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Aspartic protease inhibitors

A representative and compound technology, applied in the field of aspartic protease inhibitors, can solve the problem of not obtaining metabolic renin inhibitors and other problems

Inactive Publication Date: 2009-01-28
VITAE PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, no metabolically stable, orally available and sufficiently soluble renin inhibitors that can be prepared on a large scale have yet been obtained

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0369] Preparative HPLC refers to preparative reversed-phase HPLC on a C-18 column, eluting with a gradient of water / acetonitrile containing 0.01% TFA, and running on a Gilson 215 system.

[0370] Analytical method

[0371] LC-MS (3 minutes)

[0372] Column: Chromolith SpeedRod, RP-18e, 50×4.6mm; mobile phase: A: 0.01% TFA / water, B: 0.01% TFA / CH 3 CN; Flow rate: 1mL / min; Gradient:

[0373] Time (minutes)

[0374] Intermediate preparation example

preparation example 1

[0376] (S)-4-(3-chlorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate (31)

[0377]

[0378] Step 1. 3-(Methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid (R)-tert-butyl ester

[0379] To a stirred solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyl diimidazole (230 g, 1.42 mol). The mixture was stirred in an ice water bath for 1 hour. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. After tlc showed that the reaction was complete, the solvent was evaporated. Dissolve the residue in CH 2 Cl 2 (1.2L), use 0.5N HCl aqueous solution, saturated Na 2 CO 3 Washed with aqueous solution and brine, dried over anhydrous sodium sulfate, and evaporated to give 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylic acid (R)-tert-butyl ester (250g, ...

preparation example 2

[0393] (R)-2-((3-Chloro-2-fluorophenyl)(piperidin-3-yl)methoxy)acetamide

[0394]

[0395] Step 1. 3-(3-Chloro-2-fluorobenzoyl)piperidine-1-carboxylic acid (R)-tert-butyl ester

[0396] To a stirred solution of 1-chloro-2-fluoro-benzene (13.0g, 0.1mol) in THF (250mL) was added dropwise 2.5M BuLi in hexane (40mL, 0.1 mol). After stirring for an additional 30 minutes at -75°C, 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylic acid (R)-tert-butyl ester (21.76g , 0.08 mol) in THF (100 mL). The mixture was warmed from -70°C to 0°C. The mixture is saturated with NH 4 The aqueous Cl solution was quenched, extracted with EtOAc (3x), and the combined organic layer was washed with Na 2 SO 4 dry. The solvent was removed, flash column chromatography was performed, and washed with 5% EtOAc in petroleum ether to obtain 3-(3-chloro-2-fluorobenzoyl)piperidine-1-carboxylic acid (R)-tert-butyl ester (19.2g , 70%). 1 HNMR(400MHz, CDCl 3 ): 1.45 (s, 9H), 1.63 (m, 2H), 1.76 (m, 1H), 2.06 (m, 1H),...

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Abstract

The present invention is directed to aspartic protease inhibitors. Certain aspartic protease inhibitors of the invention can be represented by the following structural formula or a pharmaceutically acceptable salt thereof. The present invention is also directed to pharmaceutical compositions comprising the disclosed aspartic protease inhibitors. The present invention is further directed to methods of antagonizing one or more aspartic proteases in a subject in need thereof, and methods for treating an aspartic protease mediated disorder in a subject using the disclosed aspartic protease inhibitors.

Description

[0001] Related application [0002] This application claims priority to the U.S. Provisional Application 60 / 736,564 filed on November 14, 2005, the U.S. Provisional Application 60 / 845,291 filed on September 18, 2006, and the U.S. Provisional Application 60 / 845,331 filed on September 18, 2006. right. The entire teachings of the aforementioned applications are incorporated herein by reference. Background technique [0003] The class of aspartic proteases, including renin, beta-secretase (BACE), HIV protease, HTLV protease, and Plasmepsin I and II, are involved in many disease states. In hypertension, there are elevated levels of angiotensin I, the product of the renin-catalyzed cleavage of angiotensinogen. It is widely believed that elevated levels of amyloid beta, the product of BACE's activity on amyloid precursor protein, are responsible for the presence of amyloid plaques in the brains of patients with Alzheimer's disease. HIV and HTLV viruses rely on their respective aspartic ...

Claims

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Application Information

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IPC IPC(8): C07D211/26C07D211/22C07D401/12C07D407/12C07D409/06C07D417/06A61K31/445A61K31/453A61P9/00
CPCY02A50/30
Inventor J·J·鲍德温D·A·克莱尔蒙C·泰斯S·卡卡蒂安L·W·迪拉德A·V·伊什切恩科苑晶徐振荣
Owner VITAE PHARMA INC
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