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Preparation of 6-oxa-8alpha-steroid estrogen analogues - a new group of unnatural estrogens and their use in medicine

A technology for steroidal estrogens and analogs, applied in the field of novel 6-oxa-8α-steroidal estrogen analogs, can solve the problems of increasing the risk of uterine cancer and endometrial cancer, and use restrictions

Inactive Publication Date: 2010-10-06
TOPASS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] While estrogen is effective in treating conditions such as bone loss, elevated lipid levels, and cancer, long-term estrogen therapy can also lead to a variety of diseases, including increased risk of uterine and endometrial cancers
These and other side effects of estrogen replacement therapy are unacceptable to many women and its use is limited

Method used

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  • Preparation of 6-oxa-8alpha-steroid estrogen analogues - a new group of unnatural estrogens and their use in medicine
  • Preparation of 6-oxa-8alpha-steroid estrogen analogues - a new group of unnatural estrogens and their use in medicine
  • Preparation of 6-oxa-8alpha-steroid estrogen analogues - a new group of unnatural estrogens and their use in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: 6-oxa-8α-estrone methyl ether (H)

[0056]

[0057]To 3-methoxy-6-oxaestra-1,3,5(10), 8,14-penten-17-one (3-methoxy-6-oxaestra-1,3,5(10) , 8,14-pentaen-17-one) I (1 g) in THF solution (50 ml) was added 10% Pd / C (300 mg) to synthesize compound II. The hydrogenation process was monitored by UV measurements. The reaction was stopped when the aromatic characteristic wavelength disappeared. The catalyst was then filtered and washed with THF (50ml). The organic layer was collected and the solvent was removed under vacuum. Make the residue from CHCl 3 -MeOH mixture crystallized out.

[0058] The yield of the target sterol II was 64% (0.65 g), and the melting point was 149-150°C.

[0059] NMR 1 H in CDCl 3 The results shown in (δ, ppm) are as follows: 0.93s (3H, C 13 -CH 3 ), 1.43 (1H, C 12α -H), 1.68 (1H, C 11β -H), 1.84 (1H, C 12β -H), 1.90 (2H, C 15α -H and C 15β -H), 1.96 (1H, C 14α -H), 2.00 (1H, C 111α -H), 2.18(1H, C 16α -H), 2.45 (1H, C ...

Embodiment 2

[0062] Example 2: 6-oxa-8α-estrone acetate (IV)

[0063]

[0064] With 3-methoxy-6-oxa-8α-estra-1,3,5(10)-triene-17-one (3-methoxy-6-oxa-8α-estra-1,3,5 (10), 8,14-pentaen-17-one) II (573 mg) was refluxed in HBr and AcOH (20 ml, 3 / 7, v / v) at 70° C. for two hours to synthesize compound IV. The reaction mixture was poured into water; the precipitate was filtered and rinsed with water to neutral pH. The product is then air dried.

[0065] The amount of product obtained after hydrolysis was 440 mg (80.5%). This compound was used in the next stage of synthesis without further purification.

[0066] The above compound was dissolved in 10 ml of pyridine / acetic anhydride mixture (volume ratio 1:9), kept at 100° C. for 2.5 hours, and then left overnight at room temperature. The precipitate was filtered off, washed with hexane and dried under vacuum.

[0067] The final yield of the target steroid IV was 230 mg (37%) with a melting point of 135-138°C.

[0068] NMR 1 H in CDCl 3...

Embodiment 3

[0071] Example 3: 6-oxa-8α-estradiol diacetate (VI)

[0072]

[0073] To 3,17β-diacetoxy-6-oxestr-1,3,5(10),8,14-pentaene V (1 g) in THF (50 ml) was added 10% of Pd (200mg) to synthesize compound VI. The hydrogenation was carried out under the conditions described in Example 1. The catalyst was filtered off and washed with THF (10ml). The solvent was removed in vacuo and the residue was crystallized from MeOH.

[0074] The yield of the target compound was 0.51 g (50%), and the melting point was 158-160°C.

[0075] NMR 1 H in CDCl 3 The results shown in (δ, ppm) are as follows: 7.07, 1H, d, J=8.0Hz (H-C 1 ); 6.61, 1H, dd, J=2.2Hz, J=8.0Hz (H-C 2 ); 6.54, 1H, d, J=2.2Hz (H-C 4 ); 4.63, 1H, t, J=8.7Hz (H-C 17 ); 4.25-4.15, 1H, m(H α -C 7 ); 4.1-4.0, 1H, m(H β -C 7 ); 2.65-1.3, 11H, m(H-C 8 , H-C 9 , H 2 -C 11 , H 2 -C 12 , H-C 14 , H 2 -C 15 , H 2 -C 16 ); 2.26, 3H, s(H 3 CCOO-C 3 ); 2.05, 3H, s(H 3 CCOO-C 17 ); 0.84, 3H, s(H 3 -C 18 ).

[0076] ...

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Abstract

The invention is related to the area of new 6-Oxa-8a-steroid estrogen analogues and the synthesis of these new biological active steroid estrogen analogues, namely, to the preparation of 6-oxa-8a-steroid estrogens and their use as estrogen receptor modulators. These new estrogen analogues are ligands for estrogen receptors and as such may be useful for the treatment and prevention of a variety of conditions related to estrogen functioning. These conditions include bone and cartilage disorders, increased levels of LDL cholesterol, cardiovascular diseases, impairment of cognitive function, cerebral degeneration disorders, endometriosis and other types of inflammation, the metabolic syndrome, and cancer, in particular of the breast, uterus and prostate.

Description

technical field [0001] The present invention relates to a novel 6-oxa-8α-steroidal estrogen analog and a method for synthesizing these biologically active novel steroidal estrogen analogues, that is, the synthesis of 6-oxa-8α-steroidal estrogen Technical field of preparation methods and their use as receptor modulators. These novel estrogen analogs are ligands for the estrogen receptor and thus are useful in the treatment and prevention of conditions associated with estrogen functioning. These conditions include bone and cartilage disease, elevated LDL cholesterol levels, cardiovascular disease, cognitive impairment, degenerative brain disease, endometriosis and other types of inflammation, metabolic syndrome, and cancer, especially breast cancer cancer, uterus and prostate cancer. Background technique [0002] Naturally occurring and synthetic estrogens are used in a wide range of treatments, including relief of menopausal syndrome, treatment of breast and prostate cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/566A61K31/56A61P5/30
CPCC07J73/003A61P1/04A61P13/02A61P13/08A61P15/00A61P17/00A61P19/04A61P19/10A61P25/00A61P25/28A61P29/00A61P3/00A61P3/04A61P31/04A61P35/00A61P3/06A61P43/00A61P5/30A61P9/00A61P9/10
Inventor 乌尔里克·皮松亚历山大·格里戈里耶维奇·沙瓦斯韦特兰娜·尼古拉耶芙娜·莫罗兹基娜
Owner TOPASS
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