Inhibitors of methionine aminopeptidase-2 and uses thereof

A carbamoyl and thioaryloxy technology, applied in the field of methionine aminopeptidase-2 inhibitor and its application, can solve unstable blood concentration and dose limitation, central nervous system side effect limitation, etc. question

Inactive Publication Date: 2007-01-24
PRAECIS PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the utility of such inhibitors (eg, TNP-470) may be limited due to their rapid metabolic degradation, erratic blood levels, and dose-limiting central nervous system (CNS) side effects

Method used

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  • Inhibitors of methionine aminopeptidase-2 and uses thereof
  • Inhibitors of methionine aminopeptidase-2 and uses thereof
  • Inhibitors of methionine aminopeptidase-2 and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] The synthesis of embodiment 1 compound 2

[0091] Compound 1 was synthesized as described in Example 5 of US Patent 6,548,477, the teachings of which are incorporated herein by reference in their entirety. Compound 1 (1.0 g, 2.36 mmol) was dissolved in 20 mL of 1,4-dioxane. To this stirred solution was added 4.0 M HCl in dioxane (0.65 mL, 2.59 mmol, 1.1 eq) and the reaction was stirred for an additional 15 minutes before being concentrated in vacuo. It was then lyophilized from 20% acetonitrile in water and purified by reverse phase preparative HPLC using an acetonitrile-water gradient.

Embodiment 2

[0092] The synthesis of embodiment 2 compound 3

[0093] Compound 1 (502 mg, 1.2 mmol) was dissolved in 10 mL of 1,4-dioxane in a nitrogen flushed 50 mL round bottom flask. To this stirred solution was added 4.0 M HCl in dioxane (0.73 mL, 2.92 mmol, 2.5 eq) and the reaction was stirred for an additional 2 h at which time LC-MS showed complete disappearance of the starting material. The reaction mixture was concentrated in vacuo to a viscous, white oil pure enough to convert to compound 3. Alternatively, purification can be performed by reverse phase preparative HPLC using an acetonitrile-water gradient.

Embodiment 3

[0094] The synthesis of embodiment 3 compound 4

[0095] Compound 3 (500 mg, 1.2 mmol) was dissolved in 8.0 mL of anhydrous THF in a nitrogen flushed 50 mL round bottom flask. Potassium tert-butoxide (251 mg, 2.3 mmol) was added and the reaction mixture was stirred for 1 hour at which time LC-MS showed complete disappearance of starting material. The reaction mixture was concentrated under reduced pressure and resuspended in dichloromethane. The organic layer was washed with 2x saturated sodium bicarbonate, 2x water and 2x brine, then dried over sodium sulfate and concentrated to a clear, viscous oil. Purified by reverse phase preparative HPLC using acetonitrile-water gradient.

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Abstract

The present invention provides compositions and methods for treating a patient suffering from one of a variety of diseases, including angiogenic diseases, such as cancer, autoimmune disease or parasitic infection.

Description

[0001] related application [0002] This application claims priority to US Provisional Application Serial No. 60 / 533,431, filed December 29, 2003, which is hereby incorporated by reference in its entirety. Background of the invention [0003] Angiogenesis is the fundamental process of forming new blood vessels and is essential for a variety of normal bodily activities such as reproduction, development and wound repair. Although the process is not fully understood, it is thought to involve a complex interplay of molecules that stimulate as well as inhibit the growth of endothelial cells - the primary cells of capillaries. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., a state in which there is no capillary growth) for extended periods of time that can last up to weeks, or in some cases decades . However, when necessary (eg, during wound repair), these cells can undergo rapid proliferation and turnover over a period...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/00A61K31/336C07C271/34C07D303/14C07D303/16C07D303/22
CPCC07C271/34C07C2101/14C07D303/14C07D303/16C07D303/22A61P9/00A61P17/06A61P19/02A61P25/00A61P29/00A61P33/02A61P33/06A61P35/00A61P37/02A61P43/00C07C2601/14C07D407/06C07D407/08
Inventor 查尔斯·汤普森克里斯托弗·C·阿里科·马恩德尔
Owner PRAECIS PHARM INC
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