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Aralkyl heterocyclic derivative and application of aralkyl heterocyclic derivative in multi-target depression resistance

A technology of heterocycles and aranes, applied in the field of new drug design and synthesis, can solve problems such as low curative effect, large side effects, and inability to improve cognitive impairment

Pending Publication Date: 2018-01-16
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This new derivative can overcome the common defects of slow onset of action, low curative effect, large side effects and inability to improve cognitive impairment in existing antidepressant drugs, and meet the needs of depression treatment

Method used

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  • Aralkyl heterocyclic derivative and application of aralkyl heterocyclic derivative in multi-target depression resistance
  • Aralkyl heterocyclic derivative and application of aralkyl heterocyclic derivative in multi-target depression resistance
  • Aralkyl heterocyclic derivative and application of aralkyl heterocyclic derivative in multi-target depression resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] 3-(4-(1,2-Benzisothiazol-3-yl)-1-piperazin)yl-1-(3,4-dichlorophenyl)yl-propanol (IV-1) hydrochloride preparation of

[0135] 3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 14.71 g of the intermediate (white solid) was obtained, and the yield was 70%. MS(m / z): 420.1[M+1] + .

[0136] The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-(1,2-benzisothiazol-3-yl)-1- Piperazin)-1-(3,4-dichlorophenyl)-propanol hydrochloride (white solid) 4.13g, yield 90%. MS(m / z): 422.1[M+1] + .

[0137] 1 H NMR (400MHz, DMSO) δ10.85 (s, 1H), 8.12 (t, J = 7.7Hz, 2H), 7.64 (dd, J = 5.1, 3.2Hz, 2H), 7.60 (dd, J = 11.6, 4.4Hz, 1H), 7.47(dd, J=11.6, 4.4Hz, 1H), 7.39(dd, J=8.4, 1.9Hz, 1H), 5.84(s, 1H), 4.75(d, J=5.0Hz, 1H), 4.05(d, J=13.2Hz, 2H...

Embodiment 2

[0139] 3-(4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl-1-(3,4-dichlorophenyl)yl-propanol (IV-2 ) preparation of hydrochloride

[0140] 3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperidine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.06 g of the intermediate (white solid) was obtained, and the yield was 62%. MS(m / z): 421.1[M+1] + .

[0141] The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-(6-fluoro-1,2-benzisothiazol-3-yl )-1-piperidinyl-1-(3,4-dichlorophenyl)yl-propanol hydrochloride (white solid) 4.14g, yield 90%. MS(m / z): 423.2[M+1] + .

[0142] 1 H NMR (400MHz, DMSO) δ10.85(s, 1H), 8.00(dd, J=8.8, 5.3Hz, 1H), 7.69(dd, J=9.1, 2.1Hz, 1H), 7.59(t, J= 5.1Hz, 2H), 7.35(dd, J=8.3, 1.9Hz, 1H), 7.28(td, J=9.2, 2.2Hz, 1H), 5.70(s, 1H), 4.68(t, J=6.2Hz, 1H), 3.14(ddd, ...

Embodiment 3

[0144] 3-(4-([1,1'-biphenyl]-2-yl)-1-piperazinyl-1-(3,4-dichlorophenyl)yl-propanol (IV-3) salt Salt preparation

[0145] 3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.18 g of the intermediate (white solid) was obtained, and the yield was 60%. MS(m / z): 439.2[M+1] + .

[0146] The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-([1,1'-biphenyl]-2-yl)- 4.54 g of 1-piperazinyl-1-(3,4-dichlorophenyl)-propanol hydrochloride (white solid), yield 95%. MS(m / z): 441.2[M+1] + .

[0147] 1H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.67–7.57(m, 4H), 7.45(t, J=7.6Hz, 2H), 7.37–7.30(m, 3H), 7.24(dd, J=7.6,1.6Hz,1H),7.17–7.08(m,2H),4.68(s,1H),3.40(d,J=11.4Hz,2H),3.17–3.04(m,4H),3.00–2.82 (m,4H),2.09–1.91(m,2H).

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Abstract

The invention discloses an aralkyl heterocyclic compound or its medicinal salt. The aralkyl heterocyclic compound has a structure shown in a specification. The compound and a composition containing the compound have activity for 5-HT reuptake, a 5-HT1A acceptor and a 5-HT7 acceptor, and can be used in predation of a novel anti-depression medicine.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, and specifically relates to an arane heterocyclic derivative and its application in multi-target antidepressant. Background technique [0002] Depression is a common clinical mental illness that seriously affects human health and quality of life. About 350 million people worldwide suffer from depression. It is estimated that by 2020, depression will become the second disease affecting the quality of human life. [0003] To date, the mechanism of action of antidepressant drugs has not been fully elucidated. Drugs with clear curative effects basically act on the synaptic site of nerve endings, and exert therapeutic effects by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to the central five-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach) and γ-aminobuty...

Claims

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Application Information

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IPC IPC(8): C07D275/04C07D413/04C07D295/092C07D295/096C07D209/14C07D295/073C07D307/81C07D333/58A61K31/496A61K31/495A61K31/454A61P25/24
Inventor 李建其谷正松解鹏周爱南肖莹
Owner SHANGHAI INST OF PHARMA IND
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