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Metabotropic glutamate receptor antagonists for treating central nervous system disease

A representative compound technology, applied in the field of metabolic glutamate receptor antagonists for the treatment of central nervous system diseases, can solve the problem of hindering mGluR physiological therapeutic efficacy, limited value, lack of effectiveness of mGluR agonists and antagonists and issues of selectivity

Inactive Publication Date: 2001-02-28
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] It is clear from the foregoing that existing mGluR agonists and antagonists are of limited value due to their lack of potency and selectivity
In addition, most existing compounds are amino acids or amino acid derivatives with limited bioavailability, thus hampering studies on mGluR physiology, pharmacology and evaluation of its therapeutic efficacy in vivo

Method used

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  • Metabotropic glutamate receptor antagonists for treating central nervous system disease
  • Metabotropic glutamate receptor antagonists for treating central nervous system disease
  • Metabotropic glutamate receptor antagonists for treating central nervous system disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102]Capillary gas chromatography and mass spectrometry data were measured by Hewlett-Packard (HP) 5890 II gas chromatograph, which was coupled with HP5971 Series Mass Selector Detector (mass selective detector) [Ultra-2 super performance capillary column (cross-linked with 5 %PhMe polysiloxane); column length, 25m; column inner diameter, 0.20mm; helium flow rate, 60mL / min; held at 325°C for 6 minutes]. Thin layer chromatography was performed on Analtech Uniplate 250 μm silica gel HF TLC plates. Compounds on TLC plates were assayed with UV light sometimes in combination with ninhydrin and Dragendorff developer (Sigma Chemical Co.). Reagents used were purchased from Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (SaintLouis, MO), Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR) or Lancaster Synthesis (Windham, NH). Example 1: Preparation of N-[6-(2-methylquinolyl)]-1-adamantanecarboxamide (40)

[0103] 2-Methyl-...

Embodiment 2

[0118] 1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine (15 mL). The reaction was stirred for 16 hours. Water (200 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered, washed with water (3 x 50 mL), and dried under high vacuum. 1.56g (73.7%) of (41) was obtained as light brown powder: retention time=11.41min.; m / z (relative intensity) 307(M+, 2), 136(11), 135(100), 116( 11), 107(7), 93(14), 92(2), 91(8), 89(7), 79(16), 77(8). Embodiment 3: Preparation of 6-quinolinecarboxylic acid 1- Adamantyl esters (61)

Embodiment 3

[0118] 1-Adamantanecarbonyl chloride (1.37 g, 6.90 mmol) in pyridine (5 mL) was added to a solution of 6-hydroxyquinoline (1.00 g, 6.89 mmol) in pyridine (15 mL). The reaction was stirred for 16 hours. Water (200 mL) was added to the stirred reaction mixture causing precipitation of the product. The precipitate was filtered, washed with water (3 x 50 mL), and dried under high vacuum. 1.56g (73.7%) of (41) was obtained as light brown powder: retention time=11.41min.; m / z (relative intensity) 307(M+, 2), 136(11), 135(100), 116( 11), 107(7), 93(14), 92(2), 91(8), 89(7), 79(16), 77(8). Embodiment 3: Preparation of 6-quinolinecarboxylic acid 1- Adamantyl esters (61)

[0119] 6-Quinolinecarbonyl chloride hydrochloride

[0120] In thionyl chloride, 6-quinolinecarboxylic acid was refluxed for 30 minutes. Then by rotary evaporation (90° C.), excess thionyl chloride was removed to obtain 6-quinolineformyl chloride hydrochloride.

[0121] 1-adamantyl 6-quinolinecarboxylate (61)

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Abstract

The present invention provides compounds, and pharmaceutical compositions containing those compounds, that act as antagonists at metabotropic glutamate receptors. The compounds are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.

Description

field of invention [0001] The present invention provides compounds that are active at metabotropic glutamate receptors and are useful in the treatment of neurological and psychiatric diseases and disorders. Background of the invention [0002] Recent advances in elucidating the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the treatment of acute and chronic neurological and psychiatric diseases and disorders. However, a major challenge in realizing this expectation has been the development of metabotropic glutamate receptor subtype-selective compounds. [0003] Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate exerts its effects on the central nervous system by binding to and activating cell surface receptors. According to the structural characteristics of the receptor protein, the pathway through which the receptor transd...

Claims

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Application Information

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IPC IPC(8): A61K31/381A61K31/4184A61K31/425A61K31/426A61K31/428A61K31/44C07D239/42A61K31/4402A61K31/4406A61K31/4409A61K31/4418A61K31/445A61K31/451A61K31/454A61K31/47A61K31/495A61K31/496A61K31/498A61K31/505A61P25/00A61P43/00C07C49/577C07C225/04C07C233/58C07C233/60C07C233/65C07C311/13C07C323/22C07D211/52C07D213/30C07D213/40C07D213/55C07D213/63C07D213/75C07D213/81C07D213/82C07D215/12C07D215/20C07D215/38C07D215/48C07D215/54C07D217/26C07D235/10C07D241/18C07D241/20C07D241/42C07D241/44C07D277/20C07D277/44C07D277/64C07D277/68C07D277/70C07D277/72C07D333/38C07D417/04C07D491/04C07D521/00
CPCC07D277/68C07D215/12C07D215/20C07D215/54C07D215/38C07D213/81C07D215/48C07D277/70C07D217/26C07D491/04C07D231/12C07D249/08C07D233/56C07D241/44C07D241/42C07D213/82A61P25/00A61P43/00
Inventor B·C·范瓦格南S·T·莫D·L·史密斯S·M·舍汉I·斯切尔巴科瓦R·特拉瓦托R·瓦尔顿R·巴莫雷E·G·德马T·M·斯托曼
Owner ASTRAZENECA AB
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