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Biguanide derivatives as dpp-iv inhibitors

A technology for preparing medicines and medicines, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve the problems of lack of hypoglycemia, weight, etc., achieve the effect of improving or restoring function and preventing β-cell degeneration

Active Publication Date: 2016-03-02
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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  • Biguanide derivatives as dpp-iv inhibitors
  • Biguanide derivatives as dpp-iv inhibitors
  • Biguanide derivatives as dpp-iv inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0056] The preparation of formula (III) compound

[0057] 1. Preparation of 8-bromo-7-(2-butyn-1-yl)-3-methyl-1-(quinolin-2-ylmethyl)-3,7-xanthine (compound III-1)

[0058]

[0059] (1) Preparation of 8-bromo-7-(2-cyanobenzyl)-1,3-dimethyl-3,7-xanthine

[0060] Mix 3-methyl-8-bromo-xanthine with N-ethyldiisopropylamine (DIPEA) in N,N-dimethylformamide, add 2-cyanobenzyl bromide, and Stir overnight. 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-cyanobenzyl)-8-bromo-xanthine (molecular formula: C 14 h 10 BrN 5 o 2 ).

[0061] Mass spectrometry (ESI + ): m / z=36[1M+H] + ;

[0062] Elemental analysis: C, 46.69; H, 2.80; Br, 22.19; N, 19.44; O, 8.88.

[0063] (2) Preparation of 8-bromo-7-(2-cyanobenzyl)-3-methyl-1-(quinolin-2-ylmethyl)-3,7-xanthine

[0064] Add 2-bromomethylquinoline to a mixed solution of 3-methyl-7-(2-cyanobenzyl)-8-chloro-xanthine an...

Embodiment 1

[0118] Example 1: l-(quinolin-2-ylmethyl)-3-methyl-7-(2-cyanobenzyl)-8-((R)-3-(N1-n-butylbiguanide base )-piperidin-1-yl)-xanthine (compound I-1) preparation

[0119]

[0120] Dissolve dicyandiamide in isopropanol, add (R)-8-(3-n-butylaminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-1 -(quinolin-2-ylmethyl)-3,7-xanthine (compound II-1), adjust the pH to 5-6 with 36% HCl, control the temperature at 80-100°C for 6 hours, let stand after the reaction is completed After cooling, a large amount of white crystals were precipitated, filtered by suction, washed, dried and recrystallized with absolute ethanol to obtain the title compound (molecular formula: C 35 h 40 N 12 o 2 ).

[0121] Mass spectrometry (ESI + ): m / z=661[M+H] +

[0122] Elemental analysis: C, 63.62; H, 6.10; N, 25.44; O, 4.84.

[0123] 1 H-NMR (d6-DMSO): 8.06(1H), 8.01(1H), 7.83(2H), 7.75(1H), 7.63(1H), 7.52(3H), 7.46(1H), 7.30(2H), 6.62 (2H), 5.47(2H), 4.76(2H), 3.61(1H), 3.39(3H), 3.34(1H), 3.30(2H), 3...

Embodiment 2

[0124] Example 2: l-benzyl-3-methyl-7-(2-cyanobenzyl)-8-((R)-3-(N1-n-butylbiguanidinyl)-piperidin-1-yl )-xanthine (compound 1-2) preparation

[0125]

[0126] Dissolve dicyandiamide in isopropanol, add (R)-8-(3-n-butylaminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-1 -Benzyl-3,7-xanthine (compound II-2), adjust the pH to 5-6 with 36% HCl, control the temperature at 80-100°C for 6.5 hours, leave it to cool after the completion of the reaction, a large amount of white crystals precipitated, pumped Filter, wash, recrystallize with absolute ethanol after drying, obtain title compound (molecular formula: C 32 h 39 N 11 o 2 ).

[0127] Mass spectrometry (ESI + ): m / z=610[M+H] +

[0128] Elemental analysis: C, 63.04; H, 6.45; N, 25.27; O, 5.25.

[0129] 1 H-NMR (d6-DMSO): 7.84(2H), 7.55(3H), 7.20-7.53(6H), 6.63(2H), 5.46(2H), 5.01(2H), 3.60(1H), 3.35(1H) , 3.38(3H), 3.34(2H), 3.27(2H), 2.63(1H), 2.15(1H), 1.83(1H), 1.48-1.58(5H), 1.30(2H), 0.89(3H).

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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 patients 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 biguanide derivative as a DPP-IV inhibitor 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, diabetic complications and other related disease. 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 in healthy people ...

Claims

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Application Information

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