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    • 专利摘要:
    Described are 3-Ketoandrostenes having in the 17-position the substituents R1-S- and R2-S- wherein R1 and R2 are the same or different and each is alkyl, cycloalkyl or aryl, which have antiinflammatory activity.
    公开号:SU1189353A3
    申请号:SU823480340
    申请日:1982-08-19
    公开日:1985-10-30
    发明作者:Каннадиковилаком Варма Рави
    申请人:Е.Р.Сквибб Энд Санз,Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new steroid compounds, namely, 3-keto-postenes of the general formula: where R, and R 2 is lower alkyl, cyclohexyl, phenyl; - double or simple bond, R is hydrogen, provided that R j and R 2 are different, possessing valuable pharmacological properties. The purpose of the invention is to obtain new steroid derivatives with valuable pharmacological properties. Example 1. 17- (Ethylthio) -9fluoro-11/3-hydroxy-17- (methylthio) -androst-1., 4-diene-3-one. A.11 / 3 -Acetyloxy-9-fluorohydrod 1,4-diene-3, 17-dione. A solution of 9-fluoro-1Sh-oxyandrosta1, 4-diene-3, 17-dione (5.0 g) in a mixture of acetic acid (60 ml) and acetic anhydride (60 ml) containing a pair of toluenesulfonic acid (2.5 g), incubated at room temperature for 18 h. Add natTiLI acetate (2.5 g) and concentrate the mixture in vacuo at 35-40 0. The residue is diluted with water (150 ml) and the solid is filtered; washed with water and dried vacuum to obtain the title compound as a solid product (5.0 g) with corresponding spectral characteristics. Studies (silica gel, chloroform - ethyl acetate, 95: 5) showed the presence of a small amount of the original steroid as the only noticeable impurity. This material is used in the next step without further purification. A sample recrystallized from acetone-hexane is melted at 173-174 B.11 -Acetyloxy-17, 17-bis (methylthio) 9-fluorostrost-1, 4-diene-3-one To a solution of 11th-acetyloxy-9-fluorostanstro- 1, 4-Dien-3-one (5.0 g) 32 In a mixture of acetic acid (25 ml) and dichloromethane (25 ml) containing methanethiol (2.5 ml), boron trifluoride distilled ether (0.5%) was added. ml), and then the resulting mixture is stirred for one hour. Then water (150 ml) is added and extracted with chloroform. The chloroform solution is washed with water, a saturated solution of NaHCO and water, dried over anhydrous magnesium sulphate and evaporated. The residue is adsorbed onto a silica gel column (30 g). By successively elution of the column with chloroform-hexane (4: 1), chloroform and chloroform-ethyl acetate (95: 5 and 9: 1), a reacted steroid containing thiol derivatives as impurities (3.0 g), indicated in the title compound (1.7 g) and unreacted starting material. After crystallization of 1.7 g of material from acetone-hexane mixture, 1.2 g of material are obtained with a mp. 220-222 C with the corresponding spectral characteristics. C. Acetyloxy-9-fluoro-1 7 (methylthio) -androsta-1,4,16-trien3-one. 11p-Acetyloxy-17, 17-bis- (methylthio) -9-fluorostrost-1, 4-dien-3-one (1.1 g) is suspended in dry dimethylbenzene (30 ml). After refluxing for 20 minutes, the resulting solution is cooled, poured onto a column of silica gel (15 g) and the column is eluted successively with chloroform-hexane (7: 3), chloroform, and chloroform-ethyl acetate (95: 5) to the title compound (900 mg) and 1 1/3-acetyloxy9-fluorostrost-1, 4-dien-3, 17-dione (120 mg). As a result, crystalline. 900 mg of material from ethyl acetate-hexane get 800 mg of material with so pl. 192-194 C with the corresponding spectral characteristics. D. 11 / -Acethyl-17-(ethylthio) 9-fluoropropane-1 7- (methylthio) -androsta-1,4diene-3-one. To a solution of 11/3-acetyloxy-9-fluoro17- (methylthio) -androsta-1,4-dien3-one (632 mg) in dry dichloromethane (20 ml) containing dry ethanethiol (0.6 ml) is added boron trifluoride (0.25 ml). After one hour, the mixture was added to a solution of NaHCO} and extracted with chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to give the title compound (620 mg) contaminated with a small amount of 11/5-acetyloxy-9 -fluorandrosta-1,4diene-3, 17-dione. This material is used in the next step without further purification. A sample recrystallized from acetone: hexane has a mp. 140-142 C and the corresponding NMR spectrum. E. 17- (Ethylthio) -9-fluoro-11A-oxy, 17- (methylthio) -andprosta-1, 4-dien3-one. A solution of 11/3-acetyloxy-1 7- (ethyl thio) - E-fluoro-1 7 - (methylthio) -androst 1,4-diene-3-one (620 mg) in a mixture of methanol (20 ml) and tetrahydrofuran (10 ml) is stirred in a nitrogen atmosphere with a ZM aqueous sodium hydroxide (1.5 ml). After 18 hours, a slight excess of acetic acid is added. The resulting mixture was concentrated in vacuo, diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried, evaporated and chromatographed on a silica gel column (10 g), eluting the column successively with chloroform-hexane (4: 1), chloroform and chloroform-ethyl acetate (95: 5) until the title compound is obtained. (550 mg). After crystallizing it from a mixture of ethyl acetate - hexane and drying at 110 ° C, 0.3 mm Hg. within 7 h receive an analytical sample with so pl. 275 C with decomposition (compressed from approximately 200 C, melting begins at approximately 220 C and becomes stronger until spontaneously melts at 275 C with decomposition) with appropriate spectral characteristics. The NMR spectrum shows that, mainly, there is a 1: 1 mixture of two 17-stereo isomers. Elemental analysis,%: Found,%. C, 64.16; H 7.69; F 4.59; S 15.49. 534 discharged,%: C 64.35; H 7.61; F 4.63, - S 15.62. Example 2. 17- (Ethylthio) -9fluoro-11/3-hydroxy-17- (phenylthio) -androst-1, 4-diene-3-one, isomer A. A. 11/3-Acetyloxy-9-fluorostrost1, 4-diene-3, 17-dione. A solution of 20 g of 9-fluoro-11/3-hydroxyandrost-1, 4-diene-3, 17-dione, 120 ml of glacial acetic acid, 120 ml of acetic anhydride and 5 g of para-toluene sulfonic acid are stirred at room temperature under nitrogen atmosphere in 24 hours. The resulting solution is quenched with 5 g of sodium acetate. The solvent was partially removed in vacuo at 35-40 ° C and the resulting slurry was diluted with chloroform. The chloroform solution is washed with water, saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield the title compound. It was crystallized from ethyl acetate-hexane to give 20 g of the title compound with m.p. 171-174 C with the corresponding spectral characteristics. B. 11 -Acetyloxy-17, 17-bis (ethylthio) -9-fluorandrosta-1,4-dienZ-one. A solution of 20 g (55.5 mmol) of 11/3-acetyloxy-9-fluorodrost1, 4-diene-3, 17-dione in 75 ml of dry dichloromethane and 75 ml of glacial acetic acid is mixed with 10 ml of ethanethiol and 2 ml of trifluoride etherate boron at room temperature in a nitrogen atmosphere. After 2.0 hours, the resulting solution was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The gummy residue is dissolved in a mixture of 1; 1 chloroform - hexane and chromatographed on a column of 150 g of silica gel, eluting it in succession with a mixture of chloroform - hexane (1: 1, 6: 4 and 7: 3), chloroform, a mixture of chlorophoethyl acetate (5: 95 and 1: 9) and a mixture of methanol-chloroform (1: 9) to obtain 9.5 g of unreacted 11 p-acetyloxy-9-fluoro-androsta-1,4-dien-3, 1 7-dione, .8.2 g of reacted steroid product and 5.2 g of the title compound with mp. 246-250 C with the corresponding spectral characteristics.
    C. 11Y-Acetyloxy-17- (ethylthio) E-fluorandrosta-1, 4,16-trien-3-one.
    A suspension of 5.2 g of 1lp-acetyloxy17, 17-bis- (ethylthio) -9-fluorostrost 1, 4-dien-3-one in 85 ml of dry diethylbenzene is stirred at 180 ° C. (oil bath temperature) for 1 hour; the suspension gradually goes into a homogeneous solution as it is heated. The resulting solution is cooled to 0 ° C and the solid precipitated is filtered off and dried under vacuum to give 3.6 g of the title compound with mp. 211-215 C with appropriate spectral characteristics.
    The obtained filtrate is chromatographed on a column of 30 g of silica gel, eluting with successively a mixture of chloroform-hexane (1: 1) and chloroform, to obtain an additional 0.4 g of the title compound.
    D., 11/3-Acetyloxy-17- (ethylthi6) 9-Fluoro-17- (phenylthio) -androsta-1,4diene-3-one.
    A solution of 1.2 g (2.97 mmol) of 11-acetyloxy-17- (ethylthio) -9-fluoro-strost-1, 4, 16-triene-3-one, 18 ml of dry dichloromethane and, 8 ml of thiophenol is cooled to -20. C in nitrogen atmosphere. Then boron trifluoride etherate is added. The solution is stirred at (-10) - (-20) ° C for 2 hours under nitrogen atmosphere. The resulting solution is diluted with dichloromethane, washed with sodium bicarbonate and sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give gums. It is dissolved in chloroform: hexane (1: 1) and chromatographed on a silica gel column (20 g). sequentially with chloroform-hexane (1: 1), chloroform with chloroform-ethyl acetate (95: 5), and chloroform-methanol (9: 1) to obtain 1.0 g of the crude title compound. It is dissolved in a minimum amount of ethyl acetate and left at room temperature for 2 days. The solid portion, precipitated 5, is filtered to obtain 480 mg of the title compound with m.p. 152-158 0 with the corresponding spectral characteristics.
    0 E. 17- (Ethylthio) -9-FTOR-11/3-Oxy-17- (Phenylthio) -androst-1,4-dien3-one, isomer A.
    A stream of nitrogen is bubbled through a solution of 560 mg of 11y-acetylrxy-175 (ethylthio) -9-fluoro-17- (phenylthio) androsta-1, 4.-diene-3-one in a mixture of tetrahydrofuran (30 ml), methanol (15 ml) and water (1.0 ml) over 15 minutes, then sodium hydroxide 0 (12%, 1.2 ml) is added. The solution was stirred at room temperature under nitrogen for 1.5 hours, acidified with acetic acid and evaporated in vacuo to give a solid. It is washed with a small amount of water to obtain 480 mg of the title compound. As a result of recrystallization from an acetone-hexane mixture, 400 mg of an analytical sample are obtained with a mp. 272273 С with decomposition, with the corresponding spectral characteristics.
    Elemental analysis,%:
    Found,%: C 68.37; H 7.00, F 4.08; S 13.56.
    C2jH ,, FO, S2.
    Calculated,%: C 68.61; H 7.04; 0 F 4.02; S 13.57.
    Example 3. 17- (Ztiltio) -8fluoro-11-oxy-17- (phenylthio) -androst-1, 4-dien-3-one, isomer B.
    A. 11th-Acetyloxy-17, 17-bis5 (phenylthio) -9-fluorostrost-1,4-dien3-one ..
    A solution of 8.5 g of 11 and-acetyloxy-9fluorandrost-1, 4-diene-3, 17-dione (Example 1A) in 60 ml of dry dichloro methane and 60 ml of glacial acetic acid is mixed with 8.0 ml of thiophenol and 1 , 5 ml of boron trifluoride zifirata at room temperature under nitrogen atmosphere for 3.5 hours
    5 The resulting solution is diluted.
    dichloromethane, washed with water, saturated sodium bicarbonate and water, dried over anhydrous sulfa7
    t and evaporate in vacuo. The gummy residue is dissolved in chloroform-hexane (7: 3) and chromatographed on a silica gel column (100 g), eluting successively with chloroform-hexane (7: 3), chloroform, chloroform-ethyl acetate (9: 1) and chloroform - methanol (9: 1) to obtain 4.8 g of unreacted 11 acetyloxy-9-fluoro-androsta-1, 4-dien 3, 17-dione, 3.0 g of the reacted steroid product and 1.5 g of the above, in the title from m.p. 233-235 C with appropriate spectral characteristics.
    B.11 / 5-Acetyloxy-9-fluoro-17 (phenylthio) -androsta-1,4,1b-trien3-one.
    A suspension of 1.5 g of 1W-acetyloxy17, 17-bis- (phenylthio) -9-fluorostrost-1, 4-dien-3-one in 25 ml of dry diethylbenzene is stirred at 185-190 ° С (oil bath temperature) in within 1 hour. The suspension gradually turns into a homogeneous solution during heating. The resulting solution was cooled to O ° C. The precipitated solid was filtered and dried in vacuo to give 0.9 g of the title compound with mp. 228229 C with the corresponding spectral characteristics.
    The obtained filtrate is chromatographed on a column of 25 g of silica gel, eluting successively with a mixture of chloroform-hexane (1: 1) and a mixture of chloroform-ethyladetate (1: 9 to obtain another 0.25 g of the title compound.
    C.1 f-Acetyloxy-7- (ethylthio) 9-fluoro-17- (phenylthio) -androst 1, 4-dien-3-one, isomer B.
    A solution of 1.0 g of 11D-acetyloxy9-fluoro-17- (phenylthio) -androst-1, 4,6-trien-3-one, 12 ml of dry dichloromethane and 0.5 ml of ethanethiol are cooled to -10 ° C in nitrogen atmosphere Then trifluoride boron ester is added. The resulting solution was stirred under a nitrogen atmosphere for 2.5 hours. The resulting solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. 893538
    vacuum until a foamy solid is obtained. It is dissolved in chloroform and chromatographed on two pre-treated 5 silica gel plates for those (E. Merk, 20 cm-20 cm "2 mm, a mixture of ethyladetate - chloroform 1: 4 for development) to obtain 800 mg of a slightly contaminated compound, 10 specified in the title. It was crystallized from ethyl acetate-hexane to give 500 mg of the title compound with mp. 145НВ С with corresponding spectral characteristics.
    D. 17- (Ethylthio) -9-11 / -Oxy-17 (Phenylthio) -androst-1,4-diene-3-one, isomer B.
    A stream of nitrogen is bubbled through a solution of 545 mg of 1-at-acetyloxy-17 (ethylthio) -9-fluorop-17- (phenylthio) andandprosta-1, 4-dien-3-one in a mixture of tetrahydrofuran (30 ml), methanol (15 ml) and water (1.0 ml) for 25–15 min. Sodium hydroxide (12%, 1.2 ml) is then added. The solution is stirred at room temperature under nitrogen for 1.5 hours. The resulting solution is acidified with acetic acid and the solvent is evaporated off under vacuum to give a solid. It is moistened with a small amount of water and filtered. The hard part is recrystall. from acetone-hexane to give 370 mg of an analytical sample with m.p. 263-264 0 with decomposition, with corresponding spectral characteristics, e Elemental analysis,%:
    Found,%: C 68.73, H 6.81; F 4.04; S 13.52. .
    Calculated,%: C 68.61i H 7.04, 5 F 4.021 S 13.57.
    Example 4. 17- (Butylthio) 17- (ethylthio) -9-fluoro-11-oxyandrost-1, 4-diene-3-one.
    A. 11 -Aceticyloxy-17- (butylthio) g 17- (ethylthio) -9-fluorostrost-1,4-diene-3-one.
    A solution of 11E-acetyloxy-17- (ethylthio) -9-fluoroprotein-1, 4.16-triene-3. It (700 mg, cm, example 1GS and
    n-butanethiol (271 mg) is cooled and the ne55 is stirred in a bath at (-40) - (-45) C, freshly distilled etherate / boron trifluoride (0.3 ml) is added. After 2 hours, at (-40) - (-45) ° C, the solution was gradually heated to 10 ° C over 1.5 hours. The mixture was then diluted with dichloromethane, washed successively with sodium bicarbonate and brine, dried over anhydrous sulfate, and evaporated , resulting in a crude product indicated in the title. This material is chromatographed on a column of silica g (20 g), the column is eluted with chloroform-hexane (1: 1, 1: 4), chlorine form and chloroform-ethyl acetate (95: 5) to give the title compound. Studies of the NMR spectrum and the behavior of TLC show that this material contains significant amounts of the original steroid, which is difficult to separate from the more polar isomeric product in the systems studied. Under these TLC conditions, a partial separation of the two 17-isomers is achieved, V. 17- (Butylthio) -17- (ethylthio) 9-fluoro-11B-oxyandrost-1, 4-dien3-one. 11M-Acetyloxy-17- (butylthio) 7- (ethylthio) -9-fluorodrost-1,4diene-3-one (9.25 mg) was dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml). The solution is stirred, flushed with nitrogen and 3, OM sodium hydroxide is added. After 2 hours, a small excess of acetic acid was added and then the mixture was concentrated in vacuo. It is diluted with water (150 ml) and extracted with chloroform. The chloroform extracts are washed with water, dried over anhydrous magnesium sulphate and evaporated to yield the title compound (870 mg). A study of the NMR spectrum and the behavior of those compounds shows the presence of a certain amount of 17- (et thio) -9-fluoro-11p-oxyandrost-1,4, 16-triene-3-one and two 17-steroiz moat of the title compound. This material was applied onto 42.0 mm of Mgc silica gel plates and the plates were developed twice with chloroform-ethyl acetate (7: 3). Products from the upper 1/3 and lower 2/3 broad bands were separated separately, extracting a mixture of chloroform and methanol (3: 1) to obtain respectively 310,340 and 527 mg of solid product. After crystallization of 340 mg of a solid product from ethyl acetate-hexane (1: 1) and drying (10CN0.3 mm Hg, 20 h), an analytical sample of the title compound (281 mg) is obtained. 118-125с with the corresponding spectral characteristics. Elemental analysis,%: Found, C, 66.10; H 8.19, F 4.01; S 13/98. C, jH, FO, S2. Calculated,%: C, 66.33; - H, 8.24; F 4.20; S 14.16. Example 5. 17 ° C- (Ethylthio) 9-fluoro-11A-OXI-17- (methylthio) -androst-1, 4-diene-3-one. A.11 / -Acetyloxy-17o | - (ethylthio) 9-fluoro-11-hydroxy-17- (methylthio) -androsta-1, 4-dien-3-one. A solution of 11/3-acetyloxy-9-fluoro17- (methylthio) -androst-1,4,16-trienZ-one (2.1 g) in dry dichloromethane (45 ml) containing dry zthanethiol (1.5 ml), cooled in a bath at a temperature of about -40 ° C (dry ice-acetonitrile bath), add trifluoride etherate (1.5 ml). After 2 hours at -40 ° C., the reaction is quenched by adding a 10% solution of sodium carbonate with vigorous stirring at low temperature. The mixture is then warmed to room temperature, diluted with water and extracted with chloroform. The chloroform extracts are combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to give the title compound in quantitative yield (2.38 g). After crystallization of this solid from an acetone-hexane mixture, an analytical sample (1.8 g) is obtained with a mp. 170172 C with the corresponding spectral characteristics. B.17m- (Ethylthio) -9-fluoro-11 -oxy-17- (methylthio) androsta-1,4-dienZ-one. Solution 11/3-acetyloxy-17th- (ethylthio) -9-fluoro-17 - (methylthio) -androst1, 4-dien-3-one (1.85 g) in a mixture of methanol (15 ml) is stirred with a 3M solution of sodium hydroxide (2.5 ml) for an hour. A moderate excess of acetic acid is then added and the resulting mixture was concentrated in vacuo to give a suspension (about 10 ml). It is diluted with ice water, the precipitated precipitate is isolated by filtration, washed with water and. dried to yield the title compound (1.62 g). After crystallizing it from a mixture of acetone and hexane, an analytical sample (1.25 g) is obtained. 218-220C, re-curing and NOM melting at 261-265 ° C with decomposition and discoloration. Elemental analysis,%: Found,%: C 64.7; H 7.61; F 4.85, - S 15.59. 77 22 with 64.35; n 7.6i; Calculated 7, F 4.63; S 15.62. . Example 6. 17th- (Ethylthio) -9 fluoro-1S-hydroxy-17- (methylthio) -andros 1,4-dien-3-one. A. 11 -Acetyloxy-17-methylthio-9 fluoro-17- (methylthio) -androst-1,4diene-3-one. A solution of 1.71 g (2.5 mmol) of 11/3 acetyloxy-17- (ethylthio) -9-fluoro sta-1,4,16-trien-3-one in 15 ml of dry dichloromethane and 3.4 ml of methyl mercaptan solution in dichloromethane (1.82 g in .10 ml of dry dichloromethane) is cooled to -40 ° C (acetonitrile-dry ice) under nitrogen atmosphere, then ether of three boron fluoride (0.7 ml) is added. The solution is stirred at about -40 ° C under nitrogen for 3 hours, quenched with saturated sodium bicarbonate solution at -40 ° C with vigorous stirring, diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to obtain 1, 0 g of the title compound with mp. 185-186 C with the corresponding spectral characteristics. B. 17p- (Ethylthio) -9-fluoro-1 17- (methylthio) androsta-1,4-diene-Zones. A stream of nitrogen is bubbled through a solution of 1.0 g of 11A-acetyloxy-17 3 (ethylthio) -9-fluoro-17- (methylthio) androsta-1, 4-diene-3-one in a mixture of terrahydrofuran (30 ml), methanol ( 25 ml) and water (2 ml) for 15 minutes. Sodium hydroxide (12%, 2.5 ml) is then added. This solution was stirred at room temperature 312 under nitrogen for 2 hours, acidified with acetic acid and evaporated in vacuo to give a slurry. It is redissolved in chloroform, washed with water, dried over anhydrous sodium sulphate and. evaporated in vacuo to yield the title compound (855 mg). After crystallization from an acetone-hexa mixture, 710 mg of an analytical sample are obtained with a mp. 258-259 С with decomposition, with corresponding spectral characteristics. Elemental analysis,%: Found,%: C 64.57; H 7.42, F 4.79; S 15.65. .FOzS. Calculated,%: C 64.35, H 7.61; F 4.63; S 15.62. Example 7. 17ot- (Ethylthio) 11A-OXY-17- (methylthio) -androst1, 4-diene-3-one. A.11 /} - Oxy-17- (methylthio) androsta-1, 4,16-triene-3-one. A suspension of 11J-OXI-17, 17-bis (methylthio) -androsta-1,4-dien-3-one (2.6 g) in dry diethylbenzene (120 ml) is heated under reflux for 1 h in a bath at a temperature of about 200 ° C, then the resulting solution is cooled to room temperature and then in an ice bath to obtain the title compound as needles (2.1 g) after filtration and washing with hexane. The filtrate is then chromatographed on a column with 30 g of silica gel to obtain another 100 mg of product. The total yield is thus 2.2 g of the product with a mp. 240-241 With decomposition with the corresponding NMR spectrum. B.17 (ii- (Ethylthio) -11UZ-hydroxy-17 (methylthio) -androsta-1,4-diene-3-one. Suspension of 115-hydroxy-17- (methylthio) androsta-1, 4,16-triene -3-she (1.0 g) in 70 ml of dichloromethane containing ethanol (1.12 g, 1.36 ml) is cooled and stirred in a bath at -78 ° C (acetone — dry ice) and boron trifluoride etherate (860 mg, 0, 76 ml.) After -2 hours, the reaction was quenched by adding a solution of sodium hydroxide (2.0 g) in methanol: water (1: 1; 30 ml) with vigorous stirring. The mixture was then heated to room temperature.
    The cultures were diluted with 20% hydrochloric acid (50 ml) and extracted with chloroform. The chloroform solution is washed with dilute sodium bicarbonate solution and water, dried over anhydrous magnesium sulphate, evaporated and the residue chromatographed on a silica gel column (20 g), eluted with chloroform and chloroform-ethyl acetate (9: 1) to remove some 17- ketone. The title compound (1.03 g) was crystallized from ethyl acetate-hexane and dried (75 ° C; 0.3 mmHg, 7 hours) to obtain an analytical sample of the title compound (850 mg), mp . 176-178 C with appropriate spectral characteristics,
    Elemental analysis,%: Found,%: C 67.54 H, 7.92; S 16.26.
    22
    Calculated,%: C 67.30; H 8.22; S 16.33.
    Example B. 17 / 5- (Ethylthio) 11Y-OXY-17- (methylthio) -andprosta1, 4-diene-3-one.
    A.17- (Ethylthio) -11B-oxyandrost1, 4,16-triene-W-one.
    A suspension of 4.4 g of 17, 17-bis- (ethylthio) -11 / -oxnandrost-1,4-diene-Zone (see Example 2) in 100 ml of dry distilbenzene is stirred at 190-195 ° C (oil bath temperature) within 1.5 hours. The suspension, when heated, is converted into a solution, the resulting solution is cooled to 0 ° C. The solid precipitate was filtered and dried in vacuo to give 3.0 g of the title compound with mp. 21b-218 ° C with appropriate spectral characteristics. The resulting filtrate is chromatographed on a column of 50 g of silica gel, eluting successively with a mixture of chloroform-hexane (1: 1) and chloroform-ethyl acetate (9: 1) to obtain an additional 0.5 g of the title compound.
    B. (Ethylthio) -11 9-hydroxy-17 (methylthio) -androsta-1,4-dien-3-one.
    A suspension of 1.0 g of 17- (ethylthio) 11B-oxyandrost-1, 4.16-trien-3-one in 30 ml of dry dichloromethane and 1.5 ml of methyl mercaptan solution in
    8935314
    dry dichloromethane (1.34 g in 10 ml of dry dichloromethane) is cooled to -78 ° C (dry ice-acetone bath) under nitrogen atmosphere. Boron trifluoride etherate (0.4 ml) is then added and the suspension gradually goes into solution. This solution is stirred at -78 ° C under nitrogen for 5 hours, quenched 5 ml
    About a solution of sodium hydroxide in methanol (2.0 g of sodium hydroxide in 40 ml of methanol) at -70 ° C with vigorous stirring, diluted with chloroform and poured into water.
    t5 The chloroform solution is taken up, dried over anhydrous sodium sulphate and evaporated in vacuo to give 1.1 g of a foamy solid. Experience on a small scale using 100 mg of 17- (ethylthio) 11-oxyandrost-1, 4,16-trien-3-she gives 100 mg of material identical in this data and NMR.
    25 Example 9. (11/3, 17ob) -17 (Butylthio) -9-fluoro-11-hydroxy-17- (methylthio.) - androsta-1, 4-diene-3-one.
    Suspension of 696 mg (2 mol) 9-fluoro-1 1 hydroxy-17- (methylthio) -andro 30 of sta-1,4,16-trien-3-one in 20 ml of dry dichloromethane and 2.14 ml (20 mmol) 1 - butanediol is cooled to -78 ° C (in an acetone-dry bath - dry ice) in a nitrogen atmosphere. Then boron trifluoride etherate (0.5 ml) is added. The suspension is constantly becoming a homogeneous solution. This solution is stirred under a nitrogen atmosphere for four
    For hours, quench 4.5 ml of 5% sodium hydroxide in methanol at low temperature, with vigorous stirring, dilute with chloroform, wash with water, dry with anhydrous sodium sulfate and evaporate in vacuo to obtain a foamy solid. It is dissolved in chloroform and chromatographed on two pretreated silica gel plates for TLC (20 cm-20 cm-2 mm), 1.4 mixture of ethyl acetate / chloroform as a developer, until 460 mg (52, 4%) are indicated. compounds homogenous according to TLC. After crystallization from an acetone-hexane mixture, 370 mg (42.2%) of an analytical sample are obtained with a mp. 188-191 С,
    15
    with appropriate spectral
    characteristics.
    Elemental analysis. %: Found, C 65.89; H 8.05;
    F 4.27, - S 14.44.
    CiiHjsFOzS 2
    Calculated,%: C 65.72; H 8.04;
    F 4.33; S 14.62.
    Example 10. (11 / i, 17) 9-Fluoro-11-hydroxy-17- (methylthio) -17 (propylthio) -androsta-1,4-diene-3-one
    A.11 / 3-Acetyloxy-9-fluoro-1 7f (methylthio) -17- (propylthio) -androst, 1-4-dien-3-one.
    A solution of 500 mg (1.28 mmol) of 11/5-acetyloxy-9-fluoro-17- (methylthio) -androst-1,4-16-triene-3-one and 1.5 ml of 1-propanethiol in 15 ml of dry dichloromethane is cooled to (dry ice / acetone bath) under nitrogen atmosphere. Then boron trifluoride etherate (0.32 m. This solution is stirred at a temperature of approximately 6 hours, quenched with 2 ml of sodium hydroxide in methanol (2 g in 30 ml of methanol) at -78 ° C, diluted with chloroform, washed with water, drying over anhydrous sodium sulphate and evaporated in vacuo to form a foam.According to the NMR spectrum, it contains about 30-40% of unreacted starting steroid using it as a starting material, repeat the described experiment with the same amounts of reagents under the same conditions before receiving 550 mg (92,1%) It seemed the title compound (homogeneity of the data) with the appropriate spectral characteristics.
    B. (11/3, 17) -9-fluoro-11-oxy17- (methylthio) -17- (propylthio) androsta-1, 4-diene-3-one.
    A stream of nitrogen is bubbled through a solution of 550 mg (1.8 mmol) 11p-acetyloxy-9-fluoro-17 / 3- (methylthio) -17 (propylthio) -androsta-1,4-diene-3-one in a mixture of tetrahydrofuran (30 ml), methanol (20 ml) and water (1.0 ml) for 15 minutes. Sodium hydroxide (12% -; 1.2 ml) is then added. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 1 hour, acidified with acetic acid and evaporated in vacuo to give a slurry. The slurry is diluted with chloroform.
    8935316
    washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to yield the title compound with 5 small amounts of impurities. It is dissolved in chloroform-hexane 9: 1 and chromatographed on a column of 15 g of silica gel, eluting with chloroform-hexane 9: 1.
    O and chloroform to obtain 460 mg (91.8%) of material homogeneous according to those.
    After crystallization from ethyl acetate: hexane, 380 mg is obtained.
    15 (75.8%) of the analytical sample; 194-197 C with appropriate spectral characteristics.
    Elemental analysis,%: Found, Z: C 64.91J H 7.63;
    20 F 4.47; S 15.05. Cy Ej FOySy.
    Calculated,%: C 65.05; H 7.83; F 4.47, - S 15., 10.
    Example 11. (Acetyl25 hydroxy-17ob (ethylthio) -6,9-difluoro-17 (methylthio) -androst-1,4-diene-3-one. A. 11 -Acetyloxy-6,9-difluoro17-bis - (methylthio) -androst-1,4-dienZ-one.
    30 4.0 g 6oi, 9 "-difluoro-11/5-hydroxy-17, 17-bis- (methylthio) -androsta-1,4-dienZ-it is refluxed under nitrogen in pyridine ( 120 ml) and acetic
    35 anhydride (60.0 ml) for 19h. Over time, the mixture becomes dark brown. After 19 hours, the mixture is cooled and evaporated to a brown syrup. It is dissolved
    40 in 200 ml of 10% HCl solution and four washes (200 ml each), the chloroform extracts are collected, washed with 800 ml of water, dried over anhydrous
    45 Mg sulfate, filtered and evaporated to dryness, preparing for treatment in a column. Two gravity columns are used (50 g silica gel Bakeg 60-200 mesh,
    50 5%: 95% ethyl acetate: chloroform as the mobile phase to isolate the desired product) and the fractions containing the product are collected and evaporated to a foam, which is
    55 recrystallized from ethyl acetate: hexane. The NMR and TLC data (7: 3 chloroform-ethyl acetate) are respectively with the title compound, the crystals are dried (40 ° C, 15 mm Hg, 6 h) and weighed (1.3 g; 29.5% ). B. 11A-Acetyloxy-6 (U, 9-difluoro 17- (methylthio) -androst-1,4,16-trien-3-one. 1.2 g of compound A are heated under reflux for 1.5-h brownish crystals are precipitated after cooling at 195 ° C. After filtering and drying (50 ° C, 15 mmHg 12 hours). The filtrate is placed in a gravity column with 15 g of silica gel to isolate diethylbenzene. Mobile phase 5 % ethyl acetate: 95% chloroform eluted the desired product. The NMR data of those and high performance liquid chromatography (TLC, 7: 3 chloroform ethyl acetate) are in good agreement. and with the pyrolysis product, the total yield is 1.062 g, .99%. C. 1 1/3-Acetyloxy-176- (ethylthio) -6 ° (, 9-diflto p-1 Jjb- (methylthio) androsta-1, 4- dien-3-one. 817 mg (2.0 mol) of compound B is dissolved in 30.0 ml of dry dichloromethane by mechanical crossover under nitrogen atmosphere. Ethyl mercaptan is added to the homogeneous mixture at -78 ° C (dry ice / acetone bath) (1.3 ml, 18.0 mmol), and then boron trifluoride zfirat (1.13 ml, 9.0 mmol). Over time, the yellow color appears intense, and after 9 hours the reaction quenches 100 ml (1: 1) of water and methanol solution at -78 ° C. The resulting sm is then allowed to warm to room temperature before being extracted with chloroform (4 washes ml each), the chloroform layers are collected by washing with 800 ml of water, dried over anhydrous magnesium sulphate and evaporated to a brownish oil. According to analytical high performance liquid chromatography (with 1 mg / ml CH.jCNC | g j4 Bondapak column), six compounds were detected, while TLC (7: 3 chloroform - ethyl acetate) gave only one spot. The results of high-performance liquid chromatography are as follows: 3 Interpretation of peak Holding time, min 1 / 2.8 Starting material 17-ketone - a little 17-ketone impurity a little Same, a little 4 / 14.9 Vinyl sulfide - a little 5 / 19.8 Ethyl, methyl (target product) - basic 6 / 27.2 Distil - basic Sequential separation was achieved using preparative high performance liquid chromatography (Waters 500, reverse phase C | g Bondapak column, mobile phase 55%, acetonitrile 45%; 0.05 M dihydrate sodium phosphate flow rate of 250 ml / 60 s. 60 mg of the mixture is added to the 38 fractions of the whole are collected and, in fractions 25-29, the pure target product is collected. Then these fractions are dried to a few ml of volume and crystallized upon cooling. The resulting crystals are filtered, washed with cold water, dried (15 mm Hg 80 ° C 12 h) and weighed (50 mg). Analytical high performance liquid chromatography gives a single peak at .19.8 minutes corresponding to the target product. D. 1 T / -Acetyloxy-1 7od- (ethylthio) 6, 8-diprop -17y - (methylthio) -andprosta1, 4-dien-W-one. 50 mg of Compound C is dissolved in 4.0 ml of a mixture (1: 1) of a methanol - THF solution with a magnetic stirrer and under a nitrogen atmosphere. Then, 0.1 ml of a 3.0 M sodium hydroxide solution is injected, whereby the mixture becomes pale yellow. After 1.5 hours at room temperature, the reaction mixture was extracted with chloroform (3 washes with 50 ml each). The chloroform layer is washed with 150 ml of water, poured, dried over anhydrous magnesium sulphate, filtered and evaporated to a solid, which is recrystallized from ethyl acetate, resulting in an analytical sample (35 mg, 77%), which is dried (15 mm Hg). , 12 h) and find that it has the corresponding spectral characteristics. Elemental analysis,%: Found,%: C 61.77; H 7.11; S 14.73, F 8.61. . Calculated,%: C, 61.65; H, 7.05; S 14.96; F 8.87. Melting point 176-180 ° C. Example 12, (11 17,) - 17 (cyclohexylthio) -9-fluoro-11-hydroxy-17 (methylthio) -androsta-1,4-diene-3-one. A. 11/3-Acetyloxy-17- (cyclohexylo) -9-fluorop-17- (methylthio) -andprostate-1, 4-diene-3-one. To a solution stirred by a magnetic stirrer in a nitrogen atmosphere containing 11-acetyloxy-9-fluoro17- (methylthio) -androst-1,4-diene-3-o (1.13 g, 3.0 mmol) dissolved in distilled dichloromethane (45.0 ml) at -78 ° C (dry ice-acetone bath), cyclohexylmercaptan (1.83 ml, 15.0 mmol) was added and then boron trifluoride etherate (1.0 ml, 8.0 mmol ). The sample was sampled and recorded on a similar high performance chromatograph (Bonnapak) after 4 hours and 40 minutes of reaction time. The presence of a certain amount of starting material allows the reaction to continue for another 3 hours and 40 minutes before it is quenched with a saturated solution at 0 ° C. The mixture was allowed to warm and then extracted with chloroform, washed with water, dried over anhydrous magnesium sulphate and evaporated to a yellow oil (1.0 g, 68.2%). Analysis by high performance liquid chromatography showed only one main peak with a retention time of 44.61 minutes. Preparation of (11,17) -17- (cyclohexylthio) -9-fluoro-1 1 -ok si-1 7- (methylthio) -androst-1,4-diene-3-one. Compound A (1.0 g was dissolved in dry tetrahydrofuran (48.0 ml), methanol (24.0 ml) and water (6.0 ml) with stirring using a magnetic stirrer under a nitrogen atmosphere. 3 were added dropwise sodium hydroxide solution (3.0 ml), which causes the solution to stain an orange-brown color. A TLC check after 105 minutes showed that the starting material was completely converted to the desired product. After 120 minutes of reaction time, the mixture was extracted with chloroform (3- 150 ml.) The chloroform extracts are combined, washed with water, dried over anhydrous sulphate and m agni and evaporated in vacuo to a solid yellow product. It is dissolved in 30.0 ml of boiling ethyl acetate and placed in a refrigerator overnight for crystallization. Colony-like crystals are formed together with a gel-like substance. The crystals are filtered and washed with cold ethyl acetate to obtain an analytical sample (0.614 g, 67.0%, dried for 48 hours at 75 ° C under high vacuum). The title compound with the corresponding spectral characteristics. Elemental analysis,% Found,%: C 66.92; H 7.93; S 13.50; F 4.12. C H rO-jSjF. Calculated,%: C 67.20} H 8.03; S 13.80; F 4.09. Melting point 288-290 ° C. Example 13. (1 1 / 9,17oi) 2.9 Fluoro-11-OXY-17- (1-methylethylthio) 17- (methylthio) -androst-1,4-dien 3-one. To a stirred solution of 2.26 g of 1 1 / -acetyloxy-9-fluor-17 (methylthio) -andprostate-1, 4-diene-3-one in 90 ml of dry CH3C, which is maintained at a temperature of prn, is added 3 ml of isopropylthiol, and then 2 ml under nitrogen. The temperature of the solution was maintained at -78 ° C for 7 hours, after which the reaction was quenched with 5% NaOH. The product is extracted with four 50 ml portions of ethyl acetate. After evaporation of the dried extracts of EtOAc, an oil is obtained, which is converted into a solid by treatment with ethyl acetate-ether. Yield 1.5 g. Holding time 19.52 min, 94%, according to GLC (C, g C-Bondapak). To a solution of 0.8 g of the above acetate in 20 ml of MeOH and 10 ml of THF was added 10 ml of 3N. NaOH in nitrogen atmosphere, the resulting mixture pe211
    stirred overnight, partially evaporated and the product precipitated with water. The resulting solid was filtered, washed with water and crystallized from ethyl acetate to give 0.6 g of product, m.p. 285-287 С
    The anti-inflammatory activity of the steroids of the invention was tested on rats with a mixture of H-SO creton oil, inducing skin edema (edema).
    Tests using a mixture of croton oil - sulfuric acid, inducing swelling of the cat on the rat.
    8935322
    TT showed the ability of the steroid to inhibit. swelling, you. Called a mixture of croton oil H SO on the back of a rat. Steroids 5 were applied topically two hours before applying the mixture crotonic oil H-SO,. Three hours after applying the mixture, Croton HgSO oil, areas on the back were excited, the weight was determined, and a comparison was made between steroids and control sites treated with a carrier.
    The test results are 15 in the table.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 3-KETOANDROSTENES of the general formula where R and R z are lower alkyl, cyclohexyl, phenyl, ”a double or single bond,
    R * is hydrogen provided that
    R (and R 2 are different, consisting in the fact that the compound of the formula wherein R ( and = - = have the indicated “meanings;
    R 'is an acetyl group, is reacted with a compound of the formula R 2 SH SH, where R 2 has the indicated meanings, R being in an organic solvent in the presence of boron trifluoride etherate at a temperature of from -80 ° C to room temperature, followed by. the removal of the acetyl group.
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    同族专利:
    公开号 | 公开日
    IL66564D0|1982-12-31|
    CA1213270A|1986-10-28|
    DK165838B|1993-01-25|
    DD215556A5|1984-11-14|
    AT18671T|1986-04-15|
    NO822823L|1983-02-21|
    PH18594A|1985-08-12|
    PL237936A1|1984-02-13|
    NO159601C|1989-01-18|
    JPS5841900A|1983-03-11|
    ZA825260B|1983-05-25|
    FI78916B|1989-06-30|
    AU8631882A|1983-02-24|
    AU564228B2|1987-08-06|
    EP0073026A1|1983-03-02|
    KR840001183A|1984-03-28|
    IL66564A|1986-03-31|
    PT75442B|1985-01-04|
    GR76251B|1984-08-04|
    US4361559A|1982-11-30|
    JPH035400B2|1991-01-25|
    ES8406505A1|1984-07-01|
    CS235959B2|1985-05-15|
    ES8308336A1|1983-08-16|
    PL244113A1|1984-05-21|
    DE3269987D1|1986-04-24|
    IE53732B1|1989-02-01|
    DK165838C|1993-06-21|
    ES515110A0|1983-08-16|
    DD215086A5|1984-10-31|
    PL141303B1|1987-07-31|
    KR890000678B1|1989-03-24|
    PT75442A|1982-09-01|
    DD211567A5|1984-07-18|
    HU187783B|1986-02-28|
    FI78916C|1989-10-10|
    FI822890L|1983-02-21|
    DK372982A|1983-02-21|
    FI822890A0|1982-08-19|
    NO159601B|1988-10-10|
    ES521951A0|1984-07-01|
    EP0073026B1|1986-03-19|
    PH19857A|1986-07-22|
    ES521952A0|1984-07-01|
    IE821951L|1983-02-20|
    ES8406506A1|1984-07-01|
    NZ201343A|1985-08-16|
    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/294,680|US4361559A|1981-08-20|1981-08-20|Antiinflammatory 17,17-bisandrostenes|
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