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Synthesis of phenylpyridazinone derivative and application thereof

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

Active Publication Date: 2018-03-13
NHWA PHARMA CORPORATION +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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  • Synthesis of phenylpyridazinone derivative and application thereof
  • Synthesis of phenylpyridazinone derivative and application thereof
  • Synthesis of phenylpyridazinone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0100] The following examples are for the purpose of illustration only and are not intended to limit the invention.

[0101] A, the embodiment of synthetic aspect

Embodiment 1

[0102] Example 1, 2-(3,4-dichlorophenyl)-6-(3-(4-(4-methoxyphenyl)piperazin-1-yl)propoxy)pyridazine-3( 2H)-one

[0103] Reaction 1

[0104]

[0105] 1) Dissolve 14.5 g of phenylhydrazine hydrochloride and 9.8 g of maleic anhydride in 200 ml of purified water. Under stirring, slowly add 40ml of concentrated hydrochloric acid, heat to reflux after the addition, and react for 6 hours. After the reaction was completed, the mixture was cooled in an ice-water bath, and a yellow solid was precipitated. Suction filtration, the filter cake was washed twice with water. Remove the filter cake with saturated NaHCO 3 After dissolving, the insoluble matter was filtered off, and the clear liquid was adjusted to a pH value between 2 and 3 with concentrated hydrochloric acid, and a white solid was precipitated, and 17.3 g was obtained after suction filtration and drying, with a yield of 92.0%.

[0106] 2) Take 9.4g of the first step product, 13.8g of anhydrous potassium carbonate, 18.8...

Embodiment 2

[0109] Example 2, 2-(3,4-dichlorophenyl)-6-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)pyridazine-3( 2H)-one

[0110] Using 2-methoxyphenylpiperazine hydrochloride instead of 4-methoxyphenylpiperazine hydrochloride, the target compound was prepared according to the method of Example 1.

[0111] 1 H NMR (600MHz, CDCl 3 )δ7.89(d,J=2.5Hz,1H),7.65(dd,J=8.7,2.5Hz,1H),7.51(d,J=8.7Hz,1H),7.06–6.98(m,3H), 6.98–6.89(m,2H),6.87(dd,J=8.1,1.1Hz,1H),4.26(t,J=6.4Hz,2H),3.87(s,3H),3.12(s,4H),2.70 (s,4H),2.63–2.51(m,2H),2.09–1.94(m,2H).MS(ESI)m / z489.1([M+H] + )

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PUM

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Abstract

The invention relates to the field of medicine, and concretely the invention relates to a phenylpyridazine derivative and an application thereof. Concretely, the invention relates to a phenylpyridazinone derivative, a pharmaceutical composition containing the phenylpyridazinone derivative, and applications of the composition and the phenylpyridazinone derivative to preparation of medicines for preventing or treating nervous and mental diseases. The phenylpyridazinone derivative has a structure as shown in a formula (I). Experiments show that the compound can be used for preventing or treatingnervous and mental diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a phenylpyridazine derivative and its application in treating mental and nervous diseases. Background technique [0002] Schizophrenia is a disease characterized by deep cognitive and emotional dissociation, which affects the most basic human behaviors, such as language, thought, perception and self-perception. 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 Complicat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D237/16C07D413/14C07D403/12C07D405/12C07D401/14C07D417/14C07D417/12C07D409/14C07D401/12A61K31/506A61K31/501A61P25/18
CPCC07D237/16C07D401/12C07D401/14C07D403/12C07D405/12C07D409/14C07D413/14C07D417/12C07D417/14
Inventor 张桂森曹旭东张译芳邱印利赵松徐祥清刘欣刘笔锋
Owner NHWA PHARMA CORPORATION
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