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Hydrazine cathepsin K inhibitor and application thereof in treating osteoporosis

A technology for cathepsin and osteoporosis, applied in the field of cathepsin inhibitors, can solve the problems of complex action of cathepsin K and unsatisfactory selectivity

Inactive Publication Date: 2013-05-08
JILIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its attacking group has a strong binding force with the active site of cathepsin, so that their inhibitory effect on cathepsin is greatly improved; Neither is ideal [9]
Moreover, in the human body, the role of cathepsin K in physiological processes is very important and extremely complex

Method used

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  • Hydrazine cathepsin K inhibitor and application thereof in treating osteoporosis
  • Hydrazine cathepsin K inhibitor and application thereof in treating osteoporosis
  • Hydrazine cathepsin K inhibitor and application thereof in treating osteoporosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067]

[0068] In a 100mL round bottom flask, add 0.61g E4, 0.44g phenylboronic acid, 0.0653g Pd(dppf)Cl 2 and 0.5g K 2 CO 3 , use 35mL of THF as the reaction solvent, add 2mL of water, after three filling and three pumping, reflux. After 6h, evaporate the THF in the system to dryness with a rotary evaporator, add ethyl acetate to dissolve the residue, successively water (once), saturated NaHCO 3 (2 times), water (1 time), and saturated NaCl (1 time) washed the organic phase successively. Finally with anhydrous Na2 SO 4 Dry, evaporate to dryness, and then use THF:PE=1:8 system as developing solvent to carry out silica gel column chromatography separation and purification to obtain white powdery solid E5. The characterization results are as follows:

[0069] 1 H NMR (500MHz, CDCl 3 ): δ7.86(d, J=5.6Hz, 2H), 7.64(dt, J=8.6, 6.1Hz, 4H), 7.46(t, J=7.6Hz, 2H), 7.39(t, J=7.3Hz , 1H), 6.64(d, J=8.3Hz, 1H), 5.34(td, J=10.1, 3.7Hz, 1H), 3.36(s, 3H), 3.24(s, 3H), 1.82(dd, J=...

Embodiment 2

[0072]

[0073] Put 0.41g of pyridine boronic acid and 0.39g of pinacol in a 50mL round bottom flask, add an appropriate amount of toluene as a solvent, and reflux. During the whole process, the evaporated water is continuously released from the system. Stop the reaction after 4 h, and check whether the reaction is complete by thin layer chromatography (TLC). The round-bottomed flask was cooled at room temperature, and suction filtered to obtain 0.67 g of pyridine borate as a white solid. Take 0.6g of pyridine borate, and other reaction materials, conditions and post-treatment process are the same as the synthesis route of E5. Finally, E6 was obtained as a crystalline solid. The characterization results are as follows:

[0074] 1 H NMR (500MHz, CDCl 3 ): δ8.67(d, J=4.3Hz, 2H).7.64(d, J=8.1Hz, 2H), 7.53-7.40(m, 4H), δ4.23(t, J=7.4Hz, 1H) , 3.20(s, 4H), 2.58(s, 2H), δ2.10(m, 1H), 1.55(ddd, J=20.1, 17.8, 11.1Hz, 2H), 1.01-0.96(m, 6H).

[0075] MS (ESI) m / z: [M+H] + : 3...

Embodiment 3

[0077]

[0078] Take 0.46g of thiophene boronic acid, and other reaction raw materials, conditions and post-treatment process are the same as the synthesis route of E5. Finally, E7 was obtained as a crystalline solid. The characterization results are as follows:

[0079] 1 H NMR (500MHz, DMSO): δ7.64(d, J=7.7Hz, 1H), 7.52(dd, J=19.7, 4.1Hz, 1H), 7.36(t, J=7.4Hz, 1H), 7.14( dd, J=5.0, 3.7Hz, 1H), δ4.23(t, J=7.4Hz, 1H), 3.20(s, 4H), 2.58(s, 2H), δ2.10(m, 1H), 1.55 (ddd, J=20.1, 17.8, 11.1Hz, 2H), 1.01-0.96(m, 6H).

[0080] MS (ESI) m / z: [M+H] + : 342.2.

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Abstract

The invention provides a hydrazine cathepsin K inhibitor and an application of the inhibitor in treating osteoporosis, which belong to the technical field of cathepsin inhibitors. The inhibitor does not include a P2-P3 connection part but have different P3 locus structures. The structure is represented by the following formula, and in the formula, P3 is aryl and comprises para-biphenyl, para-phenyl-pyridine, para-phenyl thiophene, para-terphenyl and meta-terphenyl. The non-peptide hydrazine cathepsin inhibitor designed and synthesized in the invention has the advantages of being relatively simple in structure, easy to get in materials, convenient to synthesize and high in yield; the design and the synthesis of the matrix structure greatly facilitate the synthesis of subsequent final products. By adopting the inhibitor, the inhibiting effect to the cathepsin K is higher than sub-nano-mole level, and the inhibiting effect to B and S is on micro-mole level, and the difference of inhibiting effects of cathepsin K and cathepsin L with extremely high homology is increased, thus the possibility of developing the inhibitor as the medicine for treating osteoporosis is increased.

Description

technical field [0001] The invention belongs to the technical field of cathepsin inhibitors, in particular to a class of novel hydrazinonitrile cathepsin inhibitors with high selectivity. This type of inhibitor has a non-peptide structure (the P2-P3 site is directly connected), and has strong specificity for the inhibition of cathepsin K, so it has potential for the clinical treatment of osteoporosis and related diseases application prospects. Background technique [0002] Normal bone metabolism in humans is based on a dynamic balance between bone formation and bone resorption [1] , and osteoporosis is the imbalance of bone metabolism - the embodiment of bone resorption greater than bone formation. These diseases are more common in middle-aged and elderly people, especially in menopausal and postmenopausal women [2，3] . In the process of bone resorption, osteoclasts first attach to the bone surface, forming a relatively sealed bone resorption cavity. Osteoclasts are act...

Claims

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Application Information

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IPC IPC(8): C07C261/04C07D213/54C07D333/24A61K31/277A61K31/381A61K31/4409A61P19/02A61P19/10A61P29/00
Inventor 吴玉清原晓喻李洪伟
Owner JILIN UNIV
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