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2-cyano-4-fluoropyrrolidine derivative or its salt

A fluoropyrrolidine and pyrrolidine technology, applied in the field of 2-cyano-4-fluoropyrrolidine derivatives or their salts, can solve the problem of weakening the effect of GLP-1 incretins and hindering the binding of active GLP-1, etc. question

Inactive Publication Date: 2005-09-07
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, it is considered that the inactive GLP-1 cut off by DPP-IV binds to the GLP-1 receptor, hindering the binding of the active GLP-1, thus further weakening the incretin effect of GLP-1 (non-patent literature 4)

Method used

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  • 2-cyano-4-fluoropyrrolidine derivative or its salt
  • 2-cyano-4-fluoropyrrolidine derivative or its salt
  • 2-cyano-4-fluoropyrrolidine derivative or its salt

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[0116] Into a solution of 0.73 ml of chloroacetyl chloride in 14 ml of chloroform under ice-cooling, 1.4 g of (2S, 4S)-4-fluoro A suspension of pyrrolidine-2-carboxamide monohydrochloride and 3.0 ml of N,N-diisopropylethylamine in 10 ml of chloroform was stirred for 30 minutes under ice-cooling. The reaction mixture was concentrated under reduced pressure, 2.4 ml of trifluoroacetic anhydride was added dropwise to a solution of the obtained residue in 14 ml of chloroform under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, 0.1M aqueous hydrochloric acid solution was added to the obtained residue, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing s...

reference example 5

[0120] According to J.Med.Chem (1991), 34,656-663, J.Heterocycl.Chem.(1982), 790mg of synthesis of the method described in 485-488 outside -8-azabicyclo[3.2.1] To a suspension of tert-butyl oct-3-ylcarbamate hydrochloride in 10ml of dichloromethane and 5ml of N,N-dimethylformamide, add 1.3g of triethylamine and 1.05g of methanesulfonyl chloride, at room temperature Stir for 1 day. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 7:3), and crystallized from diethyl ether-hexane to obtain 600 mg of exo-8-(methylsulfonyl)-8 - tert-butyl azabicyclo[3.2.1]oct-3-ylcarbamate Colorless solid.

[0121] Reference Examples 6 to 16 sho...

reference example 17

[0123] To a mixed solution of 4.7 ml of acetic anhydride and 1.9 ml of formic acid was added a chloroform solution of 2.0 g of tert-butyl piperidin-4-ylcarbamate, and stirred at room temperature for 15 hours. Water was added to the reaction mixture, extracted with EtOAc, and the organic layer was washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform:MeOH=50:1) to obtain 1.7 g of tert-butyl (1-formylpiperidin-4-yl)carbamate.

[0124] Reference Example 18 shown in Table 4 was produced in the same manner as Reference Example 17 using its corresponding raw materials.

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Abstract

Provided is a compound having excellent dipeptidyl peptidase IV-inhibiting activity, and a remedy based on the activity for insulin-dependent diabetes (type 1 diabetes), especially for non insulin-dependent diabetes (type 2 diabetes), insulin-resistant disorders, and obesity.

Description

technical field [0001] The present invention relates to medicine, novel 2-cyano-4-fluoropyrrolidine derivatives or salts thereof used as drugs, especially dipeptidylpeptidase IV (dipeptidylpeptidase IV, hereinafter referred to as "DPP-IV") inhibitors, And the medicine that takes this compound as active ingredient. Background technique [0002] DPP-IV is a sequence (H-Xaa-Pro, H-Xaa-Hyp or H-Xaa-Ala) that can recognize and cut off the sequence containing proline, hydroxyproline or alanine at the second position from the N-terminus [Xaa represents an arbitrary amino acid]) serine protease. DPP-IV has a wide range of distribution in the living body. In addition to tissues such as the kidney, liver, and salivary glands, DPP-IV also exists in body fluids such as serum, urine, and saliva. Although its physiological action is not completely clear, it is considered to be related to the regulation of biological functions by cleaving various biologically active peptides (Non-Patent ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P3/10A61P43/00C07D207/16C07D401/12C07D401/14C07D403/12C07D405/12C07D407/12C07D409/12C07D451/04C07D471/06
CPCC07D401/14C07D401/12C07D403/12C07D207/16C07D409/12C07D405/12C07D451/04C07D407/12A61P3/10A61P3/04A61P43/00
Inventor 早川昌彦根来贤二宫本聡铃木贵之丸山龙也中野亮介
Owner ASTELLAS PHARMA INC
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