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Pyrrolidinyl metalloprotease inhibitor and its application

A technology of methyl pyrrolidine acid and alkyl group, applied in pyrrolidine-based matrix metalloproteinase inhibitors and their application fields, can solve the problems of unsatisfactory performance and the like

Inactive Publication Date: 2005-07-13
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these MMPs inhibitors existing in the prior art show high MMPs inhibitory activity in vitro as described in the literature, the performance in the activity analysis of anti-H22 tumor cell metastasis in vivo is not satisfactory, and its In vivo inhibition rate <30%

Method used

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  • Pyrrolidinyl metalloprotease inhibitor and its application
  • Pyrrolidinyl metalloprotease inhibitor and its application
  • Pyrrolidinyl metalloprotease inhibitor and its application

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Experimental program
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Effect test

Embodiment 1

[0061] Embodiment 1: the synthesis of compound of the present invention

[0062] The melting point of the compound was determined by a micro melting point apparatus (the thermometer was not calibrated); thin layer chromatography (TLC, silica gel 60 GF 254 , Qingdao Ocean Chemical Factory) is used to monitor the reaction and check the product purity, using saturated iodine vapor, 10% sulfuric acid ethanol solution, phosphomolybdic acid and other common color developers, 1% FeCl 3 Solution - 2% K 3 Fe(SCN) 6 Solution for detection of phenolic compounds, 1% FeCl 3 The solution is used to detect hydroxamic acid compounds; IR (NICOLET NEXUS470FT-SPECTROMETER type infrared spectrometer is measured, and sample processing adopts potassium bromide tablet method) and ESI-MS (API 4000 type mass spectrometer) by Shandong University School of Pharmacy Determination in the central laboratory; 1 H-NMR was determined by the Institute of Materia Medica, Chinese Academy of Medical Sciences ...

Embodiment 2

[0123] Embodiment 2: The activity of compound of the present invention in vitro and in vivo Inhibition of MMPs test in vitro

[0124] Gelatinase (mmp-2, -9) and TNBS (3,4,5-trinitrobenzenesulfonic acid) were purchased from sigma, and substrates were synthesized as described by Vijaykumar, M.B. et al. Gelatin, substrates and inhibitors were incubated in sodium borate solution (pH 8.5, 50mmol / L) at 37°C for 30min, then added with 0.03% TNBS and incubated for another 20min. The absorbance of the resulting solution was measured at a wavelength of 450 nm.

[0125] Inhibitory activity of compounds of the present invention (IC 50 ) are shown in Table 1 and Table 2.

[0126] Table 1. In vitro inhibitory activity of compound 6-33

[0127]

[0128]

No.

R 1

R 2

R’

4 *

IC 50

(nmol)

6

Oh

OMe

Me

S

657.9±34.6

7

Oh

OMe

Ac

S

nd *

8

OSO 2 CH 3

...

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Abstract

The present invention is pyrrolidinyl matrix metalloprotease inhibitor and its application. One kind of powerful matrix metalloprotease inhibitor is provided to treat disease with abnormal matrix metalloprotease activity expression effectively. Specifically, the present invention relates to the compound, various optical isomers, pharmaceutically acceptable salts, solution and precursor medicine. The present invention also relates to their pharmaceutical use.

Description

technical field [0001] The present invention relates to a class of compounds capable of inhibiting matrix metalloproteinases (MMPs), a preparation method, an activity test, compositions containing the compounds, and applications of these compositions. Background technique [0002] Matrix metalloproteinases (MMPs) are a class of zinc ion-dependent endopeptidases that play an important role in the degradation and remodeling of the extracellular matrix, and their activity is regulated by endogenous tissue metalloproteinase inhibitors (Gomez DE, Alonso DF, Yonshiji H, et al. Eur. J. Cell Biol. 1997; 74: 111-122). The delicate balance between them is disturbed in many pathological conditions, such as tumors, osteoarthritis, rheumatoid arthritis, etc. [0003] At least 24 members of the MMPs family have been found in mammals (Chambers A.F., Matrisian L. Changing views of the role of matrix metallo-proteinases in metastasis. J. Natl. Cancer Inst. 1997; 89: 1260-1270), according to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/40A61P1/02A61P1/04A61P29/00A61P35/00A61P43/00C07D207/10C07D207/16
Inventor 徐文方李亚林张震
Owner SHANDONG UNIV
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