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Compounds for treating spinal muscular atrophy

A kind of compound, the technology of alkyl, applied in the field of compounds used for the treatment of spinal muscular atrophy

Active Publication Date: 2014-12-24
PTC THERAPEUTICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of HDAC inhibitors or mRNA stabilizers does not address the underlying cause of SMA and may lead to a global increase in transcription and gene expression in humans with potential safety concerns

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

Embodiment 1

[0710] Preparation of Cpd 4

[0711] Part 1: Preparation of ethyl 2-(benzo[d]thiazol-2-yl)acetate

[0712]

[0713] A mixture of 2-aminobenzenethiol (5.34 mL, 50 mmol) and 3-ethoxy-3-amidinopropionate hydrochloride (9.75 g, 50 mmol) in EtOH (50 mL) was heated at 70° C. for 16 h. The mixture was partitioned between EtOAc (200 mL) and water (200 mL). Wash the organic layer with brine, use MgSO 4 Dry, filter and concentrate. The residue was purified by silica gel column chromatography (10% EtOAc in hexane) to obtain the title compound (6.0 g, 54%) as a yellow oil. MS m / z222.1[M+H] + ; 1 H NMR(500MHz, DMSO-d 6 ): δ8.05 (1H, d, J = 8.1 Hz), 7.91 (1H, d, J = 8.0 Hz), 7.51 (1H, t, J = 8 Hz), 7.43 (1H, t, J = 8 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.22 (2H, s), 1.33 (3H, t, J = 7.1 Hz).

[0714] Part 2: Preparation of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate

[0715]

[0716] A mixture of 4-fluoro-2-hydroxybenzaldehyde (10 g, 71.4 mmol), 1-boc-piperazine (15.3 g, 82.2 mmo...

Embodiment 2

[0723] Preparation of Cpd 5

[0724] Part 1: Preparation of tert-butyl 2-(4-chlorobenzo[d]thiazol-2-yl)acetate

[0725]

[0726] Step A: At 60°C, to a solution of 1-(3-chlorophenyl)thiourea (5.09 g, 27.2 mmol) in acetic acid (100 mL) was added bromine (1.82 mL, 35.4 mmol) dropwise. The mixture was heated at 80°C for 2 h, and the solvent was removed under reduced pressure. Diethyl ether was added to the mixture to produce a precipitate. The solid was collected and dried to obtain 4-chlorobenzo[d]thiazol-2-amine (5.7 g, 79%). MS m / z185.9[M+H] + .

[0727] Step B: At room temperature, add 4-chlorobenzo[d]thiazol-2-amine (4.78g, 25.8mmol) and copper(II) chloride (4.16g, 31mmol) in CH 3 Add tert-butyl nitrite (4.61 mL, 38.8 mmol) to the mixture in CN (25 mL). The reaction mixture was heated at 60°C for 30 minutes, and then the solvent was removed from the mixture. The residue was suspended in water, collected by filtration and dried to obtain 2,4-dichlorobenzo[d]thiazole (5.3 g, 81%)...

Embodiment 3

[0735] Preparation of Cpd 68

[0736] Part 1: Preparation of ethyl 2-(4-chlorobenzo[d]oxazol-2-yl)acetate

[0737]

[0738] Step A: In H 2 (1 atm), stir a mixture of 3-chloro-2-nitrophenol (18.95 g, 100 mmol) and Pd / C (10%, 0.50 g) in methanol (300 mL). After 15h, the mixture was filtered through diatomaceous earth. Concentrate the filtrate to obtain a brown solid, then use CH 2 Cl 2 It was washed to obtain 2-amino-3-chlorophenol (7.39 g, 52%) as a light brown solid. MS m / z144.1[M+H] + .

[0739] Step B: To a solution of 2-amino-3-chlorophenol (2.0g, 14mmol) in EtOH (30mL) was added ethyl 3-ethoxy-3-amidinopropionate hydrochloride (3.01g, 15.4 mmol). After heating at 80°C for 2 d, the mixture was concentrated. The residue was partitioned between EtOAc and water. The organic layer was concentrated and passed through silica gel column chromatography (CH 2 Cl 2 ) Purification to obtain ethyl 2-(4-chlorobenzo[d]oxazol-2-yl)acetate (3.17 g, 94%) as a yellow-white solid. MS m / z240.1...

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Abstract

Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy. In a specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN2 into mRNA that is transcribed from the SMN2 gene. In another specific embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 into mRNA that is transcribed from the SMN1 gene. In yet another embodiment, provided herein are compounds of a form that may be used to modulate the inclusion of exon 7 of SMN1 and SMN2 into mRNA that is transcribed from the SMN1 and SMN2 genes, respectively.

Description

[0001] The technology described in this article was not carried out with the support of the US government. [0002] Joint Research Agreement Statement [0003] One or more parties to the joint research agreement that came into effect on or before the actual filing date of the claimed invention developed the disclosed subject matter and made the claimed invention or the claimed invention represented their interests; [0004] The claimed invention is made as a result of activities carried out within the scope of the joint research agreement; and [0005] The patent application for the claimed invention discloses or amended to disclose the names of the parties to the joint research agreement. [0006] introduction [0007] Provided herein are compounds, their compositions, and their use for the treatment of spinal muscular atrophy. Background technique [0008] Spinal muscular atrophy (SMA) in its broadest sense describes a variety of hereditary and acquired central nervous system (CNS) dise...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/353
CPCC07D405/14C07D413/14C07D311/16C07D405/04C07D405/12C07D413/04C07D417/04C07D417/14C07D471/04C07D491/04C07D495/04C07D513/04C07D519/00C07D231/12C07D311/18C07D487/04A61P21/00A61P21/02A61P25/00
Inventor 马修·G·沃尔陈光明崔珣奎阿迈尔·达卡松·黄加里·米切尔·卡普长勋·李春世·李亚娜·纳拉辛汉尼柯莱·纳雷什金谢尔盖·普希金齐红彦安东尼·A·特普夫玛勒·L·威泰尔埃伦·韦尔奇天乐·杨南静·张晓燕·张新·赵伊曼纽尔·皮纳德哈撒尼·拉特尼
Owner PTC THERAPEUTICS INC
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