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6H-1,3-oxazoline-6-one compound and uses in drugs for treating attention deficit hyperactivity disorder

A ketone compound, 6H-1 technology, applied in the field of medicine, can solve the problems of adolescent height and weight growth retardation, atomoxetine hydrochloride self-injury, adverse effects of blood pressure, etc.

Inactive Publication Date: 2019-12-20
张振亭
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, methylphenidate hydrochloride and atomoxetine hydrochloride are commonly used clinical drugs, but the adverse reactions of these two drugs are more obvious and prominent.
For example, long-term abuse of the central stimulant drug methylphenidate hydrochloride can lead to addiction, and atomoxetine hydrochloride can cause self-injury tendencies
At the same time, these two drugs both affect children and adolescents with height and weight growth retardation, and have adverse effects on blood pressure

Method used

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  • 6H-1,3-oxazoline-6-one compound and uses in drugs for treating attention deficit hyperactivity disorder
  • 6H-1,3-oxazoline-6-one compound and uses in drugs for treating attention deficit hyperactivity disorder
  • 6H-1,3-oxazoline-6-one compound and uses in drugs for treating attention deficit hyperactivity disorder

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: the synthesis of intermediate 1

[0016]

[0017] Add IPrAuCl (0.050mmoL), AgNTf 2 (0.050mmoL) and dry DCE (1.0mL). After the mixture was stirred at room temperature for 10 min, a dry DCE solution (5 mL) of tert-butyl 3-phenylpropionate (1.0 mmol) and 5-bromo-1,2-benzisoxazole (1.2 mmol) was added dropwise. After the dropwise addition was completed, the temperature of the reaction solution was slowly raised to 80° C. and heated for 2 d. After the completion of the reaction monitored by TLC, it was cooled to room temperature. The reaction solution was filtered with celite, and the filter cake was rinsed with dichloromethane. The combined filtrate was concentrated and purified by column chromatography (PE / EA=3 / 1) to obtain intermediate 1. Yellow solid, yield 87%. 1 H-NMR (400MHz, CDCl 3 ):δ12.45(s,1H),8.13(s,1H),7.80(d,J=7.6Hz,2H),7.59-7.52(m,4H),6.95(d,J=8.8Hz,1H) ,6.53(s,1H). ESI-MS(m / z)=345.2[M+H] + .

Embodiment 2

[0018] Embodiment 2: the synthesis of intermediate 2

[0019]

[0020] Intermediate 1 (1.0mmoL) and acetone (8mL) were added to the round bottom flask, and potassium carbonate (5.0mmoL) was added after stirring to dissolve. After stirring at room temperature for 10 min, iodomethane (1.3 mmol) was added. The reaction solution was heated and stirred at reflux for 10 h. TLC monitored the completion of the reaction and added saturated brine and dichloromethane for liquid separation and extraction. The combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by column chromatography (PE / EA=5 / 1) to obtain intermediate 2. Yellow solid, yield 92%. 1 H-NMR (400MHz, CDCl 3 ):δ8.15(s,1H),7.82(d,J=7.6Hz,2H),7.60-7.51(m,4H),6.94(d,J=8.8Hz,1H),6.54(s,1H) ,3.81(s,3H). ESI-MS(m / z)=359.2[M+H] + .

Embodiment 3

[0021] Embodiment 3: the synthesis of compound 1

[0022]

[0023] After sealing the tube and blowing nitrogen for 5min, add intermediate 2 (4.0mmoL), piperazine (4.8mmoL), CuI (0.02mmoL), K 3 PO 4 (8.0mmoL), N,N′-bis(furan-2-methyl)oxalamide (BFMO, 0.02mmoL) and ethanol (4mL), blow with nitrogen for 5min and immediately tighten the cork. The mixture was heated at 80° C. for 10 h, and cooled to room temperature after the reaction was complete as monitored by TLC. The reaction solution was filtered with celite, and the filter cake was rinsed with dichloromethane. The combined filtrate was concentrated and purified by column chromatography (PE / EA=2 / 1) to obtain compound 1. Yellow solid, yield 65%. 1 H-NMR (400MHz, CDCl 3 ):δ8.02(s,1H),7.69(d,J=7.6Hz,2H),7.55-7.48(m,4H),6.60(d,J=8.8Hz,1H),6.37(s,1H) ,3.62(s,3H),3.41-3.38(m,4H),2.98-2.88(m,4H). ESI-MS(m / z)=364.4[M+H] + .

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Abstract

The invention discloses a 6H-1,3-oxazoline-6-one compound represented by a formula I, or pharmaceutically acceptable salt thereof. According to the present invention, the results of the in vitro influence on on norepinephrine content in rat brain tissues, the in-vivo young-stage SHR rat ADHD model open-field test, the influence of Y maze test, the physiological index detection, and the influence on rat brain tissue neuron damage repair show that the compound can well reduce the norepinephrine content in rat brain tissues, remarkably inhibit the hyperactivity of model rats, improve the learningand memory ability of model rats, and quickly and efficiently repair damaged cranial neurons, cannot affect the growth and the blood pressure of tested rats, and does not cause manic symptoms.

Description

technical field [0001] The invention relates to the field of medicine, in particular to 6H-1,3-oxazolin-6-one compounds and their application in medicines for treating attention deficit hyperactivity disorder. Background technique [0002] Attention deficit hyperactivity disorder (Attention Deficit Disorder with Hyperactivity, ADHD) is called ADHD in my country, and it is a common type of psychological disorder in childhood. Manifested by inattention and short attention span, hyperactivity, and impulsive behavior that are disproportionate to age and developmental level, often accompanied by learning difficulties, conduct disorders, and maladjustment. Investigations at home and abroad have found that the prevalence rate is 3%-7%, and the ratio of male to female is 4-9:1. Some children still have symptoms when they become adults, which obviously affects their studies, physical and mental health, family life and social skills in adulthood. [0003] At present, the drugs for t...

Claims

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Application Information

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IPC IPC(8): C07D265/10C07D413/12A61P25/14A61K31/5377A61K31/5355A61K31/535
CPCA61P25/14C07D265/10C07D413/12
Inventor 张振亭代惠杰
Owner 张振亭
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