Bis-pyridino containing compounds for the use in the treatment of CNS pathologies

a technology of cns pathologies and bispyridino, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems that quaternary ammonium compounds cannot easily access the brain, and relatively few studies have focused on the therapeutic development of nachr antagonists, etc., to achieve the effect of inhibiting dopamine releas

Inactive Publication Date: 2005-11-24
UNIV OF KENTUCKY RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, relatively few studies have focused on the therapeutic development of nAChR antagonists.
However, it is generally believed that quaternary ammonium compounds do not easily access the brain due to their charge and polarity.

Method used

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  • Bis-pyridino containing compounds for the use in the treatment of CNS pathologies
  • Bis-pyridino containing compounds for the use in the treatment of CNS pathologies
  • Bis-pyridino containing compounds for the use in the treatment of CNS pathologies

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0084] N,N′-Pentane-1,5-diyl-bis-pyridinium Diiodide (bPPeI).

[0085] 1,5-Diiodopentane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 90% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.14 (2H, d, C2&C6-H), 8.62 (1H, t, C4-H), 8.19 (2H, t, C3&C5-H), 4.62 (2H, t, C′1-CH2), 1.92 (2H, m, C′2-CH2), 1.25 (1H, m, C′3-CH2).

example 2

[0086] N,N′-Hexane-1,6-diyl-bis-pyridinium Diiodide (bPHxI).

[0087] 1,6-Diiodohexane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated. 1H NMR (300 MHz, DMSO-D6) δ 9.11 (2H, d, C2&C6-H), 8.63 (1H, t, C4-H), 8.18 (2H, t, C3&C5-H), 4.59 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.28 (2H, m, C′3-CH2).

example 3

[0088] N,N′-Octane-1,8-diyl-bis-pyridinium Diiodide (bPOI).

[0089] 1,8-Diiodooctane (mmol) was added to a solution (30 mL) of dry pyridine, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting yellow solid was isolated in a 93% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.11 (2H, d, C2&C6-H), 8.63 (1H, t, C4-H), 8.18 (2H, t, C3&C5-H), 4.59 (2H, t, C′1-CH2), 1.89 (2H, m, C′2-CH2), 1.28 (4H, m, C′3&4-CH2); 13C NMR (75 MHz, DMSO-D6) δ 145.3, 144.5, 127.9, 60.5,30.6, 28.1, 25.2.

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Abstract

N-n-Alkylation of nicotine converts nicotine from an agonist into an antagonist specifically for neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogs exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.

Description

RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Ser. No. 60 / 533,213, filed Dec. 31, 2003, which is incorporated herein in its entirety.BACKGROUND OF THE INVENTION [0002] Considerable effort has focused on the development of neuronal nicotinic receptor (nAChR) agonists as therapeutic agents. However, relatively few studies have focused on the therapeutic development of nAChR antagonists. As a result, only a few subtype-selective antagonists are currently available for use as pharmacological tools to investigate the physiological roles of specific nAChR subtypes. [0003] It has been found that nicotine stimulates all known nAChR subtypes, and that N-quaternization of nicotine converts it from an agonist into an antagonist with enhanced nAChR subtype selectivity. Several classical nAChR antagonists are bis-quaternary ammonium structures. Hexamethonium chloride and decamethonium bromide, both bis-quaternary ammonium salts, are considered simpl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/444A61K31/4709C07D213/16C07D213/22C07D215/10C07D217/10C07D401/04C07D401/14
CPCC07D213/06C07D213/22C07D401/14C07D217/10C07D215/10A61P25/00
Inventor CROOKS, PETER A.DWOSKIN, LINDA P.AYERS, JOSHUAGRINEVICH, VLADIMIRSUMITHRAN, SANGEETHA
Owner UNIV OF KENTUCKY RES FOUND
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