Substituted xanthine compounds, preparation method and applications thereof

A compound, selected technology, applied in the field of medicine, can solve the problem that GLP-1 cannot be made into a drug, etc.

Active Publication Date: 2014-12-17
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, GLP-1 secreted in the body will be rapidly degraded by serine protease dipeptidyl peptidase IV and inactivated, so pure GLP-1 cannot be used as a drug

Method used

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  • Substituted xanthine compounds, preparation method and applications thereof
  • Substituted xanthine compounds, preparation method and applications thereof
  • Substituted xanthine compounds, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0173] Synthetic route of Scheme1 intermediate a

[0174]

[0175] Preparation of the first step 6-amino-5-nitroso-1-methyluracil 2a

[0176] Dissolve 6-amino-1-methyluracil (10.00g, 70.9mmol) in a mixed solution of 50mL water and 20mL glacial acetic acid, add an aqueous solution of sodium nitrite (7.138g, 103.5mmol) at room temperature 25°C (40 mL), stirred at room temperature for 0.5 h, then raised to 50° C. and stirred for 1 h, and finally moved to room temperature and stirred overnight. After the reaction was detected by TLC, the stirring was stopped, filtered, and the filter cake was washed with water (100 mL) and 95% ethanol (50 mL) to obtain Intermediate 2a, 11.97 g of a purple solid, with a yield of about 99.3%.

[0177] 1 H NMR (DMSO-d 6 ,300MHz)δ:3.166(s,3H,CH 3 ),9.051(s,2H,NH 2 ),11.484(s,1H,NH).MS(ESI + ):m / z=170.3[M+H] +

[0178] Preparation of the second step 5,6-diamino-1-methyluracil 3a

[0179] Dissolve 6-amino-5-nitroso-1-methyluracil 2a (11.50g,...

Embodiment 1

[0222]

[0223] Compound 1 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4- (5-Methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

[0224]

[0225] 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5 Preparation of -methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

[0226] Dissolve (R)-3-aminopiperidine 1c (0.050g, 0.50mmol) and potassium carbonate (0.124g, 0.90mmol) in 20mL of anhydrous THF, add 20mg of molecular sieves, and stir at room temperature 25°C for 30min. Gradually add 7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidin-2-yl)-1-piperazinyl] Propyl}-1H-purine-2,6-dione b (0.128g, 0.25mmol), heated to 90°C and refluxed for 8h. After the reaction is complete, cool to room temperature 25°C, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is separated by silica gel (300-400 mesh) column chromatography, and the mixture of dichloromethane-methan...

Embodiment 2

[0229]

[0230] Compound 2 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4- (5-Methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

[0231]

[0232] 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5 Preparation of -methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

[0233] Using b (0.100g, 0.19mmol) and 2c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 2, 54 mg of yellow solid, with a yield of 51.9%. m.p.183-184℃;

[0234] 1 H NMR (CD 3 OD,300MHz)δ:1.707(s,3H),1.799(m,2H),1.989(m,2H),2.019(s,3H),2.391(m,4H+2H),3.039(m,2H), 3.162(m,2H),3.372(s,3H),3.584(m,4H),3.710(m,4H),3.969(m,2H),4.909(s,2H),8.068(s,2H).HR -MS(ESI-TOF + ):C 27 h 39 N 10 o 2 Calculated value 535.3252, measured value [M+H] + 535.3244.

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Abstract

The invention discloses substituted xanthine compounds, a preparation method and applications thereof, and specifically relates to compounds represented by the formula (I), stereo isomers and pharmaceutically acceptable salts thereof, wherein the R1 and R2 are defined in the description. The invention also relates to a pharmaceutical composition containing the compounds, an application of the pharmaceutical composition in preparation of drugs for treating diseases or symptoms caused by high activity of DPP-IV or overexpression of DPP-IV, and a method using the pharmaceutical composition to treat related diseases. The provided compounds can effectively inhibit the activity of DPP-IV.

Description

technical field [0001] The invention belongs to the technical field of medicine. It relates to substituted xanthine compounds represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, preparation of such compounds, pharmaceutical compositions containing them and the prevention and / or Application in treating diabetes, non-insulin-dependent diabetes, especially in inhibiting DPP-IV. Background technique [0002] Diabetes mellitus (DM) is a metabolic disease with multiple etiologies, which is caused by an absolute or relative deficiency of insulin, resulting in an increase in blood sugar and causing metabolic disorders in the body. In 2012, the number of diabetic patients worldwide exceeded 370 million, of which 4.8 million died (International Diabetes Federation, 2012 Update). Diabetes has become the third major killer of human health after cardiovascular disease and tumors. It can be divided into insulin-dependent diabetes mellitus (IDDM, ty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04A61K31/551A61K31/522A61P3/10
CPCC07D473/04
Inventor 黄海洪申竹芳汪瑾姜茜李刚环奕林紫云
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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