Asymmetric synthesis and uses of compounds in disease treatments

A technology for compounds and diastereomers, applied in the field of preparation of chiral compounds of anordrin and its analogs, can solve the problems of increased risk, decreased utilization rate, increased incidence of thromboembolism, etc.

Active Publication Date: 2020-04-21
ZHEJIANG JIACHI PHARMA DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, studies have shown an increased risk of breast and uterine cancers associated with ERT, as well as an increased incidence of thromboembolism, leading to a decline in its use
The combined administration of estrogen and progesterone can prevent the risk of breast and uterine cancer, but it can cause side effects of progesterone such as dizziness, nausea, vomiting, fatigue, anxiety, depression and headache

Method used

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  • Asymmetric synthesis and uses of compounds in disease treatments
  • Asymmetric synthesis and uses of compounds in disease treatments
  • Asymmetric synthesis and uses of compounds in disease treatments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] Embodiment 1: synthetic example

[0176]The preparation of the chemical synthesis of α-anordrin can refer to the following: method I (as shown in scheme I), or method II (scheme II), with reference to U.S. Patent 5,001,120 and organic publications, 2007,9 (9 ); 1643-6.

[0177] Method I

[0178]

[0179] Reaction step I: the preparation of Jones reagent: with 57g CrO 3 Dissolved at 400m H 2 O, then slowly add 85mlH 2 SO 4 , and then cool the resulting Jones reagent to 400 °C. Add 50g of 5α-androstane and 200ml of acetic acid into a 1L three-necked flask, heat the mixture to 55-600°C, stir and dissolve under a nitrogen atmosphere. Jones reagent was added dropwise within 1 hour, the reaction temperature was raised to 900°C and reacted for 1 hour, and acetic acid was distilled under reduced pressure. The residue was filtered, washed with water and dried to give 50 g of diacid product (b).

[0180] Reaction step I: the preparation of Jones reagent: with 57g CrO ...

Embodiment 2

[0193] Example 2: Effect of α-Anordrin or β-Anordrin

[0194] In this example, studies demonstrate estrogenic effects of alpha- and beta-anordrin on estrogen-regulated metabolic signaling and tissue atrophy. 7-week-old mice were ovariectomized. One week after the operation, mice were given isoflavones, α-anordrin or β-anordrin through food. Body weight, blood glucose, and food intake were measured monthly. Three months later, the mice were sacrificed, and the lower legs, vertebrae, liver, uterus and vagina were harvested.

[0195] Uterine and vaginal wet weights and H&E staining showed that alpha-anordrin, but not beta-anordrin, prevented vulvovaginal atrophy (Fig. 4). OVX mice treated with α-anordrin showed less symptoms of uterine atrophy compared with mice treated with β-anordrin and the blank group (Fig. 3). α-Anordrin showed less blood glucose, TG and body weight than β-anordrin, respectively ( Figure 5A with Figure 5B ), but there was no significant difference in...

Embodiment 3

[0199] Embodiment 3: material and material preparation method

[0200] Tamoxifen and Anastrozole (MPG USP grade) were provided by Okahata (Shanghai) Trading Co., Ltd. Androsterone was purchased from Jiangsu Jiaerke Pharmaceutical Group Co., Ltd. All other compounds were purchased from Sigma or Aladdin. Mouse food was produced by Nantong Trophy Feed Technology Co., Ltd., China. Mice were purchased from BK Animal Company. The animal experiment was carried out in Shanghai South Pesticide Research Center.

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Abstract

The present application discloses, among other things, asymmetric synthesis a diastereomeric compound of formula (I) (e.g., alpha-anordrin) or salt thereof. Also provided are methods and compositionsfor treatment of estrogen deficiency as well as preventing or reducing an estrogen deficiency symptom using a diastereomeric compound of formula (I) (e.g., alpha-anordrin) or salt thereof alone or incombination with at least one additional agent. Further provided are methods and compositions for reducing a side effect of an additional agent in the context of combination therapy with a diastereomeric compound of formula (I) (e.g., alpha-anordrin) or salt thereof.

Description

technical field [0001] The present invention relates to the technical field of asymmetric synthesis of steroid compounds, more specifically, relates to a method for preparing chiral compounds of anordrin and its analogues. The invention also relates to the therapeutic use of the chiral compound in the replacement therapy of estrogen deficiency symptoms. Background technique [0002] Reduced estrogen production in women following ovariectomy (OVX) or postmenopause or anti-estrogen therapy leads to symptoms of estrogen deficiency, which can adversely affect their quality of life for decades. Estrogen replacement therapy (ERT) has been used to treat these symptoms since the 1940s. [0003] During mammalian reproduction and development, estrogens bind to their receptors to regulate RNA transcription, stimulate cell proliferation and regulate metabolic signaling in many tissues. Three estrogen-binding protein genes have been identified: encoding estrogen receptor (ER) alpha and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/56A61P15/12A61P19/10
CPCA61P15/12A61P19/10C07J61/00C07J75/005A61K31/138A61K31/22A61K31/4196A61K45/06
Inventor 杨军徐文平
Owner ZHEJIANG JIACHI PHARMA DEV LTD
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