Inhibitors of Akt activity

A kind of compound, the technology of dihydrogen, be used in the compound field containing heterocyclic triazine

Inactive Publication Date: 2008-10-01
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No specific PDK1 inhibitors have been reported. Furthermore, inhibition of PDK1 may lead to inhibition of many protein kinases whose activity is dependent on PDK1, for example, atypical PKC isoforms, SGK and S6 kinases (Williams et al., Curr. Biol. 10 : 439-448 (2000)).

Method used

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no. 1 approach

[0035] The third embodiment of the present invention is a compound represented by formula B, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0036] Q selected from: optional by 1-3 R z substituted-NR 6 R 7 , phenyl and heterocyclyl;

[0037] R a For: (C 1 -C 6 ) Alkyl, (C 3 -C 6 ) cycloalkyl, aryl or heterocyclyl; and

[0038] R b For: H, (C 1 -C 6 ) Alkyl, aryl, heterocyclyl, (C 3 -C 6 ) cycloalkyl, (C = O) OC 1 -C 6 Alkyl, (C=O)C 1 -C 6 Alkyl or S(O) 2 R a ; All other substituents and variables are as defined in the second embodiment.

[0039] The fourth embodiment of the present invention is a compound represented by the following formula C, or a pharmaceutically acceptable salt or stereoisomer thereof:

[0040]

[0041] in:

[0042] Q is a heterocyclic group, and the heterocyclic group is optionally replaced by 1-3 R z replace;

[0043] R 2 Independently selected from: 1) C 1 -C 6 Alkyl, 2) aryl, 3) heterocyclyl, 4) CO...

Embodiment 1

[0277] Cloning of human Akt isoforms and ΔPH-Akt1

[0278] The pS2neo vector (deposited at ATCC on April 3, 2001 with the accession number ATCCPTA-3253) was prepared as follows: cut the pRmHA3 vector with BglII (according to the introduction in Nucl.Acid Res.16:1043-1061 (1988) method), and a 2734 bp fragment was isolated. The pUChsneo vector (prepared according to the method described in EMBO J.4: 167-171 (1985)) was also cut with BglII, and a 4029 bp fragment was isolated. The two isolated fragments ligated to generate the vector, called pS2neo-1. This plasmid contains a polylinker between the metallothionein promoter and the alcohol dehydrogenase polyA addition site. It also has a neo resistance driven by a heat shock promoter Gene. The pS2neo-1 vector was cut with Psp5II and BsiWI. Two complementary oligonucleotides were synthesized and then annealed (CTGCGGCCGC (SEQ.ID.NO.: 1) and GTACGCGGCCGCAG (SEQ.ID.NO.2)). Cut pS2neo-1 was ligated with annealed oligonucleotides to...

Embodiment 2

[0301] Expression of human Akt isoforms and ΔPH-Akt1

[0302] Using the calcium phosphate method, the DNA containing the cloned Akt1, Akt2, Akt3 and ΔPH-Akt1 genes in the pS2neo expression vector was purified, and transfected into Drosophila (Drosophila) S2 cells (ATCC). Select antibiotics (G418, 500 μg / ml) Resistant cell aggregates. Dilute the cells to a volume of 1.0L (approximately 7.0×10 6 / ml), adding biotin and CuSO 4 , so that the final concentrations were 50 μM and 50 mM respectively. The cells were grown at 27°C for 72 hours and harvested by centrifugation. The cell pellets were stored at -70°C for later use.

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Abstract

The present invention is directed to compounds which contain a heterocyclic triazine moiety which inhibit the activity of Akt, a serine / threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.

Description

Background of the invention [0001] The present invention relates to heterocyclic triazine-containing compounds that are inhibitors of the activity of one or more serine / threonine kinases, Akt isoforms (Akt is also known as PKB, hereinafter "Akt"). The invention also relates to pharmaceutical compositions containing such compounds and methods of treating cancer using the compounds of the invention. [0002] Apoptosis (programmed cell death) plays an important role in embryonic development, as well as in the pathogenesis of various diseases such as degenerative neuronal diseases, cardiovascular diseases, and cancer. Recent research has led to research on the Identification of various pro-apoptotic and anti-apoptotic gene products that are regulated or executed. Anti-apoptotic genes such as Bcl2 or Bcl-x L Expression of apoptotic cells inhibits apoptotic cell death induced by various stimuli. On the other hand, the expression of pro-apoptotic genes such as Bax or Bad can lead to...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D253/06A61K31/53A61P35/00A61KC07D401/14C07D405/14C07D409/14C07D413/14C07D417/14
CPCC07D401/14C07D253/065C07D413/14C07D405/14C07D417/14C07D409/14A61P11/06A61P29/00A61P35/00A61P37/06A61P37/08A61P43/00A61P5/48A61P9/00A61P3/10
Inventor M·T·比洛多C·W·林德斯利Z·赵
Owner MERCK & CO INC
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