• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Thio etianic acid derivatives of the formula wherein X' is hydrogen, fluoro, or chloro; X2 is hydrogen, fluoro, chloro or bromo; X3 is =C=O Cl may also be =C when X2 is chloro; H R is alkyl of 1 to 6 carbon atoms, or phenyl or benzyl optionally substituted with a substituent on the phenyl ring which is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon _ atoms or halo; R1 is hydrogen or alkanoyl of 2 to 6 carbon atoms when R2 is hydrogen, a-methyl or β-methyl or OR1 and R2 together are 16a, 17a-isopropylidenedioxy; and the solid and broken lines between C-1 and C-2 represent a double or single bond; are useful an anti-inflammatory steroids. They can be prepared by reacting the corresponding 17β-carboxylic acid or a reactive derivative thereof with an alkali metal salt of RSH.
    公开号:SU1052161A3
    申请号:SU792787402
    申请日:1979-04-04
    公开日:1983-10-30
    发明作者:А.Эдвардс Джон
    申请人:Синтекс (Ю.С.А.) Инк (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the preparation of new 3-ox-drost-4-en-or 3-oxo-androst-1 derivatives, en 17 p-thiocarboxylic acids, which surround an anti-inflammatory activity. Some of the 3-oxo-androst-4-ene carboxylic acids substituted by 9 (the position with chlorine or fluorine and the 11-position of keto or oxy or chloro groups are well known. Thus, the method of producing the steroids of the androstanol group X - H, CI is described. , F; R- is a hydroxy group, or when X is H, methylene or methyl; R is alk or phenyl; R is a lower al or steroids of the formula OCOR 0 where R and R are lower alkyl (X, H or Br). These compounds are obtained by validation in the treatment of the initial 17-o (-oxy carboxylic compounds of one or her functional products such as anhydride or chlorine hydride. They are t elune as antiinflammatory agents Cl J and C2 3. The purpose of the invention is to expand the range of agents acting on a living organism. According to the invention, a method for producing thiozoic acid derivatives of the general formula where X is hydrogen, fluorine, chlorine, X is chlorine or fluorine ; and X-gC or, in the case of, ec - 1 C -group, K .X - chlorine, C-Cg-akyl, phenyl or benzyl, which in the phenyl ring may have substituents - C., - C4-alkyl, C - C-alkoxyl or halo; R is hydrogen or C2-C (, is alkanoyl R is hydrogen, / J-methyl or note, or OR and R together represent 16d, 17o (-isopropylidenedioxy, solid or dashed lines between the carbon atoms in position 1- 2 is a double or simple bond, which means that the compound of the general formula </ BR> where .X, have the indicated meanings, is reacted with the basic salt of the compound of the formula </ BR> where R has the indicated value, followed by isolation of the desired product as a corresponding derivative. Thioetherification usually occurs with (better than at room temperature) in an inert solvent, for example dimethylformamide. As the basic salt of mercaptan, it is preferable to use alkali metal salts of the corresponding alkyl, benzyl or phenyl mercaptan. The starting 17p-carboxylic acid is obtained by a known method by oxidation of the corresponding 21-hydroxypregnane. p 1. A. Preparation of methyl bo1,9o6-difluoro-11p-hydroxy-16s1-methyl-3-oxo-17s1-propionyloxyandrost-1, 4-diene 17p-thiocarboxylate. 600 gp bsA, 9o.-difluoro-11p-hydroxy-1be -methyl-3-oxo-17-propionyloxyandrost-1, 4-diene 17/5-carbonoic acid is mixed with 8 ml of tetrahydrofuran (THF) and 0.2 ml of triethylamine (TEA) in the reactor and stirred at room temperature in a nitrogen atmosphere. 0.4 g of diethyl chlorophosphate (DCP) in 8 ml of THF are then added over 13 minutes. Stirring is carried out for 6 hours at a pH of 6. Then 0.04 ml of TEA and 0.05 g of DCP in 3 ml of THF are added. Stirring is continued for another 1.5 hours. The precipitates are filtered off, 10 g of THF sieve are distilled, and the filtrates are combined. Then, to the filtrate is added a 2.05 lp of the solution obtained in advance, which consists of 20 MP of DMF, 0.758 g of 75% sodium hydride and 0.86 g (1 ml) of methyl mercaptan. The resulting reaction mixture is stirred for another 5.5 hours, then 1 ml of DMF is added and stirring is continued with eiKe. 1.5 hours. Then the mixture is poured into 200 ml of ethyl acetate, which is washed twice with 200 ml of water, dried for 15 hours over sodium sulfate and filtered. The solvents are distilled off under reduced pressure on a rotary evaporator and 235 mg of residue is obtained, which is recrystallized from acetone / hexane and 54.3 g of methyl 6oL, 9o1-diphts p-11 oxy-16o-methyl-3-oxo-17c (- -propionyloxyandrost-1, 4-diene 17L1-thiocarboxylate with mp 305308 0 (decomp.) .. B. According to the procedure from Part A of the example, but using other mercaptans instead of methyl mercaptan, for example, ethyl mercaptan, isopropyl mercaptan, butyl mercaptan, phenyl mercaptan or benzyl mercaptan, respectively, are obtained: ethyl bo., 9Y-difluoro-11 / -oxy-; -16 ° C methyl-3-oxo-17 ° C-pro ionyloxyandrost-1, 4-dien-17-thiocarboxylate with m, pl (decomp.); isopropyl-C, 9o6-diphth6p-I / oxy-1b 1 -methyl-3-6xp-17oC-propionyloxyandrosta-1, 4- diene-17 / -thiocarboxylate with a melting point of 286289 C} 6utyl-6o1,9si-difluoro-11p-hydroxy-16o-methyl-3-oxo-17c1-propionyloxyandrost-i, 4-diene-17 / l-thiocarboxylate with 247-250 ° G phenyl-6cC9o-difluoro-11p-hydroxy-16o (.-mvtil-3-oxa-17o propyloxy onyroxy-1,4-diene-17/1-tyrcar bauxyl with mp . 281-283 C (decomp.); benzyl-bob, 9th (-difluoro-11 p-hydroxy-16o -methyl-3-to-17 -6-propionyloxyandrost -1,4-diene-17 / -thiocarboxylate with mp. 246-248s. C. Before the method from Part A of the example, the following compounds are prepared: methyl 6 L, 9o-difluoro-11 / -oxy-1b4e (.-methyl-3-ca co-17o -valerilandrosta-1,4-diene-17p-thiocarboxylate with mp. 267-268 C (decomp.); Methyl-17Y-butyryloxy-6o, 9ot-difluoro-11/5-hydroxy-16c-methylt3-oxo-androsta-1, 4-dien-17p-diocarboxyl with mp 276-280 ° C (decomp.); ethyl 17oC-acetoxy-6c., 9 "difluoro-11p-hydroxy-16 A-methyl-3-oxo-androst-1, 4-dyne 17yS-thiocarboxylate with a melting point of 285-290 C ( ,); methyl-17 ° C-acetoxy-bo1,9-difluoro-11 p-hydroxy-16 B1-methyl-3-oxo-androsta-1, 4-diene-17 / -thiocarboxylate with mp methyl 11p-hydroxy-16b-methyl-3-oxo-17c-propionyloxyandrosta-1, 4-diene-17p-thiocarbo1 silate s, mp. 123-126 C. Example 2. A. Preparation of ethyl 6B4,9cC-difluoro-11 p, 17Bi-dioxy-1bct -methyl-3-ococoandproct-1, 4-diene 17 / -thiocarboxylate. 105 mg of 6-1.96-difluoro-11 / 3.17 A-dioxy-16O1-methyl-3-oxo-androstag .1 4-diene-17 carboxylic acid is dissolved in 7 ml of daF and cooled to 80 mg of carbonyl imidazole dissolved in 30 The DMF MP and this solution are added to the DMF / acidic solution under a nitrogen atmosphere. The resulting mixture was stirred for 18 h at -5 ° C and 2 MP of ethyl mercaptan was added. The mixture was stirred at -5 ° C for an additional 16 hours. The reaction mixture was then stored in a refrigerator for 2 weeks, and the solvent was distilled off under reduced pressure. The residue is applied to a thin layer chromatography plate of 1 m 0.75 and twice developed with a mixture of 10% acetone / 90% benzene. The substance is recrystallized from glycetone-hexane and get 47 mg ethyl 6c, 9 1 difluoro-11 / 3,17 in O-dioxy-16 "-methyl-3-oxo-androst-1, 4-diene-17d-thiocarbroxylate with m.p. 235-239 C (decomp.). B. Proceed according to the described procedure, but replacing ethyl mercapt IH with other alkyl, phenyl, or benzyl mercaptans, the corresponding thioethyanic acid derivatives are obtained. Example 3. According to the procedures of Examples 1 and 2, the following compounds were obtained: methyl 17 O1-caproyloxy-9c, -fluoro-11-oxy-16 / -methyl-3-oxo-androst-1, 4-diene-17 / -thiocarboxylate with m. square 139-141 ° C; hexyl 17O1-acetoxy- 9o-fluoro-11 -oxy- 16 (α-methyl-3-oxo-androst-1, 4-diene-17 / -thiocarboxylate with mp 176-179 ° C. Example 4. Method for producing alkyl-, benzyl or phenyl-16-1,17oi-isopropylidenedioxy-3-oxo-androst-1, 4-diene-17-thiocarboxylates, which are replaced by hydrogen, fluorine or chlorine in the bob position, hydrogen, fluorine, chlorine or bromine in the 9v1-position and oxy -group in 11 | LOCATION or also chlorine in ll / ft-position, if chlorine is in the 9cC-position A. Production of methyl 6VC, 9b-d Gftor-11/5-hydroxy-16c, 17o-isopropylidene-dioxy-3- oxoandrost-1, 4-diene-17/1-thiocarboxylate. 600 mg bB, 9O1-difluoro-11-oxy-16b1, 17c6-isopropylidenedioxy-h3-oxo-androst-1, 4-diene-17 ka bovanoic acid is mixed with 8 mp THF and 0.21 ml of TEA and stirred under nitrogen at room temperature Within 6 minutes, 0.3 mp of DCP was added to the resulting mixture in 11 ml of THF and the mixture was stirred at room temperature for 17 h, then 5 drops of pure DCF was added. Stirring was continued for 3.5 h, after which the precipitate was filtered off and washed with 10 MP THF. The filtrates were combined and a 3.15 mp solution of methyl merkaltap, sodium hydride, DMF was added as in Example 1. Prepared) (the mixture was stirred at room temperature under nitrogen for 3.5 hours, then poured into 300 MP of ethyl acetate, which was then washed twice 250 ml of water Aqueous slugs are extracted with 150 MP of ethyl acetate, the emustrate is combined, dried with brine and dried over sodium sulphate for 15 hours in a refrigerator. There are 309 mg of methyl bo, EVS-dif-Tor-11 / J-hydroxy-16 rf -17oi- and 3 opropylidvioxy-3-oxo-androst-1, 4-div-17v-thiocarboxylate with mp.299aOl C (decomp.) .
    B.: According to the procedure described, other compounds are also prepared.
    ii.p and mep 5. In this example, a method for the conversion of andrbst 1, 4 diea according to the invention is shown. To a covenant 101 a androst-4-en. To a solution of 25 mg of tris- (triphenylphosphine) chlorodi in 7 MP of benzene and 15 MP of ethanol were added 244 mg of methyl bo, 94-di-fluoro-11/9, oxy-16o-methyl-3-oxo-androsta-1 4-di- 17 -thiocarboxylate and the resulting solution is stirred under a hydrogen atmosphere at room temperature and atmospheric pressure. After termination of the absorption of hydrogen, the solution is evaporated to dryness and the residue is reduced (it is taken up with a mixture of petroleum ether and methylene chloride. The pure product is isolated by chromatography on a column of silica gel, and methyl bc | C, 9BC-difluoro-11 / e, 1H-dioxy-16-L- 1: ethyl-3-oxoand growth-1, 4-he-17-thiocarboxylate.
    The compounds of the invention are
    o active anti-inflammatory agents, especially for the treatment of inflammatory dermatosis. Preferably, the steroid is first mixed and formulated with a pharmaceutical preparation that
    5 are then applied to porgies. The effective amount depends on the condition and the animal's response to treatment, but it usually varies from 0.001 to 10% by weight of the pharmaceutical composition. Use such amounts in preparation and inflammation areas. Apply an effective amount, giving an anti-inflammatory response without adverse effects on the patient. . . : .- ,; ,,;.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING THIOETHYANIC ACID DERIVATIVES of the general formula where X * 1 is hydrogen ,; fluorine, chlorine,> X g - chlorine or fluorine;
    A 1 · 9 or if X is chlorine, • CB
    -SCC-group, R - C 7 -C ft - alkyl, phenyl, or benzyl, which in the phenyl ring may have substituents - <
    I c ^ -C ^ -alkyl, 0., -04-alkksil or halogen.
    R1 - hydrogen, or C2 to alkanoyl; ^ R 2 - H, methyl or oC-methyl or OR 1 and R 2 together represent 16 <4 17L-izopropilidendioksi- group, a solid or dotted lines between the carbon atoms in position 1-2, this is a double or simple bond, the only difference being that the compound of the general formula i where Xϊ, X g , X R 1 and · R 4 · have the indicated meanings, reacted with a basic salt of a compound of the formula
    RSH, where R has the indicated value, followed by isolation of the target product in the form of the corresponding derivative.
    类似技术:
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    同族专利:
    公开号 | 公开日
    JPS54141758A|1979-11-05|
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    JPS6140648B2|1986-09-10|
    CA1134345A|1982-10-26|
    ES479271A1|1980-01-16|
    CS203956B2|1981-03-31|
    DE2960096D1|1981-03-19|
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    YU40929B|1986-08-31|
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    GR67275B|1981-06-26|
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    ATA251979A|1982-01-15|
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    PL121469B1|1982-05-31|
    YU80379A|1983-04-30|
    IT1120954B|1986-03-26|
    GB2018256B|1983-02-02|
    AU4558379A|1979-10-18|
    AR226035A1|1982-05-31|
    NO152935C|1985-12-18|
    ZA791635B|1980-11-26|
    US4188385A|1980-02-12|
    FI66393B|1984-06-29|
    SG6786G|1986-08-01|
    JPS6069019A|1985-04-19|
    FR2421912A1|1979-11-02|
    FR2421912B1|1981-03-20|
    NZ190076A|1984-07-31|
    PL214676A1|1980-01-02|
    AT368168B|1982-09-27|
    AU526025B2|1982-12-16|
    PT69409A|1979-04-01|
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    IL56972D0|1979-05-31|
    MY8500575A|1985-12-31|
    DK147735B|1984-11-26|
    DK136579A|1979-10-06|
    NO791140L|1979-10-08|
    FI791081A|1979-10-06|
    NO152935B|1985-09-09|
    HK41284A|1984-05-18|
    JPS611038B2|1986-01-13|
    EP0004741A3|1979-11-14|
    DK147735C|1985-08-19|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/893,388|US4188385A|1978-04-05|1978-04-05|Thioetianic acid derivatives|
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