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Selective foxo inhibitors for treatment of diabetes and other disorders related to impaired pancreatic function

A free and compound technology, applied in the field of selective FOXO inhibitors, can solve the problems of unsatisfactory insulin health outcomes and daily life burden of patients

Pending Publication Date: 2021-12-07
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Insulin injections are a widely used treatment with a global market size of more than US$20 billion, but they are a burden on patients' daily life and the health outcomes of insulin injections remain suboptimal

Method used

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  • Selective foxo inhibitors for treatment of diabetes and other disorders related to impaired pancreatic function
  • Selective foxo inhibitors for treatment of diabetes and other disorders related to impaired pancreatic function
  • Selective foxo inhibitors for treatment of diabetes and other disorders related to impaired pancreatic function

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0277] The purpose of this example is to demonstrate the synthesis of intermediate compounds that can be used to produce the compounds described above.

[0278]

[0279] To a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (4.3 g, 27.5 mmol) in methanol (50 mL) was added thionyl chloride (5.2 mL, 72 mmol) at 0°C. The reaction mixture was refluxed for 3 hours and concentrated to give the methyl ester (4.62g). This methyl ester (4.62 g, 27 mmol) was dissolved in DMF (30 mL). To the solution was added PMB-Br (6.5 g, 32 mmol) and potassium carbonate (7.45 g, 54 mmol). The reaction mixture was heated to 75 °C for 3 hours and water (50 mL) was added. The resulting mixture was extracted with ethyl acetate (50 mL×3), and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give crude product (8.46g). The crude product was recrystallized from ethyl acetate / hexanes (10 mL:25 mL) to afford the pure major regioisom...

Embodiment 2

[0284] The purpose of this example is to demonstrate the synthesis of intermediate compounds that can be used to produce the compounds described above.

[0285]

[0286] To the nitro compound (1 g, 3.4 mmol) in methanol (10 mL) was added Pd / C (182 mg, 10%, 0.05 equiv). The resulting mixture was stirred overnight under an atmosphere of hydrogen. The solid was filtered off and the solvent was removed on a rotavapor. The crude product was purified on silica gel using 10% methanol in dichloromethane to recover 460 mg of starting material and afford 480 mg of product (99% based on recovery of starting material).

[0287] 3-Chloro-4-methoxybenzoic acid (360 mg) was treated with oxalyl chloride (0.42 mL, 2.5 equiv) and DMF (one drop) in dichloromethane. When no bubbling occurred, the reaction mixture was concentrated and redissolved in dichloromethane (10 mL). A solution of the acid chloride was added slowly to the above amine (480 mg) in DCM (10 mL) and triethylamine (0.77 mL)...

Embodiment 3

[0290] The purpose of this example is to demonstrate the synthesis of intermediate compounds that can be used to produce the compounds described above.

[0291]

[0292] The starting material (10.8 mg) was treated with TFA (2 mL) at 70 °C for 15 min. Methanol was added and the solvent was removed under reduced pressure. The resulting mixture was triturated with ethyl acetate and hexanes (2 mL; 1:1) to afford the product (11.3 mg as TFA salt). The product was confirmed using LC / MS analysis.

[0293] To a solution of the above product (5 mg) in DCM (1 mL) was added acetic anhydride (0.02 mL). The reaction was stirred overnight. Add more Ac 2 O until the reaction was complete by LC / MS. The solvent was evaporated and the product was triturated with acetate and hexanes (1 mL; 1:1) to afford the product. The product was confirmed using LC / MS analysis.

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Abstract

Various embodiments relate to a compound (represented by Formula I) or a pharmaceutically acceptable salt or tautomer thereof. The compound may selectively inhibit a Forkhead Box O1 (FOXO1) transcription factor. Various embodiments relate to methods comprising administering to a mammal having a disease or disorder associated with impaired pancreatic endocrine function, a therapeutically effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof. Various embodiments relate to methods for producing enteroendocrine cells that make and secrete insulin in a mammal, comprising administering to the mammal an effective amount of the compound or a pharmaceutically acceptable salt or tautomer thereof.

Description

[0001] Cross References to Related Applications [0002] This application calls for an application entitled "SELECTIVE FOXO INHIBITORS FOR TREATMENT OF DIABETES AND OTHER DISORDERS RELATED TO IMPAIRED PANCREATIC FUNCTION" filed on March 25, 2019 )”, which is hereby incorporated by reference in its entirety. [0003] field of invention [0004] Various embodiments of the invention relate generally to selective FOXO inhibitors, and more particularly to selective FOXO inhibitors for use in the treatment of diabetes and other conditions associated with impaired pancreatic function. Background technique [0005] More than 50 million people with diabetes worldwide require long-term insulin therapy, including those with autoimmune type 1 diabetes and insulin-dependent type 2 diabetes. Insulin injection is a widely used treatment with a global market size of more than 20 billion US dollars, but it is a burden on patients' daily life, and the health outcomes of insulin injection are ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4162C07D471/04
CPCC07D403/04C07D401/14C07D405/14C07D413/14A61P3/10A61P1/18A61P9/12A61K45/06A61K31/4184A61K31/423A61K31/437A61K31/4439A61K31/454A61K31/4709A61K31/496A61K31/713C07D471/04
Inventor 徐小明邓世现唐纳德·W·兰德里罗伯特·J·德维塔林华李胤京多梅尼科·阿奇利桑德罗·贝尔韦代雷
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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