hydroxy-D-homo-9 (3-pregna-1,1,4-diene-3,20-dione) were stirred in 2 ml of a solution containing 1 part of urea and 1.3 parts of hydrogen fluoride, for one hour at 25 [deg.] C. The reaction mixture was poured into water and extracted with methylene chloride, and crude silica gel chromatography afforded 9-fluoro-11β, 17α-dihydroxy-D-homopregna-1,1'-diene-3,20-dione, mp 268-269 ° · UV: ε = 15200, fo'JO = + 67 ° (C = 0.1% in methanol).

Starting material, 9.11 (5-epoxy-17α-hydroxy-D-homo-? 6-pregna-1,1 +-diene-3,20-dione, mp 179-180 °, UV: = 1 ° 6θ, = "15 ° (C = 0,1% in dioxane), is obtained from 9-bromo-11β, 17α-dihydroxy-D-homopregna-1,1'-diene-3,20-dione and potassium acetate in alcohol by heating under reflux for several hours. ---

Example U

1 g of 6β-fluoro-11β, 17α-dihydroxy-D-homopreg-n-U-ene-3,20-dione and 660 mg of selenium dioxide were mixed in 50 ml of t-butanol and 0.5 ml of glacial acetic acid for 2k hours under argon at reflux. The reaction mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed successively with sodium hydrogencarbonate solution, water, ice-cold ammonium sulfide solution, dilute ammonia, water, dilute hydrochloric acid and water. The ethyl acetate solution was dried over sodium sulfate and evaporated in vacuo. Silica gel chromatography afforded 60 ° (-fluoro-11β-dihydroxy-D-homopregna-1,1'-diene-3,20-dione, mp 183-18 °, UV: £ 21 + 2 = ^ ^ 0, ^ -q = + 5 & ° (in dioxane, c = 0.1%).

Example 5 1.1 s 11/3, 17α-Dihydroxy-D-homopregna-1,1-diene-3,20-dione was dissolved in 6.2 ml of pyridine and ml of trifluoroacetic anhydride at -10 ° and stirred for 50 minutes. At 0 ° under an argon atmosphere. The reaction mixture was poured into dilute hydrochloric acid and extracted three times with methylene chloride. The methylene chloride solutions were washed neutral with sodium hydrogen carbonate solution and brine, dried and evaporated. Silica gel chromatography afforded pure non-crystalline 17α-hydroxy-11β-trifluoroacetoxy-D-homopregna-1,1'-diene-3,20-dione. UV: ^ 239 = 1 ^ 200, M-q ~ + 8 ^ ° (c = 0.1% in dioxane).

1.2 g of 17α-hydroxy-11β-trifluoroacetoxy-D-homopregna-1,1-diene-3,20-dione was dissolved in a mixture of 12 ml of butyric acid and k, 8 ml of trifluoroacetic anhydride and stirred for 4 hours. ° C. The reaction mixture was poured into aqueous pyridine, stirred for 10 minutes, acidified with 2N hydrochloric acid and extracted three times with methylene chloride. The methylene chloride solutions were washed with sodium hydrogen carbonate solution and brine until neutral, dried over sodium sulfate and evaporated. Silica gel chromatography of the residue afforded pure 17α-butyryloxy-11β-trifluoroacetoxy-D-homo-pregna-1,1-diene-3,20-dione as a foam. 0 ^: ^ 2l + o = "* 8900, [* € -q = + ^ 1 ° (dioxane, c = 0.1%).

1.1 g of 17α-butyryloxy-11β-trifluoroacetoxy-D-homopregna-1,1 +-diene-3,20-dione were reacted in 55 ml of methanol and in 1.2 ml of water h, 2 ml of saturated sodium bicarbonate solution and stirred for 88 hours at 25 ° C. The methanol was evaporated off and the residue was dissolved in methylene chloride and water. The methylene chloride solution was washed with dilute brine, dried and evaporated. 17α-Butyryloxy-11β-hydroxy-D-homopregna-1,1'-diene-3,20-dione was obtained as a thin layer chromatographically pure foam. UV / f ^ = 139 ^ + 0, [* t] D = + 22 ° (dioxane, c = 0.1, $).

Example 6

In analogy to Example 5, 17a-butyryloxy-9-fluoro-1β / β-hydroxy-D-homopregnate was obtained from 9-fluoro-11γS, 17α-dihydroxy-D-homopregna-1,1,1-diene-3,20-dione. 1, U-diene-3,20-dione, m.p. 187-188 °, UV: ε2000 = li + 000> ~ + 13 ° (dioxane, c = 0.1%).

12,576,6,6-Difluoro-1α, 7α-dihydroxy-D-homopregna-1,1 + -diene-3,20-dione from 17α-butyryl oxy-Gene, 9-d-fluoro-1,1'- hydroxy-D-homopregna-1,1-diene-3,20-dione, m.p. 22U-2250, UV: ^ 238 = 16H00, = + 1 ^ (c = 0.1% in dioxane).

Example 7

In analogy to Example 5, 6α-fluoro-11β, 17α-dihydroxy-1D-homopregna-1,1'-diene-3,20-dione was obtained from 17α-butyryloxy-6et-fluoro-11/5-hydroxy-D-homopregna- 1,1-diene-3,20-dione, m.p. 168-169 °, UV: 2 ^ + 2 = = + 13 ° (dioxane, c = 0.1%).

Example 8

If acetic acid, propionic acid, valeric acid or isobutyric acid is used instead of the butyric acid used in Example 5, 9-fluoro-11 / 8,17α-dihydroxy-D-homopregna-1,1'-diene-3,20-dione 17α-acetoxy is obtained in analogy to Example 5. 9-fluoro-11/8-hydroxy-D-homopregna-1,1-diene-3,20-dione m.p. 232-233 °, UV: £ * 239, = 13900, = + 29 ° (c = 0.1% in dioxane) 9-fluoro-11β-hydroxy-17α-propionyloxy-D-homopregna-1,1-diene- 3,20-dione, m.p. 20i + -205 °, ^: ^ 238 = 1 ^ 100, £ *} '= + 23 ° (c - 0.1% in dioxane) 9' fluoro-11β-hydroxy-17α-valeroyloxy-D-homopregna-1 , 1-diene-3,20-dione, m.p. 1 J + 1 + -li + 6 °, UV: ^ * 239 = 15 ^ 00, J ^ 1 -q ~ + 17 ° (c = 0.1% in dioxane).

or 9-fluoro-11β-hydroxy-17α-isobutyryloxy-D-homopregna-1,1-diene-3,20-dione, m.p. 217-218 ° C, = + 19 ° (c = 0.1% in dioxane), λmax = 15.00.

Example 9 300 mg of 1β, 17α-dihydroxy-6-methylene-D-homopregn-4-ene-3,20-dione, 150 mg of palladium on carbon (5%), 1.5 ml of cyclohexene and 15 ml of ethanol were boiled in 8 1/2 for one hour under argon at reflux. The mixture was cooled to 25 ° C, reacted with 25% hydrochloric acid and stirred for 1 hour. The catalyst was filtered off and the filtrate was evaporated. Silica gel chromatography afforded 11β-17α-dihydroxy-6-methyl-D-homopregn-U-ene-3,20-dione, m.p. 223-225 °, ^ 2k2 ~ 1 ^ 100 »I & j) ~ + 1 * 6 ° (c * 0.1% in dioxane).

The starting material can be prepared as follows: 11 / 8,17a-dihydroxy-D-homopregn-U-ene-3,20-dione is reacted with boiling methanol in pyrrolidine 11 / β, 17a-dihydroxy-3- (1-pyrrolidinyl) - D homopregna-3,5-dien-20-one. This gives 11β, 17α-dihydroxy-6β-hydroxymethyl-D-homopregna-U-ene-3,20-dione by reaction with formalin in benzene and methanol. Treatment with hydrochloric acid in dioxane yields 11β, 17α-dihydroxy-6-methylene-D-homopregn-U-ene-3,20-dione.

Example 10 2 1-conical flask containing 500 ml of a $ 1 corn steep liquor sterilized at 120 ° in a 120 ° autoclave, 1 # soybean powder and 0.005 # soybean oil nutrient solution adjusted to pH 6.2 ,, 57600 are inoculated with a lyophilized culture of Curvularia Lunata (NRRL 2380) and shaken for 72 hours at 30 ° on a rotary shaker. This preculture is then inoculated with 20 l of stainless steel fermenter containing 15 l of a solution sterilized at 121 ° C and 1.1 tyr, containing 1% corn steep liquor, 0.5% starch sugar and 0.005% soybean oil, adjusted to pH 6, 2. Silicone oil (Silicon SH) is added as a defoamer, germinated at 29 ° to a climate (10 l / min) at 0.7 aty pressure and with stirring (220 rpm) for 2 hours. One liter of culture solution is transferred under sterile conditions to 1 μl, such as the sterilized solution above, containing 1% corn steep liquor, 1.25% soybean powder and 0.005% soybean oil and grown under similar conditions. After 12 hours, a solution of 1 g of 17α-Acetoxy-D-homo-4-pregnene-3,20-dione in 200 ml of dimethylformamide is added. After a reaction time of 52 hours, the contents of the fermentation vessel are emptied by rinsing twice with 10 l of methyl isobutyl ketone each time. . o ..... ....

and the extract is evaporated in a 50 bath lamp vacuum. The residue is washed several times with hexane to remove the silicone oil and separated from the unchanged starting material by column chromatography through silica gel (gradient elution: hexane + hexane / ethyl acetate 1 + (1/1).) 17α-acetoxy-11/3-hydroxy-D-homo-U-pregnene- The 3,20-dione was recrystallized from isopropyl ether, mp 232 / 235-237 °, mp 212-16700.

Example 11 2 A 1-Erlenmeyer flask containing 500 ml of nutrient solution sterilized for 30 minutes at 120 ° in an autoclave from 1.5 # peptone, 1.2 # corn steep liquor and 0.2%. MgSO 4, adjusted to pH 6.5, is inoculated with a lyophilized culture of Bacillus lentus (ATCC 13805) and shaken for 2 hours at 30 °. This preculture is then inoculated with 20 l of stainless steel fermentation medium containing 15 L of a liquid nutrient solution sterilized at 121 ° and 1.1 atyr, consisting of 0.2% yeast extract, 1% corn steep liquor and 0.1% starch sugar, adjusted pHrhon 7.0. By adding silicone oil (Silicon SH) as a defoamer, germinate at 29 ° with aeration and stirring. After a growth period of 6 hours, a solution containing 1.6 g of 17α-ε-acetoxy-11β-hydroxy-D-homol-pregnene-3,20-dione in 50 ml of dimethylformamide is added. After a reaction time of 15 hours, the contents of the fermentation vessel are extracted twice with 10 ml of methyl iso-butyl ketone each time and the extract is evaporated in vacuo. The residue was washed to remove silicone oil with hexane and recrystallized from acetone-diisopropyl ether in the presence of activated carbon to give 17α-acetoxy-11β-hydroxy-D-homo-1,3 * pregnadiene-3,20-dione, m.p. 218 / 219-220 ° and £ = 15100.

"> 57600

Example 12 To 2h of 1-fluoro-17α-hydroxy-D-homopregna-1,1 *-diene-3,11,20-trione in 0.5 ml of tetrahydrofuran was added portionwise 12 g of sodium borohydride over two hours. The progress of the reaction was monitored by thin layer chromatography. After 2 hours, the reaction mixture was treated with methylene chloride and water. Preparative thin layer chromatography afforded 12 mg of 11β, 17α-dihydroxy-9-fluoro-D-homopregna-1,1'-diene-3,20-dione, m.p. 268-269 ° C.

Example 13 To 250 mg of 17α-hydroxy-D-homopregna-1,7,9 (11) -triene-3,20-dione in 10 ml of dioxane and 2 ml of water were added 750 mg of N-chlorosuccinimide and 7, 5 ml of 1-n perchloric acid. After 3 hours, 2.5 g of sodium sulfite was added and then the reaction mixture was treated with water and methylene chloride. Chromatography on silica gel gave 9-chloro-1}, β, 17α-dihydroxy-D-homopregna-1,1-diene-3,20-dione, m.p. 265_270 ° C. ~~

Example 1 20 mg of 6β-chloro-11β, 3,17α-dihydroxy-D-homopregn-1-ene-3,20-dione were allowed to stand in 1 ml of acetic acid and 0.2 ml of 25 hydrochloric acid at room temperature.

After 4 hours, the solvent was evaporated in vacuo. Acetone-hexane gave 6et-chloro-11,3,17α-dihydroxy-D-homopregn-U-ene-3,20-dione, m.p. 197-198 ° C.

Example 15 1 g of 11β, 3,17α-dihydroxy-D-homopregn-U-ene-3,20-dione was dissolved in 10 ml of hot ethanol, the solution was cooled to 25 ° C, and 10 ml of ortho-formic acid triethyl ester was added thereto, and 10 mg of p-toluenesulfonic acid. After 15 minutes, 0.1 ml of pyridine was added. The reaction mixture was diluted with methylene chloride, washed with water, dried and evaporated in vacuo. 1.1 * g of 3-ethoxy-11β, 3,17α-dihydroxy-D-homopregna-3,5-dien-20-one were obtained. This was dissolved in 60 ml of acetone, and to the solution at 0 ° C were added U70 mg of N-chlorosuccinimide and a solution containing 600 mg of sodium acetate and 0.56 ml of acetic acid in 6 ml of water. After 30 minutes, the acetone was evaporated in vacuo, the precipitate was dissolved in methylene chloride, and the solution was washed with sodium bicarbonate solution and brine. The methylene chloride solution was dried over Na 2 SO 4 and evaporated.

The residue was chromatographed on silica gel to give 6β-chloro-11β, 3,17α-dihydroxy-D-homopregn-1-ene-3,20-dione, m.p. 197-198 ° C, M + + 59 ° (dioxane, 0.1%), ^ 237 = ^ 3000, and 6/3-chloro-11β, 17α-dihydroxy-D-homopregn-U-ene-3 , 20-dione, m.p. 178-179 ° ·

Claims (4)

A process for the preparation of anti-inflammatory D-homosteroids of formula I Γ3 CO K17a19 i R6, wherein the dotted 1,2-bond represents a possible C-C bond; represents a hydrogen, fluorine or chlorine atom 9 17a or a methyl group; R represents a hydrogen, fluorine or chlorine atom; and R represents a hydroxy group or an acyloxy group having up to 15 carbon atoms, wherein in the 11,17α-dihydroxy compound R 1 represents a hydrogen atom or in the 11,17α-19 9 dihydroxy-U-ee compound R means fluorine, R becomes: n is a fluorine or chlorine atom, characterized in that a) the D-homosteroid of the formula II Γ3 CO H c ^ R1Ta I R6 16 57600 is hydroxylated in the 11-position by microorganisms or enzymes derived therefrom, for example by the species Curvularia Lunata, or b) in a D-homosteroid of the formula III CH2J CO HJC R1? a H0 \ R m R9, the iodine is replaced by hydrogen, suitably treated with a reducing agent, or c) the 1,2-saturated D-homosteroid of the formula I is dehydrated in the 1,2-position, or d) the D-homosteroid of formula IV CH: o Rna is reacted appropriately with the alichloroacid produced in the reaction mixture, or e) the D-homosteroid of formula V 57600 17 I3 H3C yP If is treated with fluorine or chlorine above, or ^ f) the 6β-isomer of a 6-fluoro, chloro or methyl-D-homosteroid of formula I is suitably isomerized by treatment with an acid to the 6β-isomer, or g) the D-homosteroid of formula VI T3 CO H0 * R1Ta is fluorinated or chlorinated at the 6-position by treatment with an appropriate fluorinating or chlorinating agent such as N-chlorosuccinimide, or 17a eh) acylation of the R-hydroxy group of a D-homosteroid of formula I, or 57600 18 i) formula IX Γ3 CO HCO · R1Ta h3c JJ 1 « the 11-keto group of the D-homosteroid of formula VI is reduced to a hydroxy group by appropriate treatment with a metal hydride complex, optionally protected with 3- and 20-keto groups, or j) to attach a 6-methyl group, the D-homosteroid of formula VI is and cleaving the hydrogen with an acid to give the 3-methylene compound, which by hydrogenation in the presence of a hydrogenation catalyst gives the 3-methyl compound. Process according to Claim 1, characterized in that 1,2-unsaturated D-homosteroids of the formula I are prepared. Process according to Claim 1 or 2, characterized in that 17α-butyryloxy-9-fluoro-1β-hydroxy-D-homopregna-1,1'-diene-3,20-dione or 17α-butyryloxy-11β-hydroxy-D -homopregna- -1,5-diene-3,20-dione. '9 57600 1. A method for the preparation of an anti-inflammatory D-homosexoid with a formula I? H 3 H3C? ° 17a V T T J R6 color 1,2-bonding, preferably with a prick line, including C-C binding; R 2 is a substituent, fluorine or chlorine or methyl; 9 17a R betecnar en väte-, fluor- eller chloroatom; and R is a hydroxyl group or an acyloxy group having up to 15 C-atoms, varied to R 11 and 11,17a-dihydroxy fatty acids, or R 11 and 11,17a-dihydroxy-U-enes are fused with 9 fluorine, Bör R is a fluorine or chlorine atom, which can be used as a) hydroxylerar and D-homosteroid in the form of II HC 00 ^ 4 ^ SR'7a in QTj i 11-strained microorganisms or in which an enzyme is used, the exempted medium is Curvularia Lunata-arten, eller b) ersätter iod i en D-homosteroid med formula 20 57600 ch2j vk, R9 I III ii R6 med Väte, ändamälsentt genom behandlande med ett reduceringsmedel, eller c) dehydrerar en en 1,2-mättad D-homosteroid with Formula I and 1, 2, or d) omsätter en D-homosteroid med Formeln IV V: J °. p17a IV R6 is undercut, in which case it is present in the reaction zone, or e) a D-homosteroid with form V (»3 v i6