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Benzisoxazole compound and application thereof

A compound, isoxazole technology, applied in the field of medicine, can solve problems affecting the DA function of the substantia nigra-striatum and tubercle-infundibulum system

Active Publication Date: 2014-04-02
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Specifically, the drug exerts pharmacological effects by blocking dopamine D2 receptors in the midbrain-cerebral cortex and midbrain-limbic system, but because it also affects the DA function of the substantia nigra-striatum and tubercle-infundibulum system, so Can cause extrapyramidal reactions (EPS), as well as adverse reactions such as endocrine and metabolic changes

Method used

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  • Benzisoxazole compound and application thereof
  • Benzisoxazole compound and application thereof
  • Benzisoxazole compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 3-{1-[3-(3,4-dihydro-2H-chromen-7-yloxy)propyl]pyridin-4-yl}-6-fluorobenzo[d]isox Preparation of azole

[0053] 2.82g (0.011mol) of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, 2.27g (0.01mol) of 7-(3-chloropropoxy)chroman mol), 5.29g (0.04mol) of anhydrous potassium carbonate and 0.17g (0.001mol) of potassium iodide were mixed in a 250mL round bottom flask, and 120mL of acetone was added as the reaction solvent, and heated to reflux for 24h. TLC monitoring showed that the reaction was complete and the product was single. Cool to room temperature, filter, wash the filter cake with acetone, combine the washing liquid with the filtrate, and concentrate to obtain a light yellow oil, which is separated by silica gel column chromatography, petroleum ether: ethyl acetate (v:v=1:2) to recover the reaction raw material 7-(3-Chloropropoxy)chroman. Ethyl acetate: triethylamine (v:v=100:1) to collect the target product. Concentration gave 2.25 g of wh...

Embodiment 2

[0054] Example 2: Preparation of 6-{3-[4-(6-fluorobenzo[d]isoxazol-3-yl)pyridin-1-yl]propoxy}chroman-4-one

[0055] According to the method of Example 1, a white solid was obtained with a yield of 54.5%, mp.135-136°C. 1 H-NMR (CDCl 3 ,600MHz)δ(ppm):7.33(1H,d,J=3.0Hz),7.25(1H,s),7.10(1H,d,J=3.0Hz),7.08(1H,d,J=3.0Hz) ,6.92(1H,d,J=9.0Hz),4.50(2H,t,J 1 =J 2 =6.6Hz), 4.05(2H,t,J 1 =J 2 =6.0Hz), 2.80(4H,m), 2.20(6H,m); ESI-MS: m / z425([M+H] + ),446.9([M+Na] + );IR,ν(cm -1 ):2952,2824,2773,1675,1613,1519,1434,1346,1282,1234,1122,1037,957,849,786,709.

Embodiment 3

[0056] Example 3: Preparation of 7-{3-[4-(6-fluorobenzo[d]isoxazol-3-yl)pyridin-1-yl]propoxy}chroman-4-one

[0057] According to the method of Example 1, a white solid was obtained with a yield of 59.7%, mp.122-123°C. 1 H-NMR (CDCl 3 ,600MHz)δ(ppm):7.83(1H,d,J=9.0Hz),7.70(1H,s),7.24(1H,q,J 1 =8.4Hz,J 2 =2.4Hz),7.05(1H,m,J 1 =8.4Hz,J 2 =8.4Hz,J 3 =2.4Hz),6.59(1H,q,J 1 =8.4Hz,J 2 =2.4Hz),6.43(1H,d,J=2.4Hz),4.51(2H,t,J 1 =J 2 =6.6Hz), 4.09(2H,t,J 1 =J 2 =6.6Hz), 3.08(3H,s), 2.75(2H,t,J 1 =J 2 =6.6Hz), 2.57(2H,s), 2.21(2H,m), 2.07(4H,m), 2.04(2H,m); ESI-MS: m / z425([M+H] + ),446.9([M+Na] + );IR,ν(cm -1 ):2957,2917,2849,2759,1675,1612,1578,1518,1495,1441,1257,1233,1197,1169,1122,1059,957,907,830,620.

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Abstract

The invention relates to a benzisoxazole compound and application thereof, in particular relates to the benzisoxazole compound, a stereisomer and pharmaceutically acceptable salt of the benzisoxazole compound, and application of the benzisoxazole compound, belonging to the technical field of medicines. The compound is characterized in that 6-fluorine-3-(4-piperidyl)-1,2-benzisoxazole hydrochloride containing an antipsychotic active structural segment is respectively connected with 6-hydroxychroman, 7-hydroxychroman, 6-hydroxy-4-chromanone, 7-hydroxy-4-chromanone, a flavonoids compound and an isoflavones compound through 1,3-dibromo chloropropane to synthesize nine benzisoxazole compounds based on the bioisosteres and splicing principle; the benzisoxazole compounds as shown in the structural formula below have high application value and wide development and application prospect. The benzisoxazole compounds and pharmaceutically acceptable acid addition salt of the benzisoxazole compound can be combined or individually used as 5-HT2 / D2 receptor antagonists for treating schizophrenia.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to benzisoxazole compounds and applications thereof, in particular to benzisoxazole compounds, stereoisomers and pharmaceutically applicable salts of the compounds and applications thereof. The compound is 5-HT 2 / D 2 Receptor antagonists are the first personalized psychiatric drugs and the first gene-targeted drugs for the treatment of schizophrenia. Background technique: [0002] The cause of schizophrenia is due to the excessive activation of dopamine neurons in the patient's brain. Antipsychotic drugs produce antipsychotic effects mainly by blocking dopamine (DA) receptors in the brain. Specifically, the drug exerts pharmacological effects by blocking dopamine D2 receptors in the midbrain-cerebral cortex and midbrain-limbic system, but because it also affects the DA function of the substantia nigra-striatum and tubercle-infundibulum system, so It can cause extrapyramidal rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/4439A61K31/454A61P25/18
CPCC07D413/14
Inventor 胡春孙宝佳金辄徐赫男刘晓平黄二芳
Owner SHENYANG PHARMA UNIVERSITY
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