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Benzothiophene compounds and their preparation and medicine use

A technology of benzothiophenes and compounds, applied in the field of a class of benzothiophenes, their preparation and its medical use, can solve the problems of increasing the risk tendency of deep vein thrombosis

Inactive Publication Date: 2010-07-28
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Raloxifene hydrochloride (Patent No. US4418068) which has been on the market and Arzoxifene (Arzoxifenehydrochloride (Patent No. EP0729956A1) which is undergoing Phase III clinical trials) can effectively prevent and treat postmenopausal osteoporosis and breast cancer in women, but Both drugs tend to increase the risk of deep venous thrombosis

Method used

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  • Benzothiophene compounds and their preparation and medicine use
  • Benzothiophene compounds and their preparation and medicine use
  • Benzothiophene compounds and their preparation and medicine use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 6-methoxy-2-(4-methoxyphenyl)-3-(4-fluoro-benzoyl)-benzothiophene-(Y-69)

[0045] To 1.0 g of 4-fluorobenzoic acid (7.14 mmol) was added 6 ml of redistilled SOCl 2 .1 drop of DME was refluxed for 1 hour. Evaporate the thionyl chloride and drain as much as possible with a water pump. Then add 30mL of dry 1,2-dichloroethane, 1.9 grams of 2-(4-methoxyphenyl)-6-methoxy-benzothiophene (7.03mmol), 3.8 grams of anhydrous trichloro Aluminum chloride (28.5 mmol). React overnight at 5°C-10°C, and quench the reaction with 20 mLTHF. Extract with dichloromethane, combine the organic phases, and dry over anhydrous sodium sulfate. After distilling off the solvent, silica gel column chromatography (petroleum ether / ethyl acetate 15 / 1) gave 2.4 g of yellow powder, with a two-step yield of 86%. NMR (400MHz, CDCl 3 ) δ3.74 (3H, s) 3.89 (3H, s) 6.74 (2H, q, J = 6.8) 6.94 (2H, t, J = 9.0, J = 8.4) 7.0 (1H, dd, J = 9.0, J = 2.4) 7.29 (2H, q, J = 6.8) 7.32 (1H, d, J = 2.4) 7.63 ...

Embodiment 2

[0046] Example 2 6-methoxy-2-(4-methoxyphenyl)-3-[4-(4-benzylpiperazine-)-1-benzoyl]-benzothiophene (Y-66 )

[0047] Dissolve 2.5g of Y-69, 1.8mL of benzylpiperazine, 3mL of triethylamine in dry 10mL of N-methylpyrrolidone, react in an oil bath at 110°C for 20 hours, pour into water, extract with ethyl acetate, anhydrous Na2SO4 dried. After distilling off the solvent, silica gel column chromatography (petroleum ether / ethyl acetate 2 / 1) gave 3.08 g of yellow crystals, with a yield of 88%. NMR (400MHz, CDCl 3 ) δ2.58 (4H, s) 3.33 (4H, s) 3.58 (2H, s) 3.75 (3H, s) 3.87 (3H, s) 6.69 (2H, d, J=9.0) 6.77 (2H, q, J = 2.2, J = 6.6) 6.92 (1H, dd. J = 8.8, J = 2.5) 7.30 ~ 7.35 (6H, m) 7.38 (2H, q, J = 2.2, J = 6.6) 7.46 (1H, d, J =9.0)7.72 (2H,d,J=9.0).

Embodiment 3

[0048] Example 3 6-methoxy-2-(4-methoxyphenyl)-3-[4-(4-piperazinyl)-1-benzoyl]-benzothiophene (Y-68)

[0049] Dissolve 1.5 grams of Y-66 in 20 mL of anhydrous methanol, add 1 gram of ammonium formate and 1 gram of 10% Pd-Cl, reflux for 1.5 hours under nitrogen protection, filter, wash the residue with methanol, evaporate the solvent and then directly perform silica gel column chromatography (two Chloromethane / methanol 25 / 1) gave 0.70 g of a foamy solid. NMR (400MHz, CDCl 3 ) 2.99 (1H, s) 3.01 (4H, t) 3.30 (4H, t) 3.73 (3H, s) 3.86 (3H, s) 6.70 (2H, d, J=9.0) 6.76 (2H, q, J = 2.2, J = 6.9) 6.92 (1H.dd. J = 2.5, J = 8.8) 7.30 (1H, d, J = 2.2) 7.38 (2H, q, J = 2.2, J = 6.9) 7.46 (1H, d , J=8.8) 7.73 (2H,d, J=9.0).

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Abstract

The present invention discloses one kind of benzothiophene compounds and their preparation process and medicine use. The present invention also discloses their physiologically acceptable salts, their preparation and the application in preparing medicine for preventing and treating women's post-menopause syndromes.

Description

technical field [0001] The invention relates to a new compound developed for the purpose of preventing and treating women's postmenopausal syndrome by benzothiophene derivatives and salts thereof. Background technique [0002] Women's postmenopausal syndrome mainly manifests in: osteoporosis, estrogen-dependent cancer (breast cancer, uterine cancer and ovarian cancer), cardiovascular disease, senile dementia, etc. [0003] Osteoporosis is a common and frequently-occurring disease in postmenopausal women. The incidence rate of Chinese women over 60 years old is about 40%. Most women lose 20%-60% of their bone mass 3-6 years after menopause. In postmenopausal osteoporosis, net resorption and loss of trabecular bone mass leads to fractures. Therefore, the spine, femur, forearm and other parts highly dependent on trabecular support are most prone to fractures. Fractures in elderly women are mainly comminuted vertebral fractures (47%), hip fractures (20%), and wrist fractures...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/64C07D333/58A61K31/4535A61K31/5355A61P19/10A61P35/00A61P9/10A61P25/28
Inventor 杨春皓李佳王明伟谢毓元
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI