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Phenylalanyl pyrrolidine derivates, preparation method and application thereof

A technology of phenylpropionylpyrrolidine and pyrrolidine, applied in the field of medicinal chemistry, can solve the problems of impaired secretion, insufficient secretion level of GLP-1 and the like

Active Publication Date: 2009-01-07
NANJING ZHONGRUI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Non-insulin-dependent diabetes mellitus (NIDDM), that is, the insulin-stimulating effect of GIP in patients with type 2 diabetes is impaired, while the insulin-stimulating effect of GLP-1 is still intact, but in the plasma of healthy people and type 2 diabetics after meals , only 1 / 3 to 1 / 2 is active GLP-1, the rest is inactive fragment form, postprandial GLP-1 secretion level is insufficient

Method used

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  • Phenylalanyl pyrrolidine derivates, preparation method and application thereof
  • Phenylalanyl pyrrolidine derivates, preparation method and application thereof
  • Phenylalanyl pyrrolidine derivates, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: 2-(S)-(2′-(S)-formamide)pyrrolidine-phenylpropionyl-(2′-(S)-cyano)pyrrolidine

[0040]

[0041] Step 1: 2-(R)-Chlorophenylpropionyl(2′-(S)-carboxamide)pyrrolidine

[0042] 61 g of 2-(R)-chlorophenylpropionyl chloride (0.3 mol) was dissolved in 20 ml of anhydrous tetrahydrofuran solution to prepare a tetrahydrofuran solution of 2-(R)-chlorophenylpropionyl chloride. Another 37.6 grams of L-proline amide (0.33mol), 55 grams of potassium carbonate (0.4mol) and 180 milliliters of anhydrous tetrahydrofuran solution were added to a 500 milliliter reaction flask, and 2-(R)-chlorine was added dropwise below 10°C. The tetrahydrofuran solution of phenylpropanoyl chloride was reacted at room temperature for 3 hours after the dropwise addition was completed. After the reaction was completed, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove tetrahydrofuran, the residue was poured into 200 ml of ice water, and the solid wa...

Embodiment 2

[0047] Example 2: 2-(S)-pyrrolidine-phenylpropionyl-(2′-(S)-formamide)pyrrolidine

[0048]

[0049] Take 14 grams (0.05mol) of the product obtained in step 1 in Example 1 and dissolve it in 30% anhydrous tetrahydrofuran solution to prepare 2-(R)-chlorophenylpropionyl-(2'-(S)-formamide)- solution of pyrrolidine in tetrahydrofuran. Dissolve 4.6 g of pyrrolidine (0.065 mol) in 100 ml of anhydrous tetrahydrofuran, cool in an ice bath to below 0°C, add 2.6 g of 60% sodium hydride (0.065mol) in batches, control the internal temperature not to exceed 5°C, and continue The reaction was stirred for 1 hour. Add 2-(R)-chlorophenylpropionyl-(2′-(S)-formamide)-pyrrolidine in tetrahydrofuran dropwise below 5°C. After the dropwise addition is complete, stir the reaction at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the residue was poured into 100 g of ice cubes, the solid was precipitated, filtered, and washed with water to obtain an off-white powder...

Embodiment 3

[0050] Example 3: 2-(S)-(2′-(S)-formic acid)pyrrolidine-phenylpropionyl-(2′-(S)-formic acid)pyrrolidine

[0051]

[0052] 17 grams (0.075mol) of the product obtained in step 2 of Example 1 was dissolved in 30% anhydrous tetrahydrofuran solution to prepare 2-(R)-chlorophenylpropionyl-(2'-(S)-cyano)-pyrrole alkanes in tetrahydrofuran. Dissolve 9.8 g of L-proline (0.085 mol) in 100 ml of anhydrous tetrahydrofuran, cool in an ice bath to below 0°C, add 6.8 g of 60% sodium hydride (0.17 mol) in batches, and control the internal temperature not to exceed 5 °C, stirred for 1 hour. Below 5°C, 2-(R)-chlorophenylpropionyl-(2′-(S)-cyano)-pyrrolidine tetrahydrofuran solution was added dropwise, and after the dropwise addition was completed, the reaction was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was poured into 100 g of ice cubes, the solid was precipitated, filtered, and washed with water to obtain a light yellow powde...

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PUM

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Abstract

The invention discloses a 2-pyrrolidine substitution-hydrocinnamoyl pyrrolidine derivant which is the compound in formula 1 or an acceptable salt thereof in pharmacy, wherein, R1 or R2 is respectively hydrogen, cyano-group, acidic group, ester group, acyl group, amide group or substitution amide group independently; the hexagram symbol stands for a chiral centre. The invention further discloses a method for preparing the compound and the application thereof for preparing or preventing noninsulin-dependent diabetes mellitus, adiposis, arthritis or other glucose tolerance abnormality diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of dipeptidyl peptidase IV inhibitor 2-pyrrolidine substituted-phenylpropionyl pyrrolidine derivatives or pharmaceutically acceptable salts thereof, a preparation method thereof and a therapeutic or prophylactic Applications in non-insulin-dependent diabetes mellitus, obesity, arthritis or disorders of impaired glucose tolerance. Background technique [0002] The insulin secretion response caused by oral glucose in normal people is much stronger than intravenous glucose, which is mainly caused by the peptide substances produced by gastrointestinal endocrine cells. These peptide substances are called incretin, including glucose Insulin-secreting polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Non-insulin-dependent diabetes mellitus (NIDDM), that is, the insulin-stimulating effect of GIP in patients with type 2 diabetes is impaired, while the insulin-s...

Claims

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Application Information

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IPC IPC(8): C07D207/08C07D207/09A61K31/341A61P3/10A61P3/04A61P19/02
Inventor 任宇苏国强
Owner NANJING ZHONGRUI PHARMA
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