Arylazanylpyrazolone Derivatives as Inhibitors of Mutant Superoxide Dismutase 1 Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis

Abstract

The arylsulfanyl- and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanyl pyrazolones, has been synthesized, and structure-activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer.

Synthesis of 2-alkyl-5-phenylaminomethyl-2,4-dihydro-3H-[1,2,4]triazol-3-ones based on 2-alkyl-6-phenyl-6,7-dihydro-3H-imidazo-[5,1-c][1,2,4]triazole-3,5(2H)-diones

“…Compounds 4a-g are readily available by alkyla tion of imidazo [5,1 c] [1,2,4]triazole 3,5(2H) dione 2 carried out in DMSO at ~20 C with anhydrous potassi um carbonate as a base. The reaction gave N substituted bicyclic products 4a-g in good yields.…”

“…7, July, 2014 a complex mixture of products. Nevertheless, we succeed ed in the regiospecific synthesis of alkylated products 5a-g, which was based on the preliminary transformation of tri azolone 1 to imidazo [5,1 c] [1,2,4]triazoledione 2 by the reaction with 1,1´ carbonyldiimidazole, 4 alkylation of compounds 2, and finally imidazole ring opening, leading to the alkylated products 5a-g (see Scheme 1). This ap proach can be considered as an indirect method for re giospecific alkylation of arylaminomethyltriazolones at the nitrogen atom at position 2 of the triazolone ring, since direct alkylation of these systems leads to a complex mix ture of products.…”

“…The method in volved the alkaline hydrolysis of 2 alkyl 6 phenyl 6,7 dihydro 3H imidazo[5,1 c] [1,2,4] triazole 3,5(2H) diones obtained by alkylation of 6 phenyl 6,7 dihydro 2H imidazo[5,1 c] [1,2,4]triazole 3,5(2H) diones. …”

“…Note that the closest structural analogs of triazolones, viz., N arylamino methylpyrazolones, exhibit biological activity toward neu rons, whose death causes rapid development of amyo trophic lateral sclerosis. 2 In this connection, the synthesis of 1,2,4 triazol 3 one derivatives containing an N aryl aminomethyl substituent at position 5 of triazolone ring is an actual problem. Earlier, we have developed a convenient methods for the preparation of triazol 3 ones 3 of the type 1 and imid azo [5,1 c] [1,2,4]triazole 3,5(2H) dione 2 (Scheme 1).…”

“…2 In this connection, the synthesis of 1,2,4 triazol 3 one derivatives containing an N aryl aminomethyl substituent at position 5 of triazolone ring is an actual problem. Earlier, we have developed a convenient methods for the preparation of triazol 3 ones 3 of the type 1 and imid azo [5,1 c] [1,2,4]triazole 3,5(2H) dione 2 (Scheme 1). 4 In the present work, we studied a possibility of alkylation of these heterocycles.…”