Thiazolidinedione derivatives as PI3 kinase inhibitors

A thiazolidine, dione technology, applied in the field of thiazolidinedione derivatives, can solve problems such as expression restriction

Inactive Publication Date: 2009-06-24
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, class Ib enzymes are activated by the G-protein-coupled receptor (GPCR) system, and their expression appears to be granulocyte-restricted

Method used

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  • Thiazolidinedione derivatives as PI3 kinase inhibitors
  • Thiazolidinedione derivatives as PI3 kinase inhibitors
  • Thiazolidinedione derivatives as PI3 kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0238] Example 1: (5Z)-5-{[4-(4-pyridyl)-6-quinolyl]methylidene}-1,3-thiazolidine-2,4-dione

[0239]

[0240] a) 4-chloro-6-vinylquinoline

[0241] 6-bromo-4-chloroquinoline (6.52 g, 26.88 mmol; see J. Med. Chem., 21, 268 (1978)), tributyl (vinyl) tin (8.95 g, 28.22 mmol) and tetra( A mixture of triphenylphosphine)palladium(0) (0.62 g, 0.54 mmol) in 1,4-dioxane (150 mL) was refluxed for 2.0 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-4% MeOH:CH 2 Cl 2 ) to afford the title compound (5.1 g) as a pale yellow solid. MS(ES)+m / e 190[M+H] + . The above material was used directly in the next step.

[0242] b) 4-Chloro-6-quinolinecarbaldehyde

[0243] 4-Chloro-6-vinylquinoline (5.1g, 26.88mmol), 2,6-lutidine (5.76g, 53.75mmol), (meta)sodium periodate (22.99g, 107.51mmol) and Osmium tetroxide (5.48g, 2.5% tert-butanol solution, 0.538mmol) in 1,4-dioxane: H 2 The mixture in O (350 mL, 3:1 mixtur...

Embodiment 2

[0248] Example 2: (5Z)-5-{[4-(3-pyridyl)-6-quinolyl]methine}-1,3-thiazolidine-2,4-dione

[0249]

[0250] Following the procedure used for the preparation of Example 1, the title compound was prepared by using 3-pyridylboronic acid in place of 4-pyridylboronic acid. MS(ES)+m / e 334[M+H] + .

Embodiment 3

[0251] Example 3: (5Z)-3-methyl-5-{[4-(4-pyridyl)-6-quinolyl]methine}-1,3-thiazolidine-2,4-dione

[0252]

[0253] Following the procedure used for the preparation of Example 1, the title compound was prepared by using 3-methyl-1,3-thiazolidine-2,4-dione in place of 1,3-thiazolidine-2,4-dione to give yellow solid. MS(ES)+m / e 348[M+H] + .

[0254] Alternatively, some of the examples were prepared by palladium-catalyzed Suzuki (or Stille) coupling of heteroarylboronic acids (or heteroarylstannanes) with 4-iodo-6-quinolinecarbaldehyde (Scheme II). The iodide intermediate was prepared by treating the corresponding chloride with 4N HCl followed by sodium iodide. The heteroaryl aldehyde was converted into the title compound following the same procedure as in Preparation Example 1.

[0255] Flowchart II:

[0256]

[0257] Conditions: a) 4N HCl in dioxane, room temperature, 5 minutes; then NaI, 105°C, 18 hours; b) heteroaryl(R)boronic acid, Pd(PPh3) 4 , 2M K 2 CO 3 , dio...

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Abstract

Invented is a method of inhibiting the activity / function of PI3 kinases using thiazolidinedione derivatives. Also invented is a method of treating one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries by the administration of thiazolidinedione derivatives.

Description

field of invention [0001] The present invention relates to the use of thiazolidinedione derivatives for regulating, especially inhibiting, the phosphoinositides 3'OH (phosphoinositides 3'OH) kinase family (hereinafter referred to as PI3 kinases), suitably PI3Kα, PI3Kδ , PI3Kβ and / or PI3Kγ activity or function. Suitably, the present invention relates to the use of thiazolidinedione in the treatment of one or more diseases selected from the group consisting of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, asthma, pancreatitis, Multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, and lung injury. Background of the invention [0002] The cell membrane represents a large store of second messengers that can participate in various signal transduction pathways. When focusing on the function and regulation of effector enzymes in the phospholipid sign...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44C07D215/04
CPCC07D417/14A61P1/04A61P1/18A61P11/00A61P11/06A61P13/12A61P15/08A61P17/06A61P19/02A61P21/00A61P25/00A61P25/14A61P25/28A61P29/00A61P31/00A61P31/04A61P31/12A61P35/00A61P35/02A61P35/04A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12C07D417/10A61K31/4709
Inventor 迈克尔·G·达西史蒂文·D·奈特尼古拉斯·D·亚当斯斯坦利·J·施密特
Owner SMITHKLINE BECKMAN CORP
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