Process for making modulators of cystic fibrosis transmembrane conductance regulator

Abstract

The invention provides a process for the preparation of a compound of Formula 1,comprising coupling a carboxylic acid of Formula 2with an aniline of Formula 3in the presence of a coupling agent.

Description

CLAIM OF PRIORITY[0001]This application is a continuation of PCT Application No. PCT / US2010 / 028069 filed Mar. 19, 2010, which claims the priority of U.S. Application No. 61 / 162,148 filed Mar. 20, 2009; U.S. Application No. 61 / 246,303 filed Sep. 28, 2009; and U.S. Application No. 61 / 248,565 filed Oct. 5, 2009, which are hereby incorporated by reference in their entirety.TECHNICAL FIELD OF THE INVENTION[0002]The present invention relates to a process for making modulators of cystic fibrosis transmembrane conductance regulator (“CFTR”).BACKGROUND OF THE INVENTION[0003]Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.[0004]CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an epithelial chloride ion channel responsible for aiding in the reg...

AI Technical Summary

Benefits of technology

The invention provides processes for preparing compounds that can be used as modulators of CFTR, which is a protein involved in cystic fibrosis. The processes involve the coupling of specific carboxylic acids and anilines in the presence of a coupling agent, followed by the addition of specific substituents to the carboxylic acid. The resulting compounds can be used to treat cystic fibrosis by targeting the CFTR protein. The invention also provides specific compounds that can be used as modulators of CFTR.

Problems solved by technology

Despite progress in the treatment of CF, there is no cure.

In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.

In patients with CF, mutations in CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.

The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.

In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.

This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane.

In addition to impaired trafficking, the mutation results in defective channel gating.

Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport.

As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane.

As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced.

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