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Small molecular oxothiazine derivative and application thereof

A technology of oxathiazine and small molecules, which is applied in the field of small molecule oxthiazine derivatives, can solve problems in the preclinical research stage or clinical trial stage, and achieve the reduction of receptor inactivation rate and inhibition of receptor desensitization , the effect of function enhancement

Active Publication Date: 2020-08-21
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing research results have pointed out the direction for the design of AMPA receptor positive allosteric modulators, but most of them are in the preclinical research stage or clinical trial stage

Method used

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  • Small molecular oxothiazine derivative and application thereof
  • Small molecular oxothiazine derivative and application thereof
  • Small molecular oxothiazine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Compound disclosed in this example: LT-1,8-(4-methoxyphenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (LT -1)

[0051]

[0052] Concrete synthetic route is as follows:

[0053]

[0054] The specific preparation method is as follows:

[0055] At 0°C, 3-bromo-2-hydroxybenzaldehyde (A01a) (5.6g, 28mmol) was dispersed in 60ml of dimethylacetamide DMA, and then aminosulfonyl chloride (10g, 86.5 mmol). The reaction system was stirred and slowly raised to room temperature until the reaction was complete. After the reaction, add water to precipitate the solid, filter and wash the filter cake with water and ethyl acetate respectively, and obtain the off-white compound as 8-bromobenzo[e][1,2,3]oxathiazine 2 with a yield of 85%. 2-dioxide (A01b).

[0056] Then A01b (2.62g, 10mmol) was dispersed in 50ml of MeOH solvent system, sodium borohydride (380mg, 10.6mmol) was added in batches at room temperature, and stirring was continued at room temperature after the add...

Embodiment 2

[0060] The compound disclosed in this example: 8-(4-methylphenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (LT-2).

[0061]

[0062] The synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid" with "p-tolueneboronic acid".

[0063] MS(ESI)276.1[M+H] + ; 1 H NMR (400MHz, DMSO) δ8.54(s, 1H), 7.39–7.23(m, 7H), 4.62(s, 2H), 2.36(s, 3H).

Embodiment 3

[0065] Compounds disclosed in this example: 8-(4-(tert-butyl)phenyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (LT- 3)

[0066]

[0067] The synthetic route is as in Example 1, replacing "p-methoxyphenylboronic acid" with "p-tert-butylphenylboronic acid".

[0068] MS(ESI)318.1[M+H] + ; 1 H NMR (400MHz, DMSO) δ8.56(s, 1H), 7.51(d, J=8.4Hz, 2H), 7.43–7.34(m, 3H), 7.33–7.21(m, 2H), 4.62(s, 2H), 1.33(s, 9H).

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Abstract

The invention belongs to the field of organic synthetic medicines, and concretely relates to a small molecular oxothiazine derivative. The general formula is shown in the specification. The small molecular oxothiazine derivative can be used as a forward allosteric regulator of an AMPA receptor, and the compound is proved to be capable of positively regulating the AMPA receptor, so that the conformation after an agonist (such as endogenous neurotransmitter glutamic acid) is combined with the receptor is more stable, the inactivation rate of the receptor is reduced, the desensitization of the receptor is inhibited, and the function of the AMPA receptor is enhanced.

Description

technical field [0001] The invention relates to the technical field of innovative chemical medicines, in particular to a small molecule oxathiazine derivative and its application. Background technique [0002] AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are an important subtype of ionotropic glutamate receptors, mainly distributed in the postsynaptic membrane of the central nervous system, Composed of four core subunits G1uR1~4, it mediates the main rapid excitatory transmission in the central nervous system, promotes neural development and outstanding plasticity, and participates in various neural activity processes. Important targets related to systemic diseases. [0003] The extracellular domain of each AMPA receptor subunit contains two domains: the amino-terminal domain (amino-terminal domain, ATD) involved in subunit assembly and the ligand-binding domain (Ligand binding domain, LBD) that provides glutamate binding. Studies have shown that t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D291/08C07D419/04C07D419/10A61P25/18A61P25/28A61P25/16A61P25/24A61K31/5415
CPCA61P25/16A61P25/18A61P25/24A61P25/28C07D291/08C07D419/04C07D419/10
Inventor 李涛漆学宇于雪莉
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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