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Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands

a technology of pyridine and aryl fused pyridine, which is applied in the field of aryl fused 2, 4disubstituted pyridines, can solve the problem of limiting the potential to evaluate these compounds in many appropriate disease models

Inactive Publication Date: 2006-06-29
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, previous non-peptide NK-3 receptor antagonists suffer from a number of problems such as species selectivity (which limits the potential to evaluate these compounds in many appropriate disease models).

Method used

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  • Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands
  • Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands
  • Aryl fused 2,4-disubstituted pyridines: NK3 receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

example i

[0118]

[0119] To a mixture of 20 g of 4-Aminopyridine and 37 mL of triethylamine in 380 mL of methylene chloride is added 28.8 mL of pivaloyl chloride in a dropwise fashion. After 1 hour at room temperature the reaction mixture is washed with water and sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed in vacuo. The residue is triturated with hexane to afford 4-trimethylacetamidopyridine as a white solid.

example ii

[0120]

[0121] A solution of 10 g of 4-trimethylacetamido pyridine in 150 mL of dry tetrahydrofuran is cooled to −78° C. and 88 mL of 1.6M n-butyllithium in hexane is added in a dropwise fashion. The mixture is then stirred at 0° C. for 3 hours, cooled again to −78° C. and 21.3 g of diethyl oxalate dissolved in 190 mL of tetrahydrofuran is added in a dropwise fashion. the reaction mixture was then gradually allowed to come to room temperature. The reaction mixture is diluted with water and the product is extracted with ether. After drying over magnesium sulfate the solvent is removed in vacuo. The residue is chromatagraphed on silica gel with hexane / ether 2:1 as the eluent to afford ethyl 4-trimethylacetamido-3-pyridylpyruvate as an orange oil.

example iii

[0122]

[0123] A mixture of 3.59 g of ethyl 4-trimethylacetamido-3-pyridylpyruvate, 2.89 g of potassium hydroxide in 10 mL of ethanol and 40 mL of water is heated at reflux for 2 hours. At this time 3.1 g of acetophenone is added and refluxing is continued for 6 hours. The ethanol is removed in vacuo, the resulting aqueous solution is washed with ether and the aqueous layer is acidified to pH5. The product is collected washed with water and dried to afford (2-phenylpyridino[4,3-b]pyridin-4-yl)carboxylic acid as a white solid.

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Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable non-toxic salts or pharmaceutically acceptable solvates thereof wherein: (II) represents (a), (b), (c) or (d) and W, X, Y, A, B, C, D, E are variables as described herein. These compounds are highly selective agonists or antagonists at NK3 receptors or prodrugs thereof. The novel tachykinin NK-3 receptor antagonists contained in this invention have potential utility in the treatment of a broad array of disorders and diseases of the central nervous system (CNS) and periphery in mammals in which activation of NK-3 receptors is of importance.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to aryl fused 2,4-disubstituted pyridines that bind to cell surface receptors, particularly neurokinin-3 (NK-3) receptors. More specifically, the invention relates to such compounds that selectively bind to such receptors. This invention also relates to pharmaceutical compositions comprising such compounds. These novel NK-3 receptor ligands are useful in the treatment of a broad array of disorders and diseases of the central nervous system (CNS) and peripheral nervous systems in mammals that are associated with pathogenic NK-3 receptor activation. [0003] 2. Description of the Related Art [0004] The tachykinins represent a family of structurally related peptides originally isolated based upon their smooth muscle contractile and sialogogic activity. These mammalian peptides include substance P (SP), neurokinin A (NKA) and neurokinin β (NKB). Tachykinins are synthesized in the central nervous sys...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4745C07D471/02
CPCC07D471/04C07D495/04
Inventor YUAN, JUNMAYNARD, GEORGEHUTCHISON, ALAN
Owner NEUROGEN
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