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Diphosphoric acid compounds, and preparation method and application thereof

A compound, bisphosphonic acid technology, applied in the field of biomedicine, can solve problems such as little effect of osteoblasts and increased fractures in patients

Active Publication Date: 2016-09-07
CHENGDU YUNKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the bisphosphonate drugs on the market today have stronger and stronger inhibitory effects on osteoclasts, they may lead to a corresponding increase in the risk of fractures in patients, and have little effect on promoting osteoblasts

Method used

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  • Diphosphoric acid compounds, and preparation method and application thereof
  • Diphosphoric acid compounds, and preparation method and application thereof
  • Diphosphoric acid compounds, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Compound XC-1

[0084] In this example, the diphosphonic acid compound is: 1-hydroxy-2-(2-amino-1,3-selenazol-5-yl)-ethylidene-1,1-diphosphonic acid. The structural formula is as follows

[0085]

[0086] The specific preparation method of this compound is as follows:

[0087] Dissolve 1.43g (26.5mmol) sodium methoxide in 40mL of anhydrous methanol, add 1.14g (13.25mmol) γ-butyrolactone dropwise to the solution at room temperature, and react for 30min after the dropwise addition. Concentrate after the reaction, then add 20mL of water, adjust the pH to 3-4 with 2mol / L hydrochloric acid, then extract with ethyl acetate, collect the ether phase, and concentrate under reduced pressure to obtain the product 4-hydroxybutyric acid methyl ester.

[0088] Dissolve 1.18g (10mmol) of methyl 4-hydroxybutyrate in 30mL of dichloromethane, then add 0.13g (1.6mmol) of sodium acetate and 3.27g (15mmol) of pyridinium chlorochromate, and react at room temperature for 1h. ...

Embodiment 2

[0096] Example 2: Compound XC-2

[0097] The diphosphonic acid compound listed in this embodiment is: 1-hydroxy-2-(2-methyl-1,3-selenazol-5-yl)-ethylene-1,1-diphosphonic acid. The structural formula is as follows:

[0098]

[0099] The specific preparation method of this compound is as follows:

[0100] Dissolve 1.43g (26.5mmol) sodium methoxide in 40mL of anhydrous methanol, add 1.14g (13.25mmol) γ-butyrolactone dropwise to the solution at room temperature, and react for 30min after the dropwise addition. Concentrate after the reaction, then add 20mL of water, adjust the pH to 3-4 with 2mol / L hydrochloric acid, then extract with ethyl acetate, collect the ether phase, and concentrate under reduced pressure to obtain the product 4-hydroxybutyric acid methyl ester.

[0101] Dissolve 1.18g (10mmol) of methyl 4-hydroxybutyrate in 30mL of dichloromethane, then add 0.13g (1.6mmol) of sodium acetate and 3.27g (15mmol) of pyridinium chlorochromate, and react at room temperature ...

Embodiment 3

[0109] Embodiment 3: Compound XC-3

[0110] The diphosphonic acid compound listed in this embodiment is: 1-hydroxy-2-(2-imino-4-oxo-1,3-selazolidine-5-yl)-ethylene-1,1-diphosphonic acid . The structural formula is as follows:

[0111]

[0112] The specific preparation method of this compound is as follows:

[0113] Add 20.3g of L-aspartic acid, 4.3g of KBr, 44g of concentrated sulfuric acid, and 400mL of water into a 1L three-necked flask, install a thermometer, stir in an ice-salt bath to cool down to below 0°C, and slowly add 8.8 g NaNO 2 150mL aqueous solution, control the temperature in the reaction bottle below 0°C, brown gas will be produced, after the drop is completed, keep the temperature for 2h to obtain a light yellow reaction liquid. Extract with 4×100mL ethyl acetate, dry the organic phase for 2h, and distill the organic phase under reduced pressure to obtain bromosuccinic acid as a white solid product.

[0114] Add 7g of bromosuccinic acid, 150mL of ethan...

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PUM

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Abstract

The invention discloses compounds disclosed as Formula II. In the Formula II, R is disclosed in the specification, wherein R1 is H, OH or halogen; R2 is disclosed in the specification, n1=0-10, n2=0-10, and n3=0-10; Ar is aryl, arylidene, R99-substituted aryl or R99-substituted arylidene; at least one of R3, R4, R5 and R6 is selenium or sulfur atom, and the rest is carbon or nitrogen atom; and R3, R4, R5 and R6 are connected through a single bond or double bond. As for old patients with osteoporosis, the compounds can keep the osteocyte bone formation and bone destroy at an ideal dynamic balance.

Description

technical field [0001] The invention relates to a novel bisphosphonate compound and a method for preparing the novel bisphosphonate compound, belonging to the field of biomedicine. Background technique [0002] Osteoporosis is a systemic bone disease characterized by low bone mass and damaged bone structure, resulting in increased bone fragility and susceptibility to fracture. At present, osteoporosis ranks 7th among common diseases and frequently-occurring diseases in the world, with a total of more than 200 million patients. More than 90 million people in my country suffer from different degrees of osteoporosis. The prevalence of osteoporosis in the elderly over 60 years old is about 50%~ 60%. [0003] Bisphosphonic acid drugs are a new class of anti-metabolic bone disease drugs developed in recent years, and have become the first-line drugs for the treatment of Paget's disease, hypercalcemia, osteolysis caused by tumors, and osteoporosis. . The anti-osteoporosis mechani...

Claims

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Application Information

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IPC IPC(8): C07F9/547A61K31/675A61P19/08A61P19/10
CPCC07F9/5475
Inventor 李明起曾永龙邓启民蒋雪段玉春潘俊男程作用王翰曹刚文德仲刘媛媛
Owner CHENGDU YUNKE PHARMA
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