Compound as dipeptidyl peptidase-4 inhibitor

A compound and alkyl technology, applied in the field of compounds as dipeptidyl peptidase-4 inhibitors, can solve the problems of lack of hypoglycemia, body weight, etc., and achieve the effect of improving or restoring function and preventing β-cell degeneration

Active Publication Date: 2015-04-01
ZHEJIANG YONGTAI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there is still a lack of single compounds with low risk of hypoglycemia, weight gain and other adverse events

Method used

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  • Compound as dipeptidyl peptidase-4 inhibitor

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0060] The preparation of formula (III) compound

[0061] 1.8-Bromo-7-(2-butyn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-xanthine (compound III-1) Preparation

[0062]

[0063] (1) Preparation of 3-methyl-7-(2-butyn-1-yl)-8-bromo-3,7-xanthine

[0064] Mix 3-methyl-8-bromo-xanthine with N-ethyldiisopropylamine (DIPEA) in N,N-dimethylformamide, add 1-bromo-2-butyne, and Stir overnight at room temperature. For work-up, the reaction mixture was poured into water. The separated precipitate is suction filtered, washed with water, and dried to obtain 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine (molecular formula: C 10 h 9 BrN 4 o 2 ).

[0065] Mass spectrometry (ESI + ): m / z=298[M+H] +

[0066] Elemental analysis: C, 40.43; H, 3.05; Br, 26.89; N, 18.86; O, 10.77

[0067] (2) Preparation of 8-bromo-7-(2-butyn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-xanthine

[0068] Add 2-(2-bromoethyl)-4-methylquinazoline to the N of 3-methyl-7-(2-buty...

Embodiment 1

[0169] Example 1: Preparation of l-((4-methyl-quinazolin-2-yl)methyl)-3-methyl-7-(2-butyn-1-yl)-8-((R) -3-(N1-n-Butylbiguanide)-piperidin-1-yl)-xanthine (Compound I-1)

[0170]

[0171] Dissolve dicyandiamide in isopropanol, add (R)-8-(3-n-butylaminopiperidin-1-yl)-7-(2-butyn-1-yl)-3-methyl -1-((4-methylquinazolin-2-yl)methyl)-3,7-xanthine (compound II-1), adjust the pH to 5-6 with 36% HCl, and control the temperature at 80-100 ℃ for 6 hours. After the reaction was completed, it was allowed to stand for cooling, and a large amount of white crystals were precipitated. After suction filtration, washing, drying, and recrystallization with absolute ethanol, the title compound (molecular formula: C 31 h 40 N 12 o 2 ;).

[0172] Mass spectrometry (ESI + ): m / z=613[M+H] + ;

[0173]Elemental analysis: C, 60.77; H, 6.58; N, 27.43; O, 5.22;

[0174] 1 H-NMR (d6-DMSO): 8.12(1H), 7.85(2H, br), 7.80(2H), 7.59(1H), 6.63(2H, br), 4.43(4H), 3.59(1H), 3.38( 3H), 3.34(1H), 3.30(2...

Embodiment 2

[0175] Example 2: l-(dimethylaminocarbonylmethyl)-3-methyl-7-(1-cyclohexenylmethyl)-8-((R)-3-(N1-cyclohexylbiguanide) Preparation of -piperidin-1-yl)-xanthine (compound 1-2)

[0176]

[0177] Dissolve dicyandiamide in isopropanol, add (R)-8-(3-cyclohexylaminopiperidin-1-yl)-7-(1-cyclohexenylmethyl)-3-methyl- 1-((4-methylquinazolin-2-yl)methyl)-3,7-xanthine (compound II-2), adjust the pH to 5-6 with 36% HCl, and control the temperature at 80-100°C Reacted for 7 hours, stood still after the completion of the reaction, cooled and crystallized, filtered with suction, washed, dried and recrystallized with absolute ethanol to obtain the title compound (molecular formula: C 30 h 47 N 11 o 3 ).

[0178] Mass spectrometry (ESI + ): m / z=610[M+H] + ;

[0179] Elemental analysis: C, 59.09; H, 7.77; N, 25.27; O, 7.87.

[0180] 1 H-NMR (d6-DMSO): 7.84 (2H, br), 6.63 (2H, br), 5.39 (1H), 4.40 (2H), 4.28 (2H), 3.59 (1H), 3.42 (3H), 3.34 ( 1H), 3.27(2H), 2.98(6H), 2.64(1H), 2.56(...

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Abstract

The invention relates to a compound as a dipeptidyl peptidase-4 (DPP-IV) inhibitor, which can be used for treating all symptoms or diseases that get benefits by inhibiting DPP-IV activity, such as type I and II diabetes, diabetes complications and other related diseases.

Description

technical field [0001] The present invention relates to a compound as an inhibitor of dipeptidyl peptidase-4 (DPP-IV) for use in the treatment of all symptoms or conditions that would benefit from inhibition of DPP-IV activity, such as type I and type II diabetes , diabetes complications and other related diseases. Background technique [0002] Dipeptidyl peptidase-4 (DPP-4) is a highly specific serine protease whose natural substrates are glucagon-like peptide 1 (GLP-1) and glucose insulinotropic polypeptide (GIP). GLP-1 has a variety of physiological functions. In the pancreas, it can increase glucose-dependent insulin secretion, inhibit the secretion of glucagon, and increase the proliferation of islet D cells; in the gastrointestinal tract, it can delay postprandial gastric emptying, thereby delaying intestinal glucose absorption. . GIP has the function of stimulating insulin secretion. DPP-4 can rapidly degrade GLP-1 and GIP in the body and make them inactive. GLP-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04C07D473/06A61K31/522A61P3/10A61P37/02A61P3/04A61P3/06A61P9/12A61P9/10A61P19/10A61P1/16A61P29/00A61P27/02A61P13/12A61P3/00A61P15/08A61P25/00
CPCC07D473/04C07D473/06
Inventor 何人宝邵鸿鸣
Owner ZHEJIANG YONGTAI TECH CO LTD
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