• 专利附录
  • 专利说明
  • 权利要求
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  • 引用文献
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    • 专利摘要:
    Diuretic pharmaceutically active steroid-spiro-oxazolidinone compounds of the formula (I), <IMAGE> (I) wherein R1 is hydrogen or methyl, R2 is C1-4 alkyl, R3 is hydrogen, C1-4 alkyl or C2-4 alkenyl, Z1 and Z2 each are hydrogen or together form a second valence bond, or Z1 is hydrogen and Z2 is R4-S-, Z3 and Z4 each are hydrogen or together form a second valence bond, or Z3 is hydrogen and Z4 is R4-S-, with at least one of the pairs Z1-Z2 and Z3-Z4 representing hydrogen and an R4-S- group, and R4 is hydrogen or alkyl, alkenyl, aralkyl or acyl with up to 7 carbon atoms, provided that when Z1 and Z2 together form a valence bond, or Z1 represents a hydrogen atom and Z2 and R4-S- group then R1 is methyl.
    公开号:SU852176A3
    申请号:SU792744750
    申请日:1979-03-29
    公开日:1981-07-30
    发明作者:Шольом Шандор；Тольд Лайош；Силадьи Каталин；Шефер Инге；Сонди Элеонора；Борвендег Янош；Херманн Илона
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт(Инопредприятие )；
    IPC主号:
    专利说明:

    Le5 form a second C – G bond, if Z and z form a second C – C bond, then they each designate each vodshyla or form a second C – C bond, and enter into interaction G with a general formula III. in which R has the above values. The reaction can be carried out in the presence or absence of a solvent, as well as with the use of a catalyst. According to the described method, -, - or th unsaturated steroid-spiro-oxazoladzinone of the general formula I is treated With,., | -Ti alkanecarboxylic acid for example, thioacetic acid or thiopropionic acid, and the resulting addition product is separated, IF the compound of general formula II reacts with the alkyl mercaptan, then prolonged heating is usually required to complete the reaction. In such cases, The action is preferably carried out in the presence of a basic catalyst, for example, piperidine or a quaternary ammonium type ion exchange resin in a hydroxyl cycle. Target products may be isolated as stereoisomers. The anti-aldosterone effect of new compounds is investigated as follows. The rat adrenal gland is removed 18 hours before treatment. The compound to be studied was administered to the animals along with subcutaneous administration of 12.5 mg of acetocate deoxycorticosterone (DOC) of quality, able to supplement the effect of scdosterone, and the content of sodium and potassium in the urine was determined by flame photometry. In a comparative experiment, an oral dose of 400 µg of spironelactone (17og-carboxyethyl-178-hydroxy-Yaz-acetylthio-androst-4-en-3-onlactone) was administered orally. The results are evaluated by calculating fog values (10 Na / K). The results are presented in the table.
    DOCK
    480
    Spironolactone
    7c acetylthioestp-4-en-4-on-17b-spiro-5 - {2-oxo-3-methyloxazolidine) 480
    DOCK:
    "
    480
    Spironolactone
    7c3t-ethyl thioand grew 4-en-3-one-17b-spiro-5 - (2-oxo-3-methyloxazolidine) 480 I / Cn is the test substance / s From the table that To-acetylthioestr-4-ene -3-he-17b-spiro-5- (2-oxo-3-methyloxazolidine) and 7C | ztil- -thio-androst-4-en-3-one-17 b -spiro-5 -; - (2-oxo-3-methyloxazolidine) significantly suppressed the effect of DOCA in rats. The uterotropic and antiestrogenic effects of the compound were studied in female mice of infant age using the Edgren method. When the compound was subcutaneously administered in daily doses of 30 mg / kg, no uterotropic effect was observed. The study of the antiestrogenic effect showed $ 6
    0.73
    108
    1.52
    0.94
    96
    1.43
    0.60
    75 1.05.
    1.04
    82
    1,09 jftO pyronolactone. This compound does not cause a significant decrease in the uterotropic effect of zstradiol benzoate with simultaneous administration for 3 days with daily doses of 0.1 µg / animal, the Androgenic and antiandrogenic effects of this compound were investigated on castrated male rats according to the Dorfman method. When the compound was administered for 7 days subcutaneously with daily doses of 1 mg / animal, no androgenic effect was observed. In this experiment, the compound did not suppress the effect of testosterone propionate, administered in daily doses of 50 µg.
    Subcutaneous administration of animal spironolactone daily doses of 1 mg showed a significant decrease in the androgenic effect of testosterone propionate, administered simultaneously with spironolactone.
    Example 1. That-Acetyltco-andpocT-4-eH-3-oH-17t-cnMpo-5 - (2 -oxo-Z-methyloxazolidine).
    A mixture of 3.50 g of androst-4,6-dien-3-one-17% -spio-5 - {2-oxo-3 -methyloxazolidine) and 3.5 ml of thioacetic acid is heated on a steam bath for 1.5 The excess thioacetic acid is distilled off under vacuum, the residue is triturated with isopropyl ether and the divided substance is filtered. The resulting crude product (4.0 g) is dissolved in 120 ml of ethyl acetate, and the solution is decolorized with activated carbon, filtered and evaporated to a final volume of approximately 35 ml. 2.20 g of Idr-acetylthio-androst-4-en-3-one-17f-spiro-5- (2-oxo-3 -methyloxazolidine) are extracted from the concentrate. M.p. 218-219 ° C, -48 (, 5 in chloroform), UV spectrum i.Jf 237mm {E 16,500).
    Example2. 1 -Acetylthio-androst-4-en-3-one-17} 7-spiro-5 - (2-oxo-3-methyl-oxazolidine).
    The test was carried out in the same manner as in Example 1, but 4.0 g of androst-1,4-diene-3-one-17b-spiro-5 - (2-oxo-3-methyloxazolidi 1a) was taken as the starting material. 3.55 g of crude 1-6-acetylthioandrost-4-en-3-one-17 -spiro-5 - (2 -oxo-3-methyloxazolidine) are obtained; m.p. 2.04-205 S. This crude product is dissolved in 35 ml of ethyl acetate and the solution is evaporated to one quarter of the original volume. 2.37 g of purified product are obtained; m.p. 204-2060С, / 0 / g + З Е- «Н (from 1 to chloroform), UV spectrum Х р, 240 JUM (300).
    Example 3. 1 (acetylthio) -androst-4-en-3-one-17b-spiro-5 - (2-oxo-z-methyloxazolidine),
    A mixture of 1.20 g of androst-1,4,6-triene 3-one-17 Te-spiro-5 - (2-oxo-3-methyloxazolidine) and 2 ml of thioacetic acid are heated on a steam bath for 1. 5 hours: . The excess thioacetic acid is distilled off under vacuum, the oily residue is triturated with isopropyl ether, then the separated crystalline substance is filtered and washed with cold isopropyl ether. The resulting crude product weighing 1.64 g is dissolved in 10 tvui of acetone at room temperature, the solution is decolorized with activated carbon, filtered, evaporated to half the original volume at room temperature under reduced pressure, and 14 ml of isopropyl ether are added to the concentrate. The separated product is filtered and 1.10 g of pure 1 is obtained (acetylthio-androst-4-en-3-one-17b-spiro-5- (2-oxo-3-methyloxazolidine). The spectroscopic data of the product are as follows: 237 im (E ); ICTs -1b15 (), 1760 and 1690 TS O cm). ,
    NMR (SOSE, 3): cf 2.85 (3N, S, -NCHj),
    o 2.40 (6H, b, acetylthio}, 5.75 (1K, broad, 4 Hz, CH) ppm
    Example 4. 7ob-Acetylthio-estr-4-en-3-one-171 -spiro-5- (2-oxose-methyloxazolidine).
    A mixture of 0.96 g of estr-4,6-diene-3-one-17b-spiro-5- (2-oxo-3xmethyloxazolidine) and 1 ml of thioacetic acid is heated on the steam bath for 1 hour. Excess thioacetic acid is distilled off at and reduced pressure
    0 the residue is subjected to double recrystallization from acetone. 0.17 g of 7c1C-acetylthio-estr-4-en-3-one-17 &amp; spiro-5- (2 -oxo-3-methyl-oxazolidine) is obtained; mp: 203 20bOs
    5 -89.7 ° (with 0.5 in chloroform), 236 JV / M (E 20,600).
    Example 5. 7o.-Acetylthio-136-ethyl-gon-4-en-3-one-17b-spiro-5 - {2-oxo-3-methyloxazolidine),
    0
    A mixture of 1.4 g of 13B-ETHIL-GON-4,6-dien-3-one-17b-spiro-5- (2-oxo-3-methyloxazolidine) and 1.4 ml of thioacetic acid is heated on a steam bath. for 1 h. Excess thioacetic acid distilled ... vacuum ri 50 ° C and the oily residue triturated with a 1: 1 mixture of ethyl acetate and isopropyl ether. The resulting solid is recrystallized from the mixture.
    0 1: 1 methanol and isopropyl ether. 0.71 g of 7ct-acetylthio-138-ethyl-gon-4-ene-3- .on-17b-spiro-5- (2 -oxo-3-methyloxazoliumine) is obtained; mp. 135-1, -73.1 ° (with 0.5 in chloroform). UV 236 | UM
    5 (E 18,800)
    Example 6, 7Q-Ethylthio-Andropst-4-en-3-one-17b-spiro-5 - (2 -oxo-3-methyloxazolidine).
    A mixture of 2.1 g of ancrost-4,6-diene-3-one-17g -spiro-5 - (2-oxo-3 -methyloxazolidine), 1.3. ml of piperidine and 12 ml of Etc.lmercaptan are heated c. reflux for 48 hours. During this time a yellow solid is separated from the mixture. At the end of the reaction, the Lump solid was dissolved by adding 50 ml of banzole to the mixture and the resulting
    权利要求:
    Claims (3)
    [1]
    the solution is evaporated in vacuo. The residue is crystallized by trituration with cold ethyl acetate. The separated crystalline crude product weighing 1.02 g is filtered off and recrystallized from 35 ml of ethyl acetate. Oj55 g of 7a-ethylthyr-androst-4-en-3-one-171 -spiro-5- (2 -oxo-3-methyloxosolidine) is obtained; m.p. 2b5-266 with, -30,80 (0 1 in chloroform) "m (E 14600). Example 7. 7cd-dgyt, io-estr7 -4-en-3-one-17b-spiro-5 - (2-oxo-3-methyloxazolidine). A mixture of 2.17 g of estr-4,6-dien-3-one--; -17L-spiro-5- (2-oxo-J-methyloxazolidine), 1.3 ml of piperidine and 12 ml of ethyl mercaptan are stirred and heated under reflux for 4 hours. Then the reaction mixture is cooled and the separated crude product is filtered. The crude product weighing 1.87 g is recrystallized from 35 ml of ethanol and 1.62 g of pure 7o-ethylthio-estE-4-en-3-one-17b-spiro-5- (2-oxo-3-methyloxazolidine); m.p. 216-218 C, -57.7 (with 0.5 in chloroform), 237 VM (E 18000). Claims 1. Process for the preparation of steroid-spiro-oxazolidinone derivatives of the general formula 0, where R is hydrogen or methyl R Ci-C-1, -alkyl; , -apkil; Z and 1 denote each hydrogen atom separately, if l denotes a hydrogen atom, Z denotes the group R -S-, if Z denotes an iodine atom or a group, and I denotes alkyl with 1-3 carbon atoms or acyl with 2t4 carbon atoms. , provided that if Z denotes a hydrogen atom and Z is a K-5 group, then R can denote only methyl, since it is a compound of the general formula OLA, 4 where K, R and R have the above values, if Z and Z denote each hydrogen atom separately, then they form a second C – C bond, if –Z and Z form a second C – C conjunction, then Z 3 gig means individually a hydrogen atom, a hydrogen atom, or form an interspersed C — C bond, which is reacted with a thiol of the general formula 4 SH in which R has the above values. 2. Method According to claim 1, they are also distinguished by the fact that the process is carried out in the presence of a solvent. 3. Method according to Claim 1 or 2, that is, that the process is carried out in the presence of a catalyst. Sources of information taken into account in the examination 1.R. Dorfman, Methods tn Hormone Research, Acad. Press, 1962.
    [2]
    2.R.M.Dodson and R.C.Tweit Addition of AlhanethiolIc Acids to L-3-0x0- and A-3-Oxo5terolds, .Amer.Chem. Soc. 81, 1224, 1959.
    [3]
    3.I.A.Cellc and R.C.Tweit Steroidal aidosterone II blockers giOrg. Chem, 24.1109, 1959.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3272801A|1964-11-19|1966-09-13|American Home Prod|Steroidal spiro-oxazolidinones|
    DE2253170C2|1972-10-30|1988-12-22|Hoechst Ag, 6230 Frankfurt|Method and device for treating a freely floating material web|
    HU179711B|1977-03-14|1982-11-29|Gyogyszerkutato Intezet|Process for preparing steroid-spiro-oxazolidinone derivatives|HU179980B|1979-12-28|1983-01-28|Gyogyszerkutato Intezet|Process for preparing substituted steroid-spiro-oxazolidinone derivatives|
    HU181066B|1980-03-12|1983-05-30|Gyogyszerkutato Intezet|Process for preparing steroid -spiro-oxathiazolidine derivatives|
    FR2493324B1|1980-11-05|1983-01-21|Roussel Uclaf|
    DE3461090D1|1983-02-18|1986-12-04|Schering Ag|11-beta-aryl-estradienes, process for their preparation and pharmaceutical compositions containing them|
    US7732432B2|2003-01-21|2010-06-08|Merck Sharp & Dohme Corp.|17-carbamoyloxy cortisol derivatives as selective glucocorticoid receptor modulators|
    WO2007025780A2|2005-09-02|2007-03-08|Recordati Ireland Limited|Aldosterone receptor antagonists|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU78GO1397A|HU178397B|1978-04-01|1978-04-01|Process for preparing substituted derivatives of steroid-spiro-oxazolidione derivatives|
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