Method of producing styroids or pharmaceutically acceptable salts

专利摘要:
6-Substituted androsta-1,4-diene-3,17-dione derivatives of formula (I) …<CHEM>… wherein… R is (1) the group-N3;… (2) a group …<CHEM>… wherein each of r1 and R2 is, independently, hydrogen or unsaturated C1-C22 alkyl;… (3) a group -NHCOR3 wherein R3 is… (a) hydrogen;… (b) C1-C3 alkoxy or carboxy;… (c) C1-C22 alkyl either unsubstituted or substituted by a carboxy group; or… (d) a group …<CHEM>… wherein R1 and R2 are as defined above; or… (4) a group -NHSO2R4 wherein R4 is unsubstituted C1-C4 alkyl, or phenyl either unsubstituted or substituted by C1-C3 alkyl, halogen or nitro;… and the pharmaceutically acceptable salts thereof are aromatase inhibitors and can be used, e.g. in the treatment of hormone-dependent tumors.
公开号:SU1540656A3
申请号:SU864027926
申请日:1986-07-25
公开日:1990-01-30
发明作者:Фаустини Франко；Дъалессио Роберто；Вилла Витториа；Ди Салле Энрико；Ломбарди Паоло
申请人:Фармиталиа Карло Эрба, С.П.А. (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing steroids, namely 6-substituted androsta-1,4-diene-3,17 diones, which are aromatase inhibitors, more specifically, the invention concerns a method for producing steroids.
 and
HZ / IJ
t
where R is the -N3 group or the -NHe group, or their Pharmaceutically acceptable salts, which possess valuable pharmacological properties.
The purpose of the invention is to obtain steroid derivatives, which have pharmacological advantages over known structural analogues of a similar effect.
Salts according to the invention are salts of the compounds of formula (I), in which R is a group -N, as defined above, with pharmaceutically acceptable acids, such as CE
cl
ze

cm
, as inorganic (hydrochloric, sulfuric, or phosphoric), organic (citric, fumaric, maleic, block, ascorbic, amber, tartaric, benzoic, acetic, phenylacetic, cyclohexylsuccine, 3-cyclohexylprolionic, mecene - suljonova, benchosulphonic, p-toluenesulphonic, p-nitrobenzene sulph-} Q s, stirring at this temperature new,
Quaternary ammonium salts and hydroxides of compounds of Formula (ij,
where R - M h, covered by the invention - 15
(3N, S), 4.31 OH, ddd), 6.44 (1HS dd), 6.26 (1H, dd), 7.02 (1H, d).
Example 3. To a solution of tansulphonyloxyandrost-1, 4-diene-3,17-dione (3.0 g) in 150 ml of dimethylformamide was added 0.67 g of sodium azide dissolved in 8.5 ml of water; the mixture is heated to 100 ° C and holding
R,
90 min.
With external cooling, the entire mixture is poured into 600 ml of water and extracted with four portions (J50 ml) of ethyl acetate. The combined extracts are washed with a saturated solution of sodium chloride to remove the residue of dimethylformamide and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo and the crude product is obtained, which is purified by chromatography on AloOj, (neutral activity), using ethyl acetate: n-hexane 40:60 as eluent. 1.95 g of pure boC-azodo-growth-1,4-3,17-dione are obtained; m.p. 167-169 ° C; M „- 92,81 (1, СНС13).
and represent, for example, quaternary alkyl (methyl, ethyl).
The following examples illustrate the invention.
Example 1. A solution of 10 g of andro-1,4-dien-3, 17-dione in 95 ml of carbon tetrachloride is boiled with 6.4 g of N-bromosuccinimide and 0.4 g of benzyl peroxide for 75 minutes . After filtration of the succinimide, the filtrate is cooled in ice until crystallization is complete. The mixture is then filtered and dried, yielding 998 g of crude 6-bromine (3H, S), 4.31 OH, ddd, 6.44 (1HS dd), 6.26 (1H, dd), 7.02 (1H, d).
Example 3. To a solution of tansulphonyloxyandrost-1, 4-diene-3,17-dione (3.0 g) in 150 ml of dimethylformamide was added 0.67 g of sodium azide dissolved in 8.5 ml of water; the mixture is heated to 100 ° C and kept stirring at this temperature
90 min.
With external cooling, the entire mixture is poured into 600 ml of water and extracted with four portions (J50 ml) of ethyl acetate. The combined extracts are washed with a saturated solution of sodium chloride to remove the residue of dimethylformamide and dried over anhydrous sodium sulfate. The solvent is then removed in vacuo and the crude product is obtained, which is purified by chromatography on AloOj, (neutral activity), using ethyl acetate: n-hexane 40:60 as eluent. 1.95 g of pure boC-azodo-growth-1,4-3,17-dione are obtained; m.p. 167-169 ° C; M „- 92,81 (1, СНС13).
Example 4. To mix
androsta-I, 4-diene, 3.17 dione, suitable - 30 Solution 6c-azido-androst-1, 4-dienone for the next stage. The sample for analysis is crystallized from diethyl ether / n-hexane; m.p. 188-190 ° C | (oOif + 116; W.F. (95% Et OH)
I (Chax 250 NM. 35
Example 2. To a solution of 6 b-bromo-androsta-1,4-diene-3, 17-dione (5.0 g) in 250 ml of dimethylformamide is added
3, -7-dione (0.6 g) in tetrahydrofuran (3 ml) triphenylphosphine (0.79 g) is added.
After the evolution of nitrogen is complete, the reaction mixture is diluted with water (1 ml) and boiled for 24 hours. The cooled reaction mixture is poured into 1N. an aqueous solution of hydrochloric acid (50 ml) and washed with methylene chloride
1.15 g powdered sodium azide,
dissolved in 4 ml of water, the mixture on the 0 P of the aqueous layer is adjusted to 10 add-.
The aqueous NaOH solution is extracted and thoroughly extracted with methylene chloride. The organic phase is dried over CaClo. and evaporated in vacuo, in half a yellow foam (0.44 g), which was extracted with diethyl ester (30 ml) and treated with gaseous HC1.
The precipitate formed is filtered to 100 ° C and kept stirring at this temperature for 120 minutes. The whole mixture is then poured into 1 liter of water and extracted with four portions (200 ml) of ethyl acetate. The combined extracts are washed with a saturated aqueous solution of sodium chloride and dried. The solvent is removed in vacuo to give the product, which is purified by chromatography, dried, and separated by an hour (neutral activity), using ethyl acetate / n-hexane 40; 60 as an eluent; 3.4 g of pure 6 ° Azoidrostrost are obtained. , 4-dien-3, 1 7-dione. The analysis sample is crystallized from
m.p. 168-170 S. c. 93.2 ° (c 1, CHCl j); UV (95% Et OH) I max 244; Ј 17.420; NMR (CDC13) 3: 0.98 (A, S), 1.3
methanol;
(SOUTH +
55
ty between methylene chloride and 2 n. NaOH aqueous solution.
The organic layer was separated, dried over CaClij, and evaporated in vacuo to give 6-amino androst-1,4-diene-3, 17-dione (0.40 g); m.p. 186-19GS; NMR (CDCJj) S: 0.93 (3N, S), 1S25 (3N, S), 3.71 (1H, ddd), 6.27 OH, dd, 6.39 (IH, dd), 7 , 01 (IH.d)
The solution 6c -azido-1, 4-di-
3, -7-dione (0.6 g) in tetrahydrofuran (3 ml) triphenylphosphine (0.79 g) is added.
After the evolution of nitrogen is complete, the reaction mixture is diluted with water (1 ml) and boiled for 24 hours. The cooled reaction mixture is poured into 1N. an aqueous solution of hydrochloric acid (50 ml) and washed with methylene chloride.
watered, dried and divided into hours
ty between methylene chloride and 2 n. NaOH aqueous solution.
The organic layer was separated, dried over CaClij, and evaporated in vacuo to give 6-amino androst-1,4-diene-3, 17-dione (0.40 g); m.p. 186-19GS; NMR (CDCJj) S: 0.93 (3N, S), 1S25 (3N, S), 3.71 (1H, ddd), 6.27 OH, dd, 6.39 (IH, dd), 7 , 01 (IH.d).
515
F (KVg) cm 1: 3450, 3380, 3000, 2940, 2860, 1730, 1655, 1615, 1600.
Example 5. A solution of 0.65 g of 6 ° C-aminoandrosta-1,4-diene-3,1 of 7-dione in 30 ml of ethanol is treated with 21.7 ml of 0.1N. aqueous solution - HC1. The yellow solution becomes discolored, then it is filtered and the alcohol is removed under reduced pressure. The resulting aqueous solution was lyophilized with 0.7 g of dry 6 th-amino-androst-1,4-diene-3,17-dione hydrochloride in the form of a light yellow powder.
IR (KBG) 3460, 3380, 1730, 1695.
The compounds of the invention have the ability to inhibit aroma in the mouth.
Aromatase (estrogen synthetase) is an enzyme responsible for the last stage of estrogen biosynthesis. As it is known, the conversion of androgens into estrogens- (for example, androstenedione and testosterone into estrone and estradiol) occurs through the aromatase of the microsomal enzyme P450, which acts on the androgen substrate.
Foods are aromatae, i.e. Estrogens, besides being essential for reproduction, may also be responsible for the growth of hormone-dependent tumors.
In view of the foregoing, the aromatase inhibitors of the invention can be used to affect growing hormone-dependent tumors, especially tumors of the breast, ovary, uterus and pancreas. Due to their ability to inhibit aromatase, compounds can also be used to treat prostate hyperplasia, in which benign prostate gland growth occurs. Moreover, these compounds cause a decrease in the formation of estradiol and therefore may be useful in the treatment of male fertility disorders.
Aromatase inhibition by the compounds of the invention was determined both in vitro (human placental aromatase) and in vivo (ovarian aromatase activity) for rats.
I
These compounds have been found to be particularly potent aromatase inhibitors in vivo,
6566
In vitro aromatae inhibition was determined as follows: the enzyme system was isolated from the microsomal fraction of human placental tissue by a standard procedure. The Thompson and Sisteri method was used (E.A. Thompson and P.C.Sery. T.Biol.Chem 249, 5364, 1974), which
allows to determine the rate of aromatization by measuring the release of 3 HgO from 4 ijb, androsten-3,17-dione.
5 All specimens were kept in a shaking water bath with air in 10 mM potassium phosphate buffer, pH 7.5, which contained 100 mM KC1, 1 mM ethylenediaminetetra acetic acid and 1 mM dithiothretiol. Experiments were performed in 1 ml of an incubation volume containing 50 nM 4-N / androstenediol, various concentrations of inhibitors, 100 μM ni5 cotinamide adenine dinucleotide phosphate, and QJ05 mg microsomal proteins. After 15 min incubation, the reaction was stopped by adding chloroform. After centrifugation at 1500 g in flow ™
After 5 minutes, an aliquot portion (0.5 ml) was removed from the aqueous phase to determine the Uij0 formed; The concentration of each compound required to reduce the effect of aromatase on 50 I (TC, was determined by recording the percent inhibition with the logarithm of the corresponding inhibitor concentration. The relative efficiency of each compound to 40H-A was calculated
l by the equation:
Relative efficiency
 J3H-A
TC so test compound Inhibition of aromatase in vivo
5 was determined in rats according to the following procedure: 100 female rats of gonadotropin serum (PM SG) from pregnant women were administered subcutaneously twice subcutaneously at 4 days in order to increase the ovarian aromatase activity according to the Brody procedure. (AMH Brody et al. Steroids, 38, 693, 1981), three days after
g of a second administration of PM SG to a group of 6 animals each orally gave an indifferent substance (0.5% metocel) or an inhibitor in the dose indicated in the following table. After 24 hours, the animals were killed, microsomes were isolated from the ovary. Their aromatase activity was determined according to a method similar to that described for assessing in vitro activity.
Incubations were carried out for 30 minutes in 1 ml of incubation volume containing 0 mg of microsomal proteins, 100 nM 4- (H) androstenedione in 100 μM nicotinamide adenine dinucleotide phosphate. The percentage of inhibition of the aromatae control activity was calculated.
Even if the in vitro compounds of the invention can only be equivalent or less effective than the known compounds, they are nevertheless more effective in vivo aromatase inhibitors.
The table lists examples of in vivo activity of the compounds of the invention b -azido-androst-1,4-diene-3, 17-dione (FCE code 24403} and 6 # -aminoand-growth-3,4-diene-3, J7-dioia ( FCE code 24968). Compared with the well-known aromatase inhibitors 4-oxyandrost-4-ene-3, 17-dione (4-OH-A), Dr-homo-L 7a-oxaandrost-1, 4-di- 3.17-dione (testolactone) and andros ta-1, 4-diene-3, 7-idion.
Although the compounds FCE 24403 and FCE 24968 are less active in vitro than, for example, 4-OH-A, they are very effective when used in vivo orally at a dose of, for example, JO mg / kg, due to unusual resistance to hepatic metabolism, while 4 OH-A is ineffective even at a dose 30 times higher (100 mg / kg), while they have low toxicity.
The main disadvantage of the therapeutic use of 4-OH-A as an antitumor agent for women is the need for parenteral administration, since the compound binds strongly after oral inhibition of the ovarian aromatase of rats in vivo
application (R.S.Cumbes et al. Lancet II, 1237, 1984),
The use of aromatase inhibitors described above will significantly improve the oral therapy of estrogen-dependent diseases.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing steroids o6nieft formula I
where R is a group -N3, or a group -NHZ, or their pharmaceutically acceptable salts, characterized in that the compound of formula II
25
9
- thirty
where L is a halogen or a C —Ce alkylsulfonyloxy group,
subjected to interacting with the compound of Formula III
M - N5,
where M is an alkali metal cation, thus obtaining a compound of Formula I, where R is a group -N5, and, if necessary, reducing a compound of formula I, where R is a group, thus obtaining a compound of formula I, where R is a group -NHU, and, if necessary, converting a compound of formula I into its pharmaceutically acceptable salt.
p 0.05 j p -c 0.01; N.Z not significantly (compared with the group formed by an indifferent substance)

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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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GB858519398A|GB8519398D0|1985-08-01|1985-08-01|Steroidic aromatase inhibitors|

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