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Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof

A technology of bisphosphonic acid compounds and heterocyclic compounds, applied in the field of imidazole heterocyclic bisphosphonic acid compounds and their preparation, can solve the problems of low osteoclast inhibitory effect, large side effects, and high toxicity

Active Publication Date: 2017-05-31
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the bisphosphonates in the prior art have low inhibitory effect on osteoclasts, high toxicity, and large side effects, so as to provide a bisphosphonate with excellent inhibitory effect on osteoclasts, non-toxicity and small side effects drug structure

Method used

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  • Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof
  • Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof
  • Imidazole heterocyclic diphosphonic acid compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] The synthesis of the imidazole heterocyclic bisphosphonic acid compound having the structure shown in the formula (I) described in this example, wherein n=1, has the structure of the formula (II):

[0069]

[0070] The synthetic route of compound II is:

[0071]

[0072] (1) Preparation of Compound II Intermediate 1

[0073] Take imidazole 6.8g (0.1mol), KOH 8.4g (0.15mol), K 2 CO 3 13.8g (0.1mol) and 0.7g (7mmol) of tetrabutylammonium bromide were dissolved in 75mL of dichloromethane, and after stirring at room temperature for 0.5h, 0.1mol (11.2mL) of ethyl bromoacetate was slowly added dropwise, and the dropwise addition was completed. Reflux at 39°C for 8 hours, filter, wash the filtrate three times with saturated brine, dry over anhydrous sodium sulfate, and distill the organic phase under reduced pressure at 25°C until the liquid drops no longer drop out to obtain an oily substance, namely compound II intermediate 1;

[0074] (2) Preparation of Compound I...

Embodiment 2

[0080] The synthesis of the imidazole heterocyclic bisphosphonic acid compound having the structure shown in the formula (I) described in this example, wherein n=2, has the structure of the formula (III):

[0081]

[0082] The synthetic route of compound III is:

[0083]

[0084] (1) Preparation of Compound III Intermediate 1

[0085] Take imidazole 6.8g (0.1mol), KOH 8.4g (0.15mol), K 2 CO 3 11.1g (0.0.08mol) and tetrabutylammonium bromide 0.97g (3mmol) were dissolved in 75mL of dichloromethane, stirred at room temperature for 0.5h, slowly added dropwise ethyl bromopropionate 0.08mol (10.4mL), dropwise After completion, reflux at 50°C for 6h. Filtrate, wash the filtrate three times with saturated saline, dry over anhydrous sodium sulfate, and distill the organic phase under reduced pressure at 25°C until the liquid drops no longer drip out to obtain an oily substance, namely compound III intermediate 1;

[0086] (2) Preparation of Compound III Intermediate 2

[00...

Embodiment 3

[0092]The synthesis of the imidazole heterocyclic bisphosphonic acid compound having the structure shown in formula (I) described in this example, wherein n=3, has the structure of formula (IV):

[0093]

[0094] The synthetic route of compound IV is:

[0095]

[0096] (1) Preparation of Compound IV Intermediate 1

[0097] Take imidazole 6.8g (0.1mol), KOH 9.5g (0.17mol), K 2 CO 3 16.6g (0.12mol) and 2.3g (7mmol) of tetrabutylammonium bromide were dissolved in 75mL of dichloromethane, and after stirring at room temperature for 0.5h, 0.12mol (17.1mL) of ethyl bromobutyrate was slowly added dropwise, and the addition was completed , reflux at 30°C for 10 h, filter, wash the filtrate three times with saturated saline, dry over anhydrous sodium sulfate, and distill the organic phase under reduced pressure at 25°C until the liquid drops no longer drop out to obtain an oily substance, namely compound IV intermediate 1;

[0098] (2) Preparation of Compound IV Intermediate 2...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and in particular relates to an imidazole heterocyclic diphosphonic acid compound as well as a preparation method and application thereof. The imidazole heterocyclic diphosphonic acid compound has a larger non-toxic concentration range for an osteoclast precursor, and can significantly inhibit the formation of osteoclasts at the same time; the imidazole heterocyclic diphosphonic acid compound can damage actin ring to the utmost extent, thus having an obvious inhibiting effect on the osteoclasts and further being used as an osteoclast inhibitor; the imidazole heterocyclic diphosphonic acid compound solves the problems that diphosphonate in the prior art is low in inhibiting effect on the osteoclasts, high in toxicity and large in side effects.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an imidazole heterocyclic bisphosphonic acid compound and its preparation method and application. Background technique [0002] Bisphosphonates (Bisphosphonates, BPs) are a new class of drugs for various bone diseases and calcium metabolism diseases. It is widely used clinically to treat osteoporosis, osteitis deformans, hypercalcemia and tumor-related bone diseases. [0003] Osteoclasts (OC) are derived from pluripotent hematopoietic stem cells in the bone marrow. Pluripotent hematopoietic stem cells first differentiate into macrophage clone-forming units, which are osteoclast precursors, under the action of factors such as M-CSF, and then further fuse under the stimulation of factors such as RANKL to form multinucleated osteoclasts with bone resorption function. bone cells. RAW264.7 cells are mouse-derived osteoclast precursors, which are derived from the cell ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6506A61K31/675A61P19/08A61P19/10A61P3/14A61P35/00
CPCC07F9/6506
Inventor 林建国彭莹邱玲吕高超李珂罗世能赵学玉王珊珊
Owner JIANGSU INST OF NUCLEAR MEDICINE