Method of producing derivatives of steroids

专利摘要:
The invention relates to derivatives of steroids, in particular compounds of the general formula R2 R where R, -C-Sf-alkyl dihydroindolip, pyridinyl, phenyl substituted with an alkylamino group or a kylamino-C-C4 alkyl group (in which nitrogen can be oxidized), pyrrolidinyl di-C, -C4-alkylamino-C-C-alkylthio, di-C-C-alkylamino-C-C, alkyloxy or trimethylsilyl group; R-C OH, CHjO, ethynyl, carbonyl, -C-NOH; H; C2-C4-alkenyl, C-C-alcadiene, C-C-alkynyl (may be substituted by “halogen, (CEj) Sit by lower alkenyl); B and C form a double bond or epoxy group that have pharmacologically valuable properties. The purpose of the invention is to create new substances with non-characteristic activity for this class. Synthesis of lead is carried out from the corresponding ketal (A is a ketal group, which can be cyclic or non-cyclic), which is dehydrated by cation-exchange sulfosmol or HC1. The crawled product is, if necessary, treated with hydroxylamine or, if R, is di-. The -C, -C4-alkylamino-C, -C-alkshphenyl, is oxidized, for example, with m-chlorophenbic acid to give the desired compound containing a group oxidized by nitrogen and 9,10-zipoxy. New substances exhibit a pronounced affinity for the glucocorticoid and progestogenic receptors, without showing activity at the mineralocorticoid and estrogen receptors with DC toxicity jd 100 mg / kg. 3 tab. i O) 4 4 :: S 00 co
公开号:SU1447289A3
申请号:SU823378150
申请日:1982-01-08
公开日:1988-12-23
发明作者:Жорж Тетш Жан；Костерусс Жермен；Филибер Даниель；Дераедт Роже
申请人:Руссель -Юклаф (Фирма)；
IPC主号:

专利说明:

one
This invention relates to a process for the preparation of novel steroid derivatives of the general formula

(I)
.X - where R, is phenyl, substituted di- (C, -C) -alkylamino group, possibly oxidized by nitrogen, di- (C 1 -C4) -alkylamino- (C, -C) -alkylgroup, possibly oxidized by nitrogen pyrrro
S
a lidinyl group, a di- (C-C) -alkylamino-CC -C) -alkylthio group, a di- (C-C4) -alkylamino - () - alkyloxy group, -trimethylsilyl group, whether R. - N - () - alkyldihydroindole;
Rj is methyl, ethyl;
R is a hydroxy group, methoxy group, ethynip, group C A - / C O or C NOH group; hydrogen, alkenyl,
-C-alkadiene, C -C-alkynyl, 15, ° solution x concentrate with pressure. which is chro-silicon, eltilene – acetonium trie of the product, to 0.1 mm of mercury receive a cent of -52 + 1.5
Stage B -1-ynil) -11
the sodium chloride solution, dried and concentrated to dryness under reduced pressure. 6 g of product are obtained, which are chromatographed on silica, eluted with a mixture of methylene chloride - acetone (-1: 1) containing 1 per thousand of triethylamine. 3.15 g of the product is isolated which is dried under vacuum in 0.1 mm of mercury at 60 ° C. Thus, the desired product, ol jj -52 + 1.5 (to 1% CHCl3), is obtained.
Stage B. 17 / E-Hydroxy-17 (/ - (prop--1-ynyl) -11p- (4-pyridyl) -estra-4.9
in some cases, substituted with a halogen, phenyl group, trimethyl group, or lower alkylene group. B and C. together form a double bond or an epoxy group with chain pharmacological properties.
The purpose of the invention is to obtain new steroid compounds with antiprogestomimetic and antiglucocorticoid activity, which is unexpected for compounds of a similar structure.
Example. 17 / h-Hydroxy-17c / - - (prop-1-ynyl) -11 ft- (4-pyridyl) -estra-4,9-diene-3-one.
Stage A, 1lp- (4-Pyridyl) -3,320
For 3 hours at room temperature and in an inert atmosphere, stir the solution, containing 2.9 g of the product obtained in stage A, 14 with methanol and 7 cm 2N. sweet and sour a solution is added containing 200 cm of ether and 90 cm of a saturated solution of sodium bicarbonate. Stir for 15 minutes at
25 at room temperature, decanted is extracted with ether. Extract the extracts with a saturated aqueous solution of sodium chloride, and then dry and concentrate to dryness under reduced pressure.
30 pressured. 2.3 g of product are obtained, which is chromatographed on silica, eluting with a mixture of methylene chloride - acetone (6: 4). 1.7 g of product is isolated, which is dried under
- 2-ethanediyl-bic- (oxy) J-l7o - (prop-35 with a pressure of 0.1 mm mercury for
40
-1-ynyl) -estra-9-en-5o (, 17p-diol.
At 20 ° C, a solution containing 6.16 g of dimethyl sulfide complex and copper monobromide in 40 cm of tetrahydrofuran is added to 100 cm of 4-chloropyridinyl magnesium bromide solution in tetrahydrofurash; (a solution of 0.5-0.6 M, obtained, starting from 15 g of 4-chloropyridine and 6 g of magnesium). The mixture is stirred at room temperature for 20 minutes under an inert atmosphere and a solution containing 3.7 g of 3, 2-ethanediyl-bis- (oxy) 1-5 ° C (, 10 ° -epoxy-17 ° - (prop- 1-ynyl) -estra-9 (11) -ene-17 3-ol. Stir for 50 hours at room temperature and mix in cold water and ammonium chlorin. The reaction mixture is stirred for 0.5 hours at room temperature. temperature is then poured into a mixture of cold water and ammonium chloride. The reaction mixture is stirred for 0.5 h at room temperature and extracted with ether.
24 hours, of which 8 hours - at. Thus, the target product is obtained with +30.5 i 1 ° (to 1%, СНС1e).
In the same way, 17/1-hydroxy-1 7c - (prop-1-ynil) -1 1 / 1- (3-piri dsh1) -estra-4,9-diene-3-one, Go J p + and (to 1% CHC1}), and 17 -hydro sig 17o (- (prop-1-inip) -1 (2-pyridyl 45 -estra-4,9-diene-3-one, Co (p -2 ° (to 1% СНС1з).
Example 2. 17p-Hydroxy-1 (K, 11-dimethylamino) propyl -17 3iI-. - (Propyl-yl) -estra-4,9-diene-3-one.
- Stage A. (K, K-Dimethyl but no) propyl-3,3-, 2-ethanediyl-bys (o si) -1 7s (- (prop-1-ynil) -estra-9-ene-5o, 17/3-diol.
When 12.33 g of copper dimethyl sulfide monobromide complex was added over a period of 5 minutes to 141 cm of 3 - (N, N-dimetsImino chloride) propylmagnesium chloride (0.85 M, obtained from 42 g of chloro-3-H, K- dimeshtaminopropane
For 3 hours at room temperature and in an inert atmosphere, the solution is stirred, containing 2.9 g of the product obtained in stage A, 14 cm of methanol and 7 cm 2 n. hydrochloric acid. a solution is added containing 200 cm of ether and 90 cm of saturated sodium bicarbonate solution. Stir for 15 minutes at
room temperature, decanted and extracted with ether. The extracts are saturated with an aqueous solution of sodium chloride and then dried and concentrated to dryness under reduced pressure.
pressure. 2.3 g of product are obtained, which is chromatographed on silica, eluting with a mixture of methylene chloride - acetone (6: 4). 1.7 g of product is isolated, which is dried under
pressure of 0.1 mm mercury for
24 hours, of which 8 hours - at. In this way, the desired product is obtained y-from +30.5 i 1 ° (to 1%, СНС1e).
In the same way, 17/1-hydroxy-1 7b - (prop-1-ynyl) -1 1 / 1- (3-pyris-1) -estra-4,9-diene-3-one, Go J p + and (to 1% CHC1}), and 17 -hydroxyg 17o (- (prop-1-inip) -1 (2-pyridyl) - -estra-4,9-diene-3-one, Co ( p -2 ° (to 1% СНС1з).
Example 2. 17p-Hydroxy- 1 p- (K, 11-dimethylamino) propyl-17 3iI- - (propyl-yl) -estra-4,9-diene-3-one.
- Stage A. (K, K-Dimethylamino) propyl-3,3-, 2-ethanediyl-bys (oxa) -1 7s (- (prop-1-ynyl) -estra-9-E- 5o, 17/3 diol.
For 5 min, 12.33 g of the copper dimethyl sulfide monobromide complex was added to 141 cm of 3- (N, N-dimethyl Imino) chloride propyl magnesium (0.85 M solution, obtained from 42 g of chloro-3-H, K-dimeshtamnopropane
Sh
25
10.5 grams of magnesium). The mixture is stirred for 25 mils: at 0 ° C and 3.70 g of 3.3, 2-ethanediyl-bis- (oxy), 1 0 (/ - epoxy-1 7 ° (-C I-pro - pinyl) -estra-9 (11) -ene-1 7 / e-ol in 50 cm of tetrahydrofuran The reaction mixture is kept under stirring for 3 hours at and poured into a mixture containing 40 g of ammonium chloride and 200 cm of iced water. The mixture is stirred at room temperature for 15 minutes and then extracted with ether, washed with saturated aqueous sodium chloride solution, dried and concentrated to dryness under reduced pressure. 4.6 g of product is obtained which is chromatographed on silica, eluted with a mixture of methylene chloride and methanol (8: 2), 2.55 g of product was isolated. 20 -86 ± 1.5 (to 1%, in CHCl).
Stage B. 1 7/5-Gnroksi-11 / - 3- - (N, N-dime tilamino) -propyl -1 7s (- (prop--1-ynyl) -estra-4,9-diene-3- he..
At room temperature, 2.4 g of the product obtained in stage A, 14 cm of methanol and 7 cm 2 of hydrochloric acid are stirred for 4 hours under an inert atmosphere. Then 200 cm of isopropyl ether and 90 cm of the complete solution of sodium bicarboate are added. Stir for 0.5 h at ambient temperature, decant and extract with ether. It is saturated with sodium chloride solution and dried. Concentrate to dryness under reduced pressure to obtain 1.8 g of product, which is chromatographed on silica, eluting with chloroform-methanol (8: 2). 1.30 g of product is obtained, which is suat at 30–40 ° C under reduced pressure of 0.1 mm of mercury. Thus, 1.25 g of the desired product WJjr t 2.5 (to 1% CHCl 3) is obtained.
Example 3. (K, L-Dimethylamino-Toe si) phenyl -1 7/3 -hydroxy-17c - (prop-1-ynyl) -estra-4, 9-di-3-one.
Stage A. 3,3-Ethanediyl-bis- (oxo) -11 (5 (H, K-dimethylaminoeth- 10x)) phenyl (prop-1-ynyl) -estra-9-en-5o (, 17p- diol
a) Organomagnesium compound 4- (K, H-dimethylaminoethyloxy) bromobenzene.
A solution containing 24 g of 4- (K, K-diethylaminoethyloxy) bromobenzene is added dropwise within 45 minutes.
35
thirty
40
45
50
55
Sh
25
is 20
90 cm of anhydrous tetrahydrofuran. The reaction is catalyzed by the addition of 0.2 cm of 1,2-dibromoethane, then the mixture is stirred for an additional hour at 25 C. Thus, a solution of 0.7 M is obtained, which is used in this form.
b) Condensation.
The prepared solution is added to a solution containing 6.16 g of a complex of dimethyl sulfide and copper monobromide in 20 cm of tetragvdrofuran. The mixture is stirred at room temperature for 20 minutes and 3.7 g of 3.3-, 2- (ethanediyl-bis- (oxy) -5o1, lOct- -epoxy-17o (- (prop-1 -inip) estra--9 (11) -en-17p-ol in 50 cm of tetrahydrofuran. Stir for 1 h in an inert atmosphere, and then pour the reaction mixture into a solution containing 15 g of ammonium chloride in 200 cm of ice-cold water is extracted with ether and washed with a saturated aqueous solution of sodium chloride. It is dried and concentrated under reduced pressure. Thus, 18.3 g of oil is obtained, which is chromatographed on idrookisi alumina, eluting with chloroform, to give 4.5 g of the desired product., -44 ± 1 (k 1% SNS1e).
Stage B. 1 (N, N-DimetsIa and nanoethyl) phenylJ-I 7/3-hydroxy-lJo (-35 (prop-1-insh1) -estra-4,9-diene-3-one.
To 4.5 g of the product obtained in stage A in 20 cm of methanol was added 9.5 cm of 2N hydrochloric acid. Maintain the solution with stirring for 2 hours at room temperature and add 260 cm of ether and PO cm of a saturated solution of sodium bicarbonate. The mixture is kept under stirring for 15 min at room temperature, decanted and extracted with ether. Dry and concentrate to dryness under reduced pressure. 3.3 g of product are obtained which is chromatographed on silica, eluting with a mixture of methylene chloride and methanol (92.5: 7.5). Thus, 1.8 g of the expected product is obtained, which is in amorphous form. +71 (to 1% СНС1з).
Example 4. 17/3-Hydroxy-Pr - - (4-dimethylaminophenyl) -I (prop-1-vinyl) -estra-4,9-diene-3-one.
Stage A. P / 1- (4-Dimethyl-innofenyl) -3,3, 2-ethanediyl-bis- (oxy) 30
40
five
0
five
(prop-1-nyl) -estra-9-en-5o; , 17 -diol.
A solution containing 38 mmol of p-dimethylaminophenipmagnesium bromide in tetrahydrofuran is added to a suspension containing 4.1 g of a complex of copper monobromide and dimethyl sulfide in 20 cm of tetrahydrofuran. Then, 2.45 g of 3,3-C1,2-ethanediyl-bic- (oxy) - -5l, 10 of-epoxy-17 od- (prop-1-vinyl) - -estr-9 (11) - en-17 g1-ol in a solution of tetrahydrofuran. The reaction mixture vyderzhivayut. with stirring for 10 minutes, hydrolyzed with 50 cm of a saturated solution of ammonium chloride. Decanted, extracted with ether, the organic layer was washed with water and dried. Solvents are added under reduced pressure to obtain 11 g of crude desired product, which is chromatographed on silica, eluting with a mixture of cyclohexane: ethyl acetate (6:40). Thus, 1.8 g of the desired product (1 1/3) and 750 mg of the product 11 s / are obtained. Recrystallized in isopropyl ether and ethyl ether and ethyl ester of acetic acid. T. pl. , WJi) -66,5 (to 1% СНС1з).
Stage B. 1 7/3-Hydroxy-1 / 3- (4-di-methylaminophenyl) - (prop-1-inshl) - -estra-4,9-dien-3-one.
1.7 g of Redex .jQ sulfonic resin is added to a solution containing 1.68 g of the product obtained in stage A in 17 cm of boiling alcohol at. Heat with reflux for 30 minutes, suck off the resin, rinse it off with chloride.
/ cm of a concentrated gg solution
hydrochloric acid is added to the solution with methylene and the filtrate is evaporated under a 1.53 g of the product obtained in diy a in
hundred cm of methanol. Stir for 30 minutes at room temperature and add 150 cm of ether, 50 cm of 1N aqueous sodium hydroxide solution. The reaction medium is stirred for 15 minutes and decanted, the organic layer is dried. The solvents are distilled off under reduced pressure to obtain 1.4 g of a crude product, which is purified on silica, eluted with a mixture of cyclohexane and ethyl acetate (7: 3). 0.932 g of the expected product is obtained. T. pl. 150 ° С, 4-138,5 ° (to 0.5% СНС1з).
Example 5. 17/5-Hydroxy-1 - (prop-1-ynyl) -1 1 / (4-trimethylsilyl) phenyl-estra-459-diene-3-one.
Stage A. 11p (4-Trimethylsilyl) phenyl-3,3-p, 2-ethanediyl-bis- (oxy) - -17o / - (prop-1-ynyl) -estr-9-en-5b (, 17 ( 5-diol.
40
45
reduced pressure. Thus, the resulting residue is taken up in methylene chloride, dried and the solvent is distilled off under reduced pressure. The resulting residue is chromatographed on silica and fused with a mixture of benzene and ethyl acetate (85:15). Thus obtained 1,217 g of the target product. T. pl. 212 s, +94 (to 0.9% СНС1з
Roxy-17 ° - (prop-1-ynyl) -1 1 p- ((Z-tri-methylsilyl) phenyl-estra-4,9-diene-3-Zn. I Jj5 +52.5 .t 2 is obtained in the same way. (to 1% SNA
Preparation of 3,, 2-ethanediyl-bis-(oxy) -17o (- (prop-1-ynyl) -estr-9 (11) -en-5, 1 0-ZPOXI-.
Stage A. 3,, 2-Ethanediyl-bis-s - (oxy) (prop-1-ynyl) estr-5 (10) 9 (11) -diene-17p-ol.
Under stirring, cool to 207 cm of a solution of 1.15% ethylmagnesium bromide in tetrahydrofuran,
50
 When in an inert atmosphere to 45 cm of a 0.65 M solution of 4-trimethylsilylfenyl magchi bromide in tetrahydrofuran, 200 mg of copper monochloride are added, and then a solution of 3.3 g is added dropwise to a temperature of 20 ° C. ,, 2-ethanediyl-bis- (oxy-), 1 oc (-epoxy-1 7c (prop-1-ynyl) -estr-9 (11) -en-17/1-bla in 25 cm-tetrahydrofuran. After 1 hour, it is hydrolyzed with an aqueous solution of ammonium chloride, then extracted with ether, dried and distilled
solvents under reduced pressure. Chromatographic on silica, eluting with a mixture of methylene chloride - acetone (94: 6) containing 0.1% triethylamine. 2.87% of the product was recovered, which was purified by recrystallization in isopropine ether and then in ethyl acetate. T. pl. , -60 ± 1.5 ° (to 0.9% CHClj).
Stage B. 17 /} - Hydroxy-17 - (prop- - - -Insh1) -1 1 / 1- (4 trimethylsilyl) phenyl-estra-4, 9-diene-3-one. I
1.7 g of Redex sulfonic resin was added to a solution containing 1.68 g of the product obtained in stage A in 17 cm of boiling alcohol at. Heated under reflux for 30 minutes, the resin is sucked off, rinsed it with chloride
methylene and evaporated the filtrate under
0
five
reduced pressure. The residue thus obtained is taken up in methylene chloride, dried and the solvent is distilled off under reduced pressure. The resultant residue is chromatographed on silica, zlyuiru mixture of benzene - ethyl ester of acetic acid (85:15). Thus, 1.217 g of the expected product are obtained. T. pl. 212 s, +94 (to 0.9% СНС1з).
17 / -Hyroxy-17 ° - (prop-1-ynyl) -1 1 p- ((3-trimethylsilyl) phenyl-estra-4,9-diene-3--one. +52.5 .t 2 (to 1% СНС1з).
Preparation of 3,, 2-ethanediyl-bis-(hydroxy) -17o (- (prop-1-ynyl) -estr- -9 (11) -en-5, 1 0-ZPOXI-.
Stage A. 3,, 2-Ethanediyl-bis-c- (oxy) (prop-1-ynyl) estra-5 (10) 9 (11) -diene-17p-ol.
Under stirring, cool to 207 cm of a solution of 1.15% ethylmagnesium bromide in tetrahydrofuran, prop0
Bake for 1 h 3Q min with propyne gas, previously dried on calcium chloride. The temperature is allowed to reach room temperature and stirred for another 1 hour, keeping the sparging all this time. Then, a solution containing 30 g of 3.3- {1,2-ethanediyl-bis- (oxy) -estra-5 (1 0) 9 (1 1) - diene-17-α-1 in 120 cm of anhydrous tetrahydrO furan and one drop of anhydrous triethylamine. Stir at room temperature for 2 hours and pour in a mixture of distilled water of ammonium chloride and ice. Stir, extract three times with ethyl ether. Rinse the organic layer with water, dry it and concentrate under reduced pressure. The residue is dried in vacuo. 35.25 g of sought product is obtained.
NMR spectrum (CBC1e), ppm:
0,83N methyl in 18 positions
1,85N type with SNS-CH3
5.65N carbon in 11 position
4H ethylene ketal
Stage B. 3,3-Cl, 2-Ethylenedioxy- -bis- (oxy) -1 7o / - (prop-G.-ynil) -estr-9 (1 1) -en-5o, 10o-epoxy 1 7 / E-ol.
While stirring and sparging with nitrogen, 30 g of the product prepared in stage A was introduced into 150 cm of methylene chloride. The mixture is cooled to 0 ° C, and then 1.8 cm of hexafluoroacetate one-and-a-half hydroxide are added at one time and, with stirring, 4.35 cm of 85% hydrogen peroxide. The reaction mixture is kept under stirring and nitrogen sparging at 0 ° C for 72 hours. Then, the reaction solution is injected into a mixture containing 250 g of ice and 500 cm of 0.2N sodium thiosulfate solution. Stir for a while and then extract with methylene chloride. The organic layer is extracted with distilled water, dried on sodium sulfate in the presence of pyridine, and then concentrated under reduced pressure. The residue is dried under reduced pressure. 31.6 g of product are obtained, the topbrti is chromatographed on silica, eluting with a mixture of benzene and ethyl acetate (90:: 10). Thus, the expected product is obtained.
NMR spectrum (CDCl1), ppm: 0.82N methyl in 18 position
1.83H methyl radical OEC-CHj
6.1N carbon in position 11
 3.92N ketal
Example 6. 17/3-ETHYNYL-17s (- -hydroxy-1 (b - (4-dimethylaminophenyl) - -3 stra-4,9-diene-3-one.
10Stadi A. 3,3-Dimethoxy-5o / -1 7s / -hydroxy-1 (4-dimethylaminophenyl) -I 7/3-ethynyl-estra-9-ene.
2.8 g of 3, 3-dimethoxy-5o -1 OO {-epoxy-1 7p-eti-15 NSh1-1 7o / -hydroxy-estra-9 (1 1) -ene is stirred in an inert gas,
56 cm3 of anhydrous tetrahydrofuran and 80 mg of anhydrous copper monochloride. Stir for 5 minutes at room temperature and then put 20 into an ice-water bath and add
33 cm of 0.95 M solution of bromide (4-dimethylaminophenyl) magnesium in tetrahydrofuran. The temperature is then allowed to rise to room temperature.
25 To a suspension of the bromide copper-dimethyl sulfide complex (6.15 g) in 30 cm of anhydrous tetrahydrofuran, add 63 cm of bromide (A-dimethyl-aminophenyl) magnesium so that the temperature remains below 28.5. .-Leave under stirring for 30 minutes, then the resulting solution is added dropwise. The mixture is kept for 18 hours with stirring and at room temperature, dissolved in ammonia (ammonium chloride solution, stirred for 10 minutes, extracted with chloroform, the organic layer is washed with water, dried and the solvent is distilled off. The residue is chromatographed on
silicon dioxide, eluting with a mixture of petroleum ether - ethyl acetate (1: 1) containing 0.5 per thousand of triethipamine;
45 1.28 g of the product. This product is purified again by chromatography on silica, eluting with the same mixture, and 0.84 g of the expected product is obtained. Stage B. 1 7/1-ETHINIL-1 7o-hydroxy gQ -1 1p- (4-dimethylaminophenes1) estra-4, 9-dien-3-one.
0.76 g of the product obtained in stage A is mixed with 15 cm-methanol and 1.6 cm 2 of hydrochloric acid. The mixture is stirred for 1.5 hours, and then poured into 8%; aqueous sodium bicarbonate solution, extracted with chloroform, the organic layer is dried and the solvent is distilled off. In this way .
111 7289.2
0.76 g of crude product, hexachloroacetone and 0.65 cm of peroxide are obtained.
hydrogen (200 volumes). After 1 hour of stirring, add 13 cm of chloroform, and then continue stirring for 18 hours. Pour 100 ml of a saturated sodium thiosulfate solution, mix for 10 minutes, extract with chloroform, rinse the organic layer with sodium chloride, dry and distill solvent. This gives 2.8 g of the desired product, which is used in this form on a chromatographic basis on silica, eluted with a mixture of petroleum ether — ethyl acetate (1: 1), and then eluted with a mixture of ethyl ether — petroleum ether (3: 1). ). This gives 0.435 g of the expected product, which is crystallized in isopropyl ether. T. pl. 142 C, JJj, +235.5+ ± 4.5 ° (to 0 „45% CHClj).
The initial product of stage a is obtained as follows.
hydrogen (200 volumes). After 1 hour of stirring, add 13 cm of chloroform, and then continue stirring for 18 hours. Pour 100 ml of a saturated sodium thiosulfate solution, mix for 10 minutes, extract with chloroform, rinse the organic layer with sodium chloride, dry and distill solvent. Obtain 2.8 g of the target product, used in this form in the following
Stage A, - 3,3-Dimethoxy-1 7 (Y-hydroxy-17-U / -ethins I-estra-5 (10) 9 (l 1) -diene. 15 of the next stage. (The product contains a MAP at room temperature during - a thin epoxide ratio). Mixing 16 min. is mixed with 16.8 g of 3,3-di-methoxy-17/3-G1 of bryus-1 7 ° / -ethynyl-estra-5 (10) 9 (P) Diena, 175 cm without water. Example 7. 17 -Hydroxy-17c-phenyl-1 (4-dimethylaminophenyl: n) -estra-4,9-diene-3-one.
Stage A. 3,, 2-ethylene. N-bic- (oxy) -l 1p- (4-dimethylaminophenyl) -estra-9-ene-5o-hydroxy-1 7-one.
20
25
tetrahydrofuran, 4.35 g of lithium bromide, and then cooled to –60 ° C and 37 cm of a solution of 1.35 M butyl in hexane was added. The mixture is stirred for 30 minutes and then 3.9 cm of methanesulfonyl chloride is added and left for 1 hour with and with stirring. It is then poured into 500 cm of a saturated aqueous solution of ammonium chloride, stirred for 10 minutes, extracted with methylene chloride, the organic layer is dried, 2.5 cm of pyridine are added, then evaporated to dryness under reduced pressure at. 75 cm of tetrahydrofuran are added to the residue obtained, and then 12.5 cm of water containing 0.75 g of silver nitrate. Stand 18 hours at, and then 4 hours at room temperature. Vystadi A. 3,, 2-ethanedia. N-bis - (oxy) -l 1p- (4-dimethylaminophenyl) - -estra-9-en-5o-hydroxy-1 7-one.
a) Preparation of an organomagnesium compound.
In an inert gas, 29 g of magnesium shavings and 50 cm of anhydrous tetrahydrofuran are mixed. Keeping at 35 + 5 ° С, a mixture of 200 g of 4-dimethylaminobromobenzene 30 in 950 cm of anhydrous tetrahydrof wound is introduced for 2.5 hours. In this way, a 0.8 M solution of the desired organomagnesium compound is obtained.
b) Addition of organomagnesium compound.
Inert gas mixed 25 g
3,3-G1,2-ethand yl bis (oxy) -5s / -1

; -epoxy-estra-9 (1-O-en-17-one, 500 anhydrous tetrahydrofuran and 0.757
pour in 500 cm in water, half-40 mono-chloride copper. Cooled to O (+5) ° C, 284 cm of the obtained organomagnesium compound solution are added dropwise over 1 hour and 15 minutes. Then. Stirred in flow
An ammonium chloride solution containing 5 g of sodium cyanide. Stir for JO min at, extract with chloroform, rinse
(+5) ° C, 284 cm of the obtained organomagnesium compound solution are added dropwise over 1 hour and 15 minutes. Then. Stirred for
on the base of an aqueous solution of chloro-45 kN, poured into a nashe; ennsh solution
sodium hydroxide, dried and the solvent is distilled off. Chromatographic on silica, eluting with a mixture of petroleum ether. - ethyl ester of acetic acid (9: 1). 3 g of the expected product are obtained. T. pl. 150 ° C Go (d +125 + + 2.5 ° (to 1% CHClj).
Stage b. 3,3-Dimethoxy-5c (-epoxy-1 7 (} - ethins 1-17 ° (-hydroxy-estr-9 (P) -en.
2.6 g of the product obtained in stage a, 12 cm of methylene chloride and one drop of pyridine are mixed. Cooled to 0 ° C, 0.12 cm added
hexachloroacetone and 0.65 cm peroxide
hydrogen (200 volumes). After 1 hour of stirring, add 13 cm of chloroform, and then continue stirring for 18 hours. Pour 100 ml of a saturated sodium thiosulfate solution, mix for 10 minutes, extract with chloroform, rinse the organic layer with sodium chloride, dry and distill solvent. Obtain 2.8 g of the desired product, used in this form in the next stage. (The product contains a low epoxide ratio).
Example 7. 17 -Hydroxy-17c-phenyl-1 (4-dimethylaminophene: p) -estra-4,9-diene-3-one.
0
25

Stage A. 3,, 2-ethylene. N-bic- (oxy) -l 1p- (4-dimethylaminophenyl) -estra-9-ene-5o-hydroxy-1 7-one.
a) Preparation of organomagnesium compound.
In an inert gas, 29 g of magnesium shavings and 50 cm of anhydrous tetrahydrofuran are mixed. Keeping at 35 + 5 ° C, a mixture of 200 g of 4-dimethylaminobromobenzene and 950 cm of anhydrous tetrahydrofuran is introduced for 2.5 hours. In this way, a 0.8 M solution of the desired organomagnesium compound is obtained.
b) Addition of organomagnesium compound.
Inert gas mixed 25 g
3,3-G1,2-ethand yl-bis- (oxy) -5s / -1 3
; -epoxy-estra-9 (1-O-en-17-one, 500 cm-anhydrous tetrahydrofuran and 0.757 g
onochloride copper. The mixture is cooled to O (+5) ° C and 284 cm of the resulting organomagnesium compound solution are added dropwise over 1 hour and 15 minutes. Then. Stirred for
ammonium chloride, extracted with ethyl acetate, the organic layer was washed with a saturated solution of ammonium chloride, and then saturated; sodium chloride solution. Dry the organic layer and evaporate to dryness under reduced pressure. 46 g of crude product are obtained, which is chromatographed on silica, eluted with a mixture of petroleum ether - ethyl acetate (1: 3) containing 1 per thousand triethylamine. This gives 17.76 g of the expected product. T. pl. 78 sec.
The impure fractions of the product obtained are rechromatographed on silica, eluting with a mixture of petroleum ether — acetone (8: 2), containing 1 per thousand of triethylamine. Again, 6.35 g of the expected product is obtained.
The initial product of stage a is obtained as follows.
11.18 g of 3.3-Fl, 2-ethanediyl-bis- (oxy) -estra-5 (1 0) 9 (1 1) -dien-17-one and 56 cm-methylene chloride are mixed, added 2 drops of pyridine are cooled. square 17b with In this way, A is obtained, and A, 3 cm half-and-half product is used in the next hexafluoroacetone hydrate, and then
stage. 10 added 1.6 to 85% peroxide
Stage B. 3,3-Cl, 2-Ethanediyl-bis-hydrogen. With stirring (hydroxy), 1-5o-17 (-dihydroxy-11 / - (4-di-vania and in an inert gas with temethylaminophenyl) -7o-fensh1-estra-9-h is kept for 23 h. Then poured into the mixture ,
- containing 200 cm 0.5 M solution
When and for 30 minutes, to sodium sodium thiosulfate and 200 g of ice. A solution of 33.3 cm of phenyllithium (1.5 M) is kept for 30 minutes with stirring, 4.51 g of the resulting product is added and then extracted with methidium A chloride in 45.1 cm of anhydrous solution containing traces of pyridine. tetrahydrofuran. The mixture is stirred in water. The organic layer is washed with water for 4 hours at room temperature, dried and the solvent is distilled off, poured into a saturated aqueous solution of ammonium chloride, extracted with ether, the organic layer is washed with a saturated aqueous solution of sodium chloride, dried .. and distilled off solvent - 25 aminophenyl) - 7/5-hydroxy-23-methylmethyl. 5.6 g of crude product is obtained, - 1.7 ° / J-l 9,21-dinorhol-4,9,23-green chromatographic on silica, eluting with a mixture of methylene chloride - acetone (9: 1) containing 1 per
Obtain 11.4 g of the desired product used in the next stage.
Example 8. (4-dimethyl-20-in-3-one.
Stage A. 3,, 2-Ethanediyl-bis- - (oxy) -1 I / 3- (4-dimethylaminophenyl)
30 23-methyl-C1 7 (J-19.21-dinorhol-9,23-dien-20-yn-5 ° (-17 fi-diol.
Thousands of triethylamine. 1.16 g of the expected product are obtained, which is crystallized in a mixture of methylene chloride - isopropyl ether. T ... PL. 240 ° С, Co (i, +53 ± 2.5 ° (to 0.5% CHClj).
Step B. 17 / L-Hydroxy-17o-phenyl--1: 1 / 5- (4-dimethylaminophenyl) -estra-4,9-dien-3-one.
In an inert gas, 1.5 g of the product obtained in stage B are mixed in 45 cm of methanol. The mixture is cooled to O - (+5) ° C and 3 cm 2 of hydrochloric acid 40 DU.K1 of anhydrous tetrahydrofuran are introduced. Stirred for 30 min at -10 ° C, and then 4 hours at O - (+5) C.
lots. Stir for 1 hour at 0 - (+5) ° C, and then add 90 cm of ether and 90 cm of a 0.25 M aqueous solution of sodium bicarbonate. The mixture is stirred with ethyl acetate and shaken for 5 minutes, decanted, the acids are washed, the organic layer is washed with ether, the organic layer is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is distilled off. 1.30 g of the product gg is obtained, which is purified chromatographically on silica; elution
It is 500 cm thick; aq. aqueous ammonium chloride solution,
with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. 5.56 g of crude target are obtained.
T. pl. 205 C. The product is used in the continuation of the synthesis.
a mixture of petroleum ether - ethyl ester of acetic acid (1: 1). Obtain 0.93 g of the desired product, which is 55 with a mixture of methylene chloride - ethyl
Acetic acid ester (9: 1) from 1 per thousand of triethylamine, and then recrystallized in ethyl acetic acid. T. pl. 215 ° C.
methylene chloride-isopropyl ether is crystallized in the mixture. T. pl. 226 ° С, Со: 3о 151.5 ° (to 0.4% СНС1з).
The initial product of stage a is obtained as follows.
11.18 g of 3.3-Fl, 2-ethanediyl-bis- (oxy) -estra-5 (1 0) 9 (1 1) -dien-17-one and 56 cm-methylene chloride are mixed, added 2 drops of pyridine are cooled, cooled before, and A, 3 cm sodium halus thiosulfate and 200 g of ice are added. It is kept for 30 minutes under stirring, and then extracted with methylene chloride containing traces of pyridine. The organic layer is washed with water, dried, and the solvent is removed, aminophenyl) - 7/5-hydroxy-23-methyl- - 17 ° / Jl 9,21-dinorhola-4,9,23-green
Obtain 11.4 g of the desired product used in the next stage.
Example 8. (sodium 4-dimethylthiosulfate and 200 g of ice. They were kept for 30 minutes with stirring, and then extracted with methylene chloride containing traces of pyridine. The organic layer was washed with water, dried, and the solvent was distilled off, aminophenyl) - 7 / 5-hydroxy-23-methyl- - 1 7o / Jl 9,21-dinorchol-4,9,23-green
-20-in-3-he.
Stage A. 3,, 2-Ethanediyl-bis- - (oxy) -1 I / 3- (4-dimethylaminophenyl)
23-methyl-C1 7 (J-19,21-dinorhol-9,23-dien-20-yn-5 o (-17 fi-diol.
In an inert gas, 4.5 g of potassium t-butylate are mixed with 90 cm of anhydrous tetrahydrofuran. The mixture is cooled to -10 ° C and 10.61 cm of 2-methyl--1-butene-3-yin is added. The solution is stirred for 15 minutes at, and then a solution of 4.5 g of anhydrous tetrahydrofuran obtained in step 7 of example 7 is added to the solution for 15 minutes. Stirred for 30 min at -10 ° C, and then 4 hours at O - (+5) C.
Rinse with ethyl acetate and wash the organic layer of the product.
500 cm in volume; aq. aqueous solution of ammonium chloride, extruded with ethyl acetate, washed organic layer of the product
with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness. 5.56 g of crude target are obtained.
T. pl. 205 C. The product is used in the continuation of the synthesis.
Crude product, chromatographed on silica, eluted
a mixture of methylene chloride - ethyl
Acetic acid ester (9: 1) from 1 per thousand of triethylamine, and then recrystallized in ethyl acetate. T. pl. 215 ° C.
15
Stage B. (4-Dimethylaminophenyl) -1 7/3-hydroxy-23-methyl-1 9, 1-dinorchol-4,9,23-triene-20-in-3-one.
In an inert atmosphere, 5 g of the product obtained in stage A are mixed with 300 cm of methanol and 10 cm 2 of hydrochloric acid ,. Stir for 15 minutes at 20 ° C, add 300 cm of ethylene chloride, and then 300 cm of a 0.25 M aqueous solution of sodium bicarbonate. After 10 minutes of stirring, it is decanted, the mixture is extracted with methylene chloride, the organic layer is washed with water, dried and evaporated to dryness. This gives 4.5 g of the desired product, which is chromatographed on silica, eluting with petroleum ether-ethyl acetate (1: 1). After recrystallization of the product in diisopropyl oxide, 2.01 g of the expected product is obtained. T. pl. 185 С, Co / Jj3 +88,5 ± 1, (to 1% CHCij).
Example 9. 1 l | E- (4-Dimethyl-aminophenyl) -17p-methoxy-23-methyl-7 (-19,21-dinorchol-4,9,23-triene-20-in-3-one.
Inert gas mix 4.5 g of tertiary potassium butylate in 90 cm of anhydrous tetrahydrofuran. The suspension is cooled to, and then 10.61CM 2-methyl--1-buten-3-yin is added dropwise. The mixture is stirred for 15 minutes at and then added for 15 minutes, - 4.5 g of the obtained in stage A of example 7, products in 45 cm of anhydrous tetrahydrofuran. Stir for 30 minutes at and then 4 hours at 0 .- (+5) 0. Subsequently, 7.5 ml of methyl iodide is added and the mixture is kept under stirring for 30 minutes on an ice bath. Then the mixture is poured onto 500 cm of 0.1 N hydrochloric acid. Stir for 30 minutes at room temperature, extract with ethyl acetate, flush the organic layer with a saturated aqueous solution of bi 144
Stage B. 21-Chloro-1 7- / -hydroxycarbonate sodium, and then saturated gQ -11 / 1- (4-dimesh1aminophenyl) -GI 9- aqueous solution of sodium chloride, -norpregna-4,9-diene-20-in -3-he.
6.38 g of the product obtained in the previous step and 191.4 cm of 95% ethanol are mixed in an inert gas. 55 Add 15 cm of 2N hydrochloric acid, stir for 1 hour, add 300 cm of methypen chloride, and then 200 cm of a 0.25 M aqueous solution of sodium bicarbonate. Decant,
The crusher is dried and distilled. A chromatographic one on silicon dioxide, eluting with methyl chloride-ethyl ester of acetic acid (95: 5), yields 2.7 g of the desired product, which is recrystallized in methanol. T, pl. 105 C.

. 47289
) 6
Example 10. 21-Chloro-17/3-hydroxy Si-1 1 (4-dimethyl ffofenyl) -C 11c (- 1 9-norpregna-4.9-: diene-20-ii-3-one.

Stage A. 2-Chloro-3,3-G1, 2-ethane- -diyl-bice- (oxy) Jl 1 / 5- (4-dimethytaminophenyl) -G1 7 9-nrrpregna-9-en-20- -in-5o / -17 / z-diol.
10 Preparation of organolithium compound.
77.5 cm of a 1 M solution of bottle of hexane in a mixture of 310 cm of anhydrous ethyl ether are mixed in an inert gas.
15 Cool to O - (+5) C and add a solution of 7 cm of trichloroethylene to 28 cm of anhydrous ethyl ether over 45 minutes. Stir for 1 h, allowing the temperature to rise to 20 ° C.
20 Condensation.
The mixture is cooled to O - (+5) C and added dropwise over 30 minutes. a solution of 7 g of the product of Example 7 obtained in stage A
25 70 cm of tetrahydrofuran. Stir for 30 minutes at 0 - (+5) ° C, and then allow the temperature to rise to 20 ° C, slowly inject into a complete aqueous solution of ammonium chloride,
30 are decanted, extracted with methylene chloride, washed with water, the organic layer is added and the solvent is distilled off. 8.5 g of crude product are obtained (mp: 220 ° C), which is introduced into 42.5 cm of diisopropyl oxide. Stir for 30 minutes, drain, and obtain 6.38 g of the desired product, mp. .
It is not necessary to purify the product by the chromatographic method on silicon dioxide, eluting with a mixture of benzene — ethyl acetate acetic acid (7: 3) containing 1 per thousand of triethylamine. By dissolving this product in methylene chloride 45 and digesting with diisopropyl oxide, a crystallized product is obtained. With so pl. 240 С, -83.5 + +1.5 ° (to 1% СНС1з).
Stage B. 21-Chloro-1 7- / -hydroxygQ -11 / 1- (4-dimesh1aminophenyl) -GI 9- -norpregna-4,9-diene-20-yn-3-one.
extract with methylene chloride, flush the organic layer with water, dry and distill off the solvent. 6 g of crude product are obtained, which is chromatographed on silica, eluting with a mixture of benzene and ethyl acetate (7: 3). 3.95 g of the expected product are obtained, which is crystallized in ethyl acetate. T. pl. (v +111 ± 2 (to 1% СНС1з).
Example 11. N-Oxide 21-chloro--1 7/5-HYDROXY-11 / 5- (4-dimethylaminoethene methylene-methanol (8: 2) and get 1 g of the target product. Mp. 270 s, Y + 39.5 + 2.5 (to CHClj).
Example 13. 21-Chloro-9s / -10 h - -epoxy-1 7/3-HYDROXY-1 / 1- (4-dnmethyl-aminophenyl) 9-norpregn-A-ene-20-in-3-one .
In an inert gas, 0.63 g of the product obtained in Example 12 is mixed with 6.3 cm of acetic acid. 0.34 g of triphenylphosphine is added, the mixture is stirred for 45 minutes at room temperature, temenyl) -C17o 1-19-norpregna-4,9-diene-20-15, and poured into water, extracted with in-3-one.
1.2 g of the product obtained in Example 10 are mixed in 24 cm of methylene chloride in an inert gas. It is cooled to O - (+5) ° C and a mixture of 0.54 g of 85% metachloroperbenzoic acid in 10.8 cm of methyl chloride is added.
with methylene chloride, the organic layer is washed with water, dried, and the solvent is distilled off. About 9 g of product is obtained, which is chromatographed on silica, eluting with a mixture of petroleum ether-ethyl acetate (1: 1). Thus, the resulting product is crystallized in
on. Stirred for 1 h at O -. (+ 5), C, poured into 2 N. the solution
with methylene chloride, the organic layer is washed with water, dried, and the solvent is distilled off. About 9 g of product is obtained, which is chromatographed on silica, eluting with a mixture of petroleum ether-ethyl acetate (1: 1). Thus, the resulting product is crystallized in
mixtures of methylene chloride - sodium isopropitiosulfate, extracted with chlorine ether and obtain 0.346 g of the desired product. T. pl. 265 C,)
D +45 + 2 ° (to 0.8% CHClj).
Example 14. 17 5-Hydroxy-11 / e- (4-dimethylaminophenes1) -21-phenyl-30 -Cl7c (J-1 9-norpregna-4,9-diene-20-in-3-one.
Stage A. 21-Phenyl-3,3-G1,2-ethanediyl-bis- (oxy)} -1 1 / i- (4-dimetypamino-phenyl) 5o / -1 7 / δ-dihydroxy- 1 9 -nor-pregn-9-en-20-in.
35
with methylene methanol, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then with water, dried and the solvent was distilled off. 1.3 g of crude product are obtained. This product is purified by chromatography on silica, eluting with methylene chloride-methanol (7: 3). 1.15 g of the expected product are obtained. , +47.5 + 2.5 (to 0.7% CHCl j). Example 12. N-Oxide 21-chloro-9o / -1 Oo-epoxy-1 7/3-hydroxy-1 1 / 3- (4-dimethylaminophenyl) -P 7o Jl 9-norpreg-4-ene 20-in-3-she.
1.18 g of the product obtained in Example 10 is dissolved in 23.6 cm of methylene chloride, cooled to O - (+5) C and added over 15 minutes
a mixture of 1.17 g of metachloroperbenzoic is then added dropwise at
acid (85%) in 23.4 cm — chloride-45 solution of 4.17 g of the product obtained by methylene. Stir for
add
40
In an inert gas, 4.17 g of tertiary potassium butylate in 83 cm of anhydrous tetrahydrofuran are mixed. Stir for 5 minutes and then cool to 4.5 cm of phenylacetylene is added dropwise. Stir the suspension for 5 minutes, and
-.0,
; 2 h at 20 ° C, again
: 0.117 g of metachloroperbenzoic acid, stirred for an additional 1 h, poured the mixture into 0.2 n. At the end of the introduction, the temperature is adjusted to. then after 1 hour, the mixture is boiled out into a full solution of ammonium chloride. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried, concentrated
in stage A of example 7, in 41 cm of anhydrous tetrahydrofuran. At the end of the introduction, the temperature is adjusted to. then after 1 hour, the mixture is boiled out into a full solution of ammonium chloride. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried, concentrated
sodium thiosulfate, extracted with methylene chloride, the organic layer was washed with saturated sodium bicarbonate and then with water, dried and evaporated to dryness. When dry, 4.7 g of product is obtained, 1.14 g of crude product is obtained. T. pl. which is chromatographed on dioxide. Silica, eluted with chloride mixture
The product is purified chromatographically with methylene - acetone (95: 5). Prepared on silica, eluting with a mixture of 3.71 g of the intended product. T. pl.
methylene chloride - methanol (8: 2) and receive 1 g of the target product. T. pl. 270 s, L +39.5 + 2.5 (to CHClj).
Example 13. 21-Chloro-9s / -10 h - -epoxy-1 7/3-HYDROXY-1 / 1- (4-dnmethyl-aminophenyl) 9-norpregn-A-ene-20-in-3-one .
In an inert gas, 0.63 g of the product obtained in Example 12 is mixed with 6.3 cm of acetic acid. 0.34 g of triphenylphosphine is added, stirred for 45 minutes at room temperature, poured into water, extracted
with methylene chloride, the organic layer is washed with water, dried, and the solvent is distilled off. About 9 g of product is obtained, which is chromatographed on silica, eluting with a mixture of petroleum ether-ethyl acetate (1: 1). Thus, the resulting product is crystallized in
product. T. pl. 265 C,)
D +45 + 2 ° (to 0.8% CHClj).
Example 14. 17 5-Hydroxy-11 / e- (4-dimethylaminophene 1) -21-phenyl-Cl 7c (J-1 9-norpregna-4,9-diene-20-in-3-one.
Stage A. 21-Phenyl-3,3-G1,2-ethanediyl-bis- (oxy)} -1 1 / i- (4-dimetypamino-phenyl) 5o / -1 7 / δ-dihydroxy- 1 9 -nor-pregn-9-en-20-in.
 then added dropwise at
0
In an inert gas, 4.17 g of tertiary potassium butylate in 83 cm of anhydrous tetrahydrofuran are mixed. Stir for 5 minutes and then cool to 4.5 cm of phenylacetylene is added dropwise. Stir the suspension for 5 minutes, and
-.0,
45 solution of 4.17 g of the product obtained
in stage A of example 7, in 41 cm of anhydrous tetrahydrofuran. At the end of the introduction, the temperature is adjusted to. then after 1 hour, the mixture is boiled out into a full solution of ammonium chloride. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried, concentrated
55 to dryness to obtain 4.7 g of product, which is chromatographed on silica, eluted with chloride mixture.
 , -119,5 t 2 ° (to 1%
СНС1з).
Stage B. 17/1-Hydroxy-17 / 3- (4-di-methylaminophenyl) -21-phenyl-1 7ofJ-19 -norpregna-A, 9-diene-20-yn-3-one.
3.49 g of the product obtained is dissolved in 68 cm of methanol, and then 6.3 cm of 2N hydrochloric acid is added. After 30 minutes of stirring, 180 cm of ethyl ether and 90 cm of a 0.25 M sodium bicarbonate solution are mixed in. The mixture is stirred for 5 minutes, decanted, extracted with ether, the organic layers are washed with a 0.25 M sodium bicarbonate solution and then with a saturated sodium chloride solution. Dry, distill off the solvent and obtain 4.35 g of pro-
3.4 g of product are obtained, which is chromatographed on silica, eluted with a mixture of petroleum ether and ethyl acetate (1: 1) with 1 per thousand triethylamine. Thus, the following are distinguished:
a) 1.73 g of isomer 17c (- (prop-1, 2- -disnyl), mp. 178 Cj o Jj; -32 +
 10 + 2 (to 0.7% CHClg);
b) 1, 5 g of isomer 17c / -prop-2-ynil, t. pl. ,, -15 + 2 Cq 0.9% CHCl j).
Stage B. 17/3-Hydroxy-1 1 / 3- (4-di-15 methylaminophenyl) (prop-1, 2-diene-yl) -estra-4,9-diene-3-one.
In an inert gas, 1.73 g of the isomer obtained in stage A, (prop-1, 2-dienyl), 51.8 cm of the 95% product that is mixed with chromatography — 20 ° ethanol and 3.5 cm 2 n — are mixed. saline acidic on silica, eluting lots. The mixture is stirred at 20 ° C for 1 hour, 50 cm of methane: foam, (95: 5) are added with a mixture of methylene chloride and acetone, to obtain 2.13 g of the desired solution, then 50 cm of a 0.25 M solution of sodium bicarbonate, decant extracted with methylene chloride, washed with water, dried and the solvent was distilled off. 1.51 g of product are obtained, which is dissolved in 10 cm of hot methylene chloride. 15 cm of iso-Stade A is added. 11/3- (4-Dimeshchamochnafe-30 propyl ether, concentrate and the nyl) -3, 2-ethanediyl-bis- (oxy) -step at rest. 1.23 g of the expected product are thus isolated, which is recrystallized in a mixture of methylene chloride - isopropyl (prop-2-1-dayl) -estr-9-en-5o-17/1-ZB. Finally, 1.11 g -diol is obtained. target product. T. pl. 228 ° C
Preparation of organolithium L Jp +139.5 + 3 ° (to 0.8% СНС1з).
Compounds. Example 16. 17/5-Hydroxy-1 1 / JB 50 cm anhydrous tetrahydrofu - (4-dimethylaminophenyl) -1 (prop-2ran at O - (+5) C is bubbled by al-40 yl) -estra-4 , 9-diene-3-one. flax d (At absorption 2.1 g. Cool
to -70 ° C and 0.94 g of the 1.3 M solution of butyl-stage A of Example 15 of the Md isomer in hexane, mixed in 23.9 cm of a 1.3 M solution of butyl-stage A of Example 15 are mixed. The resulting mixture ne - (prop-2-ynil), 28.2 cm 95%
stirred for 15 min at. 45 ethanol and 2 cm 2 of hydrochloric acid.
Stir for 1 h at 20 ° C, add 50 cm of methylene chloride and 50 cm of 0.25 M bicarbonate solution
duct after crystallization in isopropyl ether. Co / 7 j3 +22.5 + 1 (to% CHCl3).
Example 15. 17 / C-Hydroxy--11 (1- (4-dimetipaminophenyl) -17 | x - (prope-1,2-dienyl) -estra-4,9-diene-3-one.
-1 7 "- (propa-1,2-dienyl) -estr-9-ene-5o / -17 / 1-diol and 1 l / 3- (4-dimethylaminophenyl) -3,3-Cl 1 , 2-ethanediyl-bis- (oxy) Condensation.
To the resulting solution of the lithium organic compound is added at
sodium stirred for 5 min
-70 C for 25 minutes, a solution of 3.5 g 50 is decanted and extracted with chloride
the product obtained in Step A of Example 7 in 35 cm of anhydrous tetrahydrofuran. The mixture is stirred for 1 h at -70 ° C, and then poured into a saturated ice-cold aqueous solution with chlorine-elution with a mixture of ammonium petroleum. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off.
sodium stirred for 5 min
methylene. The organic layer is washed with water, dried, and the solvent is distilled off. The resulting chromate product is captured on silica.
ethyl acetate (1: 1). Thus, 0.42 g of the expected product is obtained in amorphous form. +143 + (to 0.8% CHClj).
Example 17. 1 7o-Ethynyl-1 7/3-β-hydroxy-1 1 / 2- (4-dimethylaminophenyl) -estra-4,9-diene-3-one.
Stage A. 1 7 / z-Cyano-1 (4-dimethyl-infenyl) -3,3-P, 2-ethanediyl-bis- (oxy) -1 (trivtilsilyloxy) -Estra-9-en-5 -ol.
At room temperature and in
1 cm 2 of n hydrochloric acid is added. Stir for 40 minutes at 20 ° C, drink into water containing 2.5 cm of 1N sodium hydroxide, extract with ether, dry the organic layer and distill off the solvent. The residue is chromatographed with silicon dioxide, eluting with a mixture of benzene and ethylene gas, a suspension of 2.05 g of a com-IQ lovy ester of acetic acid (7: 3), and
0.25 g of the desired product is obtained.
a solution of copper bromide - dimethyl sulfide in 10 cm of anhydrous tetrahydrofuran, a solution of 18 mmol of (4-dimethylaminophenyl) magnesium bromide in anhydrous tetrahydrofuran is added. Then, 0.95 g of 1 7/5-cyano-1 (trimethyl-bromoyl) -3, 2-ethanediyl-bis- (oxy) -5o - OO-epoxy-estr-9 (1 1) - Enna in anhydrous tetrahydrofuran, stirred for 15 hours at room temperature, poured into 50 cm of a saturated solution of ammonium chloride, decanted, extracted with ether, the organic layer was washed with water, dried, and the solvent was distilled off. The residue is purified by chromatography on silica, eluting with a mixture of benzene and ethyl acetate (8: 2). 1.1 g of the expected product are obtained, which are recrystallized in isopropyl ether, mp. 247 ° C, -12.5 ° (to G% CHClj).
Stage B. 1 7o-EtinshI-3,3-tetadi-yl-bis-(oxy) J-1 1 / h- (4-dimethylaminophenyl) -estr-9-en-5o (-1 7/3 -diol
To 0.8 g of the product obtained in stage A is 8 cm of ethylene diamine, 1 g of the complex of lithium acetylenic ethylene diamine is added, and then suspended with stirring and in an inert gas at 50 ° C for 1.5 hours. C, and then vtyvayut in a solution of ammonium chloride. Extracted with ether and methylene chloride. Dry the organic layer and distill off the solvent. The residue is chromatographed on silica and eluted with a mixture of benzene and ethyl acetate (7: 3), and the product obtained is recrystallized from isopropyl ether to obtain 0.43 g of the expected product. T. pl. 199 ° C. -43 ± 1.5 (to 1% CHClp.
15
20
25
40
45
50
0.25 g of the desired product is obtained.
Calculated,%: C, 80.92; H 8.00; N 3.37.
C gHjjNO (415, 54).
Found,%: C 80.7; H 8.1; N 9.1.
Example 18: 17 ° C-Etinip-17/5-β-hydroxy-1 1 (4-dimethylaminophenyl) -estra-4,9-diene-3-one.
Stage A. (4-Dimethylaminophenip) -3, 2-ethanediyl-bis- (oxy) -7 / 3-dihydroxy 7c-ethynyl-estr-9-α.
6 g of the product obtained in Stage A of Example 7 are dissolved in inert gas in 180 cm of tetrahydrofuran, and then 12.25 g of a complex of lithium acetylenylity — ethylene diamine are added. Heated to 55 C, stirred for 4 h, cooled, and then
ammonium chloride solution. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off. The residue obtained is purified by chromatography on silica, eluted with a mixture of benzene and ethyl acetate (7: 3) containing 1 per thousand tri-ethtamine, and 4.5 g of the expected product are obtained, which is recrystallized in a mixture of methylene chloride and diisopropyl oxide . T. pl. 202 С, 1а (- -47,5 ± 1,5 (to 1% СНС1з).
Stage B. 17o / -Etinip-17 / E-hydroxy-1 1 /-(4-dimethylaminophenyl) -estra-4,9-diene-3-one.
2 g of the product obtained in stage A are mixed in 50 cm of 95% ethanol. To the suspension was added 5 cm of 2N hydrochloric acid. While stirring, hold for 1 hour at 20 seconds, add 100 cm of ethyl
30 for 4 h, cooled, poured into 600 cm
35
Stage B. 17c-Etch1-17 / 3-hydroxy-gg ester, and then 100 cm of 0.25 M raptwo-11p- (4-dimethylaminophenyl) -estra-4,9-ra sodium bicarbonate. Decant
extracted with ether, the organic layer is washed with a high-grade aqueous rad-3-one.
To a solution of 0.25 g obtained in
stage B product in 6 cm of methanol
1 cm 2 of n hydrochloric acid is added. Stir for 40 minutes at 20 ° C, drink into water containing 2.5 cm of 1N sodium hydroxide, extract with ether, dry the organic layer and distill off the solvent. The residue is chromatographed on silicon dioxide, eluting with a mixture of benzene — these
Lovy ester of acetic acid (7: 3), and
0.25 g of the desired product is obtained.
Calculated,%: C, 80.92; H 8.00; N 3.37.
C gHjjNO (415, 54).
Found,%: C 80.7; H 8.1; N 9.1.
Example 18: 17 ° C-Etinip-17/5-β-hydroxy-1 1 (4-dimethylaminophenyl) -estra-4,9-diene-3-one.
Stage A. (4-Dimethylaminophenip) -3, 2-ethanediyl-bis- (oxy) -7 / 3-dihydroxy 7c-ethynyl-estr-9-α.
6 g of the product obtained in Stage A of Example 7 are dissolved in inert gas in 180 cm of tetrahydrofuran, and then 12.25 g of a complex of lithium acetylenylity — ethylene diamine are added. Heated to 55 C, stirred for 4 h, cooled, and then
ammonium chloride solution. Extracted with ether, washed the organic layer with a saturated aqueous solution of sodium chloride, dried and the solvent was distilled off. The residue obtained is purified by chromatography on silica, eluted with a mixture of benzene and ethyl acetate (7: 3) containing 1 per thousand tri-ethtamine, and 4.5 g of the expected product are obtained, which is recrystallized in a mixture of methylene chloride and diisopropyl oxide . T. pl. 202 С, 1а (- -47,5 ± 1,5 (to 1% СНС1з).
Stage B. 17o / -Etinip-17 / E-hydroxy-1 1 /-(4-dimethylaminophenyl) -estra-4,9-diene-3-one.
2 g of the product obtained in stage A are mixed in 50 cm of 95% ethanol. To the suspension was added 5 cm of 2N hydrochloric acid. While stirring, hold for 1 hour at 20 seconds, add 100 cm of ethyl
within 4 h, cooled, poured into 600 cm
with sodium chloride, and
evaporated. Chromatograph the resulting residue on silica using a mixture of petroleum ether and ethyl acetate (6: 4), and emit 1, fJ2 g of the desired product, which is recrystallized in diisopropyl oxide. T. pl. , +182 ± 2.5 ° (to 1% CHClj),
Example 19. 17p-Hydroxy--1 1p- (3-dimethylaminophenyl) -1 (prop--1-vinyl-estra-4, 9-diene-3-one.
Stage A. 1 1 / e- (3-Dimethylaminophenyl) -3,3-П, 2-ethanediyl-bis- (oxy) 3 - -1 7th - (prop-1-vinyl) -estr-9-ene -5y -1 7 / 3- -diol ..
Preparation of organomagnesium compound.
1.46 g are mixed in inert gas
100 cm of methanol, cooled to O - (+5) ° C and 10 cm 2 of n hydrochloric acid are added, Pepe: is sutured for 1 hour at O - (+5) C, 200 cm of diethyl oxide are added, and then 200 cm of a 0.25 M sodium bicarbonate solution. The mixture is stirred for 5 minutes, decanted, extracted with diethyl oxide, the organic layer is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is distilled off. 3 g of product are obtained, which are chromatographed on silica, eluted with a mixture of benzene and ethyl ester of acetic acid (7: 3). 1.43 g of the amorphous desired product is isolated, j} +43 + 2.5 ° (to 1% CHClj),
Example 20, N-Oxide
/
magnesium and 5 cm of anhydrous tetrahydro-20 roxy-1 1 / L- (4-dimethylaminophenes1) -1 7o furan. Keeping temperature around- (prop-1-ynil) -estra-4,9-diene-3-one.
, injected within 45 min. 10 g of metabromodimethylaniline in 45 cm of anhydrous tetrahydrofuran.
1.5 g of the product obtained in addition to 4 are mixed with 30 cm of methylene chloride. Cooled to 0.5 ° C and added over a period of 10 minutes, a solution of 0.71 g of metachlorobenzoic acid
with stirring for 1 hour, a solution is obtained in 0.95 M of the desired organomagnesium compound. Kondensa.tsi,
Inert gas mix 3.7 g of 3, 2-ethylenedioxy-bis (oxy)} - -1 7 ° / - (prop-1-1Sh1) -estr-9 (1 1) -en-5o (- -1 Oo (-epoxy-1 7 / o-ol, 74 cm of anhydrous tetrahydrofuran and 99 mg of copper monochloride. Cooled to O - (+5) C, and then 42.2 cm of the resulting solution of magnesium-organic compound was added in 30 minutes. The mixture is stirred for 30 minutes at O - (+5) ° C, poured into a saturated aqueous solution of ammonium chloride, extracted with ether G, the organic layer is removed with a saturated aqueous solution of sodium chloride, sugate and the solvent is distilled off. The residue is chromatographed silica, eluting with a mixture of methylene chloride - acetone (9: 1) containing 1 per thousand of triethylamine. 3.5 g of the expected product are obtained, T, mp, 262 ° C, -64 ± 1.5 ° (to 1% CHClj ),
0.66 g of the corresponding isomer 5 OH, T, pl. 210 С, +32.5 + -1 ° (to 0.8% СНС1з), Stage B,
1 7 / ь-Hydroxy-1 1 / 4- (3-dimethylaminophenyl) - (p) po-l-ynyl) -extra-4,9-di-3-one.
In an inert gas mix 3.3 g of the product obtained in stage A with
100 cm of methanol, cooled to O - (+5) ° C and 10 cm 2 of n hydrochloric acid are added, Pepe: is sutured for 1 hour at O - (+5) C, 200 cm of diethyl oxide are added, and then 200 cm of a 0.25 M sodium bicarbonate solution. The mixture is stirred for 5 minutes, decanted, extracted with diethyl oxide, the organic layer is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is distilled off. 3 g of product are obtained which are chromatographed on silica, eluted with a mixture of benzene and ethyl acetate (7: 3). 1.43 g of the amorphous desired product is isolated, j} +43 + 2.5 ° (to 1% CHClj),
Example 20, N-Oxide 17 -guid /
five
five
0 0 5 0
five
Mix 1.5 g obtained in when. measure 4 products with 30 cm of methylene chloride. Cooled to 0.5 ° C and added over a period of 10 minutes, a solution of 0.71 g of metachlorobenzoic acid
methylene chloride (85%) in 14.2 cm flax. Stirred at O - (+5) ° C for 1 h, poured into 100 cm of 0.2 N sodium sodium thiosulfate solution, decanted, extracted with methylene chloride, washed the organic layer with 0.5 M sodium bicarbonate solution, dried and the solvent was distilled off . The residue is dissolved in 20 cm of methylene chloride and 20 cm of diisopropyl oxide are added. The crystals are seeded, quenched, sucked off, the crystals and dried. 1.4 g of the expected product are obtained. T, pl, 210 ° C, +73.5 + 2 ° (to 1% CHClj),
Example 21, 11p- (4-Dimethyl-aminophenyl) -1 7p-hydroxy-estra - 4,9-dien-3-one.
1 g of the product obtained in Step A of Example 7 is mixed in 20 cm of tetrahydrofuran containing 10% water. After dissolving, 106 mg of sodium borohydride are added, stirred for 1 hour, poured into 200 cm of water, extracted with methylene chloride, the organic layer is washed with high-grade sodium chloride solution, sutaate, and the solvent is distilled off. 1.3 g of product 5o-17p-dihydroxy are obtained,
0.63 g of the product obtained is added to a mixture of 12 cm of methanol and 2.4 cm 2 of hydrochloric acid. Stirring 1st
1 h 30 min at room temperature, dried in sodium bicarbonate solution, extracted with ether, the organic layer is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is distilled off. The residue is chromatographed on silica, eluted with a mixture of petroleum ether and ethyl acetate (6: 4). The residue is triturated in petroleum ether, sucked off and 0.39 g of the expected product are obtained. T, pl. , CC / JD +277 ± 5 (to 0.5% СНС1з).
Example 22. 1 7/5-Hydroxy-1 l / e- (4-dimethylaminophenyl) -1 (prop-2-yl) -estra-4,9-diene-3-one.
Stage A. 3,3-f1,2-Etandiyl-bis- (oxy) j -1 1 / 3- (A-dimethylaminofensh1) -1 -1 (yrop-2-enyl) estr-9-en-5 - 1 7 / 3- -diol.
In 55.5 cm of a 0.7 M solution of allyl-anne-bromide in ether, in an inert gas are introduced, during 15 minutes, 3.5 g of the product obtained in Step 7 of Example 35 in 35 cm of tetrahydrofur
on. Stir at 20 ° C for 1 h, pour into a saturated aqueous solution of ammonium chloride, extract with ether, wash the organic layer with a saturated aqueous solution of sodium chloride, dry and distill off the solvent. The residue obtained is dissolved in 10 cm of methylene chloride. 14 cm of diisopropyl oxide are added, the mixture is concentrated and then left at rest. The crystals formed are filtered off with suction, rinsed with diisopropyl oxide, dried, and 2.76 g of the expected product are obtained. T. pl. WITH.
Calculated,%: C, 74.42; H 8.87; S 2.83.
 (93.69)
 C, 74.0; H 8.7;
Found, N 2.9.
Stage B,
1 7/3-Hydro-rock C-1 1 / 3- (4-dimethylaminophenyl) - (propyl-2-enyl) - -estra-4,9-diene-3-one.
2.2 g of methanol obtained in stage A are introduced into suspension in 66 cm, and then 4.5 cm 2 of hydrochloric acid are added. Stir for 30 min at 20 ° C. 132 cm of diethyl oxide are added, followed by 132 cm of a 0.25 M aqueous solution of sodium bicarbonate. Decanted, extracted with diethyl oxide, washed with all (with an aqueous solution of chloride
five
about .
go sodium, dry and distill off the solvent. The residue is chromatographed on silica, eluted with a mixture of benzene and ethyl acetate (7: 3), the resulting product is introduced into a mixture of 15 cm of diisopropyl oxide and 7.5 cm of methylene chloride, concentrated and then left at rest.
Q Sucked off and rinsed the resulting crystals with diisopropyl oxide and get 1,365 g of the target product. T. pl. 182 С, +206.5 + 3 ° (to s% CHClj).
15 Example 23. 17/5-Hydroxy-1 1 / 3- -J 4- (N, N-Dimethylaminomethyl) phenylJ- -1 7e / - (prop-1-ynyl) -estra-4,9-di- 3- -one
Stage A. 3,, 2-Ethanediyl-bisQ - (hydroxy) 1-1 (N, N-dimethylaminomethyl) phenyl -1 (prop-1-insh1) -estr-9-en-5o1-1 7p - diol
Preparation of organomagnesium compound.
5 In an inert gas, 5.5 g of magnesium and 10 cm of anhydrous tetrahydrofuran are mixed. Maintaining a temperature of 45-
50 ° C, injected over 1 hour 30 minutes, 42.8 g of 4- (S, N-dimethylaminomethyl) -bromobenzene in 190 cm of anhydrous tetrahydrofuran. The reaction is seeded with the addition of dibromoethane. After completion of administration, stirring is maintained for 1 hour. In this way, the target is obtained. radar 0.85 M magnesium-organic compound. The addition of epoxide. In an inert gas, 10 g of 3.3- 1, 2-ethanediyl-bis- (oxy) Jl 7c (- - (prop-1 -inyl) -estr-9 (1 1) -en-5o -1 -epoxy- 17 / z-ol, 200 cm of anhydrous tetrahydrofuran and 0.27 g of monochlorine
five
0
five
yes, copper. The mixture is cooled to O - (+5) C and 127 cm of the prepared organomagnesium compound solution is introduced within 1 hour. Then it is stirred for 15 minutes, diluted with water; an aqueous solution of ammonium chloride is added, extracted with ether, the organic layer is washed with an aqueous aqueous solution of sodium chloride, dried and the solvent is distilled off. The residue is chromatographed on silica, eluting with a mixture of methylene chloride - methanol (9: 1) containing 1 per thousand of triethylamine. 10.1 g of product are obtained, which is crystallized by dissolving in methylene chloride and adding several CM of methanol, and then diisopropane 1447289OQ
2728
saw. After concentration and rest for 1 h, poured into the prescribed
for 6 hours, the resulting product is an octa-aqueous solution of ammonium chloride,
sow and get 7.37 g of the target. extracted with diethyl oxide, prodrug. T, pl. , Ct / Jp -63 + have an organic layer at a premium.
t 2,5 (to 0, 5% CHCl j), aqueous solution of ammonium chloride,
and then saturated aqueous solution
Stage B, 1 7 (e-Hydroxy-1 l / 5-f4-sodium chloride, dried and distilled off
- (H, H-dimethylaminomete.) PhenylZ-1 7o (-solvent. The residue is purified by chromo- (prop-ynyl) -estra-4,9-diene-3-one, thographically on silica;
Inert gas is mixed with 7.37 gelüru with a mixture of methylene chloride of the product obtained in stage A of the vacetone (95: 5) containing 1 per thousand 147, 4 cm. methanol and 15 cm 2 n.sool triztilamina. Thus, the poloic acid. 8.3 g of the desired product is stirred for a while. At 20 ° C, 300 cm oxy-15 is added. The recrystallized solid is recrystallized in a mixture of diethyl chloride v and 300 cm of 0.25 M methylen-isopropyl ether.
Sodium bicarbonate solution leg, T. square 185 ° C, -67 + 1.5
decanted, extracted with di- oxide (to 1% CHCls),
ethyl, washed the organic layer. Step B. 1 7p-Hydroxy-1 1 / 9- (4-pyrivaturated aqueous solution of chloride-20 rolidinylphenyl) (prop-1-ynyl) sodium, dried and distilled dissolve the estra-4, 9-diene-3-one.
tel. The resulting product is recrystallized — 6.4 g of the product obtained in stage A is lysed, its solution in an oxide – duct mixture is dissolved in 128 cm methanol
diisopropyl and i. methylene chloride and then add 13 cm 2 n salt
on, and then concentrate the solution 25 acid. Stir at 20 ° C in leaks and leave it in place. Suction for 1 hour and then add 256 cm.
and dry the resulting crystals. Takimoki diethyl and 256 cm of 0.25 M water content get 3.74 g of the desired pro-sodium bicarbonate solution. Dedukta. T. pl. 190 ° C. +84.5 tquitt, extracted with diethyl oxide + 2 ° (to 0.8% СНС1 з) .30 la, organic layer is produced, 25M
PRI and MER 24. A 17 -Hydroxy-aqueous solution of sodium bicarbonate, -P / 5- (4-pyrrolidinylphenyl) -1 7 ° (- (prop-and then with a full aqueous solution of -1-ins1) -estra-4, 9-diene-3-one. Sodium chloride, dried and distilled by Step A. 3, 2-Ethanediyl-bis-solvent. The residue by chromatography is - (oxy) 7-1 I C4-pyrrolidinylphenyl) - js silica, Eluira (prop-1-ynil) -estr-9-en-5 (3 -17 / 3-mixture of petroleum ether-ethyl-diol. ester of acetic acid (1: 1), and semi-organic magnesium; 5.25 g of the target the product, which is a compound, which is recrystallized in a mixture of chlorine, is mixed in A gaseous gas 4 g mag- / Q butt methylene - diisopropyl oxide.
Neither and 10 cm anhydrous tetragndro-T. square 190 ° C, JD +120 ± 2,, 5
furan. Higher temperature 45 - (to 1.2% CHCl3).
, introduced over 1 hour 34 g of 4-Example 25. 17 / s-Hydroxy-1 1 p-pyrrolidinyl bromobenzene in 140 (4-dimethylaminophenyl) -17 s (-ethenyl anhydrous tetrahydrofuran. Reaction 45 estra-4,9-di- 3-one. It is seeded with the addition of dibromet-Stage A. 3,, 2-Ethanediyl bis-. Thus, 1 M rast - (oxy) -11 (3- (4-dimethylamino-iff; neil) is a thief of the target organosilicon --1 7c / -ttenyl-estr-9-en-5c -1 7 / d-diol, dinene. 3 g of the product obtained in the Condensation step on an epoxide. 50 of Example 17 is mixed with 60 cm without- In an inert gas is mixed 8 g of 3,3-aqueous pyridine and add 0.6 g, 2-ethanedin I- bis- (oxy) J-5c / -10o / -5% palladium on carbonic -cal-β-epoxy-1 7c / - (prop-1-ynyl) -estr-9 (11) -ion. Hydrogen is passed into this mixture is -17/3-ol,: 60 cm of anhydrous tet-at room temperature for raghidrofuran and 216 mg of monochloride55 The catalyst is evaporated off, the evaporation of the copper is cooled to 0 - (+5) 0 and the filter is injected dry introduced into toluene; precipitated for 1 hour 30 minutes 86.4 and again evaporated to dryness. In this prepared solution of magnesium oxide, g of the desired protic compound is obtained. Stir in the product used in the continuation
In an inert gas, 4.12 g of magnesium and 10 cm of tetrahydrofuran are swept up. A few cm of M-methyl-H1- (3-methylbutyl) -A-bromobenzenamine in tetrahydrofuran are introduced and the reaction is seeded by adding 0.2 cm of 1,2-dibromoethane. Then the rest of solution K is added over 40 minutes. -methyl-K- (3-methylbu-type) -4-bromobenzene amine in anhydrous tetrahydrofuran (32.6 g in 90 cm). The temperature is allowed to reach room temperature and then held while stirring for 1 hour. In this way, a 0.9 M solution of the desired organomagnesium compound is obtained.
Condensation.
8 g of 3,, 2-ethanediyl- -bis- (oxy) -5 ai- Oo-epoxy-17 d- (pro-1-ynyl) -estr-9 (11) -en-17-ol with
90 cm of anhydrous tetrahydrofuran and 3.77 g of copper monochloride. Stir for 20 minutes at + 5 ° C in an inert gas, and then add 100 cm of the prepared solution of the magnesium organic compound. Then the mixture is drunk into an aqueous solution of ammonium chloride, extracted with ether containing triethipamine, and then with methylene chloride containing triethylamine. The combined organic layers are washed with a saturated aqueous solution of sodium chloride V, dried and evaporated to dryness. 31.2 g of the expected product are obtained, which are used in the next stage. The product can be purified chromatographically on silica, eluted with a mixture of methylene chloride - acetone triethylamine (96.5: 4.5: 0.5). -59.5 ± 2.5 ° (to 0.7% СНС1e)
Stage B. 17 / 2g-Hydroxy-P / - 4-metsh1 (3-methylbutyl) amino-phenyl J-17c (- - (prop-1-insh1) -estra-4,9-diene-3-one. 26 g of the product obtained in stage A are dissolved in 200 cm of methanol, then 52 cm of 2N hydrochloric acid are added. After 1 hour of stirring, stir the mixture into aqueous sodium bicarbonate solution, extract with ether
rum, and then with methylene chloride, washing: combine the organic layers with saturated aqueous sodium chloride solution, dry and distill off the solvent. The product is purified by chromatography on silica, eluted with a mixture of TURL – ethyl acetate (92: 8) and yield 3.23 g of the expected product. ) +125 ± 3.5 ° (to 0.6% CHClj).
Higher value,%: C 81.6; H 8.92; N 2.88,
С „Н, ЗШ, (485,71)
Found,%: C 81.4; H 9.0; N 2.7.,
The amine used in step A is prepared as follows.
Stage a. N-metsht-K- (3-methylbutyl aniline.
86 g of N-methylaniline, 500 cm of anhydrous benzene and 81 g of anhydrous triethylamine are mixed. By drop m
121 g of isoamyl bromide are added, the mixture is heated under reflux for 100 hours. The mixture is filtered, the filtrate is washed with water, dried and the solvent is distilled off. The residue is distilled y and 90 g of the expected product are obtained. T. Kip. 132 ° C.
Stage b. K-Methyl-M- (3-methyl-bu-, tyl) -4-bromoaniline.
64 g of the product obtained in stage a are mixed with 300 cm of acetic acid, and then 58 g of bromine in 60 cm of acetic acid are added dropwise over 1 hour at 15 ° C. The mixture is heated to 80 ° C, stirred for 8 hours, then poured into ice water, extracted with methylene chloride, the organic layer is washed with sodium bicarbonate solution and then with water, dried and the solvent is distilled off. The residue is distilled and 70 g of the expected product are obtained. T. Kil. (0.5).
Example 28. 1 7 / J-Hydro and -11p-G4- (K, K-dimethylaminoethylthio) phenyl (prop-l-ynyl) -estra-4,9-diene-3-on.
Stage A. 3,3-Cl, 2-Ethanediyl-bis- (oxy) -1 1/5-G4- (H, K-dimethylaminoethyl) phenyl-17s1 (- (prop-1-ynyl) -estr -9-ene-5-17 / 3-diol.
Preparation of organomagnesium compound.
In an inert gas mix 2 g of magnesium and 15 cm of anhydrous tetrahydrofuran. Then, within 45 minutes, letting the temperature rise to 56 ° C, a solution of 20 g of 4- (K, K-dimethyl-aminoethylthio) -1-bromobenzene in 40 cm-anhydrous tetrahydrofuran is introduced. Seed the reaction with 1,2-dibromoethane. The temperature is then allowed to go down to 20 ° C and then kept moving. punching for 45 minutes in an inert gas. Thus, get 1.05 M
synthesis. T, pl. . The product can be recrystallized in a mixture of methylene chloride - diisopropyl. T. pl. 182 C, c / J5 -6,5 ± 2 (to 0.7% СНС1з).
Stage B. 1 7 / e-Hydroxy-1 (4-dimethylaminophenyl) -l 7 ° (-ethenyl-estra-4,9-diene-3-ene.
In an inert gas, 2.94 g of the product obtained in stage A are mixed with 60 cm of methanol, and then 6.2 cm of 2N hydrochloric acid are added. At 20 ° C and this solution is stirred for 1 h, 120 cm of ether and 120 cm of a 0.25 M aqueous solution of sodium bicarbonate are added, stirring is held for 10 minutes, decanted, and extra: digested with ether. Wash the organic layer with a 0.25 M aqueous solution of sodium bicarbonate, and then nacbmieHHbiM with an aqueous solution of sodium chloride. Dry and distill off the solvent. 2.65 g of product is obtained which is chromatographed on silica, eluted with a mixture of benzene and ethyl ester of ethyl acetate (7: 3), and then diisopropyl oxide — methylene chloride is crystallized in a mixture. Finally 1.51 g of the desired product is obtained. T. pl. 150 ° C. +243 ± 3 (to 0.8% CHClj).
Example 26, 17p-Hydroxy-1 1/3 - (4-diethylaminophenyl) -1 (npon-l - -inyl) -estra-4,9-diene-3-one.
Stage A. 3,3-Cl, 2-ethanediyl-bis- - (oxy) -1 1 | 3- (4-diethylaminophenyl) - -I 7o {- (prop-1-ynyl) -estr-9-en - diol
The formation of organomagnesium is connected:.
In an inert gas, 3.9 g of magnesium are mixed in 10 cm of tetrahydrofuran. 34.2 g of 4- (K, K-diethypamino) bromobenzene are added dropwise to 110 cm of tetrahydrofuran, keeping the temperature at about 35 ° C. A solution of the desired organomagnesium compound is obtained. neither
Condensation.
7.4 g of 3,3-D, 2-ethanediyl-bis- (oxo) -5o 10 | epoxy-17 - (prop-1-ynyl) -estr-9 (11) -ene-17/1-ol is dissolved in 150 cm of anhydrous tetrahydrofuran. 0.25 g of copper monochloride is added. The mixture is stirred at 0 - (+5) ° C in an inert gas and 80 cm of the irradiated organomagnesium compound solution are slowly added. The mixture is kept for 17 hours with stirring and at room temperature in an aqueous solution of ammonium chloride, the organic layer is extracted with ether with an aqueous solution of sodium bicarbonate, dried and the solvent is distilled off. The residue is concentrated in petroleum ether and then treated with activated carbon in ether and recrystallized in isopropyl ether. In this way, 4 g of the expected product is obtained. -61 t 2.5 ° (to 0.7% СНС1з).
Stage B. I 7 / E-Hydroxy-1 1 / 3- (4-diethylaminophenyl) -1 (prop-1-vinyl) - -estra-4,9-diene-3-one.
8 cm 2 of hydrochloric acid was added to a solution of 3.12 g of the product obtained in stage A in 45 cm of methanol and stirred at 45 ° C in an inert gas for 45 minutes. It is poured into water, neutralized with an addition of 2 N sodium hydroxide, extracted with methylene chloride, dried and the solvent is distilled off. The residue is chromatographed on silica, the elucras are benzene-ethyl acetate (1: 1), and 1.34 g of the expected product is obtained. +144.5 W (to 0.8% chloroform).
Calculated,%: C 81.36; H 8.59; N 3.06.
S. e. Nzeko (457.63),
Found,%: C 81.7; H 8.8; N 2.09.
The 4- (N, N- -diethylamino) bromobenzene used in step A was prepared as follows,
93 g of bromine are added dropwise to a solution of 86 g of H, N-diethylaniline in 400 cm of acetic acid. After the completion of the addition, water is poured into the mixture. - ice, extracted with methylene chloride,. The organic layer is washed with an aqueous solution of sodium bicarbonate, dried and the solvent is distilled off. 125 g of the expected product are obtained. T. Kip. (0.6) 97 ° C.
Example 27. 1 7/5-D) zdroxy-1 l / 3- - 4-methyl (3-methylbutyl) amino-phenyl-17 o (- (prop-1-vinyl) -estra-4,9-diene “W-he.
Stage A. 3,3-fl, 2-Etapdiyl-bis- (oxy) -11p-4-methyl (3-methylbutyl) amino-phenyl J-17c / - (pro p-1-vinyl) -estr-9 en-5o / -1 7p-diol.
Preparation of magnesium anicin.
a solution of the target organomagnesium side is dissolved with 23.5 g of the hydrochloride compound. to chloroethyldimethylamine in 75 cm of ethano-Condensation, and then 160 cm is obtained. The inert gas is cooled to a strong solution of caustic soda. Dissolve the 38 cm of the solution obtained magnesiumnauy 30 g of parabromothiophenol 100 cm
ethanol, and then add 160 cm of the resulting sodium hydroxide solution. It is then added over 2 minutes at
chemical compound added
1.730 g of copper monochloride, superior
with stirring for 20 minutes
and then 5 g 3, 2-ethane 20 ° C, the resulting amine solution is added. Nagrediyl-bis- (oxy) Oc-epoxy-P / -. under reflux for 3 hours, the solvent is distilled off, water is added, the mixture is extracted with methylene chloride, and the organic
- (prop-1-ynil) -estr-9 (11) -en-1 7p-opa in 50 cm of anhydrous tetrahydrofuran. Withstand in inert gas
within 2 h 45 min. Drink a mixture of 15 layer of 0.1 N. aqueous solution of caustic
sodium and then with water, dried and the solvent is distilled off. The residue is distilled and 35.5 g of the expected product are obtained. T. Kip. (0,1).
Example 29. 1 1 / 5- (4-Dimethyl-aminophenyl) -7 / 3-hydroxy-21- (trimethylsilyl) -G1 7of J-1 9-norpregna-4,9-diene-20-in “W-he.
Stage A. I 1 / L- (4-Dimethylaminoh 600 cm ice water containing 60 g of ammonium chloride. Hold for 45 min with stirring, decant, extract the aqueous layer with diethyl oxide containing triethyl amine, mix the organic layers the residue is chromatographed on alumina, eluting with 25 nip) -3, 2-ethanediyl-bis- (oxy) 7-. a mixture of methylene chloride - acetone-21- (trimethylsipsh1) -sl 7sz-19-norgh
(95: 5) and 10.3 g of the desired progred-9-ene-20-yn-5-o / -17 / 3-diol are obtained. duct .. 13 cm is mixed in inert gas
Spectrum-IR: absorption at 3600 cm of a 1.6 N solution of ethylmagnesium bromide in (OH); 2240 cm (C: C); 1705 and 1670 tetrahydrofuran with 13 cm anhydrous (CO and CO conjugated); 1615 and 1490 cm of tetrahydrofuran. Stir in those (aromatic bands). For 5 minutes at O - (+5) C, and then
3.4 cm of trimethylsilylacetylene is added dropwise. Give the temperature - (prop-1-yl) -estra-4,9-dien-3-one. gg underneath to 20 ° C and continue pere- In 10.1 mixing in an inert gas is mixed for 20 minutes, and then
a solution of 1.12 g of the product obtained in Stage A of Example 7 is introduced dropwise in 10 cm of anhydrous tetrahydro 40 Furan. Stand 16 hours at room temperature with stirring.
Stage B. 1 7 / E-Gyroxy-1 - (S, K-dimethylaminoethypto) phenyl-17 product obtained in stage A with .72 cm of methanol, and then 20.6 cm 2 of hydrochloric acid are added. Under stirring at 1 h 15 min, neutralized by adding saturated aqueous solution is poured into an aqueous solution of chloride
sodium bicarbonate, add 200 cm of ammonium, stir over diethyl oxide, decant, extract at 20 min at room temperature, rut with diethip oxide, wash the saturated with 45 ml of methylene chloride, wash the organic layer with an aqueous solution of chloride and wash the organic sodium the layers, dried with an aqueous solution of chloride, are dried and concentrated to dryness. The residue, dried and the solvent is distilled off, chromatographed on silica. The residue is chromatographed on dioxide in elution with a mixture of methylene chloride - 50 silicon, eluting with a mixture of petroleum
ether - ethyl acetate acetic acid (9: 1) and get 3 g of the target product, which is crystallized, condensed in diisopropyl oxide, So pl. 145 ° С, +125 t 2 ° (to 1% chloroform) .55
In the A-stage, the semi-Stage A amine is used. 1 I / 3- (4-Dimethylamino-solvent is as follows) -1-7 / E-hydroxy-21- (trimethylsilyl) 20 g of sodium hydroxide in tablets is dissolved in 500 cm of ethanol. With another
you (6: 4) and get 680 mg of the target product..D -76,5 ± 3 (to 0.5% СНС1e).
- 1 7o (J-1 9-norpregna-4, 9-diene-20-in-3-one,
sodium and then with water, dried and the solvent is distilled off. The residue is distilled and 35.5 g of the expected product are obtained. T. Kip. (0,1).
Example 29. 1 1 / 5- (4-Dimethyl-aminophenyl) -7 / 3-hydroxy-21- (trimethylsilyl) -G1 7of J-1 9-norpregna-4,9-diene-20-in “W-he.
Stage A. I 1 / b- (4-dimethylaminophenip) -3, 2-ethanediyl-bis- (oxy) 7-. -21- (trimethylsipsh1) -C1 7sz -19-norght
you (6: 4) and get 680 mg of the target product..D -76,5 ± 3 (to 0.5% СНС1e).
nyl) -1 7 / e-hydroxy-21- (trimethylsilyl) -170 (J-1 9-norpregna-4, 9-diene-20-in-3--one,
35
562 mg of the product obtained in stage A are mixed with 15 methanol and 1 cm 2 of hydrochloric acid. While stirring at room temperature for 40 minutes, stirring is poured into an aqueous solution of sodium bicarbonate, extract with ether, draw the organic layer with an appreciable aqueous solution of sodium chloride, dry and distill off the solvent. The residue is chromatographed on silica, eluted with a mixture of petroleum ether and ethyl acetate (6: 4), and 364 mg of the expected product are obtained. , +97.5 + (to 0.35% CHClb).
Calculated, ° /. N 2.87.
Found,%: 2.8. Example
: C, 76.33; H 8.47;
(487.76) C 76.4; H 8.7; .
N
30. N-Oxide 17/3-hydroxy-1/5-C4- (K, H-dimethylaminomethyl) phenyl (prop-1-vinyl) -estra-4,9-dien-3-one.
1.4 g of the product obtained in Example 23 is dissolved in 28 cm of methylene chloride, and then a solution of 0.64 methylene chloroperbenzoic acid in 12.8 cm of methylene chloride is introduced over 15 minutes at O - (+5) ° C. The mixture is stirred for 1 hour at O - (+5) ° C, and then it is taken up in a 0.2 N aqueous solution of sodium thiosulfate, decanted, extracted with methylene chloride, washed with an aqueous solution of sodium bicarbonate, dried and evaporated to dryness. The residue is chromatographed on silica by elution with methylene chloride-methanol (8: 2) and obtaining 1.28 g of the expected product, which is dissolved in methylene chloride-diisopropyl mixture. The crystals formed are filtered off with suction, dried, and 1.075 g of the expected product is obtained. T. pl. 215 C, +74.5 + 2.5 ° (to 0.7% SCS1).
Example 31. Semifumarate 1 7p- -hydroxy-1 1 (S, K-dimethylamino-mn1) phenyl-17 (- (prop-1-ynyl) -estra-4,9-que n-3-one.
1.44 g of the product obtained in Example 23 in 2.88 cm of ethanol are mixed, and then a mixture of 0.378 g of fumaric acid in 4.54 cm of ethanol is added. This suspension is stirred for 30 minutes at 60 ° C, allowed to go down to 20 ° C and maintained

ten
15
20

36
mixing The solvent is distilled off, the residue is taken up in ether, filtered off with suction, dried and 1.70 g of the expected product is obtained. T. pl. 160 ° С, fa jj, +70.5 + ± 2.5 ° (to 0.8% CHClj).
P. and meper 32.7 - -Hydroxy- -1 1 - / 5- 4- (N, L-dipropylamino) -phenyl J- -i 7el- (prop-1-vinyl) -estra-4,9- dien-3-one.
Stage A. 3,3-P 2-Ethanediyl-bis- (oxy) -1lp-f4- (N, N-dipropylamino) -phenip J-1 7rt- (prop-1-vinyl) -estr-9- EN-7/3-diol.
Preparation of organomagnesium compound.
5 g of magnesium and 15 cm of anhydrous tetrahydrofuran are mixed in an inert gas. A solution of 52 g of 4-bromo-S, K-dipropipaniline in 110 cm of tetrahydrofuran is added dropwise, keeping the temperature at 40 ° C. In this way, a 1.1 M solution of the desired organomagnesium compound is obtained.
Condensation.
In an inert gas, a solution of 5.55 g of Example 73 obtained in stage A is swept; , 2-ethanediyl-bis- (oxy) - -5o / -1 OC / -epoxy-17 o (- (prop-1-inip) - -estr-9 (1 P-ene-1 7 / 3-0л 200 mg of copper dichloride., Mixed at O, + 5 ° C, and then 50 CM of the organomagnesium solution obtained above is added in 15 minutes. Then it is stirred at for 1 hour, drunk into a full aqueous ammonium chloride solution, extracted with ether. , the organic layer is dried and the solvent is distilled off. The residue is chromatographed on silica, eluting with a mixture of toluene-ethyl acetate (7-5), and 6.3 g of the desired product are obtained, d -56 ± 2 ° (to 0, 8% CHCl j).
Calculated,%: C 76.74; H 9.02; 2.56.
C3jH45N04 (547.75)
Found,%: C 76.6; H 9.2; 2.5
25
thirty
35
45
N
N
Stage B. 1 7/1-Hydroxy-1 l / 3-f4- (N, N-dipropylamino) -lough I-1 - (prop-1-ynil) -estra-4,9-diene-3-one.
To a solution of 5.83 g of the product obtained in stage A in 80 cm of methanol was added 10 cm of 2N hydrochloric acid and stirred at 20 ° C for 50 minutes. Neutralized by the addition of 1 n. sodium hydroxide solution, the solvent is distilled off under reduced pressure and the residue is taken up in methylene chloride. The organic layer is washed with water, dried and the solvent is distilled off. The residue is chromatographed on silica, eluting with a mixture of toluene — this catch of acetic acid ester (75:25), and 3.81 g of the expected product are obtained. IR spectrum (chloroform): absorption at 3600 cm-CHON); 1654 cm-Fc 0); 1610-1595-1558 and 1517 cM- (i) 4.9 + + aromatic bands); 2240 ().
The following products can be obtained by the proposed method:
(N-ethyl-N-methyl-amino) phenyl -1 7/1-hydroxy-1 (prop-1-ynyl) estra-4,9-dien-3-one, m.p. Go / 7o l 2 ° (to 1% CHClg);
17; b-hydroxy-11 / y-yl-methyl-2,3-di-hydro-1H-INDOL-5-IL-17o / - (prop-1 - .. -inyl) -estra-4,9- diene-3-one, t. pl. , + 133 ± 3 ° 1 (to 0.8% CHCl j) (A);
1 1 / 3- (4-dimethylaminophene1) -3-hydroxyimino-17 al- (prop-1 -inyl) -estra-4,9-diene-1 7 / e-ol (Z isomer); m.p. , 141 ± 3.5 ° (to 0.8% СНС1з) (В);
11 / h- (4-dimethylaminofensh1) -3-hydroxyimino-7o (- (prop-1-ynyl) -estra-4,9-diene-17 -ol (isomer E), mp 220 ° C, MI, +164 ± 3.5 ° (to 0.8% CHClj); (C);
N-oxide 17/5 -hydroxy-11 / 3- (4-pyrro-didylphenip) (prop-1-ynyl) -estra-4,9-diene-3-one, so pl. 220 ° C, Go (7p +88 ± 2.5 (to 0.75% CHClj);
1 7/3-hydroxy-11 / 3- 4-N-MeTHn-N- (1 - -methylethyl) -aminophenylJ-l 7c / - (prop-1-vinyl) -e stra-4,9-di- Z-he. fo / +140 + 3.5 (to 0.5% CHC);
N-oxide 1 l / s-G4- (N, N-dimethylamino-ershloksi) phenylJ-l 7/3-HYDROXY-1 7o / - - (prop-1-ynyl) -gaster-4, 9-diene-3 - it, + 60,5 ° (to 1.2% СНС1з);
N-oxide 17/1-hydroxy-1 l -LN-methyl -2,3-dihydro-H-indole-5 - B11-1 7d- - (prop-1-ynyl) -estra-4,9-diene -Z-she, CO (JD +103 ± 2.5 ° (to 0.8% CHClj);
17/3-HYDROXY-11 ((N-methyl-L-trimethylsilyl p) aminophenyl J-1 7 o (- - (prop-1-ynyl) -estra-4,9-diene-3-one;
17p-hydroxy-1lp-C4- (N-methyl-N-di-methylaminoethip) aminophenyl 3-17 (prop-l-ynyl) -estra-4,9-diene-3-one;
0
five
0
1.7 / 3-hydride i-1 (N-methyl-pi-razin-1-yl) phenyl J-1 (prop-1-in1-sh) - -estra-4,9-diene-3-one;
1 7-HYDROXYMINO-11 / 3- (4-dimethylg aminophenyl) e-4,9-dien-3-one, +207.5 ± 3.5 (to 1% CHCls);
3 (E) -hydroxymino-17-hydroxyimino-1 1 - (4-dimethylaminophenyl) -estra-4,9-diene-3-one, C.J.i, +195 ± 3 ° (to 1% CHClj);
3 (Z) -hydroxyimino-17-hydroxyimino-1 1/3 - (4-dimethylaminophenyl) -estra-4,9-diene-3-one, fo / Ji, +163 + 2.5 ° (k 0.6% CHCl,) ..
Example 33. 1 1 / t-G4- (Dimethylamino) phenyl-1 7/3-hydrox-1 (3-hydroxyprop-1-ynyl) -estra-4,9-di--3-one.
To a solution of 1.6 M methyl lithium in ether, is added dropwise in argon at 10–15 ° C and with stirring 3.1 g of tetrahydropyranyl ether of propargyl (, 20H) alcohol in 6 cm
5 ether.
The temperature is kept below, stirred for 10 minutes, then a solution of 2 g of 3,3-C1, 2-ethanediyl-bis-g (ox0 si)} -1 1p-G4- (dimesh1aminophenyl) -hydroxyestrone is added over 15 min. 9-ene-17-she, prepared as in example 7A, in 15 cm of tetrahydrofuran. At the end of the addition operation, add another 15 cm of tetra5 hydrofuran and continue mixing. for 30 min at ambient temperature. The medium is diluted with ammonium chloride solution, ethyl acetate is separated, washed with sodium chloride solution, dried and subjected to dry distillation.
The resulting oil is dissolved in 20 cm-methanol. Add 5 cm of hydrochloric acid 1/2 (or about 5 N) and leave for 2 hours at ambient temperature. Ice, 5 cm of concentrated ammonia are added, and ethyl acetate is separated. It is washed first with water and then with a solution of sodium chloride, dried, subjected to dry distillation, and the precipitate is crystallized in ethyl ether. Isopropyl ether is added, filtered, washed and dried at. 1.42 g of the desired is obtained.
g of the product that is purified as follows: dissolve the product in chloroform, filter the solution and dry it. Add 3 cm of chloroform, solution 0
five
0
39
heated with heating and 3 cm of isopropyl ether added. Seed out the crystallization and leave to cool slowly. Isopropyl alcohol (6 cm) is added, left at ambient temperature for 2 hours, then dehydrated. It is washed with a mixture of chloroform and isopropyl ether (1: 3) and dried at 50 C.
1.36 g of product is obtained, which is redissolved in 4 cm of chloroform and 2 times 4 cm of isopropyl ether are added. Obtain 1.3 g of the product, So pl. 229 С, CofJi, +133 + ± 2.5 ° (q. 1% CHClg).
Calculated,%: C 76.45; H 7.57; N 2.23 C1 2.23.
C.gHjjNOg
X Found,%: C 76.8; H 8.0; N 3.1; Ci 2.3.
Example 34. H- (4-Aminophenyl) -17 / 3-hydroxy-17 ° (- (prop-1-ynyl) est-I-4,9-diene-3-one.
Stage A. 3,3-Dimethoxy-11p-C4- (diallylamino) phenyl (prop-1-vinyl) -estra-9-one-5o-17/3-diol.
a) Preparation of K, K-diallyl-4-bromo-aniline. ,
At ambient temperature, a solution of 300 cm of benzene, 11.8 g of methyl ammonium bromide, 60.2 g of 4-bromoaniline and 60 cm of allyl bromide in 150 g of sodium dissolved in 300 cm of water are added. Stir for 87 hours at ambient temperature. Ethyl acetate is isolated, washed, dried, and reduced under reduced pressure to give 89 g of oil, which is purified by filtration through silica (cyclohexane extract). 81.7 g of a yellow liquid is separated by distillation and a pure compound is obtained (Eg 105 ° C / 1 x 10 mm Hg).
Calculated,%: C 57.16; H 5.59; Br 31.69; N 5.55.
C11H1 BrN
Found,%: C 56.9; H 5.7; Br 31.9; In 5.5.
b) Preparation of organomagnesium compound.
Nitrogen heated to 55 ° C
5.6 g of 3,3-dimethoxy-5d-OOC-epoxy-1 7C / - (propane-1) -estra-9 (11) -1 7/3-ol are dissolved in 50 cm of tetrahydrofuran. 560 mg of copper chloride are added and cooled under nitrogen to O - (5) ° C. Within 40 minutes, 125 cm of the magnesium-containing compound obtained by the process described above are added dropwise. Allow to react for 18 hours, pour the reaction medium into an ammonium chloride solution, and inject ethyl acetate. After drying the solvent, approximately 16 g of a yellow oil is obtained after evaporation of the solvent, which is chromatographed on silica, mixed with a mixture of benzene and ethyl acetate (85:15) with 1% triethylamine and 7.3 g of product is isolated. After crystallization in isopropyl ether with 1.52 g of the product obtained by chromatography, 1.04 g of pure product is obtained.
Stage B. 3,3-Dimethoxy-11p- (4-α-aminophenyl) - (prop-1-ynyl) -estra--9-one-5s / -1, 7 / z-diol.
4.3 g of the product obtained in step A are dissolved in 80 cm of ethanol and 5 cm of water. 215 cm diazabicyclooctane and 430 mg Wilkinson reagent chloroform (triphenylphosphine) rhodium are added. The mixture is heated for 30 minutes in reverse flow, cooled, dissolved in water and ethyl acetate is separated. The desired product is obtained after evaporation of the organic phase.
Stage B. 1 1 / 3- (4-Aminofensh1) -1 7/3-hydroxy-17c - (prop-1-ynyl) -estra- -4,9-diene-3-one.
The product obtained in stage B is dissolved in 50 cm of methanol and 15 cm of methanol and 15 cm of hydrochloric acid 2 N. The solution is left for 1 h 15 min at ambient temperature, and then poured into a solution of sodium carbonate bi-gQ and ethyl acetate is recovered. It is washed, dried and the organic phase is introduced into it and 4 g of crude product are obtained, which is dissolved in methylene chloride. Clear by hro30
35
45
5.25 g of magnesium in 10 cm of tetrahydrofluorography on silica, mixing the wound, add a few drops of broth first with ethyl ether, and then
with a mixture of ether and ethyl acetate (9: 1) to obtain 1.5 g of the expected product. 2.4 g of the obtained tamy ethylene and a solution of 15.3 g 1; 1, K-diallyl-4- -bromoaniline in tetrahydrofuran (added in 1447289
40
0
five
lice, sufficient for 120 cm). Maintain an ambient temperature for 40 minutes.
c) Condensation.
5.6 g of 3,3-dimethoxy-5d-OOC-epoxy-1 7C / - (propane-1) -estra-9 (11) -1 7/3-ol are dissolved in 50 cm of tetrahydrofuran. 560 mg of copper chloride are added and cooled under nitrogen to O - (5) ° C. Within 40 minutes, 125 cm of the magnesium-containing compound obtained by the process described above are added dropwise. Allow to react for 5 hours, pour the reaction medium into an ammonium chloride solution and inject ethyl acetate. After drying, the solvent gives about 16 g of a yellow oil, which is chromatographed on silica, mixed with a mixture of benzene and ethyl acetate (85:15) with 1% triethylamine, and 7.3 g of product is isolated. After crystallization in isopropyl ether with 1.52 g of the product obtained by chromatography, 1.04 g of pure product is obtained.
Stage B. 3,3-Dimethoxy-11p- (4-α-aminophenyl) - (prop-1-ynyl) -estra--9-one-5s / -1, 7 / z-diol.
4.3 g of the product obtained in step A are dissolved in 80 cm of ethanol and 5 cm of water. 215 cm diazabicyclooctane and 430 mg Wilkinson reagent chloroform (triphenylphosphine) rhodium are added. The mixture is heated for 30 minutes in reverse flow, cooled, dissolved in water and ethyl acetate is separated. The desired product is obtained after evaporation of the organic phase.
Stage B. 1 1 / 3- (4-Aminofensh1) -1 7/3-hydroxy-17c - (prop-1-ynyl) -estra- -4,9-diene-3-one.
The product obtained in stage B is dissolved in 50 cm of methanol and 15 cm of methanol and 15 cm of hydrochloric acid 2 N. The solution is left for 1 h 15 min at ambient temperature, and then poured into a solution of sodium carbonate bi-Q and ethyl acetate is isolated. The organic phase is washed, dried, and entrained, and 4 g of crude product is obtained, which is dissolved in methylene chloride. Cleared by chro0
five
five
41
The IMF of the product is dissolved in methylene chloride. The filtered solution is diluted with isopropyl ether and then concentrated in order to separate the methylene chloride. Cool, drain, and obtain 2.18 g of crystallized product. Purified product Obtained by recrystallization in a mixture of methylene chloride and ethanol and subsequent condensation in ethanol under reflux, T, mp, +112.5 ± 1.5 ° (with 1% CHCl1).
Calculated,%: C 80.76; H 7.78; IN 3.49. .C HatNO
Found,%: C 80.6; H 8.1; N 3.3.
Example 35. 17p-Hydroxy- -11 / L-G4- (metipamino) fensch1 -1 7a1 (prop--1-ynyl) -estra-4,9-diene-3-one,
Stage A. 3,3- (Dioxyethanediyl) -1 (N-methyl-N-amine dipl) phenyl} - -17 / O- (prop-1-ynyl) -estra-9-one-5s (-1 7ft- -diol
Preparation of 4-bromo-N-methyl-N-All-1-aniline
a) N-Metsh1-4-bromaniline,
In an inert atmosphere, a solution containing 179 g of bromine in 120 cm of acetic acid is added to a mixture of 120 g of N-methipaniline with 600 cm of acetic acid at a temperature below during 45 minutes. The mixture is stirred for 1 hour and 15 minutes to ambient temperature. poured into a mixture of water and ice, alkalized with sodium to pH 10, methylene chloride is separated, the chloromethylene phases are crushed with a solution of saturated sodium chloride, dried, concentrated under dry pressure, and 213 g of expected product is obtained,
b) 4-Bromo-K-methyl-N-allilangestin,, In an inert medium, 280 cm of ethereal solution of ethylmagnesium bromide in 50.05 g of the product obtained in stage a is added dropwise, keeping the temperature below.
within 30 minutes, then 28 cm of allyl bromide is added over 15 minutes and heated at low tide for 40 minutes. Allow to cool, add dropwise to 25 cm of a 1 N solution of ethylmagnesium bromide and stir for 25 minutes. Pour the reaction mixture into a cooled ammonium chloride solution, defend the aqueous
447289
42
phase, the methylene chloride is separated, dried, concentrated dry and get 61.35 of the expected product.
Preparation of magnesium compound.
A suspension of 1.4 g of magnesium in 10 cm of tetrahydrofuran is heated to 40 ° C and a few drops of the solution are added.
Q.9.4 g of 4-bromo-K-methyl-K-allylaniline in 26 cm of tetrahydrofuran; Seeding the magnesium-containing compound by adding a few drops of ethylene bromide, then continuing into
5 for 30 minutes adding the methyl bromide. Maintain the temperature with an oil bath for another 30 minutes. Cool and Titrate with iodine 2; 0.93 Mo / Lit.
0 Condensation
The solution of 4.4 g of OL - -epoxy-3,3-С1,2-ethanediyl-bis- (oxy)} -1 (prop-1-insh1) -estra-9 (1) is cooled by means of a bath with a temperature of 0 ° C. 1) -EN 5 -17 / E-ol in 44 cm-tetrahydrofuran, to which 450 mg of copper chloride is added, and then 34 cm of the magnesium-containing compound 0.93 M obtained
0 as described. It is left for 1 hour, diluted with 50 cm of tetrahydrofuran, then poured into an ammonium chloride solution and extracted with ethyl acetate. Washed. Organic
5 phase, dried, evaporated under low pressure and get 10.7 g of an impure product. The product is filtered on silica (eluant benzene - ethyl acetate, 7: 3). Obtain 5.2 g of the desired product, which is used in the next stage.
Stage B, 3.3- (Ethandish-bist - (hydroxy) 7-1 7 (methylamino) phenyl} - 5 1 7o / -prop-1-ynil) -estr-9-en-5o / -1 7/3 - -diol
100 mg of Wilkinson's reagent chlor-tris (triphensthophosphine) rhodium is added to a solution of 1 g of the product obtained in stage A in 10 cm of ethanol and heated under reflux. After 30 min heating, evaporated under slight pressure and filtered.
5, the product obtained is on silica (eluant chlormethylene, then ether), Compound the eluates, washed, dried and obtain 805 mg of crystals. T, pl,. ,
43
Calculated,%: C, 75.44; H 8.23; N 2.93.
Sao H39N04 (477.65).
Found,%: C 75.77; H 8.4; N 2.9.
Stage B. 17/5-Hydroxy-1 I / J-C4- (methylamino) phenyl 1-1 (prop-1-in-estra-4,9-diene-3-one.
770 mg of the product obtained in stage B are dissolved in 7.7 cm of methanol and 7.7 cm of hydrochloric acid 2 N. After 1 h of the reaction, it is diluted with 10 cm of water. Filter, dilute sodium bicarbonate solution, precipitate and dry under slight pressure. 640 mg of crude product is obtained, which is crystallized in a mixture of methylene chloride and isopropyl ether. Get 567 mg of purified product.
A sample for analysis is obtained by purification by chromatography and recrystallization in a mixture of chlorofor and isopropyl ether, m.p. 238 ° C.
Calculated,%: C 79.96; H 7.9; N 3.32; C1 1.2. jno
Found,%: C 80.1; H 8.1; N 3.3; C1 1.2.
Co (Jjj +128,5 ± 3 (with 1% CriClj
 (415.58).





Example 36. N-f 4-Gl7 / i-Hydro-ox-3-oxo-1 7 ° / - (prop-1-vinyl) -estra-4,9-diene-11 -yl phenyl acetamide.
1.42 g of 1 (4-aminophenip) -1 7 / i- -hydroxy-1 7s / - (prop-1-inip) -Extra-4,9-diene-3-one is suspended in 14 cm of benzene and 3 , 5 cm of tetrahydrofuran. 0.37 cm of acetic anhydride is added and stirred at ambient temperature for 1 hour, then poured into a saturated solution of sodium hydrogencarbonate. Extragent The resulting solution was stirred for 10 minutes, then 452 mg of 3.3- (ethanedi-ibisbis-oxy) -5o-hydroxy-11p- (4-dimethylaminophenyl) -estra-9-7- was added over 15 minutes - it dissolved in 4 cm3 of tetrahydrofuran. Stir for 1 hour at -70 ° C. Then add 0.5 cm hydrochloric acid. Allow to warm to ambient temperature, add sodium hydrogen carbonate, extract with ethyl acetate, wash with water, and dry to obtain 750 mg of product, which is chromatographed on silica, eluting with a mixture of benzene and ethyl acetate (3: 2) and 1% triethylamine. The purity analysis product is obtained by dissolving 470 mg of the product in 8 cm of methylene chloride, filtering, adding 20 cm of isoprop1; starch ether, concentration before crystallization, freezing, dehydration, rinsing with isopropyl ether and drying with a slight pressure ,. Obtain 370 mg and pure product, T. pl. 2554.
Stage: B. 1 (} - (Dimethylamino) Phenyl J-17 p-hydroxy-3-oxo-19-nor-1735
40
YT with ethyl acetate, washed with aqueous rag g of pregna-4,9-diene-20-one-21-ethyl 1 sarboksvorom, nash; with sodium chloride, then dried. After evaporation of the solvent, 1.62 g of a crude product is obtained, which is purified by chromatography on silica, eluting with ethyl acetate. 1.524 g of purified product is obtained, which is dissolved in a minimum amount of methylene chloride, then precipitated by the addition of isopropyl ether. Dehydrated, washed with isopropyl ether, then dried under slight pressure. 1.47 g of pure product are obtained, R 0.28 (pure ethyl acetate).
44
five
0
SHO (SVS1z), ppm: 0.51 (8-Ie); 1.91 (CHj-C C-); 2.16 (); 4.4 (H at 11) 5.8 (H at 4).
Example 37. 11/1- (4-Dimethyl-aminophenyl) -7 / o-hydroxy-3-oxo-1 9-nor-1 7o (-pregna-4, 9-diene-20-nn-21 - - carboxylic acid.
Stage A. 3,3- (Ethanedyl-bis-oxy) - 7K-digvdroxy-11; 3- (4-dimethylaminophenyl) - 9-nor-1 7c / -pregna-4, 9-diene. - -20 en-21-ethylcarboxylate.
In a solution of 10 cm of tetrahydrofuran and 0.51 cm of ethyl propiolate, 3 cm of a solution of 1.68 M p-butyl lithium in hexane is added in 30 minutes at -70 ° C.
The resulting solution was stirred for 10 minutes, then 452 mg of 3.3- (ethanedi-ibisbis-oxy) -5o-hydroxy-11p- (4-dimethylaminophenyl) -estra-9-ene-7 was added over 15 minutes. - it dissolved in 4 cm3 of tetrahydrofuran. Stir for 1 hour at -70 ° C. Then add 0.5 cm hydrochloric acid. Allow to warm to ambient temperature, add sodium hydrogen carbonate, extract with ethyl acetate, wash with water, and dry to obtain 750 mg of product, which is chromatographed on silica, eluting with a mixture of benzene and ethyl acetate (3: 2) and 1% triethylamine. The purity analysis product is obtained by dissolving 470 mg of the product in 8 cm of methylene chloride, filtering, adding 20 cm of isoprop1; starch ether, concentration before crystallization, freezing, dehydration, rinsing with isopropyl ether and drying with a slight pressure ,. Obtain 370 mg and pure product, T. pl. 2554.
Stage: B. 1 (} - (Dimethylamino) Phenyl J-17 p-hydroxy-3-oxo-19-nor-170
35
40
0
five
silat
360 mg of the product obtained in Stage A are suspended in 7 cm of ethanol in a nitrogen atmosphere at ambient temperature and 0.7 ml of hydrochloric acid is added per half. The resulting solution is heated to 50 ° C for 1 hour, ethanol is distilled off, sodium hydrogen carbonate is added, stirred, extracted with ethyl acetate, washed with water, and dried. 300 mg of product are obtained which is chromatographed on silica, eluting with a mixture of petroleum ether (m.p.
 60-80 ° C) with ethyl acetate (1: 1). 190 mg of the desired product is obtained.
Calculated,%: C 76.35; H 7.65; N
2.87.
With „H.NO,
N
Found,%: C 76.1; H 7.8; 29.
+78 + 1.5 ° (to 1%
i)
o (s +78 + 1.5 ° (to 1% CHCl ,, Stage B. 1 1/3-C4- (Dimetipamino) - phenyl} - 7 V-hydroxy-3-oxo-1 9-nor-17o (-pregna-4, 9-diene-20-in-21-carboxylic acid.
0.4 cm sodium 211 is added to a solution of 350 mg of the product obtained in Step B in 7 cm of ethanol. Heated to 30 minutes, allowed to cool to ambient temperature, neutralized with 0.4 cm hydrochloric acid 2 N. Distil-.
20 eat Chromatograph the precipitate on silica, eluted with a mixture of benzene and ethyl acetate (4: 1), to give 5.3 of the desired product.
Step B. 1 1 / 3- (4-DimethylaminoEnIlE is ethanol, the residue is taken up with 20 cm of methylene chloride, washed with water, dried. 300 mg of product is obtained which is chromatographed
on silica (eluant: methylene chloride, 25) -3.3, 2-ethanediyl-bis- (oxy) lvn-methanol, 8: 2). -1 W / L-ethyl-W-hydroxy-7o (- ( Prop-1 Dry fractions Co. 0.15 to obtain 200 mg of an amorphous desired product.
Example 38. 11p- (4-Dimethyl-aminophenyl) -3-ethyl-1 7/3-hydroxy 17 ° - - (prop-1-inic) -gon-4,9-diene-3-one.
- vinyl) -gon-9 (11) -en-17-ol.
5.3 g of 3.3-Cl, 2-danediyl-bis (oxy) -1 -1 (prop-1-vinyl) -13 / 1-ethyl-5 (5) is stirred in an inert atmosphere at a temperature of 0-5 ° C. (-1 Oo (-eprxigon-9 (10) -en-17- / 5-ol in 106 cm of tetrahydrofuran and 0.158 g of copper chloride) 60 cm of solution of 0.815 M methyl bromide (4 -dimethyl-amino-magnesium in tetrahydrofuran After the addition, stir for another 15 minutes and pour the reaction medium into 300 cm of an aqueous solution saturated with ammonium chloride. Wash the organic phase with ammonium chloride solution and dry under slight pressure. Get 10, .55, g raw target product, which is used in the next step.
Stage A. 3,, 2-Ethanediyl-bis- (oxy) J-13 / -Ethyl- (prop-1-inip) - -gon-5 (10) 9 (11) -diene-17/3-ol .
Preparation of propynyl magnesium bromide.
Cooled to 0 ° C 57 cm
solution
methyl magnesium 0.9 M in ethyl ether and sparged with propyne for 0.5 hours, then another 1 hour at ambient temperature: the resulting solution is added dropwise. l m solution of 9.28 g of 3,3-f1,2-ethanediyl-bic- (oxy) J-13/3-ethylhona-5 (l 0) 9 (1 1) - -diene-17-one in 50 see tetrahydrofuran. Stir for 2 hours under an inert atmosphere and drink the reaction medium on 170 g of ice and 20 g of ammonium chloride. It is extracted with ethyl ether, dried and concentrated under low pressure. The precipitate is crystallized in isopropyl ether and 2.14 g of the expected product are obtained. T. pl. . Purify the mother liquors by crystallisation, chromatography on silica, and 3.61 g of the expected product are obtained. T. pl. 176-178 C.


Stage B. 3,3-G1,2-Ethanediyl-bis- (oxy) J-1 7l - (prop-1-ynyl) -1 3/3-ethyl-5o-10o-epoxygon-9 (1 1 -en-1 7 / E-ol. .
Cool to 5.7 g of the product obtained in step A in 27 cm of methylene chloride and 0.2 cm of pyrite dine and immediately add 0.3 cm of sesquihydrate to hexafluoroacetone, and then
1 dropwise 2 cm 50% hydrogen peroxide (200 vol.). Stir at 48 h. The reaction medium is poured into 100 cm of a cooled solution of sodium thiosulfate (0.2 M),
5, then a very small amount of triethylamine is added and extracted with methylene chloride. The organic phases are washed with water, dried and concentrated dry under low pressure. The residue is chromatographed on silica, eluted with a mixture of benzene and ethyl acetate (4: 1), and 5.3 g of the expected product are obtained.
Stage B. 1 1 / g- (4-DimethylaminophE
25 nil) -3,3, 2-ethanediyl-bic- (oxy) -1 C / l-ethyl-3-hydroxy-7o (- (prop-1zo
40
45
- vinyl) -gon-9 (11) -en-17-ol.
Stir in an inert atmosphere at a temperature of 0-5 ° C with 5.3 g of 3.3-Cl, 2- -thanediyl-bis- (oxy) 1 -1 (prop-1- -inyl) -13 / 1-ethyl-5 (/ -1 Oo (-eprxigon- -9 (10) -ene-17- / 5-ol in 106 cm of tetrahydrofuran and 0.158 g of copper chloride. 60 cm of solution of 0.815 M bromide is added over 50 minutes (4-dimethyl-aminofvnil) magnesium in tetrahydrofuran. After the addition is stirred for another 15 minutes and the reaction medium is poured into 300 cm of an aqueous solution saturated with ammonium chloride. The organic phase is washed with a solution of ammonium chloride and dried under slight pressure. .55, g raw target product, which is used in the next step.
Preparation of methyl (4-dimethyl-aminophenyl) magnesium.
Heat to 40 ° C with 3 g of magnesium 3
0
5 cm tetrahydrofuran chips, 20 g of 4-bromo-S, A-di3 are added dropwise.
methylaniline in 100 cm of tetrahydrofuran for 0.5 h and stirred for an additional 1.5 h.
Stage G, I 1 / z-4- (Dimethylaminophen-5nyl) -13 / 1-ethyl-1 7/3-HYDROXY-1 7o (- (prop--1-ynyl) -gona-4,9-diene “W-he.
10.55 g of the product obtained in step B are stirred for 30 minutes at ambient temperature.
100 cm of methanol and 20 cm of hydrochloric acid 2 N. 300 cm of ethyl ether are added, then 150 cm of sodium bicarbonate solution is 0.25 M permutated, settled, reextracted with ether, and the organic phase is washed with sodium bicarbonate 0.25 M then aqueous solution saturated with sodium chloride. Dry, concentrate dry under slight pressure. Chromatograph the precipitate on silica-t “eluted with a mixture of petroleum ether (T. boil 60-80 ° C) and ethyl acetate (3: 2), concentrate the dry 15 fraction corresponding to the expected product, recrystall it in isopropyl ether and get 3.42 g of the desired product, mp. 162 C. After chromatography and crystallization, the product melts at 164 C. +138 + 2 ° (with 1% CHCl 3).
Example 39. 11p- (4-Dimethyl-aminophenyl) -33-hydroxyimino-1 7oi. Sprague-Dawley E male rats weighing 140 -160 g, in which the adrenal glands are born in 4-8 days. They were sacrificed and, in their kidneys, 50 ml of a buffer solution (Tris 10 mM, sucrose HC1 pH 7.4) were injected by perfusion in place. The kidneys are then removed by decapsulation and subjected to genization with the Pott method using polytetrafluoroethylene glass (1 tissue for 3 ml of buffer solution. The product of centrifuges is homogenized for 10 min at 800 g and
To avoid fixation of tritiated aldosterone on the gl corticoid receptor, add 7/2 -dihydroxy-21-methyl-pre. -1, 2t, 6-trien-20-in-3-one steroids are fixed only on the glucodic receptor, to the product on the surface at a concentration of 10 M. This is on the surface of the product.
(-proc-1-insho-estra-4,9-diene-17/3-ol 25 with ultracentration during
105000 g for 60 min at 0 Aliquot parts of the thus-formed surface product were incubated with about 30 tritium aldosterone at a constant concentration (T) in the presence of an increasing concentration (0-2500 10 M) of cold aldron or cold studied substance that After a time (t) the concentration of bound tritiated aldosterone has expired (B is measured using carbon-dextran adsorption techniques).
In the form of anti-isomers and syn-isomers. 4 g of 17 -hydroxy- (4-dimethylaminophenyl) -1 7cil- (npon--1-ynyl) -estra-4,9-diene-3-one, prepared according to example 4, is stirred under reflux for 1 h. ml of ethanol, 7.6 ml of pyridine and 1.3 g of hydroxylamine hydrochloride. The reaction mixture is cooled, taken into ice water, stirred for 0.5 h, the precipitate is separated, washed with water, isolated and dried vacuum. This gives 4.18 g of the starting product, which is purified by chromatography on silica, eluting with a mixture of methylene-ethyl acetate (7: 3).
2.34 g of an anti-isomer of a solid product, Rn 0.33; 1.31 g of the syn-isomer of the desired product, p 0.26; 925 mg of a mixture of two isomers. Recrystallization of the anti-isomer with R.f 0.33 in a mixture of diisopropyl oxide and methylene chloride gives the product with m.p. 220 ° C, +164 + 3.5 °; 0.8% CHCl j).
Recrystallization of the syn-isomer with Rf 0.26 in this mixture yields a product with mp 26 (f C, +14 ± 3.5 (0.8% CHCl)).
Pharmacological study. Study of the activity of products on hormone receptors. Mineralocorticoid receptor of the rat kidney.
Sprague-Dawley EOPS male rats weighing 140 -160 g, in which the adrenal glands are removed in 4-8 days. before that, 50 ml of buffer solution (Tris 10 mM, sucrose 0.25 M HCl pH 7.4) was injected into the kidneys by perfusion in place in their kidneys. The kidneys are then removed, decapsulated and homogenized using Potter's polytetrafluoroethylene-glass method (1 g of tissue for 3 ml of buffer solution). The homogenization product is centrifuged for 10 minutes at 800 g and.
To avoid fixation of the tritiated aldosterone on the glucocorticoid receptor, 7/2 -dihydroxy-21-methyl-pregna- is added. -1, 2t, 6-trien-20-in-3-one sterovd, which is fixed only on the glucocorticoid receptor, to the product on the surface at a final concentration of 10 M. This product on the surface is subjected to ultracentration at
105,000 g for 60 min at 0 ° C. The liquor parts of the thus obtained surface product are incubated with a tritium-treated aldosterone at a constant concentration (T) in the presence of increasing concentrations (0-2500 10 M) of cold aldosterone or a cold product under study. At the end of the incubation time (t), the concentration of tritiated aldosterone treated (B) is measured by adsorption with a carrier, charcoal-dextran.
Androgen receptor prostate rat.
Rats male Sprague Dawlgy EOPS weighing 160-200 g are subjected to castration. 24 hours after castration, the animals are sacrificed, the prostates are taken, weighed and subjected to homogenization using Potter's method of polytetrafluoroethylene - glass in TS buffer solution (Tris 10 mM, sucrose 0.25 M, HC1 pH 7.4). Take 1 g of tissue per 5 ml of TS. The homogenization product is then subjected to ultracentrifugation (105,000 X 60 min) at 0 ° C. Aliquots of the thus obtained surface product are incubated at 0 ° C for 2 hours with product P (17 H-hydroxy-1 7 ° -methyl-estra-4,9,11-triene-3-one) constant concentration ( T) in the presence of either ho
either P or cold testosterone or an increasing concentration of the product being studied (O - 1000 x X 10 M). The concentration of the tritiated bound product P (B) is then measured in the incubation product using the adsorption technique with a carrier, coal - dextrans,
Progestogenic receptor in the rabbit uterus.
Rabbits (females) that have not reached puberty, weighing about 1 kg, are obtained subcutaneously by 25 μg of tra-diol. 5 days After the animals die, the uterus is sampled, suspended and homogenized using Potter's polytetrafluoroethylene glass in a buffer solution (Tris 10 mM, sucrose 0.25 M, HC1 pH 7.4). Take 1 g of tissue per 50 ml of solution.
The homogenization product is then subjected to ultracentrifugation (105,000.GH 90 min) at 0 ° C. Aliquots of the thus obtained surface product are incubated with a constant concentration (T) (17.21-dimethyl-19 nor-4,9-pregnadien-3, 20 - - dion) in the presence of either cold R, or cold progesterone, or a cold studied product of increasing concentrations (O - 2500 x X 10 M). The concentration of tritiated bound product R (B) is then determined in each incubation product using a carbon-dextran adsorption technique.
The glucocorticoid receptor of the goiter of the rat.
After 4-8 days after removal of the kidney glands, male Sprague Dawley EOPS rats, weighing 160–200 g, are killed, and the goiter glands are sampled and homogenized with
in a buffer solution (Tris 10 mM, sucrose 0.25 M, dithiothreitol 2 mM, HC1 pH 7.4) by the method of Potter polytetrafluoroethylene - glass (1 g of tissue per 10 MJi TS) ,. The homogenization product is then subjected to ultracentrifugation (105,000 g x, 90 min) at 0 ° C. Aliquots of the surface product thus obtained are incubated at 0 ° C for a time (t) with a saturated tritium of dexamethasone constant concentration (T) in the presence of either a cold dexamethan-5 zone or a cold product of increasing concentrations ( 0-2500-10 M). The concentration of tritiated bound dexamethasone (B) is then measured in each incubation product using a carbon-dextran carrier adsorption technique. Estrogen receptor of the uterus Not attained puberty mishi (females) aged 18 to 21 days. 5 are killed, the uterus is collected, and then subjected to homogenization at 0 ° C using Potter's method of polytetrafluoroethylene glass in a TS buffer solution (Tris 10 mM, sucrose 0.25 M, HC1 0 pH 7.4). Take 1 g of tissue per 25 ml of TS. . The homogenization product is then subjected to ultracentrifugation (105,000 gx X 90 min) at 0 ° C. Aliquots of the thus obtained surface product are incubated at 0 ° C for a period of time (t) with a saturated tritium of steady-state concentration (T) in the presence of either cold estradiol or cold studied product of increasing concentrations (.0-1000 - one ) . Then, the concentration of bound tritium bound estradiol (B) is measured in each incubation product by adsorption technique 5 with a carbon-dextran carrier.
(tab. 1 and 2). , tar face 1
G f, + I I 2 saturated L max J-MMH J max
HIS tritium bound hormone to incubate this tritiated
P
hormone concentration (T)
 min,% tritiated saturated bound hormone to incubate this tritiated hormone at a concentration (T) in the presence of a large excess of cold hormone (2500 x 1).
The intersections of the direct LCjo and curves allow to determine the concentration of cold hormone (CH) and the cold product under study (CX), which inhibit the 50% linkage of the tritium hormone on the receptor.
The relative affinity of communication (SLA) of the product being studied. Determines / HSR
with the OAS 100 equation.
(.)
The results of calculating the relative affinity of communication are shown in Table. 2.Table2
Antiglycorticoid activity
Product 5-10 dec. - Percentage of bracamethasone + effect application
dexamethasone test
product
5 10 m 70
10 m 84
Thus, the products studied (especially the products of examples 4, 17, 10, 16, and 22) show a pronounced affinity for the glucocorticoid and progestogenic receptors, as well as a slight affinity for the androgen receptor. However, these products show no activity at the mineralocorticoid and estrogen receptors.
From the results obtained, it can be concluded that the products can show the activity of agonism or antagonism of glucocorticoids, progestogens and androgens.
The study of the anti-inflammatory properties of the product of example 4.
Anti-inflammatory activity was studied by the classical granuloma test.
According to the well-known technique, conditional Wistar female rats weighing 100 to 110 g are injected under the skin of the thorax 2 pellets of 10 mg each. Subcutaneous injection, which begins immediately after implantation, lasts 2 days. by
53
2 injections a day 16 hours after the last injection, i.e. on the third day, the animals are killed.
The pelae wool, which is surrounded by the granuloma formed by the tissue, is weighed fresh and then after, staying for 18 hours, the weight of the granuloma is determined by pressing the per: initial weight of the wool. Thymus gland: also selected and weighed to determine the goiter activity of the product.
At a dose of 50 mg / kg administered over the skin, the product of Example 4 does not show any anti-inflammatory glucocortic or goiter effect.
Antiglucocord-icoid activity.
Thyroid gland cells, in which the adrenal glands are removed, are incubated for 3 hours in a nutrient medium containing 5 x X of dexamethasone in the presence or absence of the product under study at various concentrations. Add tritium to the uridine and continue incubation for 1 hour. Cool the incubation products, treat it with 5% trichloroacetic acid solution, filter on GF / A paper. wash-p three times with a 5% trichloroacetic acid solution. The radioactivity retained by the filter is determined (Table 3).
447289
54 Continued table. 3
five
0
five
0
five
 At a dose of 10 M, the inhibition of the effect of dexamethasone was complete.
Glucocorticoids, and in particular, dexamethasone, result in a decrease in the assimilation of tritiated uridine. The products studied and in particular the products of examples 4; 14, 8, 10, II, 16, 6, 20, and 22 resist this effect. On the other hand, it was noted that the products studied did not show any effect of the glucocorticoid type when used alone.
The products studied exhibit a distinct anti-glucocorticoid activity, and at the same time these products lack glucocorticoid activity.
Acute toxicity test.
Substance: product of example 4 (product A); substance activity; antiprogesterone (antiglucocorticoid); formulation: dispersion; carrier: 0.25% sodium carboxymethyl cellulose with p, 2% polysorbate 80; nature of the study: determination of acute toxicity after oral administration.
Species of experimental animals: Sprague Dawley GDI rat, devoid of a specific pathogen, sex - males and females, 10 animals of each sex per dose of 0-1000 mg / kg. Observation period: after IA days. after drug administration.
Results: Product A dispersed in 0.25% sodium carboxymethyl cellulose, with 0.2% polysorbate 80, orally injected into the body of males and females of rats, did not cause the animals to die when the compound was micronized. One rat (male), treated with the non-micronized form of the product, died on the first day. Thus, the lethal dose of 50 exceeded 100 mg / kg.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of steroids of the general formula
.g
AgAh
, d; w
(I)
de R, is phenyl, substituted by kch- (. -alkylamino group, possibly oxidized by nitrogen, di-- (4) -alkylamino- (C, -C4) - 35-alkna group, possibly oxidized by nitrogen, pyrrolidinyl group, di - (C, -C4) - -alkylamino (with -C 4) -alkylthio, di - () - alkyl-4o-HO- (CI-C) -alkyloxy, trimethylsilyl group, or R - N- () -appkyl-dihydroindolyl, pyridinyl, mark 1 L, ethyl, ox group, methoxy group.
R.
45
R.
ethinyl, group
or C NOH-rpynna; hydrogen. C - € 4 - alkenyl; C, -C-Alkadien, C i-C-Alkynyl, in some cases a halogen, a phenyl group, a trimetypsilyl group or a lower alkenyl group,
in and with together form a double. link or. an epoxy group, characterized in that the compound of the general formula
R
.B:
(Ii)
ffema / fti
where have the indicated meanings;
ketal may be cyclic or
non-cyclic,
subjected to the action of a dehydrating agent, such as a cation exchange sulfonic resin or an acid, such as hydrochloric acid, to give a compound of the general formula
- (la)
zg
35 4o
where R, - R have the indicated meanings, which, if necessary, are subjected to the action of free hydroxylamine to obtain the compound total
form
AT,
one.
Yb
CGG ZhgNhh
B, (Yu
HON
where R - R have the indicated meanings, or, in the case where the substituent R, in the general formula (1a) is a dialkip -amino- (C, -C4-alkyl) -fensh1, is exposed to an oxidizing agent, such as metachloroperbenzoic acid, with obtaining the corresponding product in which R is dialkyl C, -C4-amino -... - () -alkyl) -phenyl, oxidized by nitrogen, and in the corresponding cases containing 9,10-epoxy.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1447289A3|1988-12-23|Method of producing derivatives of steroids

---

SU1715205A3|1992-02-23|Method for the synthesis of steroid, substituted with spirane cycle

---

AU2007321848B2|2013-09-19|Progesterone receptor antagonists

---

SU1340593A3|1987-09-23|Method of producing derivatives of delta 4-9-19-norsteroids

---

US20180155386A1|2018-06-07|Progesterone antagonists

---

HU191739B|1987-04-28|Process for producing 11-beta-estradiene derivatives and pharmaceutical compositions containing them

---

KR960013446B1|1996-10-05|Steroids with a 3,4 or 6 ring members spiro ring at position 17, their preparation, intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing theh

---

US4943566A|1990-07-24|Novel 17-aryl-steroids

---

HU196825B|1989-01-30|Process for producing 10-substituted steroids and pharmaceutical compositions comprising the same

---

FR2598421A1|1987-11-13|NOVEL 19-NOR OR 19-NOR D-HOMO STEROID PRODUCTS SUBSTITUTED IN POSITION 11B BY A RADICAL PHENYL CARRYING AN ALKYNYL RADICAL, PROCESS FOR PREPARING THEM, APPLICATION AS MEDICAMENTS AND COMPOSITIONS COMPRISING SAME

---

IE892141L|1990-01-01|13-alkyl-11ß-phenylgonanes

---

DK168444B1|1994-03-28|7beta-methyl or 7beta-ethyl-11-aminophenyl steroid compounds, processes for their preparation and pharmaceutical preparations containing them

---

HU191131B|1987-01-28|Process for preparing 13-alpha-alkyl-gonanes and pharmaceutical compositions containing such compounds

---

HU9903515A2|2000-03-28|21-substituted progesterone derivatives as new antiprogestational agents medicoments containing the same, use thereof

---

AU2007217095B2|2012-05-03|17-phosphorous steroid derivatives useful as progesterone receptor modulators

---

HU209949B|1994-12-28|Process for the production of 11beta-4-estrene-derivatives and pharmaceutical compositions containing them

---

EP1776378B1|2009-11-04|Process for the preparation 2-substituted-derivatives of estrone and estradiol

---

FI94349C|1995-08-25|Process for Preparation of Therapeutically Active 11-Phenyl-4,9,15-Estratrienes

---

IE893002L|1990-03-20|11ß-phenyl-14ßH steroids

---

US5336686A|1994-08-09|17 Methylene lactones of steroids

---

FI82699B|1990-12-31|FOERFARANDE FOER FRAMSTAELLNING AV NYA STEROIDER, VILKA AER SUBSTITUERADE I 10-STAELLNINGEN MED EN GRUPP SOM INNEHAOLLER EN DUBBEL- ELLER TRIPPELBINDNING.

---

Rewinkel et al.2008|11-| steroids—A new class of mixed-profile progesterone agonists/antagonists

---

PT99911B|1999-06-30|PROCESS FOR THE PREPARATION OF 11BETA-ARYL-4-STRENOS MODIFIED IN POSITION 6,7 AND OF PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

---

US5446178A|1995-08-29|Process for preparing 19,11β-bridged steroids

---

Cleve et al.1996|11β-Aryl steroids in the androstene series. The role of the 11β-region in steroid progesterone receptor interaction

同族专利:

---

公开号 | 公开日

---

IE52595B1|1987-12-23|

---

EP0057115B1|1985-03-20|

---

BG60768B2|1996-02-29|

---

AU7929682A|1982-07-15|

---

NL300001I1|2000-04-03|

---

FI77872C|1989-05-10|

---

JPH0234958B2|1990-08-07|

---

MD207B1|1995-05-31|

---

US4386085A|1983-05-31|

---

US4634695A|1987-01-06|

---

ES8305786A1|1983-04-16|

---

AU5123685A|1986-04-17|

---

FI77872B|1989-01-31|

---

JPS57168000A|1982-10-16|

---

LT2618B|1994-04-25|

---

ES508588A0|1983-04-16|

---

DE19975073I1|2000-03-09|

---

KR870001936B1|1987-10-22|

---

JPH0466879B2|1992-10-26|

---

ES517764A0|1983-12-01|

---

US4447424A|1984-05-08|

---

FR2497807A1|1982-07-16|

---

EP0057115A2|1982-08-04|

---

KR840000581A|1984-02-25|

---

NL300001I2|2000-08-01|

---

PT74263A|1982-02-01|

---

SG45987G|1987-11-13|

---

AU579211B2|1988-11-17|

---

AU550334B2|1986-03-20|

---

DE19975073I2|2004-01-08|

---

DE3262580D1|1985-04-25|

---

FI820042L|1982-07-10|

---

DK4082A|1982-07-10|

---

HU185158B|1984-12-28|

---

DK166680B1|1993-06-28|

---

US4519946A|1985-05-28|

---

JPH01279897A|1989-11-10|

---

FR2497807B1|1983-07-29|

---

MD207C2|1995-12-31|

---

IE820044L|1982-07-09|

---

ES8401498A1|1983-12-01|

---

CA1193246A|1985-09-10|

---

EP0057115A3|1982-09-29|

---

ZA8231B|1982-11-24|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3190796A|1963-04-25|1965-06-22|Upjohn Co|Process for inhibiting the growth of micrococcus agilis with 11beta-hydroxy-11--pregnane-3, 20-dione|

---

FR2377417B1|1977-01-13|1979-04-20|Roussel Uclaf|

---

FR2377418B1|1977-01-13|1979-04-20|Roussel Uclaf|

---

US4197296A|1977-03-23|1980-04-08|Glaxo Group Limited|Androstanes|

---

ZA8231B|1981-01-09|1982-11-24|Roussel Uclaf|New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained|JP2785023B2|1987-12-30|1998-08-13|ルセル―ユクラフ|Novel derivative of 17β-OH-19-norsteroid substituted at 17α position, process for its preparation, its use as drug and pharmaceutical composition containing it|

---

ZA8231B|1981-01-09|1982-11-24|Roussel Uclaf|New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained|

---

US4978657A|1981-01-09|1990-12-18|Roussel Uclaf|Novel 11β-substituted-19-nor-steroids|

---

FR2522328B1|1982-03-01|1986-02-14|Roussel Uclaf|NEW PRODUCTS DERIVED FROM THE STRUCTURE 3-CETO 4,9 19-NOR STEROIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS|

---

FR2640977A2|1982-06-11|1990-06-29|Roussel Uclaf|New position-11 substituted 19-norsteroids and their application as medicinal products.|

---

FR2528434B1|1982-06-11|1985-07-19|Roussel Uclaf|NOVEL 19-NOR STEROIDS SUBSTITUTED IN 11B AND POSSIBLY IN 2, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS A MEDICAMENT|

---

DE3231827A1|1982-08-24|1984-03-01|Schering AG, 1000 Berlin und 4709 Bergkamen|11SS-ARYL-17-ALKINYL-17SS-HYDROXY-4.9- ESTRADIEN-3-ON DERIVATIVES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

DE3231828A1|1982-08-24|1984-03-01|Schering AG, 1000 Berlin und 4709 Bergkamen|17 alpha -Alkynyl-3,3-alkylenedioxy-5 alpha ,10 alpha -epoxy-9-oestren-17 beta -ol derivatives, process for the preparation thereof and the use thereof for further processing|

---

DE3306121A1|1983-02-18|1984-09-06|Schering AG, 1000 Berlin und 4709 Bergkamen|11 beta -Arylspirolactones in the steroid series, process for the preparation thereof and pharmaceutical products containing these compounds|

---

DE3461090D1|1983-02-18|1986-12-04|Schering Ag|11-beta-aryl-estradienes, process for their preparation and pharmaceutical compositions containing them|

---

IL68222A|1983-03-24|1987-02-27|Yeda Res & Dev|Contraceptive compositions comprising a progesterone antagonist and a blocker of progesterone activity|

---

DE3320580A1|1983-06-03|1984-12-06|Schering AG, 1000 Berlin und 4709 Bergkamen|D-HOMO-4,9,16-ESTRATRIENE, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

NO162241C|1983-06-14|1989-11-29|Roussel Uclaf|NEW RADIOACTIVE ESTRADIA DERIVATIVES LABELED WITH JOD125, THE PROCEDURE OF THEIR PREPARATION AND THEIR USE OF RADIO DIMMUNOLOGICAL RESEARCH AND QUANTITY DETERMINATION OF STEROIDS IN BIOLOGICAL LIQUIDS.|

---

FR2549067B1|1983-06-14|1985-12-27|Roussel Uclaf|TRITIUM-MARKED RADIOACTIVE ESTRADIAN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION FOR THE STUDY AND RADIO-IMMUNOLOGICAL ASSAY OF STEROIDS IN BIOLOGICAL FLUIDS|

---

ES533260A0|1983-06-15|1985-02-01|Schering Ag|PROCEDURE FOR THE PREPARATION OF 13A-ALQUILGONANOS|

---

FR2548192B1|1983-06-20|1985-11-22|Roussel Uclaf|IODINE-MARKED RADIOACTIVE ESTRADIAN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO RADIOIMMUNOLOGICAL ASSAYS|

---

IT1212835B|1983-08-18|1989-11-30|Lehner Ag|BILIARY ACID DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS.|

---

DE3337450A1|1983-10-12|1985-04-25|Schering AG, 1000 Berlin und 4709 Bergkamen|PROSTAGLANDINE AND ANTIGESTAGE FOR PREGNANCY ABORT|

---

AU572589B2|1983-12-14|1988-05-12|Upjohn Company, The|11-difluoromethyl and -and -11-fluoromethylene steroids|

---

DE3347126A1|1983-12-22|1985-07-11|Schering AG, 1000 Berlin und 4709 Bergkamen|11SS-ARYL-ESTRADIENE, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

FR2566779B2|1984-06-29|1987-03-06|Roussel Uclaf|NOVEL 11B SUBSTITUTED STEROID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS|

---

US5116830A|1984-08-17|1992-05-26|Sri International|Stereoisomerically pure 17α-ethynyl-estra-2-en-17β-ol and the 17β esters thereof, methods of preparation and uses|

---

DE3438500C1|1984-10-18|1986-05-28|Schering AG, 1000 Berlin und 4709 Bergkamen|Process for the preparation of 11 beta -substitutedDELTA <9>-19-norsteroids|

---

FR2573657B1|1984-11-29|1989-05-12|Roussel Uclaf|PRODUCT COMPRISING AN ANTIPROGESTOMIMETIC SUBSTANCE AND A UTEROTONIC SUBSTANCE|

---

DE3446661A1|1984-12-18|1986-06-19|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW 13-ALKYL-17-GONANA|

---

AU580843B2|1985-02-07|1989-02-02|Schering Aktiengesellschaft|11``-phenyl-gonanes, their manufacture and pharmaceutical preparations containing them|

---

DE3504421A1|1985-02-07|1986-08-07|Schering AG, 1000 Berlin und 4709 Bergkamen|11 beta -Phenylgonanes, the preparation thereof and pharmaceutical products containing these|

---

DE3506785A1|1985-02-22|1986-08-28|Schering AG, Berlin und Bergkamen, 1000 Berlin|11SS-N, N-DIMETHYLAMINOPHENYL ESTRADIENE, THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

GB8513723D0|1985-05-31|1985-07-03|Erba Farmitalia|11-beta substituted steroids|

---

DE3531903A1|1985-09-05|1987-03-12|Schering Ag|OXYTOCIN AND ANTI-DAYS FOR THE INTRODUCTION OF BIRTH OR ON THE THERAPEUTIC STOP OF GRAVIDITY|

---

DE3533175A1|1985-09-13|1987-03-19|Schering Ag|ANTIGESTAGES TO SHIFT ENDOMETRIAL MATURATION|

---

FR2596395B1|1986-03-26|1989-05-26|Roussel Uclaf|NOVEL STEROIDS COMPRISING A SPIRANIC CYCLE IN POSITION 17, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM|

---

FR2598421B1|1986-05-06|1988-08-19|Roussel Uclaf|NOVEL 19-NOR OR 19-NOR D-HOMO STEROIDS SUBSTITUTED IN POSITION 11B BY A RADICAL PHENYL CARRYING AN ALKYNYL RADICAL, THEIR PREPARATION METHOD, THEIR APPLICATION AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM|

---

EP0254341B1|1986-07-23|1990-01-03|Akzo N.V.|Novel 18-phenyloestrane derivatives|

---

DE3625315A1|1986-07-25|1988-01-28|Schering Ag|11SS--ESTRA-4,9-DIENES, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

US4774236A|1986-09-17|1988-09-27|Research Triangle Institute|17α--17β-hydroxy/esterified hydroxy steroids and pharmaceutical compositions containing them|

---

IE60780B1|1987-01-23|1994-08-10|Akzo Nv|New 11-aryl steroid derivatives|

---

US5272140A|1987-01-23|1993-12-21|Akzo N.V.|11-aryl steroid derivatives|

---

US5446178A|1987-03-18|1995-08-29|Schering Aktiengesellschaft|Process for preparing 19,11β-bridged steroids|

---

DE3708942A1|1987-03-18|1988-09-29|Schering Ag|19.11SS-BRIDGED STEROIDS, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

AT69820T|1987-04-24|1991-12-15|Akzo Nv|11-ARYLESTRANDERIVATIVES AND 11-ARYLPREGNANDERIVATIVES.|

---

JPH085909B2|1987-07-24|1996-01-24|協和醗酵工業株式会社|UCY1003 derivative|

---

FR2618783B1|1987-07-30|1991-02-01|Roussel Uclaf|NOVEL 17-ARYL STEROIDS, THEIR PROCESSES AND INTERMEDIATES AS A MEDICAMENT AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

US5208227A|1987-08-25|1993-05-04|University Of Southern California|Method, compositions, and compounds for modulating brain excitability|

---

US5319115A|1987-08-25|1994-06-07|Cocensys Inc.|Method for making 3α-hydroxy, 3β-substituted-pregnanes|

---

AT85342T|1987-12-12|1993-02-15|Akzo Nv|11-ARYLSTEROID DERIVATIVES.|

---

US4954490A|1988-06-23|1990-09-04|Research Triangle Institute|11 β-substituted progesterone analogs|

---

DE3822770A1|1988-07-01|1990-01-04|Schering Ag|13-ALKYL-11SS-PHENYLGONANE|

---

DE3832303A1|1988-09-20|1990-04-12|Schering Ag|11SS-PHENYL-14SSH STEROIDS|

---

FR2643638B1|1989-02-24|1991-06-14|Roussel Uclaf|NOVEL 19-NOR STEROIDS HAVING IN THE 11BETA POSITION A CARBON CHAIN COMPRISING AN AMIDE OR CARBAMATE FUNCTION, THEIR PREPARATION METHOD AND INTERMEDIATES THEREOF, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

DE3917274A1|1989-05-24|1990-11-29|Schering Ag|9-HYDROXY-19, 11-BRIDGED STEROIDS, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM|

---

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|

---

US5276023A|1989-08-08|1994-01-04|Roussel Uclaf|19-nor-steroid esters|

---

FR2651435B1|1989-09-07|1994-04-22|Roussel Uclaf|

---

FR2654337B1|1989-11-15|1994-08-05|Roussel Uclaf|NOVEL BIODEGRADABLE INJECTABLE MICROSPHERES PREPARATION METHOD AND INJECTABLE SUSPENSIONS CONTAINING THEM.|

---

FR2659233B1|1990-03-06|1994-01-21|Roussel Uclaf|NEW USE OF ANTI-PROGESTOMIMETIC COMPOUNDS IN FARMING ANIMALS.|

---

DE4018168A1|1990-06-01|1991-12-05|Schering Ag|INITIAL CONNECTIONS FOR THE PRODUCTION OF 10SS-H STEROIDS AND A METHOD FOR THE PRODUCTION OF THESE OUTPUT CONNECTIONS|

---

US5407928A|1990-08-15|1995-04-18|Schering Aktiengesellschaft|11β-aryl-gona-4,9-dien-3-ones|

---

JPH0464052U|1990-10-05|1992-06-01|

---

US5439913A|1992-05-12|1995-08-08|Schering Aktiengesellschaft|Contraception method using competitive progesterone antagonists and novel compounds useful therein|

---

CA2100514C|1992-07-29|2005-03-29|Johannes A. M. Hamersma|17-spiromethylene steroids|

---

AU1439595A|1993-12-22|1995-07-10|Salk Institute For Biological Studies, The|Methods for reducing multidrug resistance|

---

US5681817A|1994-02-04|1997-10-28|The Medical College Of Hampton Roads|Treatment of ovarian estrogen dependent conditions|

---

FR2718354B1|1994-04-08|1996-05-03|Roussel Uclaf|Application of the anti-glucocorticoid compounds for the preparation of medicaments intended for the prevention or the treatment of the manifestations linked to the narcotic withdrawal syndrome and the compositions containing them.|

---

DE4415590A1|1994-04-28|1995-11-02|Schering Ag|Process for the stereoselective introduction of an alkynyl side chain to 11β-aryl-substituted 13alpha-alkylgonan-17-ones|

---

CA2149496C|1994-05-19|2006-12-19|Ronald Gebhard|11,21-bisphenyl-19-norpregnane derivatives|

---

US5639598A|1994-05-19|1997-06-17|The Trustees Of The University Of Pennsylvania|Method and kit for identification of antiviral agents capable of abrogating HIV Vpr-Rip-1 binding interactions|

---

US5780220A|1994-05-19|1998-07-14|Trustees Of The University Of Pennsylvania|Methods and compositions for inhibiting HIV replication|

---

US5521166A|1994-12-19|1996-05-28|Ortho Pharmaceitical Corporation|Antiprogestin cyclophasic hormonal regimen|

---

ZA9510926B|1994-12-23|1996-07-03|Schering Ag|Compounds with progesterone-antagonistic and antiestrogenic action to be used together for female contraception|

---

US5929262A|1995-03-30|1999-07-27|The United States Of America As Represented By The Department Of Health And Human Services|Method for preparing 17α-acetoxy-11β--19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates|

---

US5767113A|1995-05-10|1998-06-16|The Salk Institute For Biological Studies|Compounds useful for concurrently activating glucocorticoid-induced response and reducing multidrug resistance|

---

IL118974A|1995-08-17|2001-09-13|Akzo Nobel Nv|11--estra-4,9-diene derivatives, their preparation and pharmaceutical compositions containing them|

---

WO1997041145A1|1996-05-01|1997-11-06|The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services|21-substituted progesterone derivatives as new antiprogestational agents|

---

US6900193B1|1996-05-01|2005-05-31|The United States Of America As Represented By The Department Of Health And Human Services|Structural modification of 19-norprogesterone I: 17-α-substituted-11-β-substituted-4-aryl and 21-substituted 19-norpregnadienedione as new antiprogestational agents|

---

DE19706061A1|1997-02-07|1998-08-13|Schering Ag|Anti-gestagen effective steroids with fluorinated 17alpha alkyl chain|

---

DE19745085A1|1997-10-11|1999-04-15|Jenapharm Gmbh|11β-Benzaldoxim-9alpha, 10alpha-epoxy-estr-4-ene derivatives, processes for their preparation and pharmaceutical preparations containing these compounds|

---

DE19809845A1|1998-03-03|1999-09-09|Jenapharm Gmbh|S-substituted 11beta-benzaldoxime-estra-4,9-diene-carbonic acid thiol esters, processes for their preparation and pharmaceutical preparations containing these compounds|

---

US6020328A|1998-03-06|2000-02-01|Research Triangle Institute|20-keto-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties|

---

EP1076562B1|1998-05-15|2006-02-15|The Board Of Trustees Of The Leland Stanford Junior University|Glucocorticoid receptor antagonists for the treatment of dementia|

---

WO1999061055A1|1998-05-22|1999-12-02|The Board Of Trustees Of The Leland Stanford Junior University|Bifunctional molecules and therapies based thereon|

---

US5962444A|1998-05-29|1999-10-05|Research Triangle Institute|17β-nitro-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties|

---

US6262042B1|1998-05-29|2001-07-17|Research Triangle Institute|17β-amino and hydroxylamino-11β-arylsteroids and their derivatives having agonist or antagonist hormonal properties|

---

AU4701299A|1998-06-23|2000-01-10|Stuart R. Adler|Therapeutic applications of estrogenic carboxylic acids|

---

US20020169205A1|1998-09-29|2002-11-14|Krzysztof Chwalisz|Implantation rates after in vitro fertilization, and treatment of infertility and early pregnancy loss with a nitric oxide donor or substrate alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors in combination with antiprogestins or other agents|

---

CN1117759C|1999-09-02|2003-08-13|上海中西药业股份有限公司|Steroid and its preparation method, medicine composition and application|

---

US20030013694A1|2001-05-25|2003-01-16|Jens Hoffmann|Use and compositions of antiprogestins for treatment of prostate diseases|

---

FR2826004B1|2001-06-13|2008-03-28|Aventis Pharma Sa|PROCESS FOR THE PREPARATION OF ESTROGENIC DERIVATIVES|

---

EP1285927A3|2001-08-16|2005-06-29|Schering Aktiengesellschaft|Use of glucocorticoid antagonists for the prevention and treatment of diseases of the male reproductive system|

---

US7326697B2|2002-04-29|2008-02-05|Corcept Therapeutics, Inc.|Methods for increasing the therapeutic response to electroconvulsive therapy|

---

DE10221034A1|2002-05-03|2003-11-20|Schering Ag|New 17-alpha-fluoroalkyl-11-beta-benzaldoxime-estradiene derivatives, useful as antigestagens in post-menopausal hormone replacement therapy or for treating e.g. gynecological disorders|

---

US7250408B2|2002-12-16|2007-07-31|Bayer Schering Pharma Ag|Glucocorticoid receptor antagonists for prophylaxis and therapy of glucocorticoid-mediated hypogonadism, of sexual dysfunction and/or infertility|

---

FR2850022B1|2003-01-22|2006-09-08|Centre Nat Rech Scient|NOVEL USE OF MIFEPRISTONE AND ITS DERIVATIVES AS MODULATORS OF THE HEDGEHOG PROTEIN SIGNALING PATH AND ITS APPLICATIONS|

---

WO2004078709A2|2003-02-28|2004-09-16|The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services|METHOD FOR PREPARING 17 α-ACETOXY-11β--19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIATES THEREOF, AND METHODS FOR THE PREPARATION OF SUCH INTERMEDIATES|

---

AU2004249280A1|2003-06-20|2004-12-29|Viral Genomix, Inc.|Antiviral compositions and methods of using the same|

---

JP2008539047A|2005-04-28|2008-11-13|プロテウスバイオメディカルインコーポレイテッド|Pharma Informatics System|

---

US20070105828A1|2005-08-19|2007-05-10|Glenmark Pharmaceuticals Limited|Novel polymorph form M of mifepristone and process for its preparation|

---

WO2007035716A2|2005-09-16|2007-03-29|Raptor Pharmaceutical Inc.|Compositions comprising receptor-associated proteinvariants specific for cr-containing proteins and uses thereof|

---

JP4382735B2|2005-10-06|2009-12-16|独立行政法人科学技術振興機構|Neuropathic pain treatment|

---

DE102005059222B4|2005-12-08|2007-10-11|Bayer Schering Pharma Ag|11β-Benzaldoxime derivatives of D-homoestra-4,9-dien-3-ones|

---

ES2389113T3|2006-02-17|2012-10-23|Janssen Pharmaceutica, N.V.|Oxa-steroid derivatives as selective progesterone receptor modulators|

---

US20070270393A1|2006-02-17|2007-11-22|Theresa Buckley|Methods and compositions for modulation of sleep cycle|

---

DE102006018888A1|2006-04-18|2007-10-25|Bayer Schering Pharma Ag|Process for the preparation of 4- [17beta-methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-diene-11beta-yl] benzaldehyde-oxime |

---

US20100160275A1|2006-09-26|2010-06-24|Lee Eva Y H P|Methods and compositions for cancer prevention and treatment|

---

US9517240B2|2006-09-26|2016-12-13|The Regents Of The University Of California|Methods and compositions for cancer prevention and treatment|

---

LT3263112T|2006-10-24|2020-10-12|Allergan Pharmaceuticals International Limited|Compositions and methods for suppressing endometrial proliferations|

---

KR20090105944A|2007-01-17|2009-10-07|레프로스 쎄라피우틱스 아이엔씨.|Methods for improved stability of steroid derivatives|

---

HU228636B1|2007-06-27|2013-04-29|Richter Gedeon Nyrt|Industrial method for the synthesis of 17-acetoxy-11betha-4[--phenyl]-21-methoxy-19-norpregna-4,9-dien-3,20-dione and the key intermediates of the process|

---

TWI539953B|2008-04-28|2016-07-01|瑞波若斯治療學公司|Compositions and methods for treating breast cancer|

---

CN104208718B|2009-02-20|2017-12-29|2-Bbb医疗股份有限公司|drug delivery system based on glutathione|

---

DE102009034368A1|2009-07-20|2011-01-27|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-acyloxyalkylenephenyl derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102009034362A1|2009-07-20|2011-01-27|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-aryl derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102009034366A1|2009-07-20|2011-01-27|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-methyleneoxyalkylene aryl derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102009034367A1|2009-07-20|2011-01-27|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-benzylidene derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102009034525A1|2009-07-21|2011-01-27|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-aryl derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102009034526A1|2009-07-21|2011-02-10|Bayer Schering Pharma Aktiengesellschaft|17-Hydroxy-17-pentafluoroethyl-estra-4,9-diene-11-ethynylphenyl derivatives, process for their preparation and their use for the treatment of diseases|

---

DE102010007719A1|2010-02-10|2011-08-11|Bayer Schering Pharma Aktiengesellschaft, 13353|Progesterone receptor antagonist|

---

DE102010007722A1|2010-02-10|2011-08-11|Bayer Schering Pharma Aktiengesellschaft, 13353|Progesterone receptor antagonist|

---

EP2550288A1|2010-03-22|2013-01-30|Repros Therapeutics Inc.|Compositions and methods for non-toxic delivery of antiprogestins|

---

PL2576582T3|2010-05-26|2020-06-29|Corcept Therapeutics, Inc.|Treatment of muscular dystrophy|

---

DE102011004899A1|2011-03-01|2012-09-06|Bayer Pharma Aktiengesellschaft|New 17-hydroxy-17-pentafluoroethyl-estra-4,9-dien-11-aryl-derivatives are progesterone receptor antagonists useful to treat and prevent e.g. uterine fibroids, endometriosis, heavy menstrual bleeding and meningioma|

---

US20130029953A1|2011-07-28|2013-01-31|Klaus Nickisch|Progesterone antagonists|

---

EP2868320A1|2013-11-03|2015-05-06|Flamina Holding AG|A composition or group of compositions for the treatment of human cells|

---

SG11201707525TA|2015-03-30|2017-10-30|Corcept Therapeutics Inc|Use of glucocorticoid receptor antagonists in combination with glucocorticoids to treat adrenal insufficiency|

---

CN113797210A|2015-05-18|2021-12-17|拜耳医药股份有限公司|Selective Progesterone Receptor Modulatorregimens|

---

MX2018001803A|2015-08-13|2018-05-16|Corcept Therapeutics Inc|Method for differentially diagnosing acth-dependent cushing's syndrome.|

---

JP6906525B2|2015-12-23|2021-07-21|オリック ファーマシューティカルズ，インク．|Inhibitor of glucocorticoid receptor|

---

JP6995757B2|2015-12-23|2022-01-17|オリック ファーマシューティカルズ，インク．|Inhibitor of glucocorticoid receptor|

---

WO2017112904A1|2015-12-23|2017-06-29|Oric Pharmaceuticals, Inc.|Inhibitors of glucocorticoid receptor|

---

EP3405101B1|2016-01-19|2020-12-23|Corcept Therapeutics, Inc.|Differential diagnosis of ectopic cushing's syndrome|

---

EP3214092A1|2016-03-04|2017-09-06|Bayer Pharma Aktiengesellschaft|Prodrugs of the selective progesterone receptor modulator-17-hydroxy-11-[4-phenyl]-17-estra-4,9-dien-3-one|

---

DK3523315T3|2016-10-07|2021-05-03|Oric Pharmaceuticals Inc|Glucocorticoid receptor inhibitor|

---

CN108070016B|2017-12-29|2020-07-07|广西万德药业有限公司|Cyclic utilization method of steroid epoxy isomer|

---

WO2021127376A1|2019-12-21|2021-06-24|Corcept Therapeutics Incorporated|Treatment of, and differential diagnosis between, acth-dependent cushing's syndrome and acth-independent cushing's syndrome|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

FR8100272A|FR2497807B1|1981-01-09|1981-01-09|MD94-0265A| MD207C2|1981-01-09|1994-08-08|Method of steroid derivatives preparation|