IE49178B1 - Steroidal(16a,17a-b)tetrahydronaphthalenes and(16a,17a-d)cyclohexenes - Google Patents

Abstract

Steroids having the formula wherein X is hydrogen or halogen; Y is hydrogen, methyl or fluorine; R4 is chlorine, fluorine or hydroxy and R5 is hydrogen or R4 and R5 together are = O; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; R6 and R7 are the same or different and are hydrogen, alkyl, alkoxy, formyl, phenyl or cyano and in addition hydroxy, halogen carboalkoxy and alkylcarbonyl when R2 and R3 are separate with the proviso that when R6 and R7 are different, one of R6 and R7 is hydrogen; R8 is hydrogen or CHR9R10 wherein R9 and R10 are the same or different and are hydrogen or alkyl may be used as intermediates in preparing compounds having antiinflammatory activity. The invention extends to acetals of the 21-aldehydes.

Description

The invention provides steroids having the formula and esters thereof which are useful as topical antiinflammatory agents. In formula I, and throughout the specification, the symbols are as defined below: X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; is chlorine, fluorine or hydroxy and Rg is hydrogen or R4 and Rg together are =0; R2 and R3 are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached, form a benzene ring; R, and R- are the same or different and are 67 2 hydrogen, alkyl, alkoxy, formyl, alkyl-C-Ο-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R2 and Rg are separate with the proviso that when R. and R-, are different, o / one of Rg and R^ is hydrogen; Rg is hydrogen or-CH RqR^q wherein Rg and R^q are the same or different and are hydrogen or alkyl; and ( - 3 the dotted line in the 1,2-position represents the optional presence of ethylenic unsaturation.

The terms alkyl and alkoxy, as used throughout the specification (unless otherwise defined), refer to both straight and branched chain groups having 1 to 6 carbon atoms.

The term aryl, as used throughout the specification, refers to phenyl or phenyl substituted with one or more halogen, alkyl and alkoxy groups.

The term halogen, as used throughout the specification, refers to fluorine, chlorine, bromine and iodine.

The esters contemplated are the C^-ϋ^θ alkyl, aryl and aralkyl esters.

The steroids of formula I can be prepared from the corresponding 21-hydroxy-steroidal[16a, 17-b]cycloalkenes having the structural formula II wherein the symbols are as previously defined. The steroids of formula II are generally known in the art; see, for example, United States patents 3,927,720 issued February 10, 1976; 3,994,935 issued November 30, 1976 and 3,944,584 issued March 16, 1976.

A steroid of formula II can be oxidized to the corresponding aldehyde having the formula III using a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.

If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula III, the corresponding steroidal-21-acetal formed with the alcohol solvent (R^-OH); i.e., a steroid having the formula The oxidation reaction will generally be completed within a relatively short period of time, i.e., about 1 hour.

If the above-described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20hydroxy-21-carboxylic acid ester having the formula If water is present as a co-solvent in the oxidation reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20hydroxy-21-carboxylic acid ester of formula V, the corresponding 20-hydroxy-21-carboxylic acid will be of the 20a- and 205-hydroxysteroids. Reacting a steroid of formulas III or IV or a mixture thereof in an inert solvent with an inorganic cyanide catalyst, an oxidizing agent, an alcohol and an organic acid yields the product of formula I. More specifically, a product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula III or the corresponding steroidal-21-acetal of formula IV or a mixture thereof with a mixture of (i) an inorganic r cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); (ii) an oxidizing agent, e.g., a heavy metal oxide such as activated manganese dioxide or lead dioxide, (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) a primary or secondary alcohol, R£-OH (throughout the specification R£ is any primary or secondary R^ group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction The 20 a- and 20β-hydroxysteroids of formulas V and VI can be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas 48178 Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20a- and 206-hydroxysteroids being oxidized have an HS-hydroxy substituent, the products of formulas I and VIII will be mixtures of llfi-hydroxy and 11keto steroids.

The intermediates of formulae III, IV, V and VI are novel and form a part of the invention. The esters of formula I can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula VIII.

(A steroid of formula VIII can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic acid ester of formula I.) Still another route for the preparation of the products of formula I wherein is a non-tertiary alkyl group of 1 to 10 carbon atoms or aryl is the transesterification of another' ester of formula I.

The starting steroid is reacted with the appropirate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide) or, preferably, a source of cyanide ion (e.g., an alkali metal cyanide such as sodium cynaide or potassium cyanide to yield the transesterification product.

The steroids of formula I are useful topical antiinflammatory agents which can be used in lieu of known glucocorticoids in the treatment of conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema and anogenital pruritus. The steroids may be administered in a conventional cream, ointment, lotion, or spray in the range of 0.01 to 5.0% by weight, preferably 0.025 to 2.0% by weight.

In an alternative process, steroids of the formula 10 I can be prepared from the corresponding 21-hydroxyΔ16 steroids having the formula Y by first converting the 21-hydroxy group to a 2120 carboxylic acid group and then fusing the cyclohexene and tetrahydronaphthalene groups in the 16,17position.

The 21-hydroxy-i1^-steroids of formula IX, which form the starting point for the alternate process, or the corresponding 21-acyloxy steroids, are known in the art. The 21-acyloxy steroids are readily converted to the corresponding 21-hydroxy steroids using conventional techniques.

A steroid of formula IX can be oxidized to the corresponding aldehyde having the formula 48178 HC=O using oxygen (or air) and a catalyst such as copper acetate. The reaction can be run in an alcohol solvent.

If the above described oxidation reaction is carried out in the presence of oxygen (e.g., by bubbling air through the reaction mixture), the reaction will generally yield, in addition to a steroidal-21-aldehyde of formula X, the corresponding steroidal-21-acetal formed with the alcohol solvent (R^-OH); i.e., a steroid having the formula I Y The oxidation reaction will generally be completed within a relatively short period of time, i.e., about 1 hour.

If the above described reaction is allowed to proceed for an extended period of time, e.g., more than about 24 hours, the major product will be the 20-hydroxy-21-carboxylic acid ester having the formula ( -ΙΟ- Υ If water is present as a co-solvent in the oxidation 10 reaction, and the reaction is allowed to proceed for an extended period of time, in addition to the 20hydroxy-21-carboxylic acid ester of formula XI, the corresponding 20-hydroxy-21-carboxylic ^cid vijl ke produced; i.e., a steroid having the formula The steroids of formulas XII and XIII exist as mixtures of the 20a- and 20B-hydroxy-steroids.

Reacting a steroid of formulas X or XI or a mixture thereof in an inert solvent with an inorganic cyanide catalyst, an oxidizing agent, an alcohol and an organic acid yields the product of formula I. A product of formula I can be obtained by reacting a steroidal-21-aldehyde of formula X or the corresponding steroidal-21-acetal of formula XI or a mixture thereof with a mixture of (i)an inorganic cyanide catalyst (e.g., an alkali metal cyanide such as potassium cyanide); (ii) an oxidizing agent, e.g., a heavy metal oxide such as - 11 activated manganese dioxide or lead dioxide; (iii) an inert solvent, e.g., a halogenated hydrocarbon solvent such as dichloromethane or chloroform; (iv) I a primary or secondary alcohol, R^-OH (throughout the specification Rj is any nontertiary group); and (v) an acid, e.g., acetic acid, which serves to neutralize the alkali cyanide catalyst. The products of the above reaction have the formula Y The 20a- and 20B-hydroxysteroids of formulas Xll and XIIIcan be oxidized to obtain the corresponding 20-ketosteroids, having the respective formulas XVI ι Y Exemplary of suitable oxidizing agents are manganese dioxide and chromium dioxide. In the instance wherein the 20a- and 20f?-hydroxysteroids being oxidized have an 11β-hydroxy substituent, the steroids of formulas XV and XVI will be mixtures of Ιΐβ-hydroxy and 11-β keto steroids.

The intermediates of formula XV can also be prepared by esterification of the corresponding steroidal-21-oic acid of formula XVI. (A steroid of formula XVI can be prepared as described above, or alternatively, by saponification of a corresponding steroidal-21-oic acid ester of formula XV).

Still another route for the preparation of the intermediates of formula XV wherein is a non15 tertiary group is the transesterification of another ester of formula XIV or XV. The starting steroid is reacted with the appropriate alcohol in the presence of a basic alkoxide (e.g., sodium ethoxide or aluminum isopropoxide), or preferably, a source of cyanide ion (e.g., an alkali metal cyanide such as sodium cyanide or potassium cyanide) to yield the transesterification product.

A steroid of formulas XIV, XV or XVI can be converted to the corresponding product of formula I by reacting it with a benzocyclobutene having the formula XVII R.

R, 48178 - 13 or with a butadiene having the fonnula R.,HC= C-C= CHR XVIII 7 I I 6K2 K3 using the Diels-Alder reaction.

In the case of the XVII reactant, the reaction can be run neat or in an inert solvent, e.g., odichlorobenzene or diethylbenzene. Preferably the reaction will be run neat, in an inert atmosphere, at temperatures up to the boiling point of the solution.

A free radical inhibitor may be added to the mixture.

In the case of the XVIII reactant, the preferred catalysts for the reaction are anhydrous aluminum chloride and anhydrous aluminum bromide. The reaction can be run in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane. The above described Diels-Alder reaction is highly selective and takes place exclusively at the double bond in the 1 4 16-position, even in the presence of the Δ ' -3-ketofunction. In those instances wherein the butadiene is unstable in the presence of a Lewis acid catalyst, the Diels-Alder reaction is run in the presence of a free radical inhibitor at elevated temperatures.

If the steroid of formula XIV, XV or XVI contains an 110-hydroxy group, it is desirable to first protect the group before running the Diels-Alder reaction. While many means of protecting the 11-functional group will be apparent to a person skilled in the steroid art, one particularly desirable method is the acylation of the group. The acylation reaction can be run using an acid anhydride, e.g., acetic anhydride in the presence of a Lewis catalyst, e.g., boron trifluoride etherate. After the Diels-Alder reaction has been run, the protective group can be removed using a conventional technique. 48178 - 14 Example 1 9-Fluoro-1',2'3'4'-tetrahydro-llp-hydroxy-3,20dioxopregna-1,4-dieno[16a,17-b]naphthalen -21-oic acid, methyl ester 5 9-Fluoro-l',2',3',4'-tetrahydro-ΙΙβ,214 · dihydroxy pregna -1,4-dieno[16a,17-b]naphthaleqe* 3,20-dione (1.0 g) is dissolved in anhydrous methanol (170 ml) by warming and the solution is cooled to room temperature. Cupric acetate 1° hydrate (250 mg) is added and under stirring, 4 slow stream of air is passed into the solution. Within 10 minutes, the starting steroid disappears to give essentially a single less polar material, as judged by thin-layer chromatography (TLC).

The methanol is mostly evaporated in vacuo at room temperature; some steroid precipitates out. The concentrate is diluted with water and extracted with chloroform. The chloroform solution is washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to leave 0.98 g of 9-fluoro-1',2',3',4'-tetrahydro-llp-hydroxypregna-1,4-dieno[16a,17-b] naphthalene-21-al-3,20-dione. This material shows a single spot on TLC (chloroform-methanol, 93:7; silica gel) and an IR spectrum consistent with the structure. However, the NMR spectrum shows that it is contaminated with a small amount of the corresponding 21-dimethyl acetal. - 15 A mixture of the impure aldehyde (950 mg), anhydrous methanol (50 ml), dry dichloromethane (50 ml), glacial acetic acid (0.9 ml), potassium cyanide (200 mg) and active manganese dioxide (2.1 g) is stirred at room temperature for 10 hours. It is then filtered through a bed of diatomaceous earth. The cake is resuspended in chloroform which is refluxed and filtered again. The filtrates are combined, washed with a dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 0.86 g of a solid. This is dissolved in a mixture of dichloromethane and methanol. The dichloromethane is removed under reflux to precipitate 675 mg of a solid. This is again subjected to purification as above to afford 630 mg of the title compound, melting point 319-321°C (dec., discoloration starts from about 260°C) with consistent spectral data.

Anal. Calc'd for CggHggFOg: C, 73.15; H, 6.75; F, 3.86 Found: C, 72.85; H, 6.95; F, 3.65 Example 2 9-Fluoro-l1,2',3',41-tetrahydro-lip-hydroxy-3,20dioxopregna-l, 4-dieno[16tt, 17-bjnaphthalen-21-oic acid, isopropyl ester A suspension of 9-fluoro-l,,2',3,,4'tetrahydro-110-hydroxy-3,20-dioxopregna-l,449178 - 16 10 dieno[16α,17-b]naphthalen-21-oic acid, methyl ester (490 mg., see Example 1) in dry isopropanol (30 ml, freshly distilled from magnesium turnings) containing sodium cyanide (10 mg) is refluxed under an atmosphere of nitrogen for 20 minutes when a clear solution results. A TLC examination at this point shows complete conversion of the starting steroid into a less polar compound. The mixture is then evaporated in vacuo, the residue is dissolved in chloroform, washed with dilute brine and water, dried over anhydrous magnesium sulfate and evaporated to afford 516 mg of the title compound. One crystallization from ethyl acetate affords the analytical specimen of the title compound as colorless needles (410 mg), melting point 269-271°C (dec., discoloration 0 starts from about 250 C) with consistent spectral data.

Anal. Calc'd for C3. H-^PO_: C, 73.82; - 32375 H, 7.16; F, 3.65 Found: C, 73.45; H, 7.11; F, 3.47 Example 3 9-Fluoro-l',2',3',4'-tetrahydro-Ιΐβ-hydroxy -3,20dioxopregna-1,4-dieno[16a,17-b]naphthalen-21-oic acid, n-butyl ester 9-Fluoro-l',2',3',41-tetrahydro-11β,21dihydroxypregna-1,4-dieno[16a,17-b]naphthalene3,20-dione (800 mg) is dissolved in n-butanol - 49178 - 17 (150 ml) by warming. The solution is- cooled to room temperature, cooper acetate hydrate (250 mg) is added and air is bubbled into the solution with sitrring for 30 minutes. Most of the n-butanol is then removed by evaporation in vacuo at 40-42°C. The concentrate is diluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute ammonium chloride solution and water, dried over anhydrous magnesium sulfate and evaporated to afford 850 mg of 9-fluoro-l',21,3’,4'-tetrahydro-lip-hydroxypregna-l,4dieno[16a,17-b]naphthalene-2l-a1-3,20-dione.

(This material is characterized spectroscopically. A TLC examination shows the presence of one major compound, traces of starting material and traces of another impurity, less polar than the starting material, and believed to be 9-fluoro1',2',3',4'-tetrahydro-110-hydroxy-21,21-di-nbutoxy-pregna-1,4-dienoI16a,17-b]naphthalene-3,20dione) .

The above crude mixture (840 mg) is dissolved in a mixture of dry n-butanol (20 ml) and dichloromethane (50 ml). Acetic acid (0.8 ml), potassium cyanide (200 mg)and active manganese dioxide (2.0 g) are added and the mixture is stirred at room temperature for 60 hours. (A shorter reaction time would be adequate). The mixture is then filtered through a bed of diatomaceous earth. The solids are washed with chloroform, the filtrate and the washings are 4-9178 - 18 10 combined, washed with water, dried over anhydrous magnesium sulfate and evaporated to afford the crude product as a gum. From this the major component is isolated by preparative TLC (four, 2.0mm silica gel plates developed with chloroform-ethyl acetate 1:1) and identified as the title compound (487 mg). One crystallization from ethyl acetate gives 381 mg of the analytical specimen of the title compound, melting point 245-246°C with consistent spectral data.

Anal. Calc'd for CggHggFOg: C, 74.13; H, 7.35; F, 3.55 Found: C, 74.37; H, 7.41; F, 3.46 Example 4 9-Fluoro-l1,21,3',4'-tetrahydro-lig-hydroxy-3,20dioxopregna-l,4-dieno[16ot,17-b]naphthalen -21oic acid, t-butyl ester A) 9-Fluoro-l',2',3',41-tetrahydro-11β-hydroxy3, 20-dioxopregna-l,4-dieno[16«,17-b]naphthalen 21-oic acid A solution of O-fluoro-l'^'fS'^'tetrahydro-110-hydroxypregna-l,4-dieno[16a, 17-b)naphthalene-21-al-3,20-dione (3.0g, see Example 1) in a mixture of dichloromethane (150 ml) and tetrahydrofuran (150 ml) containing acetic acid (3.0 ml) and water (4.0 ml) is stirred with activated manganese dioxide (6.0g) and potassium cyanide (700 mg) for 20 hours. The mixture is ' 48178 - 19 then filtered and the solids are washed with warm chloroform-methanol (7:3). The filtrate and the washings are combined and evaporated in vacuo.

The residue is washed with water, dried, purified by chranatography, crystallized frcm methanol-chloroform to afford the title compound, melting point 280-281°C (dec.).

B) 9-Fluoro-l1,2',31,4'-tetrahydro-110-hydroxy3,20-dioxopregna-l,4-dieno[16a,17-b]naphthalene21-oic acid, t-butyl ester To a suspension of 9-fluoro-1',2’,3',4'tetrahydro-110-hydroxy-3,2 0-dioxopregna-1,4-dieno [16a,17-b]naphthalen -21-oic acid (325 mg.) in dry dioxane (60 ml) containing sulfuric acidphosphoric acid catalyst (0.4 ml.; prepared by the addition of the calculated amount of phosphorous pentoxide to 96% sulfuric acid to react with all of the water) in a pressure reaction vessel is passed a stream of isobutylene (until about 6 ml is added). The reaction vessel is closed and maintained at ambient temperature for 30 hours with stirring. The mixture is poured into a solution of sodium acetate hydrate (5.0g) in water (500 ml) and extracted successively with chloroform and ethyl acetate. The extracts are washed with brine, combined, dried over anhydrous magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel to afford 145 mg. of the title compound, melting point 293-296°C (dec., discoloration starts from about 275eC) after crystallization from acetonehexane. * 49178 - 20 Example 5 9-Fluoro-l',2',31,4'-tetrahydro-llg-hydroxy-3, -dioxopregna-l,4-dieno[16a,17-b]naphthalen-21 oic acid, 2,2-dimethylpropyl ester A solution of 9-fluoro-l',2,,3,,4'tetrahydro-llg-hydroxy-3,20-dioxopregna-l,4dieno[16a,17-b]naphthalene-21-oic acid, methyl ester in dry dioxane (20 ml, distilled over q sodium) and dry pyridine (15 ml) is refluxed with neopentyl alcohol (2.2 g) and sodium cyanide (100 mg) under a nitrogen atmosphere for 18 hours. The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform. The chloroform solution is washed with dilute sodium chloride solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (9:1) and θ chromatographed on a 35 g-silica gel column. Elution with chloroform-hexane (9:1) gives 540 mg of material. Crystallization from acetone-hexane gives 460 mg of an analytical specimen of the title compound, melting point 329-331°C (dec.). Anal. Calc'd for C^H^FOg! C, 74.42; H, 7.53; F, 3.46. Found: C, 74.39; H, 7.73;. F, 3.37. - 21 Example 6 9-Fluoro-lip-hydroxy-3,20-dioxopregna-l,4-dieno[16«,17-d3cyclohexen-21-oic acid, methyl ester A solution of 1.2 g of 9-fluoro-110,21dihydroxypregna-1,4-dieno[16a, 17-d]cyclohexene3, 20-dione and 300 mg of copper acetate in 150 I ml of methanol is stirred at room temperature for 1 hour while a stream of air is bubbled through the solution. The solvent is evaporated in vacuo at 30°C. The residue is diluted with water and extracted with chloroform, and then, ethyl acetate. The chloroform solution and ethyl acetate solution are washed with aqueous ammonium chloride solution (10%) and water, dried over anhydrous sodium sulfate, evaporated in vacuo and combined to give 1.3 g of a solid. The NMR spectrum of the solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-dimethylacetal derivatives of the starting steroid.

The solid product of the above reaction (1.3 g) is stirred in a mixture of 50 ml dry methanol and 50 ml dry dichloromethane at room temperature for about 16 hours with activated manganese dioxide (2.0g), glacial acetic acid (1.0 ml) and potassium cyanide (200 mg). The suspension is filtered through a bed of Hyflo and washed with chloroform.

The filtrate and washings are combined, washed with water and dried over anhydrous magnesium sulfate.

The solvent is evaporated in vacuo to give 1.1 g of a solid. This is dissolved in chloroform and chromatographed on a 35 g-silica gel column.

Elution with chloroform gives 930 mg of material. 48178 - 22 Crystallization from acetone-hexane gives 650 mg of the title compound, melting point 256-258°C, with consistent spectra data.

Analysis Calc'd for C28H3iF°5: C, 70.57, H, 7.06; F, 4.29 Found: C, 70.66; H, 7.11; F, 4.02 Example 7 9-Fluoro-llp-hydroxy-3,20-dioxopregna-l,4-dieno[16a,17-d]cyclohexen-21-oic acid, isopropyl ester A solution of 480 mg of 9-fluoro-lip15 hydroxy-3,20-dioxopregna-l,4-dieno[16a,17-d] cyclohexen-21-oic acid, methyl ester (see Example 1) and 85 mg of sodium cyanide in 65 ml of dry isopropyl alcohol is stirred under a nitrogen atmosphere at 100°C for about 16 hours.

The resulting solution is evaporated in vacuo and the residue is dissolved in chloroform and washed with 25 ml of water. The aqueous layer is saturated with sodium chloride and extracted with chloroform. The chloroform solutions are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in chloroform-hexane (7:3) and chromatographed on a 25 g-silica gel column.

Elution with chloroform-hexane (7:3)gives 370 mg 2q of material. Crystallization from acetonehexane gives 300 mg of the title compound, melting 48178 - 23 point 226-228°C, with consistent spectral data.

Analysis calc'd. for C28H35FO5- C, 71.46? H, 7.50; F, 4.04 Found; C, 71.47; H, 7.44; F, 3.82 Example 8 9-Fluoro-lip-hydroxy-3,20-dioxopregna-l,4-dienoH6ct,17-d]cyclohexen-21-oic acid, n-butyl ester A mixture of 1.0 g of 9-fluoro-ΙΙβ,21dihydroxypregna-1,4-dieno[16α,17-d]eyeIohexene3, 20-dione and 250 mg of copper acetate in 50 ml of dichloromethane and 30 ml of n-butanol is stirred at room temperature for 1 hour while a slow stream of air is bubbled through the solution. Since the rate of oxidation is extremely slow, the dichloromethane is evaporated and replaced with 50 ml of n-butanol. Another 200 mg of copper acetate is added and the reaction is continued for 1.5 hour when the starting material disappears. The solvent is then evaporated in vacuo at 35-40°C and the residue is diluted with 200 ml of water and extracted with dichloromethane, and then ethyl acetate. The dichloromethane solution and ethyl acetate solution are washed with ammonium chloride solution (10%) and water, combined, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.2 g of solid. The NMR spectrum of the - 24 solid shows that it is an approximately equimolar mixture of the 21-aldehyde and 21-di-n-butylacetal derivatives of the starting steroid.

The solid product of the above reaction 5 (1.2 g) is dissolved in 50 ml of dry dichloromethane and 30 ml of dry n-butanol and stirred at room temperature for about 16 hours with 2.0 g of activated manganese dioxide, 1.0 ml of glacial acetic acid and 200 mg of potassium cyanide. A dry calcium chloride tube is attached to the flask to avoid contact with moisture.

After 20 hours another 2.0 g of activated manganese dioxide and 200 mg of potassium cyanide are added. The suspension is stirred at room temperature for 7 hours, filtered through a bed of Hyflo, and washed thoroughly with dichloromethane. The filtrate and washings are combined and washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo. The title compound in the residue cannot be successfully separated from impurities on precoated silica gel TLC plate. It can, however, be successfully purified on E. Merck precoated silica gel TLC plate (2 mm, 2.5:97.5 methanol-chloroform) to give 400 mg of a foam. Crystallization from ethyl acetate-hexane gives 330 mg of the title compound, melting point 203-209°C, with consistent spectra data. 48178 Analysis calc'd for C^gH^FC^: c, 71.87; H, 7.70; F, 3.92 Found: c, 71.98 H, 7.73 F, 3.62 Example 9 9-Fluoro-llB-hydroxy-l1,2'-dimethyl-3,20dioxopregna-l, 4-dieno [16α, 17-d]cyclohexen-21oic acid, methyl ester A solution of 4.9 g of 9-fluoro-lip,21dihydroxy-1',2'-dimethyl-3,20-dioxopregna-l,4dieno[16a,17-d] cyclohexene and 1.1 g of copper acetate in 800 ml of methanol is reacted with air following the procedure described in Example 1 (first paragraph) to yield 5.0 g of an approximately equimolar mixture of the 21aldehyde and 21-dimethylacetal derivatives of the starting steroid.

The solid product of the above reaction (4.5 g) is stirred in a mixture of 250 ml dry methanol and 250 ml dry dichloromethane at room temperature for about 16 hours under a nitrogen atmosphere with activated manganese dioxide (7.0 g), glacial acetic acid (4.0 ml) and potassium cyanide (700 mg). The resulting suspension is filtered through a bed of diatomaceous earth and washed with chloroform-methanol (9:1).

The filtrate and washings are combined and evaporated in vacuo to give 5.6 g of a solid.

This is dissolved in chloroform-hexane (9:1) and chromatographed on a 100 g silica gel column. Elution with chloroform-hexane (9:1) yields 4.2 g of material, 1.5 g of which is crystallized from acetone-hexane to give 900 mg of an analytical specimen of the title compound, melting point 256-258°C.

Analysis Calc'd for C28H35^°5: c, 71.46; H, 7.50; F, 4.04 Found; c, 71.38; H, 7.50; F, 3.95 Example 10 9-Fluoro-11β-hydroxy-1',21-dimethyl-3,20-dioxopregna-l , 4-dieno [16a, 17-d] cyclohexen-21-oic acid, ethyl ester A) 9-Fluoro-llp-hydroxy-l' ,2'-dimethyl-3,20dioxopregna,1,4-dieno[16a,17-d]cyclohexen-21oic acid A solution of 9-fluoro-Ιΐβ-hydroxy-l',2', dimethy1-3,20-dioxopregna-l,4-dieno[16a,17-d] cyclohexen-21-oic acid, methyl ester (2.5 g) in a mixture of methanol (110 ml) and tetrahydrofuran (200 ml) is stirred with a solution of potassium hydroxide (640 mg) in water (10 ml) for 1.0 hour under a nitrogen atmosphere. The reaction mixture is then acidified with 5% hydrochloric acid and is evaporated in vacuo. The resulting slurry is mixed with water and filtered to afford 700 mg of the title compound, melting point 234-238°C.

The filtrate is evaporated in vacuo and washed with chloroform-methanol (4:1). The solvents are evaporated to afford 1.4 g of the hydrated form of the title compound, melting point 215240°C. • 49178 - 27 B) g-Fluoro-llg-hydroxy-l1,2'-dimethyl-3,20dioxopregna-1,4-dieno[16α,17-d] cyclohexen-21oic acid, ethyl ester To a suspension of 235 mg of 9-fluoro-liphydroxy-1',2'-dimethy1-3,20-dioxopregna-1,4-dieno [16a,17-d]cyclohexen-21-oic acid in 5.0 ml of dry dichloromethane is added successively, 0.5 ml of triethylamine and 0.068 ml of pivaloyl chloride. After the resulting solution is stirred at room temperature for 15 minutes, 0.116 ml of absolute ethanol is added. After 3.0 hours, the mixture is acidified with 50% hydrochloric acid, poured into water and extracted with chloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and evaporated.

The residue is subjected to preparative thinlayer chromatography to isolate 97 mg of the title compound, melting point 198-200°C.

Example 11 9-Fluoro-lip-hydroxy-l',21-dimethyl-3,20-dioxopregna-l, 4-dieno [16a,17-d]cyclohexen-21-oic acid, t-butyl ester A solution of 700 mg of 9-fluoro-llphydroxy-1',2'-dimethyl-3,20-dioxopregna-l,4-dieno [16a,17-d]cyclohexen-21-oic-acid (see Example 10A) in 60.ml of dry dioxane containing 12 ml of isobutylene and 0.7 ml of a sulfuric acid/ phosphoric acid catalyst (prepared by adding phosphorous pentoxide to 96% sulfuric acid) is maintained in a pressure reaction vessel at room - 28 temperature for 24 hours. A stream of dry nitrogen is then passed through the solution to remove the excess isobutylene and the mixture is poured into a saturated sodium bicarbonate solution. The steroid is isolated by extraction with chloroform and the chloroform solution is washed with water, dried over anhydrous magnesium sulfate and the solvents are evaporated. The residue (760 mg) is subjected to chromatography on a column of silica gel to isolate 500 mg of the title compound, melting pount 209-210°C after crystallization from acetone-hexane.

Example 12 9-Fluoro-116-hydroxy-3,20-dioxopregna-l,4-dieno15 [16a,17-d]cyclohexen-21-oic acid, 2,2-dimethylpropyl ester A solution of 0-fluoro-lip-hydroxy-3,20dioxopregna-l , 4-dieno-[16a,17-d]cyclohexen-21oic acid, methyl ester (25 mg) in dry dioxane (2.0 ml) containing dry neopentyl alcohol (400 mg) and sodium cyanide (5.0 mg) is refluxed under anhydrous conditions for 2.0 hours. The mixture is then cooled, added to water, and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous magnesium sulfate, evaporated and the residue is crystallized from ethyl acetate-chloroform to afford 23 mg. of the title compound, melting point 288°C (dec., discoloration starts before melting point). 48178 - 29 Example I3 9-Fluoro-l',2',3',4 '-tetrahydro-118-hydroxy-3,20dioxopregna-l ,4-dieno[16a,17-b]naphthalen -21-oic acid,methyl ester A) 9-Fluoro-llB-hydroxy-3,20-dioxopregna-l,4,16triene-21-carboxaldehyde and 9-fluoro-llBhydroxy-21-dimethoxypregna-l,4,16-triene-3, -dione A solution of 9-fluoro-llB,21-dihydroxypregna1,4,16-triene-3,20-dione (1.7g) is dissolved in methanol (300ml) by warming and the solution is cooled to room temperature. Copper acetate (lOOmg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated in vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to afford an essentially equimolar mixture (1.9g) of the title aldehyde (as its hydrate) and the title acetal as indicated by the NMR spectrum. When dried in vacuo (125-130°C, 0.5mm of Hg) for 2.0 hours, this material is converted into an essentailly equimolar mixture (1.77g) of the title aldehyde and acetal as shown by NMR and IR spectra. - 49178 -30B) 9-Fluoro-l I H-hydroxy-3,20-dioxopregna-l, 4 , 16-trien - 21-oic acid, methyl ester To a stirred solution of the mixture of 5 aldehyde and acetal prepared in part A (1.75g), in a mixture of anhydrous dichloromethane (100ml) and anhydrous methanol (20ml) is added successively activated manganese dioxide (4.0g), potassium cyanide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichloromethane) yields 1.4g of the title compound, melting point 284-286°C.

C) 9-Fluoro-l1,21,31,41-tetrahydro-11B-hydroxy20- dioxopregna-l,4-dieno[16n,17-b]naphthalen 21- oic acid, methyl -ester A solution of 9-fluoro-HB-hydroxy-3, -dioxopregna-l,4,16-trien- 21-oic acid, 48178 - 31 methyl ester (lOOmg) in benzocyclobutene (5.0ml) containing 4,4'-thiobis-6-t-butylm-cresol (6.0mg) is refluxed under an atmosphere of nitrogen for 10 hours; a solid separates from the solution. The unreacted benzocyclobutene is recovered by vacuum distillation and the pot residue is crystallized from methanol-dichloromethane (by evaporative removal of the dichloromethane) to yield the title compound, melting point 325-326°C (discoloration starts from about 295°C).

Example 14 9-Fluoro-llg-hydroxy-3,20-dioxopregna-l,4,16trien -21-oic acid A solution of 9-fluoro-llg-hydroxy-3,20dioxopregna-l, 4,16-trien -21-oic acid, methyl ester (lOOmg; see Example IB) in a mixture of methanol (15ml) and tetrahydrofuran (15ml) is stirred with 3M sodium hydroxide (1.0ml) under a nitrogen atmosphere for 2.0 hours. The mixture is then acidified with 5% hydrochloric acid and evaporated to a residue. The residue is washed with water and crystallized frcm chloroformmethanol to yield the title compound. This material turns black when heated to 400°C, but does not melt.

The steroid of this Example can be esterified using conventional techniques and then reacted with a benzocyclobutene as described in Example 13C to-yield a product of formula X. - 32 Example 15 t 9-Fluoro-llg-hydroxy-l , 21-dimethyl-3,20-dioxopregna-l ,4-dieno[16a, 17-d]cyclohexen -21-oic acid, n-butyl ester A) 9-Fluoro-llB-hydroxy-3,20-dioxopreqna-l,4,16triene-21-carboxaldehyde and 9-fluoro-llBhydroxy-21-dimethoxypregpa-l,4,16-triene-3 , -dione A solution of 9-fluoro-llB,21-dihydroxypregna 1,4,16-triene-3,20-dione (1.7g) is dissolved in methanol (300ml) by warming and the solution is cooled to room temperature. Copper acetate (lOOmg) is added and a stream of air is passed into the solution under stirring. In about 20 minutes the starting material disappears to give less polar compounds as indicated by thin layer chromatography. The solution is then evaporated in vacuo, the residual solid is washed successively with a dilute ammonium chloride solution and water and is dried to afford an essentially equimolar mixture (1.9g) of the title aldehyde (as its hydrate) and the title acetal as indicated by the NI1R spectrum. When dried in vacuo (125-130°C, 0.5mm of Hg) for 2.0 hours, this material is converted into an essentially equimolar mixture (1.77g) of the title aldehyde and acetal as shown by NMR and IR spectra. - 33 B) 9-Fluoro-llB-hydroxy-3,20-dioxopregna-l,4, 16-trien -21-oic acid, methyl ester To a stirred solution of the mixture of aldehyde and acetal prepared in part A, in a mixture of anhydrous dichloromethane (100ml) and anhydrous methanol (20ml) is added successively activated manganese dioxide (4.0g), potassium cyanide (500mg) and glacial acetic acid (0.5ml). In less than 1.0 hour, the starting materials disappear to give essentially a single less polar compound as indicated by thin layer chromatography. The reaction mixture is filtered through a bed of diatomaceous earth and the filter cake is washed with several small portions of a warm mixture of dichloromethane-methanol. The filtrate and the washings are combined and evaporated to a solid residue which is washed with water and dried. Crystallization of the resulting material from methanol-dichloromethane (with evaporative removal of dichloromethane) yields 1.4g of the title compound, melting point 284-286°C.

C) llg- (Acetyloxy)-9-fIuoro-3,20-dioxopregna1,4,16-trien - 21-oic acid, methyl ester A solution of 9-fluoro-llB-hydroxy-3,20dioxopregna-l, 4, 16-trien -21-oic acid, methyl ester (400mg) in a mixture of glacial acetic acid (9.0ml) and acetic anhydride (9.0ml) containing p-toluenesulfonic acid (200mg) is stirred at room temperature for 24 hours. Sodium acetate (300mg) is added and the mixture is poured into ice water (200ml) with stirring.

The solid that separates is isolated by filtration, washed with water and dried to yield 400mg of the title compound that is contaminated with only trace amount impurities as judged by thin layer chromatography. Crystallization of this material from ethyl acetate-hexane yields 350mg of the title compound, melting point 235-236°C.

D) 11B-(Acetyloxy)-9-fluoro-1', 21-dimethyl-3,20dioxopregna-l, 4-dieno-[16 a, 17-d]cyclohexen-21oic acid, methyl ester To a stirred solution of 11B~(acetyloxy)-9fluoro-3,20-dioxopregna-l,4,16-trien - 21-oic acid, methyl ester (320mg) in anhydrous dichloromethane (25ml) containing aluminum chloride (lOOmg) is added 2,3-dimethyl-l,3-butadiene (0.25ml).

The mixture is stirred at room temperature for 1.5 hour, poured into water and extracted with dichloromethane. The dichloromethane extract is washed with water, dried over anhydrous magnesium sulfate and evaporated to a residue (300mg). This is subjected to chromatography on a column of silica gel (lOg) to isolate the title compound (265mg). Crystallization from ethyl acetate-hexane gives needles (160mg), melting point 172-173°C. - 35 E) 9-Fluoro-llB-hydroxy-l',2'-dimethyl-3,20dioxopregna-l ,4-dieno[16a,17-d]cyclohexen21-oic acid A solution of 116-(acetyloxy)-9-fluoro-1', 21-dimethy1-3,20-dioxopregna-l,4-dieno[16a,17-d] cyclohexen-21-oio acid, methyl ester (235mg) in a mixture of 90% methanol (100ml) and tetrahydrofuran (10ml) containing 3M sodium hydroxide (2.0ml) is stirred under an atmosphere of nitrogen in a bath at 60-70°C for 2-3 hours. The mixture is acidified with the minimum amount of 5% hydrochloric acid and evaporated in vacuo. The residue is worked up with water and dried to yield 195mg of the title compound. Crystallization from a mixture of chloroform-methanol gives the analytical specimen of the title compound, melting point 236-239 C.

F) 9-Fluoro-llB-hydroxy-l',2'-dimethy1-3,20dioxopregna-1,4-dieno[16a,17-d]cyclohexen21-oic acid, n-butyl ester.

To a solution of 9-fluoro-llB-hydroxy-l', 2'-dimethyl-3,20-dioxopregna-l,4-dieno[16a,17-d] cyclohexen-21-oic acid (175mg) in dichloromethane (40ml) containing a few drops of methanol is added an excess of an ethereal solution of diazobutane. After 5 minutes, the excess diasobutane is destroyed by the addition of a few drops of acetic acid.

The solution is evaporated to dryness and the residue is crystallized from acetone-hexane to yield 127mg of the title compound melting point 209-211°C. - 36 Example 16 9-Fluoro-l', 2 1,3', 4 '-tetrahydro-11g-hydroxy-3,20-dioxopregna-1,4-dieno[16 a,17-b]naphthalen-21-oic acid, n-octyl ester A solution of 500 mg (0.96 mmole) of 9fluoro-1',2',3',4'-tetrahydro-11p-hydroxy-3,20-dioxopregna 1,4-dieno[16a,17-b]naphthalen-21-oic acid, isopropyl ester and 40 mg of sodium cyanide in 40 ml of dry n-octanol (distilled over calcium hydride) was stirred at 130° under nitrogen atmosphere for 1.5 hour. The resulting solution was evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over anhydrous Na^O^ and evaporated in vacuo to give a residue which was dissolved in chloroform-hexane (7:3) and chromatographed on a 20g silica gel column. Elution with chloroform-hexane (7:3) gave 485 mg (97%) of product. Crystallization from acetone-hexane gave 370 mg (74%) of product, m.p. 215-216°.

Anal. Caled. for C.-,Η ._,F0_ : - 37 47 5 Found: C, 75.22; H,8.02 F, 3.22 C,75.34; H,8.23; F,3.21

Claims (23)

1. and esters thereof, or the 1,2-dehydro derivative 5 thereof, wherein X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or hydroxy and Rg is hydrogen or R^ and Rg together are =0; R 2 and Rg are the same or different and are hydrogen, alkyl or aryl, or taken together 10 with the double bond to which they are attached, form a benzene ring; R, and R-, are the same or different D / Q and are hydrogen, alkyl, alkoxy, formyl, alkyl-C-0-, phenyl or cyano and in addition hydroxy, halogen, carboalkoxy and alkylcarbonyl when Rg and Rg are 15 separate with the proviso that when Rg and Ry are different, one of Rg and Ry is hydrogen; R g is hydrogen or -CH R g R^ 0 wherein Rg and R-^θ are the same or different and are hydrogen or alkyl.

2. A steroid according to claim 1 having the 20 formula 4 917 8 - 38 or the 1,2-dehydro derivative thereof, wherein R^ is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl.

3. A steroid according to claim 1 having the formula or the 1,2-dehydro derivative thereof, wherein R^ is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or hydroxy and Rg 10 ίθ hydrogen or R^ and Rg together are =0; R g and R ? are the same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-C-O- phenyl or cyano with the proviso that when Rg and are different, one of R g and R 7 is hydrogen; Rg is hydrogen or -CH RgR 1Q 15 wherein Rg and R^g are the same or different and are hydrogen or alkyl.

4. A steroid according to claim 1 having the formula * 49178 - 39 or the 1,2-dehydro derivative thereof, wherein Rg is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; R 2 and Rg are the same or different and are hydrogen, alkyl or aryl; is hydroxy and Rg is hydrogen . or together R 4 and Rg are =0; X is hydrogen or halogen; and Y is hydrogen, methyl or fluorine.

5. A steroid according to claim 1 having the or the 1,2-dehydro derivative thereof, wherein Rg is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; R 2 and Rg are the same or different and are hydrogen, alkyl or aryl; R 4 is hydroxy and Rg is hydrogen or together R 4 and Rg are =0; and Y is hydrogen, methyl or fluorine. 6. A steroid in accordance with claims 1 to 3 wherein X is fluorine, 7. A steroid in accordance with claims 1 to 6 wherein Y is hydrogen. 8. A steroid in accordance with claims 1 to 7 wherein R 4 is hydroxy and Rg is hydrogen. 9. A steroid in accordance with claims 1 to 3 wherein R 6 and R? are hydrogen. 10. A steroid in accordance with claims 1 to 3 wherein R 8 is hydrogen. 11. A steroid in accordance with claims 1 to 3 wherein R 8 is methyl. - 40 12. The steroid in accordance with claims 1 to 3 having the name 9-fluoro-1',2',3 1 ,4'-tetrahydro-110hydroxy-3,20-dioxopregna-l,4-dieno[16α,17-b]naphthalen 21-oic acid, methyl ester. 5 13. The steroid in accordance with claims 1 to 3 having the name 9-fluoro-1',2 1 ,3',4'-tetrahydro-110hydroxy-3,20-dioxopregna-l,4-dieno[16a,17-b]naphthalen 21-oic acid, 1- isopropyl ester. 14. The steroid in accordance with claims 1 to 3

6. 10 having the name 9-fluoro-l',2',3',4'-tetrahydro-13-Shydroxy-3,20-dioxopregna-l,4-dieno[16α,17-b]naphthalen 21-oic acid, n-butyl ester.

7. 15. The steroid in accordance with claims 1 to 3 having the name 9-fluoro-1 1 ,2 1 ,3 1 ,4 1 -tetrabydro-llp15 hydroxy-3,2O-dioxopregna-1,4-dieno[16α ,17-b]naphthalen 21-oic acid, t-butyl ester.

8. 16. The steroid in accordance with claims 1 to 3 having the name 9-fluoro-1',2 1 ,3',4 1 -tetrahydro-110 hydroxy-3,20-dioxopregna-l,4-dieno[16α ,17-b]naphthalen· 20 21-oic acid, 2,2-dimethylpropyl ester.

9. 17. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-£luoro-110-hydroxy-3,20dioxopregna-l ,4-dieno[16a, 17-d]cyclohexen-21-oic acid, methyl ester. 25

10. 18. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-fluoro-110-hydroxy-3,20dioxopregna-l ,4-dieno[16a,17-d]cyclohexen-21-oic acid, isopropyl ester.

11. 19. The steroid in accordance with claims 1, 2, 30 4 and 5 having the name 9-fluoro-110-hydroxy-3,20dioxopregna-l , 4-dieno [16a,17-d]cyclohexen-21-oic acid, n-butyl ester.

12. 20. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-fluoro-110-hydroxy-l 1 ,2'35 dimethyl-3,20-dioxopregna-l,4-dieno[16α,17-d]cyclohexen-

13. 21-oic acid, methyl ester. 48178 - 41 21. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-fluoro-11β-hydroxy-l',2’dimethyl-3,20-dioxopregna-l,4-dieno[16a,17-dJ cyclohexen-21-oic acid, ethyl ester.

14. 22. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-fluoro-llg-hydroxy-3,20dioxopregna-l, 4-dieno [16a, 17-d] cyclohexen-21-oic acid, 2,2-dimethylpropyl ester.

15. 23. The steroid in accordance with claims 1, 2, 4 and 5 having the name 9-fluoro-llB-hydroxy-l 1 ,2'dimethyl-3,20-dioxopregna-l,4-dieno[16a,17-d]cyclohexen-21-oic acid, t-butyl ester.

16. 24. A steroid having the formula or the 1,2-dehydro derivative thereof, wherein X is hydrogen or halogen; Y is hydrogen;, fluorine or methyl; R 4 is chlorine, fluorine or hydroxy and is hydrogen or R 4 and R g together are =0; R 2 and R g are the same or different and are hydrogen, alkyl or aryl or taken together with the double bond to which they are attached form a benzene ring; Rg and R? are the same or differ^it and are hydrogen, alkyl, alkoxy, formyl, alkyl-C-O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R 2 and Rj are separate, with the proviso that when Rg and R^ are different, one of Rg and R? is hydrogen; Rg is hydrogen or -CH Kg R 10 wherein R g and R^g are the same of different and are hydrogen or alkyl. -4225. A steroid according to claim 24 having the formula or the 1,2-dehydro derivative thereof, wherein X is 5 hydrogen or halogen; Y is hydrogen, fluorine pp methyl; R 4 is chlorine, fluorine or hydroxy and Rg is hydrogen or R^ and Rg together are =0; Rg and R ? are the same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-C-O-, 10 phenyl or cyano with the proviso that when R g and R^ are different, one of Rg and R ? is hydrogen; Rg is hydrogen or -CH RgR^g wherein Rg and R 1Q are the same or different and are hydrogen or alkyl.

17. 26. A steroid according to claim 24 having the 15 formula Y 4SI 78 - 43 27. A steroid according to claim 24 having the formula or the 1,2-dehydro derivative thereof, wherein R^ is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Ύ is hydrogen, fluorine or methyl; R 4 is chlorine, fluorine or hydroxy and Rg is hydrogen 10 or and Rg together are =0; R 2 and Rg are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached form a benzene ring; R, and R_ are the same or different 6 7 β and are hydrogen, alkyl, alkoxy, formyl, alkyl-6-0-, 15 phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R 2 and Rg are separate with the proviso that when Rg and R ? are different, one of R g and R ? is hydrogen; R g is hydrogen or -CH R gR 10 wherein R g and R lfl are the same or ίύ different and are hydrogen or alkyl. - 44 29. A steroid according to claim 28 having the formula or the 1,2-dehydro derivative thereof, wherein is 5 alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or methyl; R^ is chlorine, fluorine or hydroxy and R g is hydrogen or R 4 and R g together are =0; R g and R^ are the same or different and. are hydrogen, alkyl, alkoxy, 10 formyl, alkyl-C-0-, phenyl or cyano with the proviso that when R g and R? are different, one of R g and R^ is hydrogen; R g is hydrogen or -CH R g R^ g wherein R g and R^ g are the same or different and are hydrogen or alkyl. 15 30. A steroid according to claim 28 having the formula - 45 or the 1,2-dehydro derivative thereof, wherein Rg is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; R 2 and Rg are the same or different and are hydrogen, alkyl or aryl; R^ is hydroxy and Rg is hydrogen or 5 together R 4 and Rg are =0; and Y is hydrogen, methyl or fluorine.

18. 31. A steroid according to claim 28 having the formula 10

19. 32. A steroid having the formula 48178 or the 1,2-dehydro derivative thereof, wherein Rg is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or 5 methyl; R 4 is chlorine, fluorine or hydroxy and Rg is hydrogen or R^ and Rg togehter are =0; Rg and Rg are the same or different and are hydrogen, alkyl or aryl, or taken together with the double bond to which they are attached, form a benzene ring; Rg and R^ are the 10 same or different and are hydrogen, alkyl, alkoxy, formyl, alkyl-8-O-, phenyl or cyano and in addition, hydroxy, halogen, carboalkoxy and alkylcarbonyl when R 2 and Rg are separate with the proviso that when Rg and R-, are different, one of R. and R_ is hydrogen; 15 R g is hydrogen or -CH R g Rgg wherein Rg and Rg Q are the same or different and are hydrogen or alkyl.

20. 33. A steroid according to claim 32 having the formula ( - 47 - in ρζ or the 1,2-dehydro derivative thereof, wherein Rg is alkyl of 1 to 10 carbon atoms, aryl or arylalkyl; X is hydrogen or halogen; Y is hydrogen, fluorine or 5 methyl; R^ is chlorine, fluorine or hydroxy and R is hydrogen or R^ and R g together are =0; R g and are the same or different and are hvdrogen, alkyl, alkoxy, formyl, alky1-C-0-, phenyl or cyano with the proviso that when R g and R? are different, 10 one of R g and R_, is hydrogen; Rg is hydrogen or -CH Rg R lo wherein Rg and R 1o are the same or different and are hydrogen or alkyl. A steroid according to claim 32 having the

21. 34. formula or according to claim 32 having the A steroid 48178 - 49 36. A process for preparing a steroid according to any of the preceding claims, substantially as herein described.

22. 37. A steroid of any of claims 1-35, when prepared 5 by a process according to claim 36.

23. 38. A pharmaceutical composition comprising a steroid of claim 1,substantially as herein described.