Method of producing substituted androsta-1,4-diene-3,17-dions

专利摘要:
The invention relates to 6-alkylidenandrosta-1,4-diene-3,17-dione derivatives, having the following general formula <IMAGE> wherein each of R and R2, independently, is hydrogen or C1-C6 alkyl and R1 is hydrogen, halogen or C1-C6 alkyl, which are useful in therapy, in particular in the treatment of hormone-dependent cancers.
公开号:SU1501923A3
申请号:SU874203488
申请日:1987-10-15
公开日:1989-08-15
发明作者:Буззетти Франко；Барбугьян Натале；Ломбарди Паоло；Ди Салле Энрико
申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new steroid derivatives, namely, substituted androsta-1,4-diene-3, 17-dione, of the general formula
R, SI,
where R is halogen,
which, in addition to the strong inhibitory effect on aromatase in laboratory conditions, also have a high efficacy in vivo compared with the known structural analogues.
The purpose of the invention is to obtain new steroid derivatives of the Androstan series, which have pharmacological advantages over the known compounds of a similar structure.
Example 1. a). A solution of 4,5-β-epoxy-6-methylene-androst-1-ene-3,17-β-dione (1.0 g) in glacial acetic acid (10 mp) is treated with gas
 cm
3130
different in 1 M hydrogen chloride for 30 min at. The precipitate is separated by filtration, washed with diethyl ether, dried and chromatographed on silica gel using hexane-ethyl acetate to give 0.8 g of pure A-chloro-6-methylenandrost--1,4-diene. H, 1 7 - Dione, so pl 148-150 g
 Found,%: C 72.40; H 6.91 C1 10.53.
C, H ,,
Calculated,%: C, 72.61; H 7.01, C1 10.72.
NMR S, parts per million; 0.84 (ZN, singlet), 1.24 (ZN, singlet) I 5.13 (1H, singlet); 5.43 (1H, singlet); 6.37 (1H, doublet); 7.08 (1H, doublet).
MS (M / Z): 330.
c) Following the procedure described and starting from the corresponding 4,5-epoxy derivative and using the corresponding hydrohalic acid, 4-bromo-6-methylene androsta-1,4-diene-3, 17-dione compounds were obtained.
Found,%: C 63.90; H 6.03; Br 21.15.
.
Calculated Z: C 64.00; H 6.18; Br 21.29.
Example 2. A solution of 4,5-epoxy-6-methylenavdrost-1-ene-3,17-dione (1.0 g) in diethyl ether (100 mp) is treated with boron etherate trifluoride (1.4 mp) in for 3 h at 0 ° C. Then the solution is washed with a 5% sodium carbonate solution, with water, dried over sodium sulfate and evaporated under vacuum. The residue was dissolved in pyridine (20 kp) and 0.4 ml of thionyl chloride was added at O. After 5 minutes, water is added and the product is isolated with ether. The ether extracts are washed with 2N hydrochloric acid, with water, dried over sodium sulfate and evaporated. The resulting crude product is subjected to chromatography on silica gel using a mixture of hexane-ethyl acetate as eluent, resulting in 0.6 g of pure 4-fluoro-6-methylenandand - 1,4-diene-3, 17-dione.
Found,%: C 76.30; H 7.35;
F 5.91;
five
0
50
0
five
Lined, Z: C 76.40 / H 7.37; F 6.04.
And p-mep 3. 6-Methylenandrost-4-en-3, 17-dione (5 g) is dissolved in 200 ml of methanol and cooled to 0 ° C. Ice cold is then added.
36% HjO (17 ml) and 2% NaOH (9 np). The mixture was stirred for 1 h, then kept for 20 h and poured into 1400 ml of ice water with vigorous stirring, the product was separated by filtration, washed with water and dried, yielding 4.2 g (80%) of 4.5- epoxy-6-methylenendrost-3, 17-dione / oi M-epoxy mixture D;
NMR, ppm: 0.90 (EG, singlet); 0.97 (3N, singlet), 3.52 (1H, singlet); 4.92 (1H, pshroky), 5.06 (1H, wide).
4,5-Epoxy-6-methylenandrost-3,17-Dion (3 g) and dichlorodicyanobenzoquinone (1.7 g) are dissolved in 60 ml of anhydrous dioxane and heated to reflux for 15 hours. The cooled solution is filtered through alumina and the solvent is evaporated under vacuum. The residue is taken up in ethyl acetate, the organic layer is washed with water, dried and the solvent is removed under vacuum. The crude product is chromatographed on silica gel using a mixture of hexaacetate 10-40% in order to obtain 1.5 g of pure 4,5-epoxy-6-methylenandrost-1-ene-3,17-dione.
NMR 8, ppm: 0.93 (GZ, singlet); 1.13 (SA, singlet); 3.71 (1H, doublet); 5.03 (2H, multiplet); 5.86 (1H, doublet); 6.78 (1H,
doublet).
)
Aromatase inhibition in vivo - in rats (in vivo).
Adult female rats were twice treated subcutaneously with a dose of 100 m. gonadotropic hormone serum of pregnant horses (GSL) with an interval of 4 days. in order to increase the activity of aromatase of the ovaries in accordance with the procedure described in the prototype. After 3 days after the second treatment with the help of GSBL, groups of 6 animals each were given a stomatological solvent (0.5% metocell) or an inhibitor at a concentration of 30 mg / kg. The animals were put to sleep, after 24 h the microsomes were removed from the ovaries and their activity
15
aromatases were determined using a technique similar to that described in a.
Incubation was carried out for 30 minutes in 1 ml of incubation volume containing 0 mg of microsomal proteins, 100 nM 4- (3N) androstenedione and 100 UM NADRH. Inhibition in percent of controlled aromatase activity was calculated based on the data obtained.
The results of inhibition of aromatase of the human placenta in the laboratory and of aromatase of rat ovary in a living organism are shown in the table.
The table shows that the new compound 4-chloro-6-methylvnandrosta-1,4-dien-3,17-dione (FCE 24919) is a very strong aromatase inhibitor, both when tested in laboratory conditions and when tested on living organism.
In oral testing in vivo, the new compound was very effective, which was a consequence of its unique persistence relative to epic metabolism, while compound 4-OH-A was ineffective.
The main disadvantage of the therapeutic use of compound 4-OH-A as an antitumor agent in the treatment of women is the need for its parenteral use, since this compound is very intensively degraded after dental use.
five
0
In view of the high therapeutic index, the proposed compounds can be safely used for medical purposes. For example, the approximate acute toxicity () of these compounds when applied to MI.I-sham, determined by a single application of increasing doses
| And measured on the 7th day after application, was negligible
small. For example, the value of LD $ (for the described compound (FCE 24919) is higher than 800 mg / kg by oral administration in humans.

权利要求:
Claims (1)
[1]
Invention Formula
one . The method of obtaining substituted androsta-1,4-diene-3, 17-diones of the general formula
tlljO
"1, G5
25
And, SI
2
where R, is a halogen, characterized by the unity of the formula
that cor
ABOUT
35
they are subjected to interaction with a hydrohalogenating agent in the medium of an organic solvent at 0– () C.

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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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GB858517360A|GB8517360D0|1985-07-09|1985-07-09|Substituted androsta-1,4-diene-3,17-diones|

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