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Piperidine derivatives and methods of use thereof

A diabetic, pyridyl-based technology applied in the field of piperidine derivatives, which can solve the problems of nausea and diarrhea, lactic acidosis, etc.

Inactive Publication Date: 2010-03-17
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs can induce lactic acidosis, nausea, and diarrhea

Method used

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  • Piperidine derivatives and methods of use thereof
  • Piperidine derivatives and methods of use thereof
  • Piperidine derivatives and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0274] Synthesis of intermediate compound 5A

[0275] step 1

[0276]

[0277] To a solution of 10.81 g (100 mmol) of 2-amino-4-picoline in 250 mL of tert-butanol was added 26.19 g (120 mmol) of BOC anhydride. The reaction mixture was stirred overnight at room temperature, concentrated, dry-loaded onto silica gel, and subjected to flash chromatography (from 30% hexane / CH2 Cl 2 to 0-2% acetone / CH 2 Cl 2 ), yielding 15.25 g (73.32 mmol; 73%) of 1A as a white solid.

[0278] step 2

[0279]

[0280] To a solution of 1A (35.96 g, 173 mmol) in THF (1.4 L) at -78 °C was added 1.4 M BuLi in hexane (272 mL, 381 mmol) in portions over 30 min. The reaction mixture was then allowed to warm and stirred at room temperature for 2 hours, an orange precipitate formed. The mixture was cooled back to -78°C and pre-dried oxygen (through a Drierite column) was bubbled through the suspension over 6 hours while maintaining the temperature at -78°C. The color of the reaction mixtu...

Embodiment 2

[0291] Synthesis of intermediate compound 7A

[0292]

[0293] Compound 6A (42mmol), NBS (126mmol) and Bz 2 o 2 (4.2 mmol) of CCl 4 (400 mL) of the solution was refluxed at 80°C for 5 hours, cooled, and stirred at room temperature overnight. The reaction was filtered, concentrated, and the residue was purified by flash column (30% EtOAc / Hexanes) to afford target compound 7A (3.1 g, 23%).

Embodiment 3

[0295] Synthesis of intermediate compound 11A

[0296] step 1

[0297]

[0298] To a solution of 8A (10 g, 79.4 mmol) and DMAP (0.029 g, 0.24 mmol) in dichloromethane (150 mL) at 0 °C was added phthaloyl dichloride (16.1 g, 79.4 mmol) dropwise. The reaction mixture was stirred overnight at room temperature. After stirring overnight, the reaction was washed with saturated NaHCO 3 Washed with aqueous solution, water, dried and concentrated to give compound 9A (20 g, 99.8%) as a yellow solid, which was used directly without further purification.

[0299] step 2

[0300]

[0301] In a manner similar to that described in Example 2, compound 9A (20 g, 79.3 mmol) was converted to compound 10A.

[0302] step 3

[0303]

[0304] Compound 10A (0.5 g, 1.5 mmol) was mixed with hydrazine (0.5 M in ethanol, 5 mL, 2.5 mmol) and stirred at room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was dried, co...

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Abstract

The present invention relates to Compounds of Formula (I), compositions comprising the compounds, and methods of using the compounds to treat or prevent pain, diabetes, a diabetic complication, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) in a patient.

Description

field of invention [0001] The present invention relates to piperidine derivatives, compositions comprising said piperidine derivatives and use of said piperidine derivatives for the treatment or prevention of pain, diabetes, diabetic complications, impaired glucose tolerance (IGT) or abnormal fasting glucose ( IFG) method. Background of the invention [0002] Diabetes mellitus refers to a disease process caused by multiple predisposing factors and characterized by high plasma glucose levels, or hyperglycemia after glucose administration in the fasted state or during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and early-onset morbidity and mortality. Abnormal glucose homeostasis is associated with alternation of lipid, lipoprotein, and apolipoprotein metabolism, as well as other metabolic and hemodynamic disorders. Thus, diabetic patients are at high risk of macrovascular and microvascular complications, including co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4545A61P25/04A61P3/10A61P25/06A61P3/00A61P29/00A61P3/08A61P29/02
CPCA61K31/4545A61K45/06A61P13/12A61P19/02A61P25/00A61P25/04A61P25/06A61P27/02A61P27/06A61P27/12A61P29/00A61P29/02A61P3/00A61P3/10A61P3/04A61P3/08A61P37/02A61P5/50A61P9/10A61K2300/00
Inventor R·G·艾斯兰安J·E·拉克威兹M·Y·柏林J·J·华
Owner SCHERING AG
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