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Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases

A technology of somatic mutation and compound, applied in nonsense mutation related diseases and nonsense mutation related premature translation termination field, can solve the problems of no disclosure of clitocine, no report of development of clitocine analogs or derivatives, etc.

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 with efficacy as therapeutic agents for cancers or diseases associated with nonsense mutations

Method used

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  • Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases
  • Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases
  • Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation-related diseases

Examples

Experimental program
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preparation example Construction

[0363] B, the preparation of the compound of the present invention

[0364] 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 methods described below for single azine ring center structures. For example, the compound wherein V of formula 1 is N can be prepared according to the method shown in the following scheme A:

[0365]

[0366] Illustration A

[0367] According to Scheme A, the unsubstituted nitrogen atom on the azole ring of compound A1 can be substituted in the cross-coupling reaction. This type of reaction can be accomplished by using substrates such as Ar 1 -X (where X is a halogen such as bromine or iodine, or a halide-like compound such as methyl sulfonate) or Ar 1 -M (wherein M is a group such as boronic acid or trialkoxysilane). Catalysts used for this reaction may include copper salts (for example: copper(II) oxide,...

Embodiment 1

[0480] Embodiment 1: the preparation of compound of the present invention

[0481] A. Preparation of pyrrole

[0482] Generally, the pyrroles of the present invention can be prepared as follows:

[0483] Preparation of 3-[1-(4-trifluoromethylphenyl)-]-1H-pyrrol-3-yl]benzoic acid sodium salt (compound 14)

[0484] Part A. To 1-(triisopropylsilyl)pyrrole-3-boronic acid (according to Alvarez, A.; Guzman, A.; Ruiz, A.; Velarde, E., J.Org.Chem.1992, 57, prepared by the method of 1653-1656) (6.12g, 22.9mmol) in anhydrous dimethoxyethane (76ml) was added methyl 4-iodobenzoate (96.61g, 25.2mmol), dichloro Bis(triphenylphosphine)palladium(II) (0.484g, 0.69mmol) and cesium fluoride (6.96g, 45.8mmol). The mixture was heated to reflux under nitrogen atmosphere for 17 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (4 x 25 mL). The extract was washed with water, MgSO 4 Dry and concentrate to give crude product....

Embodiment 2

[1102] Example 2: Nonsense inhibitory activity

[1103] A functional cellular translation-based assay based on luciferase-mediated chemiluminescence (incorporated by reference in International Application PCT / US2003 / 023185, filed July 23, 2003) can evaluate normal stop codons in mRNA The translation reads through. Human embryonic kidney cells (293 cells) were cultured in medium containing fetal bovine serum (FBS). These cells were stably transfected with the luciferase gene containing a premature stop codon at amino acid 190 in place of the threonine codon (ACA) normally present in the luciferase gene at this position. One of three possible nonsense codons (TAA, TAG, or TGA) was introduced by site-directed mutagenesis, along with four possible nucleotides of an important downstream +1 site immediately following the nonsense codon ( adenine, thymine, cytosine or guanine). As such, amino acid 190 in the luciferase gene contains a premature stop codon of TAA, TAG or TGA. For ...

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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 priority to U.S. applications 60 / 617,633, 60 / 617,634, 60 / 617,655, and 60 / 617,670, filed October 13, 2004, which The application is incorporated by reference in its entirety. Pursuant to 35 U.S.C. §119 of the United States, this application also claims priority to U.S. applications 60 / 617,653, filed October 13, 2004, and 60 / 624,170, filed November 3, 2004 right. US Application Serial No. 60 / 624,170, filed November 3, 2004, is incorporated by reference in its entirety. This application also introduces the international patent application titled "Compounds for Nonsense Suppression, and Methods for Their Use (compounds for nonsense mutation suppression and methods of use)" proposed on October 13, 2005, and its agency volume number is 19025.040, 19025.041, 19025.042 and 19025.044, the entire contents of which are incorporated by reference. technical field [0003] The present invention relat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/415A61K31/4164A61K31/4152A61K31/4192A61K31/4155A61K31/433A61K31/4162
Inventor N・阿尔姆斯戴德G・M・卡普R・怀尔德E・韦尔奇J・A・坎贝尔任洪玉陈光明
Owner PTC THERAPEUTICS INC
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