Benzopyrone derivative and application thereof

A technology of benzopyrone and benzopyran, which is applied in the field of benzopyrone derivatives and their application in the treatment of mental and neurological diseases, and can solve the problems of EPS side effects, low ratio, QT gap prolongation, etc.

Active Publication Date: 2011-10-05
HUAZHONG UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Typical antipsychotic drugs generally have severe EPS side effects and are ineffective for one-third of schizophrenic patients
[0005] After the 1960s, a series of new-generation antipsychotic drugs were successively developed, including ziprasidone (Ziprasidone), risperidone (Risperidone), etc., which are called second-generation antipsychotic drugs, namely new antipsychotic drugs Although their respective pharmacological effects are not exactly the same, they have common pharmacological characteristics, that is, they are sensitive to 5-hydroxytryptamine (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) The affinity of the body (α1, α2) is much higher than that of the D2 receptor, resulting in a lower ratio of D2 / 5-HT2A
Compared with the first-generation antipsychotic drugs, its clinical effect has more advantages. It is not only as effective as traditional antipsychotic drugs for positive symptoms, but also effective for negative symptoms and cognitive deficit symptoms, and has a wider spectrum of action. However, these drugs have QT Adverse effects such as gap prolongation, hyperprolactinemia and weight gain

Method used

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  • Benzopyrone derivative and application thereof
  • Benzopyrone derivative and application thereof
  • Benzopyrone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1, 7-(4-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-butoxy))-2hydro-benzopyran-2 -ketone(1)

[0079] Reaction 1

[0080]

[0081] 1) get resorcinol 5.5g, d, l-malic acid 6.7g, add 70% HCl0 4 50ml, heated to 90°C to react, the solution gradually became clear, the reaction was completed after 4 hours, cooled to room temperature, the reaction solution was poured into the ice-water mixture, a large amount of solids precipitated, filtered, the filter cake was washed with 95% ethanol Recrystallization gave 4.5 g of white crystals with a melting point of 226-228° C. and a yield of 60.8%.

[0082] 2) Take 5g of the first step product, 6g of anhydrous potassium carbonate, 50ml of acetone, and 8.2g of 1,4-dibromobutane, heat and reflux for 6 hours, cool to room temperature, filter, and evaporate the solvent to obtain a light yellow oil , through the column to obtain 5.4 g of white solid, melting point 55-57 ° C, yield 60.7%.

[0083]3) Take 0.52g of the secon...

Embodiment 2

[0085] Example 2, 7-(4-(4-(3-(1,2-benzisothiazole)-1-piperazinyl)-n-butoxy))-2hydro-benzopyran-2- Ketones (2)

[0086] Replace 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride with 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride , The target compound was prepared according to the method of Example 1.

[0087] Melting point: 103-105°C.

[0088] 1 H NMR (CDCl 3 )δ1.75-1.76 (m, 2H), 1.87-1.91 (m, 2H), 2.51 (t, 2H, J=14.8Hz), 2.68-2.71 (m, 4H), 3.56-3.59 (m, 4H) , 4.06(t, 2H, J=12.4Hz), 6.23(d, 1H, J=9.6Hz), 6.80-6.85(m, 2H), 7.33-7.37(m, 2H), 7.44-7.48(m, 1H ), 7.62 (d, 1H, J=9.6Hz), 7.80 (d, 1H, J=8Hz), 7.91 (d, 1H, J=8Hz) MS (ESI) m / z 436.2 ([M+H] + )

Embodiment 3

[0089] Example 3, 7-(3-(4-(3-(6-fluoro-benzoisoxazole)-1-piperidinyl)-n-propoxy))-2hydro-benzopyran-2 - Ketones (3)

[0090] Using 1,3-dibromopropane instead of 1,4-dibromobutane, the target compound was prepared according to the method of Example 1.

[0091] Melting point: 128-130°C.

[0092] 1 H NMR (CDCl 3 )δ2.03-2.19(m, 8H), 2.60(t, 2H, J=14.4Hz), 3.07-3.10(m, 3H), 4.12(t, 2H, J=12.8Hz), 6.25(d, 1H , J=9.2Hz), 6.84-6.87(m, 2H), 7.05-7.06(m, 1H), 7.23-7.27(m, 1H), 7.37(d, 1H, J=8.4Hz), 7.63-7.70( m, 2H) MS (ESI) m / z 423.2 ([M+H] + )

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Abstract

The invention belongs to the field of pharmaceutical chemistry and in particular relates to a benzopyrone derivative and application thereof. The benzopyrone derivative has a structure shown in a formula (I). Discovered by the experiment, the compound can be used for preparing drugs for treating neuropsychiatric diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a benzopyrone derivative and its application in treating mental and nervous diseases. Background technique [0002] Schizophrenia is a disorder characterized by deep cognitive and emotional dissociations that affect the most basic human behaviors, such as language, thought, perception, and self-awareness. The symptoms of the disease include a wide range, the most common being mental disorders, such as hallucinations, paranoia and delusions. [0003] Schizophrenia is the most serious mental illness, affecting about 1% of people worldwide, and only 5% of all treated patients eventually fully recover. In addition, since schizophrenia often causes comorbidities, such as anxiety disorders, depression, or psychotropic substance abuse, etc., according to a survey by Datamonitor, more than 1 / 3 of patients with schizophrenia suffer from at least one or more Complicated by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07D417/12A61K31/454A61K31/496A61P25/18
CPCA61K31/496C07D413/14A61K31/454C07D417/12A61P25/18C07D405/12C07D405/14C07D413/12C07D417/14
Inventor 张桂森陈寅徐祥清刘笔锋刘欣赵松刘世成于民权张恒刘星华
Owner HUAZHONG UNIV OF SCI & TECH
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