Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Novel DPP-4 inhibitor, and preparation method and medicinal application thereof

A pharmacy and mixed solvent technology, which is applied in the field of preparation of anti-diabetes and its complication drugs and DPP-4 inhibitors, can solve the problems that the application prospect of alogliptin remains to be seen, and achieves short preparation route, cheap and easy-to-obtain raw materials, The effect of simple process

Inactive Publication Date: 2014-03-26
CHINA PHARM UNIV
View PDF6 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the application prospect of alogliptin remains to be seen

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Novel DPP-4 inhibitor, and preparation method and medicinal application thereof
  • Novel DPP-4 inhibitor, and preparation method and medicinal application thereof
  • Novel DPP-4 inhibitor, and preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Synthesis of 1-(2-butyn-1-yl)-6-chloro-2,4-(1H,3H)pyrimidinedione (III)

[0030] To 6-chlorouracil (71g, 480mmol), add 200ml DMF, DIPEA (110ml, 624mmol), cool to 0°C, dropwise add 1-bromo-2-butyne (48ml, 528mmol), stir overnight at room temperature, add water 200ml of precipitated solid was filtered, washed with water, washed with ethyl acetate, and dried to obtain 81g of off-white solid with a yield of 85%. mp: 216-217°C; 1 H NMR (300MHz, CDCl 3 )δ9.36(s, 1H), 5.90(s, 1H), 4.75(s, 2H), 1.81(s, 3H).HRMS-ESI(m / z) calcd for C 8 h 8 N 2 o 2 Cl[M+H] + : 199.0274, found 199.0276

Embodiment 2

[0031] Example 2: 1-(2-butyn-1-yl)-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]-2,4-(1H,3H) Pyrimidinedione (IV)

[0032]Take 1-(2-butyn-1-yl)-6-chloro-2,4-(1H,3H)pyrimidinedione (III) (14.6g, 73.5mmol), 2-chloromethyl-4-form Quinazoline (15.6g, 80.8mmol), lithium bromide (5.69g, 58.8mmol), 60% sodium hydride (3.82g, 95.6mmol), after adding DMF 150ml, react overnight at 80°C under a nitrogen atmosphere, and remove by distillation under reduced pressure Add 100ml of ethyl acetate and 200ml of isopropyl ether to DMF, cool to -20°C to precipitate a solid, filter, wash with ethyl acetate and isopropyl ether, and obtain 21g of a light yellow solid with a yield of 80%. mp: 153°C; 1 H NMR (300MHz, CDCl 3 )δ8.08 (d, J=8.3Hz, 1H), 7.94 (d, J=8.2Hz, 1H), 7.85 (ddd, J=8.4, 6.9, 1.3Hz, 1H), 7.60 (ddd, J=8.1 , 6.9, 1.2Hz, 1H), 6.12(s, 1H), 5.54(s, 2H), 4.89(dd, J=4.5, 2.2Hz, 2H), 2.95(s, 3H), 1.89(t, J= 2.3Hz,3H).HRMS-ESI(m / z)calcd for C 18 h 16 N 4 o 2 Cl[M+H] + : 355.0962, foun...

Embodiment 3

[0033] Example 3: 1-(2-butyn-1-yl)-6-[3(R)-aminopiperidin-1-yl]-3-[(4-methylquinazolin-2-yl) Methyl]-2,4-(1H,3H)pyrimidinedione (I)

[0034] Take 1-(2-butyn-1-yl)-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]-2,4-(1H,3H)pyrimidinedione (IV) (8 g, 22.5 mmol), NaHCO 3 (9.45g, 112.5mmol), 4A molecular sieves (2.6g), (R)-3-aminopiperidine dihydrochloride (4.67g, 27mmol), add 150ml isopropanol, react for 2 hours at 100°C, cool to At room temperature, the solid was removed by filtration, concentrated under reduced pressure, and column chromatography (dichloromethane / methanol / triethylamine 100:0.5:0.5) yielded 8 g of light yellow solid, yield 85%. 1 H NMR (300MHz, CDCl 3 )δ8.00(d, J=8.2Hz, 1H), 7.87(d, J=8.3Hz, 1H), 7.76(t, J=7.5Hz, 1H), 7.51(t, J=7.5Hz, 1H) , 5.47(s, 2H), 5.32(s, 1H), 4.58(d, J=1.9Hz, 2H), 3.39(d, J=10.9Hz, 1H), 3.27(d, J=11.7Hz, 1H) , 3.13-2.98(m, 1H), 2.98-2.82(m, 3H), 2.76(dd, J=15.4, 6.2Hz, 1H), 2.65-2.47(m, 1H), 2.05-1.86(m, 5H) , 1.80(s, 3H), 1.76-1.62(m,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
weightaaaaaaaaaa
Login to View More

Abstract

The invention relates to the field of medicaments, and particularly relates to a compound shown in Formula I, a preparation method thereof and application thereof as a novel DPP-4 inhibitor medicament, especially application in preparation of antidiabetic medicaments. In vivo / in vitro pharmacodynamic experiment results indicate that the compound shown in Formula I has obvious inhibiting action on DPP-4, shows superior blood sugar reducing effect and has higher acting effect in comparison with a similar medicament linagliptin. Meanwhile, the compound provided by the invention is short in preparation route, accessible in raw materials, simple in process and suitable for industrial large-scale production, and has great developing prospects.

Description

technical field [0001] The present invention relates to the pharmaceutical field, in particular to 1-(2-butyn-1-yl)-6-[3(R)-aminopiperidin-1-yl]-3-[(4-methylquinazoline- 2-yl)methyl]-2,4-(1H,3H)pyrimidinedione, the invention also discloses the preparation method and medical use of this compound, especially as a DPP-4 inhibitor for the preparation of anti-diabetic and The use of its complication medicine. Background technique [0002] Diabetes is a slowly progressive disease. It is estimated that there are about 240 million diabetic patients in the world at present, and its incidence is increasing rapidly. A considerable number of patients died from AIDS, and it has become the third most harmful disease to human health after tumors and cardiovascular diseases. More than 90% of diabetic patients are type 2 diabetes, so the current major antidiabetic drug research is launched for type 2 diabetes. Type 2 diabetes mellitus is a metabolic disease with chronic hyperglycemia main...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/517A61P3/10A61P3/06A61P3/00A61P3/04A61P35/00A61P25/00A61P37/00
CPCC07D401/14
Inventor 孙宏斌赖增伟柳军张陆勇
Owner CHINA PHARM UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com