Benzothiazine and benzothiadiazine compounds, preparation and application

A technology of benzothiadiazine and benzothiazine, which is applied in the field of medicine and can solve problems such as toxic and side effects

Active Publication Date: 2017-08-11
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as the only PI3Kδ selective inhibitor currently on the market, the drug insert of idelalisib is accompanied by a black box warning that idelalisib may induce side effects such as liver toxicity, pneumoni

Method used

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  • Benzothiazine and benzothiadiazine compounds, preparation and application
  • Benzothiazine and benzothiadiazine compounds, preparation and application
  • Benzothiazine and benzothiadiazine compounds, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment 1: the synthetic route of class I compound (benzothiadiazines)

[0083]

[0084] Step 1: Benzyl(2-fluoro-6-nitrophenyl)sulfide (1a)

[0085] Dissolve 2,3-difluoronitrobenzene (5.00g, 31.3mmol), benzylthiol (3.7mL, 31.3mmol) in anhydrous DMF (30mL), add anhydrous K 2 CO 3 (4.51g, 32.7mmol), stirred overnight at room temperature. Add an appropriate amount of ethyl acetate to the system, wash with water and saturated brine successively, and wash the organic layer with anhydrous Na 2 SO 4 Drying and concentration gave a light yellow solid, which was directly used in the next reaction. Yield 95%; mp 60-61 °C.

[0086] Benzyl(2-chloro-6-nitrophenyl)sulfide (1b)

[0087] The preparation of intermediate 1b refers to the synthesis of 1a, replacing 2,3-difluoronitrobenzene with 2,3-dichloronitrobenzene. Pale yellow solid. Yield 93%; mp 55-57°C.

[0088] Step 2: 2-fluoro-6-nitrobenzenesulfonyl chloride (2a)

[0089] Dissolve 1a (7.82g, 29.7mmol) in dichloro...

Embodiment 2

[0248] Embodiment 2: the synthetic route of class I compound (pyridothiadiazines) compound

[0249]

[0250] 2-Phenyl-3-(1-((9H-purine-6-)amino)ethyl)-2H-pyridin[2,3-e][1,2]thiadiazine-1,1-dioxide Things (I-22)

[0251] Using 2-chloro-3-nitropyridine as raw material, according to the method of Example 1, the target product was prepared. ESI-MS: m / z=421[M+H] + .

[0252] 2-Phenyl-3-(1-((4-amino-5-cyano-pyrimidine-6-)amino)ethyl)-2H-pyridin[2,3-e][1,2]thiadiazine -1,1-dioxide (I-23)

[0253] Using 2-chloro-3-nitropyridine as raw material, replacing 6-chloropurine with 4-amino-5-cyano-6-chloropyrimidine, according to the method of Example 1, the target product was prepared. ESI-MS: m / z=421[M+H] + .

[0254] 2-Phenyl-3-(1-((9H-purine-6-)amino)ethyl)-2H-pyridin[4,3-e][1,2]thiadiazine-1,1-dioxide Object (I-24)

[0255] According to the method of Example 1, using 3-chloro-4-nitropyridine as raw material, the target product was prepared. ESI-MS: m / z=420[M+H] + .

[0256...

Embodiment 3

[0258] Embodiment 3: the synthetic route of class I compound (pyrazinothiadiazines) compound

[0259]

[0260] 2-Phenyl-3-(1-((9H-purine-6-)amino)ethyl)-2H-pyrazine[2,3-e][1,2]thiadiazine-1,1-di Oxide (I-26)

[0261] Using 2-chloro-3-nitropyrazine as raw material, according to the method of Example 1, the target product was prepared. ESI-MS:m / z=422[M+H] + .

[0262] 2-Phenyl-3-(1-((9H-purine-6-)amino)ethyl)-2H-pyrazine[2,3-e][1,2]thiadiazine-1,1-di Oxide (I-27)

[0263] According to the method of Example 1, 2-chloro-3-nitropyrazine was used as raw material, and 6-chloropurine was replaced with 4-amino-5-cyano-6-chloropyrimidine to prepare the target product. Yield: ESI-MS: m / z=421 [M+H] + .

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Abstract

The invention provides benzothiazine and benzothiadiazine compounds as well as analogues, pharmaceutically acceptable salts, stereoisomers and solvates of the compounds having a structure shown in a general formula a. Repeated experiments prove that the compounds have an inhibition action on PI3Kdelta, wherein most compounds selectively have a remarkableinhibition action on PI3Kdelta, the compounds can be applied to preparation of anti-inflammation and anti-tumor drugs, the range of involved tumor and inflammatory diseases is wide, and the compounds particularly have a better inhibition effect on FL (follicular B-cell non-Hodgkin lymphoma) relapsing in a treatment period, recurrent CLL (chronic lymphocytic leukemia) and recurrent SLL (small lymphocytic lymphoma). Prepared drugs can be combined with other anti-tumor drugs for use and have an obvious effect, and novel treatment drugs are provided for clinically resisting tumors and inflammation diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a benzothiazine, benzothiadiazines and their analogues, their preparation method, and their application in the preparation of anti-tumor and anti-inflammatory drugs. The benzothiazine, benzothiadiazine and their analogs also include their pharmaceutically acceptable salts, stereoisomers and solvates. Background technique [0002] The PI3K / Akt / mTOR pathway is an abnormally activated signal transduction pathway in human cancer, which is closely related to the occurrence and development of malignant tumors. PI3K is a key kinase in this signaling pathway. At present, nearly 30 PI3K inhibitors have entered clinical research successively, and they are popular targets for anti-tumor drug development. [0003] PI3K can be divided into three types, with different structures and functions. There are four catalytic subunits of Class I PI3Ks, namely p110α, β, δ, and γ. Thus c...

Claims

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Application Information

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IPC IPC(8): C07D473/34C07D473/40C07D417/12C07D487/04C07D519/00C07D513/04A61K31/5415A61K31/542A61K31/549A61P35/00A61P29/00A61P35/02A61P37/08A61P11/06A61P19/02A61P19/08A61P27/02A61P11/00A61P17/06A61P17/00A61P13/12
CPCC07B2200/07C07D417/12C07D473/34C07D473/40C07D487/04C07D513/04C07D519/00A61K31/5415A61K31/542A61K31/549
Inventor 胡永洲盛荣马晓东危俊
Owner ZHEJIANG UNIV
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