Substituted chromanes and method of use

a technology of substituted chromanes and chromane compounds, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, organic chemistry, etc., can solve the problems of premature death of affected patients, irreversible lung damage, and mucus dehydration, and achieve low drug-drug interaction potential, low effect on cyp3a4 expression, and improved potency

Inactive Publication Date: 2017-07-06
ABBVIE SARL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0044]In another particular aspect, certain compounds of the invention have improved potency, in addition to exhibiting low effects on CYP3A4 expression, which suggest low drug-drug interaction potential, and accordingly may be advantageous for patients under multiple therapies.

Problems solved by technology

Aberrations in CFTR function result in imbalance of the airway surface liquid, leading to mucus dehydration, inflammation, recurrent bacterial infection and irreversible lung damage, which lead to premature death in affected patients.
Besides respiratory disease, CF patients suffer from gastrointestinal problems and pancreatic insufficiency.
The F508del mutation, the most common of the approximately 1900 identified polymorphisms in CFTR, results in defective processing of CFTR in the endoplasmic reticulum (ER) (http: / / www.cftr2.org / index.php).
The defective processing of CFTR results in early CFTR degradation, which leads to reduced trafficking or absence of the protein on the membrane.

Method used

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  • Substituted chromanes and method of use
  • Substituted chromanes and method of use
  • Substituted chromanes and method of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid

[1738]To a solution of Example 6 (25 mg, 0.047 mmol) in tetrahydrofuran (233 μL) was added lithium hydroxide hydrate (233 μL of a 0.8 M solution in water). The resulting biphasic mixture was stirred vigorously for 16 hours at room temperature, followed by addition of more lithium hydroxide hydrate (233 μL of a 0.8 M solution). The reaction mixture was stirred for an additional 5 hours at room temperature, acidified by the addition of 6 M HCl (0.040 mL) and the resulting biphasic mixture loaded directly onto a 4 g silica gel cartridge and eluted with 30% ethyl acetate / heptanes over 15 minutes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.06 (dd, J=7.9, 1.5 Hz, 1H), 7.71-7.61 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.13 (dd, J=8.2, 1.7 Hz, 1H), 7.09 (d, J=1.7 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.52 (d...

example 2

3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid

[1739]To a solution of Example 5E (35 mg, 0.065 mmol) in tetrahydrofuran (326 μL) was added lithium hydroxide hydrate (326 μL of a 0.8 M solution). The resulting biphasic mixture was stirred vigorously for 16 hours at room temperature, followed by addition of more lithium hydroxide hydrate (326 μL of a 0.8 M solution). The reaction was stirred for an additional 5 hours at room temperature, acidified by the addition of 6 M HCl (0.050 mL) and the resulting biphasic mixture was loaded directly onto a 4 g silica gel cartridge and eluted with 30% ethyl acetate / heptanes over 15 minutes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.13 (t, J=1.8 Hz, 1H), 8.12-8.04 (m, 1H), 7.72-7.61 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.20-7.11 (m, 2H), 7.04 (dd, J=8.4, 4.1 Hz, 2H), 6.53 (dd, J=8.5, 2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 5.60 (d, J=6.6 Hz, ...

example 3

1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[(2R,4R)-2-(3,4-dimethoxyphenyl)-7-methoxy-3,4-dihydro-2H-chromen-4-yl]cyclopropanecarboxamide

[1740]To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (CAS 68015-98-5) (120 mg, 0.496 mmol) in DMF (1239 μL) was added HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (245 mg, 0.644 mmol). The mixture was stirred for 5 minutes at room temperature, and then 2-(3,4-dimethoxyphenyl)-7-methoxychroman-4-amine (156 mg, 0.496 mmol) was added, followed by dropwise addition of triethylamine (276 μL, 1.982 mmol). After 45 minutes, the mixture was quenched with saturated aqueous sodium bicarbonate, and the aqueous layer removed. The resulting oil was triturated with water and filtered to give 283 mg of a white solid. The solid was dissolved in dichloromethane and purified using a 24 g silica gel cartridge with a gradient of 5-50% ethyl acetate / heptanes to give 189 mg of a mixture of the ...

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Abstract

The invention provides for compounds of formula (I)
wherein R1, X, Y, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, m, and R″ have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 14 / 925,649 filed on Oct. 28, 2015, which claims priority to U.S. Provisional Patent Application No. 60 / 073,573, filed Oct. 31, 2014, which is incorporated herein by reference for all purposes.BACKGROUND[0002]The invention relates to substituted chromane compounds that are modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, useful in treating diseases and conditions mediated and modulated by CFTR. Additionally, the invention relates to compositions containing compounds of the invention and processes for their preparation.[0003]Cystic fibrosis (CF), one of the most common autosomal recessive genetic diseases in the Caucasian population, is caused by loss of function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which is located on chromosome 7 (http: / / www.cff.org / AboutCF / ; Rowe S. M et al. (2005); N En...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D407/12
CPCC07D407/12A61K45/06A61K31/00C07D405/14C07D413/14A61K31/436A61K31/353A61K31/397A61K31/4025A61K31/435A61K31/4433A61K31/453A61K31/5377C07D491/052C07D491/107A61P1/00A61P11/00A61P43/00A61K2300/00C07D311/58A61K31/352A61K31/36C07D417/14
Inventor ALTENBACH, ROBERT J.BOGDAN, ANDREWGRESZLER, STEPHEN N.KOENIG, JOHN R.KYM, PHILIP R.LIU, BOSEARLE, XENIA B.VOIGHT, ERICWANG, XUEQINGYEUNG, MING C.
Owner ABBVIE SARL
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