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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, pneumonia, severe diarrhea, enteritis, and intestinal perforation
Therefore, there is an urgent need to find and discover new PI3Kδ inhibitors, which can overcome its toxicity and side effects while retaining high activity

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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