Structure utilizing benzothiadiazine and pyrazolothiadiazine derivatives as aldose reductase inhibitor, synthetic method and application

A technology of compound structure and use, applied in drug combination, metabolic diseases, organic chemistry, etc., can solve problems such as poor therapeutic effect, low bioavailability, side effects and allergic reactions

Inactive Publication Date: 2012-07-25
BEIJING INSTITUTE OF TECHNOLOGYGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nevertheless, many aldose reductase inhibitors still have problems such as low bioavailability, poor therapeutic effect or serious side effects and allergic reactions, and even some drugs that have been on the market have been withdrawn from the market due to sensitization

Method used

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  • Structure utilizing benzothiadiazine and pyrazolothiadiazine derivatives as aldose reductase inhibitor, synthetic method and application
  • Structure utilizing benzothiadiazine and pyrazolothiadiazine derivatives as aldose reductase inhibitor, synthetic method and application
  • Structure utilizing benzothiadiazine and pyrazolothiadiazine derivatives as aldose reductase inhibitor, synthetic method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080]

[0081] Add 2-aminobenzenesulfonamide (17.2g, 100mmol) and 150mL triethyl orthoformate 150mL into the round bottom flask, stir and reflux for 2h, after returning to room temperature, filter, the filter cake is washed with anhydrous ether, and dried to obtain 4H- 1,2,4-benzothiadiazine 1,1-dioxo (16.2g, 89%): melting point: 226-228°C; 1 HNMR (400MHz, DMSO-d 6 ): δ7.28(m, 1H), 7.43(m, 1H), 7.65(m, 1H), 7.78(m, 1H), 7.96(s, 1H), 12.28(s, 1H).

[0082] A round bottom flask was charged with 4H-1,2,4-benzothiadiazine 1,1-dioxo (14.6 g, 80 mmol), potassium carbonate (12 g), methyl bromoacetate (13.4 g, 88 mmol) and acetonitrile (180 mL), react at 70°C for 2 h, remove the solvent by rotary evaporation, filter, wash repeatedly with water, and dry. The crude product was recrystallized from ethyl acetate to give white crystals of methyl (4H-1,2,4-benzothiadiazine-1,1-dioxo-4-alkyl)acetate (16.9 g, 83%): mp : 154-156°C; 1 H NMR (400MHz, DMSO-d 6 ): δ3.74(s, 3H), 5.10(s, 2H...

Embodiment 2

[0087]

[0088] Substitute 3-nitrobenzyl bromide for 4-bromo-2-fluorobenzyl bromide in Example 1, and prepare according to the preparation method described in Example 1.

[0089] Melting point: 166-169°C; 1 H NMR (400MHz, DMSO-d 6 ): δ4.20(s, 2H), 4.42(s, 2H), 4.95(s, 2H), 6.76(d, 1H), 6.89(m, 1H), 7.46(m, 1H), 7.65(m, 2H), 8.17(m, 1H), 8.20(m, 2H), 12.98(s, 1H); elemental analysis (C 16 h 15 N 3 o 6 S): theoretical value C: 50.92%, H: 4.01%, N: 11.13%; actual value C: 51.00%, H: 4.05%, N: 11.12%.

[0090] Example 3 [2-(4-trifluoromethylbenzyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxo-4-alkyl]acetic acid (compound 3 )

Embodiment 3

[0091]

[0092] Substitute 4-trifluoromethylbenzyl bromide for 4-bromo-2-fluorobenzyl bromide in Example 1, and prepare according to the preparation method described in Example 1.

[0093] Melting point: 152-155°C; 1 H NMR (400MHz, CDCl 3 ): δ3.98(s, 2H), 4.39(s, 2H), 4.79(s, 2H), 6.58(d, 1H), 6.96(m, 1H), 7.43(m, 1H), 7.51(d, 2H), 7.62(d, 2H), 7.78(m, 1H); elemental analysis (C 17 h 15 f 3 N 2 o 4 S): theoretical value C: 51.00%, H: 3.78%, N: 7.00%; actual value C: 50.64%, H: 3.88%, N: 6.93%.

[0094] Example 4 [2-(2,4,5-trifluorobenzyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxo-4-alkyl]acetic acid ( Compound 4)

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Abstract

The invention provides a compound structure showed in a formula I, a synthetic method and application of pharmaceutically acceptable salt or mixture thereof in terms of preparation of medicines for preventing and / or curing diabetes complications. The compound is used as an aldose reductase inhibitor, accumulation of sorbite in a human body is reduced effectively by means of suppressing activity of aldose reductase, and accordingly an effect of preventing and / or curing the diabetes complications is achieved. The invention further provides a medicine composition which comprises the compound and has an effect of preventing and / or curing diabetes.

Description

technical field [0001] The present invention relates to the fields of organic chemistry, medicinal chemistry and pharmacotherapy, in particular to the structure, preparation method, inhibitory effect on aldose reductase (Aldose Reductase, ALR2) of a class of novel aldose reductase inhibitors and the prevention of And / or applications in the treatment of diabetic complications. Background technique [0002] Diabetes Mellitus (DM) is a worldwide disease that seriously endangers human health. The danger of diabetes mainly lies in its complications. Diabetic complications include metabolic syndromes such as nephropathy, retinopathy, neurological diseases and cardiovascular and cerebrovascular diseases. Due to the high disability rate and high mortality rate of diabetes complications, it has become one of the main threats to the health and life expectancy of residents in most countries in the world. However, there are almost no drugs for diabetic complications in the world at pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/549A61P3/10C07D285/24C07D513/04
Inventor 朱长进马兵陈鑫杨彦春郭凡
Owner BEIJING INSTITUTE OF TECHNOLOGYGY
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