13-ethyl-gona-1,3,5( 10), 8 (9)-tetraene-3,17β-diol diacetate, having anti-implantation and antioxidant activity

FIELD: chemistry.

SUBSTANCE: invention relates to a diacetate of racemic 18-ethyl-gona-1,3,5(10),8(9)-tetraene-3,17β-diol, having anti-implantation and antioxidant activity with low uterotropic action. Presence of antioxidant activity in said steroid is essential since compounds with such action can be agents for preventing oestrogen-dependent breast cancer.

EFFECT: compounds exhibit anti-implantation and antioxidant activity with low uterotropic action, which is an advantage over agents used in practice.

1 cl, 1 ex, 4 tbl

 

The invention relates to medicine and can be used in the synthesis of biologically active analogues of steroidal estrogens, in particular, upon receipt of the diacetate of racemic 18-atilgan-1,3,5(10),8(9)-tetraen-3,17β-diol with antiinflammation and antioxidant activity at low uterotrophic activity that involves its use as a contraceptive pill.

Known patent, in which a method is proposed for the synthesis of 13-Alkylgona-1,3,5(10),9(11)-tetraenes [1], and also reported the existence of estrogen and lipid-lowering activity, which is the closest to the claimed invention and is selected as a prototype. Later this steroid in optically active form used as an intermediate substance for other compounds, but its biological properties are not studied [2].

The technical result of the claimed invention to provide compounds having antiinflammation and antioxidant effect at low uterotrophic activity.

This technical result is achieved by the synthesis of diacetate 13-atilgan-1,3,5(10),8(9)-tetraen-3,17β-diol.

The scheme of synthesis of steroid given in example 1.

Example 1. To a solution of 1 g of the known compound (3-hydroxy-13-atilgan-1,3,5(10),8(9)-tetraen-17-one) [3] in 40 ml of THF was added when paramesh the processes in 10 ml of 1M solution of lithium aluminum hydride in THF, the mixture is boiled for 2 hours Then the reaction mixture is cooled to room temperature, the excess solvent is decomposed with ethyl acetate and poured into 1 l of 3%aqueous hydrochloric acid solution. The reduction products are extracted with three portions of ethyl acetate, 100 ml), the combined extracts washed with water until neutral, dried with anhydrous sodium sulfate. The drying agent is filtered off, the residue is dissolved in 40 ml of pyridine, add 25 ml of acetic anhydride, the reaction mixture is left for a day at room temperature. After conventional treatment [1] the target compound allocate crystallization from methanol. Obtain 1.03 g (78%) steroid TPL 145-146 .5°C (lit. data TPL 141-143°C [1]).

Mass spectrum, m/z (IRel, %): 368 (35, M+), 326 (51), 266 (19), 237 (100), 209 (27), 181 (14), 160 (37), 133 (12), 107 (16).

Range13C NMR, δ, ppm: 9.81; 18.41; 21.00; 21.15; 21.91; at 23.66; 24.44; 27.95; 28.16; 29.92; 43.88; 48.28; 82.56; 118.77; 120.21; 122.55; 125.97; 133.53; 133.76; 136.62; 148.39; 169.67; 171.10.

Found, %: C, 74.99; H, 7.70. C23H28O4. Calculated, %: C at 74.97; H, 7.66.

Mass spectra obtained by the gas chromatography-mass spectrometry instrument Aligent 6850 with mass-selective detector Aligent 5973. Chromatographic analysis was performed on a capillary column HP-5MS length 30 m, internal diameter 0.25 mm and film thickness of stationary phase 0.25. The speed of the carrier gas (helium) through a column of 1.3 ml/min was Used linear programming temperature the tours thermostat column from 220 to 230°C at 5 C/min The evaporator temperature 330°C, the division of the flow of 20:1. Mass-selective detector was provided by the scan mass spectra obtained by electron impact ionization (70 eV) in the range from 50 to 800 m/z at a rate of 2 scans per second. The information obtained was processed using the program ADMIS.

Spectra were obtained at 295 °K spectrometer DPX-300 (Bruker) with an operating frequency of 75.468 MHz. For registration used a solution of 50 mg in 0.6 ml CDCl3. Chemical shifts are measured relative to TMS by setting the signal of the solvent (CDCl3/CHCl3=99.9/0.1) standard values 76.90 M. D.

Antiinflammation activity of racemic diacetate 3,17β-dihydroxy-18-atilgan-1,3,5(10),8(9)-tetraene investigated as follows. To the rats-females weighing 160-180 g with established estrous cycle was helping males, daily for 3 days, from the date of detection of sperm in the vaginal smears (the first day of pregnancy) were injected subcutaneously drug in an oil solution. After 20 days recorded the number of fruits. Experimental results are presented in table 1.

Table 1
Antiinflammation action diacetate 3,17β-dihydroxy-13-atilgan-1,3,5(10),8(9)-tetraene (1)
Injected drug theDose, mg/kg of body weight per dayThe number of animals in the experienceContraceptive effect, %
Control-100
10.11587
10.515100

In addition, the investigation revealed no pathology in the development of fruits and malformations in fetuses exposed to the drug in animals, retained pregnancy. Dimensions and weight of fetuses and placentas in this case did not differ from those in animals of the control group.

Uterotrophic effect of the drug in effective doses are considerably lower than those used in medical practice 17α-ethinyl estradiol (table 2).

Table 2
Uterotrophic action of racemic diacetate 3,17β-dihydroxy-13-atilgan-1,3,5(10),8(9)-tetraene (1)
Injected drug theDose, mg/kg of body weight per day The number of animals in the experienceThe weight of the uterus mg
Control-613.4±0.8
Levonorgestrel0.05698.5±11.5
10.1516.6±1.4
10.5634.6±2.8
11.5671.0±8.4
15.0588.5±10.5

Antioxidant properties diacetate 3,17β-dihydroxy-18-methyl-östra-1,3,5(10),8(9)-tetraene investigated in accordance with the literature [5-9]. The research results presented in tables 3 and 4, processed by the Student's t - reliably indicated significant differences compared with the control experiments.

Table 3
Antioxidant properties diacetate 3,17β-Digi the Roxy-13-atilgan-1,3,5(10),8(9)-tetraene in the brain of rats (dose 1.5 mg/kg of body weight per day)
The group of animalsSchiff's base, $/mg lipidsDiene conjugates, nmol/mg of lipidsTranvia conjugates cu/mg lipidsThe coefficient KleinMalonic dialdehyde, nmol/mg protein
The intact
rats133±93.7±0.40.067±0.0050.186±0.0171.35±0.08
The intact
rats91±52.6±0.10.050±0.0050.148±0,101.14±0,06
receivingP<0,01P<0,01P<0,05P<005 P<0,05
steroid 1

Table 4
Antioxidant properties diacetate 3,17β-dihydroxy-13-atilgan-1,3,5(10),8(9)-tetraene (1) in the liver of rats (dose of 1.5 mg/kg of body weight per day)
The group of animalsSchiff's base, $/mg lipidsDiene conjugates, nmol/mg of lipidsTranvia conjugates, $/mg lipidsThe coefficient KleinMalonic dialdehyde, nmol/mg protein
Intact rats173±115.8±0.40.123±0.0080.248±0.0101.43±0.10
The intact134±64.6±0.30.163±0.0090.214±0,140.98±0,03
rats treated erased the ID 1 P<0,01P<0,05P<0,05P<0,05P<0,01

Thus, as shown by numerous experimental studies conducted on laboratory base of St. Petersburg state University and the research Institute of obstetrics and gynecology, steroid [1] used in doses is antiinflammation and antioxidant activity at low uterotrophic activity, which is an advantage compared to the actually used drugs. The presence of antioxidant activity alleged steroid is very important because of the connection with this action can be used as a means of prevention estrogenozawisimah breast cancer [4], which is particularly relevant today for health, given the recent tendency of this disease to a considerable increase.

Literature

1. 13-Alkylgona-1,3,5(10),9(11)-tetraenes // U.S. Pat. 3391170 (1968) - prototype

2. 8(9)-Dehydroestradiol derivatives // PCT Int. Appl. WO 98/16544.

3. Sorokin IB, Barkov TI, Saharicus AV, Chigir R.N., Ananchenko S.N., Trades IV // Estrogenic and anti-tumor activity in several transformed counterparts of estrone and estradiol. WPI. An SSSR, ser. chem. 1973, No. 5. S-670.

4. Felty Q., Singh, K., Ro D. Estrogen-induced G1/S transition to go-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling // Oncogene. 2005. V.24. N 31. P.4883-4893.

5. Folch, J., Less, M., Sloane-Stanly G.M. A simple method for the isolation and purification of total lipids from animal tissues // J. Biol. Chem. 1957. V.226. P.497-509.

6. Bartlet G. Phosphorus assay in colomn chromathography // J. Biol. Chem. 1959, V.23 supported. P.466-473.

7. Shvedova AA, Polanski NB // Method definition conjugates of lipid hydroperoxides in extracts of tissues. The study of synthetic and natural antioxidative (edited Ebbehoj): M. - 1992. P.74-75.

8. W.R. Bidlack, Tappel A.L. Fluorescent products of phospholipids during lipid peroxidation // Lipids. 1973. P.8.

9. Andreeva LI, Kozhemyakin L.A., CASCON A.A. Modification method determination of lipid peroxides in the test with TBQ // laboratory. case. 1988. No. 11. P.41-43.

Antiinflammation and antioxidant agent representing

diacetate-atilgan-1,3,5(10),8(9)-tetraen-3,17β-diol.



 

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