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Compounds and their use for treating somatic mutation-related diseases

A compound and hydrate technology, applied in the field of inhibiting premature translation termination associated with nonsense mutations in mRNA, treating or preventing diseases related to nonsense mutations in mRNA, can solve the problem of developing clitocine analogs or derivatives without reports , did not disclose clitocine and other issues

Inactive Publication Date: 2007-11-21
PTC THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of clitocine as a therapeutic agent for diseases associated with nonsense mutations has not been disclosed so far
There is also no report on the development of clitocine analogs or derivatives that can be used as therapeutic agents for cancers or diseases associated with nonsense mutations

Method used

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  • Compounds and their use for treating somatic mutation-related diseases
  • Compounds and their use for treating somatic mutation-related diseases
  • Compounds and their use for treating somatic mutation-related diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0234] B, the preparation of the compound of the present invention

[0235] The compounds of the invention may be prepared in any manner known in the art. By way of example, compounds of the invention can be prepared according to the general schemes described below for the core structure of a single azine ring. For example, the triazine compounds of formula 1-A and formula 2-A can be prepared according to the method shown in the following route A:

[0236]

[0237] Route A

[0238] According to route A, the benzamide substrate of formula A1 is used with formula (R N ) 2 NCH(O alkyl) 2 Reagent processing, where R N Usually small alkyl, or two R N The groups together form a five- or six-membered ring (eg, pyrrolidine, piperazine, morpholine, etc.); Oalkyl is a small alkoxy group such as methoxy or ethoxy. The condensation reaction can be carried out either by pure formamide acetal reagent or in a higher boiling point solvent such as ethanol o...

Embodiment 1

[0343] Embodiment 1: the preparation of compound of the present invention

[0344] A: Preparation of 3,5-triazine

[0345] Triazines of Formulas 1-A and 2-A can generally be prepared according to Scheme A as follows.

[0346] Preparation of 3-(4-p-tolyl-[1,3,5]triazin-2-yl)benzoic acid (compound 43)

[0347] Step A: To a 10 mL microwave tube was added 4-methylbenzamide (0.99 g, 7.32 mmol) and N,N-dimethylformamide dimethyl acetal (2.23 g, 18.67 mmol). The microwave tube was heated to 150° C. at 250 psi, 300 W for 10 minutes. A white solid was precipitated by adding ether / hexane (1:1). The desired product (1.26 g, 91% yield) was collected by filtration and washed with hexane. As determined by liquid chromatography-mass spectrometry (LC-MS), the purity of the obtained compound N-dimethylaminomethylene-4-methyl-benzamide is >90%, MS (ES+): m / e191. 17.

[0348] Step B: To a mixture of tert-butanol (3.50 g, 47.22 mmol), pyridine (3.72 g, 46.78 mmol) and catalyst DMAP in dichl...

Embodiment C

[0419] Example C: 4,6-pyrimidine

[0420] 4,6-Pyrimidines of formula 1-C and 2-C can generally be prepared according to Scheme C as follows.

[0421] Preparation of 4-(6-m-tolyl-pyrimidin-4-yl)-benzoic acid (Compound 2)

[0422] Step A: 2,4-dichloropyrimidine (0.58g, 3.89mmol), 3-methylphenylboronic acid (0.31g, 2.28mmol), Na 2 CO 3 (0.73g, 6.88mmol), tetrakis (triphenylphosphine) palladium (13.0mg, 1.12×10 -2 mmol). The flask was evacuated and refilled with nitrogen. Dimethylformamide (DMF) (15 mL, anhydrous) was then added to the flask. The flask was evacuated again and refilled with nitrogen two more times. The reaction was heated to 100 °C overnight. The reaction mixture was partitioned between ether and water. The resulting organic layer was washed with brine, MgSO 4 Dry on top, then remove. The resulting residue was purified by flash column chromatography eluting with dichloromethane / hexane (1:10) to afford 45.7 mg (5.8% yield) of the desired product. The puri...

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Abstract

The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

Description

[0001] related application [0002] Pursuant to 35 U.S.C. §119, this application claims U.S. Application 60 / 617,634, filed October 13, 2004, U.S. Application 60 / 617,655, filed October 13, 2004, U.S. Application 60 / 617,655, filed October 13, 2004 Priority to Application 60 / 617,633 and US Application 60 / 617,670, filed October 13, 2004. All of the aforementioned applications are hereby incorporated by reference in their entirety. Pursuant to 35 U.S.C. §119, this application also claims priority to U.S. Application 60 / 617,653, filed October 13, 2004, and U.S. Application 60 / 624,170, filed November 3, 2004. Filed November 3, 2004 US application 60 / 624,170 filed on . is hereby incorporated by reference in its entirety. This application also fully introduces the international patent application filed on October 13, 2005, with the title of the invention "Compounds for Nonsense Suppression, and Method for Their Use", and the attorney numbers identified as 19025.041, 19025.042, 19025.04...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61K31/53A61K31/495
Inventor N・阿尔姆斯戴德G・M・卡普R・怀尔德E・韦尔奇任洪玉
Owner PTC THERAPEUTICS INC
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