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Diphosphonic acid derivative containing NO donors, preparation method thereof and application thereof

A technology of bisphosphonic acid and derivatives, which is applied in the fields of chemical instruments and methods, drug combinations, and pharmaceutical formulations, can solve the problems of long synthetic routes and cumbersome preparation methods, and achieve strong practicability, simple and convenient synthetic methods, and reduced toxicity. side effects

Inactive Publication Date: 2010-02-24
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The purpose of the present invention is to overcome the disadvantages of the bisphosphonate in the prior art, such as long synthetic route and cumbersome preparation method, and to design a NO donor bisphosphonic acid with simple and convenient synthesis method, stronger practicability and anti-osteoporosis effect. derivatives, and disclosed their synthetic routes and methods, which can be used for the prevention and treatment of osteoporosis

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  • Diphosphonic acid derivative containing NO donors, preparation method thereof and application thereof
  • Diphosphonic acid derivative containing NO donors, preparation method thereof and application thereof
  • Diphosphonic acid derivative containing NO donors, preparation method thereof and application thereof

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Embodiment 1

[0033] Embodiment 1: prepare NMBBDP

[0034] According to the synthetic route of previous NMBBDP, the specific preparation method of NMBBDP is as follows:

[0035] 1.1 Preparation of 4-nitroxymethylbenzoic acid (4)

[0036] In a 250ml three-necked flask, add 3g (0.02mol) p-cyanobenzyl chloride (2) and 50mLH 2 O, stir, heat to dissolve. Concentrated HCl (1.28mol, about 80ml) was added dropwise in three batches, refluxed for 5-6h, and cooled to room temperature. Let it stand overnight, adjust the pH value to about 3-4 with NaOH, filter, wash, and wash the solid with H 2 O was washed three times and dried in vacuo to give p-hydroxymethylbenzoic acid as a white solid (3).

[0037] Under cooling in an ice-water bath, in a 100ml three-neck flask, add 15ml of Ac 2 O and 7.6mlHNO 3 , stirred for 30min. Add 2g of p-hydroxymethylbenzoic acid prepared by the above steps dropwise and 15ml of Ac 2 The slurry composed of O, kept stirring during the dropwise addition and kept the tem...

Embodiment 2

[0047] Embodiment 2: Preparation of NHEBDP

[0048] 1.1 Dissolve 0.01mol 6-bromohexanoic acid (7) in 10ml of anhydrous acetonitrile, add dropwise to 3.4g of silver nitrate in 20ml of acetonitrile solution, maintain the temperature at 50°C, after the dropwise addition, raise the temperature to 70°C, and react for 6h. This reaction process should be protected from light. Cool, filter, remove the solvent by rotary evaporation under reduced pressure, add 8ml of water to the residue, extract with ethyl acetate (15mL×3), and dry over anhydrous sodium sulfate. Ethyl acetate was evaporated, and 50ml of ether was added to the residue, and filtered. The filtrate was distilled to remove the solvent to obtain light yellow liquid 6-nitrohexanoic acid (8).

[0049] 1.2 Add 10mmol of 6-nitrohexanoic acid (8) prepared in step 1.1 into the three-necked flask, add 20mL of SOCl dropwise under stirring 2 After the dropwise addition is completed, the temperature is slowly raised to 60-70°C unti...

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Abstract

The invention discloses diphosphate containing NO donors, which has the following structural general formula, wherein R1 is an aliphatic hydrocarbon, an aromatic ring or a nitrogen-containing heterocyclic ring containing 1 to 2 NO-donors; X is a group of -H, -OH, -NH2 and the like; Y is oxygen, sulfur or amino; and n is an integer between 2 and 9. A derivative of the diphosphate not only has the effect of inhibiting bone absorption, but also has the effect of promoting bone cells, and can be used for preventing and treating bone metabolic diseases such as osteoporosis and the like. The invention also discloses preparation and application of the diphosphate containing the NO donors.

Description

technical field [0001] The present invention relates to a new class of bisphosphonic acid derivatives, in particular to bisphosphonic acid derivatives with NO-donors introduced into their structures. The present invention also relates to the preparation method and application of the bisphosphonic acid derivative. Background technique [0002] With the aging of the population, the incidence of osteoporosis is increasing year by year, and the resulting serious medical and social burden has become a global social problem. It is estimated that the number of osteoporosis patients in the world has reached 200 million, of which there are approximately 75 million osteoporosis patients in the United States, Europe and Japan, and the number of osteoporosis patients in China has reached 63 million, of which 15 million people have had osteoporosis Osteoporotic fractures. [0003] Bisphosphonates have a strong affinity for calcium and bone minerals, inhibit the formation, growth, and d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/38A61K31/663A61P19/10A61P3/14
Inventor 王学斌刘键张现忠唐志刚张俊波陆洁
Owner BEIJING NORMAL UNIVERSITY
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