Prophylactic or therapeutic agent for spinal muscular atrophy

A compound, C-R2 technology, applied in muscular system diseases, organic active ingredients, compound screening, etc., can solve problems such as protein reduction

Pending Publication Date: 2021-03-09
利伯纳生物科学株式会社
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, even in the presence of the SMN2 gene, the loss of SMN1 gene function results in a significant decrease in the amount of the protein with its normal function, leading to the onset of SMA

Method used

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  • Prophylactic or therapeutic agent for spinal muscular atrophy
  • Prophylactic or therapeutic agent for spinal muscular atrophy
  • Prophylactic or therapeutic agent for spinal muscular atrophy

Examples

Experimental program
Comparison scheme
Effect test

experiment Embodiment 1

[0406] [Experimental Example 1] Method for producing compound

[0407] The term "room temperature" in the following examples generally refers to about 10°C to about 35°C. The ratios used in mixed solvents are expressed by volume unless otherwise stated. Percentages are by weight unless otherwise indicated.

[0408] Fractions of the eluates were analyzed by thin-layer chromatography (TLC) while carrying out column chromatography in Examples unless otherwise stated. Specifically, using 60F 254 A plate (Merck) was used as a TLC plate, and the solvent used as an eluent for column chromatography was used as an eluent for TLC. A UV detector was used for detection. For silica gel column chromatography, the notation "NH" indicates the use of aminopropylsilane bound to silica gel, and the notation "Diol" indicates the use of 3-(2,3-dihydroxypropoxy)propylsilane bound to silica gel. For preparative high performance liquid chromatography (HPLC), the notation "C18" indicates the use ...

Embodiment 1

[0443] 2-(4,6-Dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-fluoro-6-(1-methylpiperidin-4-yl)quinazoline- 4(3H)-keto

[0444] (A) 2-Amino-4-fluoro-5-(1-methylpiperidin-4-yl)benzamide

[0445]

[0446] Stirring 2-amino-5-bromo-4-fluorobenzamide (820 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (942 mg), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (237 mg), 2.0M aqueous sodium carbonate solution (5.28 mL) and toluene (15 mL) overnight. To the resulting mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile components were distilled off under reduced pressure. The remaining solid was purified by silica gel column chromatography (NH, methanol / ethyl acetate). To the obtained solid were added palladium hydroxide on activated carbon (20% palladium) (100 m...

Embodiment 2

[0477] 2-(4,6-Dimethylpyrazolo[1,5-a]pyrazin-2-yl)-6-(1-methylpiperidin-4-yl)quinazoline-4(3H) -ketone

[0478] (A) 2-Amino-5-(1-methylpiperidin-4-yl)benzamide

[0479]

[0480]2-Amino-5-bromobenzamide (2.7g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,2,3,6-tetrahydropyridine (3.36g), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (845mg), 2.0M carbonic acid A mixture of aqueous sodium solution (18.8 mL) and toluene (50 mL) was stirred at 100°C overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile components were distilled off under reduced pressure. The remaining solid was purified by silica gel column chromatography (NH, ethyl acetate / hexane and NH, methanol / ethyl acetate), and then palladium hydroxide-activated carbon (20% palladium) (160 mg) and me...

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PUM

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Abstract

This prophylactic or therapeutic agent for spinal muscular atrophy includes a compound represented by formula (I) or a salt thereof (in the formula: W1, W2, and W3 are each independently selected fromthe group consisting of C-R2, C-R3, C-Rc, and C-Rd, and are defined as in any of (i) to (iv); (i) when W3 is C-R2, W1 is C-R3, W2 is C-Rc or N, and R1 is a hydrogen atom; (ii) when W3 is C-R3, W1 isC-R2, W2 is C-Rc or N, and R1 is a hydrogen atom, a C1-8 alkyl, or a C1-8 alkoxy; (iii) when W1 is C-R2, W2 is C-Rc or N, W3 is C-Rd, and R1 is an aliphatic heterocycle that contains at least one nitrogen atom and is optionally substituted with a non-aromatic substituent; (iv) when W2 is C-R2, W1 is C-Rc, W3 is C-Rd, and R1 is an aliphatic heterocycle that contains at least one nitrogen atom and is optionally substituted with a non-aromatic substituent; R2 is an aromatic ring of at least six members that is optionally substituted with a non-aromatic substituent; R3 is an aliphatic heterocyclethat contains at least one nitrogen atom and is optionally substituted with a non-aromatic substituent; Q1 is selected from C-Ra and N; Q2 is selected from C-Rb and N; and Ra, Rb, Rc, and Rd are eachindependently selected from the group consisting of a hydrogen atom, halogen, a C1-8 alkyl, a C1-8 alkoxy, and a cyano group).

Description

technical field [0001] The present invention relates to a preventive or therapeutic agent for spinal muscular atrophy. Background technique [0002] Spinal muscular atrophy (SMA) is a neuromuscular atrophy caused by the degeneration of the anterior horn cells of the spinal cord. It is an autosomal recessive disorder, and its causative gene is located on chromosome 5. [0003] The known causative gene for SMA is the Survival Motor Neuron 1 (SMN1) gene, which is located on chromosome 5q13d. SMA develops in individuals who are homozygous for a mutation that inactivates the gene, such as a null or deletion mutation. [0004] Chromosome 5q13d also contains the SMN2 gene, which is an inverted copy of the SMN1 gene with a C to T mutation at nucleotide position 6 in exon 7. Although this mutation is a nucleotide change that does not involve any amino acid substitutions, it is more likely to cause alternative splicing events outside of exon 7. As a result, about 90% of the protei...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/517A61P21/00A61P43/00C07D401/14C07D403/04C07D413/14C07D417/14C07D471/04C07D487/04C07D491/048C07D498/04C07D498/10C12Q1/686G01N33/50G01N33/53G01N33/68
CPCA61P21/00A61P43/00C07D401/14C07D403/04C07D401/04C07D413/14C07D417/14C07D471/04C07D487/04C07D498/10C07D519/00C12Q2600/136C12Q1/6883C12Q2600/156G01N2500/10A61K31/517C07D491/048C07D498/04C12Q1/686G01N33/50G01N33/53G01N33/68A61K31/506A61K31/519A61K31/5377A61C8/0096G01N33/5023
Inventor 富士晃嗣山崎健铃木俊也小野宏司高萩洋希
Owner 利伯纳生物科学株式会社
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