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Uracil derivatives

A compound and stereoisomer technology, applied in the field of medicinal chemistry, can solve the problems of inconvenient use and carrying

Inactive Publication Date: 2017-03-29
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned DPP-4 inhibitors must be taken every day, and from the perspective of maximizing the benefits of diabetic patients, one or more long-acting drugs are still needed. However, there are few long-acting hypoglycemic drugs on the market at present, only glargine Insulin injections, exenatide injections, etc., and mostly injections, are easy to cause inconvenience for diabetic patients to use and carry. Therefore, the market is in urgent need of an oral long-acting drug to change this situation. The compound of the present invention is A DPP-IV inhibitor that exhibits excellent blood sugar-lowering effects, is suitable for type 2 diabetes, and can maintain long-acting effects after administration, thereby improving patients' medication compliance

Method used

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  • Uracil derivatives
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation of Compound 1

[0047]

[0048] The preparation method is shown in the following formula:

[0049]

[0050] The preparation of the first step compound 1a

[0051]The starting material a (500mg, 1.4mmol) was dissolved in dichloromethane (5ml), and Boc-L-phenylalanine (398mg, 1.5mmol), EDCI (326mg, 1.7mmol), HOBT (189mg, 1.4 mmol), K 2 CO 3 (580mg, 4.2mmol), react overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, the reaction solution was washed with water, 1N hydrochloric acid solution, and water successively, and the liquid was separated. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 1a (800 mg, yellow solid). Yield: 94.6%.

[0052] MS m / z(ES): 605.3[M+1]

[0053] The preparation of the second step compound 1

[0054] Compound 1a (800mg, 1.3mmol) was dissolved in dichloromethane (...

Embodiment 2

[0057] Example 2 Preparation of Compound 2

[0058]

[0059] The preparation method is shown in the following formula:

[0060]

[0061] The preparation of the first step compound 2a

[0062] The starting material a (500mg, 1.4mmol) was dissolved in dichloromethane (5ml), and Boc-L-tyrosine (422mg, 1.5mmol), EDCI (326mg, 1.7mmol), HOBT (189mg, 1.4mmol) were added ), K 2 CO 3 (580mg, 4.2mmol), react overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, the reaction solution was washed with water, 1N hydrochloric acid solution, and water successively, and the liquid was separated. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 2a (780 mg, yellow solid). Yield: 89.9%.

[0063] MS m / z(ES): 621.3[M+1]

[0064] The preparation of the second step compound 2

[0065] Compound 2a (780mg, 1.3mmol) was dissolved in dichlorom...

Embodiment 3

[0068] Example 3 Preparation of compound 3

[0069]

[0070] The preparation method is shown in the following formula:

[0071]

[0072] The preparation of the first step compound 3a

[0073] The starting material a (500mg, 1.4mmol) was dissolved in dichloromethane (5ml), and di-tert-butoxycarbonyl-L-histidine (533mg, 1.5mmol), EDCI (326mg, 1.7mmol), HOBT ( 189mg, 1.4mmol), K 2 CO 3 (580mg, 4.2mmol), react overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, the reaction solution was washed with water, 1N hydrochloric acid solution, and water successively, and the liquid was separated. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain compound 3a (810 mg, yellow solid). Yield: 83.3%.

[0074] MS m / z(ES): 695.3[M+1]

[0075] The preparation of the second step compound 3

[0076] Compound 3a (810mg, 1.2mmol) was dissolved in d...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and specifically relates to uracil derivatives / stereoisomers of uracil derivatives and a preparation method thereof. Compared with positive controls (1 and 2), the results of OGTT experiments show that the uracil derivatives have an excellent and long-lasting blood sugar reducing effect, so the uracil derivatives can be used to prepare drugs for treating II type diabetes or diseases with symptoms of impaired glucose tolerance.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of uracil derivatives or stereoisomers thereof, a preparation method and the use of derivatives thereof as dipeptidyl peptidase IV (DPP-IV) inhibitors. Background technique [0002] Diabetes patients in my country account for about 1 / 3 of the total number of diabetes in the world, among which type Ⅱ diabetes patients account for more than 90%. Dipeptidyl peptidase IV (DPP-IV) is a new target for the treatment of type II diabetes, it can rapidly inactivate incretin glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin releasing peptide ( GIP) and other hormones, while DPP-IV inhibitors prolong and increase the activity of endogenous GLP-1 and GIP, promote insulin secretion, and lower blood sugar. At present, the DPP-IV inhibitors marketed at home and abroad include sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemagliptin, tiagliptin, etc. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D401/14A61K31/506A61P3/10
CPCC07D401/04C07D401/14Y02P20/55
Inventor 王颖向永哲刘建
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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