N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions

A heterocyclic and carbocyclic technology, applied in the field of N-linked heterocyclic antagonists of P2Y1 receptors for the treatment of thrombotic symptoms, can solve the lack of pharmacological properties and other problems

Inactive Publication Date: 2008-08-27
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although inhibition of platelet reactivity is often seen as strong evidence for antithrombotic activity, these antagonists lack the necessary pharmacological properties for in vivo studies

Method used

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  • N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
  • N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
  • N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions

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preparation example Construction

[0463] Scheme 6 describes the preparation of compounds of the invention wherein the A ring is derived from a functionalized intermediate of formula 6.1 wherein Z is nitrogen or sulfur. Intermediate 6.1 is treated with reagents such as α-haloketones in solvents such as ethanol with or without a base such as 2,6-lutidine or NaOAc at temperatures from 0°C to 110°C Or α-haloaldehydes or equivalent reagents treat the intermediates to give compounds of formula 6.3 (for analogous chemistry with Z=sulfur see: Udapudi, V.T. et al. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1986, 25B(12), 1269-72. Singh, S.P.; et.al. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 1985, 24B(1), 119-23).

[0464] Option 6

[0465]

[0466] Scheme 7 describes the preparation of compounds of the invention wherein the A ring is a substituted oxazole from a functionalized intermediate of formula 7.1. Intermediate 7.1 is...

Embodiment 1

[0553] N-(2-(4,4-Dimethyl-3,4-dihydroquinolin-1(2H)-yl)phenyl)-4-(trifluoromethyl)thiazol-2-amine

[0554]

[0555] 1a. 4,4-Dimethyl-3,4-dihydro-1H-quinolin-2-one:

[0556] Aniline (7.26 g, 45.2 mmol) and 3-methylbut-2-enoyl chloride (53.2 g, 45.2 mmol) were heated to reflux in chloroform for 2 hours. After cooling, the mixture was filtered. The filtrate was concentrated to dryness and dried in vacuo. Crude 3-methyl-but-2-enoic acid phenylamide (about 10 g) was dissolved in toluene (50 mL). This toluene solution was added portionwise to the stirred AlCl 3powder (27g). After the addition, the resulting dark brown solution was heated at 80 °C for 2.5 hours. The warm slurry was carefully poured over stirred crushed ice. The resulting mixture was extracted with EtOAc (3x), washed with saturated NaHCO 3 、H 2 O and brine washed and washed with MgSO 4 dry. The residue was subjected to silica gel flash chromatography (CH 2 Cl 2 , followed by EtOAc) to yield 2.2 g of p...

Embodiment 2

[0572] N-(2-(3,3-Dimethylindolin-1-yl)phenyl)-4-(trifluoromethyl)thiazol-2-amine

[0573]

[0574] 2a. 1-Acetyl-1,3-dihydro-indol-2-one:

[0575] Indolin-2-one (6.65 g, 50 mmol) and acetic anhydride (9 mL) were heated to reflux for 15 hours. After cooling, the product was filtered and washed with Et 2 After washing with O and drying in vacuo, 2a (8.2 g, 93.7% yield) was obtained as a solid.

[0576] 2b. 3,3-Dimethylindolin-2-one:

[0577]

[0578] To a stirred solution of 2a (3.2 g, 18.29 mmol) in anhydrous THF (100 mL) was added MeI (2.6 mL, 41.75 mmol, 2.3 eq) followed by 18-crown-6 ( 0.51 g, 4.57 mmol, 0.25 eq). Potassium tert-butoxide (5.12 g, 45.73 mmol, 2.5 eq) was added in portions. The resulting slurry was stirred at -78°C for 1 hour. The mixture was stirred at -78°C to room temperature for 3 hours. Cool in an ice bath, add saturated NH 4 Cl. It was extracted with EtOAc, washed with H 2 O and brine washed with MgSO 4 Dry, filter, and concentrate to d...

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Abstract

The present invention provides novel ureas containing N / -aryl or N-heteroaryl substituted heterocycles of Formula (I): or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are defined herein. These compounds are selective inhibitors of the human P2Y, receptor which can be used as medicaments for treating thromboembolic disorders.

Description

[0001] Cross-references in relation to applications [0002] This application claims the benefit of priority to US Provisional Application No. 60 / 694596, filed June 27, 2005, and US Provisional Application No. 60 / 797064, filed May 2, 2006. All disclosures of the foregoing applications are incorporated herein by reference in their entirety. technical field [0003] The present invention provides novel N-aryl or N-heteroaryl substituted heterocycles and analogs thereof, which are human P2Y 1 Selective inhibitors of receptors. The present invention also provides their various pharmaceutical compositions and response P2Y 1 Methods of treatment for diseases in which receptor activity is modulated. Background technique [0004] Purinoceptors bind to and are activated by various ribosylated (nucleotides) and nonribosylated (nucleosides) purines. This distinction has been used to divide these receptors into two main groups: P1 receptors (A1, A2a, A2b, and A3), which bind to and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D401/04C07D401/10C07D401/12C07D417/14A61K31/40A61K31/427A61P7/00
Inventor 乔晓新王传明詹姆斯·C·萨顿蒂默·冈戈
Owner BRISTOL MYERS SQUIBB CO
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