Benzothiadiazine, derivatives

Pirotte (2) prepared benzothiadiazine derivatives, (II), which were effective as selective AMPA receptor activating agents and used in the treatment of depression-related illnesses. 

The benzimidamides 3 react with sulfur dichloride with concomitant chlorination to yield the 1-chloro-l A4,2,4-benzothiadiazine derivatives 4.131 Similarly, A -arylguanidines react with thionyl chloride to give 1,2,4-benzothiadiazin-3-amine 1-oxides.132... 

The original inhibitors of Na -Ct symport were benzothiadiazine derivatives, hence this class of diuretics became known as thiazide diuretics. Subsequently, drugs that are pharmacologically similar to thiazide diuretics but are not thiazides were developed and are called thiazide-like diuretics. The term thiazide diuretics is used here to refer to all members of the class of inhibitors ofNa —Ct symport. 

Recently, Barnish and Gibson ( ) treated hydrazidoyl halides, substituted in the o-position of the phenyl ring attached to nitrogen by fluoro and bromo groups, with potassium thioacetate, and the authors obtained 1,3,4-benzothiadiazine derivatives XXXVIII. 

A thiadiazete intermediate has been considered in the decomposition of a benzothiadiazine derivative. "... 

Accepting their well-known side effects the benzothiadiazine derivatives remain a mainstay in the treatment with diuretics, especially in hypertension. The need for caution before prescribing antihypertensive diuretics to patients with myxoedema is indicated by a case reported by Takeda of an adverse reaction to trichlormethiazide (17 -). In this myxoedemic patient, sinus arrest occurred during treatment with the drug. Renewed treatment with the diuretic after substitution with thyroid hormone was possible without complications. 

This reactivity of A-unsubstituted amino-pyrazoles and -indazoles which can be regarded as 1,3-diamino derivatives has been used to build a great variety of fused six-membered heterocycles such as the 1,2,4-triazine derivatives (540) and (541), the 1,3,5-triazine derivatives (542) and (543), and benzothiadiazines (544). 

As described in U.S. Patent 3,025,292, the desired product may be made by hydrogenation of chlorothiazide. Three grams of 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide (chlorothiazide) is suspended in 100 ml of methanol. Then 1.0 gram of a 5% ruthenium on charcoal catalyst is added, and the mixture is reduced at room temperature and at an initial hydrogen pressure of 39 psig. The theoretical amount of hydrogen to form the 3,4-dihydro derivative is absorbed after a period of about 10 hours. 

Chloro-4//-l,2,4-benzothiadiazine 1,1-dioxides have been made from the oxo or hydroxy derivatives [90AHC(50)256 91CHE343]. Reaction of 27/-1,2,4-benzothiadiazine 1-oxides (106) with chlorine formed the S-chloro products [90AHC(50)256]. 

Fully saturated systems can be oxidized to the corresponding didehydro derivatives. For example, oxadiazine (83) gives (84) on oxidation with mercury(II) oxide (78KGS1208), and oxidation of (85) with DDQ gives the 3ff-2,l,3-benzothiadiazine dioxide (86), which can also be represented as the dipolar form (22) (79JHC1069). 

The availability of o-benzoylbenzenesulfonyl chlorides, prepared by diazotization of o-aminobenzophenones followed by reaction with sulfur dioxide in the presence of cuprous ions, can be exploited in the reaction with hydrazine or methylhydrazine to give 1,2,3-benzothiadiazine 14. Product 14 (R1 = Me) can also be obtained by methylationof 14(R = H) with methyl iodide and sodium hydroxide. The reduced form 15 results from catalytic hydrogenation of 14 (R = H, R2 = H)(68JHC453). Hydra-zobenzene reacts with 2-chlorosulfonylbenzoyl chloride in the presence of triethylamine to give diphenyl derivative 16 (79MI1). 3,1,2-Benzothia-... 

Ethyl chloroformylformate in the presence of triethylamine reacts with o-aminobenzenesulfonamides to yield N-carbalkoxycarbonylacyl derivatives 87, and these can be cyclized in high yield with sodium methoxide to give the 2//-l,2,4-benzothiadiazines 88 (R1 = OEt) (83MI1). Alternatively, 88 (R1 = OEt) can be made directly (see Section III,A,2,b). By reacting 88 (R1 = OEt) with ammonia or primary amines, R2NH2... 

Not much is known about the properties of 1,2,5-thiadiazines. However, there is one outstanding property the contraction of the 1,2,5-thiadiazine ring, which is shown both by monocyclic 1,2,5-thiadiazines and 2,1,4-benzothiadiazines. For instance, 1,2,5-thiadiazine 187, which is stable at low temperatures, tends to revert to 1,2,5-thiadiazolium cyanide 185 on standing at room temperature for several days (79TL1281). In this contraction, the ring sulfur atom is retained. Usually the sulfur atom is extruded to give imidazole derivatives, e.g., 1,2,5-thiadiazine 184 (R = i-Pr), when heated, yields thiazolidinethione 194 (49JOC946). In the 2,1,4-... 

In Section II, the chemistry of 1,2,6-thiadiazine 1,1-dioxides and fused systems will be described, but no attempt has been made to cover all the literature dealing with benzothiadiazinones. Numerous derivatives related to the herbicide bentazone (3-isopropyI-lH-2,l,3-benzothiadiazin-4-one 2,2-dioxide) have been prepared and are described in various patents, which will not be included. The reactivity of bentazone and related 2,1,3-benzo-thiadiazinones has also been extensively studied (81AG(E)151). 

Mesoionic 2,1,3-benzothiadiazine 2,2-dioxide (26) is spontaneously formed from the corresponding 4-methoxy derivative by loss of methanol (79LA1130). 

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