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COMT inhibitor comprising terminal olefinic bond and hydrazide structure and application of COMT inhibitor

A technology of hydrazine hydrate and cyclopentadiene, which can be used in the fields of nervous system diseases, organic chemistry, drug combination, etc., and can solve problems such as limited applications

Inactive Publication Date: 2018-06-08
FOSHAN SAIWEISI MEDICINE SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although clozapine, Zyprexa, Vistron, and other antipsychotics have been used to treat both positive and negative (controversial) symptoms of schizophrenia and bipolar disorder, these drugs have not been free from side effects such as Cytopenia, sedation, weight gain, hyperlipidemia and hyperglycemia, all of which limit their use

Method used

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  • COMT inhibitor comprising terminal olefinic bond and hydrazide structure and application of COMT inhibitor
  • COMT inhibitor comprising terminal olefinic bond and hydrazide structure and application of COMT inhibitor
  • COMT inhibitor comprising terminal olefinic bond and hydrazide structure and application of COMT inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Synthesis of Compound I-1

[0021]

[0022] Step 1. Synthesis of compound VI-1

[0023] Compound II (1.32g, 20mmol) was dissolved in 20mL DMSO, stirred at room temperature, KOH solid (2.24g, 40mmol) was added, and stirring was continued for 1 hour at room temperature. Then MeI (III-1,2.84g, 20mmol) was added, and stirring was continued overnight at room temperature. Then tert-butyl bromoacetate V (3.90 g, 20 mmol) was added, and stirring was continued for 12 hours. TLC detection revealed that the reaction was complete. The reaction mixture was carefully poured into 200mL ice water, stirred, and 50mL×3CH 2 Cl 2 After extraction, the extract phases were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain compound VI-I, 2.99 g (combined yield 77%). ES...

Embodiment 2

[0028] Example 2 Synthesis of Compound I-2

[0029]

[0030] Step 1. Synthesis of compound VI-2

[0031] Compound II (1.32g, 20mmol) was dissolved in 20mL DMSO, stirred at room temperature, KOH solid (2.24g, 40mmol) was added, and stirring was continued for 1 hour at room temperature. Then add III-2 (2.42g, 20mmol), continue to stir at room temperature overnight. Then, V (3.90 g, 20 mmol) was added, and stirring was continued for 12 hours. TLC detection revealed that the reaction was complete. The reaction mixture was carefully poured into 200mL ice water, stirred, and 50mL×3CH 2 Cl 2 After extraction, the extracts were combined, washed with 100 mL of 5% brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain compound VI-2. ESI-MS, m / z=221([M+H] + ).

[0032] Step 2. Synthesis of compound VII-2

[0033] ...

Embodiment 3

[0036] Example 3 Compound Inhibition of COMT Analysis in Vitro

[0037] The COMT inhibitory activity of the compound of the present invention is determined by the experimental method described below. The fluorescence analysis is based on the substrate (6,7-dihydroxycoumarin) being methylated by COMT to generate a highly fluorescent product (7-hydroxy-6-methoxycoumarin). The reaction requires the presence of magnesium ions and a methyl donor [in this case S-adenosylmethionine (SAM)]. A stock solution of 10 mM compound in DMSO was used to prepare a 10-point 3-fold dilution series and 1 μL of the appropriate dilution was placed in the assay wells (black 96-well round bottom polystyrene plates from Costar; catalog number 3792). Dilute the recombinase in assay buffer (100mM Na 2 HPO 4 pH 7.4, 1 mM DTT, 0.005% Tween-20) and 35 μL was added to the analysis well containing 1 μL of compound. The pre-incubation of COMT enzyme and compound was performed at room temperature for 2 hours....

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PUM

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Abstract

The invention relates to the field of COMT inhibitors, and particularly relates to a COMT inhibitor comprising a terminal olefinic bond and a hydrazide structure, a preparation method of the COMT inhibitor, and application of the COMT inhibitor to preparation of medicines for treating schizophrenia and the like.

Description

Technical field [0001] The present invention relates to the field of COMT inhibitors. Specifically, the present invention relates to a COMT inhibitor containing a terminal ethylenic bond and a hydrazide structure that has a therapeutic effect on inhibiting COMT, its preparation method, and its use in the treatment of schizophrenia. Background technique [0002] The symptoms of schizophrenia are usually divided into three categories: positive, negative and cognitive. Positive symptoms include hallucinations, delusions, and confused behavior, while negative symptoms are characterized by a lack of pleasure and / or interest in life. Cognitive deficits include difficulties in organizing ideas and prioritizing tasks. Patients with bipolar disorder usually show periodic mood changes (with or without features of psychosis) from severe depression to severe mania. Schizophrenia and bipolar disorder are among the most serious types of mental disorders that cause overlapping cognitive defi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D251/50A61P25/18
CPCC07D251/50
Inventor 蔡子洋
Owner FOSHAN SAIWEISI MEDICINE SCI & TECH
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