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Pyrrolidine borate dipeptidyl peptidase inhibitor and pharmaceutical composition thereof

A composition and drug technology, applied in the field of pyrrolidine borate DDP-IV inhibitors, can solve the problems that DDP-IV inhibitors have not yet been studied on a large scale

Inactive Publication Date: 2017-10-03
MAI DE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DDP-IV inhibitors have not been studied on a large scale so far, especially in diseases other than diabetes

Method used

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  • Pyrrolidine borate dipeptidyl peptidase inhibitor and pharmaceutical composition thereof
  • Pyrrolidine borate dipeptidyl peptidase inhibitor and pharmaceutical composition thereof
  • Pyrrolidine borate dipeptidyl peptidase inhibitor and pharmaceutical composition thereof

Examples

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preparation example Construction

[0258] In a specific preferred technical scheme, the invention provides a method for preparing a borate compound containing chemical formula (1) by freeze-drying a mixture of pyrrolidine boronic acid compound and sugar, sugar alcohol or polyribose . The method comprises: (a) preparing a mixture comprising (i) water, (ii) a pyrrolidine boronic acid compound, and (iii) a sugar, sugar alcohol, polymeric alcohol or hydroxycarboxylic acid; (b) lyophilizing the mixture dry.

[0259] In a more preferred specific technical scheme, the invention provides the preparation of pyrrolidine boronic acid containing chemical formula (2) by spray-drying a mixture of pyrrolidine boronic acid compound and sugar, sugar alcohol, polymeric alcohol or hydroxycarboxylic acid Method for ester synthesis. The method comprises: (a) preparing a mixture comprising (i) water, (ii) a pyrrolidine boronic acid compound, and (iii) a sugar, sugar alcohol, polymeric alcohol or hydroxycarboxylic acid; (b) lyophil...

Embodiment 1

[0329] Example 1: Preparation of [(2R)-1-{N-[(3R)-pyrrolidin-3-yl]glycyl}pyrrolidin-2-yl]boronic acid compound e

[0330] The synthesis of compound e is completed according to Synthesis Scheme 2 (Scheme-2), involving three main steps. The first step is to combine compound a with compound b to generate compound c. This process undergoes a deprotection from the protecting group at the amino terminal of compound d the process of. Compound d is hydrolyzed under acidic conditions to generate boronic acid compound e.

[0331] Pinanediol borate (25mmol) added to compound a (25mmol) dissolved in 50mL of dichloromethane at an internal temperature lower than 5°C, and then added with DIPEA (13ml 75mmol) was added dropwise over 2 hours. Stir the reaction mixture at 0-5°C for at least 4 hours, then raise the temperature to 15-25°C, and continue stirring for at least 3-5 hours until the reaction is complete. Dilute the compound with 90 ml of ethyl acetate (EtOAc) and wash with Wash once ...

Embodiment 2

[0336] Example 2: Preparation of [(2R)-1-{N-[(3R)-pyrrolidin-3-yl]glycyl}pyrrolidin-2-yl]D-mannitol borate to [(2R) )-1-{N-[(3R)-pyrrolidin-3-yl]glycyl}pyrrolidin-2-yl]boronic acid (1.75g, 7.5mmol) in water and ethanol (25ml, 90:10, v / v) D-mannitol (10 mmol) was added to the solution. The suspension was heated to about 45°C for 5 minutes to completely dissolve the compound. Stir to dissolve the compound and then cool to room temperature, and filter the solution through a 0.45Am nylon membrane. This solution was frozen at minus 45°C shelf temperature by lyophilization. After one hour the vacuum was reduced. Let the temperature rise slowly to minus 35C and hold at minus 35C to evaporate all the freeze (about 40 hours). Turn off the rack temperature control and allow the temperature to gradually rise to 0°C. The secondary drying process is to allow the shelf temperature to rise to 25 degrees Celsius in three gradients within 4 hours. Then keep the shelf temperature at 25 d...

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Abstract

The invention relates to a pyrrolidine boronate (boronate ester) DDP-IV inhibitor, which plays a beneficial role in the treatment and prevention of diseases involving dipeptidyl peptidase-IV, such as diabetes, especially type 2 diabetes, tumors or other diseases. The invention relates to pharmaceutical compositions comprising these compounds and their use in the prevention or treatment of these diseases in which dipeptidyl peptidase-IV is involved.

Description

field of invention [0001] The invention relates to a pyrrolidine boronate ester (boronate ester) DDP-IV inhibitor, which plays a beneficial role in the treatment and prevention of diseases involving dipeptidyl peptidase-IV, such as diabetes, especially type 2 diabetes, tumors or other diseases. The invention relates to pharmaceutical compositions comprising these compounds and their use in the prevention or treatment of these diseases in which dipeptidyl peptidase-IV is involved. Background of the invention [0002] Diabetes mellitus is a disease of multiple etiologies that is characterized by elevated plasma glucose levels or hyperglycemia in the fasting state or following glucose administration in an oral glucose tolerance test. Often abnormal glucose homeostasis is directly and indirectly related to the metabolism of fats, lipoproteins and apolipoproteins as well as other metabolic and hemodynamic diseases. Patients with type 2 diabetes are therefore at high risk for mac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/04C07H9/00C07H1/00A61K31/7056A61K31/69A61P3/10A61P35/00
Inventor 黄才古
Owner MAI DE
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