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Azolidinone-vinyl fused-benzene derivatives

Inactive Publication Date: 2009-12-10
MERCK SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]wherein A, X, Y, Z, n, R1 and R2 are described in details in the description hereinafter, as well as pharmaceutically acceptable salts thereof, for the preparation of pharmaceutical compositions for the treatment and / or prophylaxis of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation complications, graft rejection or lung injuries. Compounds of this invention are inhibitors of Phosphato-inositides 3-kinases (PI3Ks), particularly of Phosphatoinositides 3-kinases gamma (PI3Kγ).

Problems solved by technology

However, in as much as these compounds do not distinguish among the various isoforms of PI3K, it remains unclear which particular PI3K isoform or isoforms are involved in these phenomena.

Method used

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  • Azolidinone-vinyl fused-benzene derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione

[0559]

[0560]In a 100 ml round bottom flask were placed 20 g of thiazolidine, 15.6 g of piperonal and 7.7 g of beta-alanine in 80 ml of acetic acid. The reaction was stirred for 3 h at 100° C. and then slowly cooled to room temperature, while the desired condensation product crystallized. The crystals were filtered, washed with acetic acid (rt.) and water than recrystallized from DME (25 ml), affording 28 g (84%) of pure 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione. The corresponding potassium salt was obtained via the following route: 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione was suspended in THF, followed by the addition of 1N solution of KOH in water (1.0 eq.). A clear solution has been obtained, which upon lyophilization gave pure potassium salt of 5-(1,3-benzodioxol-5-ylmethylene)-1,3-thiazolidine-2,4-dione.

[0561]HPLC: 3.48 min. LC-MS: M / Z ESI: 1.31 min, 248.12 (M−1). NM...

example 2

Preparation of 5-(1,3-benzodioxol-5-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one

[0566]

[0567]In a 24 ml vial was placed 1 g of commercially available rhodanine, 1.3 g of piperonal and 0.5 ml of TEA in 10 ml of DME. The reaction was stirred for 5 h at 120° C. and then cooled to room temperature upon which the final product precipitated. The solid was filtered and washed with DME affording 1.6 g (80%) of orange powder.

[0568]LC-MS: M / Z ESI: 1.46 min, 266.00 (M+1), 264.08 (M−1). NMR (parent): 1H NMR (DMSO-d6) δ 13.75 (br. s, 1H), 7.58 (s, 1H), 7.08-7.18 (m, 3H), 6.14 (s, 2H).

example 3

Preparation of 5-(2,3-dihydro-1,4-benzodioxin-6-ylmethylene)-1,3-thiazolidine-2,4-dione:

[0569]

[0570]Following the general method as outlined in Example 1, starting from 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 1,3-thiazolidine-2,4-dione, the title compound was obtained.

[0571]HPLC: 2.58 min. LC-MS: M / Z ESI: 1.32 min, 262.16 (M−1). 1H NMR: (DMSO-d6) δ 12.52 (br. s, 1H), 7.68 (s, 1H,), 7.09 (dd, 2H, J=1.9, 7.1), 7.00 (d, 1H, J=9.0 Hz), 4.36-4.22 (m, 4H).

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Abstract

The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and / or prophylaxis of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries.wherein A, X, Y, Z, R1, R2 and n are as described in the description.

Description

FIELD OF THE INVENTION [0001]This present invention is related to the use of azolidinone-vinyl fused-benzene derivatives of formula (I) for the treatment and / or prophylaxis of autoimmune disorders and / or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Specifically, the present invention is related to substituted azolidinone-vinyl fused-benzene derivatives for the modulation, notably the inhibition of the activity or function of the phospho-inositide-3′OH kinase family, PI3K, particularly of the PI3Kγ.BACKGROUND OF THE INVENTION [0002]Cellular plasma membranes can be viewed as a large store of second messenger that can be enlisted in a variety of signal transduction pathways. As regards function and regulation of effector enzymes in phospholipid signalling pathways, these enzymes generate second messengers from the membrane phospholipid pool (cla...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/536A61K31/426A61K31/4709A61K31/517A61K31/498A61K31/454A61P37/06A61P9/00A61P35/00A61P11/00A61P31/12A61K31/00A61K31/427A61K31/5377A61P1/04A61P7/02A61P9/10A61P9/12A61P11/06A61P13/12A61P17/06A61P19/02A61P21/00A61P25/00A61P25/14A61P25/28A61P29/00A61P31/00A61P35/04A61P37/02A61P37/08A61P43/00C07D277/18C07D277/20C07D277/34C07D417/06C07D417/14
CPCA61K31/426A61K31/427A61K31/4709A61K31/498C07D417/14A61K31/538C07D277/20C07D417/06A61K31/517A61P1/04A61P1/18A61P11/00A61P11/06A61P13/12A61P17/06A61P19/02A61P21/00A61P25/00A61P25/14A61P25/28A61P29/00A61P31/00A61P31/04A61P31/12A61P35/00A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00A61P7/02A61P9/00A61P9/08A61P9/10A61P9/12
Inventor RUECKLE, THOMASJIANG, XULIANGGAILLARD, PASCALECHURCH, DENNISGRIPPI VALLOTTON, TANIA
Owner MERCK SERONO SA
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