GB1603911A - Steroidal (16,17-b)benzodioxins - Google Patents

Description

(54) STEROIDAL [16cr,17-b] BENZODIOXINS (71) We, E.R. SQUIBB & SONS INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method for which it is to be performed, to be particularly described in and by the following statement: This invention provides novel steroids having the formula

and the 1 ,2-dehydrn derivatives thereof, wherein A is R6-X- or

R2 is fluoro, chloro, bromo, iodo, or cyano;R3 is hydrogen, fluoro, chloro, bromo or iodo; R4 is carbonyl, EB-hydroxymethylene or P-acyloxymethylene; R5 is hydrogen or fluoro; R6 is alkyl, aryl or acyloxy-alkyl; and R7 is hydrogen, fluoro, chloro, bromo, iodo, alkoxy or acyloxy; wherein the term "aryl" refers to phenyl or phenyl substituted with 1 or 2 alkyl, alkoxy, fluoro, chloro, bromo or iodo groups; the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms; and the term "acyloxy" refers to groups of the formula

wherein Y is alkyl or aryl. These new steroids can be used as antiinflammatory agents.

In formula I above, and throughout the specification, the symbols are as defined above.

A dotted line in the 1,2 position of a structural formula in this disclosure indicates the optional presence of ethylenic unsaturation. The term "halo" or "halogen", as used throughout the specification, refers to fluoro, chloro, bromo or iodo.

Those steroids of this invention which are of the androstene series and which have the formula

can be prepared utilizing as starting materials androstenes having the formula

In formula II, and throughout the specification, R'4 is carbonyl or B-hydroxymethylene.

Reaction of an androstene of formula II with a thiol compound having the formula III R'6-SH in the presence of a Lewis acid (e.g., boron trifluoride etherate), yields an intermediate having the formula

In formulas III and IV, and throughout the specification, R'6 is alkyl or aryl. The reaction can be run in an organic solvent (e.g., a halogenated hydrocarbon), or mixture of organic solvents. The use of some glacial acetic acid improves yields. Reaction conditions are not critical, and the reaction can be conveniently run at room temperature, preferably in an inert atmosphere (e.g., argon or nitrogen). Better yields may be obtained with relatively short reaction times (less than 1 hour).

An androstene of formula lV can be converted to the corresponding steroid having the formula

by simply heating the steroid in an inert solvent (e.g., diethylbenzene or dichlorobenzene).

The steroid products of formula Ia wherein R6 is alkyl or aryl, R4 is carbonyl or ss-hydroxymethylene and X is divalent sulfur can be obtained by reacting a steroid of formula V with an o-benzoquinone having the formula VI The reaction proceeds at room temperature, yielding a product having the formula

Oxidation of an androstene of formula VII with a peracid (,e.g., m-chloroperbenzoic acid), a peracid salt (e.g, sodium m-periodate) or a peroxide (e.g., hydrogen peroxide) yields the corresponding sulfinyl product having the formula

or the corresponding sulfonyl product having the formula

The use of one equivalent of oxidizing agent will yield predominantly the sulfinyl derivative of formula VIII and the use of two or more equivalents of oxidizing agent will yield predominantly the sulfonyl derivative of formula IX. Meta-chloroperbenzoic acid is the referred oxidizing agent. The oxidation reaction can be run in an organic solvent, e.g., a alogenated hydrocarbon such as chloroform.

Those steroids of formula Ia wherein R6 is acyloxy-alkyl can be prepared by first oxidizing a steroid of formula V, wherein R'6 is alkyl, using one equivalent of oxidizing agent, to obtain a steroid having the formula

A 17-alkylsulfinyl steroid of formula X can be reacted with an appropriate acid anhydride, and a basic catalyst such as the sodium salt of the corresponding acid, to yield the corresponding 17-t[(acyloxy)alkyl]thio]steroid having the formula

Reaction of a steroid of formula XI with an o-benzoquinone of formula VI yields a product of formula Ia wherein R6 is acyloxyalkyl and X is divalent sulfur.These steroids can be oxidized as described above to yield the corresponding steroids of formula Ia wherein X is

The 11ss-acyloxy derivatives of formula Ia can be obtained by acylating the corresponding 11ss-hydroxy steroid of formula Ia, by acylating the corresponding 11ss-hydroxy steroid of formula II and proceeding as described above, or by acylating a corresponding 11ss-hydroxy steroid intermediate and proceeding as described above.

Many alternative processes for preparing the steroids of formula I will be readily apparent to a person ot ordinary skill in the art. For example, any of the 17-sulfonyl products can be obtained by oxidizing the corresponding 17-sulfinyl steroids of formula Ia.

The oxidation of a 17-thio product to yield a 17-sulfinyl steroid of formula I results in a mixture of two isomers, which may be separated using conventional techniques.

Those steroids of this invention which have the formula

are of the pregnene series.

Many steroids of the pregnene series are known to have antiinflammatory activity. More particularly, steroids of the pregnene series having heterocyclic rings fused in the 16,17-positions are known. United States patent 3,971,772, issued July 27, 1976, discloses steroidal [16a,17-b1[1 ,4]dioxanes and steroidalt16a-17-b][1,4]dioxins. United States patent 3,971,773, issued July 27, 1976 discloses steroldal 9,11-dihalo[16a,17-b][1,4]dioxanes and steroidal 9,11-dihalo 16a,17-b][1,4-dioxins. The steroids described in both patents are steroids of the pregnene series that are useful as antiinflammatory agents. However, neither reference discloses a steroid having a substituted or unsubstituted benzodioxin substituent fused in the 16,17-position.

The steroids of formula Ib can be prepared utilizing as starting mterials Al6-pregnenes having the formula

In formula XII and throughout the specification, R'7 is hydrogen, acyloxy or halogen and R'4 is carbonyl or ss-hydroxymethylene.

A steroid of formula XII wherein R'4 is ss-hydroxymethylene can be reacted with a mixture of acetic acid and acetic anhydride in the presence of an acid catalyst such as p-toluenesulfonic acid, followed by the addition of an acetate salt, to yield the corresponding 11ss-acetyloxy steroid having the formula

Reaction of a Al6-pregnene of formula XII or XIII with an organic base and trimethylchlorosilane, an organic base and trimethylsilyl trifluoromethanesulfonate or bis-trimethylsilyltrifluoroacetamide, yields a 20-trimethylsilyl enol ether pregnene having the formula

When the A16-pregnene reactant is an 11ss-hydroxy steroid of formula XII, the reaction also yields (as a minor product) a steroid having the formula

Reaction conditions are not critical, but the reaction proceeds more rapidly when the reactants are maintained at a temperature of about 110-115"C.

An intermediate of formula XIV can be reacted with an o-benzoquinone having the formula

preferably at room temperature, and then treated with an aqueous acid to yield a steroid product having the formula

When preparing a steroid of formula XVII wherein R4 is ss-hydroxymethylene, it is convenient to use the crude mixture of intermediates XIV (wherein R4 is (3- hydroxymethylene) and XV to react with the o-benzoquinone. This will result in a mixture of steroids comprising, in addition to a steroid of formula XVII (wherein R4 is (3-hydroxymethylene), a steroid having the formula

The product of formula XVII can be isolated from the mixture using conventional separation techniques.

Those steroids of formula Ib wherein R7 is alkoxy of 1 to 10 carbon atoms can be prepared by reacting a corresponding 21-halo steroid of formula XVII with the appropriate lower alkanol having 1 to 10 carbon atoms and a base such as an alkali metal carbonate.

Modifications of the above-described processes for preparing the steroids of formula Ib will be apparent to the person of ordinary skill in the art. For example, the 11ss-acyloxy steroids of formula Ib can be prepared by acylating the corresponding 11ss-hydroxy steroid of formula Ib. Those steroids of formula Ib wherein R7 is alkoxy can be prepared by converting a 21-halo-Al6-pregnene of formula XII to a 21-alkoxy-A16-pregnene and then proceeding as described above.

The by-products of formula XVIII can be converted to the corresponding 11ss-hydroxy steroids o formula Ib. As such, they are valuable intermediates, and an integral part of this invention. The conversion is carried out in an organic solvent (e.g., tetrahydrofuran) at a reduced temperature (about -78 C) and comprises adding a quaternary fluoride base, such as tetrabutylammonium fluoride, to the 11ss-trimethylsilyl ether of formula XVIII.

The steroids of formula I can be used in lieu of known glucocorticoids in the treatment of inflammatory conditions; e.g., rheumatoid arthritis. They can be administered in the same manner as hydrocortisone, the dosage being adjusted for the relative potency of the particular steroid. Additionally, the steroids of this invention can be used topically in lieu of known glucocorticoids in the treatment of skin conditions such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema or anogenital pruritus.

When given orally, the steroids of this invention may be used in a dosage range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams, for a 70 kg. mammal. If administered topically, the steroids of this invention may be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream, ointment, lotion or the like.

The following Examples are specific embodiments of this invention.

EXAMPLE 1 5', 6', 7', 8' - Tetrachloro-9-fluoro-2 3, -dihydrn-11 (3-hydrnxy-1 7- (methylthio) androsta-1, 4- dieno[16α, 17α-b] [1,4]benzodioxin-3-one A) 9-Fluoro-11ss-hydroxy-17,17-bis(methylthio)androsta-1,4-dien-3-one A solution of 9-fluoro-113-hydroxyandrosta-1,4-diene-3,17-dione (2.0 g) in glacial acetic acid (25 ml) is mixed at room temperature with a solution of methanethiol (2.4 g) in dichloromethane (16 ml) and boron trifluoride etherate (0.5 ml). After 1.5 hours, the mixture is poured into water and diluted with chloroform. The organic layer is then separated, washed with a dilute sodium bicarbonate solution and water, dried and evaporated in vacuo. The residue is absorbed on a column of silica gel (50 g).Elution of the column with chloroform removed the non-steroidal impurities and a product resulting from thiol addition to A1 Subsequent elution with chloroform affords the desired material as a solid (957 mg). Finally, elution with chloroform-ethyl acetate (95:5) affords the unreacted steroid (345 mg). A specimen of the 957 mg solid is crystallized once from chljoroformmethanol to afford the analytical sample of the title compound, melting point 305 C (dec.).

Anal. Calc'd. for C2lH29FO2S2: C, 63.60; H, 7.37; F, 4.79; S, 16.17 Found: C, 63.48; H, 7.21; F, 4.95; S, 16.21 B) 9-Fluoro-11ss-hydroxy-17-(methylthio)androsta-1,4,16-trien-3-one A suspension of 9-fluoro-11ss-hydroxy-17,17-bis-(methylthio)androsta-1,4-diene-3-one (3.6 g) in diethylbenzene (250 ml) is slowly distilled from a bath at 220"C. In a few minutes, a clear solution results and the starting material disappears. On cooling in an ice bath, the solution deposits small needles of the analytical specimen of the title compound, (2.9 g), melting point 268 C (dec.) (discoloration starts at 263 C).

Anal. Calc'd. for C20H25FO2S: C, 68.93; H, 7.23; F, 5.00; S, 9.20 Found: C, 68.68; H, 7.20; F, 4.92; S, 9.09 C) 5',5',7',8'-Tetrachloro-9-fluoro-2', 3'-dihydro-11ss-hydroxy-17-(methylthio)androsta 1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one A suspension of 523 mg off 9-fluoro-11ss-hydroxy-17-(methio)androsta-1,4,16-trien-3one in 100 ml of dry tetrahydroffuran is gently warmed on a steam bath until a homogeneous solution is obtained. The solution is cooled to room temperature and 369 mg of tetrachloro-o-benzoquinone is added. After about 16 hours stirring the solution is evaporated in vacuo to give a foam. This is rinsed with 1:1 chloroform-ethyl acetate, and the insoluble material is filtered and recrystallized from chloroform-methanol to give 460 mg of the title compound, melting point 301-302"C.

Anal. Calc'd. for C26H25Cl4FO4S: C, 52.54; H, 4.24; Cl, 23.86; F, 3.20; S, 5.40 Found: C, 52.75; H, 4.21; Cl, 23.64; F, 3.48; S, 5.68 EXAMPLE 2 5', 6', 7', 8'- Tetrachloro-9-fluoro-2 ',3' -dihydro-1 I (3-hydroxy-1 7-(methylsulfinyl)androsta 1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one A suspension of 380 mg of 5',6'7',8-tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxy-17 (methylthio)androsta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one in 400 ml of chloroform is gently warmed on a steam bath until a homogeneous solution is obtained. After cooling to room temperature, a solution of 130 mg of m-chloroperbenzoic acid (-850/0) in 40 ml of chloroform is added in the course of 15 minutes.The resulting solution is stirred for 40 minutes, washed with a diluted sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 440 mg of a foam. This is redissolved in chloroform and chromatographed on pre-coated silica gel TLC (thin layer chromatography) plates (2 x 200 x 200 mm, 3:97 methanol-chloroform development) to give two isomers: isomer A (230 mg) and isomer B (115 mg). Isomer A is crystallized from chloroform-methanol to give 170 mg of tlc-homogeneous title compound, melting point 288-289"C (dec.) with consistent spectral data. Isomer B is crystallized from chloroformmethanol to give 100 mg of the title compound, melting point 284-285"C (dec.).

EXAMPLE 3 5', 6 ', 7', 8' - Tetrachloro-9-fluoro-2 ',3 '-dihydro-li (3-hydroxy-1 7-(methylsulfonyl)androsta 1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one A solution of 375 mg of 5',6',7',8-tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxy-17 (methylsulfinyl)androsta-1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one (isomer A, see Example 2) in 300 ml of dichloromethane is stirred with 137 mg of m-chloroperbenzoic acid (85%) at room temperature for about 16 hours. The solution is washed with a saturated sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and filtered. The filtrate is passed through a 20 g silica gel column and eluted with chloroform. The solvent is evaporated in vacuo to give the tlc-homogeneous title compound (400 mg). One crystallization from chloroform-methanol gives 310 mg of the title compound, melting point 348-350"C, with consistent spectral data.

Anal. Calc'd. for C26H25Cl4FO6S: C, 49.85; H, 4.02; Cl, 22.64; F, 3.03; S, 5.12 Found: C, 50.10; H, 3.91; Cl, 22.79; F, 3.30; S, 5.03 EXAMPLE 4 5', 6', 7', 8'- Tetrachloro-1 7-(ethylthio) -9-fluoro-2 ',3 '-dihydro-li (3-hydroxyandrosta-1, 4 dieno[16a, 1 7a-b][l, 4]benzodioxin-3-one A) 17,1 7-Bis(ethyltho)-9-fluoro-11 ss-hydroxyandrosta-l, 4-den-3-one A solution of 9.5 g of 9-fluoro-llss-hydroxyandrosta-1,4-diene-3,17-dione in 50 ml of dichloromethane and 50 ml of glacial acetic acid is stirred with 11.2 g of ethanethiol and 7.5 ml of boron trifluoride etherate at room temperature under nitrogen. After 1.5 hours the solution is diluted with 350 ml of chloroform.The chloroform solution is washed with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 11 g of a foam. This is dissolved in hexane-chloroform (2:1) and chromatographed on a 200 g-silica gel column. Elution with hexane-chloroform (2:1 and 1:1) gives 2.1 g of a tlc-homogeneous material. Crystallization from acetone-hexane gives 1.05 g of the title compound, melting point 276-277"C (dec.), with consistent spectral data.

Anal. Calc'd. for C23H33FO2S2: C, 65.05; H, 7.83; F, 4.47; S, 15.10 Found: C, 65.31; H, 7.80; F, 4.71; S, 15.01 B) 17-(Ethylthio)-9-fluoro-11ss-hydroxyandrosta-1,416-trien-3-one A suspension of 1.8 g of 17,17-bis(ethylthio)-9-fluoro-11ss-hydroxyandrosta-1,4-dien-3one in 120 ml of diethylbenzene is stirred at 190 C (oil bath temperature for 1 hour. The solution is cooled to 0 C and the solid that precipitates is filtered. This is redissolved in 1:9 hexane-chloroform and chromatographed on a 60 g-silica gel column. Elution with 1:9 hexane-chloroform gives 1.35 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 680 mg of the title compound, melting point 282-283"C (dec.), with consistent spectral data.

Anal. Calc'd. for C2lH27FO2S: C, 69.58; H, 7.51; F, 5.24; S, 8.85 Found: C, 69.46; H, 7.32; F, 5.47; S, 8.71 C) 5', 6', 7', 8'- Tetrachloro-1 7-(ethylthio)-9-fluoro-2',3'-dihydro-11 ss-hydroxyandrosta1, 4-dieno[16a, 1 7a-b][1, 4]benzodioxin-3-one To a solution of 1.35 g of 17-(ethylthio)-9-fluoro-llss-hydroxyandrosta-1,4,16-trien-3-one in 110 ml of dry tetrahydrofuran is added 1.0 g of tetrachloro-o-benzoquinone. The red solution is stirred at room temperature under nitrogen for about 16 ours, and more tetrachloro-o-benzoquinone (180 mg) is added. The solution is stirred at room temperature under nitrogen for 4 hours. Water (2 ml) is added and the solution is evaporated in vacuo.

The residue is dissolved in 1:3 hexane-chloroform and chromatographed on a 100 g-silica gel column. Elution with 1:3 hexane-chloroform gives 1.85 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 0.9 g of the title compound, melting point 287-288"C (dec.), with consistent spectral data.

Anal. Calc'd. for C27H27Cl4FO4S: C, 53.30; H, 4.47; Cl, 23.31; F, 3.12; S, 5.27 Found: C, 53.10; H, 4.38; Cl, 23.47; F, 3.42; S, 5.29 EXAMPLE 5 5', 6', 7', 8' - Tetrachloro-1 7-(ethylsulfinyl)-9-fluoro-2',3'-dShydro-ll ss-hydroxyandrosta-1,4- dieno[16a, 1 7a-b][1, 4]benzodioxin-3-one A suspension of 1.5 g of 5',6',7' ,8'-tetrachloro-17-(ethylthio)-9-fluoro-2 ,3'-dihydro-llp- hydroxyandrosta-1,4-dieno[16a,17a-b][1,4jbenzodioxin-3-one (see Example 4) in 550 ml of chloroform is gently warmed on a steam bath until a homogeneous solution is obtained.

After cooling to room temperature, a solution of 549 mg of m-chloroperbenzoic acid (85%) in 30 ml of chloroform is added in the course of 5 minutes. The resulting solution is stirred for 1.5 hours at room temperature under nitrogen, washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.35 g of a foam. This is dissolved in chloroform and chromatographed on precoated silica gel TLC plates (2 x 200 x 200 mm, 1:4 ethyl acetate-chloroform development) to give two isomers; isomer A (600 mg) and isomer B (298 mg). Isomer A is crystallized from methanol-chloroform to give 420 mg of tlc-homogeneous title compound, melting point 252-253"C, with consistent spectral data.Isomer B on similar crystallization affords 260 mg of the title compound, melting point 217-218"C.

EXAMPLE 6 5', 6', 7', 8'-Tetrachloro-1 7-(ethylsulfonyl)-9-fluoro-2',3'-dEhydro-11 ss-hydroxyandrosta-1, 4 dieno[16a, 1 7a-b]l1, 4]benzodioxin-3-one A solution of 350 mg of 5',6',7',8'-tetrachloro-17-(ethylsulfinyl)-9-fluoro-2',3'-dihydro- 11 (3-hydroxyandrosta-1 ,4-dieno[16a,17a-b][ 1 ,4]benzodioxin-3-one (isomer A, see Example 5) in 200 ml of chloroform is stirred with 125 mg of m-chloroperbenzoic acid (85%) at room temperature for about 16 hours. The resulting solution is washed with 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 360 mg of solid. This is dissolved in chloroform and chromatographed on a 25 g-silica gel column. Elution with chloroform gives 320 mg of a tlc-homogeneous material.

Crystallization from chloroform-methanol gives 260 mg of the title compound, melting point 342-343"C (dec.), with consistent spectral data.

Anal. Calc'd. for C27H27Cl4FO6S: C, 50.64; H, 4.25; Cl, 22.15; F, 2.97; S, 5.01 Found: C, 50.51; H, 4.07; Cl, 22.40; F, 3.55; S, 4.95 EXAMPLE 7 5',6',7',8'-Tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxy-17-(phenylthio)androsta-1,4 dieno[16a, 1 7a-b][1, 4]benzodioxin-3-one A) 9-Fluoro-11 ss-hydroxy-17, 17-bis(phenylthio) -androsta-1, 4-dien-3-one A solution of 9.0 g of 9-fluoro-11(3-hydroxyandrosta-1,4-diene-3,17-dione in 50 ml of dichloromethane and 50 ml of glacial acetic acid is stirred with 18.68 g of thiophenol and 7.5 ml of boron trifluoride ethereate at room temperature under nitrogen. After 50 minutes the solution is diluted with 350 ml of chloroform.The chloroform solution is washed successively with water, saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 11.6 g of an oil. This is dissolved in 1:3 hexane-chloroform and chromatographed on a 200 g-silica gel column. Elution with 1:3 hexane-chloroform and chloroform gives 3.5 of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 2.0 g of the title compound, melting point 249-250"C (dec.), with consistent spectral data.

Anal. Calc'd. for C3lH33FO2S2: C, 71.50; H, 6.39; F, 3.65; S, 12.32 Found: C, 71.66; H, 6.49; F, 3.92; S, 12.41 B) 9-Fluoro-11 (3-hydroxy-1 7- (phenylthio) androsta-1 , 4, 16-trien-3-one A suspension of 3.0 g of 9-fluoro-11(3-hydroxy-17,17-bis(phenylthio)androsta-1,4-dien-3- one in 150 ml of diethylbenzene is stirred at 190"C for 45 minutes. The solution is cooled at 0 C and a solid crystallizes. This is filtered and dried in vacuo to give 2.3 g of material.

Recrystallization from chloroform-methanol gives 1.1 g of the title compound, melting point 250-251"C (dec.), with consistent spectral data.

Anal. Calc'd. for C25H27FO2S: C, 73.14; H, 6.63; F, 4.63; S, 7.81 Found: C, 73.28; H, 6.74; F, 4.52; S, 7.84 C) 5',6',7',8'-Tetrachoro-9-fluoro-2',3'-dihydro-11ss-hydroxy-17-(phenylthio)androsta 1,4-dieno[16a,i 7a-b][1,4]benzodioxin-3-one To a solution of 1.8 g of 9-fluoro-llss-hydroxy-17-(phenylthio)androsta-1,4,16-trien-3- one in 200 ml of dry tetrahydrofuran is added 1.19 g of tetrachloro-o-benzoquinone. The red solution is stirred at room temperature under nitrogen for 65 hours (the reaction is completed after 24 hours). Water (2.0 ml) is added and the solution is evaporated in vacuo.

The residue is dissolved in 1:2 hexane-chloroform and chromatographed on a 120 g-silica gel column. Elution with hexane-chloroform (1:2 and 1:3) gives 2.5 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 1.6 g of the title compound, melting point 279-280"C (dec.), with consistent spectral data.

Anal. Calc'd. for C3lH27Cl4FO4S: C, 56.72; H, 4.14; Cl, 21.61; F, 2.89; S, 4.88 Found: C, 56,51; H, 4.17; Cl, 21.79; F, 3.10; S, 4.85 EXAMPLE 8 5',6',7',8'-Tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxy-17-(phenylsulfinyl)androsta 1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one To a solution of 2.1 g of 5',6',7',8'-tetrachloro-9-fluoro-2',3'-dihydro-llss-hydroxy-17- (phenylthio)androsta-1,4-dieno[16a,17cx-b][1,4]benzodioxin-3-one (see Example 7) in 500 ml of chloroform is added a solution of 715 mg of m-chloroperbenzoic acid ?v85%) in the course of 6 minutes.The resulting solution is stirred for 3 hours at room temperature under nitrogen, washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.2 g of a foam. This is dissolved in chloroform-hexane (4:1) and chromatographed on a 120-gram silica gel column.Elution with chloroform-hexane (4:1 and 9:1) and chloroform-ethylacetate (9:1) gives isomer A (1.0g) and a mixture of isomer A and isomer B (900 mg). [5',6',7',8'-tetrachloro-9-fluoro 2' ,3' -dihydro-11ss-hydroxy-17-(phenylsulfonyl)androsta-1,4-dieno[16α,17α- b][1,4jbenzodioxin-3-one (200 mg) is also isolated from this chromatographyj. Isomer A is crystallized from chloroform-hexane to give 650 mg of the tlc-homogeneous title compound, melting point 219-220"C (dec.), with consistent spectral data. The mixture of Isomer A and Isomer B (900 mg) is further subjected to chromatography over silica gel to isolate isomer B (600 mg) which on recrystallization from chloroform-hexane has a melting point of 215-217"C (dec.).

EXAMPLE 9 5',6',7',8'-Tetrachloro-9-fluoro-2',3' -dihydro-11ss-hydroxy-17-(phenylsulfonyl)androsta 1, 4-dieno[16a, 1 7a-b][1, 4]benzodioxin-3-one A solution of 400 mg of 5',6',7',8'-tctrachloro-9-fluoro-2',3', -dihydro-11ss-hydroxy-17 (phenylsulfinyl)androsta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one (Isomer A, see Example 8) in 200 ml of chloroform is stirred with 113 mg of m-chloroperbenzoic acid (85%) at room temperature for 4 hours. The resulting solution is washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give a gum (425 mg). This is dissolved in chloroform-hexane (9:1) and chromatographed on a 25 g-silica gel column. Elution with chloroform-hexane (9:1) gives 400 mg of a tlc-homogeneous material.Crystallization from chloroform-methanol gives 310 mg of the title compound, melting point 310-313"C (dec.) with consistent spectral data.

Anal. Calc'd. for C3lH27Cl4FO6S: C, 54.08; H, 3.95; Cl, 20.60; F, 2.76; S, 4.66 Found: C, 54.03; H, 3.71; Cl, 20.48; F, 3.84; S, 4.89 EXAMPLE 10 17-[[(Acetyloxy) methyl] thio]-5',6',7',8'-tetrachloro-9-fluoro-2',3' -dihydro-11ss hydroxyandrosta-1, 4-dieno[1 6a, 1 7a-b][1, 4]benzodioxin-3-one A) 9-Fluoro4 1 (3-hydroxy-1 7-(methylsulffnyl)androsta-1, 4, 16-trien-3-one To a stirred solution of 1.0 g of 9-fluoro-llss-hydroxy-17-(methylthio)androsta-1,4,16- trien-3-one (see Example 1B) in chloroform (500 ml) is added a solution of 85% m-chloroperbenzoic acid (552 mg) in chloroform (10 ml) in the course of 3.0 minutes. In less than 10 minutes, the peracid and the starting steroid disappear.The solution is then washed with a dilute potassium carbonate solution and water, dried, concentrated (to about 10 ml) and diluted with ethyl acetate resulting in the precipitation of small, light needles of the analytical specimen of the title compound, (1.0 g), melting point 268-269 C (dec.). This is a mixture of the two sulfinyl isomers.

Anal. Calc'd. for C20H25FO3S: C, 65.90; H, 6.90; F, 5.00; S, 8.80 Found: C, 65.76; H, 6.98; F, 4.92; S, 9.09 B) 17-[[(Acetyloxy)methyl]thio]-9-fluoro-11ss-hydroxyandrosta-1,4,16-trien-3-one A mixture of 1.5 g of 9-fluoro-11ss-hydroxy-17-(methylsulfinyl)androsta-1,4,16-trien-3one, 70 ml of acetic anhydride and 2 g of fused sodium acetate is heated at 110 C under nitrogen for 2 hours. The acetic anhydride is partially removed by distillation under vacuum and the resulting slurry is diluted with 1:1 chloroform-water. The organic layer is separated, washed with diluted sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 4:1 chloroform-hexane and chromatographed on a 40 g-silica gel column. Elution with 1:4 hexane-chloroform gives 940 mg of slightly impure material.Two crystallizations from acetone-hexane give 350 mg of the title compound, melting point 193-194 C, with consistent spectral data.

Anal. Calc'd. for C22H27FO4S: C, 65.00; H, 6.70; F, 4.67; S, 7.89 Found: C, 64.75; H, 6.73; F, 4.39; S, 8.15 C) 17-[[(Acetyloxy)methyl]thio]-5',6',7',8'-tetrachloro-9-fluoro, -2',3'-dihydro-11ss hydroxyandrosta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one To a solution of 406 mg of 17-[[(acetyloxy)methyl]thio]-9-fluoro-llss-hydroxyandresta- 1,4,16-triene-3-one in 50 ml of dry tetrahydrofuran is added 246 mg of tetrachloro-obenzoquinone. The red solution is stirred under nitrogen at room temperature for about 16 hours. More of the tetrachloro-o-benzoquinone (246 mg) is added two more times after every 20 hours until the starting material disappears (tlc). Water (10 drops) is added to the dark red solution and stirred for another 1 hour.The solvent is evaporated in vacuo and the residue is dissolved in chloroform and passed through a 15 g-silica gel column. Elution with chloroform gives 600 mg of slightly impure product. Two crystallizations from chloroformmcthanol give 310 mg of the title compound, melting point 298-299 C (dec.) with consistent spectral data.

Anal. Calc'd. for C28H27Cl4FO6S: C, 51.55; H, 4.17; Cl, 21.74; F, 2.91; S, 4.92 Found: C, 51.25; H, 4.31; Cl, 21.53; F, 3.17; S, 5.00 EXAMPLE 11 17-[[(Acetyloxy)methyl]sulfinyl]-5',6',7',8' -Tetrachloro-9-fluoro-2',3' -dihydro-11ss hydroxyandrosta-1,4-dieno[16α,17α-b] [1,4]benzodioxjin-3-one A suspension of 482 mg of 17-[[(acetyloxy)methyl]thio-5',6',7',8'-tetrachloro-9-fluoro 2' ,3'-dihydro-1 1B-hydroxyandrosta-l ,4-dieno116a,17a-bl[1 ,4]benzodioxin-3-one (see Ex ample 10) in 500 ml of chloroform is gently warmed on a steam bath until a homogeneous solution is obtained. After cooling to room temperature, a solution of 152 mg of m-chloroperbenzoic acid (85%) in 40 ml of chloroform is added in a 15-minute period.The solution is stirred for 1 hour, washed with a diluted sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give a foam. This is redissolved in chloroform and chromatographed on precoated silica ge TLC plates (2 x 200 x 200 mm, 3:97 methanol-chloroform development) to give two isomers; isomer A (220 mg) and isomer B (100 mg). Isomer A is crystallized from chloroform-methanol to give 165 mg (33.4%) of the tlc-homogeneous title compound, melting point 289-290"C (dec.), with consistent spectral data. Isomer B is crystallized in a similar manner to give a product having a melting point 292-294 C.

EXAMPLE 12 17-[[(Acetyloxy)methyl]sulfonyl]-5',6',7',8'-tetrachoro-9-fluoro-2',3'-dihydro-11ss hydroxyandrosta-1,4-dieno[16α,17α-b] [1,4]benzodioxin-3-one Oxidation of 17-[[(acetyloxy)methyl]sulfinyl]-5',6',7',8'-tetrachloro-9-fluoro-2',3' dihydro-11ss-hydroxyandrosta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one (isomer A, Example 11) with 1.1 equivalents of m-chloroperbenzoic acid, following the procedure described in Example 3, yields the title compound, melting point 291-293 C (dec.) EXAMPLE 13 11ss-(Acetyloxy)-5',6',7',8'-tetrabromo-9-fluoro-2',3'-dihydro-17-(phenylthio)androsta-1,4 dieno[16α,17α;-b] [1,4]benzodioxin-3-one A) 11 (Acetyloxy) -9-fluoroandrosta-1, 4-diene-3, 1 7-dione A solution of 9-fluoro-llp-hydroxyandrosta-l ,4-diene-3,17-dione (2.0 g) in a mixture of acetic anhydride (20 ml) and acetic acid (10 ml) containing p-toluenesulfonic acid (200 mg) is kept at room temperature for 40 hours. Sodium acetate (1.0 g) is added and the mixture is evaporated in vacuo. The residue is diluted with water and extracted with chloroform. The chloroform extracts are combined, washed with a dilute sodium bicarbonate solution and water, dried, evaporated and the tesidue is chromatographed on a columm of silica gel to afford the title compound (1,6 g), melting pont 229-230 C.

B) 11(3- (Acetyloxy) -17,1 7-bis(phenylthio) -9-fluoroandrosta-1, 4-dien-3-one A solution of 11P-(acetyloxy)-9-fluoroandrosta-l ,4-diene-3,17-dione (6.8 g) in a mixture of dichloromethane (35 ml) and glacial acetic acid (35 ml) is mixed with thiophenol (18.0 g) and borontrifluoride etherate (4.5 g) and the solution is stirred at room temperature for one hour. The mixture is then diluted with chloroform, washed successively with water, a dilute sodium bicarbonate solution and water, dried and evaporated in vacuo. The residue is chromatographed over silica gel to afford the title compound (2.3 g), melting ponint 180-184 C.

C) 11ss-(Acetyloxy)-9-fluoro-17-(phenylthio)-androsta-1,4,16-trien-3-one A solution of 11ss-(acetylosy)17-,17-bis(phenylthio)-9-fluoroandrosta-1,4-diene-3-one (2.3 g) in diethylbenzene (150 ml) is heated in a bath at 1900C for 60 minutes. The solution is then cooled in an ice bath and the sparated title compound is isolated by filtration and washed with hexane to afford 2.15 g of the title compound, melting point 229-231 C.

D) 11ss-(Acetyloxy)-5',6', 6', 7',8' -tetrabromo-9-fluoro-2',3' -dihydro-17- (phenylthio)androsta-1, 4-dieno[16a, 1 ia-b][1, 4]benzodioxin-3-one To a solution of 2.0 g of 11ss-(acetyloxy3-9-fluoro-17-(phenylthio)-androsta-1,4,16-trien- 3-one in 300 ml of dry tetrahydrofuran is added 2.0 g of tetrabromo-o-benzoquinone. The solution is stirred under nitrogen for 24 hours to yield the title compound.

EXAMPLE 14 17-[[(Benzoyloxy)rnethyl]thio]-5', 6', 7', 8', 9-pentafluoro-2 ',3'-dihydro-11 (3- hydroxyandrostaq, 4-dieno[1 6a, 1 7a-b][1, 4]benzodioxin-3-one A) 17-[[(Benzoyloxy)methyl]thio]-9-fluoro-11ss-hydroxyandrosta-1,4,16-trien-3-one A solution of 9-fluoro-11ss-hydroxy-17-(methylsulfinyl)androsta-1,4,16-trien-3-one (100 mg, see Example 10A) in 30 ml of xylene containing 4.0 g of benzoic anhydride and 300 mg of sodium methoxide is stirred at 1300C for 48 hours. The product is then isolated and chromatographed over silica gel to yield 80 mg of the title compound, melting point 220-222 C.

B) 17-[[(Benzoyloxy)methyl]thio]-5',6',7',8',9-pentafluoro-2',3'-dihydro-11ss hydroxyandrosta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one To a solution of 75 mg of 17-[[(benzoyloxy)methyl]thio]-9-fluoro-11ss-hydroxyandrosta1,4,16-trien-3-one in 50 ml of dry tetrahydrofuran is added 200 mg of tetrafluoro-obenzoquinone. The solution is stirred under nitrogen for 24 hours to yield the title compound.

EXAMPLES 15-18 Following the procedure of Example 1, but substituting the steroid listed in column I for 9-fluoro-llss-hydroxyandrosta-1,4-diene-3,20-dione, the compound listed in column II for methanethiol and the compound listed in column III for tetrachloro-o-benzoquinone, yields the steroid listed in column IV.

Column I Column II Column III Column IV 15 11ss-hydroxyandrosta- thiophenol tetraiodo-o-benzoquinone 2',3'-dihydro-11ss-hydroxy1,4-diene-3,17-dione 5',6',7',8'-tetraiodo-17 (phenylthio)androsta-1,4dieno[16α,17α-b][1,4]benzo dioxin-3-one 16 androsta-1,4-diene- n-butanethiol tetrachloro-o-benzoquinone 17-(butylthio)-5',6',7',8'3,11,17-trione tetrachloro-2',3',-dihydroandrosta-1,4-dieno[16α,17α-b] [1,4]benzodioxin-3,11-dione 17 11ss-hydrjoxyandrost- n-propanethiol tetrabromo-o-benzoquinone 5',6',7',8'-tetrabromo-2',3'4-ene-3,17-dione dibydro-11ss-hydroxy-17-(propylthio)androst-4-eno[16α,17α-b] [1,4]benzodioxin-3-one 18 6α-9-difluoro-11ss- thiphenol tetrabromo-o-benzoquinone 5',6',7',8'-tetrabromo-6α,9hydroxyandrosta-1,4- difluoro-2',3',-dihydro-11ssdiene-3,17-dione hydroxy-17-(phenylthio)androsta1,4-dieno[16α,17α ;-b][1,4]benzodioxin-3-one EXAMPLE 19 11ss-(Acetyloxy)-5',6'7',8'-tetrachloro-9-fluoro-2',3'-dihydropregna-1,4-dieno[16α,17- b][1,4]benzodioxin-3,20-dione A) 11 ss-(Acetyloxy)-9-fluoropregna-1,4,16-triene-3,20-dione A solution of 9-fluoro-llss-hydroxypregna-1,4,16-triene-3,20-dione (1.0 g) in a mixture of acetic acid (70 ml) and acetic anhydride (70 ml) containing p-toluenesulfonic acid hydrate (500 mg) is stirred at room temperature for 60 hours. Sodium acetate (2.0 g) is added and the mixture is concentrated in vacuo. The residue is mixed with water and washed with dilute sodium bicarbonate solution and water, dried and the residue is crystallized from ethyl acetate-hexane to afford 0.9 g of the title compound, melting point 202-203"C.

B) 11ss-(Acetyloxy-9-fluoro-20-trimethylsilyoxypregna-1,416,20-tetraen-3-one A solution of 11 P-acetyloxy-9-fluoropregna-l ,4,16-triene-3 ,20-dione (77 mg) in dry acetonitrile (1.0 ml) containing bis-trimethylsilyltrifluoroacetamide (0.3 ml) and trimethylchlorosilane (0.05 ml) is heated in a closed presure vial in a bath at 110 C for 17 hours. The mixture is evaporated in vacuo and the residue is crystallized from ethyl acetate-hexane to afford 40 mg of the title compound as a solid.

C) 11ss-(Acetyloxy)-20-trimethylsilyloxy-5',6',7',8'-tetrachloro-9-fluoro-2',3' dihydropregna-1,4,20-trieno[16α,17-b][1,4]benzodioxin-3-one A solution of 11ss-(acctyloxy)-9-fluoro-20-trimethyloxypregna-1,4,16,20-tetraen-3one (28 mg) in dry toluene (4.0 ml) is mixed with tetrachloro-o-benzoquinone (15 mg) and let stand at room temperature. It is concentrated in vacuo and the residue is purified by preparative thin-layer chromatography on silica gel plates using chloroform-ethyl acetate (7:3) for development to afford 15 mg of the title compound as a solid, which is characterized by its nmr spectrum.

D) 11ss (Acetyloxy) 5',6',7',8'-tetrachloro-9-fluoro-2',3'-dihydropregna-1,4 dieno[16α,17-b][1,4]benzodioxin-3,20-dione A solution of 11ss-(acetyloxy)-20-trimethylsilyoxy-5',6',7',8'-tetrachloro-9-fluoro-2',3' dihydroprena-1,4,20-trieno[16α,17α-b][1,4]benzodioxin-3-one (14 mg) in 90% methanol (0.5 ml) is mixed with 1.0N hydrochloric acid (0.05 ml). After 1.0 hour, the solution is diluted with water, and the product is isolated by extraction with chloroform. The chloroform solution is dried, evaporated and the residue is crystallized from ethyl acetate-hexane to afford 9.0 mg of the title compound as a solid, which is characterized by its nmr spectrum.

EXAMPLE 20 11 ss,21 -bis- (Acetyloxy) -5 6', ',7',8'-tetrachloro-9-fluoro-2 ',3 dieno,'16a, 1 7-b][1, 4]benzodioxin-3, 20-dione A) 11 ss,21-bis-(Acetyloxy) -9-fluoropregna-1,4,1 6-triene-3, 20-dione A suspension of 21-(acetyloxy)-9-fluoro-l 1(3, 17-dihydroxypregna-1 ,4-diene-3 ,20-dione (25 g) in a mixture of acetic acid (60 ml) and acetic anhydride (60 ml) containing p-toluenesulfonic acid hydrate (7.5 g) is stirred at room temperature for 60 hours. Sodium acetate (15 g) is added and the mixture is concentrated in vacuo. The resulting solid is washed well with water and then dried, yielding 31 g of material.The solid is dissolved in dry dimethylformamide containing fused potassium acetate (17 g), the mixture is stirred at 1200C for 4.5 hours and poured into water. The separated solid is isolated by filtration, dried and crystallized from dichloromethane-methanol to yield 18.2 g of the title compound, melting point 294-296"C.

B) 11ss,21-bis(Acetyloxy)-9-fluoro-20-trimethylsilyloxypregna-1,4,16,20-tetraen-3-one A solution of 11ss, 21-bis(acetyloxy)-9-fluoropregna-1,4,16-triene-3,20-dione(3.0 g) in dry dimethylformamide (20 ml) containing bis-trimethylsilyltrifluoroacetamide (6.0 ml) and trimethylchlorosilane (60 1ill) is heated in a pressure vial in a bath at 115-120"C for 12 hours.

The mixture is cooled, poured into an excess of saturated sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane solution is washed with cold water, dried, evaporated and the residue crystallized from ethyl acetate-hexane to afford 1.22 g of the title compound as a solid which is characterized by its nmr spectrum.

C) 11ss,21-bix(Acetyloxy)-5',6',7',8'-tetrachloro-9-fluoro-2',3' -dihydro-20 trimethylsilyoxypregna-1,4,20-trieno[16α,17-b][1,4]benzodioxin-3-one To a solution of 11ss,21-bis(acetyloxy)-9-fluoro-20-trimethylsilyloxypregna-1,4 16,20tetraen-3-one (696 mg) in dry dichloromethane (15 ml) is added a solution of tetrachloro-o-benzoquinone (302 mg) in dry dichloromethane. An NMR analysis of the residue after evaporation of the solvent showed the reaction mixture to contain the title compound in an amount of about 45%. This mixture is used in the next step without further purification.

D) 11ss,21-bis(Acetyloxy)-5',6',7',8'-tetrachloro-9-fluoro-2',3'-dihydropregna-1,4- dieno[16a, 1 7-b][1, 4]benzodioxin-3,2O-dione The impure 11ss,21-bis (acetyloxy)-5',6',7',8'-tetrachloro-9-fluojro-2',3'-dihydro-20 trimethylsilyloxypregna-1,4,20-trieno[16α,17α-b][1,4]benzodioxin-3-one (900 mg) prepared as described above, is dissolbed in a mixture of 1,2-dimethoxyethane (10 ml) and 75% acetic acid (10 ml) and is heated in a bath at 1000C for 1.5 hours. The solution is then cooled, diluted with water and extracted with chloroform.The chloroform extracts are combined, washed with a dilute sodium bicarbonate solution and water, dried, evaporated and the residue subjected to preparative thin-layer chromatography on silica gel plates (using chloroform-methanol, 97:3, for development) to isolate 260 mg of the title compound, melting point 273-274"C (dec.) EXAMPLE 21 5',6',7',8',21-Pentachloro-9-fluoro-2',3'-dihydro-11ss-hydroxypregna-1,4-dieno[16α,17-b]- [1,4]benzodioxin-3,20-dione A) 9-Fluoro-11ss-hydroxy-21-methanesulfonyloxypregna-1,4,16-triene-3,20-dione A solution of 16 grams of 9-fluoro-11ss, 21-dihydroxypregna-1,4,16-triene-3,20-dione in dry pyridine (200 ml) is reacted with methanesulfonyl chloride (5.0 ml) for 2 hours at OOC.

The mixture is poured into an excess of cold 2N-hydrochloric acid. The solid that separates from the resulting solution is isolated yielding 17.5g of the title compound, which is characterized by its nmr spectrum.

B) 21-Chloro-9-fluoro-l l ss-hydroxypregna-1,4,16-triene-3,20-dione To a solution of 17.5 g of 9-fluoro-llss-hydroxy-21-methanesulfonyloxypregna-1,4,16- triene-3,20-dione in dry dimethylformamide (250 ml) is added lithium chloride (30 g). The mixture is heated, with stirring, from 30 to 1000C over a 30-minute period. It is cooled and poured into cold water (1.5 1) and the precipitated solid is isolated and crystallized from methanol to afford 12 g of the title compound, melting point 258-260"C (dec.).

C) 21-Chloro-9-fluoro-l 1 ss-hydroxy-20-trimethylsilyloxypregna-1,4,16,20-tetraen-3-one A solution of 21-chloro-9-fluoro-1 1 Bhydroxypregna-1,4, 16-triene-3,20-dione (456 mg) in dry dimethylformamide (9.0 ml) containing 1.2 ml of bis(trimethylsilyl)trifluoroacetamide (Regisil, Regis Chemical Company; contains 1% trimethylsilyl chloride) is heated in a tightly stoppered flask for 1.0 hour in a bath at 110-1150C. The solution is cooled, poured into dilute sodium bicarbonate solution and the steroid product is extracted into chloroform.The chloroform solution is washed several times with cold water, dried and evaporated to a gum that contains traces of dimethylformamide. (By dissolving this gum in ethyl acetate and diluting the solution with hexane, it is possible to isolate homogeneous 21-chloro-9-fluoro- 11 ss-hydroxy-20-trimethylsilyloxypregna-1,4,16,20-tetraen-3-one). The nmr spectrum shows the gum to be essentially a mixture of the title compound, the 11ss-trimethylsilyl derivative of the title compound and small amounts of other impurities.

D) 5',6',7',8',21-Pentachloro-9-fluoro-2',3'-dihydro-11ss-hydroxypregna-1,4 dieno[16α,17-b][1,4]benzodioxin-3,20-dione The impure 2 1-chloro-9-fluoro-1 1 (3-hydroxy-20-trimethylsilyloxypregna-1 ,4, 16,20- tetraen-3-one prepared as described above is dissolved in dry dichloromethane (15 ml) and a solution of tetrachloro-o-benzoquinone (312 mg) in dry dichloromethane is added. After 24 hours at room temperature, the solution is diluted with methanol (10 ml), 5% hydrochloric acid (0.3 ml) is added and the solution is kept at room temperature for 1.0 hour. The solution is then poured into water and the products are isolated by extraction with chloroform. The chloroform extract is washed with water, dried and the residue is subjected to preparative thin-layer chromatography on silica gel plates using chloroformethyl acetate (8:2) for development to isolate 460 mg of the title compound and 218 mg of the 1 11ss-trimethylsilyl derivative of the title compound. Two crystallizations of the 460 mg material from acetone-hexane yields 350 mg of the title compound, melting point 300-302"C (dec., discoloration starts long before melting).

EXAMPLE 22 21- (Acetyloxy) -5',6',7',8'-tetrachloro-9-fluoro-2',3'-d ihyd ro-11 ss-hydroxypregna-1,4- dieno[16a,17-b][1, 4]benzodioxin-3,20-dione A) 21 -(Acetyloxy) -9-fluoro-11 ss-hydroxy-20-trimethylsilyloxypregna-1,4,16,20-tetraen- 3-one A solution off 21-(acetyloxy)-9-fluoro-11ss-hydroxypregna-1,4,16-triene-3,20-dione (2,1g) in dry dimethylformamide and 7.0 ml of bis(trimethylsilyl)trifluoroacetmide (Regisil, Regis Chemical Company; contains 1% trimethylsilyl chloride) is heated in a tightly stoppered flask at 110-1150C for 3.0 hours. An additional 2.0 ml of Regisil is added and heating is continued for an additional hour. The solution is cooled and is added into a vigorously stirred 15% sodium bicarbonate solution (200 ml).The steroid product is then isolated by extraction with chloroform, washed with cold water, dried and evaporated to yield 3.1 g of a gum. On the basis of the NMR spectrum and thin-layer chromatograhy behavior, it is determined that this gum is mainly a mixture of the title compound and its 11 (3-trimethylsilyl derivative.

B) 21-(Acetyloxy)-5',6',7',8'-tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxypregna 1, 4-dieno[16o, 1 7-b][1, 4]benzodioxin-3,20-dione The above gum (3.1 g) is dissolved in dry dichloromethane (20 ml) and a solution of tetrachloro-o-benzoquinone (1.06 g, 4.33 mmole) in dry dichloromethane (7 ml) is added.

The solution is allowed to stand at room temperature for 20 hours. It is then evaporated in vacuo, mixed with dimethoxyethane (20 ml) and 75% acetic acid (10 ml), and heated in a bath at 100-105"C for 1.0 hour. The solution is cooled, diluted with water and extracted with chloroform. The chloroform solution is washed with a dilute sodium bicarbonate solution and water, dried (MgSO4 anh.) and evaporated to afford a gum. The gum is chromatographed over a column of silica gel (60 g). Elution of the column with chloroform-hexane (1:1) affords 708 mg of the 11ss-trimethylsilyl ether of the title compound as a foam. Further elution of the column with chloroform-hexane (3:1) and chloroform-ethyl acetate (3:1) affords 1.89 g of a gum which is a mixture of four compounds.

The gum (1.89 g) is exposed to acetic anhydride-pyridine for 3.0 hours and the product, after work-up, is chromatographed over silica gel (40 g). Elution of the column with chloroform gives 1.1 g of a mixture of 21-(acetyloxy)-9-fluoro-llss-trimethylsilyloxypregna- 1,4,16-triene-3,20-dione and 21-(acetyloxy)-5' ,6' ,7' ,8'-tetrachloro-9-fluoro-2' ,3'-dihydro 11ss-trimethylsilyoxypregna, 1,4-dieno[16α,17α-b][1,4]benzodioxin-3,20-dione. Further elution with chloroform-ethyl acetate (9:1) gives 600 mg of a semi-solid which is essentially a mixture of the title compound and another compound. The mixture is subjected to preparative thin-layer chromatography on silica gel plates (development with chloroformethyl acetate (2:8)) to isolate 230 mg of the title compound.

A solution of 415 mg of the 11ss-trimethylsilyl ether of the title compound in5.0 ml of dry tetrahydrofuran is cooled and stirred in a bath at -78 C. To this solution is added a solution of freshly prepared and dried tetrabutylammonium fluoride (350 mg) in dry tetrahydrofuran. After 15 minutes the solution is warmed to, and maintained, in a bath at -35 to -45"C for 1.0 hour and is then quenched with acetic acid (0.5 ml). The mixture is diluted with water and extracted with chioroform. The chloroform solution is washed with a dilute sodium bicarbonate solution and water, dried and evaporated. The residue is subjected to preparative thin-layer chromatography on silica gel plates to isolate 130 mg of the title compound.

The two crops of the title compound are combined and crystallized from ethyl acetate to afford 216 mg of the title compound, melting point 196-199"C.

EXAMPLE 23 11ss-(Acetyloxy)-5',6',7',8',21-pentachloro-9-fluoro-2',3',-dihydropregna-1,4-dieno[16α,17b][1,4]benzodioxin-3,20-dione A) 11 ss-(Acetyloxy)-21-chloro-9-fluoropregna-1,4,16-triene-3,20-dione A suspension of 21-chloro-9-fluoro-11ss-hydroxypregna-1,4,16-triene-3,20-dione (2.1 g) in a mixture of glacial acetic acie (30 ml) and acetic anhydride (30 ml) containing p-toluenesulfonic acid hydrate (2.1 g) is stirred at room temperature. After 30 hours the solution is mixed with sodium acetate hydrate (5.0 g) and evaporated in vacuo. The residue is dissolved in chloroform, washed with water, dried and evaporated to afford the title compound. One crystallization from acetone affords 1.85 g of the title compound, melting point 222-223"C (dec).

B) 11 (A cetytoxy) -21-chloro-9-fluoro-20-trimethylsilyloxypregna-1,4,16,20-tetraen-3- one A solution of 11ss-(acetyloxy)-21-chloro-9-fluoropregna-1,4,16-triene-3,20-dione (1,35 g) in dry acetonitrile (20 ml) containing 3.5 ml of bis(trimethylsilyl)trifluoroacetamide (Regisil, Regis Chemical Company; contains 1% trimethylsilyl chloride) is heated in a pressure vial at about 1500C for 1.0 hour. The solution is then cooled and evaporated in vacuo to leave 1.6 g of the title compound contaminated with trace amounts of less polar impurities. This is used in the next step without further purification.

C) 11ss-(Acetyloxy)-5',6',7',8',21-pentachloro-9-fluoro-2',3' -dihydropregna,1,4 dieno[16a, 1 7-b][1, 4]benzodioxin-3,20-dione The crude material from the previous experiment (1.6 g) is dissolved in dry dichloromethane (20 ml), mixed with a dichloromethane solution of tetrachloro-o-benzoquinone (984 mg), and the solution is left at room temperature for 18 hours. 10% Hydrochloric acid (10 ml) is added and the solution is stirred for 10 minutes. The resultant organic layer is separated, washed with a dilute sodium bicarbonate solution and water, dried and evaporated to a residue. This is subjected to column chromatography on silica gel (30g).

Elution with chloroform-hexane (1:1) removes first the non-steroidal impurities. Further elution with the same solvent system and chloroform affords 2.05 g of the title compound contaminated with a more polar impurity. This material is subjected to preparative thin-layer chromatography on silica gel plates (development with chloroform-ethyl acetate, 9:1) to isolate 1.67 g of the title compound which contains only traces of impurities. One crystallization of this from methanol affords 1.37g of the title compound, melting point 191-193"C.

EXAMPLE 24 5',6', 7', 8'- Tetrachloro-9- Iuoro-2 "3 '-dihydro-li hyd ro-11 ss-hyd roxy-21 4- dieno[16α,17-b'[1,4]benzodioxin-3,20-dione To a solution of 11ss-(acetyloxy)-5',6',7',8',21-pentachloro-9-fluoro-2',3'-dihydropregna 1,4-dieno 16a,17-b][1,4]benzodioxin-3,20-dione (1.07 g) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) containing water (2.0 ml) is added a solution of potassium carbonate (420 mg) in water (4.0 ml). The mixture is stirred at room temperature for 2.0 hours, acidified with 5% hydrochloric acid and concentrated in vacuo. From the residue the steroid is isolated by extraction with a mixture of chloroform and ethyl acetate. The material thus obtained is subjected to preparative thin-layer chromatography on silica gel plates (development with chloroform-ethyl acetate, 3:1) to isolate 410 mg of the title compound. This is crystallized from acetone-hexane to afford 280 mg of the title compound, melting point 203-204"C (dec.).

WHAT WE CLAIM IS: 1. A steroid having the formula

or the 1 ,2-dehydro derivative thereof, wherein A is %-X- or

R2 is fluoro, chloro, bromo, iodo, or cyano; R3 is hydrogen, fluoro, chloro, bromo or iodo; R4 is carbonyl, ss-hydroxymethylene or (3-acyloxymethylene; R5 is hydrogen or fluoro; R6 is

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (42)

**WARNING** start of CLMS field may overlap end of DESC **. B) 11 (A cetytoxy) -21-chloro-9-fluoro-20-trimethylsilyloxypregna-1,4,16,20-tetraen-3- one A solution of 11ss-(acetyloxy)-21-chloro-9-fluoropregna-1,4,16-triene-3,20-dione (1,35 g) in dry acetonitrile (20 ml) containing 3.5 ml of bis(trimethylsilyl)trifluoroacetamide (Regisil, Regis Chemical Company; contains 1% trimethylsilyl chloride) is heated in a pressure vial at about 1500C for 1.0 hour. The solution is then cooled and evaporated in vacuo to leave 1.6 g of the title compound contaminated with trace amounts of less polar impurities. This is used in the next step without further purification. C) 11ss-(Acetyloxy)-5',6',7',8',21-pentachloro-9-fluoro-2',3' -dihydropregna,1,4 dieno[16a, 1 7-b][1, 4]benzodioxin-3,20-dione The crude material from the previous experiment (1.6 g) is dissolved in dry dichloromethane (20 ml), mixed with a dichloromethane solution of tetrachloro-o-benzoquinone (984 mg), and the solution is left at room temperature for 18 hours. 10% Hydrochloric acid (10 ml) is added and the solution is stirred for 10 minutes. The resultant organic layer is separated, washed with a dilute sodium bicarbonate solution and water, dried and evaporated to a residue. This is subjected to column chromatography on silica gel (30g). Elution with chloroform-hexane (1:1) removes first the non-steroidal impurities. Further elution with the same solvent system and chloroform affords 2.05 g of the title compound contaminated with a more polar impurity. This material is subjected to preparative thin-layer chromatography on silica gel plates (development with chloroform-ethyl acetate, 9:1) to isolate 1.67 g of the title compound which contains only traces of impurities. One crystallization of this from methanol affords 1.37g of the title compound, melting point 191-193"C. EXAMPLE 24 5',6', 7', 8'- Tetrachloro-9- Iuoro-2 "3 '-dihydro-li hyd ro-11 ss-hyd roxy-21 4- dieno[16α,17-b'[1,4]benzodioxin-3,20-dione To a solution of 11ss-(acetyloxy)-5',6',7',8',21-pentachloro-9-fluoro-2',3'-dihydropregna 1,4-dieno 16a,17-b][1,4]benzodioxin-3,20-dione (1.07 g) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) containing water (2.0 ml) is added a solution of potassium carbonate (420 mg) in water (4.0 ml). The mixture is stirred at room temperature for 2.0 hours, acidified with 5% hydrochloric acid and concentrated in vacuo. From the residue the steroid is isolated by extraction with a mixture of chloroform and ethyl acetate.The material thus obtained is subjected to preparative thin-layer chromatography on silica gel plates (development with chloroform-ethyl acetate, 3:1) to isolate 410 mg of the title compound. This is crystallized from acetone-hexane to afford 280 mg of the title compound, melting point 203-204"C (dec.). WHAT WE CLAIM IS:

1. A steroid having the formula

or the 1 ,2-dehydro derivative thereof, wherein A is %-X- or

R2 is fluoro, chloro, bromo, iodo, or cyano; R3 is hydrogen, fluoro, chloro, bromo or iodo; R4 is carbonyl, ss-hydroxymethylene or (3-acyloxymethylene; R5 is hydrogen or fluoro; R6 is

alkyl, aryl or acyloxyalkyl; and R7 is hydrogen, fluoro, chloro, bromo, iodo, alkoxy or acyloxy; wherein the term "aryl" refers to phenyl or phenyl substituted with 1 or 2 alkyl, alkoxy, fluoro, chloro, bromo or iodo groups; the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms; and the term "acyloxy" refers to groups of the formula

wherein Y is alkyl or aryl.

2. A steroid in accordance with claim 1 wherein A is R,,X-.

3. A steroid in accordance with claim 2 wherein X is -S-.

4. A steroid in accordance with claim 2 wherein X is

5. A steroid in accordance with claim 2 wherein X is

6. A steroid in accordance with any one of claims 2-5 wherein R6 is alkyl.

7. A steroid in accordance with any one of claims 2-5 wherein R6 is aryl.

8. A steroid in accordance with any one of claims 2-5 wherein R6 is acyloxyalkyl.

9. A steroid in accordance with any one of claims 2-5 wherein R6 is alkyl, aryl, or acyloxymethyl; R2 is chloro, R3 is fluoro; R4 is (3-hydroxymethylene; and R5 is hydrogen.

10. A steroid in accordance with claim 1 wherein A is

11. A steroid in accordance with claim 10 wherein R7 is hydrogen.

12. A steroid in accordance with claim 10 wherein R7 is chloro.

13. A steroid in accordance with claim 10 wherein R, is methoxy.

14. A steroid in accordance with claim 10 wherein R7 is acetyloxy.

15. A steroid in accordance with any one of the preceding claims wherein R2 is halogen.

16. A steroid in accordance with any one of the preceding claims wherein R2 is chloro.

17. A steroid in accordance with any one of the preceding claims wherein R3 is fluoro.

18. A steroid in accordance with any one of the preceding claims wherein R4 is (3-hydroxymethylene.

19. A steroid in accordance with any one of claims 1 to 17 wherein R4 is (3-acyloxymethylene.

20. A steroid in accordance with any one of the preceding claims wherein R5 is hydrogen.

21. The steroid in accordance with claim 1, 5',6',7',8'-tetrachloro-9-fluoro-2',3'dihydro- 11 (3-hydroxy-17-(methylthio)androsta-1 ,4-dieno[16a, 17c:-bj[1 ,4jbenzodioxin-3- one.

22. The steroid in accordance with claim 1, 5',6',7',8'-tetrachloro-9-fluoro-2',3'- dihydro-1 1 (3-hydroxy- 17-(methylsulfinyl)androsta- 1 ,4-dieno[16a, 17a-b] [1 ,4jbenzodioxin- 3-one.

23. The steroid in accordance with claim 1, 5',6',7',8'-tetrachloro-9-fluoro-2',3'- dihydro- 11 (3-hydroxy- 17-(methylsulfonyl)androsta- 1 ,4dieno[16a, 17a-bj[1 ,4]benzodioxin- 3-one

24. The steroid in accordance with claim 1,5',6',7',8'-tetrachloro-17-(ethylthio)-9 fluoro-2',3'-dihydro-11ss-hydroxyandrosta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one.

25. The steroid in accordance with claim 1,5',6',7',8'-tctrachloro-17-(ethylsulfinyl)-9 fluoro-2',3'-dihydro-11ss-hydroxyandrosta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one.

26. The steroid in accordance with claim 1,5',6',7',8'-tetrachloro-17-(ethylsulfonyl)-9fluoro-2',3' -dihydro-11ss-hydroxyandrosta-1,4-dicno[16α17α-b][1,4]benzodioxin-3-one.

27. The steroid in accordance with claim 1,5',6',7',8'-tetrachloro-9-fluoro-2',3' dihydro-11ss-hydroxy-17-(phenylthio)androsta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3- one.

28. The steroid in accordance with claim 1, 5',6',7' ,8'-tetrachloro-9-fluoro-2' ,3'-dihydro- 11ss-hydroxy-17-(phenylsulfinyl)androsta-1,4-dieno[16α,17α-b][1,4]benzodioxin-3-one.

29. The steroid in accordance with claim 1, 5',6',7',8'-tetrachloro-9-fluoro-2',3' dihydro-11ss-hydroxy-17-(phenylsulfonyl)androsta-1,4-dieno[16α,17α-b][1,4]benzodioxin- 3-one.

30. The steroid in accordance with claim 1, 17-[[(acetyloxy)methyl]thio]-5',6',7',8' tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxyandrosta-1,4-dicno{16α,17α- b][1,4]benzodioxin-3-one.

31. The steroid in accordance with claim 1,17-[[(acetyloxy)methyl]sulfinyl]-5',6',7',8'tetrachljoro-9-fluoro-2',3' -dihydro-11ss-hydroxyandrosta-1,4-dieno[16α,17α- b][1,4]benzodioxin-3-one.

32. The steroid in accordance with claim 1, 17-[[(acetyloxy)methyl]sulfonyl]-5',6',7',8' tetrachloro-9-fluoro-2',3'-dihydro-11ss-hydroxyandrosta-1,4-dieno[16α,17α- b][1,4]bcnzodioxin-3-one.

33. The steroid in accordance with clain 1 having the name 11ss-(acetyloxy)-5',6',7',8'tetrachloro-9-fluoro-2' ,3 '-dihydropregna- 1 ,4-dieno[16a, 17-b] [1 ,4jbenzodioxin-3 ,20-dione.

34. The steroid in accordance with claim 1 having the name 11(3,21-bis-(acetyloxy- 5' ,6' 7' ,8'-tetrachloro-9-fluoro-2' ,3 '-dihydropregna-1 ,4-dieno[16a, 17-b][1 ,4jbenzodioxin- 3.20-dione.

35. The steroid in accordance with claim 1 having the name 5',6',7',8',21-pentachloro 9-fluoro-2',3'-dihydro-11ss-hydroxyprcgna-1,4-dieno[16α,17-b][1,4]benzodioxin-3,20- dione.

36. The steroid in accordance with claim 1 having the name 21-(acctyloxy)-5',6',7',8' tetrachloro-9-fluoro-2',3' -dihydro-11ss-hydroxypregna-1,4-dieno[16α,17- b][1,4]benzodioxin-3,20-dione.

37. The stcroid in accordance with claim 1 having the name 11ss-(acctyloxy)5',6',7',8',21-pentachloro-9-fluoro-2',3' -dihydropregna-1,4-dieno[16α,17- b][1,4]benzodioxin-3,20-dione.

38. The steroid in accordance with claim 1 having the name 5',6',7',8'-tetrachloro-9 fluoro-2',3'-dihydro-11ss-hydroxy-21-methoxypregna-1,4-dieno[16α,17-b][1,4]benzodioxin- 3,20-dione.

39. A steroid having the formula

or the 1,2-dehydro derivative thereof, wherein R'7 is hydrogen, fluoro, chloro, bromo, iodo or

wherein Y is alkyl of 1 to 10 carbon atoms or aryl; R2 is halogen or cyano; R3 is hydrogen or halogen; and R5 is hydrogen or fluorine.

40. A process for the preparation of a steroid having the formula

or the 1,2-dehydro derivative thereof, wherein A is R6-X- or

R2 is fluoro, chloro, bromo, iodo, or cyano; R3 is hydrogen, fluoro, chloro, bromo or iodo; R4 is carbonyl, ss-hydroxymethylene or (3-acyloxymethylene; R5 is hydrogen or fluoro;R6 is alkyl, aryl or acyloxy-alkyl; and R7 is hydrogen, fluoro, chloro, bromo, iodo, alkoxy or acyloxy; wherein the term "aryl" is phenyl or phenyl substituted with 1 or 2 alkyl, alkoxy, fluoro, chloro, bromo or iodo groups; the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms; and the term "acyloxy" refers to groups of the formula 0 o Y-C-Owherein Y is alkyl or aryl, which comprises reacting a steroid of the formula

or a steroid of the formula

wherein R', is hydrogen, acyloxy or halogen, with an o- benzoquinone having the formula

to form a steroid product, and when the steroid product contains X as divalent sulfur, optionally oxidizing this product to form the corresponding sulfinyl product or the corresponding sulfonyl product; or when the steroid product contains R'7 as 21-halo, optionally reacting this product with an alkanol of 1 to 10 carbon atoms to form the corresponding 21-alkoxy product.

41. A steroid in accordance with claim 1 as named in any of Examples 13-18.

42. A steroid in accordance with claim 1 when prepared by a process in accordance with claim 40.