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2,6-diketone-piperazine (piperidine) type derivative and application thereof

A derivative, piperidine technology, applied in the field of medicinal chemistry, can solve problems such as QT gap prolongation

Active Publication Date: 2013-08-14
NHWA PHARMA CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs have adverse effects such as QT gap prolongation, hyperprolactinemia and weight gain

Method used

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  • 2,6-diketone-piperazine (piperidine) type derivative and application thereof
  • 2,6-diketone-piperazine (piperidine) type derivative and application thereof
  • 2,6-diketone-piperazine (piperidine) type derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 1-(4-(4-(3-(6-fluoro-benzoisoxazole))-1-piperidinyl)butyl)-4-(4-chlorophenyl)-piperidine-2,6 - Diketones (No. 1)

[0067] (1) Add 52 g (0.4 mol) of ethyl acetoacetate and 28 g (0.2 mol) of p-chlorobenzaldehyde in a 500 ml three-necked flask equipped with a reflux condenser, magnetic stirring and dropping funnel. Under stirring, a mixed solution of ethanol (20ml) and piperidine (2ml) with a volume concentration of 95% was added dropwise, the solid gradually dissolved, and the stirring was continued until the reaction solution began to solidify again, about 1 hour. When the reactants are completely solidified, heat them in an electric constant temperature water bath, and place them in the dark at 40°C for 5 hours to complete the reaction. The solidified product was recrystallized with ethanol with a volume concentration of 95%, and 52.2 g of white needle crystals were obtained, with a yield of 68.2%. Melting point: 152-155°C.

[0068] (2) Add 100g of potassium hydroxid...

Embodiment 2

[0075] 1-(4-(4-(3-(6-fluoro-benzoisoxazole))-1-piperidinyl)butyl)-4-(4-fluorophenyl)-piperidine-2,6 - diketones (number 2)

[0076] Using p-fluorobenzaldehyde as the starting material, the target compound was obtained according to the method in Example 1. Melting point: 137-139°C

[0077] 1 H NMR (CDCl 3 )δ1.52-1.61 (m, 4H), 2.06-2.12 (m, 6H), 2.42 (t, 2H, J=13.6Hz), 2.75-2.83 (m, 2H), 2.96-3.07 (m, 5H) , 3.34-3.37(m, 1H), 3.83(t, 2H, J=14Hz), 7.03-7.07(m, 3H), 7.18-7.24(m, 3H), 7.71-7.74(m, 1H)

Embodiment 3

[0079] 1-(4-(4-(3-(6-fluoro-benzoisoxazole))-1-piperidinyl)butyl)-4-(phenyl)-piperidine-2,6-dione (number 3)

[0080] Using benzaldehyde as the starting material, the target compound was obtained according to the method in Example 1. Melting point: 114-116°C

[0081] 1 H NMR (CDCl 3 )δ1.55-1.59 (m, 4H), 2.05-2.13 (m, 6H), 2.42 (t, 2H, J=14.4Hz), 2.77-2.84 (m, 2H), 2.98-3.08 (m, 5H) , 3.34-3.38(m, 1H), 3.84(t, 2H, J=14Hz), 7.03-7.08(m, 1H), 7.20-7.40(m, 6H), 7.68-7.71(m, 1H)

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Abstract

The invention discloses a 2,6-diketone-piperazine (piperidine) type derivative and an application thereof. The derivative can be applied to preparation of medicines for preventing or treating central nervous system diseases. Animal experiment results show that the derivative has smaller ED50 and stronger action in MK-801-induced high activity and apomorphine-induced climbing animal models as well as has larger ED50 and larger therapeutic indexes in an animal catalepsy model. The derivative is a compound or salt thereof with a general formula (I).

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of novel 2,6-diketone-piperazine (piperidine) derivatives and their 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. Worldwide, about 1% of people suffer from schizophrenia, and only 5% of all treated patients eventually recover fully. Typical antipsychotic drugs (eg, chlorpromazine, haloperidol) block dopamine D2 receptors, leading to severe blockade of dopamine receptors including extrapyramidal side effects (EPS), tardive dyskinesia, and increased prolactin secretion. In addition, typ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/88C07D413/12C07D417/12A61K31/4545A61K31/496A61P25/00A61P25/04A61P25/06A61P25/08A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28
Inventor 张桂森陈寅徐祥清赵松于民权
Owner NHWA PHARMA CORPORATION
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