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AKT protein kinase inhibitors

a technology of akt protein and kinase, which is applied in the field of inhibitors of serine/threonine protein kinases, can solve the problems of extreme cell death (apoptosis), and the potential consequences of disease are enormous

Inactive Publication Date: 2005-06-16
ARRAY BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0037] In a further embodiment, the present invention provides a method of providing AKT protein kinase inhibiting effect comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo cleavable prodrug thereof.

Problems solved by technology

Often, an interconnected series (or cascade) of protein kinases is necessary to exert the overall effect of this initial signal, which can ultimately result in effects as extreme as cell death (apoptosis).
Should this kinase / phosphatase relationship become disregulated, the potential consequences relating to disease are enormous.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1a

[0303]

Preparation of 4-Piperazinylquinazoline Amino Amides

[0304] Step 1: To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) (Tobe, Masanori, et al., Bioorg. Med. Chem. 2003, 11(3), 383) and DIEA (3.2 mL, 18.2 mmol) in 40 mL IPA was added Boc-piperazine (1.96 g, 12.81 mmol). The reaction mixture was heated to reflux and stirred for 20 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was dissolved in 25 mL dioxane, and 4M HCl / dioxane (46 mL, 182 mmol) was added dropwise. The suspension was sonicated for 2 minutes and stirred 13 hours at room temperature, after which the reaction mixture was concentrated to dryness by rotary evaporation. The resulting amine HCl salt was dissolved in 2N NaOH and extracted with DCM. The organic layer was dried (Na2SO4), filter...

example 1b

[0306] The following amino acids were introduced as Boc-protected amino acids to the 4-piperazinylquinazoline in Example 1, Step 2:

[0307] The compounds described in Examples 2-21 were prepared as described in Example 1, Step 2, using 4-piperazinylquinazoline and the appropriate amino acid shown in Example 1B.

example 2

[0308]

(2R)-2-Amino-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one

[0309] Rt 2.15. MS (ESI+) [M+H]+ 362.

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Abstract

The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula: A-L-CR where CR is a cyclical core group, L is a linking group and A is as defined herein. Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 524,003, filed Nov. 21, 2003, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to novel inhibitors of serine / threonine protein kinases (e.g., AKT and related kinases), pharmaceutical compositions containing the inhibitors, and methods for preparing these inhibitors. The inhibitors are useful for the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals and especially in humans. [0004] 2. Description of the State of the Art [0005] Protein kinases are a class of enzymes that catalyze the transfer of the γ-phosphorate group from ATP to a recipient protein, acting as a substrate. The specific target of the kinase is the hydroxyl group of a serine, threonine or tyrosine residue. As a result of this specific targeting, kinases are gen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61KA61K31/496A61K31/519A61K31/53
CPCC07D237/28C07D401/12C07D239/47C07D239/48C07D239/94C07D401/04C07D403/04C07D403/12C07D409/04C07D409/12C07D471/04C07D487/04C07D491/048C07D495/04B41M3/008B44F1/10G09F13/16C07D231/56C07D239/42A61P29/00A61P35/00A61P43/00C07D409/14C07D401/14A61K31/496Y10T428/24802Y10T428/24851Y10T428/25Y10T428/31507Y10T428/31551Y10T428/31786Y10T428/31855
Inventor MITCHELL, IAN S.SPENCER, KEITH L.STENGEL, PETERHAN, YONGXINKALLAN, NICHOLAS C.MUNSON, MARKVIGERS, GUY P.A.BLAKE, JAMESPISCOPIO, ANTHONYJOSEY, JOHNMILLER, SCOTTXIAO, DENGMINGXU, RIURAO, CHANGWANG, BINBERNACKI, APRIL L.
Owner ARRAY BIOPHARMA
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