Unlock instant, AI-driven research and patent intelligence for your innovation.

A 2-alkyl-substituted imidazolyl bisphosphonic acid compound and its preparation method and application

An acid compound and compound technology, which can be used in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, and metabolic diseases, etc., can solve the problems of low osteoclast inhibitory effect, large side effects, and high toxicity.

Active Publication Date: 2019-04-12
JIANGSU INST OF NUCLEAR MEDICINE
View PDF1 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A 2-alkyl-substituted imidazolyl bisphosphonic acid compound and its preparation method and application
  • A 2-alkyl-substituted imidazolyl bisphosphonic acid compound and its preparation method and application
  • A 2-alkyl-substituted imidazolyl bisphosphonic acid compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] The synthesis of the 2-position alkyl-substituted imidazolyl bisphosphonic acid compound with the structure represented by the formula (I) described in this example, wherein R1 is a methyl group and has the structure of the formula (II):

[0077]

[0078] The synthetic route of compound II is as follows:

[0079]

[0080] (1) Preparation of compound II intermediate 1

[0081] 8.2 g (0.1 mol) of 2-methylimidazole, 8.4 g (0.15 mol) of KOH, K 2 CO 3 13.8 g (0.1 mol) and 1.6 g (0.005 mol) of tetrabutylammonium bromide were dissolved in 75 mL of dichloromethane, and after stirring at room temperature for 0.5 h, 0.1 mol (11.2 mL) of ethyl bromoacetate was slowly added dropwise, and the dropwise addition was completed. , refluxed at 39°C for 8h, filtered, washed the filtrate three times with saturated brine, dried over anhydrous sodium sulfate, distilled the organic phase under reduced pressure at 25°C until the droplets no longer dripped, to obtain an oily substance,...

Embodiment 2

[0088] The synthesis of the 2-position alkyl-substituted imidazolyl bisphosphonic acid compound with the structure represented by the formula (I) described in this example, wherein R1 is an ethyl group and has the structure of the formula (III):

[0089]

[0090] The synthetic route of compound III is:

[0091]

[0092] (1) Preparation of compound III intermediate 1

[0093] Take 2-ethylimidazole 9.6g (0.1mol), KOH 8.4g (0.15mol), K 2 CO 3 13.8 g (0.1 mol) and 1.6 g (0.005 mol) of tetrabutylammonium bromide were dissolved in 75 mL of dichloromethane, and after stirring at room temperature for 0.5 h, 0.1 mol (11.2 mL) of ethyl bromoacetate was slowly added dropwise, and the dropwise addition was completed. , refluxed at 39°C for 8h, filtered, washed the filtrate three times with saturated brine, dried over anhydrous sodium sulfate, distilled the organic phase under reduced pressure at 25°C until the droplets no longer dripped, to obtain an oily substance, namely the co...

Embodiment 3

[0100] The synthesis of the 2-position alkyl-substituted imidazolyl bisphosphonic acid compound with the structure shown in this example, wherein R1 is a propyl group, has the structure of formula (IV):

[0101]

[0102]

[0103] The synthetic route of compound IV is:

[0104]

[0105] (1) Preparation of compound IV intermediate 1

[0106] Take 2-propylimidazole 11.0g (0.1mol), KOH 8.4g (0.15mol), K 2 CO 3 13.8 g (0.1 mol) and 1.6 g (0.005 mol) of tetrabutylammonium bromide were dissolved in 75 mL of dichloromethane, and after stirring at room temperature for 0.5 h, 0.1 mol (11.2 mL) of ethyl bromoacetate was slowly added dropwise, and the dropwise addition was completed. , refluxed at 39 °C for 9 h, filtered, washed the filtrate with saturated brine three times, dried over anhydrous sodium sulfate, distilled the organic phase under reduced pressure at 25 °C until the droplets no longer dripped, to obtain an oily substance, that is, the compound IV intermediate 1 ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a 2-alkyl substituted imidazolyl diphosphonic acid compound as well as a preparation method and application thereof. The 2-alkyl substituted imidazolyl diphosphonic acid compound has a larger nontoxic concentration interval for a precursor of an osteoclast, meanwhile, can obviously inhibit the formation of the osteoclast, can furthest destroy an actin ring, and regulates and controls the expression of a relevant gene, inhibits the formation of the osteoclast through decreasing the rise of the mRNA (messenger Ribonucleic Acid) level expression of marker genes, which are related to the formation of the osteoclast, of MMP-9 (Matrix Metallopeptidase-9), Cathepsin K, c-Fos, NFATcl, RANK (Receptor Activator of Nuclear factor Kappa-B) and the like in the osteoclast, inhibits the bone resorption function of the osteoclast through decreasing the expression rises of TRPV5 and integrin beta 3, which are caused by RANKL (Receptor Activator of Nuclear factor Kappa-B Ligand), and can be used as an inhibitor for the osteoclast; the problems that diphosphonate has a low inhibition effect on the osteoclast, is high in toxicity, and further high in side effect in the prior art are solved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a 2-position alkyl substituted imidazolyl bisphosphonic acid compound, a preparation method and application thereof. Background technique [0002] Bisphosphonates (BPs) are a new class of drugs used for various bone diseases and calcium metabolism diseases. They can specifically bind to hydroxyapatite in bone and inhibit the activity of osteoclasts, thereby inhibiting bone It is widely used in clinical treatment of osteoporosis, osteitis deformans, hypercalcemia and tumor-related bone diseases. [0003] Osteoclasts (OCs) are derived from pluripotent hematopoietic stem cells in the bone marrow. Pluripotent hematopoietic stem cells are first differentiated into macrophage clone-forming units under the action of factors such as M-CSF, which are osteoclast precursors, and then further stimulated by factors such as RANKL to fuse to form multinucleated and bone-absorbing osteoclasts...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6506A61K31/675A61P19/08A61P19/10A61P3/14
CPCC07F9/6506
Inventor 邱玲林建国吕高超李珂彭莹罗世能王珊珊赵学玉
Owner JIANGSU INST OF NUCLEAR MEDICINE