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Imidazo[1,2-a]pyridine derivative

A compound, -CONH2 technology, applied in the direction of drug combination, organic active ingredients, nervous system diseases, etc., can solve the problem of no inhibitory activity

Inactive Publication Date: 2013-01-02
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The synthetic method of the compound represented by formula (G) and formula (H) is disclosed in non-patent literature 3, but there is no expression related to PDE4 (PDE4B) inhibitory activity or to schizophrenia, Alzheimer's disease, dementia , depression and other useful records

Method used

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  • Imidazo[1,2-a]pyridine derivative

Examples

Experimental program
Comparison scheme
Effect test

test approach 1

[0153] Test method 1: Human PDE4B inhibitory activity

[0154] (1) Purification of human PDE4B enzyme

[0155] A plasmid DNA encoding FLAG-tagged human PDE4B2 was produced, introduced into Escherichia coli and cultured in large quantities. After the plasmid DNA was extracted and purified from Escherichia coli, it was transfected into COS-1 cells and cultured. After the cells were disrupted, the expressed enzyme was purified using a FLAG peptide affinity column.

[0156] (2) Human PDE4B activity inhibition test

[0157] 1 μl / well of DMSO solutions dissolved with various concentrations of test compounds, 74 μl / well of purified enzyme diluted with buffer were added to a 96-well plate, and incubated at room temperature for 10 minutes. Add 25 μl / well containing 40nM [ 3 H]-cAMP (Amersham, TRK559) and 4 μM cAMP buffer, and reacted at room temperature for 30 minutes. Add the suspension (18mM ZnSO 4 , 5mM IBMX, distilled water), the reaction was stopped. After standing at room ...

test approach 2

[0162] Test method 2: Improvement effect on spontaneous transformation behavior disorder in mice induced by MK-801

[0163] MK-801-induced cognitive impairment also reflects the hypothesized glutamate decline in schizophrenia and decreased glutamate transport function in dementia. Spontaneous transformation behavior is a task reflecting working memory, and impairment of working memory is evident in both schizophrenia and dementia. Therefore, the improvement effect of the compound of formula (I) on cognitive impairment was evaluated by the following test method known as a model of short-term learning impairment.

[0164] (1) animals

[0165] Type: Male ddY mice / number (number of cases in one group): 6 to 9 cases in one group

[0166] Age of use: 5 weeks old

[0167] Provider or producer: 日本ェスェルシ-

[0168] (2) Measurement method

[0169] Mice were moved into the laboratory 1 h before the start of the experiment. The mouse was placed at one end of an arm of a maze (Y-shaped...

test approach 3

[0175] Test Method 3: Toxicity Test

[0176] The safety of the compound of formula (I) in terms of genotoxicity can be confirmed by conducting the toxicity test described below.

[0177] (1) Ames test

[0178] The Ames test can be carried out using a general method known to those skilled in the art, for example, the method described in Mutation Research, 113 (1983) 173-215.

[0179] (2)umu test

[0180] The umu test can be carried out using a general method known to those skilled in the art, for example, the method described in Mutation Research, 253 (1991) 215-222.

[0181] The results of the above tests show that the compound of formula (I) has PDE4B inhibitory effect, and is useful as an active ingredient of a therapeutic or preventive pharmaceutical composition for schizophrenia, Alzheimer's disease, dementia, depression and the like.

[0182]A pharmaceutical composition containing one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof as an ...

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Abstract

Disclosed is a compound useful as an active ingredient for medicines having PDE4B inhibiting activity, in particular, therapeutic or preventive medicinal compositions for schizophrenia, Alzheimer's disease, dementia, depression and the like. Specifically, the present inventors examined compounds having PDE4B inhibiting activity and found that a tricyclic or tetracyclic imidazo[1,2-a]pyridine derivative or salts thereof had superior PDE4B inhibiting activity. This imidazo[1,2-a]pyridine derivative can be used in therapeutic and preventative agents for schizophrenia, Alzheimer's disease, dementia, depression, and the like.

Description

technical field [0001] The present invention relates to a pharmaceutical composition, in particular to an imidazo[ 1,2-a] pyridine derivatives. Background technique [0002] Schizophrenia is a mental illness that exhibits various symptoms such as delusions, hallucinations, hyperactivity, and depression. These symptoms are roughly divided into positive symptoms, negative symptoms, and cognitive impairment. In the past, in the treatment of schizophrenia, D2 receptor blockers such as haloperidol, which are typical first-generation antipsychotics, and risperidone, a Azapine, etc., have played a certain effect on the treatment of positive symptoms. However, it is reported that the first-generation haloperidol and the like have side effects of extrapyramidal symptoms, and the second-generation risperidone and olanzapine have side effects such as metabolic abnormalities such as obesity and hyperglycemia (Am.J.Psychiatry, 2003,160:1209-1222;Neuropsychopharmacology,2003,28:1400-1...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/438A61K31/4545A61P25/18A61P25/24A61P25/28A61P43/00C07D495/14C07D519/00
CPCC07D471/04C07D519/00C07D495/14A61P25/00A61P25/18A61P25/24A61P25/28A61P43/00C07D211/48C07D221/04C07D471/08C07D471/10C07D471/14C07D491/044A61K31/437C07D401/04
Inventor 三水清宽增田直之饭久保一彦小金丸阳平河野则征大森淳弥三谷泰之倪健伟
Owner ASTELLAS PHARMA INC
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