The synthetic protocol for compounds 2k 2o was validated implementing commercially readily available building blocks with two methyl one,4 naphthoquinone and ytterbium trifluoromethanesulfonate in anhydrous dioxane beneath reflux. The crude response mixtures were purified by SiO2 chromatography to get the wanted compounds with minimal to moderate yields. To examine the effects of hydrophobic and hydrophilic substitutions at the three position with the naphthoquinone ring in PI 083 , a set of analogs was produced by way of a two phase synthesis. These last compounds with amine groups on the three place have been prepared in reasonable yields with microwave assisted heating reactions of PI 083 with appropriate secondary amines. Intermediates 5a and 5b were created via reductive amination on the commercially on the market sulfapyridine 4 with requisite aldehydes as proven in Scheme 2.
Attempts to react 5a and 5b with commercially readily available two,3 dichloronaphthoquinone to obtain alkylated amine analogs of PI 083 have been not successful. In an option method, PI 083 was reacted with either an alkyl bromide or an alkyl iodide in DMF . Underneath these disorders, selleck TH-302 concentration we observed the alkylation within the sulfonamide group of PI 083 . The library six was purified using flash chromatography to get the wanted compounds with better than 95 purity as assessed by 1H NMR and LCMS evaluation. Intermediates seven had been synthesized in beneficial yields by means of coupling commercially available five and 6 nitro two,3 dichloro 1,four naphthoquinone together with the sulfapyridine 4 in refluxing ethanol. Compounds 7a and 7b have been obtained as mixtures of regioisomers somewhere around 1:2 ratios . The five nitro 2,three dichloronaphthoquinone is reported for being more reactive towards amines affording regioisomeric mixtures of mono substituted items.
21 Diminished goods of eight had been obtained from 7a implementing the hydrogenation circumstances described from the Scheme two. Attempts to separate the pure isomers of compounds seven or 8 by chromatography have been not productive. The possible binding interactions dimebon from the sulfonamide moiety of PI 083 using the proteasome were more investigated by means of the synthetic modifications outlined in Scheme 3. A series of nitrosulfonamide developing blocks 11 had been created implementing normal reagents in very good yield by coupling commercially available sulfonyl chlorides and anilines. The corresponding amine intermediates 12 had been obtained in superior yields by way of NiCl2 NaBH4 mediated reduction.22 The final library 13 was prepared as described previously by reacting anilines with 2,three dichloronaphthoquinone with 95 purity.
Starting from four nitrobenzenesulfonyl chloride and five aminotetrazole, intermediate 11l was obtained as reported in the literature23 . The 4 nitrobenzenesulfonylguanyl azide 11l intermediate was diminished to N guanidine with NaBH4 during the presence of NiCl6 to obtain 12l in good yield.