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Substituted xanthine compounds containing five-membered aromatic heterocycles and their preparation methods and uses

A compound, unsubstituted technology, applied in the field of medicine, can solve the problem of short half-life of active GLP-1

Active Publication Date: 2019-04-09
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inactivation of GLP-1 by DPP-IV is rapid and irreversible, resulting in an extremely short half-life of endogenously produced active GLP-1

Method used

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  • Substituted xanthine compounds containing five-membered aromatic heterocycles and their preparation methods and uses
  • Substituted xanthine compounds containing five-membered aromatic heterocycles and their preparation methods and uses
  • Substituted xanthine compounds containing five-membered aromatic heterocycles and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0211] Synthetic route of route 1 intermediate 3a-1

[0212]

[0213] The first step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1H - Preparation of purine-2,6-dione 2a

[0214] 8-Bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione 1a (2.08g, 7.00mmol), (R)- 3-(tert-butoxycarbonyl)aminopiperidine (1.75g, 8.75mmol) and potassium carbonate (1.94g, 14.00mmol) were placed in a 50mL single-necked bottle, DMF (15mL) was added, and reacted at 75°C under the protection of argon After 7 hours, TLC detected that the reaction was complete. DMF was evaporated to obtain a tan solid, which was slurried by adding 50 mL of water, filtered, and dried under infrared light to obtain 2a, 2.60 g of a tan solid, with a yield of 89.7%. 1 H NMR (400MHz, CDCl 3 )δ:7.84(brs,1H),5.60(brs,1H),4.85(m,2H),3.86(m,1H),3.54(m,1H),3.53(s,3H),3.36(m,2H ),3.28(m,1H),1.89(m,2H),1.82(s,3H),1.73(m,2H),1.45(s,9H).

[0215] The second step 8-[(3R)-3-(tert-bu...

Embodiment 1

[0379]

[0380] Compound 18-[(3R)-3-aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-( 3-Phenyl-1,2,4-oxadiazol-5-yl)piperazin-1-yl]propyl}-1H-purine-2,6-dione

[0381] method one:

[0382]

[0383] Method Two:

[0384]

[0385] The first step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 -{3-[4-(3-Phenyl-1,2,4-oxadiazol-5-yl)piperazin-1-yl]propyl}-1H-purine-2,6-dione 1c preparation

[0386] method one:

[0387] 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidinyl-1-]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-( 3-bromopropyl)-1H-purine-2,6-dione 3a-1 (0.42g, 0.77mmol) and 1-(3-phenyl-1,2,4-oxadiazol-5-yl) Piperazine 1b (0.18g, 0.78mmol) was dissolved in 3mL of anhydrous DMF, then DIPEA (0.40mL, 2.32mmol) was added, and reacted at 75°C for 8h under the protection of argon. It was detected by TLC that the reaction of the raw material was complete, the solvent was evaporated, 20 mL of deionized water was added, extra...

Embodiment 2

[0394]

[0395]Compound 28-[(3R)-3-aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-( 3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl]propyl}-1H-purine-2,6-dione

[0396]

[0397] The first step 8-[(3R)-3-(tert-butoxycarbonyl)aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1 -{3-[4-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl]propyl}-1H-purine-2,6 - Preparation of diketone 2c

[0398] Starting from 3a-1 (0.20g, 0.37mmol) and 1-[3-(4-pyridyl)-1,2,4-oxadiazol-5-yl)piperazine 2b (0.09g, 0.39mmol) , using the steps similar to the first step in Example 1, the intermediate 2c was obtained, 0.14 g of white solid, and the yield was 54.7%.

[0399]

[0400] The second step 8-[(3R)-3-aminopiperidin-1-yl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4 Preparation of -(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl)piperazin-1-yl]propyl}-1H-purine-2,6-dione 2

[0401] Using 2c (0.13g, 0.19mmol) as the starting material, the second step in Example 1 wa...

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Abstract

The present invention discloses a five-membered-aromatic-heterocycte-containing substituted xanthine compound and a preparation method and use thereof. More specifically, the present invention relates to a compound of formula (I) and stereoisomers and pharmaceutically acceptable salts thereof which are as described in specification. The present invention also relates to a pharmaceutical composition comprising the compound, use of the compound in the manufacture of drugs for treatment and / or prevention of diseases or disorders related to too high DPP-IV activity or DPP-IV overexpression, and a method for using the compound for treatment of the related diseases. The compound has efficient DPP-IV inhibitory activity.

Description

technical field [0001] The invention belongs to the technical field of medicine. It relates to substituted xanthine compounds containing five-membered aromatic heterocycles represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, preparation of such compounds, pharmaceutical compositions containing them and the The application of the compound in preventing and / or treating diabetes, hyperlipidemia, obesity and metabolic syndrome, especially the application in inhibiting DPP-IV. Background technique [0002] Diabetes Mellitus (DM) is a chronic metabolic disease with multiple etiologies, which seriously affects the health and quality of life of patients. At the end of 2013, there were approximately 382 million people with diabetes worldwide, and it is estimated that the number of people with diabetes will reach 592 million by 2035. According to statistics, the number of diabetics in China was about 98.4 million in 2013, ranking first in the w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/04A61K31/522A61P3/10A61P3/06A61P3/04A61P3/00
Inventor 黄海洪申竹芳李刚袁保昆环奕姜茜林紫云唐武刘泉刘率男李彩娜
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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