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Substituted indole compound, and preparation method and use thereof

A compound, nitrogen oxide technology, applied in the field of medicine, can solve problems such as general promotion effect

Inactive Publication Date: 2014-11-26
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with traditional SSRIs, vilazodone's own 5-HT 1A Receptor agonist activity theoretically speeds up its onset time, but the promoting effect on the overall antidepressant effect is general (Frampton JE.Vilazodone: in major depressive disorder. CNS Drugs2011,25(7):615-27)

Method used

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  • Substituted indole compound, and preparation method and use thereof
  • Substituted indole compound, and preparation method and use thereof
  • Substituted indole compound, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0310] Example 15-Methoxy-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

[0311]

[0312] Step 1) Ethyl 6-oxohexanoate

[0313]6-Caprolactone (15.0 g, 0.13 mol) was dissolved in ethanol (125 mL), and heated at 80° C. for 24 hours. Then the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, then ice water (150 mL) was added successively, ethyl acetate (150 mL) was extracted three times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain ethyl- 6-Hydroxycaproic acid 10.3 g. Then ethyl-6-hydroxyhexanoic acid (10.3g, 68.6mmol) was dissolved in dichloromethane (20mL), and at 0°C, the above solution was added dropwise into a dichloromethane solution of PCC (16.2g, 75.5mmol) ( 140mL), the dropwise addition was completed, and the reaction was continued at room temperature for 2h. Then the reaction mixture was cooled to room temperature, ethyl acetate (100 mL) was a...

Embodiment 25

[0335] Example 25-Chloro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

[0336]

[0337] step Step 1) 4-(5-chloro-1H-indol-3-yl) ethyl butyrate

[0338] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, ethyl 6-oxyhexanoate (2.0 g, 12.6 mmol) and p-chlorophenylhydrazine hydrochloride (2.4 g, 13.6 mmol) were suspended in Prepared by reaction in ethanol (125mL). The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=4 / 1) to obtain the title compound as a white solid (1.16 g, 35.0%).

[0339] LC-MS(ESI,pos.ion)m / z:266.2[M+H] + ;

[0340] 1 H NMR (CDCl 3 ,400MHz)δ(ppm):8.06(br s,1H),7.55(d,J=1.4Hz,1H),7.26-7.24(m,1H),7.11(dd,J=8.6,1.8Hz,1H) ,7.00(s,1H),4.15-4.10(m,2H),2.75(t,J=7.4Hz,2H),2.36(t,J=7.4Hz,2H),2.05-2.00(m,2H), 1.27-1.24 (m,3H).

[0341] Step 2) 4-(5-Chloro-1H-indol-3-yl)butan-1-ol

[0342] The title compound of this step was prepar...

Embodiment 35

[0353] Example 35-fluoro-3-(4-(4-(pyridin-2-yl)piperazin-1-yl)butyl)-1H-indole

[0354]

[0355] Step 1) Ethyl 4-(5-chloro-1H-indol-3-yl)butanoate

[0356] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, ethyl 6-oxyhexanoate (1.0 g, 6.3 mmol) and p-fluorophenylhydrazine hydrochloride (0.86 g, 6.8 mmol) were suspended in Prepared by reaction in ethanol (125mL). The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=4 / 1) to obtain the title compound as a white solid (0.94 g, 60.0%).

[0357] LC-MS(ESI,pos.ion)m / z:250.2[M+H] + ;

[0358] 1 H NMR (CDCl 3 ,400MHz)δ(ppm):8.04(br s,1H),7.27-7.22(m,2H),7.02(d,J=2.0Hz,1H),6.93(td,J=9.1,2.6Hz,1H) ,4.15-4.10(m,2H),2.76(t,J=7.4Hz,2H),2.37(t,J=7.4Hz,2H),2.06-1.99(m,2H),1.25(t,J=7.1 Hz, 3H).

[0359] Step 2) 4-(5-fluoro-1H-indol-3-yl)butan-1-ol

[0360] The title compound of this step was prepared by referrin...

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Abstract

The invention provides a new indole compound, pharmaceutically acceptable salts and medicinal preparations thereof, and a use of the new indole compound in selective inhibition of 5-hydroxytryptamine reuptake and / or excitation of a 5-HT1A receptor. The invention also relates to medicinal compositions comprising the compounds, and a method for treating the central nervous system dysfunction of mammals, especially humans by using the medicinal compositions.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to compounds and compositions for treating central nervous system dysfunction, as well as methods and applications thereof. In particular, what is described in the present invention can be used as a serotonin reuptake inhibitor or / and 5-HT 1A Agonists of piperazine compounds. Background technique [0002] Serotonin, a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in central nervous system (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. Antagonizing or stimulating certain types of 5-HT receptors can effectively regulate central nervous system dysfunction. To date, at least 14 serotonin receptors have been identified. These receptors can be divided into different families, respectively recorded as 5-HT 1 , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5 , 5-HT 6 and 5-HT 7 , and the differen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/496A61P25/00A61P25/18A61P25/20A61P25/22A61P25/24A61P25/14A61P15/00A61P25/16A61P25/28A61P25/30
CPCC07D401/12
Inventor 张英俊金传飞周荣奇张霁张时群王朝禾李静
Owner SUNSHINE LAKE PHARM CO LTD
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