Pyrazole-containing betulinic acid derivative as well as preparation method and application thereof

A technology of betulinic acid and pyrazolo, which is applied to medical preparations containing active ingredients, pharmaceutical formulas, drug combinations, etc., and can solve problems such as low solubility, poor solubility, and poor solubility

Pending Publication Date: 2022-07-29
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

Animal experiments have proved that pyrazolo betulinic acid derivatives can effectively inhibit the occurrence of osteoporosis in osteoporosis model mice, but their solubility is poor, the solubility in water is less than 1 mg / L, and the solubility in most organic solvents is also low. Poor, low solubility leading to poor bioavailability is the main problem for this class of compounds

Method used

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  • Pyrazole-containing betulinic acid derivative as well as preparation method and application thereof
  • Pyrazole-containing betulinic acid derivative as well as preparation method and application thereof
  • Pyrazole-containing betulinic acid derivative as well as preparation method and application thereof

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preparation example Construction

[0091] According to an embodiment of the present disclosure, there is provided a preparation method of a pyrazolobetulinic acid-based compound, comprising:

[0092] method one:

[0093] (a 1 ) compound 6 and side chain compound R 2 -Y undergoes a substitution reaction to obtain formula Ia 1 Compound:

[0094]

[0095] or

[0096] Method Two:

[0097] step (a 1 ) as in Method 1 above;

[0098] (a 2 ) will Ia 1 reduction to prepare formula Ia 2 Compound:

[0099]

[0100] or

[0101] Method three:

[0102] (b) Compound 6 and side chain compound The acylation reaction was carried out to prepare the Ib compound:

[0103] or

[0104] Method four:

[0105] (c) Compound 5 and side chain compound The Ic compound is prepared by an addition reaction:

[0106]

[0107] In the formula, Y is a leaving group selected from the following groups: chlorine, bromine, iodine, mesylate, p-toluenesulfonate, triflate, etc.; the remaining groups are defined as above ...

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Abstract

The invention relates to betulinic acid derivatives containing pyrazole and a preparation method and application of the betulinic acid derivatives, in particular to compounds with the structure shown in the general formula I. Definitions of all groups are shown in the specification. A rat arthritis model is induced through sodium iodoacetate, and the change of the degree of arthralgia is observed; an in-vitro induced differentiation system is adopted, and the osteoclast differentiation and inflammatory factor generation level of the osteoclast precursor is observed. Results show that the compound adopted by the invention has inhibitory activity on osteoclast differentiation and inflammatory factor generation, has a good treatment effect on osteoarthritis and joint inflammation diseases with bone destruction, bone erosion and synovitis as pathological characteristics, and has an ideal clinical application prospect.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry and drug therapy. Specifically, it relates to a class of pyrazole-containing betulinic acid derivatives, pharmaceutically acceptable salts and hydrates thereof, their preparation methods and their use in medicines for treating diseases related to abnormal osteoclast activity. Background technique [0002] Osteoporosis (OP) is a systemic bone disease characterized by decreased bone mass and degeneration of bone tissue microarchitecture, resulting in decreased bone density, increased fragility, and susceptibility to fractures. Osteoporosis is associated with an imbalance between bone resorption and bone formation during bone remodeling. Human bones are constantly metabolized, osteoclasts (OC) promote bone resorption, and osteoblasts (OB) promote bone formation. Osteoclasts are activated, migrate and adhere to the bone surface for bone resorption after differentiated and mature, resulting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P37/00A61P29/00A61P19/10A61P19/02A61P1/02A61P19/08A61P35/00A61P35/04
CPCC07J71/0047A61P37/00A61P29/00A61P19/10A61P19/02A61P1/02A61P19/08A61P35/00A61P35/04
Inventor 杨春皓左建平王洁何世君张小飞林泽民
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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