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New type compound, its preparation method and application

A compound and prodrug technology, applied in the field of new pharmaceutical compounds, can solve the problems of poor oral bioavailability, short half-life, high inhibitory thrombin activity, etc.

Active Publication Date: 2012-05-23
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A series of compounds that changed NAPAP’s benzamidine to piperidine formamidine also had higher thrombin-inhibiting activity. Among them, napsagatran synthesized by Hoffmann-La Roche Company had the strongest activity and had an effect on blood fibrinase. It had been used in phase II clinical trials Studies, but short half-life and poor oral bioavailability
[0008] Astra company disclosed a class of benzamidine analogues in WO9429336, wherein melagatran (melagatran) has a strong inhibitory effect on thrombin activity, and can be safely used for deep venous thrombosis (DVT) without significant bleeding problems, but oral bioavailability low concentration, and further synthesized its double prodrug ximelagatran (ximelagatran), which was launched in 2004

Method used

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  • New type compound, its preparation method and application
  • New type compound, its preparation method and application
  • New type compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Embodiment 1: Synthesis of N-benzenesulfonyl-D, L-leucyl-L-prolyl-{[4-(N'-hydroxyl) formamidinophenyl]methyl}amide

[0203] a) N-benzenesulfonyl-D, the preparation of L-leucine

[0204] Dissolve D, L-leucine (2g) in 1.5N sodium hydroxide solution (10ml), add dioxane (15ml), cool and control the temperature at 0-5°C; slowly add benzenesulfonyl chloride (3g) dropwise and 1.5N sodium hydroxide solution to maintain a pH value of 9 to 10; react at 0 degrees for 2 hours, and naturally rise to room temperature for 2 hours. Under cooling, dilute hydrochloric acid was added dropwise to adjust the pH to 3, concentrated under reduced pressure to remove dioxane, and a large amount of solid precipitated; filtered, and the obtained solid was recrystallized with ethyl acetate / petroleum ether to obtain 3.7 g of white solid. Content 99% (HPLC, mobile phase 1, method 2).

[0205] Rf=0.8 developing agent n-butanol: water: acetic acid: ethyl acetate = 1:1:1:1 color development: ultraviol...

Embodiment 2

[0221] Embodiment 2: N-benzenesulfonyl-D, the preparation of L-leucyl-L-prolyl-[(4-formamidinophenyl) methyl] amide acetate

[0222] The compound obtained in Example 1 was dissolved in acetic acid (7ml), acetic anhydride (277mg) and 10% palladium carbon (150mg) were added, hydrogen was passed for 24 hours, filtered, concentrated under reduced pressure to remove the solvent, ether (20ml) was added, Place in the refrigerator overnight, the solid precipitated, filtered and dried (250mg, 66%)

[0223] MS: 560(M+H)

Embodiment 3

[0224] Example 3: N-benzylsulfonyl-D, L-leucyl-L-prolyl-{[4-(N'-hydroxyl) formamidinophenyl]methyl}amide

[0225] a) N-benzylsulfonyl-D, the preparation of L-leucine

[0226] Dissolve D,L-leucine (2g) in 1.5N sodium hydroxide solution (10ml), add dioxane (15ml), cool and control the temperature at 0-5°C; slowly add benzylsulfonyl chloride (3.2g ) and 1.5N sodium hydroxide solution to maintain a pH value of 9 to 10; react at 0 degrees for 2 hours, and naturally rise to room temperature for 2 hours. Under cooling, dilute hydrochloric acid was added dropwise to adjust the pH to 3, concentrated under reduced pressure to remove dioxane, and a large amount of solid precipitated; filtered, and the obtained solid was recrystallized with ethyl acetate / petroleum ether to obtain 3.5 g of white solid. Content 99% (HPLC, mobile phase 1, method 2).

[0227] Rf=0.8 developing agent n-butanol: water: acetic acid: ethyl acetate = 1:1:1:1 color development: ultraviolet, iodine and 1% ninhydri...

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PUM

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Abstract

The invention discloses a compound of formula (1), its pharmaceutically acceptable salt and its pharmaceutically acceptable prodrug. The invention also discloses a preparation method of the compound of formula (1), its application on inhibition of thrombin and its application on prevention of thrombin mediated and thrombin related diseases.

Description

technical field [0001] The present invention relates to new pharmaceutical compounds, and specifically relates to the preparation method of the compounds, their use as medicine and the pharmaceutical compositions containing them. The novel pharmaceutical compounds of the present invention act as competitive inhibitors of tryptase-like serine proteases, especially thrombin. Background technique [0002] The mortality rate of cardiovascular and cerebrovascular diseases has been ranked second in the world, among which thromboembolism is the main cause of high rate of morbidity and death of cardiovascular and cerebrovascular diseases. Especially with the changes in people's lifestyles and the increasing aging of the population, the incidence of such diseases shows a continuous upward trend. This makes it extremely urgent to explore and study drugs that can effectively prevent and treat such diseases, which is of great significance in both clinical application and basic research...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P9/10A61P7/02
CPCC07D207/16A61K9/00A61K47/12A61K47/38A61K9/2054A61K9/2059A61K9/4858A61K9/4866A61P7/02C07K5/06034C07K5/06043A61K38/00A61K38/06C07K5/06165C07D205/04C07D211/60C07K5/0215
Inventor 单汉滨黄雨袁哲东俞雄李敏
Owner LIVZON PHARM GRP INC
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