Compounds for treating spinal muscular atrophy

Inactive Publication Date: 2016-05-26
F HOFFMANN LA ROCHE & CO AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Symptoms include muscle weakness, poor muscle tone, weak cry, limpness or a tendency to flop, difficulty sucking or swallowing, accumulation of secretions in the lungs or throat, feeding difficulties, and increased susceptibility to respiratory tract infections.
The legs tend to be weaker than the arms and developmental milestones, such as lifting the head or sitting up, cannot be reached.
The severe forms of the disease are fatal and all forms have no known cure.
Infants with a severe form of SMA frequently succumb to respiratory disease due to weakness in the muscles that support breathing.
Nevertheless, SMN2 is unable to compensate completely for the loss of SMN1 function due to alternative splicing of exon 7 caused by a translationally silent C to T mutation in exon 7.
Medical care for SMA patients at present is limited to supportive therapy including respiratory, nutritional and rehabilitation care; there is no drug known to address the underlying cause of the disease.
The major management

Method used

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  • Compounds for treating spinal muscular atrophy
  • Compounds for treating spinal muscular atrophy
  • Compounds for treating spinal muscular atrophy

Examples

Experimental program
Comparison scheme
Effect test

examples

[0534]The invention will be more fully understood by reference to the following examples. They should however not be construed as limiting the scope of the invention.

Preparation of Intermediates

example a.1

Preparation of N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide

[0535]

[0536]To a mixture of 6,8-dimethylimidazo[1,2-a]pyrazin-2-amine trihydrochloride (Example B.1) (134 mg, 494 μmol) and N-Ethyldiisopropylamine (320 mg, 420 μl, 2.47 mmol) in dioxane (2.0 ml) was added dropwise a solution of 4-fluorobenzoyl chloride (80 mg, 60.3 μl, 494 μmol) in dioxane (0.5 ml) at room temperature. The mixture was stirred for 1 hour. The solvent was removed in vacuo. The solid was taken in water and the suspension was stirred for 15 minutes. The solid was filtered and dried to provide 125 mg (89%) of the title compound as an off-white solid. MS (m / e): 285.4 (M+H+)

[0537]In analogy to Example A. 1, Examples A.2 to A.7 of the following table were prepared from the acylchloride and amine derivatives:

ExampleNo.StructureSystematic NameStarting materialsA.2N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-2,4- difluorobenzamide6,8-dimethylimidazo[1,2- a]pyrazin-2-amine trihydrochloride (Example B.1)...

example a.8

Preparation of 6-Chloro-N-(2-methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-yl)-nicotinamide

[0538]

[0539]To a solution of 6-chloronicotinic acid (332 mg, 2.11 mmol) in DMF (4 ml) under argon at room temperature, were added HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (1.2 g, 3.16 mmol) and N,N-diisopropylethylamine (1.4 ml, 8.42 mmol). After 5 minutes stirring, 2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine hydrochloride (Example B.2) (530 mg, 2.11 mmol) was added. The mixture was stirred at room temperature for two days. The solvent was removed in vacuo. The residue was taken in aqueous bicarbonate. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5%) to provide the title compound.

[0540]In a...

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Abstract

The present invention provides compounds of formula (I) wherein A, B, X, Y, R1 and R2 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.

Description

INTRODUCTION[0001]The present invention provides compounds which are SMN2 gene splicing modulators, their manufacture, pharmaceutical compositions comprising them and their use as medicaments for the treatment of spinal muscular atrophy (SMA).[0002]In particular, the present invention relates to compounds of formula (I)wherein A, B, X, Y, R1 and R2 are as described herein, and pharmaceutically acceptable salts thereof.BACKGROUND[0003]Spinal muscular atrophy (SMA), in its broadest sense, describes a collection of inherited and acquired central nervous system (CNS) diseases characterized by progressive motor neuron loss in the spinal cord and brainstem causing muscle weakness and muscle atrophy. The most common form of SMA is caused by mutations in the Survival Motor Neuron (SMN) gene and manifests over a wide range of severity affecting infants through adults (Crawford and Pardo, Neurobiol. Dis., 1996, 3:97).[0004]Infantile SMA is the most severe form of this neurodegenerative disord...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D263/56C07D413/12C07D487/04C07D471/04
CPCC07D519/00C07D487/04C07D263/56C07D413/12C07D471/04C07D487/10A61P21/00A61P21/04A61P25/00A61P25/02A61P25/28A61P43/00A61K31/437A61K31/496A61K31/4985C07D413/14
Inventor DAKKA, AMALGREEN, LUKEKARP, GARYNARASIMHAN, JANANARYSHKIN, NIKOLAIPINARD, EMMANUELQI, HONGYANRATNI, HASANERISHER, NICOLEWEETALL, MARLAWOLL, MATTHEW
Owner F HOFFMANN LA ROCHE & CO AG
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