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1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof

A technology of carboxylic acid derivatives and dihydrothiophene, which is applied in the direction of drug combination, metabolic diseases, cardiovascular system diseases, etc., and can solve problems such as inability to provide

Inactive Publication Date: 2014-03-12
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Furthermore, neither raloxifene nor any other currently available selective estrogen receptor modulator provides all the benefits of currently available ERT, such as controlling postmenopausal syndrome and preventing Alzheimer's disease, without causing uterine Adverse side effects such as increased risk of endometrial and breast cancer and bleeding

Method used

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  • 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof
  • 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof
  • 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] 1-(1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-phenylpiperazine (Compound No. 1) (Compound No. 1)

[0128] Step A: Preparation of 3-(thiophene-2-thio)propionic acid (II)

[0129] Add 4.64g of 2-mercaptothiophene (I) and 40mL of tetrahydrofuran into a 100mL round-bottomed flask, and add 11mL of triethylamine dropwise under stirring, and the reaction solution becomes orange turbid. Continue to add 3.3mL of acrylic acid, and the reaction solution turns from orange turbid to clear. Heating to reflux for 12h, the reaction solution changed from orange to yellow, and then from yellow to dark green. After the reaction was completed, tetrahydrofuran was distilled off. After cooling, 40 mL of ethyl acetate and water (2:1) were added, and 18% hydrochloric acid was added to adjust the pH to 2. The organic layer was taken, and the aqueous layer was extracted with ethyl acetate (50 mL×3). Combine the organic layers. Dry over anhydrous magnesium sulfate for 2 ...

Embodiment 2

[0139] 1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-phenyl Piperazine (Compound No. 36)

[0140] Step F: 1-(6-Acetyl-1,4-dihydrothieno[3',2':5,6]thiapyrano[4,3-c]pyrazole-3-formyl)-4 - Preparation of phenylpiperazine (Compound No. 36).

[0141] In 0.50 g of 1-(1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-formyl)-4-phenylpiper 0.14 g of acetic anhydride was added to a dichloromethane solution of oxazine (Compound No. 1). After stirring at room temperature for 12h, a yellow precipitate appeared, and the crude product was obtained by suction filtration. Recrystallized with acetone to obtain 0.34 g of yellow solid (compound 36). Yield 61.5%

[0142] Compounds 1-35 were prepared using Example 1, and Compounds 36-70 were prepared using Example 2. The table below (Table 1) shows the characterization data for the compounds of the invention.

[0143] Table 1

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] Pharmacologi...

Embodiment 3

[0151] Estrogen Receptor Alpha Rapid Plate Assay

[0152] This assay detects the binding of radiolabeled estrogen to the estrogen receptor. The assay was performed on a BioMek2000 (Beckman). Plates were read on a scintillation counter (Packard Topcount) and a decrease in counts indicated binding of the compound to the receptor. The assay was carried out according to the method introduced by Allan et al., Anal. Biochem (1999), 275(2), 243-247.

[0153] On the first day, to each well of a 96-well FlashPlate Plus cross-linked with goat anti-mouse antibody (NEN Life Sciences), 100 μL containing 5 mM dithiothreitol (DTT, Panvera), 0.5 μg Receptor monoclonal antibody (SRA-1010, Stressgen) and 50 ng of purified human estrogen receptor alpha (Panvera) in estrogen selection buffer (ESB, Panvera). The plate was sealed and incubated overnight at 4°C.

[0154] The next day, each well was washed three times with 200 μL PBS pH 7.2 at room temperature, and then 98 μL radiolabeled estroge...

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Abstract

The invention belongs to the technical field of medicine and relates to a 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and application thereof used as an estrogen receptor, in particular to a 1,4-dihydrobithiophene [3', 2': 5, 6] bithiapyran [4, 3-c] pyrazol-3-carboxylic acid derivative and a pharmaceutically acceptable salt, or a stereoisomer thereof and a prodrug as well as a pharmaceutically acceptable vector in compatibility or a diluent used as an estrogen receptor. The structural general formula of the derivative is disclosed in the specification, and in the structural formula, n R1 can be independently selected from a substituted or unsubstituted amido group, and R2 can be independently selected from H or an acetyl group. The derivative can be used for treating and preventing various diseases related to estrogen functions, such as diseases related to estrogen deficiency, estrogen sensitive cancer and hyperplasia, endometriosis, uterus myoma and osteoarthritis. Compounds or compositions of the derivative can also be independently used or combined with progestogen or a hormoneantagonist as a contraceptive.

Description

technical field [0001] The present invention relates to 1,4-dihydrothieno[3',2':5,6]thiapyro[4,3-c]pyrazole-3-carboxylic acid derivatives or pharmaceutically acceptable salts thereof. The present invention also relates to preparation methods of said compounds and pharmaceutically acceptable compositions containing them and their application in treating diseases. Background technique [0002] Estrogens are known as female sex hormones. However, there have been many recent reports on the tissue specificity of estrogens in organs, properties not traditionally considered estrogen-sensitive or estrogen-responsive. The secretion of estrogen significantly decreases during menopause. Decreased estrogen induces short- and long-term symptoms of disorders of the vasomotor, genitourinary, cardiovascular, skeletal, and central nervous systems: e.g., hot flashes, genitourinary atrophy, increased risk of cardiovascular disease, osteoporosis Alzheimer's disease, cognitive decline and psy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/14A61K31/496A61K31/5377A61K31/4162A61P15/00A61P19/10A61P3/06A61P25/28A61P25/00A61P9/00A61P35/00A61P15/14A61P13/08A61P19/02A61P15/18
Inventor 胡春孙蕊王欣宋菁黄二芳徐赫男刘晓平李大伟
Owner SHENYANG PHARMA UNIVERSITY
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