Synthesis and application of fused heterocycle derivative

A compound, quinoline technology, applied in the synthesis of fused heterocyclic derivatives, fused heterocyclic derivatives, and the preparation of drugs for the prevention or treatment of neuropsychiatric diseases, can solve the side effects of EPS, QT gap prolongation, ratio low level problem

Inactive Publication Date: 2017-05-03
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 and application of fused heterocycle derivative
  • Synthesis and application of fused heterocycle derivative
  • Synthesis and application of fused heterocycle derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1, 9-(2-(4-(3-(6-fluorobenzisoxazole)-1-piperidinyl)acetyl)-1,2,6,7-tetrahydropyridin[3, 2,1-ij] quinolin-3(5H)-one

[0120] Reaction 1

[0121]

[0122] 1) Take 5.0 g of 1, 2, 3, tetrahydroquinoline, add 50 ml of acetone, then slowly add 5.1 g of 3-chloropropionyl chloride, stir until reflux, and the reaction is completed after 4 hours. Cool to room temperature, concentrate the reaction solution, dissolve with ethyl acetate, wash with water, dry over anhydrous magnesium sulfate, filter with suction, and concentrate to obtain 8.0 g of oily substance, yield 96.4%.

[0123] 2) Take 8 g of the product of the first step, add 7.2 g of anhydrous aluminum trichloride, stir and heat for 3 hours, cool to room temperature, add ice water to quench the system, filter, extract with ethyl acetate, wash with water, anhydrous sulfuric acid Magnesium was dried, suction filtered, and concentrated to obtain 6.05 g of solid, with a yield of 90.3%.

[0124] 3) Take 5.0g of the...

Embodiment 2

[0127] Example 2, 9-(3-(4-(3-(6-fluorobenzisoxazole)-1-piperidinyl)propionyl)-1,2,6,7-tetrahydropyridin[3, 2,1-ij] quinolin-3(5H)-one

[0128] Using 3-chloropropionyl chloride instead of 2-chloroacetyl chloride, the target compound was prepared according to the method of Example 1.

[0129] 1H NMR (600MHz, CDCl3) δ7.76(s,1H),7.72(s,1H),7.21–7.11(m,2H),7.03–6.86(m,1H),3.93(dt,J=12.9,6.4 Hz,4H),3.42(t,J=6.8Hz,2H),3.20(t,J=7.3Hz,2H),3.11(s,4H),3.05–2.89(m,2H),2.87(d,J =6.2Hz,2H),2.79–2.65(m,2H),2.05–1.92(m,3H).MS(ESI)m / z462.5([M+H]+)

Embodiment 3

[0130] Example 3, 9-(3-(4-(3-(6-fluorobenzisoxazole)-1-piperidinyl)-1-hydroxypropyl)-1,2,6,7-tetrahydro Pyridin[3,2,1-ij]quinolin-3(5H)-one

[0131] Reaction 2

[0132]

[0133] Take 0.5 g of the target compound in Example 2, dissolve it in 20 mL of anhydrous methanol, cool down to zero in an ice-water bath, add 0.08 g of sodium borohydride, continue stirring for 1 h, and add 10 mL of water to quench the reaction. The solvent was evaporated to dryness, an appropriate amount of dichloromethane was added, washed with water, and the water layer was separated. The organic layer was dried by adding anhydrous magnesium sulfate, and the solvent was evaporated to give a light yellow oil. Column chromatography gave 0.40 g of a white solid.

[0134] 1H NMR (600MHz, CDCl3) δ7.71(dt, J=11.6,5.8Hz,1H),7.68(s,1H),7.66(s,1H),7.26(dd,J=8.5,2.0Hz,1H) ,7.12–7.02(m,1H),3.94–3.88(m,2H),3.20(t,J=7.3Hz,2H),3.10(dd,J=15.3,7.3Hz,3H),3.00–2.95(m ,2H),2.92(t,J=7.3Hz,2H),2.87(t,J=6.2Hz,2H),2.73–2....

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to synthesis and application of a fused heterocycle derivative. The fused heterocycle derivative is of a structure shown in a general formula (I) (shown in the specification). Experiments prove that the compound can be used for treating nervous and mental diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to the synthesis and application of condensed heterocyclic derivatives. More specifically, the present invention relates to fused heterocyclic derivatives, pharmaceutical compositions containing the fused heterocyclic derivatives and the use of the composition and the fused heterocyclic derivatives in the preparation of prevention or treatment of neuropsychiatric diseases use in medicines. 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 p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/04C07D471/06A61K31/4745A61K31/496A61P25/18
CPCC07D455/04C07D471/06A61K31/4745A61K31/506A61K31/496A61P25/18
Inventor 张桂森曹旭东陈寅张译芳于民权邱印利徐祥清张探刘笔锋刘欣
Owner NHWA PHARMA CORPORATION
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