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Deferoxamine derivative compound with bone affinity, preparation method and application thereof

A compound and hydrate technology, applied in the direction of medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve the problem of increasing DFO dose and medication time, limiting the effect of DFO bone action, slow subcutaneous or intravenous infusion And other issues

Active Publication Date: 2016-10-12
上海市伤骨科研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although DFO is relatively safe to use, it has a short half-life and requires slow subcutaneous or intravenous infusion. Due to the water solubility of DFO and the relatively low bone blood flow and metabolism, the distribution rate of DFO in bone tissue is low; increase DFO dose and medication time can cause adverse reactions such as hearing or visual impairment, growth retardation, bone deformation, etc., thus limiting the effect of DFO on bone, and it is still difficult to apply systemic drug treatment for progressive bone loss diseases

Method used

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  • Deferoxamine derivative compound with bone affinity, preparation method and application thereof
  • Deferoxamine derivative compound with bone affinity, preparation method and application thereof
  • Deferoxamine derivative compound with bone affinity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0077] Desferoxamine, deferoxamine derivative compound a, deferoxamine derivative compound b, and defersoxamine derivative compound c used in the following synthesis examples 1-4 were all purchased from Sigma; iminodiacetic acid and 2,2'- Hydrazine-1,2-diyldiacetic acid, 2,2'-methylene-diureadiyldiacetic acid, 2,2'-propyl-1,3-diureadiyldiacetic acid were purchased from Aladdin Company; succinic anhydride and adipic anhydride were purchased from Sinopharm and Aladdin respectively; PyBOP was purchased from Sigma; Pd / C was purchased from Sigma, and its Pd doping amount was 10%; the rest of the chemical reagents were purchased from Sigma The company's analytical grade reagents; the water used is deionized double distilled water. The reaction is carried out under normal temperature and pressure conditions. The melting points of the compounds were determined with a Fisher-John melting point apparatus. NMR spectra were measured with a Bruker AM-400 spectrometer. The mass spectrum ...

Embodiment 5

[0098] Embodiment 5 Ferric ion complex performance test

[0099] In this example, the complexing ability of the compounds prepared in the above examples to ferric ions was characterized. Specifically, ferric ammonium citrate (FAC) was used as a ferric ion donor, dissolved in double distilled water to form a solution, and the same molar amounts of the compounds prepared in the above synthesis examples 1-4 were added thereto As well as deferoxamine that has not been substituted and modified as described in the present invention, use a Beckman DXC600 automatic biochemical analyzer to detect the content of free iron ions in the solution to know whether the compound of the present invention has good characteristics of complexing iron ions. figure 2 The DFO-SF prepared in Example 1 and the unsubstituted DFO are shown to be complexed to iron ions, figure 2 The control in is the iron ion content measured using only double distilled water without adding FAC. The compounds prepared ...

Embodiment 6

[0101] Embodiment 6 Stimulates the performance of cells expressing hypoxia-inducible factor (HIF)-α and its downstream target genes

[0102] In this example, the ability of the compounds of the present invention to stimulate cells to express hypoxia-inducible factor (HIF)-α and its downstream target genes was investigated. Specifically, the mouse calvaria 48 hours after birth was removed and cut into 1×1×1mm 3 Small pieces, digested with trypsin and type Ⅰ collagenase, isolated and purified newborn mouse calvarial osteoblasts; 2×10 4 / cm 2 The cell density was inoculated to a 6-well culture plate; when the cells adhered to the bottom of the culture plate and grew to 80% mixed, the conditioned medium with a compound concentration of 200 μM (DFO net concentration) of the embodiments of the present invention was used respectively for the above all The newborn mouse calvarial osteoblasts were cultured, and the conditioned medium with a concentration of 200 μM of unsubstituted mo...

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Abstract

The invention develops a deferoxamine derivative with bone affinity, a preparation method and application thereof. More specifically, the invention provides a compound with a structure shown as formula (1) and its pharmaceutically acceptable salt, ester, amide, acyl halide, hydrate or solvate. The invention also provides a preparation method of the compound shown as formula (1) and application thereof in preparation of drugs for treatment of osteoporosis, osteonecrosis, delayed union or nonunion and bone defect. (formula I).

Description

technical field [0001] The invention relates to a deferoxamine derivative compound, which has excellent iron complexing ability and bone affinity through structural modification of the compound. The invention also provides a preparation method of the deferoxamine derivative compound and its application in the preparation of medicines for treating osteoporosis, osteonecrosis, delayed union or nonunion of fractures and bone defects. Background technique [0002] Osteoporosis (OP) is a bone metabolic disease characterized by progressive decrease in bone mass, destruction of bone microarchitecture, and increase in bone fragility. Susceptibility to fracture is one of the most serious consequences of osteoporosis. Osteoporosis is not only a medical problem that endangers the health of the elderly, especially postmenopausal women and affects their quality of life, but also has become a serious social problem in today's aging society. On the basis of its occurrence mechanism, a rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C239/16C07C243/28A61K31/198A61P19/08A61P19/10
CPCC07C239/16C07C243/28
Inventor 邓廉夫陆俊齐进江敏
Owner 上海市伤骨科研究所
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