Application of benzo-six-membered ring derivatives as DPP-4 long-acting inhibitors

A kind of DPP-4, inhibitor technology, applied in the application field of medicine

Pending Publication Date: 2019-09-17
SHANDONG BIOPOLAR DICHANG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, long-acting inhibitors are only listed in Japan and have not yet entered China. The development of long-acting DPP-4 inhibitors deserves continuous attention

Method used

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  • Application of benzo-six-membered ring derivatives as DPP-4 long-acting inhibitors
  • Application of benzo-six-membered ring derivatives as DPP-4 long-acting inhibitors
  • Application of benzo-six-membered ring derivatives as DPP-4 long-acting inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1. Synthesis of Compounds

[0050] The compound of the present invention was synthesized with reference to the applicant's prior application CN 105566276A.

Embodiment 2

[0051] Embodiment 2. In vivo long-acting activity experiment (0.3mg / kg)

[0052] Instrument: microplate reader (PerkinElmer, USA).

[0053] Materials: Human recombinant DPP-4, which was expressed in insect cells by using the baculovirus expression system Bac-to-Bac (purchased from GIBCO) in our laboratory according to conventional experimental techniques; the substrate Ala-Pro-AMC was obtained by Synthesized by Jill Biochemical (Shanghai) Company.

[0054] Principle of activity test: DPP-4, DPP-8 and DPP-9 can specifically hydrolyze the substrate Ala-Pro-AMC to generate product AMC, AMC is excited by 355nm ultraviolet light to produce 460nm emission light, dynamic measurement unit time 460nm wavelength The fluorescence value changes linearly at the position, and the DPP-4 activity is calculated.

[0055] Sample treatment: The sample was dissolved in DMSO and stored at low temperature. The concentration of DMSO in the final system was controlled within the range that did not ...

Embodiment 3

[0060] Example 3. DPP-4 Activity Study in Normal ICR Mice (Dose Dependency)

[0061] Animal: ICR mouse (8-10 weeks old, sex: male, body weight 25g-30g, purchased from Shanghai Slack Experimental Animal Center).

[0062] Steps: ICR mice were starved for 2h, orally administered test compound (0.03, 0.1, 0.3, 1 and 3mg / kg), positive drug MK-3102 (0.03, 0.1, 0.3, 1 and 3mg / kg); As a blank control, before oral administration, 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 144h and 168h after oral administration, blood was taken from the mouse orbital plexus vein, and added to an Eppendorf tube (Qizhong Industrial Co., Ltd. (Shanghai) Co., Ltd.), the serum was taken after centrifugation, and the DPP-4 activity was determined.

[0063] Results: Within 48 hours after a single administration of HL012, HL012 can significantly inhibit the DPP-4 activity of normal ICR in vivo, and presents a significant dose-dependent manner, in which HL012 0.3mg / kg and 1mg / kg DPP-4 within 2 hours after admin...

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PUM

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Abstract

The invention discloses usage of a compound shown as a formula I below, or pharmaceutically acceptable salts or prodrugs thereof, or optically active isomers thereof or solvated substances thereof for preparing dipeptidyl peptidase-4 (DPP-4) long-acting inhibitors.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; Specifically, the present invention relates to novel benzo six-membered ring derivatives as DPP-4 long-acting inhibitors and their use in the preparation of therapeutic or prophylactic dipeptidyl peptidase-4 (DPP-4) Drugs for related diseases, or as diuretics or drugs for the treatment and prevention of inflammation. Background technique [0002] According to the latest statistics from the International Diabetes Federation, there are currently 114 million diabetics in my country, ranking first in the world. At present, the mainstream type 2 diabetes hypoglycemic drugs on the market include insulin and oral hypoglycemic drugs. Traditional oral hypoglycemic agents include sulfonylureas, glinides, biguanides, thiazolidinediones, and beta-glucosidase inhibitors. Although these drugs can control blood sugar levels, their long-term therapeutic effects are limited and tolerated Most of them ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/353A61P7/10A61P29/00A61P3/10A61P1/00A61P3/04A61P3/00
CPCA61K31/353
Inventor 李静雅赵文娟赵振江李丹
Owner SHANDONG BIOPOLAR DICHANG PHARM CO LTD
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