Synthesis and evaluation of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives as KATP channel agonists

3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides as ATP-Sensitive Potassium Channel Openers: Effect of 6,7-Disubstitution on Potency and Tissue Selectivity

“…Another interesting hydrocarbon chain on the nitrogen atom in the 3-position appeared to be cyclobutyl ( 27 , 31 , 35 , 51 ). These results are in accordance with the SAR related to the nature of the alkylamino chain in the 3-position and the SAR deduced from previous studies on 7-substituted 3-alkylamino-4 H -1,2,4-benzothiadiazine 1,1-dioxides. , Moreover, on looking at the calculated IC 50 values (Tables and ), it is noted that these disubstituted compounds appear to be more potent than their respective 7-monosubstituted analogues ( 24 vs 2 , 34 , 43 vs 3 , and 50 vs 4 ) and up to 150 times more potent than diazoxide. So in general the introduction of a halogen atom in the 6-position appeared to favor activity on the pancreatic tissue.…”

Synthesis of 3-Amino-1,2,4-benzothiadi- azine 1,1-Dioxides via a Tandem Aza-Wittig/Heterocumulene Annulation

“…3-Amino-1,2,4-benzothiadiazine 1,1-dioxides, which have been shown to exist predominantly in the tautomeric form 1 , possess diverse biological activities including potassium − and calcium channel modulation and adrenergic antagonism effects. These compounds are typically prepared (Figure ) by reaction of amines with thioethers 2 or their sulfone derivatives.…”

“…These compounds are typically prepared (Figure ) by reaction of amines with thioethers 2 or their sulfone derivatives. The thioethers 2 are obtained either by cyclization of a chlorosulfonylthiourea or by reaction of o- aminobenzenesulfonamides 3 (R 2 = H) with CS 2 (or an equivalent reagent) followed by methylation. − 2- N -Alkyl derivatives 5 can only be accessed by this second route from 3 (R 2 = alkyl) because reaction of 2 with alkylating agents takes place at the 4-position . Hence, analogues 5 are quite rare despite their isosteric relationship to the well studied quinazolinone system 6.…”

Synthesis of Modified 4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides and Determination of their Affinity and Selectivity for Different Types of KATP Channels

“…NH 2 , OMe), respectively. [24] By varying the diazoxide core substituted with cyclobutylamino in C-3, Peat and co-workers [24] could show that a chloro substituent at C-7 increased activity of the compound by tenfold in patches of oocytes transfected with SUR1/Kir6.2, whereas an amino group at C-7 decreased activity by tenfold as compared with the unsubstituted analogue. Similar findings were reported on the inhibition of insulin secretion from pancreatic b-cells by various alkylamino substituents of the diazoxide core, whereby a five-to tenfold increase in potency was observed by the introduction of chlorine in position 7.…”