775304-57-9

Usage

Uses

Used in Genetic Disorders Treatment:
Ataluren (PTC124) is used as a therapeutic agent for the treatment of genetic disorders caused by nonsense mutations, such as Duchenne's muscular dystrophy (DMD) and cystic fibrosis (CF). It works by rendering ribosomes less sensitive to premature stop or 'read-through' codons, thus allowing the production of full-length, functional proteins.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Ataluren (PTC124) is used as a drug candidate for the development of treatments targeting genetic disorders with nonsense mutations. It has been approved by the European Union in May 2014 for the treatment of Duchenne’s muscular dystrophy (DMD) and is in clinical testing for other genetic disorders.
Used in Research and Development:
Ataluren (PTC124) is used as a research tool in the study of nonsense mutations and their role in genetic disorders. It helps researchers understand the mechanism of action and potential therapeutic applications in diseases such as DMD and cystic fibrosis. The target activity of PTC-124 was initially evaluated by firefly luciferase reporter cell-based nonsense codon assay (IC50 = 7 nM), providing valuable insights into its potential effectiveness.

Features

Demonstrates oral bioavailability, and an appropriate safety toxicology profile.

In vitro

Compared with Gentamicin which is only active at much higher concentrations, PTC124 is a more potent nonsense-suppressing agent and exhibits 4-to 15-fold stimulation of read-through relative to controls. PTC124 (0.01-3 μM) promotes dose-dependent read-through of all three nonsense codons in HEK293 cells harboring LUC-190 nonsense alleles with the highest read-through at UGA, followed by UAG and then UAA, but it does not suppress multiple proximal nonsense codons. Like Gentamicin, PTC124 is most active when a pyrimidine (in particular cytosine, C) follows the nonsense codon. Consistent with the stable cell line reporter assay, PTC124 (17 μM) promotes significant production of dystrophin in primary muscle cells from Duchenne muscular dystrophy (DMD) patients or MDXMDX mice expressing dystrophin nonsense alleles. PTC124 selectively promotes ribosomal read-through of premature termination but not normal termination codons, even at concentrations substantially greater than the values achieving maximal activity.

In vivo

Due to functional recovery of dystrophin production, oral, intraperitoneal or combined dosing of PTC124 for 2-8 weeks partially rescues functional strength deficit in dystrophic muscles of MDX mice, and results in partial protection against contraction-induced injury in the extensor digitorum longus (EDL) muscles, as well as significant reductions in serum creatine kinase values. In Cftr-/-mice expressing a human CFTR-G542X transgene, subcutaneous or oral administration of PTC124 (~60 mg/kg) suppresses the G542X nonsense mutation in a dose-dependent manner, leading to a significant restoration of human (h)CFTR protein expression and function without any effect on nonsense-mediated mRNA decay (NMD) or other aspects of mRNA stability. PTC124 treatment (60 mg/kg) restores 29% of the normal intestinal transepithelial cAMP-stimulated shortcircuit currents observed in Cftr+/+ mice, displaying a significant advantage compared with Gentamicin.

Synthesis

The sequence to construct ataluren, which was described by the authors at PTC Therapeutics, commenced with commercially available methyl 3-cyanobenzoate (38). This ester was exposed to hydroxylamine in aqueous tert-butanol and warmed gently until the reaction was deemed complete. Then this mixture was treated with 2-fluorobenzoyl chloride dropwise and subsequently triethylamine dropwise. To minimize exotherm and undesired side products, careful control of the addition of reagents was achieved through slow dropwise addition of these liquid reagents. Upon complete consumption of starting materials and formation of amidooxime 39, the aqueous reaction mixture was then heated to 85 ℃ to facilitate 1,2,4-oxadiazole formation, resulting in the tricyclic ester 40 in excellent yield across the three steps. Finally, saponification of ester 40 through the use of sodium hydroxide followed by acidic quench gave ataluren (V) in 96% over the two-step sequence.

InChI:InChI=1/C15H9FN2O3/c16-12-7-2-1-6-11(12)14-17-13(18-21-14)9-4-3-5-10(8-9)15(19)20/h1-8H,(H,19,20)

Synthetic route

3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester (775304-60-4)

Conditions	Yield
Stage #1: 3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester With sodium hydroxide; water at 100℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In water	96%
Stage #1: 3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester With sodium hydroxide; water In tetrahydrofuran at 100℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In water	96%
Stage #1: 3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester With sodium hydroxide; water In tetrahydrofuran at 100℃; for 2h; Heating / reflux; Stage #2: With hydrogenchloride In water	96%

Conditions	Yield
Stage #1: 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzaldehyde With potassium dihydrogenphosphate; dihydrogen peroxide In water; acetonitrile at 20 - 30℃; Stage #2: With sodium chlorite In water; acetonitrile at 0 - 30℃; for 5h;	90%

→ ataluren (775304-57-9)

Conditions	Yield
In tert-butyl alcohol at 80℃; for 24h;	88.4%

5-(2-fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole (692771-01-0) → ataluren (775304-57-9)

Conditions	Yield
With basic cobalt(II) carbonate; sodium bromide In acetic acid at 95℃; for 11h; Green chemistry;	85%
With pyridine; potassium permanganate In water at 85℃; for 6.5h;	40%

2-Fluorobenzoyl chloride (393-52-2) → ataluren (775304-57-9)

Conditions	Yield
Stage #1: 3-Cyanobenzoic acid With hydroxylamine In water; tert-butyl alcohol at 38 - 41℃; for 21h; Stage #2: 2-Fluorobenzoyl chloride With triethylamine In water; tert-butyl alcohol at 27 - 40℃; for 7h; Stage #3: With hydrogenchloride; water Product distribution / selectivity; more than 3 stages;	76%

3-(N'-hydroxycarbamimidoyl)benzoic acid (199447-10-4) + o-fluoro-benzoic acid (445-29-4) → ataluren (775304-57-9)

Conditions	Yield
With tetrachloromethane; diethoxymethylsilane; Bis(p-nitrophenyl) phosphate; triphenylphosphine In toluene at 120℃; for 24h; Reflux; Large scale;	65%

3-(N-hydroxycarbamimidoyl)-benzoic acid methyl ester (1141475-82-2, 1227154-43-9, 775304-79-5) + 2-Fluorobenzoyl chloride (393-52-2) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: boron trifluoride diethyl etherate / 1,4-dioxane / 12.5 h / 0 °C / Reflux 2: sodium hydroxide; water / ethanol / 3 h / 20 °C View Scheme

C15H13FN2O → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; acetic acid / 3.5 h / 80 °C 2: pyridine; potassium permanganate / water / 6.5 h / 85 °C View Scheme

o-fluoro-benzoic acid (445-29-4) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 20 °C 2: hydroxylamine hydrochloride; acetic acid / 3.5 h / 80 °C 3: pyridine; potassium permanganate / water / 6.5 h / 85 °C View Scheme

3-methylbenzenecarboximidamide hydrochloride (20680-59-5) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 20 °C 2: hydroxylamine hydrochloride; acetic acid / 3.5 h / 80 °C 3: pyridine; potassium permanganate / water / 6.5 h / 85 °C View Scheme

3-Cyanobenzoic acid (1877-72-1) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 4.33 h / 20 °C 2.1: hydroxylamine / ethanol; water / 1 h / 100 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.33 h / 20 °C 4.1: toluene / 22 h / 5 - 130 °C / Dean-Stark 5.1: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate; hydroxylamine hydrochloride / water; ethanol / 3 h / Reflux 2.1: potassium carbonate / water; toluene / 0.08 h / 20 - 30 °C 2.2: 1 h / 0 - 10 °C 3.1: tert-butyl alcohol / 24 h / 80 °C View Scheme

methyl 3-cyanobenzoate (13531-48-1) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydroxylamine / ethanol; water / 1 h / 100 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.33 h / 20 °C 3: toluene / 22 h / 5 - 130 °C / Dean-Stark 4: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1: hydroxylamine / ethanol; water / 20 °C / Reflux 2: trifluoroacetic acid / 0.58 h / 20 - 60 °C 3: palladium diacetate; triphenylphosphine; silver(I) acetate / toluene / 0.5 h / 150 °C / Microwave irradiation; Sealed tube 4: lithium hydroxide monohydrate / water; tetrahydrofuran / 1 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: hydroxylamine / ethanol; water / 1 h / 100 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.33 h / 5 - 20 °C 3: toluene / 22 h / 5 - 130 °C / Dean-Stark apparatus 4: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium ethanolate / ethanol / 20 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 5 - 20 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 24 h / 20 °C 4: lithium hydroxide / tetrahydrofuran; water / 24 h / 20 °C View Scheme

3-(carbamimidoyl)benzoic acid methyl ester (15676-11-6) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.33 h / 20 °C 2: toluene / 22 h / 5 - 130 °C / Dean-Stark 3: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme

methyl 3-(1,2,4-oxadiazol-3-yl)benzoate → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate; triphenylphosphine; silver(I) acetate / toluene / 0.5 h / 150 °C / Microwave irradiation; Sealed tube 2: lithium hydroxide monohydrate / water; tetrahydrofuran / 1 h / 20 °C View Scheme

3-(N-hydroxycarbamimidoyl)-benzoic acid methyl ester (1141475-82-2, 1227154-43-9, 775304-79-5) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: trifluoroacetic acid / 0.58 h / 20 - 60 °C 2: palladium diacetate; triphenylphosphine; silver(I) acetate / toluene / 0.5 h / 150 °C / Microwave irradiation; Sealed tube 3: lithium hydroxide monohydrate / water; tetrahydrofuran / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1.33 h / 5 - 20 °C 2: toluene / 22 h / 5 - 130 °C / Dean-Stark apparatus 3: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme

3-cyanobenzaldehyde dimethyl acetal → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydroxylamine / water; methanol / 2.5 h / 50 °C 2.1: sodium hydrogencarbonate / water / 0.08 h / 20 - 30 °C 2.2: 1 h / 20 - 30 °C 3.1: toluene / 18 h / 85 °C 4.1: potassium dihydrogenphosphate; dihydrogen peroxide / water; acetonitrile / 20 - 30 °C 4.2: 5 h / 0 - 30 °C View Scheme

3-Cyanobenzaldehyde (24964-64-5) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / water / 3.08 h / 20 - 45 °C 2.1: hydroxylamine / water; methanol / 2.5 h / 50 °C 3.1: sodium hydrogencarbonate / water / 0.08 h / 20 - 30 °C 3.2: 1 h / 20 - 30 °C 4.1: toluene / 18 h / 85 °C 5.1: potassium dihydrogenphosphate; dihydrogen peroxide / water; acetonitrile / 20 - 30 °C 5.2: 5 h / 0 - 30 °C View Scheme

3-(dimethoxymethyl)-N'-hydroxybenzimidamide → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water / 0.08 h / 20 - 30 °C 1.2: 1 h / 20 - 30 °C 2.1: toluene / 18 h / 85 °C 3.1: potassium dihydrogenphosphate; dihydrogen peroxide / water; acetonitrile / 20 - 30 °C 3.2: 5 h / 0 - 30 °C View Scheme

N'-((2-fluorobenzoyl)oxy)-3-formylbenzimidamide → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 18 h / 85 °C 2.1: potassium dihydrogenphosphate; dihydrogen peroxide / water; acetonitrile / 20 - 30 °C 2.2: 5 h / 0 - 30 °C View Scheme

3-(N-2-fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester (775304-80-8) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene / 22 h / 5 - 130 °C / Dean-Stark apparatus 2: sodium hydroxide; water / tetrahydrofuran / 2 h / 100 °C View Scheme

3-(N-hydroxyamidino)benzoic acid methyl ester (1141475-82-2, 1227154-43-9, 775304-79-5) → ataluren (775304-57-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 5 - 20 °C 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 24 h / 20 °C 3: lithium hydroxide / tetrahydrofuran; water / 24 h / 20 °C View Scheme

ataluren (775304-57-9) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid sodium salt

Conditions	Yield
With sodium hydroxide; water at 100℃; for 2h; Heating / reflux;	96%
With sodium hydroxide In ethanol; water

ataluren (775304-57-9) → 5-(2-fluorophenyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole

Conditions	Yield
Stage #1: ataluren With tetrakis(acetonitrile)copper(I)tetrafluoroborate; tetrabutylammonium tetra(tert-butyl alcohol) coordinate fluoride; copper(II) bis(trifluoromethanesulfonate) In acetonitrile at 23℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: In acetonitrile at 35℃; for 24h; Irradiation; Sealed tube; Inert atmosphere;	45%

ataluren (775304-57-9) + 2-(4,5-Dihydro-1,3-oxazol-2-yl)aniline (3416-93-1) → N-(2-(4,5-dihydrooxazol-2-yl)phenyl)-3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzamide

Conditions	Yield
Stage #1: ataluren With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #3: 2-(4,5-Dihydro-1,3-oxazol-2-yl)aniline In dichloromethane at 20℃; for 72h; Inert atmosphere;	25%

ataluren (775304-57-9) + ATP (56-65-5) → PTC124-AMP (1227154-38-2)

Conditions	Yield
With Photinus pyralis luciferase aq. buffer; Enzymatic reaction;

ataluren (775304-57-9) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid magnesium salt

Conditions	Yield
With magnesium methanolate In methanol; dichloromethane Reagent/catalyst; Solvent;

ataluren (775304-57-9) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid potassium salt

Conditions	Yield
With potassium hydroxide In tetrahydrofuran; water

ataluren (775304-57-9) + 2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid tromethamine salt

Conditions	Yield
In methanol; acetone Solvent;

ataluren (775304-57-9) + L-lysine (56-87-1) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid L-lysine salt

Conditions	Yield
In tetrahydrofuran; water

ataluren (775304-57-9) + L-arginine (74-79-3) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid L-arginine salt

Conditions	Yield
In ethanol; water Sonication;

ataluren (775304-57-9) + L-histidine (71-00-1) → 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid L-histidine salt

Conditions	Yield
In ethanol; water Solvent; Sonication;

Upstream product

• 1141475-82-2 3-(N-hydroxyamidino)benzoic acid methyl ester 
• 393-52-2 2-Fluorobenzoyl chloride 
• 775304-80-8 3-(N-2-fluorobenzoylcarbamimidoyl)-benzoic acid methyl ester 
• 199447-10-4 3-(N'-hydroxycarbamimidoyl)benzoic acid 
• 445-29-4 o-fluoro-benzoic acid 
• 24964-64-5 3-Cyanobenzaldehyde 
• 1141475-82-2 3-(N-hydroxycarbamimidoyl)-benzoic acid methyl ester 
• 15676-11-6 3-(carbamimidoyl)benzoic acid methyl ester 
• 13531-48-1 methyl 3-cyanobenzoate 
• 1877-72-1 3-Cyanobenzoic acid 
• 20680-59-5 3-methylbenzenecarboximidamide hydrochloride 
• 692771-01-0 5-(2-fluorophenyl)-3-(3-methylphenyl)-1,2,4-oxadiazole 
• 775304-60-4 3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester 

Downstream Products

• 1032614-16-6 5-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-2-hydroxybenzoic acid 
• 775304-60-4 3-((5-(2-fluorophenyl))-(1,2,4-oxadiazol-3-yl))benzoic acid methyl ester 

Relevant academic research and scientific papers

Preparation method of Ataluren

The invention discloses a preparation method of Ataluren. The preparation method comprises an addition step in which under an alkaline condition, 3-cyanobenzoate reacts with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate as shown in a formula III, a condensation step in which in a first organic solvent, a condensation reaction is conducted on the intermediate shown in the formula III and o-fluorobenzoic acid to obtain an intermediate shown in a formula IV, a cyclization step in which in a second organic solvent, catalyzing is conducted by using Lewis acid, and intramolecular dehydration is conducted on the intermediate in the formula IV to obtain an intermediate in a formula V, and an ester hydrolysis step in which under an alkaline condition, ester hydrolysis is conducted on the intermediate in the formula V by using a second mixed solvent to obtain the product. Cheap raw materials are subjected to addition, condensation, cyclization and ester hydrolysis, the reaction conditions are mild, the process is simple, the cost is low, and industrial production is facilitated. Meanwhile, the solvent in the reaction process can be basically recycled, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and the product purity of the target compound Ataluren are high.

Method for preparing ataluren

The invention discloses a method for preparing ataluren, (PTC124, a commodity name of ataluren) and belongs to the field of organic synthesis. The preparation method comprises the following steps: (1)reacting methyl m-cyanobenzoate with hydroxylamine hydrochloride in a lower alcohol or a mixed solvent of a lower alcohol and water to generate 3-(N-hydroxyamidino)-methyl benzoate; (2) carrying outO-acylation reaction between the 3-(N-hydroxyamidino)-methyl benzoate and o-fluorobenzoyl chloride in an organic solvent to obtain 3-((5-(2-fluorophenyl))-3-(1,2,4-oxadiazolyl)-methyl benzoate; (3) under the catalytic action of tetra-alkyl ammonium halide, carrying out cyclization to obtain 3-((5-(2-fluorophenyl))-3-(1,2,4-oxadiazolyl)-methyl benzoate; and (4) hydrolyzing to obtain ataluren. The synthesis method is a simple and efficient synthesis method of ataluren.

Novel method for synthesizing Ataluren

The invention discloses a novel method for synthesizing Ataluren. The method comprises the following steps that 1, a compound 2 reacts with hydroxylamine hydrochloride under the alkaline condition to obtain an intermediate 3; 2, in the presence of a reducing agent diethoxymethylsilane and bis(4-nitrobenzophenone)phosphate, a catalytic amount of triphenylphosphine and an equivalent amount of carbon tetrachloride and compound 4 react to obtain the target compound Ataluren (1). According to the method, the raw materials are easy to obtain, the synthesizing steps are brief, environmental friendliness is achieved, aftertreatment is convenient, and high industrial production value is achieved.

PROCESS FOR PREPARING ATALUREN AND ITS INTERMEDIATES

The present invention provides processes for the preparation of ataluren. Intermediates for preparing ataluren are also provided.

Palladium-Catalyzed, Silver-Assisted Direct C-5–H Arylation of 3-Substituted 1,2,4-Oxadiazoles under Microwave Irradiation

A direct C-5–H arylation of 3-substituted 1,2,4-oxadiazoles with aryl iodides in the presence of a palladium catalyst and silver acetate is reported. This method provides a rapid, reliable way to obtain versatile 3,5-diaryl-1,2,4-oxadiazole derivatives, which are common moieties of many biologically active molecules. The synthetic applications of this novel method have been demonstrated in the concise syntheses of Ataluren and a potent RET inhibitor Yhhu251. (Figure presented.).

Oxdiazole compound solvate and preparation method thereof

The present invention relates to the dimethyl sulfoxide solvate of 3-[5-(2-fluorophenyl)-[1,2,4]oxdiazole-3-yl]benzoic acid, wherein the dimethyl sulfoxide solvate has characteristics of good stability, high purity, excellent particle and excellent shape, and is suitable for pharmaceutical preparation applications. The present invention further relates to a preparation method of the dimethyl sulfoxide solvate, a pharmaceutical composition of the dimethyl sulfoxide solvate, and uses of the dimethyl sulfoxide solvate in preparation of drugs for treatment of genetic diseases.

Synthesis of benzoic acids containing a 1,2,4-oxadiazole ring

A new approach to the synthesis of 4and 3-(5-R-1,2,4-oxadiazol-3-yl)benzoic acids via a selective oxidation of 5-R-3-tolyl-1,2,4-oxadiazoles with air oxygen in the presence of a catalytic system based on cobalt acetate was suggested. This synthesis allowed us to obtain the products in higher yields and with shorter sequence of steps as compared to the known procedures.

A metal-free tandem approach to prepare structurally diverse N-heterocycles: Synthesis of 1,2,4-oxadiazoles and pyrimidinones

A metal-free one-pot approach to the diversity oriented synthesis of N-heterocycles, 1,2,4-oxadiazoles and 2,6 disubstituted pyrimidin-4-ones is described via carboxamidation of amidines with aryl carboxylic acids and aryl propargylic acids. The reactions occur at room temperature forming N-acylamidines which undergo tandem nucleophilic addition-deamination- intramolecular cyclisation to give the corresponding heterocyclic compounds in good to excellent yields. This one pot approach has led to the successful synthesis of the drug lead molecule, ataluren, 3-(5-(2-fluorophenyl)-1,2,4- oxadiazol-3-yl) benzoic acid in two steps. the Partner Organisations 2014.

Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor

Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis-aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis-aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles.

METHODS FOR DOSING AN ORALLY ACTIVE 1,2,4-OXADIAZOLE FOR NONSENSE MUTATION SUPPRESSION THERAPY

The present invention relates to specific doses of and dosing regimens for using a 1,2,4-oxadiazole benzoic acid compound in treating or preventing diseases associated with nonsense mutations. In particular, the invention relates to specific doses and dosing regimens for the use of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid in mammals having diseases associated with nonsense mutations.