Method of producing 11beta-substituted steroids or their pharmaceutically or veterinarily acceptable

专利摘要:
The invention relates to substituted steroids, in particular, the preparation of compounds of the general formula @, where R 1 -C 1 -C 3 is alkyl R 2 -AZ A-phenylene Z-NR 5 R 6 R 5 and R 6 -C 1 -C 3 -alkyl R 3 -OH R 4 -C 2 -C 5 -quinil or their pharmaceutically or veterinary acceptable salts with anti-glucocorticoid activity. The goal is to create more active and low-toxic substances of the specified class. Synthesis is carried out by dehydration and deketalization of the compound of the general formula @ where R 1 -R 4 is above [R 1 + R 11 ] is a protected oxo group in the form of a cyclic ketal. If necessary, the selected product is converted to the desired salt. New substances are less toxic and more active than cartexolone. 1 tab.
公开号:SU1508963A3
申请号:SU864027509
申请日:1986-05-29
公开日:1989-09-15
发明作者:Фаустини Франко；Дъалессио Роберто；Вилла Витториа；Ди Салле Энрико
申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new steroid derivatives, namely 11 | 3-substituted steroids of general formula I
where R, C, - C is alkyl;
2. group -A-Z, where A is phenylene; .
Z is a group, 5, where each R,
6
and Rg C, - C, -alkyl; R is a hydroxyl group; Rij - Cj - C5 quinil,

s
31508963
whether they are pharmaceutically or veterinarian- about acceptable salts, which have prices pharmacological properties.
The purpose of the invention is to obtain new 1p-substituted steroid derivatives with advantages in comparison with known structural taxes, for example, cortexolone.
The abbreviations THF, DMSO, and TLC are used to denote, respectively, ethehydrofuran and dimethyl sulfoxide thin layer chromatography.
Example. Sludge-12, B9 g 19-nor-5 o / -oxy-5-p-methyl-3 oxo-1 J-jb-5-oxyandrostan-3,3 ethylenedioxy-1J-acetate in 190 ml of pyridine is cooled. using an external bath, and then with stirring, 12.7 ml of 20 thionyl chloride is added dropwise to the reaction vessel, keeping the temperature below 5 ° C. When the addition operation is complete, the mixture is agitated for 10 minutes, then 200 ml of water is added and the 25 aqueous layer is subjected to extraction with several portions of ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and the solvent is removed to obtain , 2 hZO crude 6- | 5-methyl-17- / 3-hydroxy-5,10-ecstren-5,10-3-one-3,3-ethylenedioxy-17-acetate.
NMR spectrogram (CDCl1), S: 0.8l (3N, s), 1.05 (3N, d), 2.03 (3N, 35 s); 3.98 (, s.) -, it, 66 (1H, dd.). This crude product is dissolved in 130 ml of diethyl ether and the solution is treated with ml of an aqueous solution of acetic acid and stirred for 2 hours and at room temperature (20 ° C). The reaction mixture is then diluted with 1.3 liters of water and subjected to extraction with ethyl acetate several times. The organic phase is dried, the solvent is removed under vacuum, and the acetic acid is distilled off as an azeotropic mixture with cyclohexane. The crude product is purified on silica gel using a mixture of diethyl ether and n-hexane in a 1: 1 ratio as eluent, whereby 7.85 g of pure oil-like 6-A-methyl-17-beta-oxy-5,10-extra is obtained -3 he-1 7 acetate.
NMR spectrogram (CBC),: 0.8 (3N, s., C, a); 1.0i (3N, d., Cg); 2.04 (3N, s.), 2.63 (1H, d., C),
50
55
ABOUT
5 Q,
0
five
2.98 (1H, d., C), 4.65 (1H, dd., 17
P r I m e r 2. In a solution of 7.85 g of 6-p-methyl-17- / 5-OXY-5,10-extra-3-one-17 acetate in 380 ml of dry pyridine in a dry nitrogen atmosphere with cooling using an external bath, 9.9 g of pyridinium hydrobromide perbromide are added in separate portions. The mixture is stirred for 15 minutes, then heated to 50 ° C and stirred for 1 hour. The reaction mixture is then rapidly cooled by adding 500 ml of water, acidified to pH 2 by adding sulfuric acid and extracted with ethyl acetate. The organic phase is dried, the solvent is removed in vacuum and crude 6-p | -methyl-17- / 5-hydroxy-4,5-9,10-extradien-3-one-17 acetate is chromatographed on silica gel using diethyl ether mixed with n- hexane ratio 6: 4, resulting in 6.12 g pure 6-rm til-17/2-hydroxy- -4,5-9,1O ekstradien-W-one-17-acetate into- as white crystals, m.p. 97 994.
UV spectrogram (ethanol): L (., 304; 19.429; o1. „-215 ° (s 1, chloroform).
NMR spectrogram (cn Cl), S: 0.92 (3N, s); 1.04 (3N, d); 2.02 (3N, s.), 4.64 (1H, dd.); 5.70 (1H, s.).
Froze To a solution of 9.2 g of 6-p-methyl-17- (5-hydroxy-4,5-9,10-extr-diene-3-one-17 acetate in 100 ml of dry dichloromethane and dosing with 6.3 ml of ethylene) glycol, 7.5 ml of ethyl orthoformate and 0.24 g of p-toluenesulfonic acid, after which the mixture is heated and stirred for 1.5 hours. The reaction mixture is neutralized with triethylamine, diluted with 100 ml of ethyl acetate, washed with a saturated solution of potassium carbonate and dried, then the solvent is removed, resulting in 10 g of crude 6- | 5-methyl-17-hydroxy-5,10-9, 11-estradien-3-one-3,3-ethylenedioxy-17 acetate. The crude product is dissolved in 150 ml of methanol and .. treated with 6 g of lithium oxide hydrate and 50 ml of water. The solution is stirred for 1.5 hours at room temperature and then neutralized with 2N. hydrochloric acid, methanol is distilled off, and the residue is subjected to an extraction process
treating with ethyl acetate. The organic phase is dried and evaporated in vacuo to yield 9.7 g of 6-B-methyl-17-ox-5,10-9,11-estradien-3-one-3,3-ethylenedioxy. 6, it4 g of crude 6-p | -methyl-1 7-2-OXY-5,10-9,11-α-estradien-3-one-3,3-ethylenedioxy in 60 ml of dry DMSO / benzene in the ratio of 1: 1, 12.1 g of dicyclohexyl-carbodiimide, 1.57 ml of pyridine and

0.77 ml of trifluoroacetic acid and then the mixture is stirred at 20 ° C for 5 - After completion of the oxidation operation (monitored by mes), the mixture is diluted with 90 ml of benzene, the solid material is filtered under vacuum in the organic phase, and evaporated in vacuo. The resulting crude product is chromatographed on silica gel (mixture of diethyl ether and n-hexane and triethylamine in a ratio of 50: 50: 0.2 as eluent), resulting in a yield of 5.7 g of pure 6- / 3 -methyl-5,10-9,11-estradien-3,3-ethylenedioxy-3,17-Dione, Co (, jjj 267 ° (s 1, chloroform).
NMR spectrogram (CD Cl,), 5: 0.88 (3N, p.); 1.12 (3N, d), 3.98 (H, p.); 5.56 (1H, m.).
Prim pF After a 2.2 M solution of ethyl magnesium bromide in 120 ml of dry THF, methyl acetylene, dried on calcium chloride, is bubbled in for 2 hours and then cooled to 30 ° C using an external thermostatic bath. Then in a dry, argon atmosphere
in this mixture is added dropwise the solution to it 1.20 g of monovalent chloride
yard 8.6 g of 6- | 5-methyl-5,10-9,11-estradien. -3,3-ethylenedioxy-3,1 7-dione in 35 ml of dry THF. The reaction mixture is stirred for 1 h, and then
copper. The mixture is stirred for 20 minutes, after which it is cooled with an external bath to -30 ° C and a solution of 15 g is added dropwise to it
cooled by addition in 500 ml of a mixture of 6-p-methyl-5,10-cJC-epoxy-17- / 3-oxybd with water and ammonium chloride and subjected several times to chromatographic treatment with diethyl ether. The organic phase is washed with water, dried and the solvent is removed. The crude residue with hexane is purified on alumina using a mixture of ethyl acetate and hexane in a ratio of 10:90 as eluent, resulting in a yield of 8.7 g of pure -methyl-17-oxy-1 J-oL- (1-propionyl) - -3.3 ethylenedioxy-5, -1 0-9,11 -estradi-.
Coi .. + 1b1 ° (s 1, chloroform).
 (1-propinyl) -3,3-ethylenedioxy-9,11-estren-3-one in 80 ml of THF. The temperature for 1 h, maintaining at -30 ° C, and then the solution was
50 to heat to room temperature. The mixture is cooled by adding in 500 ml of a mixture of ammonium chloride solution with ice and subjected to extraction with ethyl acetate,
55 the organic phase is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is removed. The crude product is purified on a silica gel column using cm.
0
NMR spectrogram (CD Sc),: 0.8 (3N, s); 1.08 (3N, d); 1.83 (3N, s.), 3.98 (kH, s.); 5.55 (.1H, .m-.).
PRI me R 5. A solution of 7.78 g of 6-p-methyl-1 7-oxy-1 7-o (1-propynyl) -3,3-ethylenedioxy-5,10-9,11 -estradien-3-it in 100 ml of dichloromethane is cooled to a temperature of from -5 to and treated by adding 4.78 g of m-chloro benzenebenzoic acid in separate portions, followed by stirring for 5 minutes. After stirring, 4.62 g of potassium carbonate was added and the slurry was allowed to warm to room temperature over 30 minutes. The solid material is filtered, and the organic phase is diluted with ethyl acetate and washed with sodium bicarbonate in water, and then dried and the solvent is removed. The crude product is chromatographed on silica gel using a mixture of n-hexane and
5 with ethyl acetate and triethylamine in a ratio of 70: 30: 0.2 as eluent, resulting in 3.85 g of 6- / 3-methyl-5,1 0-o-epoxide-1 7- -oxy--1 ( 1-propynyl) -3,3-ethylenedioc Si-9,11-estren-W-one.
oij.p -1,1 (with 1, chloroform). NMR spectrogram (CD Cl), $: 0.83 (3N, s.), 1.14 (3N, e); 1.85 (3N, s); 3.93 (4H, m.); 6.04 (1H, m.).
Example A 1 M solution of p-dimethylaminophenyl magnesium bromide in 240 ml of THF is cooled to -30 ° C under a dry nitrogen atmosphere, after which
five
copper. The mixture is stirred for 20 minutes, after which it is cooled with an external bath to -30 ° C and a solution of 15 g is added dropwise to it.
 6-p-methyl-5,10-cJC-epoxy-17- / 3-oxy-17 o (1-propinyl) -3,3-ethylenedioxy-9,11-estren-3-one in 80 ml of THF . The temperature is maintained at -30 ° C for 1 hour and then the solution is allowed to warm to room temperature. The mixture is cooled by adding a solution of ammonium chloride with ice in 500 ml of a mixture and subjected to extraction with ethyl acetate,
55 the organic phase is washed with a saturated aqueous solution of sodium chloride, dried and the solvent is removed. The crude product is purified on a silica gel column using mixture 11508.
n-hexane with ethyl acetate and triethylamine in a ratio of, 2 as elgoenta, resulting in 14.1 g of 6-p-methyl-5-o6-17- / 3-dioxy-1 (1-propynyl) -11 (4-di-methylamino, phenyl) -3.3 ethylenedioxy-9,. 10-extra-3 he.
 -13 ° (with 1, chloroform).
NMR spectrogram (CDCl-.,), 8: 0.4i (3R, s) 1.05 (3N, d); 1.96 (3N, p.), 2.90 (6n, p.); i, oo (N, m.);
4.16 (1H, m.); 6.70 (2H, d), 7.10 (2H, d).
Example 7. In a solution of 11.3. g b-p-methyl-5-oi, 17- / 3-DI-OXI-17-oi- - (1-propynyl) -p-p- (4-dimethylaminophenyl) -3, 3-ethylenedioxy-9 , 10-estren-in ml of methanol was added to And ml of concentrated hydrochloric acid, and the solution was stirred at 25 ° C for 30 minutes. After that, the decalization is completed into the reaction mixture, diluted with 1 ppm of 1000 ml of diethyl ether and neutralized with 350 ml of 1N. an aqueous solution of sodium hydroxide. The organic phase is separated and the aqueous layer is extracted with diethyl ether. The combined organic extracts are washed with an aqueous solution of sodium chloride, dried and the diethyl ether is removed. The residue is purified on a silica gel column using a mixture of n-hexane and ethyl acetate at a ratio of 50:50 as eluent, resulting in 9.2 g of pure b-β-methyl-17- / b-hydroxy-17-o (. - (1-propynyl) - (4-dimethylaminophenyl) - ,, 10-est-radien-3-one ..
MV, 5 ° (with 1, chloroform).
UV spectrogram (ethanol): Dmo1Xc 262, - 17.76ifi mo, 306; 19, +03.
NMR spectrogram (SB C1a): .0.55 (3N, s); 1.28 (3N, d) -, 1.87 (3N, s.); - 2.88 (6H, s.); , 36 (H, m.); 5.80 (1H, s.}, 6.68 (2H, d.), 7,. (2H, d.).
Example8. 6-Methyl-17p-ok-: -17o (, - (1-propynyl) -11 |) - 4-dimethylaminophenyl), 5-9,10-estradien-3-one mg, 1 mmol) are dissolved in simple diethyl ether (10 ml) and the stirred solution is treated with 3.5 and a solution of hydrochloric acid in ethanol (0.31 ml, 1.1 mmol).
0 5 o
five
five
0
eight
After a few minutes, the salt formed is collected by filtration and washed with diethyl ether.
The crude product is recrystallized from ethanol to obtain 310 mg of pure 6 / L-methyl-1 7p-hydroxy-1 7oi-1-propynyl-11 hydrochloride) - 4.5-9,10-estrone. Dien-3-she.
Calculated,%: C, 75.98; H, 8.08; N 2-, 92; C1 7.0.
СзоИ "(t79,5)
Found,%: C 7.9b; H 8.11; N 2.91; C1 7.86.
Biological testing.
The antiglucocorticoid activity of the compounds obtained was evaluated in comparison with the known glucocorticoid antagonist, Cortexolone (11-deoxycarthisol X).
Anti-glucocorticoid activity has been tested on glycogen accumulation tests in rat liver, according to S.P. Cuthrie.
Male rats of the breed. Spray Doules (weighing 175-200 g) before being treated were put to fasting for hours. Antagonists suspended in methylcellulose 0.5 were prescribed for oral administration at various dosages and after 15 minutes intraperitoneally administered constant dose (0.05 mg / kg) of decactanosis agonist (glucocorticoid effect inducer).
One group of animals was treated with dexamethasone, while the other group was diluted with diluents.
The animals were sacrificed by clipping. . heads 1 hour after the antagonist, the liver is quickly removed and weighed. The glycogen content in the liver is determined by B according to known data.
The results obtained are shown in the table. .
Effect of FCE 23560 (6- / -methyl-17th-hydroxy-17-oi-1-propinyl) -11 | 3- (methylaminophenyl) -4,5-9,10-estradien-3-one) and cortexolone on the accumulation of glycogen in the liver caused by dexamethasone (0.05 mg / kg when administered intraperitoneally) in post-treated male rats. The antagonist is assigned 15 minutes before the agonist and the animals are killed after 7 hours.
The table shows that the compounds according to the invention, for example, 6- -methyl
where R - C - C.-alkyl;
R, the group -A-Z, where A is phenyl,
group-ng where each r
b and R C - C. j-alkyl;
hydroxyl group; R -. - C-alkynyl, or their pharmaceutically or veterinary acceptable salts, characterized in that the compound of general formula II
R
91508963
-17- | 3 oxy-17-oi- (1-propynyl) -11- / 3- - (- dimethylaminophenyl) -4,5-9,10-est-radien-3-one, indicated by the internal code FCE 235bO, antiglucocorticoids are more effective than cortexolone.
Indeed, FCE 23560 significantly reduces the accumulation of glycogen in the liver caused by dexamethasone, starting with a dosage of 5 mg / kg, Cortexolon at the same dosage was ineffective and only at a dosage of 40 mg / kg leads to a significant decrease in glycogen (as a result 5 at least. 8 times less effective compared to FCE 23560).
In addition, the toxicity of compounds, such as FCE 23560, is insignificant and they can be safely used in therapy: they do fall into the category of low-toxic compounds.
.,. where R., R. ,, R, and R, have the indicated

权利要求:
Claims (1)
[1]
Claims 25 values of j
.,.,., R and R taken together to obtain 11-substituted protected
Steroids of General Formula Ip Cyclics.
whom ketal oxr- group
subjected to dehydration with simultaneous deketalization and, if necessary, the obtained compound I is transformed
g
R — C — C — alkyl;
R, the group -A-Z, where A is phenyl,
group-ng where each r
b and R C - C. j-alkyl;
hydroxyl group; R - .- C-alkynyl, their pharmaceutically or veterinally acceptable salts, characterized in that the compound of common ula II

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引用文献:

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CH488682A|1965-07-30|1970-04-15|Ciba Geigy|Process for the preparation of 4,9,11-trienes of the 19-nor-androstane series|

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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|

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AU580843B2|1985-02-07|1989-02-02|Schering Aktiengesellschaft|11``-phenyl-gonanes, their manufacture and pharmaceutical preparations containing them|AT69820T|1987-04-24|1991-12-15|Akzo Nv|11-ARYLESTRANDERIVATIVES AND 11-ARYLPREGNANDERIVATIVES.|

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FR2665901B2|1989-02-24|1994-07-29|Roussel Uclaf|NEW 19-NOR STEROUIDES HAVING IN THE 11BETA POSITION A CARBON CHAIN COMPRISING AN AMIDE FUNCTION, THEIR PREPARATION, THEIR APPLICATION AS MEDICAMENTS.|

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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|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB858513723A|GB8513723D0|1985-05-31|1985-05-31|11-beta substituted steroids|

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