Application of a group of thiomatrine derivatives and their salts in the preparation of anti-osteoporosis drugs

A technology of thiomatrine and anti-osteoporosis, which is applied in drug combinations, pharmaceutical formulas, bone diseases, etc., can solve problems such as unreported effects, achieve high bioavailability, reduce loss, and good stability Effect

Active Publication Date: 2019-11-26
SHANGHAI CHANGHAI HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no report on the anti-osteoporosis effect of the matrine compounds and their pharmaceutically acceptable salts

Method used

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  • Application of a group of thiomatrine derivatives and their salts in the preparation of anti-osteoporosis drugs
  • Application of a group of thiomatrine derivatives and their salts in the preparation of anti-osteoporosis drugs
  • Application of a group of thiomatrine derivatives and their salts in the preparation of anti-osteoporosis drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Preparation of 15-thiosophocarpine

[0033] 10.0 g (0.04 mol) of sophocarpine and 20.0 g (0.05 mol, purchased from Alfa Company) of sophocarpine were placed in a 500 ml reaction bottle, 200 ml of toluene was added, and the reaction was heated under reflux for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, and the crude product was passed through a silica gel column with dichloromethane:methanol (25:1) as the eluent to obtain 9.6 g of the product with a yield of 91.2%.

Embodiment 2

[0034] Example 2: Preparation of 13-(N-methyl)-amino-15-thiomatrine (M19)

[0035] 10 g (4 mol) of 18-thiosophocarpine was placed in a 500 ml reaction bottle, 200 ml of methylamino alcohol solution and 10 ml of triethylamine were added, and the reaction was stirred for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the crude product was passed through a silica gel column with dichloromethane:methanol (20:1) as the eluent to obtain 9.8 g of the product with a yield of 83.5%.

Embodiment 3

[0036] Example 3: Preparation of 13-(N-methyl, N-difluorobenzyl dithioformate)-amino-18-thiomatrine (ZSM-1 in the table)

[0037] Put 240mg (0.8mmol) of 18-thiomatrine (M19) and 160mg (2mmol) of carbon disulfide in a 25ml reaction bottle, add 5ml of acetonitrile, add 374mg (2mmol) of p-fluorobenzyl bromide under stirring, and react at room temperature for 4 hours , After the reaction was completed, the organic solvent was distilled off under reduced pressure, and the crude product was passed through a silica gel column, and the eluent was dichloromethane: acetone (10:1) to obtain 354 mg of a white solid, with a yield of 92.5%.

[0038] The H NMR spectrum and mass spectrometry data of the product are:

[0039] 1 H-NMR (300MHz, CDCl 3 )δ7.41–7.29(m,2H),7.09–6.90(m,2H),6.10(s,1H),5.37(dd,J=12.0,3.8Hz,1H),4.49(d,J=14.5Hz ,3H),3.64–2.95(m,6H),2.84(s,2H),2.37–1.13(m,19H).

[0040] 13 C-NMR (75MHz, CDCl 3 )δ163.87,160.60,131.39,131.34,131.09,130.98,115.67,115.38,77.47,77.25,77....

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Abstract

The invention relates to application of a group of thio-matrine derivative and salts thereof to preparation of an anti-osteoporosis medicament. The structural general formula of the thio-matrine derivative is shown in the description, where X is a sulfur atom, and an R group is selected from a hydrogen atom, an alkyl group, halogen, nitryl and a cyano group. The group of compositions is proven by bioactivity tests to remarkably reduce the bone mass loss of an ovariectomized mouse, represented by increase of the number of bone trabeculae, the bone surface and bone volume ratio, the relative bone volume or bone volume fraction and the number of bone trabecula connections, and remarkably suppress differentiation of RAW264.7 cells and primary monocytes of the mouse to osteoclasts, and thus can be developed into an anti-osteoporosis medicament or used for preparing a reagent for researches on pathological mechanism of osteoporosis and evaluation of the curative effect of the anti-osteoporosis medicament.

Description

technical field [0001] The invention relates to a new application of the compound, in particular to the application of a group of thiomatrine derivatives and their salts in the preparation of anti-osteoporosis drugs. Background technique [0002] Osteoporosis (Osteoporosis, OP) is a bone disease characterized by decreased bone mass, changes in the microstructure of bone tissue, increased bone fragility, decreased bone strength, and easy fracture [Cosman, F., et al., Clinician's Guide to Prevention and Treatment of Osteoporosis, Osteoporos Int. 2014, 25(10), 2359-81.]. Severe osteoporosis can lead to pain, fractures, and disability, and is known as the silent killer. Recent studies have shown that the imbalance between bone resorption and bone formation is the pathophysiological basis of osteoporosis, which is regulated by osteoblasts that promote bone formation and osteoclasts that promote bone resorption [Del Puente, A., et al., Physiopathology of Osteoporosis: From RiskF...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4375A61P19/10
CPCA61K31/4375
Inventor 苏佳灿赵庆杰陈晓胡宏岗智信卓小斌曹烈虎
Owner SHANGHAI CHANGHAI HOSPITAL
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