4H-1,2,4-Pyridothiadiazine 1,1-Dioxides and 2,3-Dihydro-4H-1,2,4-pyridothiadiazine 1,1-Dioxides Chemically Related to Diazoxide and Cyclothiazide as Powerful Positive Allosteric Modulators of (R/S)-2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors:  Design, Synthesis, Pharmacology, and Structure−Activity Relationships

Abstract

A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2, 3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl substituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. Many compounds were found to be more potent than the reference compounds diazoxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possible interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activity on AMPA receptors are different from those responsible for an inhibitory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyridothiadiazines were found to be ineffective as inhibitors of insulin release from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conversely, the pyridothiadiazines active on B-cells were found to be ineffective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor modulator. This compound may be considered as a new pharmacological tool, different from diazoxide and cyclothiazide, for studying AMPA receptors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.

Regioselective Synthesis of Novel N2- and N4-Substituted 7-Methylpyrazolo[4,5-e][1,2,4]thiadiazines

“…10°C, was pure enough for use in the next ring closure step without further purification. Thus, by refluxing compound 3 in anhydrous toluene, a classical Curtius rearrangement took place through the intermediacy of isocyanate 4 to afford compound 5, a new regioisomer of 6-methylpyrazolo [4,5-e] [1,2,4]thiadiazin-3(2H, 4H)-one 1,1-dioxide prepared by our previous work [7]. (Scheme 1).…”

“…After the solvent was evaporated under reduced pressure, the products were separated by flash column chromatography (1:3 ethyl acetate/cyclohexane) to give the compounds 6 and 6' respectively, which were purified by recrystallization from ethanol. [4,5-e] [1,2,4]thiadiazine (6'a). Compound 5 was alkylated with benzyl bromide at 30°C for 12h to give 6a and 6'a, which after purification gave white solids: 6a: IR (KBr, [4,5- [4,5- …”

“…Benzyl-7-methyl-1,1,3-trioxo-2H,4H-pyrazolo[4,5-e][1,2,4]thiadiazine (7a). Compound 5 was reacted with benzyl bromide at 30°C for 10 h to give 7a as a white solid after by flash column chromatography separation (CH 2 Chlorobenzyl)-7-methyl-1,1,3-trioxo-2H,4H-pyrazolo [4,5-e] [1,2,4] [4,5- [4,5-e] [1,2,4] …”

“…For example, 1,2,4-benzothiadiazines, such as chlorothiazide and diazoxide, are widely used as diuretic and antihypertensive drugs, respectively [1,2]. Heterocycle-fused thiadiazine derivatives, such as pyrido-, pyrazino-, imidazo-and triazolothiadiazines, show unique potential for the treatment of cerebro-and cardiovascular diseases, cognitive disorders, cancers, viral and bacterial infections [3][4][5][6].…”

“…The lead compounds QM96639, QM96539 and QM96652 ( Figure 1) showed highly potent activity and selectivity against HIV-1 replication in cell culture at low concentration ranges (IC 50 0.05-0.10µM) [8,9]. In continuation of our research, we decided to undertake a study of the pyrazole series, specifically regarding the 7-methylpyrazolo [4,5-e] [1,2,4]thiadiazines, because of the known thiophene-pyrazole bioisosterism [10]. In this paper, we report the preparation of the new regioisomer 7-methylpyrazolo [4,5- …”