84201-40-1

Usage

InChI:InChI=1/C10H12N2S2/c1-7-9(13-2)8-6-11-4-5-12(8)10(7)14-3/h4-6H,1-3H3

Upstream product

• 101623-05-6 8-Mercapto-7-methyl-2H-pyrrolo[1,2-a]pyrazine-6-thione 
• 74-88-4 methyl iodide 
• 811-51-8 sodium thioethylate 
• 64224-21-1 Oltipraz 

Relevant academic research and scientific papers

Thiolytic chemistry of alternative precursors to the major metabolite of the cancer chemopreventive oltipraz

The compounds 7-methyl-6,8-bis(methyldisulfanyl)pyrrolo[1,2- a]pyrazine (5; "bis disulfide") and methanethiosulfonic acid S-((6-(methanesulfonylsulfanyl)-7-methyl)pyrrolo[1,2-a]pyrazin -8-yl) ester (6; "bis methanesulfonic acid thioester") have been synthesized to serve as alternative precursors to the major metabolite, 4, of the cancer chemopreventive oltipraz, 1, to test whether they possess similar biological activities. In the present work the mechanisms by which these compounds react with glutathione have been investigated in order to validate the assumption that they would be chemically competent in the presence of the biological thiols to give the oltipraz metabolite. A kinetic and product study was carried out in mainly aqueous media, ≤15% ethanol by volume, at 37 °C. The kinetic analysis and identification of intermediates by electrospray HPLC/MS indicate that compound 5 decomposes in two sequential reactions via thiol-disulfide interchange involving removal of the two thiomethyl groups. In contrast, 6 decomposes in three sequential steps, the first entailing formation of the diglutathionyl adduct, followed by two subsequent thiol disulfide interchange reactions involving loss of the glutathionyl moieties. Both 5 and 6, as well as oltipraz itself, give nearly quantitative yields of the metabolite 4 in reactions with glutathione. Analysis of the decay of 6 by EPR spin trapping methods indicates that less than 0.2% of the reaction flux proceeds through radicals more stable than the hydroxyl radical.

Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz

Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication in vitro (ED50 ≈ 10 μM), undergoes extensive metabolism in vivo. Most of the orally administered drug undergoes opening of the dithiolethione ring, reduction, recyclization, and methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine ( metabolite III ). We report here that metabolite III inhibits viral replication in vitro (ED50 ≈ 25 μM) in acutely infected H9 and CEM T cell lymphoma cell lines. Although both metabolite III and oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in the chronically infected U1 promonocytic leukemia cell line, only metabolite III was able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2 cells suggest that oltipraz inhibits an early stage of the viral life cycle, whereas metabolite III affects human immunodeficiency virus type 1 replication at a step distal to viral integration. This is consistent with the finding that oltipraz inhibits reverse transcriptase, whereas metabolite III does not. Although the mean ED50 for metabolite III in acutely infected peripheral blood mononuclear cells was 18 μM, the ED50 was below 5 μM in three of eight independent experiments. Studies of metabolite III in combination with oltipraz in acutely infected peripheral blood mononuclear cells demonstrated significant antiviral synergy. These results raise the possibility that the in vitro potency of oltipraz may underestimate its antiretroviral activity in vivo. Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia.

Electro-organic Synthesis and X-Ray Crystal Structure of the Novel Complex 2,7-Dimethyl-6,8-bis(methylthio)pyrrolopyrazinium Tri-iodomercurate(II)

Electroreduction of oltipraz (INN), 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione and methylation leads to the known metabolite, 6,8-bis(methylthio)-7-methylpyrrolopyrazine on a glassy carbon cathode or to the novel mercury(II) title complex on a mercury cathode.The crystal structure of this complex is presented.The comlex crystallizes in the triclinic space group P1- with a = 10.620(2), b = 11.944(2), c = 9.665(2) Angstroem, α = 121.16(1), β = 102.68(1), γ = 95.38(1) degree, Z = 2.The structure was solved and refined on the basis of 3162 significant data, to a final R value of 0.026.The electrochemical behaviour has been investigated by voltammetry.

REACTIVITY OF SUBSTITUTED 1,2-DITHIOLE-3-THIONES WITH SODIUM ETHANETHIOLATE: A CONVENIENT ROUTE TO A NOVEL HETEROCYCLE.

Sodium ethanethiolate reacts at the S-2 position of substituted 1,2-dithiole-3-thiones to give various products depending on the substituents at the C-4 and C-5 positions.In particular, the presence of a pyrimidinyl substituent induces some noticeable changes in the reaction pathway, yielding a novel heterocycle whose synthesis has not been previously reported.

STUDY OF THE REDUCTIVE METABOLISM PATHWAY OF 4-METHYL-5-(2-PYRAZINYL)-1,2-DITHIOLE-3-THIONE. AN ELECTROCHEMICAL APPROACH.

In slightly basic aqueous-ethanol medium or in acetonitrile, electrochemical reduction of 4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (OLTIPRAZ 35972 R.P., antischistosomal drug) affords a convenient route to pyrrolopyrazine derivatives, which are found as metabolites of the drug in host urine.A transient species in the reduction process which is endowed with schistosomicidal activity is isolated.

STUDIES ON THE REACTION OF 1,2-DITHIOLE-3-THIONES WITH NUCLEOPHILES

Substituted 1,2-dithiole-3-thiones react with nucleophiles (alkoxides, thiolates) to give various reaction products depending on the nucleophiles and on the substituents on the 1,2-dithiole-3-thione ring.The mechanistic aspects of these reactions are discussed.

Comparison of the metabolism of oltipraz in the mouse rat and monkey and in man. Distribution of the metabolites in each species

4-Methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione (35 972 R.P., oltipraz) and its metabolites were extracted from human urine and from mouse, rat and monkey urine using Amberlite XAD4 resin. The metabolites were identified by GLC, TLC and HPLC and isolated by preparative TLC or HPLC. The structures of 11 compounds were determined by spectroscopic examination (MS, IR, NMR). Six of the principal metabolites isolated in sufficient quantity from human urine were administered to the mouse, confirming the metabolic pathway of oltipraz.

UNE NOUVELLE REACTION DE CYCLISATION CONDUISANT A DES PYRROLOPYRAZINES

Reduction of 5-(2-pyrazinyl-1,2-dithiole-3-thiones by sodium sulphide, followed by alkylation of the intermediates yields pyrrolo(1,2-a)pyrazines.