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    • 专利摘要:
    Products of formula (I): …<IMAGE>… in which:… R1 = optionally substituted carbocyclic or heterocyclic aryl or aralkyl radical,… R2 = in position alpha or beta = hydrocarbon radical of 1 to 18 carbon atoms,… X = -(CH2)n- with n = 1, 2 or 4 or X = -CH=CH-CH2-CH2-… A, B and C = especially: …<IMAGE>… process and intermediates for their preparation, their application as medications and pharmaceutical compositions containing them.
    公开号:SU1665877A3
    申请号:SU884356859
    申请日:1988-09-16
    公开日:1991-07-23
    发明作者:Неделек Люсьен；Клосснер Андре；Филибер Даниель；Могилевский Мартин
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    cl
    with
    This invention relates to a process for the preparation of novel steroid derivatives of the general formula
    where RI is dialkyl-C1 C4-aminophenyl, possessing valuable pharmacological properties.
    The purpose of the invention is to obtain new steroid derivatives with pharmacological advantages over the known structural analogue of a similar action.
    Example 1. (17R) -11-beta- (4- (dimethylamino (phenyl) spiro) estra-4,9-diene-17,2-oxetane) -3-one.
    In the first stage, (1,1-dimethylethyl) 3,3- (1,2-ethanediyl) bis-oxy) - (17-beta-hydroxy-19-nor-17-alpha-pregna-5) is obtained. (10), 9 (11) -diene-21-oic acid.
    A solution of 568 cm of diisopropylamide, a titer of 0.51 M, 1.4 l of tetrahydrofuran is cooled to -73 ° C, injected for 20 minutes at (-73) - (- 72) ° C 37.3 cm 3 ter - butyl ester of acetic acid and stirred for 1 h at -73 ° C. The temperature is allowed to rise to -60 ° C, 17.38 g of 3,3- (1,2-ethanediyl) cyclic acetal extra-5 (10), 9 (11) -di- 3 , 17-dione in 260 cm3 of tetrahydrofuran and then stirred for 1 h 20 min at -60 ° C.
    The temperature of the medium is brought to 0 ° C and 520 cm3 of ammonium chloride in a saturated aqueous solution are added over 15 minutes. The mixture is stirred at room temperature for 1 h, decanted and the aqueous layer is extracted with methylene chloride. ORGAO ON SL 00 VJ XI
     WITH
    The layers are washed with sodium chloride s saturated aqueous solution, dried and brought to dryness. The residue is chromatographed on silica and eluted. A mixture of cyclohexane-ethyl acetate / triztilamine, taken in a ratio of 95: 5: 1.
    NMR spectrum (CDCIa + 1 drop of CsDsN), ./million: 3.97 (H ethylenedioxy in 3); 5.6 (Ni); 0.9 (His); 4.55 (OH); 1.47 (H, owned by t-Bu).
    In the second stage, (1,2-ethanedi- (ll) cyclic acetal 17,21-dihydroxy- | 19-nor-17-alpha-pregna-5 (10), 9 (11} -diene-3-pka) is obtained.
     In an inert atmosphere, 20.3 g of the product obtained in the first stage are dissolved in 400 cm3 of tetrahydrofuran and 14.38 g of lithium lumohydrate are added during 5 minutes at 18-22 ° C. Heat for 1 h at 40 ° C. After cooling to 15-20 ° C, 600 cm3 of methylene chloride are adjusted, 330 cm3 of a saturated aqueous solution of sodium bicarbonate are added and slowly added.
    The precipitate obtained is filtered off, washed with it, concentrated in methylene chloride, the filtrate is decanted and the aqueous layer is extracted with methylene chloride. The organic layers are washed with a saturated aqueous solution of sodium chloride, dried to dryness. The residue is concentrated in ether, sucked off, dried under reduced pressure, and 12.47 g of the expected product are obtained.
    NMR spectrum (+ 1 drop CsDsN), ppm: 3.96 (H ethylenedioxy); 5.59 (Ni); 0.88 (His); 3.97 (N21); 3.33 (H, belonging to OH).
    In the third stage, (17R) - (1,2-ethanediyl) cyclic acetal spiro (estra-5- {10), 9 (11} -diene-17,2-o1 setan) -3-one is obtained.
    12.47 g of the product obtained in the second stage are dissolved in 250 cm3 of pyridine. A little bit, 24.94 g of chloride was added and stirred for 2 hours at room temperature. Ice and water are added, the mixture is extracted with ethyl acetate, the organic layers are washed with a saturated aqueous solution of sodium chloride, dried and brought to dryness by distillation with toluene. 19.80 g of the obtained tosylate are kept in suspension in 890 cm3 of 5% ethyl potassium hydroxide and mixed with reflux for 40 minutes. Ethanol is distilled off under reduced pressure, water and ice are added, stirred for 10 minutes, the precipitate is filtered off with suction, washed with water to neutrality, dissolved in methylene chloride, decanted, and dried to dryness. Chromatograph the residue on silica (eluant: cyclohexane ethyl acetate - triethylamine, taken in a ratio of 90: 10: 1) and isolate
    8.97 g of the desired product m.p. 13b ° C.
    NMR spectrum (CDCIa), ppm: 3.99 (H ethylenedioxy); 5.64 (Ni); 0.76 (Hie); 4.30- 4.50 (H21).
    In the fourth stage, (17R) 0 (1,2-ethanediyl) cyclic acetal 5-alpha, 10-alpha-epoxy-spiro- (estra-5 (10), 9 (11) - diene-17,2-oxetane) are obtained -3-one and its isomer 5-beta, 10-beta epoxy.
    8.97 g obtained in the third stage
    5 products are dissolved in 180 cm3 of methylene chloride, 9 cm3 of hexachloroacetone is added, cooled to -30 ° C and introduced over 15 min at -33 ° C to 27 cm3 of 50% hydrogen peroxide, and then stirred
    0 3 h at 0-2 ° С. The reaction mixture is poured-south to 300 cm3 of saturated sodium bicarbonate solution, sodium thiosulfate is added at 15-20 ° C until no peroxide is present and decanted. The aqueous layer is extracted
    5 methylene chloride, the organic layers are washed with water and a saturated aqueous solution of sodium chloride, dried to dryness. Chromatographic on silica (residue / eluant: cyclohexane - ethyl
    0 ester of acetic acid - triethylamine,
    taken at a ratio of 80: 20: 1) and isolate
    1.82 g of the product 5-beta, 10-beta epoxy and
    5.36 g of the product 5-alpha, 10-alpha epoxy.
    IR spectrum (), cm 1: 975,823 (epoxy
    5 alpha); 981, 830 (epoxy beta).
    NMR spectra (COClS), h, ppm: epoxy alpha: 0.76 (Hie), 3.92 (ketal), 6.09 (Ni), 4.30- 4.66 (Hzi); epoxy beta: 0.75 (Hw), 3.91 (ketal), 5.92 (Ni), 4.30-4.46 (H21J.
    0 At the fifth stage, get (17B) - (1,2-ethanediyl) cyclic acetal 5-alpha-hydroxy-11-beta- (4- {dimethylamino (phenyl) spiro) - extra-9-e- 17, -2-oxetane) -one.
    In an inert atmosphere is dissolved
    5 0.861 g of 5-alpha-10-alpha a 18 cm3 tetrahydrofuran obtained in the fourth stage, 24 mg of copper monochloride are added, cooled to 0-5 ° C, 8.3 cm of 4-dimethyl0 minophenyl magnesium are introduced in 30 minutes in solution (0.87 M in tetrahydrofuran) and stirred for 1 hour at this temperature. The reaction mixture at 15-20 ° C is poured onto 40 cm3 of ammonium chloride in a saturated aqueous solution,
    5 is stirred for 10 minutes, decanted, the aqueous layer is extracted with ethyl acetate. The organic layers are washed with a saturated solution of sodium chloride, dried and brought to dryness. Residue Chromatograph on silica
    (eluant: cyclohexane - acetate - ethyltriethylamine, taken in the ratio 70: 30: 1). 1 g of the desired product is isolated, mp. 178 ° C.
    NMR spectrum (CDCIa), ppm: 4.00 (H ethylenedioxy); 2.91 (H dimethylamino); 4.28-4.45 (Ni and H2i); 0.40 (Hie); 4.31 (OH).
    In the sixth stage, (17R) -11-beta-{4- (dimethylamino (phenyl) spiro) estra-I 4,9-diene-17,2 oxetane) -3-one is obtained.
    0.944 g of the product obtained in the fifth stage are dissolved in 6.6 cm3 of 70% acetic acid, heated at 41-43 ° C and stirred for 2 hours and 15 minutes. It is cooled to, ammonium hydroxide is added to a pH higher than 8, extracted with methylene chloride, washed with a saturated solution of sodium chloride and dried to dryness. The residue is chromatographed on silica (eluant: cyclohexane-ethyl acetate, taken in a 80:20 ratio) and 0.468 g of the expected product is isolated.
    After recrystallization in isopropanol, the product melts at 108 ° C.
    IR spectrum (), cm 1: 1654 (conjugated ketone); 1612 (); 1561 (aromatic compound).
    UV spectrum (EUN): max. 260 MMK, e 17,400; Max. 302 MMK, e 20,500.
    UV spectrum (EtOH HCl, 0.1 N): max. 300 MMK, E 18.900; kink 218-240 mmk.
    NMR spectrum (COClS), ppm: 2.92 (H dimethylamino); 5.76 (H / 0; 0.48 (Same); 4.40 (Nc and H21); 6.67-7.07 (aromatics).
    Example 2. (17Р) -11-beta- (4- {methyl-thio (phenyl) spiro-) estra-4,9-diene-17,2-oxetane) -3-one.
    In the first stage, a solution of 2.4 cm 3-butynol in 20 cm ethanediyl) cyclic acetal 5-alpha-hydroxy-11-beta- (4- {methylthio (phenyl) spiro) ect is obtained (17RH1.2-40) - pa-9-en-17,2-oxetane) -3-one.
    In an inert atmosphere, cool to
    tetrahydrofuran, stirred for 1 h and poured into 200 cm3 of saturated solution
    0-5 C for 15 minutes 55.3 cm of 4- (methylthio) phenyl magnesium in tetrahydrofuran (titer 0.81 M) and 0.148 g of copper chloride. During 25 minutes at 3.5-5 ° C, 5.36 g (17RH1.2-ethanediyl) cyclic acetal 5-alpha, 10-alpha epoxy (spiro) estra-5 (10), 9 (11 ) -diene-17,2-oxetane-3-one in 53 cm of tetrahydrofuran and stirred at 0-5 ° C 1.5. The reaction is then continued as in the fifth step of Example 1, yielding 0.24 g of the intended product.
    NMR spectrum (CDCIs), ppm: 2.46 (H3C); 3.9-4.1 (H ethylenedioxy); 0.38 (His); 4.30-4.45 (Nc, H21 and OH); 7.16 (aromatics).
    sodium phosphate and then the aqueous layer is extracted with methylene chloride.
    45 and dried to dryness. The residue is purified on silica, eluting with a mixture of cyclohexane-ethyl acetate (1: 1) and then ethyl acetate containing 1% ammonium hydroxide
    50 Collect 1.775 g of the desired product.
    NMR spectrum (CDCIs + 1 drop of CsDsN), ppm: 2.90 (H dimethylamino); 3.97 (H ethylenedioxy); 0.5 (His); 3.73 (CHa-OH); 6.62 and 55 7.04 (aromatics).
    In the second stage, 11-beta- {4- (dimethylamino (phenyl) -17-beta-hydroxy-17-afa-4) hydroxybutyl) estra-4,9-diene-3-one is obtained.
    In the second stage, (17R} -11-6e-ta- (4- (methylthio (phenyl) spiro-) estra-4,9-diene-17,2-oxetane) -3-one is obtained.
    2 g of the product obtained in the first stage are dissolved in 40 cm3 of ethanol, 2 g of Amberlite IRC 84 resin (Rum Haas) are added and heated with reflux for 7 hours in an inert atmosphere. At room temperature, the mixture of resin and product is sucked off, rinsed with ethanol, methylene chloride and the filtrate is brought to dryness to obtain 1.194 g of the desired product, m.p. 154 ° C.
    After recrystallization in 99.8% ethanol, a product is obtained which melts at 160 ° C.
    IR (CHCI3), 1653 (); 1603 (); 1556 and 1493 (aromatics).
    0 UV spectrum (EtOH): max. 260 MMK, E 16,500; Max. 300 MMK, Ј 20.10.
    NMR spectrum (s), ppm: 5.77 (H-j); 2.46 (S-CH3); 0.44 (Hie): 4.3-4.5 (H2l); 7.12 and 7.18 (aromatic compounds). 5 Example. (17S) -11-beta- (4- (dimethylamino (phenyl) -3,4,5,6-tatrahydro-spiro) estra-4,9-diene-17,2- (2H) -pyran } -3-he.
    In the first stage, (1,2-ethanediyl) cyclic acetal 5-alpha, 17-beta-0 dihydroxy-11-beta- (4- (dimethylamino- (phenyl) -17- (alpha -) -2 -hydroxy-1-butynyl) estra-9-en-3-one.
    5 g of potassium t-butylate are dissolved in 20 cm3 of anhydrous tetrahydrofuran, cooled to -5 ° C and 1.9 g (1,2-ethanediyl) cyclic acetal 5-alpha-hydroxy-11-beta is added over 5 min. - (4- (dimethyl-amino (phenyl) -ester) -9-en) -3-one. Stir for 10 minutes and then for 15 minutes.
    a solution of 2.4 cm 3-butynol is introduced in 20 cm
    tetrahydrofuran, stirred for 1 h and poured into 200 cm3 of saturated solution
    a solution of 2.4 cm 3-butynol is introduced in 20 cm
    sodium phosphate and then the aqueous layer is extracted with methylene chloride
    and dried to dryness. The residue is purified on silica, eluting with a mixture of cyclohexane-ethyl acetate (1: 1) and then ethyl acetate containing 1% ammonium hydroxide,
    1.755 g of the desired product is collected.
    NMR spectrum (CDCIs + 1 drop of CsDsN), ppm: 2.90 (H dimethylamino); 3.97 (H ethylenedioxy); 0.5 (His); 3.73 (CHa-OH); 6.62 and 7.04 (aromatic compounds).
    In the second stage, 11-beta- {4- (dimethylamino (phenyl) -17-beta-hydroxy-17-afa-4) hydroxybutyl) estra-4,9-diene-3-one is obtained.
    871 g of the product obtained in the first stage are hydrogenated to 40 cm 3 of methanol in the presence of 0.4 g of a palladium / coal mixture. After filtration, removal of solvents, the residue is taken up in 10 cm3 of 10% acetic acid and stirred for 1 hour at 45 ° C. The mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with methylene chloride. The organic layer is dried, brought to dryness under reduced pressure. The residue is chromatographed on silica, eluted with ethyl acetate and 640 mg of expected product is obtained.
    IR Spectrum (CHCl 3), 1654 (); 1612,
    1561, 1518 (-N); 3615 (OH).
    NMR spectrum (CDCI3), ppm: 2.9 ());
    4.33 (Hz); 0.57 (Hie); 5.73 (H4); 3.67 (CH2OH); 6.65 and 7.02 (aromatic compounds).
    In the third stage, (17S) -11-beta- (4- (dimethylamino (phenyl) - (3,4,5,6-tetrahydrospiro) estra-4,9-diene-17,2 (2H pyran) -3- he.
    A solution containing 788 mg of the product obtained in the second stage and 15 cm3 of anhydrous pyridine is cooled to 0 ° C, 1.5 g of tosyl chloride is added and stirred for 1 hour at room temperature. 30 cm3 of ice are added and 14.5 cm3 of concentrated hydrochloric acid are neutralized. The aqueous layer was extracted with methylene chloride and dried. The residue is purified by passage on silica, with the eluant methylene chloride - acetone (95-5), and 0.2 g of the desired product is collected,
    NMR spectrum (CDCIa), h, ppm: 2.90 (H dimethylamino); 4.33 (Hz); 0.53 (-CHAO); 5.74 (H4); 7.02 and 6.4 (aromatics). PRI me R 4. (17SH 1-beta- (4- (dimethylamino (phenyl) spiro) estra-4,9-diene-17,2 -oxyran) -3-one.
    Similarly, the second stage of Example 2 is based on 2.42 g (1,2-ethanediyl) cyclic acetal 11-beta-4- (dimethylamino (phenyl-5-alpha-hydroxy-spiro) estra-9-e-17, 2-oxiran) -3-it with Amberlite IRC84 resin.
    After cooling, the resin is filtered off, rinsed with 60 cm3 of ethanol and brought to dryness. The residue is concentrated in 30 cm3 of isopropyl ether while stirring at 40 ° C. Ice nt, sucked off, rinsed with isopropyl ether, dried under reduced pressure and get 9,844 g
    target product. From stock solutions
    another 0.273 g of product is collected, mp. 228 ° C.
    After purification by chromatography on
    silica, eluant: cyclohexane-ethyl acetate (70:30), isolated 0.750 g of product, m.p. 234 ° C; (alpha) o - + 270 ± 3.5 ° (to 0.5%).
    NMR spectrum (CDCts). h / m n: 2.92 (H di0 methylamino); 5.8 (H4); 4.33 (Hz); 0.6 (Same); 2.63 and 2.98 (H oxirane); 6.67 and 7.01 (aromatics).
    EXAMPLE 5. (175) -11-beta- {4- (methylthio (phenmyl) spiro-) estra-4,9-diene-17.2 -ox5 syran) -3-one.
    In the first stage, 3,3- (1,2-ethanediyl) cyclic acetal of 5-alpha hydroxy-11-beta-{4- {methylthio (phenyl) -estra-9-ene) -3,17-diene is obtained .
    0 Cool to -6 ° C 0.672 g of copper chloride, 0.212 g of lithium chloride, 165 cm of anhydrous tetrahydrofuran, and 16.6 g of 3,3- (1,2-ethanediyl) cyclic acetal 5-alpha, 10-alpha epoxy-estra 9- (11) -EN5 of 3,17-dione and dropwise are added dropwise over 1 hour 15 minutes 100 cm of a 0.75 M solution of 4- (methylthio) phenylmagnesium bromide. In an inert atmosphere at -10 ° C, stir for 1 h, add 100 cm3 of saturated ammonium chloride solution and stir for 10 min.
    Extracted with ethyl acetate, washed with water, dried, and concentrated to dryness under reduced pressure.
    5 pressure. The residue is taken in a little hexane, sucked off, washed with hexane and obtained after drying under reduced pressure at 60 ° C for 1 h, 22.2 g of crude product, so pl. 202 ° C.
    0 After chromatography of this product on silica, eluant cyclohexane-ethyl acetate (1/1) + 1% triethylamine, recrystallization in ethyl acetate, get
    5 product melting at 209 ° C.
    In the second stage, (17SHL2-zthanedyl) cyclic acetal 11-beta- (4- (methylthio (phenyl) spiro) estra-9-ene-17,2-oxirane) -3-one is obtained,
    0 12.7 cm3 of a solution (0.9 M) of potassium potassium tbutylate, 22 cm3 of tetrahydrofuran and 27 cm3 of anhydrous dimethylsulfoxide are cooled to 5 ° C; WITH. Then, 2.45 g of the product obtained in the first stage in 30 cm3 of anhydrous tetrahydrofuran is poured at 5 ± 1 ° C for 7 minutes and stirred for 1 hour at 0-5 ° C. Reaction mixture
    poured into 300 cm of water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dried to dryness. The residue is taken up in 15 cm3 of ethyl ether, frozen, sucked off, concentrated with a minimum amount of cold ethyl ether, dried under reduced pressure, and 2.1 g of the expected product are obtained, mp. 130 ° C (moment).
    IR (CHCI3), 3508 (OH); 1592, 1555, 1493 (aromatics).
    In the third stage, (17S) -11 -beta- (4- (methylthio (phenyl) spiro) -estra-4,9-diene-17,2-oxirane) -3-one is obtained.
    In an inert atmosphere, dissolve 2.1 g of the product obtained in the second stage in 100 cm3 of ethanol. 4.2 g of Amberlite IRC 84 / POM-XAA resin are added and heated with reflux for 15.5 hours. After cooling, filtered, washed with ethanol, the filtrate is evaporated, kept for 1 hour in the cold, sucked off and concentrated with a minimum amount of cold ethanol. , dried under reduced pressure, and 0.49 g of the expected product was isolated, m.p. 121-122 ° C.
    After recrystallization in a mixture of ethanol and methylene chloride (4: 5), a product is obtained which melts at 122 ° C and then at 167 ° C.
    UV spectrum (ETON) MB 406.6: max 259 m / h, 15.700; Max. 300 MMK, e 18.700.
    NMR spectrum (s), ppm: 2.43 (CH3); 5.76 (Hb); 4.32 (Ni); 0.55 (Nu); 2.61 and 2.94 (H of oxirane); 7.02 and 7.13 (aromatic compounds).
    Conduct a pharmacological study of the products obtained by the proposed method.
    The study of the activity of the proposed products is carried out on hormone receptors.
    Progestogenic receptors of the uterus rabbit.
    Rabbits weighing about 1 kg, not reaching sexual age, receive skin application of 25 g of estradiol. 5 days later, the animals are sacrificed, the uterus is taken out, weighed and homogenized at 0 ° C using Potter Teflon / glass in TS buffer solution (tris 10 mM, sucrose 0.25 M, HCI pH 7.4 / 1 g tissue on 50 ml TS).
    The homogenization product is then ultracentrifuged (105,000 g × 90 min) at 0 ° C. The resulting aliquot parts of the surface are incubated at 0 ° C for a time t at a constant concentration (T)
    tritiated product P (17,21-dimethyl-19-nor-4,9-pregnadien-3,20-dione) in the presence of increasing concentrations (0-2500-UM) of either cold R, or cold progesterone, or cold product under investigation. The concentration of tritiated R (bound B) is then measured in each incubation product by the carbon-dextran absorption technique.
    The glkocorticoid receptor of the rat gland.
    Female Sprague-Dawley EOPS rats weighing 160-200 g are subjected to adrenal gland removal. Four to eight days after removal, the animals are killed and the forks are removed and homogenized at 0 ° C in a buffer solution (tris 10 mM, sucrose 0.25 M, dithiothreitol 2 mM, HCI pH 7.4) using Potter polytetrafluoroethylene glass (1 g of tissue per 10 ml of vehicle). The homogenization product is subjected to ultracentrifugation (105,000 g × 90 mn) at 0 ° C. The resulting aliquots of the surface product are incubated at 0 ° C for a time t with a constant concentration (T) of tritiated dexamethasone in the presence of increasing concentrations (0-2500 M) of either cold dexamethasone or the cold product under study. The concentration of bound tritiated dexamethasone (B) is measured on each incubation product by the carbon-dextran absorption technique.
    A relative affinity affinity (ARL), which is the same for all receptors, is calculated.
    Damn two curves: the percentage of bound
    AT
    tritiated hormone depending on logarithm
    T
    concentration of X
    boat control hormone and-in
    depending on the logarithm of the concentration of the cold product studied. Direct equations are determined.
       Vmax Vmin p J 50 I p). ,
    Where
    at,
    t
    t t
    the percentage of tritiated hormone bound to incubate this tritiated hormone at a concentration (T);
    D
     - Percent bound tritiated hormone to incubate this tritium saturated hormone at a concentration (T) in the presence of a large excess of cold hormone (2500 M).
    The intersection of direct JBO and curves provides an estimate of the concentrations of the cold control hormone (CH) and the cold studied product (CX), which inhibits by 50% the bond of tritiated saturated rmon on the receptor.
    The relative affinity of communication (ARL) of the product being studied is determined by urinary:
    ARL iЈJ ± L L icxi
    Get the results given in TB. one.
    The products studied, especially the product of Example 1, exhibit a specific affinity for glucocorticoid and prog / gogenic receptors.
    From the results obtained, it can be concluded that the products can produce “(gonistic or antagonistic activities of glucocorticoids and progestohegeses.
    , Investigate anticycorticoid activity.
    The equipment used is derived from the well-known Dausse and all method. Molecular Pharmacology, 1977, 13, 948-955 For the cells of the retrosternal gland of the mouse.
    In the rats with the adrenal glands removed, the cells of the thoracic gland are incubated with fipn 37 ° C for hours, in a nutrient medium containing dexamethasone M in the presence or absence of the Product under study at various concentrations. Saturated uridine is added with tritium and the incubation is continued for 1 hour. The incubation products are cooled, treated with 5% trichloroacetic acid solution, filtered on Wattman GF / A paper, washed with 5% trichloroacetic acid three times. Determine. radioactivity retained on the filter. Glucocorticoids, in particular dexamethasone, cause a decrease in the inclusion of tritiated uridine, the products of examples 1-3 counteract this effect (Table 2).
    If the test products are consumed alone, no effect of the glycocorticoid type is noted.
    The test products exhibit antiglucocorticoid activity and, at the same time, do not exhibit glucocorticoid activity.
    Examine the abortive activity in the female rat.
    The day of the DI pregnancy is determined by the presence of spermatozoa in a vaginal smear. On day Dg of pregnancy, the product is administered in suspension in carboxymethylcellulose containing 0.5% tween.
    Animals are sacrificed 72 hours after treatment and the uterus is examined to determine the state of pregnancy.
    A complete abortion is established on all animals of the group with the product of Example 1, administered at a dose of 3 mg / kg.
    They work according to the proposed conditions in determining the affinity (affinity) of the compounds for hormone receptors and determine the relative affinity of the bond (AP) on the progestogen and glucocorticoid receptors in the following products (Table 3). The product of example 1 (product A) and the lactone 3- (11-beta- (4-dimethyl aminophenyl) -17-beta-hydroxy-3-oxo-4,9- (10) - estradiene-17-alpha-yl ) -propionic acid (product X).
    The proposed compound has a higher affinity for the progestogen receptor and glucocorticoid than the known product.
    thirty
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of steroids of the general formula
    R
    40
    where RI is a dialkyl-C1-C4-aminophenyl, characterized in that the compounds of the general formula
    45
    ABOUT
    ABOUT
    50
    to
    he
    where RI has the indicated meanings;
    K - a group of cyclic ketal, is subjected to dehydration with simultaneous release of the ketone function.
    Table 1
    table 2
    Table 3
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    US3983112A|1976-09-28|17β-Ethynyl-3,17α-estradiol and derivatives thereof
    US4022892A|1977-05-10|17β-Ethynyl-3,17α-estradiol and derivatives thereof
    DE602005003564T2|2008-10-23|PROGESTERONE RECEPTOR MODULATORS
    同族专利:
    公开号 | 公开日
    GR3008221T3|1993-09-30|
    DK509088A|1989-05-23|
    MX13052A|1993-09-01|
    MX174142B|1994-04-25|
    PT88536B|1992-11-30|
    HUT48275A|1989-05-29|
    JP2794297B2|1998-09-03|
    CN1034207A|1989-07-26|
    EP0308345B1|1993-04-28|
    JPH01106899A|1989-04-24|
    ES2054844T3|1994-08-16|
    KR890005143A|1989-05-13|
    ZA886820B|1989-11-29|
    DK509088D0|1988-09-13|
    EP0308345A1|1989-03-22|
    FR2620707B1|1989-12-08|
    DE3880601D1|1993-06-03|
    DK174268B1|2002-10-28|
    CN1031942C|1996-06-05|
    KR960013446B1|1996-10-05|
    US4921846A|1990-05-01|
    PT88536A|1988-10-01|
    IE882813L|1989-03-18|
    AT88716T|1993-05-15|
    CA1340344C|1999-01-26|
    IE61751B1|1994-11-30|
    HU199505B|1990-02-28|
    FR2620707A1|1989-03-24|
    DE3880601T2|1993-10-07|
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    DK0471612T3|1990-08-14|1999-02-22|Hoechst Marion Roussel Inc|New 19-nor carbon chain steroids comprising an amide group at the 11-beta position, process for their preparation, the|
    DE3921059A1|1989-06-23|1991-01-10|Schering Ag|11-ARYL-4-ESTRENE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT|
    AT172469T|1989-08-04|1998-11-15|Schering Ag|11 BETA-ARYL-GONA-4,9-DIEN-3-ONE|
    FR2651233B1|1989-08-23|1991-12-13|Roussel Uclaf|NOVEL OMEGA-PHENYLAMINO ALKANOUIC ACIDS SUBSTITUTED ON THE AROMATIC CORE BY A RADICAL DERIVATIVE OF 19-NORSTEROUIDES, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM.|
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    US6020328A|1998-03-06|2000-02-01|Research Triangle Institute|20-keto-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties|
    WO1999061055A1|1998-05-22|1999-12-02|The Board Of Trustees Of The Leland Stanford Junior University|Bifunctional molecules and therapies based thereon|
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    CN104208718B|2009-02-20|2017-12-29|2-Bbb医疗股份有限公司|drug delivery system based on glutathione|
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    DE102010007722A1|2010-02-10|2011-08-11|Bayer Schering Pharma Aktiengesellschaft, 13353|Progesterone receptor antagonist|
    DE102010007719A1|2010-02-10|2011-08-11|Bayer Schering Pharma Aktiengesellschaft, 13353|Progesterone receptor antagonist|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8712937A|FR2620707B1|1987-09-18|1987-09-18|NOVEL STEROIDS COMPRISING A 3, 4 OR 6-CHAIN SPIRANIC CYCLE IN POSITION 17, THEIR PROCESS AND PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
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