前苏联专利SU1574178A3 Lubricating composition for hot working of metals by pressure

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优先权

专利摘要:
The invention discloses 4-substituted androstendione derivatives of the following formula (I) <IMAGE> (I) wherein R is amino or substituted amino or azido, one of R1 and R2 is hydrogen and the other is hydrogen, alkyl, alkenyl or alkynyl, and (x) and (y) are each, independently, a single bond or a double bond. The compounds of formula (I) are useful aromatase inhibitors.
公开号:SU1574178A3
申请号:SU864021024
申请日:1986-02-14
公开日:1990-06-23
发明作者:Фаустини Франко；Дъалессио Роберто；Вилла Виттория；Ди Салле Энрико；Ломбарди Паоло
申请人:Фармиталиа Карло Эрба С.Р.Л.(Фирма)；
IPC主号:

专利说明:

H)
HrUNH,
The invention relates to a process for the preparation of new derivatives of 4-substituted androstenedione, of the formula
ABOUT
where - - - and (X) and (Y) independently mean a single or double bond, or pharmaceutically acceptable salts thereof with valuable pharmacological properties.
The purpose of the invention is to obtain new derivatives of androstenedione, which have advantages in comparison with the known, for example, A-tesgololactone.
3
with
Example 1. 4-Azidoandrost-4-en-3,1 7-dione (Formula (II), where (X) 1 (Y) is an ordinary bond).
To the stirred solution, consisting of J, 0 g of 4-methanesulfocycloxiandrost-4-en-3, 17-dione in 5 ml of dimethylformamide, was added 220 mg of powdered sodium azide dissolved in 3 ml of water. The mixture is heated at 60 ° C for 1 h, cooled, poured into 250 ml of cold water, and extracted with ethyl acetate (ml). The stirred extracts are washed with a saturated aqueous solution of NaCl, dried over a vacuum flask to entrust the residue, which is purified by flash chromatography on a neutral A120 $. Elution with a mixture of n-hexane: Diethyl ether gave 0.52 g of compound, m.p. 142-14J3 S.
UV (95% EtOH), VMaKC 284 nm, 8 "9.844.
IR (Nujol): Hmaks - 2100, 1730, 4670, 1590 cm-1.
NMR (CDC13 + DM CO) 8: 0.91 (3N s) s 1.21 (3N, s), 3.10 (1H, s).
Example 2. 4-Azidoandrost-4-ene-3.17 dione (formula (II), where (X) (Y) is an ordinary bond).
To a solution of 1.5 | 4,5-epoxy-androst-3.17 dione in 26 m of dimethyl sulfoxide and 0.35 ml of concentrated sulfuric acid, 5.2 g of powdered sodium azide are added to the solution. The mixture is heated at 40 ° C for 40 minutes, cooled, poured into 250 ml of ice water and extracted with ethyl acetate (ml). Mixed extras are processed. 115 g of compound are obtained, m.p. 142-143 ° C.
Example 3. 4-Azido-Androst-4-en-3,17-dione (formula (II), where (X) (Y) is an ordinary bond).
0.250 g of sodium azide is added to a stirred solution of 1.1 bromoandrost-4-en-3, 17-dione in 57.4 mp of dimethylformamide. The resulting mixture is heated at 30-35 ° C for 72 hours, cooled and worked up. 0.467 g of compound is obtained, m.p. (MeOH) 143-144 ° С (decomp.).
W - + 237 ° (С 1, СНС1,). UV (95% W): MO, Cs 284 nm, .Ј 10.495.1
Example 4. 4-Azidoandrost--1,4,6-trien-3, 17-dione (formula (II

,
0
five
where R is N ,, R 1 R H, (X) (X) is a double bond).
To a stirred solution of 0.5 g of 6-bromo-7-acetoxyandrost-1, 4-dien-3,17-dione in 30 ml of dimethylformamide and 1.2 ml of water was added 0.11 g of sodium azide. The reaction mixture is heated at 100 ° C for 45 minutes, cooled, poured onto 500 ml of ice-water and extracted with ethyl acetate. The stirred extracts are washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo to give a residue, which is purified by capillary chromatography on silica gel. Elution with a mixture of n-hexane: ethyl acetate in a ratio of 30-70 gives 0.28 g of compound, m.p. J23-125 ° C (decomp.). EOU + 155 ° (С 0.5, СНС1Э).
IR (Nujol): MqKC 2120, 1740, 1650, 1630, 1605, 1575 cm-1.
NMR (CBC1) 5: 0.92 (3H, s), 1.18 (3H, s); 6.22 (lH, dd) i 6.26 (lH, d) J 6.66 (lH, dd); 7.29 (lH, d).
In the same way, the compound is obtained from 6I, 7p6-dibromo-androst-1,4-diene-3, 17-dione.
. Example 5. 4 Azidoandrost-1,4-diene-3,17-dione (formula (II), where R N4, R, R H, (X) is a double bond, (Y) is a single bond).
The compound is obtained from 4-methanesulfonyl-oxyandrost-1,4-diene-3, 17-β-dione and sodium azide according to the procedure of Example 1.
Alternatively, the compound is prepared from 4,5-epoxy-androst-1-ene-3,17-dione and sodium azide, following Example 4, mp. 144-146 ° C (decomp.).
UV (95% EtIH): Max 239 nm, Ј 15.945, b.a. and 303 nm, b. 4,490.
IR (Nujol): # MaKc 2110, 1730, 1650, 1630, 1595.
NMR (CDC13X: 0.93 (3H, s); 1.25 (3H, s); 3S15 (1H, m); 6.27 (1H, d); 7.08 (1H, d).
Example 6. 4-Aminoandrost-4-ene-3,17-dione (formula (I), where (X) (Y) is an ordinary bond).
To a suspension consisting of 3.83 g of 4-azido-androst-4-ene-3,17-dione in 600 ml of freshly distilled anhydrous methanol, 9 ml of propane-1,3-dithiol and 12 ml of triethyl amine are added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 7 hours, poured into water, the pH was raised to 2 by adding 1N HCl aqueous solution, washed with diethyl ether. The aqueous phase is neutralized with 2N aqueous NaOH solution, the resulting precipitate is filtered off, dried and crystallized from ethyl acetate. 2.60 g of compound are obtained, mp 166-188 ° C.
tcGj +1670 (С 1, СНСЬ).
UV (95% EtOH): ,, 294 nm, e 7.354. ,
NMR (CDC1,),: 0.93 (3H, s) J 1.20 (2H, s); 290 (2H, m).
Using the procedure of Example 6, the following compounds were obtained:
4-aminoandrost 4,6-diene-3, 1 7-dione- (1, R NHi} R ,, (X) is a single bond, (Y) is a double bond), in the form of a yellow solid m.p. 148-150 ° C (decomp.).
MW + 199, G (C 1, CHC13).
UV (95% EtOH): max 347 nm, 6 12.395.
NMR (CDC1,),: 0.87 (3H, s); 1.00 (3H, s); 4.46 (2H, ds), 6.01 (IH.dd); 6.40 (IH.dd);
4-aminandrost-1,4-dien 3, 1 7-dione with so pl. 162-9 ° C.
IR (KBG) 3460.3370, 1735, 1665, 1620, 1580 cm-1.
UV (95% 3tOH): 1 max 226, 15.509, 332, 3.293.
NMR (CDC1,), 8: 0.94 (3N, s); 1.23 (3N, s); 3.65 (2H, s) 6.32 (lH, d) i, 7.10 (IH.d);
4-aminoandrost-1,4,6-trien-3, 17-tion with mp 206-8 ° C.
F (KBr): 0MqitC 3460, 3380, 1730, 1645, 1620, 1560.
NMR (CDClI), S: 1.00 (ZN, s), 1.19 (ZN.c); 4.00 (3N, s) 5.93 (1H, dd); 6.33 (1H, d); 6.52 (1H, dd); 7.10 (1H,
, D)
Example 7. 4-Aminoandrost-4-en-3,17-dione (formula (I), where (X) (Y) is a simple bond).
To a stirred solution of 0.45 g of 4-aminoandrost-4,6-diene-3, 17-pion in 20 ml of diethyl ether and 40 ml of liquid ammonia, 0.28 g of lithium metal is added in small portions. The resulting blue reaction mixture is stirred for an additional 30 minutes, quenched with absolute ethanol until the blue color disappears and is allowed to reach room temperature. The resultant solution is dissolved in water, extracted with ethyl ether and purified. 0.280 g of compound is obtained having a mp of 185-187 ° C.
Example 8. 4-Aminoandrost--1,4,6-trien-3, 17-dione (formula (I), where (X) (Y) is a double bond).
A solution of 0.400 g of 4-aminoandrost-4,6-diene-3, 17-dione in 25 ml of dehydrated benzene is treated with 0.400 g1
2, 3-dichloro-5,6-dicyano-1,4-benzoxy- | Noina and heated at a temperature of reflux. The reaction mixture give
5 to stand at 80 ° C for 20 hours, then cooled to room temperature, filtered and the solid was washed with ethyl acetate.
The selected organic phases are washed with a 5% solution of NaHCOj, a saturated aqueous solution of NaCl and then the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel.
five
using ethyl acetate: methanol (95: 5) to obtain 0.180 g of pure compound.
NMR (CDC1,), Ј: 1.00 (3N, C); 1.19 (ЗН, С); 4.00 (3N, C); 5.93 (1H, dd); 0 6.33 (1H, d); 7.10 (1H, d).
IR (KBr): V, v, ouc 3460, 3380, 1730, 1645, 1620, 1560 cm-1.
Example 9. 4-Aminoandrost-4,6-dien-3, 17-dione hydrochloride (Formula 5 (1), where (X) is a simple bond, (Y) is a double bond, like hydrochloride) .
A solution of 0.5 g of 4-aminoandrost-4,6-dien-3,17-dione in 20 ml of ethanol is watered with 16.7 ml of 1N. an aqueous solution of HC1. Then the yellow solution is treated with 0.02 g of carbon, filtered and the alcohol is distilled off under reduced pressure. The resulting aqueous solution 5 is lyophilized to obtain 0.54 g of a dry compound as a slightly yellow powder.
By analogous procedure, starting with other 4-amine compounds (examples 0, Fish 7 and 8), the corresponding hydrochlorides are obtained.
Example 10. Tablets, each weighing 0.150 g, containing 25 mg of active substances, are manufactured with the following composition (for 10,000 tablets), g:
4-Aminoandrost-4,6-diene-3, 17-dione250
Lactose 800
Corn starch 415
five
Talc powder 30 Magnesium stearate 5
4-aminoandrost-4,6-di-3,17-dione, lactose and half of the cornstarch are mixed. The mixture is then passed through a 0.5 mm mesh sieve. Corn starch (10 g) is suspended in warm water (90 g), the resulting paste is used to grind powder. The granulate is packed with a tin, 1 is passed through a 1.4 mm mesh sieve, then the remaining amount of starch, talc and magnesium stearate is added, mixed thoroughly and turned into tablets.
EXAMPLE 11 Each capsule is prepared, each weighing 0.200 grams, containing 20 mg of active vesicle. Ingredients - 500 capsules, g: 4-Acetylamino-androst-4,6-di-3,17-dione10
Lactose80
Corn starch 5 Magnesium stearate 5 These release forms are placed in two-part hard gelatin capsules, the dose in each capsule is 0.200 g.
The compounds of the invention are inhibitors of the biotransformation of endogenous androgens, i.e. steroid aromatase inhibitors.
Aromatase (estrogen syntheta-ea) is an enzyme that is responsible for the last step in estrogen biosynthesis, androgen conversion to estrogens, for example, androstenedione and testosierone to estrone and estradiol, respectively. Aromatase is a microsomatic complex of the Enzyme P450, which acts on the androgenic substrate. Since the products are aromatase, i.e. estrogens, which are responsible for the growth of hormone-induced tumors, then the compounds are the aromatase inhibitors of the invention can be used to treat these tumors, Uchi50
In addition, the aforementioned compound of the invention can be used as an alternative to the removal of endocrine glands, for example, oophorectomy, hypothysectomy or andrenaelectomy in the treatment of already developed tumors that are inhaled by hormones, for example, breast, pancreas, endometrial cancer and ovarian cancer, in particular glands. Inhibitor15741788
The aromatase agents of Formula (I) can also be used to control reproduction. In vivo reduction of estrogen levels leads to suppression of gonadal activity and insufficient development of the uterus, aromatase inhibitors can simultaneously be implantation inhibitors. Other area
(The use of the compounds of the invention is to treat prostatic hypertrophy or hyperplasia, related to excessive estrogen production and to a shift in estrogen / anti-Drogen ratio higher rates. Compounds of the invention that cause a decrease in the formation of extradiol can be used to treat disorders fertility in men (Drugs
2j 2S.263, 1984). It is known that estradiol can regulate spermatogenesis and can also indirectly inhibit spermatogenesis by preventing Leydig cells from producing testosterone in
25 large quantities, responding to the action of LH. A correspondingly reduced estradiol production achieved by the compounds of the invention results in both an increase in the amount of
30 spermatozoa and fertility increase in patients suffering from infertility due to oligozoospermia. The degree of inhibition of aromatase by the compounds of the invention is determined, for example,
as in vitro (aromatase of human placenta), following the following test method,
When suppressing aromatase Enzyme-. The nasal system was isolated from a microsomotic Thrace of human placenta tissue in accordance with the standard method. Used the article Thompson and Siiter (Thompson E.A. and Siiter P.K., I. Biol. Chem., 249, 5364,
45 1974), where the degree of aromatization is determined, as established upon release from, 2fb-3H) andro-wall-3,17-dione. All cases of incubation in a stirred water bath at 37 ° C in air atmosphere in a buffer solution of 10 N potassium phosphate at pH 7.5, in which 100 mM KC1 EDA and 1 mM dithiothreitol. These experiments were carried out in an incubation volume of 1 ml containing 50 nM 4- (H) androstenedione, inhibitors in various concentrations, 100 mM NADO and 0.05 mg of microsomatic proteins. After incubation for 15 min, the reaction
stop by addition of chloroform (5 ml). After centrifugation at 1500 vol. within 5 min, aliquots (0.5 ml) are removed from the aqueous phase in order to determine the amount of P20 formed. The concentration of each compound required to reduce the level of control aromatase by 50% (IC 50) is determined according to a percent inhibition schedule from 1 to the inhibitor concentration. Thus, in particular, four compounds of the invention were tested under the code numbers FGE 24210, FGE 24566, FGE 24661 and FGF 24928 according to the procedure described above with the known aromatase inhibitor D - testololactone (Cancer Research Suppe, 42, 3327S - 3333S, 1982).
The results of in vitro human placenta inhibition of aromatase are shown in the table.
IC50 (relative in vitro activity)} nM
& -Testololactone 4-Aminoandrost-4,6-di-3,17-dione (FGE 24210) 4-Aminoandrost-4-E-3,17-dione (FGE 24566) 4-Amino androst-1,4-que - 3.17-dione (FGE 24661) 4-Aminoandrost-1,4,6-trien-3,17-dione (FGE 24928)

The data in the table indicate that the compounds of the invention are very potent aromatase inhibitors in vitro. Ho- (new compounds, as established, are approximately 55 times more potent than P1-testolol.
Considering the high therapeutic index of these compounds, they are safe enough for use in medicine. For example, the acute toxicity (LD5b) of the compounds of the invention for a mouse, determined by one administration of increasing doses and measured on the seventh day after peroral - | His administration, as it turns out, is very insignificant
At the tested doses, the compounds of the invention show no signs of toxicity and can be classified as low toxic.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 4-substituted androstenedione total
formulas
about
where the symbol - - - indicates that (X) and (Y) independently means a single bond or a double bond, or their pharmaceutically acceptable salts, characterized in that the compound of the formula
ABOUT
(Ii)
- uh
where (X) and TY have the indicated meanings,
subjected to reduction to give a compound of formula I and, if necessary, a compound of formula (I), where (X) is an ordinary bond, a (Y) is a double bond, is subjected to reduction to obtain the corresponding compound of Formula (I), where a) and (Y) is both an ordinary bond, and, if necessary, a compound of formula (I), where (X) is an ordinary bond, is oxidized to obtain the corresponding compound of Formula (I), where (X) is a double bond if necessary, the compounds of formula (I) obtained are salified.

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同族专利:

公开号 | 公开日

CZ413691A3|1994-03-16|

GB8503940D0|1985-03-20|

AT396239B|1993-07-26|

ES557215A0|1987-10-01|

GB2171100A|1986-08-20|

CH669199A5|1989-02-28|

ES552052A0|1987-06-01|

SE468515B|1993-02-01|

IE58864B1|1993-11-17|

ES8708235A1|1987-10-01|

DK71486D0|1986-02-14|

SE8600668D0|1986-02-14|

HK94090A|1990-11-23|

NL8600383A|1986-09-01|

JPS61189295A|1986-08-22|

FR2577556B1|1988-01-08|

MY102038A|1992-02-29|

US4757061A|1988-07-12|

HU194909B|1988-03-28|

FR2577556A1|1986-08-22|

PT82030A|1986-03-01|

GB2171100B|1988-11-30|

PT82030B|1988-07-01|

IE860413L|1986-08-15|

DK167221B1|1993-09-20|

DK71486A|1986-08-16|

ES8706165A1|1987-06-01|

HUT40454A|1986-12-28|

FI860672A|1986-08-16|

AU577667B2|1988-09-29|

GB8603265D0|1986-03-19|

IT8619361D0|1986-02-11|

SE8600668L|1986-08-16|

DE3604179A1|1986-08-21|

FI84272C|1991-11-11|

FI84272B|1991-07-31|

BE904226A|1986-08-14|

ATA38886A|1992-11-15|

AU5343386A|1986-08-21|

NZ215163A|1988-02-29|

SG80890G|1990-11-23|

GR860430B|1986-06-12|

JPH0469638B2|1992-11-06|

ZA861118B|1986-10-29|

IT1190335B|1988-02-16|

FI860672A0|1986-02-13|

CA1319362C|1993-06-22|

KR860006485A|1986-09-11|

KR930005994B1|1993-07-01|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

GB858503940A|GB8503940D0|1985-02-15|1985-02-15|4-substituted androstendione derivatives|

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