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Pyrrolidine matrix metall oprotease inhibitor and preparing method thereof

The technology of methyl pyrrolidine acid and alkyl group is applied in the field of pyrrolidine matrix metalloproteinase inhibitor and its preparation, which can solve the problems of unstable hydroxamic acid group, short half-life, toxicity and the like, and achieve high anti-cancer effect. active effect

Inactive Publication Date: 2004-09-15
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The most active chelating group currently known is a hydroxamic acid group, see Borkakoti N., etc., Nature Structural Biology, 1994 Feb; 1 (2): 106-110 (Borkakoti N, et al.Nat Struct Biol.1994Feb; 1(2):106-110), but in vivo, the hydroxamic acid group has metabolic and pharmacokinetic problems, such as its in vivo Short half-life, see Mulder G.J. et al., Environmental Health Perspective, 1983 Mar; 49:27-32 (Mulder GJ, et al., Environ Health Perspect. 1983 Mar; 49:27-32); also has problems in toxicity, many isohydroxy The hydroxamic acid group is unstable and hydrolyzed into hydroxylamine, resulting in toxicity; and the water solubility of hydroxamic acid is poor, which increases the difficulty in the choice of drug administration route and preparation, see Wesley S. et al., Journal of Medicinal Chemistry, 1999 Jul 15; 42(14):2610-20 (Vassiliou S, et al. J Med Chem. 1999 Jul 15; 42(14):2610-20)

Method used

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  • Pyrrolidine matrix metall oprotease inhibitor and preparing method thereof
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  • Pyrrolidine matrix metall oprotease inhibitor and preparing method thereof

Examples

Experimental program
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Effect test

Embodiment 11

[0085] Example 1.1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-4-hydroxy-2-pyrrolidinic acid methyl ester (intermediate II)

[0086] (1) Preparation of 4-hydroxyproline methyl ester hydrochloride.

[0087]Suspend 20g (0.15mol) of 4-hydroxyproline in 150mL of anhydrous methanol, pass through HCl until the solution is clear, reflux for 3 hours, remove the methanol by rotary evaporation until a white precipitate precipitates, stand at low temperature for 2 hours, and filter to obtain white crystals , washed the filter cake with acetone and ether, respectively, and dried under reduced pressure to obtain 25.0 g of white crystals. Yield 90%. The melting point is 162-164°C.

[0088] (2) Preparation of (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid.

[0089] Dissolve 18g (0.1mol) of caffeic acid in 90mL of cold 4N NaOH, control the internal temperature below 20°C, add 20mL of Me 2 SO 4 , after reacting for 20min, 50mL 4N NaOH and 20mL Me 2 SO 4 After the dropwise addition is complet...

Embodiment 2

[0094] Example 2.4-amino-1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-2-pyrrolidinic acid methyl ester (intermediate III)

[0095] (1) Preparation of 1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-4-(methylsulfonyloxy)-2-pyrrolidinic acid methyl ester.

[0096] In a nitrogen atmosphere, 3.35g (10mmol) of 1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-4hydroxy-2-pyrrolidinic acid methyl ester was dissolved in 20mL Anhydrous CH 2 Cl 2 , shake the solution, add 4.5mL Et at 0°C 3 N, add dropwise 5 mL of anhydrous CH containing 0.8 mL of methanesulfonyl chloride 2 Cl 2 solution, remove the cold bath, stir at room temperature for 4h, CH 2 Cl 2 Dilute the reaction solution, respectively, with saturated NaHCO 3 aqueous solution, distilled water, saturated brine to wash the organic phase, anhydrous Na 2 SO 4 dry. The organic phase was distilled off to obtain a light yellow oil, which was separated by column chromatography under reduced pressure. The eluent was petroleum ether: acetone ...

Embodiment 31

[0101] Example 3. Preparation of 1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-2-N-hydroxyamido-4-(2-phenylacetyl)aminopyrrolidine

[0102] (1) 1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-4-[(2-phenylacetyl)amino]-2-pyrrolidinic acid methyl ester preparation.

[0103] Dissolve 334 mg (1 mmol) of methyl 4-amino-1-[(E)-3-(3,4-dimethoxyphenyl)-2-acryloyl]-2-pyrrolidinate in 2 mL of anhydrous CH 2 Cl 2 and 0.5mL Et 3 In N, add dropwise 2 mL of CH containing 155 mg phenylacetyl chloride 2 Cl 2 solution, stirred at room temperature for 3h, during which a white solid was formed, adding CH 2 Cl 2 Dilute the reaction solution with 1% hydrochloric acid, 5% Na 2 CO 3 , the organic phase was washed with distilled water, anhydrous Na 2 SO 4 dry. The solvent was removed by rotary evaporation to obtain a yellow fluffy solid, which was separated by column chromatography under reduced pressure. The eluent was petroleum ether: ethyl acetate (4:1-1:4), and 268 mg of white crystals were ob...

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Abstract

The invention is a pyrrol alkyl matrix metalloproteinase inhibitor and preparing method, relating to the corresponding compound preparation, active test of inhibiting matrix metalloproteinase and the drug combination in which it acts as active component.

Description

(1) Technical field [0001] The invention relates to a class of compounds capable of inhibiting matrix metalloproteinases (MMPs), a preparation method, an activity test, and applications of these compositions. (2) Background technology [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, see Gomos D.E. et al , European Journal of Cell Biology 1997;74:111-122 (Gomez D.E., 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, see Chambers A.F. et al., Journal of National Cancer Institute, 1997; 89:1260-1270 (Chambers A.F., J.Natl.Cancer Inst.1997; 89: 1260-1270), whi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/14C07D207/16
Inventor 徐文方李亚林张震
Owner SHANDONG UNIV
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