Unlock instant, AI-driven research and patent intelligence for your innovation.

Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors

An alkoxyl, polyhaloalkyl-based technology for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction that addresses poor oral bioavailability, lack of mGluR5 receptor selective positive allosteric modulators, lack of water solubility and other issues

Inactive Publication Date: 2015-06-24
VANDERBILT UNIV
View PDF4 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Unfortunately, selective positive allosteric modulators of the mGluR5 receptor are lacking
Furthermore, conventional mGluR5 receptor modulators often lack satisfactory water solubility and exhibit poor oral bioavailability

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors
  • Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors
  • Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0771] The in vivo efficacy of the disclosed compounds and the products of the disclosed preparation methods can be measured in a number of preclinical rat behavioral models in which known clinically useful antipsychotics show similar positive responses. For example, disclosed compounds in the dose range of 1 to 100 mg / kg p.o. can reverse amphetamine-induced tachymosia in male Sprague-Dawley rats.

[0772] D. Methods of Preparing Compounds

[0773] In one aspect, the invention relates to methods for the preparation of compounds useful as positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5), which compounds are useful in the treatment of neurological and psychiatric disorders associated with glutamate dysfunction disorders and other diseases involving metabotropic glutamate receptors.

Synthetic example B1

[1103] ** Synthetic example B1 is 2-(benzyloxy)-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one ; Synthetic example B2 is 2-(benzyloxy)-5-(2-methoxypyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4( 5H)-ketone; Synthetic Example B3 is 2-(benzyloxy)-5-(6-cyclopropylpyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyridine Oxyzin-4(5H)-one; Synthetic Example B4 is 2-[(2-fluorobenzyl)oxy]-5-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5 -a]pyrazine-4(5H)-one; synthetic example B39 is 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)- Ketone; and Synthetic Example B44 is 2-(benzyloxy)-5-(cyclopropylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)- ketone.

[1104] Table II.

[1105]

[1106] *Synthesis example B48 is 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -4-one; synthetic example B49 is 2-(benzyloxy)-5-(4-fluorophenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a ][1,4]diazepine -4-ketone; Synthetic Example B50 is 2-(benzyloxy)-5-(5-fluoropyr...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

In one aspect, the invention relates to substituted bicyclic alkoxy pyrazole analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 662,287, filed June 20, 2012, which is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Sponsored Research [0004] This invention was made with government support under Grant Nos. MH73676, MH62646, and MH89870 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical background [0005] Glutamic acid (L-glutamic acid) is the main excitatory transmitter in the mammalian central nervous system, and it exerts its effect through two kinds of glutamate receptors, ionotropic and metabotropic. Metabotropic glutamate receptors (mGluRs) belong to family C (also known as family 3) of G protein-coupled receptors (GPCRs). They are characterized by a seven-transmembrane (7TM) alpha-helical domain linked by a cysteine-rich region to a large bi-lobed extracellular N-t...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/55A01N43/54
CPCA61P1/14A61P3/04A61P3/10A61P25/00A61P25/06A61P25/08A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/00A61P43/00C07D487/04A61K31/4985A61K31/55
Inventor 杰弗里·P·康恩C·W·林德斯列肖恩·R·斯托弗乔斯·曼纽尔·巴托洛梅-内夫雷达格雷戈里·詹姆斯·麦克唐纳苏珊娜·康德-塞德翰闵·佟米格尔·安琪尔·皮纳-皮农曼纽尔·吉瑟斯·阿卡莎-巴卡乔斯·伊格纳西奥·安德里斯-吉尔
Owner VANDERBILT UNIV