US3163644A

US3163644A - Derivatives of 2-h-1, 2, 4-benzo thiadiazine-1, 1-dioxide

Info

Publication number: US3163644A
Application number: US846779A
Authority: US
Inventors: Stevens George De; Werner Lincoln Harvey
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1959-10-16
Filing date: 1959-10-16
Publication date: 1964-12-29
Anticipated expiration: 1981-12-29
Also published as: ES254767A1

Description

United States Patent DERIVATIVES 0F Z-H-LZA-BENZO THIADIA- ZlNE-LLDIOXIDE George de Stevens, New Providence, and Lincoln Harvey 'Werner, Summit, N43,, assignors to iba Corporation, a corporation oi. Delaware No Drawing. Filed (Pet. 16, 1959, Ser. No, 846,779

'40 Claims. (Cl. 268-243) in turn is a continuation-in-part application of our application Serial No. 740,582, filed June 9, 1958 (now abandoned), which in turn is a continuation-in-part application of our application Serial No. 727,242, filed April 9, 1958 (now abandoned).

The present invention concerns 2-subs tituted-3,4-dihydro-ZH-1,2,4-benzothiadiazine-1,l-dioxides. More par, ticularly, it relates to compounds of the formula:

in which R represents hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon, carbocyclic aryl, car- .bocyclic aryl-lower aliphatic hydrocarbon, heterocyclic aryl .or heterocyclic ary-l-lower aliphatic hydrocarbon, R stands for aliphatic hydrocarbon, substituted aliphatic hydrocarbon or carbocyclic aryl-aliphatic hydrocarbon, R represents hydrogen or lower alkyl, and R stands for halogen, lower alkyl or halogeno-lower alkyl or salts thereof, as well as process for the preparation of such compounds. 8

, Apart from being hydrogen, R may also stand for aliphatic hydrocarbon radicals, for example, lower aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, propyl, isopropyl butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like, lower alkenyl, e.g. vinyl, l-propenyl, allyl and the like, lower alkynyl, e.g. ethynyl and the like, carbocyclic aliphatic hydrocarbons, particularly monocyclic carbocyclic aliphatic hydrocarbons, which contain from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or may contain from one to two double bonds depending on the number of ring carbon atoms, such as cycloalkyl, which contains from five to six ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, or cycloalkenyl, which contains from five to six carbon atoms as ring members, e.g. 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like, or carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon, primarily monocyclic carbocyclic aliphatic 3,153,844 Patented Dec. 29, 1964 hydrocarbon-lower alkyl, which contains from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or contain from one to two double bonds depending on the number of the ring carbon atoms, and in which lower alkyl represents a lower alkylene radical containing from one to seven, particularly from one to three, carbon atoms, such as oycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as hing members, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentyletl1yl, l-cyclopentylpropyl, 3-cyclopentylpropyl, cyclohexylmethyl, l-cyclohexylethyl, 2-cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, which contain from five to six ring carbon atoms, e.g. 2-cyclopentenylmethyl, 3-cyclopenten-ylmethyl, 2-(2-cyclopentenyD-ethyl, 2 cyclohexenylrnethyl, 3 cyclohexenylmethyl, l-( 3 cyclohexenyl) -ethyl, 2-(2 cyclohexenyl)- ethyl, 3-(2-cyclohexenyl)-propyl, and the like.

These aliphatic hydrocarbon radicals may contain functional groups as additional substituents. Such substituents are primarily attached to lower alkyl radicals, which may be represented by a lower alkylene radical containing from one to five carbon atoms, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, l,l-dimethyl-l,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3-propylene, 2,2-propylene, 1,1-butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 2,2-butylene, 2,3-butylene, 1,5- pentylene, 2,5-pentylene and the like.

Substituents are, for example, one or more than one halogen atom, e.g. fluorine, bromine, or particularly chlorine; halogeno-substituted lower alkyl radicals, representing R are, for example, trifluoromethyl, chloromethyl, 2 chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.

Other substituents are amino groups, such :as primary amino groups, secondary amino groups, such as N-lower alkyl-amino, e.g. N-rnethylamino, 'N-ethylamino and the like, N-carbocyclic arylamino, e.g. N-phenylamino and the like, or N-carbocyclic aryl-lower alkyl-amino, e.g. N benzylamino and the like, or primarily tertiary amino groups, particularly N,=N-di-lower alkylamino, in which lower alkyl contains from one to seven carbon atoms, e.g. N,N-dimethylamino, N-ethyl-N-methyhamino, lN,N-dlethylamino, N,N-dipropylamino, -N,'N-di-isopropylamino, N,N-dibutylamino and the like, N-cycloalkyl-N lower alkyl amino, e.g. N-cyclopentyl-N-methyl-amino, N-cyclohexyl-N-methyl-amino and the like, vN-carbocyclic aryllower :alkyl- N-lower alkyl-amino, e.g. -N-benZyl-N-methylamino, N-methyl-N-(2-phenylethyl)-amino and the like, 1-N, N-lower alkylene-imino group, in which the lower alkylene radical contains from four to six carbon atoms, such as l-pyrrolidino, e.g. l-pyrrolidino, 2-methyl-1-pyrrolidino and the like, '1pip eridino, e.g. l-piperidino, 2- methyld-piperidino, 3-metliyl-lapiperidino, 4-methyl-1- piperidino, 3-hydroxy-l-piperidino, 3-acetoxy-l-piperidino, 3-hydroxymethyl-l-piperidino and the like, or l-N,N- hexamethylene-imino, 1-N,N-lower oxa-alkylene-imino, in which oxa-alkylene contains preferably four carbon atoms, exg; l-mol'pholino and the like, or l-N,N-lower aza-alkylene-imino, in which aza-alkylene contains preferably four carbon atoms, e.g. 1-piperazino, 4-rnethyl-1-piperazino, 4-hydroXyethyl-l-piperazino, 4-acetoxyethyl-l-piperazino and the like. The tertiary amino group and the lower alkyl radical to which the amino group is attached may represent together a heterocyclic radical, in which the tertiary amino group is part of the heterocycle and one of the carbon atoms of the heterocyclic ring is connected directly or through a lower alkylene radical, e. g. methylene or 1,2-ethyleue, with the 13-POSltlOI1 of the 1,2,4-thiadiazine-l,l-dioxide portion. Such radicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl-3-piperidinomethyl, 2-( l-methyl-Z-piperidino)-ethyl, l-methyl-4-piperidino and the like.

Other substituents attached to aliphatic hydrocarbon, particularly lower alkyl, radicals are also N-acylamino groups, in which acyl represents the acyl radical of an organic carboxylic acid, for example, a substituted carbonic acid, e.g. methoxy-ca r bonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, mcthylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, particularly monocyclic carbocyclic 'aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, particularly monocyclic carbocyclic aryl-lower alkyl canboxylic acids, e.g. phenylacetic, diphenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g. cinnamic acid or substituted cinnamic acids; substituents attached to these carboxylic acids are, for example, lower alkyl, e.g. methyl,'ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylene-dioxy, nitro, amino, particularly tentiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. ttrifluoromethyl.

Acyl groups are additional substituents of aliphatic hydrocarbon, particularly lower alkyl, radicals, primarily acyl radicals of organic carboxylic acids, such as lower alkanoic acid, e.g. acetic, propionic, butyric acid and the like, as well as substituted carbonic acids, e.g. methoxycarbonic acid, ethoxy-car-bonic acid, benzyloxy-carbonic acid and the like, lower alkenoic acids, e.g. acrylic, methacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, canbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl canboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic acids. Additional substituents of these carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifiuorornethyl.

Other substituents attached to aliphatic hydrocarbon, particularly lower alkyl, radicals, are hydroxyl groups. Esterified hydroxyl groups may also be suitable as substituents, especially hydroxyl groups esterified by organic carboxylic acids, for example, substituted carbonic acids, e.g. methoxy-carbonic, ethoxy-carbonic, benzyloxy-carbonic and the like, lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic acids. substituents of such carboxylic acids, are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkylamino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl.

Further substituents of aliphatic hydrocarbon radicals, particularly lower alkyl radicals, are etherified hydroxyl groups, which may be represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethoxy, n'propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g. l-naphthyloxy or Z-naphthyloxy or substituted napthyloxy, or carbocyclic arylaliphatic hydrocarbonoxy, such as monocyclic carbocyclic aryl-lower alkoxy, e.g. benzyloxy or substituted benzyloxy. The aliphatic hydrocarbon, and particularly the carbocyclic aryl portions of the etherified hydroxyl groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N- diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like or halogeno-lower alkyl, e.g. trifluoromethyl.

In addition, aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbonmercapto, such as lower alkyl-mercapto, e.g. methylmercapto, ethyl-mercapto, n-propyl-mercapto, isopropylmercapto, n-butyl-mercapto, isobutyl-mercapto and the like, lower alkenyl-mercapto, e.g. vinyl-mercapto, allylmercapto and the like, carbocyclic aryl-mercapto, such as monocyclic carbocyclic aryl-mercapto, e.g. phenylmercapto or substituted phenyl-mercapto, or bicyclic carbocyclic aryl-mercapto, e.g. l-naphthyl-mercapto or Z-naphthyl-mercapto or I substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g. benzyl-mercapto, l-phenylethyl-mercapto, Z-phenylethyl-mercapto and the like, or substituted benzyl-mercapto, substituted l-phenylethyl-mercapto, substituted 2- phenylethyl-mercapto and the like. The aliphatic hydrocarbon portions and, particularly, the carbocyclic aryl portions of the etherified mercapto groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, such as primary or secondary amines, or, particularly, tertiary amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylarnino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.

Apart from aliphatic hydrocarbon radicals R may represent carbocyclic aryl groups, such as monocyclic carbocyclic aryl, e.g. phenyl or substituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naphthyl or 2-naphthyl or substituted naphthyl radicals, or .carbocyclic ary1- aliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, 1- phenylethyl, Z-phenylethyl, 3-phenylpropyl, l-naphthylmethyl and the like or these radicals substituted in the carbocyclic aryl portion, or monocyclic or bicyclic carbocyclic aryl-lower alkenyl, e.g. 2-phenyl-ethenyl and the like, as well as such radicals containing in the carbocyclic portion additional substituents. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e. g. methylenedioxy, lower alkyl mercapto, e.g. methylmercapto and .the like, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. dimethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl. Substituents attached to carbocyclic aryl, particularly monocyclic carbocyclic aryl portions may be in an any of the available positions, whereby one or more than one of the same or of different substituents may be present.

Additional groups representing R are heterocyclic aryl radicals, particularly monocyclic or bicyclic heterocyclic aryl radicals, which may contain from five to six atoms as ring members in the heterocyclic portion, such as pyridyl, e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl and the like, thienyl, e.g. Z-thienyl and the like, furyl, e.g. 2-furyl and the like, or quinolyl, e.g. 6-quinolyl and the like, or heterocyclic aryl-aliphatic hydrocarbon, such as monocyclic heterocyclic-aryl-lower alkyl, for example, thenyl, e.g. 2-thenyl and the like. These radicals may contain additional substituents, particularly lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogen, e.g. fluorine, chlorine, bromine and the like.

Aliphatic hydrocarbon and substituted aliphatic hydrocarbon radicals representing R have the same meaning as the corresponding radicals representing the group R More especially, R stands for alkyl, particularly for lower alkyl containing from one to seven, primarily from one to four, carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and the like, as well as n-pentyl, isopentyl, n-hexyl and the like.

The radical R may also stand for alkenyl, primarily for lower alkenyl containing from two to seven, especially from three to five, carbon atoms. Such radicals are, for example, allylic lower alkenyl groups, e.g. 2-propenyl (or allyl), 2-methyl-2-propenyl (or Z-methyl-allyl), Z-butenyl (or 3-methyl-allyl), Z-pentenyl (or 3ethyl-allyl), 3-methy1-2-butenyl (3,3-dimethyl-allyl) and the like, as well as vinyl, 3-pentenyl and the like.

' Other aliphatic hydrocarbon radicals representing R are, for example, lower alkynyl radicals, cycloaliphatic hydrocarbon radicals, cycloaliphatic hydrocarbon-lower aliphatic hydrocarbon radicals and the like, as well as aliphatic hydrocarbon radicals, substituted by functional groups, such as hydroxy, etherified hydroxy, esterified hydroxy, etherified mercapto, carboxyl, amino, halogen,

lower alkanoyl, carbocyclic aroyl and the like. Such radicals, as well as the functional groups attached to these aliphatic hydrocarbon radicals have been described in detail hereinabove.

The radical R also represents carbocyclic aryl-lower aliphatic hydrocarbon, particularly monocyclic carbocyclic-lower alkyl, in which lower alkyl contains preferably from one to four carbon atoms, e.g. benzyl, l-phenylethyl, Z-phenylpropyl, 3-phenylpropyl, a,ot-dimethyl-benzyl, 2- phenyl-isopropyl and the like, or these radicals containing substituents in the aromatic portion, such as lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, lower alkyl-mercapto, e.g. methylmercapto, ethylmercapto and the like, nitro, amino, particularly N,N-di-lower alkyl-amino, e.g. N,N- dimethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl, and the like. Such substituted monocyclic carbocyclic aryl-lower alkyl radicals are, for example, substituted benzyl radicals, such as lower alkylsubstituted benzyl, e.g. 3-methyl-benzyl, 4-methyl-benzyl and the like, lower alkoxy-substituted benzyl, e.g. 2- methoxy-benz-yl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,4,5-trimethoXy-benzyl and the like, lower alkylenedioxysubstituted benzyl, e.g. 3,4-methylenedioxy-benzyl, lower alkyl-mercapto-substituted benzyl, e.g. 4-methylmercaptobenzyl and the like, ni'tro-substituted benzyl, e.g. 3- nitrobenzyl, 4-nitrobenzyl and the like. N,N-di-lower alkyl-amino-substituted benzyl, e.g. 3-N,N-dimethylaminobenzyl, 4-dimethylamino-benzyl and the like, halogenosubstituted benzyl, e.g. 3-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 3,4-dichlorobenzyl, 2,5-dibromobenzyl and the like, or halogeno-lower alkyl-benzyl, e.g. 4-trifiuoromethyl-benzyl and the like. Substituted 2-phenylethyl radicals are, for example, 2-(lower alkyl-substituted phenyl)-ethyl, e.g. 2-(3-methyl-phenyl)-ethyl, 2-(4-methyl-phenyl)-ethyl, 2-(4-isopropyl-phenyl)-ethyl and the like, 2-(lower alkoxy-substi'tuted phenyl)-ethyl, e.g. 2-(2- methoxy-phenyl)-ethyl, 2-(4-methoxy-phenyl)-ethyl, 2- (3 ,4-dimethoxy-phenyl) -ethyl, 2- 3 ,4,5-trimeth0xy-phenyl)-ethyl and the like, 2-(lower alkylenedioXy-substituted phenyl)-ethyl, e.g. 2-(3,4-methylenedioxy-phenyl)-ethyl, 2-(lower alkylmercapto-substituted phenyl)-ethyl, e.g. 2- (4-methylmercapto-phenyl)-ethyl and the like, Z-(nit-rosubstituted phenyl)-ethyl, e.g. 2-(3-nitro-phenyl)-ethyl, 2-(4-nitro-phenyl)-ethyl and the like, 2-(di-lower alkyl-amino-substituted phenyl)-ethyl, e.g. 2-(3-dimethylamino-phenyl) -ethyl, 2- (4-dimethylamino-phenyl) -e thyl and the like, or Z-(halogeno-substituted pheny l)-ethyl, e.g. 2-(3-fluoro-phenyl)-ethyl, 2-(4chloro-phenyl)-ethyl, 2- 4-bromo-phenyl) -ethyl, 2- (3 ,4-dichloropheny1)-ethyl, 2-(2,5-dibromo-phenyl)-ethyl and the like. In other monocyclic carbocyclic aryl-lower alkyl radicals, such as those mentioned hereinbefore, the aromatic portion may be substituted with the above-mentioned substituents; 1- (4 chloro phenyl)-ethyl, l-(3,4,5-trimethoxy-phenyl)- ethyl, 2-( 3-methyl-phenyl)-propyl, 3-(3,4-dimethoxyphenyl)-propyl, 2-(3,4-dichloro-phenyl)-isopropyl, 1-(3- fluoro-phenyl)-isopropy1 and the like illustrate such substituted groups.

The radical R may also stand for bicyclic carbocyclic aryl-lower alkyl radicals, such as l-naphthylmethyl, 2- naphthylmethyl, 2-(1-naphthyl)-ethyl, 2-(2-naphthyl)- ethyl and the like, as well as those radicals substituted by the previously mentioned substituents present in monocyclic carbocyclic aryl-lower alkyl radicals.

Also included as radicals R are monocyclic or bicyclic carbocyclic aryl-lower alkenyl radicals, e.g. 3-

phenyl-prop-Z-enyl, 4-phenyl-but-2-enyl, 3-(2-naphthyl)- prop-Z-enyl and the like, as well as such radicals substituted in the carbocyclic portion by substituents, such as those present in the monocyclic carbocyclic ar l-lower alkyl radicals.

The radical R attached to the second, aniline-type amino group of the 1,2,4-thiadiazine-portion of the compounds of this invention, represents primarily hydrogen, but may also stand for lower alkyl, e.g. methyl, ethyl and the like.

The group R attached to the 6-position of the 3,4-dihydro-Zl-I-1,2,4-benzothiodiazine-1,l-dioxide, stands for halogen, e.g. fluorine, bromine, or particularly chlorine and the like, lower alkyl, e.g. methyl and the like, or halogeno-lower alkyl, particulary trifluoromethyl, and the like. 1

Salts of the compounds of this invention are primarily those with metals, particularly alkali metals, e.g. sodium, potassium and the like; monoor poly-salts may be formed.

The compounds of the present invention have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly in which R represents hydrogen, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, or lower alkyl substituted by halogen, lower alkoxy, lower alkyl-mercapto, phenyl-lower alkyl-mercapto, and the like, e.g. chloromethyl, dichloromethyl, ethoxymethyl, ethylmercaptoethyl, benzylmercaptoethyl, and the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkyl containing from five to six ring carbon atoms, e.g. cyclopentyl and the like, or phenyl-lower alkyl, e.g. benzyl, 2- phenylethyl and the like, R' represents lower alkyl containing from one to four carbon atoms,, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, allylic lower alkenyl containing from three to five carbon atoms, e.g. allyl, 2-methylallyl, 3-methylallyl, 3,3-dimethylallyl and the like, or phenyl-lower alky, in which lower alkyl contains from one to four carbon atoms, e. g. benzyl, l-phenylethyl, 2-phenylet hyl and the like, R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof. This group of compounds may be represented by the compounds of the formulae:

N (lower alkyl) S HZNOZS N (lower alkyl) R CH- (phenyl-lower alkyl) N a H in which compounds R stands for chlorine or triiluoromethyl, and lower alkyl contains from one to four carbon atoms. Particularly active compounds are, for example, 6-chloro-2-methyl-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide, 6-trifluoromethyl-2-methyl-7-sulfamy1-3,4-dihydro-ZH- 1,2,4-benzothiadiazine-1,l-dioxide, 6-ohloro-2,3-dimethy1-7-sulfamyl-3,4-dihydro-2H-l,2,4- benzothiadiazine-l,l-dioxide,

6-trifiuoromethy1-2,3-dimethyl-7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-l,l-dioxide,

6-ehloro-3 -isobutyl-2-methyl-7-sulfamyl-3 ,4-dihydro-2H- l,2,4-benzothiadiazine-l,l-dioxide,

6-trifiuoromethyl-3 -isobutyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 -dichloromethyl-2-methyl-7-sulfan1yl-3 ,4-(lihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

3-dichloromethyl-6-trifluoromethyl-2-methyl-7 sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-l, l-dioxide,

3-benzyl-6-ei.loro-2-methyl-7-sulfarnyl-3 ,4'-dihydro-2H- l,2,4-benzothiadiazine-l,l-dioxide,

3 -benzyl-6-trifluoromethyl-2methyl-7-sulfamy1-3 ,4-dihydro-2H4,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-2-ehhyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide,

2-ethyl-6-trifiuoromethyl-7-sulfamyl-3 ,4-dihydro-2H- 1,2,4-benzothiadiazine-1, l-dioxide,

6-ohloro-2-ethyl-3 -methyl-7-sulfamyl-3 ,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide,

2-ethyl-6-trifluoromethyl-3-methyl-7-methyl-sulfamyl- 3 ,4-dihydro-2l-i-1,2,4-benzothiadiazine-l,l-dioxide,

6-chloro-2-ethyl-3 -isobutyl-7-sulfamyl-3 ,4-dihydro-2H- l,2,4-benzothiadiazine-l,l-dioxide,

2-ethyl-6-trifiuoromethyl-3 -is obutyl-7-sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-3 -dichloromethyl-2-ethyl-7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-l,l-dioxide,

3 -clichloromethyl-Z-ethyl-6-trifluoromethyl-7-sulfamyl- 3,4-dihydro-2l-I-1,2,4-benzothiadiazine-1, l-dioxide,

3-benzyl-6-chloro-2-ethyl-7-sulfamyl-3 ,4-di'hydro-2H- 1,2,4-benzothiadiazine-1, l-dioxide,

3 -benzyl-2-ethyl-6-trifiuoromethyl-7-sulfamyl-3 ,4-dihydro- ZP-l,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-2n-propyl-7-sulfamyl-3,4-dihydro-2H-l,2,4-

enzothiadiazine-l,l-dioxide,

6-trifiuoromethyl-2-n-propyl-7-sulfamy1-3 ,4-dihydro-2H- l,2,4-benzothiadiazine-1,1-dioxide, 6-chloro-2-isopropyl-7-sulfamyl-3,4-dihydro-2H-l,2,4-

benzothiadiazine-l,l-dioxide, 6-trifiuoromethyl-2-isopropyl-7-sulfamyl-3,4-dihydro- 2H-l,2,4-benzothiadiazine-1,l-dioxide, 2-n-butyl-6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4-

benzothiadiazine-l,l-dioxide, Z-n-butyl-e-trifiuoromethyl-7-sulfamyl-3 ,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide and the like.

An additional group of compounds with outstanding pharmacological properties may be represented by the compounds of the formulae:

III- (allylic lower alkenyl) N- (allylie lower alkenyl) CH- (lower alkyl) in which compounds R stands for chlorine or trifluoromethyl, allylic lower alkenyl contains from three to five carbon atoms and lower alkyl contains from one to four carbon atoms. Particularly active compounds are, for example,

2-allyl-6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4-

benzothiadiazine-l l-dioxide, 2-a1lyl-6-triliuor-omethyl-7-sulfamy1-3,4-dihydro-2H- 1,2,41benzothiadiazine-1, l-dioxide, 2-allyl..6-.chloro.- 3 -mcthyl -7-sulfamyl-3,4-diihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide, 2-allyl-6-1trifluoromethyl-3-methyl-7 -sulfamy1-3,4-

dihyd-ro-ZH-1,2,4-benzthiadiazine-l l-dioxide, 2-allyl-6-ch1-oro-3 -isobu tyl-7-sul famyl3,4adihydro- 2H-1,2,4-benzothiadiazine-l, l-dioxide, 2-allyl-6-trifluoromethyl-3 -isobutyl-7-sulfamyl-3 ,4- dihyd-ro-ZH-1,2,4-benzothiadiazine-1, 1dioxide, 2-allyl-6-chloro-3-dichloromethyl-7-sulfamyl 3,4-

dihydro-ZH-l,2,4-benzomiadiazine-1,1-dioxide, 2-allyl-3-dichloromethyl-6-trifiuoromethyl-7-sulfamyl- 3,4-dihydro-2H-1,2,4-benZothiadiazine-1,1-dioxide, 2-.ally1-3-benzyl-6-chloro-7-sulfarnyl-3,4dihydro-2H- 1,2,4-benz0thiadiazine-1, l-dioxide, Z-allyl-B -benzyl-6-trifiuoromethyl-7-sulfamyl-3,4-

dihydro-ZH- 1 ,2,4-b enzothiadiazine- 1, l dioxide, 6-chloro-2- Z-methyl-zallyl -7-sul-fiamyl-3 ,4,-dihydro- 2H-l,2,4-benzothiadiazine-l, l-dioxide, G-trifiuoromethyl-Z- (Zimethyl-allyl -7-sulfamyl- 3 ,4- dihydro-ZI-I-l,2,4-benzothiadiazine-1, l-dioxide, 6-chloro-2- (3 methyl-allyl -7-sulf-amyl-3 ,4-dihydro- 21-1-1 ,2,4-b enzothiadiazine- 1 l-dioxide, 6-trifluoromethyl-2-(3-methyl-allyl)-7-sulfamyl-3,4- di-hydro-ZH-1,2,4 benzothiadiazine-1, l-dioxide and the like.

A further group of highly active diuretic and saliuretic compounds may be represented by the compounds of the fiormulae:

2 B HZN 02s (phenyl-lower alkyl) Rs- Hz n 112N028 N (phenyllower alkyl) /OH (lower alkyl) 2 S 112N023" N- (phenyl-lower alkyl) 3H-(ha1ogeno-1ower alkyl) 2 HQN III (pheny1-lower alkyl) R3? /CH-(pheny1-lower alkyl) in which compounds R3 stands for chlorine or trifluoromethyl and low alkyl contains from one to four carbon atoms. Particularly outstanding compounds are, for example, Z-benzyl-6-chloro-7-sulfamyl-3,4-dihydr-o-2H-1,2,4-

benzothiadiazine-Ll-dioxide, 2-benzyl-6-trifluoromethyl-7-sul-fa.myl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l-dioxide,

i 2-benzyl-6-chlor0-3-methyl-7-suliamyl-3,4-dihydro- 2H-1 ,2,4-benzothi adiazine- 1, l-di oxide, 2-benzyl-6-trifluoromethyl-3-m-ethyl-7-sulfamyl-3,4- dihydro-ZH-l ,2,4-benzo-thi=adiazine- 1, l-dioxide, 2-benzyl-6-chl0ro-3-isobutyl-7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l-dioxide, 2-benzyl-6-trifluoromethyl-3-isobutyl-7-sulfamyl-3,4- dihydro-2H-1,2,4-benzothiadiazine-l, l-dioxide, 2-benzyl-6-chloro-3-dichloromethyl-7-sulfiamyl-3,4-

dihydro-ZH-l ,2,4-b enzo thiacliazinel l-dioxide, 2-benzyl-3-dichloromethyl-6-trifiuorornethyl-7sulfamyl- 3 ,4-dihydro-2H-1,2,4 benzothiadiazine-l l-dioxide, 2,3*dibenzyl-6-chloro-7-sulfamyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine-l l-dioxide, 2,3-dibenzyl-6-trifluoromethyl-7 sulfamyl-3,4-dihydro 2H-1,2,4-henzothiadiazine-1, l-dioxide, 6-chl-oro-2-( l-phenylethyl -7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide, 6-trifiuo-romethyl-2- laphenylethyl) -7-sulfamyl-3,4- dihydro-ZH-l ,2,4-b enzothi adiazine-l l-dioxide, 6-chl oroa2- (Zaphenylethyl) -7-sulfiamyl-3 ,4-dihydro- 2I-I-1 ,2,4-benzothiadiazine-1, l-dioxide, 6-trifluoromethyl-2-(Z-gihenylethyl)-7-sulfamyl-3,4 dihydro-ZH-1,2,4-benzothiadiazine-l, l-dioxide and the like.

'The pharmaceutical preparations may be in solid form,

for example, as capsules, tablets or dragees, or in liquid form, for example, as solutions, suspensions or emulsions. If desired, they may contain auxiliary substances such a preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or butters. They may also contain, in combination, other 1 therapeutically useful substances; particularly useful are antihypertensive compounds, such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Vetratrum alkaloids, e.g. germine, .protoveratrine and the like, synthetic antihypertensive compounds, e.g. hydralazine, dihydralazine and the like, or ganglionic blockers, e.g. chlorisondamine and the like.

The compounds of the present invention may be prepared according to methods which are known in themselves.

Thus, compounds of the formula:

in which R R R and R have the previously given meaning may be prepared, for example, by treating a 3,4- dihydro-2H-1,2,4 benzothiadiazine 1,1-dioxide of the formula:

in which R R R and R have the previously given ing, or an alkali metal salt thereof, with the reactive ester of an alcohol of the formula R -OH, in which R has the previously given meaning and isolating the desired product, and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a free compound into a salt thereof.

In the above reaction the 2-unsubstituted 3,4-dihydro- 2H-l,2,4-benzothiadiazine-l,l-dioxide is preferably used in the form of an alkali metal, e.g. lithium, sodium, potassium and the like, salt thereof. Advantageously, such salt is formed in situ, i.e. the reaction with the reactive ester of an alkanol is carried out in the presence of an alkali metal salt forming reagent. Such reagents are primarily alkali metal hydroxides, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. In addition, alkali metal hydrides and amides e.g. lithium, sodium, potassium hydride and amide, or alkali metal lower alkanolates, e.g. sodium or potassium methanolate or ethanolate and the like, may be employed for such purpose.

Reactive esters of alcohols of the formula R2'-OH, in which R has the previously given meaning, are primarily those with strong mineral acids, e.g. sulfuric, hydrochloric, hydrobromic, hydriodic acid and the like, or with strong organic sulfonic acids, e.g. p-toluene sulfonic, methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic acid and the like.

Specific examples of esters of alcohols of the formula R 'OH are those with sulfuric acid, for example, dialkyl sulfates, particularly di-lower alkyl sulfates in which lower alkyl contains from one to four carbon atoms, e.g. dimethyl sulfate, diethyl sulfate, di-n-propyl sulfate and the like, as well as di-alkenyl sulfates, particularly di-allylic lower alkenyl sulfates, in which lower alkenyl contains from three to five carbon atoms, e.g. diallyl sulfate and the like, or di-carbocyclic aryl-lower aliphatic hydrocarbon sulfates, particularly di-phenyllower alkyl-sulfates, in which lower alkyl contains from one to four carbon atoms, e.g. dibenzy-l sulfate, bis-(2 phenylethyl) sulfate and the like.

Other esters are those of alcohols of the formula R 'OH are those with hydrohalic, e.g. hydrochloric, hydrobromic, hydriodic and the like, acids, especially alkyl halides, particularly lower alkyl halides, in which lower alkyl contains from one to four carbon atoms, e.g. methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl bromide, isopropyl chloride, n-butyl bromide and the like, alkenyl halides, particularly allylic lower alkenyl halides, in which lower alkenyl contains from three to five carbon atoms, e.g. allyl chloride, allyl rbomide, 2-methyl-allyl bromide, 3-

'methyl-allyl bromide, 3,3-dimethyl-allyl bromide, allyl iodide and the like, or carbocyclic aryl-lower aliphatic hydrocarbon halides, particularly phenyl-lower alkyl halides or substituted phenyl-lower alkyl halides, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl chloride, benzyl bromide, benzyl iodide, l-phenylethyl chloride, l-phenylethyl bromide, 1- phenylethyl iodide, 2-phenylethyl chloride, 2-phenylethyl bromide, 2-phenylethyl iodide, 4-chloro-benzyl bromide, 2,5-dichloro-benzyl bromide, 4-methoxy-benzyl bromide, 3,4-dimethoxy-benzyl chloride, 4-methylbenzyl bromide, 2-(4-chlorophenyl)-ethyl bromide and the like.

An additional group of reactive esters of the alcohol R -OH are those with strong organic sulfonic acids, for example, alkyl alkane sulfonates, particularly lower alkyl lower alkane sulfonates, in which lower alkyl and lower alkane contain from one to four carbon atoms, e.g. methyl, ethyl, n-propyl methane, ethane or 2-hydroxyethane sulfonate and the like, or alkyl carbocyclic aryl sulfonates, particularly lower alkyl p-toluene sulfonate, in which lower alkyl contains from one to four carbon atoms, e.g. methyl or ethyl p-toluene sulfonate and the like, alkenyl sulfonates, especially allylic lower alkenyl lower alkane sulfonates, in which lower alkenyl and lower alkane contain from three to five carbon atoms, e.g. allyl methane, ethane, Z-hydroxy-ethane sulfonate and the like, or alkenyl carbocyclic aryl sulfonates, particularly allylic lower alkenyl p-toluene sulfonate, in which lower alkenyl contains from three to five carbon atoms, e.g. allyl p-toluene sulfonate and the like, carbocyclic aryl-lower aliphatic hydrocarbon sulfonates, such as phenyl-lower alkyl lower alkane sulfonates, in which lower alkyl and lower alkane contain from one to four carbon atoms, e.g. benzyl or 2- phenylethyl methane, ethane or 2-hydr0xyethane sulfonate and the like, or carbocyclic aryl lower aliphatic hydrocarbon carbocyclic aryl sulfonate, particularly phenyllower alkyl p-toluene sulfonate, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl or 2-phenylethyi p-toluene sulfonate and the like.

The reaction is advantageously carried out in the presence of a solvent; water, lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, tertiary butanol and the like, or mixtures of water and such lower alkanols are preferred diluents. Other water-miscible solvents, such as, for example, glycols, e.g. diethyleneglycol dimethylether and the like, lower alkanones, e.g. acetone, ethyl methyl ketone and the like, or N,N-dimethylformamide may be employed as well. The reaction may proceed under cooling or at room temperature; if necessary, the temperature may be raised to complete the conversion.

The desired product is isolated from the reaction mixture according to usual methods; ordinarily a resulting precipitate, if necessary after concentration of the reaction mixture, is filtered off and is purified by recrystallization, to remove any poly-substituted product.

The 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxides used as the starting materials are known or may be prepared according to procedures used for the known analogs. For example, an aniline compound of the formula:

in which R and R have the previously given meaning is reacted with an aldehyde of the formula R CHO, in which R has the previously givenmeaning, or a reactive derivative thereof, to form the desired 3,4-dihydro- 2H-1,2,4-benzothiadiazine-l,l-dioxide.

Although the disulfamyl-aniline compound is preferably treated with approximately an equivalent amount of the aldehyde, particularly when formaldehyde or a reactive derivative, e.g. a polymer thereof is used, an excess of an aldehyde other than formaldehyde or a derivative thereof may be present. The reaction may advantageously be carried out in the presence of a small amount of an acid, for example, a mineral acid, e.g. hydrochloric, hydrobromic acid, sulfuric acid and the like, if desired, in anhydrous form. An acid is necessary, if the aldehyde is Present in the form of a reactive derivative, such as a polymer or an acetal, thereof. It may also be performed in the absence of a condensing reagent, or in the presence of a base, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, whereby the aldehyde is used in its reactive form. As mentioned above, the aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ. Thus, for example, an acetal of an aldehyde R CHO with lower alkanols, for example, with methanol or ethanol, may be used in the presence of a mineral acid; such acetals are, for example, 1,1-dimethoxy-ethane, 1,1-dimethoxyisobutane, 1,1-diethoxy-isobutane, 2,2-dichloro-1,l-dimethoxy-ethane, 2,2-dichloro-1,l-diethoxy-ethane and the like. Formaldehyde may also be employed in the form of a polymer such as, for example, paraformaldehyde and the like or another formaldehyde furnishing reagent, e.g. hexamethylenetetramine and the like; acetaldehyde may be present in the form of a polymeric substance yielding 13 acetaldehyde under the condition of .the reaction, e.g. metaldehyde and the like.

The reaction :is preferably carried out in the presence of a solvent, for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkaa no], e.gfmethanol, ethanol and the like, a formamide, e.g. dimethylformamide and the like, or an aqueous mixture of such solvents or water.- If desired, it may be completed at an elevated temperature, for example, .on the steam bath or at the boiling temperature of the solvent and, if necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g. nitrogen.

The 5-R -2,4-disulfamyl anilines, used as the intermediates in the above reaction are known or, if new, may be prepared according to known procedures.

The compounds of the present invention may also be prepared by reacting a 2,4-disulfamyl-aniline of the formula:

modification of the process of this invention. For example, the two reactants may be heated in a solution using one of the previously described diluents, if desired, in the presence of an acid or a base as a condensing reagent. As pointed out, the aldehyde may also be used in the form of a reactive derivative, such as an racetal with a lower alkanol, e.g., methanol, ethanol and the like. Formaldehyde may be present in the form of a polymer thereof, e.g., 'paraformaldehyde and the like, or another formaldehyde furnishing derivative, e.g. hexamethylenetetramine and the like, and acetaldehyde may also be in a reactive polymeric form, e.g., metaldehyde and the like. The reactive derivatives are preferably used in the presence of an acid, such as a minenal acid, e.g., hydrochloric acid and the like. v

The 2- (N-R -s ulfamy -4-sultamyl-5-R -N-R "-aniline compounds, used as the starting materials, are new and are intended to be included within the scope of the invention. The compounds of the formula:

in which R R and R have the previously given meaning, may be obtained by reacting an aniline-2,4-disulfonyl halide of the formula:

in which R and R have the previously given meaning, and Hal stands for halogen, particularly chlorine, with approximately two molar equivalents of an amine of the a formula R '-NH in which R has the above-given meaning, and reacting the resulting compound of the form, methylene chloride and the like, or lower alkanones,

e.g., acetone and the like, may be used as diluents. Amines of the formula R '-NH are aliphatic hydrocarbon-amines or substituted aliphatic hydrocarbonamines, particularly alkyl-amines, such as lower alkylamines, in which lower alkyl contains from one to four carbon atoms, e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine and the like, alkenylamines, such .as allylic lower alkenyl-amines, in Which lower alkenyl contains from three to five carbon atoms, e.g., allylamine, Z-methyl-allylamine and the like, or oarbocyclic aryl-lower aliphatic hydrocarbon-amines, particularly phenyl-lower alkyl-arnines or substituted phenyl-lower alkyl-amines, in which lower alkyl contains from, one to four carbon atoms, e.g., benzylamine, l-phenylethylarnine, Z-phenylethylamine, 4-chlorobenzylamine, 2,5-dichloro-benzylamine, 4-methoxy-benzylamine, 3,4 dimethoxy benzylamine, 4 methyl benzylamine, 2-(4 chloro-phenyl)-ethylamine and the like.

The resulting 2-(N-R -sulfamyl)-aniline-4-sulfonyl halide compound may be separated from any 2,4-di-(N- R -sulfamyl)-aniline formed in the reaction, for example, on the basis of their different solubilities in a given solvent, e,g. the diluent used in the reaction. Thus, the 2,4-bis-(N-R -sulfamyl)-aniline compound may precipitate from the reaction mixture and be removed by filtration, whereas the desired 2-(N-R '-sulfarnyl)-aniline-4- sulfonyl halide compound may be recovered from the filtrate.

The resulting 2-(N-R -sulfamy1)-aniline-4-sulfonyl halide derivative is then reacted with ammonia. Liquid ammonia may be used and may simultaneously serve as a diluent, or the compound may be dissolved in an organic solvent, e.g. acetone and the like, or less favorably, in water, and be treated with concentrated aqueous ammonia, to give the desired 2-(N-R -sulfamyl)-4-sulfamylaniline compound.

It may also be possible to omit the separation of the desired 2-(N-R -sulfamyl)-aniline-4-sulfony1 halide from any 2,4-bis-(N-R '-sulfamyl)-aniline compound simultaneously formed as a by-product; a resulting mixture may be reacted with ammonia directly and separation of the two products may be achieved after such treatment.

Especially useful as intermediates are the compounds of the formula:

R3 NHz in which R represents lower alkyl having from one to four carbon atoms, e.g. methyl, ethyl, n propyl, isopropyl, n-butyl and the like, allylic lower alkenyl, in which lower alkenyl contains from three to five carbon atoms, e.g.

allyl, Z-m'ethyl-allyl, 3amethyl-allyl and the like, or

phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2;- phenylethyl and the like, and R represents halogen, e.g. fluorine, bromine, or particularly chlorine, or halogenalower alkyl, e.g. trifiuoromethyl. This group may be represented by 2 (N-benzyl-sulfamyl -5-trifluoromethylt-sulfamylaniline and the like.

15 Also new and valuable as intermediates are the compounds of the formula:

in which R R R and Hal have the previously given meaning, which are formed in the two-step synthesis for the preparation of the starting materials. A preferred group of such new intermediate compounds are those of the formula:

in which R represents lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, allylic lower alkenyl, in which lower alkenyl contains from three to five carbon atoms, e.g. a-llyl, Z-methyl-allyl, 3-methyl-allyl and the like, or phenyl-lower alkyl, in which lower alkyl coni tains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, Z-phenylethyl and the like, and R represents halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl. This group may be represented, for example, by

Also included within the scope of the present invention are the compounds of the formula:

in which R R R and R have the previously given meaning, and R stands for aliphatic hydrocarbon, substituted aliphatic hydrocarbon or carbocyclic aryl-lower aliphatic hydrocarbon, or metal, particularly alkali metal, salts thereof.

The radical R stands for the same groups as R more extensively defined hereinbefore, but may not have to be identical with the latter; it stands primarily for lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, allylic lower alkenyl containing from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, 3-methyl-allyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like.

The compounds of the above-given formula have diuretic and saliuretic, particularly natriuretic properties and are intended to be used as diuretic or saliuretic, particularly natriuretic agents having improved and out- Sta d ng properties to relieve conditions of excessive uretic and saliuretic activities of these compounds is a strong antihypertensive eifect, which renders the compounds especially useful as antihypertensive medicaments in hypertensive conditions, which are coupled with water and salt retention, such as, for example, in heart ailments. Particularly outstanding diuretic and saliuretic effects are shown by compounds of the formula:

in which R represents hydrogen, lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, or lower alkyl substituted by halogen, lower alkoxy, lower alkyl-mercapto, phenyl-lower alkyl-mercapto and the like, e.g. chloromethyl, dichloromethyl, ethoxymethyl, ethylmercaptoethyl, benzylrnercaptoethyl, and the like, lower alkenyl, e.g. l-propenyl, and the like, cycloakyl containing from five to six carbon atoms as ring members, e.g. cyclopentyl and the like, or phenyl-lower alkyl, e. g. benzyl, Z-phenylethyl and the like, the radicals R and R have the same meaning, standing for lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like, allylic lower alkenyl containing from three to five carbon atoms, e.g. allyl, Z-methyl-allyl, 3-methyl-allyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2- phenylethyl and the like, and R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogenolower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof. This group of compounds may be represented by the compounds of the formulae:

(phenyl-lower alkyl) 'HN O2S I (Phenyl-lower alkyl) 0 Hz Ra in which formulae R represents chlorine or trifiuoromethyl, lower alkyl contains from one to four and lower alkenyl from three to five carbon atoms, as well as compounds of the above formulae, which contain in the 3- position a lower alkyl radical containing from one to four carbon atoms, particularly methyl, ethyl, isobutyl and the like, halogeno-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. chloromethyl, dichloromethyl and the like, or phenyl-lower alkyl, in which lower alkyl contains from one to four carbon atoms, e.g. benzyl, l-phenylethyl, 2-phenylethyl and the like. Such compounds are, for example,

6- chloro -2-methyl7- (N-methyl-sulfamyl -3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-trifiuoromethyl-2-methyl-7- N-methyl-sulfamyl -3 ,4-

dihydro-ZH-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro -2-ethyl-7- N-ethyl-sulfamyl) -3 ,4-dihydro-2H- 1,2,4-benzothiadiazinel l-dioXide,

2-ethyl-7- N-ethyl-sulfamyl -6trifluoromethyl-3 ,4- dihydro-ZH-l ,2,4-benzothiadiazine- 1, l-dioxide,

2-n-butyl-7- N-n-butyl-sulfamyl) -6-chloro-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1,1-dioxide,

6-chloro-2, 3 -dirnethyl-7- (N-methyl-sulfamyl) -3 ,4-

dihydro-ZH-l,2,4-benzothiadiazine-1, l-dioxide,

6-chloro-3 -isobutyl-2-methyl7- (N-methyl-sulfamyl) -3 ,4-

dihydro-ZH-1,2,4-benzothiadiazine-1,1-dioxide,

6 -chloro-2-ethyl-7- N-ethyl-sulfamyl) -3 -isobutyl-3 ,4- dihydro-ZH-l,2,4-benzothiadiazine-l,l-dioxide,

6-chloro-3 -dichloromethyl-2-methyl-7- (N-methyl-sulfamyl)-3,4-dihydro-2H-l,2,4-benzothiadiazine 1,1-dioxide,

6-chloro-3-dichloromethyl-2-ethyl-7-(N-ethyl-sulfamyl)- 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,

3-dichlorornethyl-2-ethyl-7-(N-ethyl-sulfamyl)-6-trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide,

6 -chloro-2-methyl-7 (N-methyLsulfamyl) -3 (Z-phenylethyl) 3,4-dihydro-2H-l ,2,4-benzothiadiazine- I 1,1-dioxide,

2-allyl-7- (N-allyl-sulfamyl) -6-chloro-3 ,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide, 2-allyl-7-(N-allyl-sulfamyl)-6-trifiuoromethyl-3,4- dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

2-allyl-7- N-allyl-sulfamyl) -6-chloro-3 -isobutyl-3 ,4-dihydro-ZH-l,2,4-benzothiadiazine-1, l-dioxide,

2-all'yl-7- (N-allyl-sulfamyl) -6-chloro-3-dichloromethyl- 3 ,4-dihydro-2H-l,2,4-benzothiadiazine-1, l-dioxide, 2-allyl-7-(N-allyl-sulfamyl)-3-dichloromethyl-6-tritluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide, 2-allyl-7-(N-allyl-sulfamyl)-3-benzyl-6-chloro-3,4-dihydro-2H- 1 ,2,4-benzothiadiazine- 1, 1-dioxide,

2-benzyl-7-(N-benzyl-sulfamyl)-6-chloro-3,4-dihydro- H 2H-1,2,4-benzothiadiazine-1,1-dioxide,

2-benzy1-7- N-benzyl-sulfamyl -6-trifluoromethyl-3 ,4-

dihydro-ZH-l,2,4-benzothiadiazine-1, l-dioxide,

2-benzyl 7- (N-benzyl-sulfamyl) -6-chloro-3'-dichloromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide,

2-benzyl-7-(N-benzyl-sulfamyl)-3-dichloromethyl-6-trifluoromethyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,

2, 3 -dibenzyl -7- (N-benzyl-sulfamyl) -6-chloro-3 ,4-dihydr'o- ZP-l,2,4-benzothiadiazine-l,1-dioxide, and the like.

As the previously described compounds containing an N-unsuostituted sulfamyl group in the 7-position, the compounds of the above formula may be formulated into pharmaceutical compositions for enteral, e.g. oral, or parenteral application; such compositions may be prepared according to known procedures, using standard vehicles and fillers.

The above-described compounds may be prepared, for example, by treating a compound/of the formula:

in 'WhichR R R and R have the previously given meaning, with a reactive ester of an alcohol of the formula R "'OH, in which 'R has the above-given meaning, or treating a compound of the formula:

in which R R R and R have the previously given V I8 meaning, with an aldehyde of the formula R CHO, in which R has the above-given meaning, or a reactive derivative thereof and, if desired, converting a resulting salt into the free compound, and/or, if desired, conventing a free compound into a salt thereof.

The above reactions are carried out according to the previously described procedures. For example, an ester of a reactive alcohol'of the formula 'R "'-OH is particularly an ester with a strong acid, particularly a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like, or an organic sulfonic acid, e.g. methane sulfonic, ethane sulfonic', Z-hydroxy-ethane sulfonic, p-toluene sul-fonic acid and the like; such esters are preferably reacted with a salt, particularly'an'alkali metal salt of the starting material. Or, an aldehyde of the formula R CHO may also be used in the form of an aeetal with a lower alkanol, e.g. methanol, ethanol and the like. Formaldehyde or acetaldehyde may be present as a polymeric form thereof, eg. paraformaldehycle, metaldehyde and the like; other reactive forms furnishing formaldehyde are, forexample, hexamethylenetetramine and the like. Reactions with such acetals and polymeric forms of aldehydes are carried out in the presence of an acid, for example, a mineral acid, eg hydrochloric acid and the like.

Compounds of the formula:

H-Rr T v R2! and R have the previously R stand for the identical prepared by reacting a compound of in which R R R R5 given meaning, and R and group, may also be in which R R and R have the above given meaning with an excess of a reactive ester of an alcohol of the formula R 'OH, in which R has the previously given meaning, and isolating the desired compound, and, if

desired, carrying out the optional steps.

The reaction may be performed a previously shown;

the desired product is separated from any simultaneously formed 3,4.-dihydro-2H-1,2,4-benZothiadiaZine 1,l-dioxide containing an unsubstituted sulfamyl group in the 7-po'si tion, on the basis of differing solubil-ities in solvents, for example, by recrystallization and the like,

The resulting product may be obtained in the form of the free compound or as a salt thereof. An alkali metal salt may be converted into the free compound by treatment with an aqueous acidic reagent, such as a mineral acid, eg hydrochloric, sulfuric. acid and the like. A

free compound may be converted into an alkali metal salt, for example, by treatment with an, alkali metal hydroxide, e.g. sodium or potassium hydroxide, in a solvent, such as in a lower alkanol, e.g. methanol, ethanol and the like, or in water and evaporating the solvent. Mono-or polysalts may be obtained. 3

Any resulting racemate may be converted into the antipocles thereof according to methods used for resolving racemates.

The following examples illustrate the invention; they are not to be construed as being limitations thereon. Temperatures are given in degress Centigrade.

Example 1 1 30.0 g. of 6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide is dissolved in 110 ml. of l N aqueous sodium hydroxide and 400 ml. of water. The solution is cooled to 12.1 g. of dimethyl sulfate is added and the mixture is stirred at 10" for one hour and at room temperature for an additional hour. The solid material is filtered oil to yield 28 g. of a wet material, which is recrystallized three tirnes from a mixture of ethanol and water, to yield the 6-chloro-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, M.P. 253-255 From the mother liquor, the 6-chloro-2 methyl-7-(N-methyl-sulfamyl)-3,4 dihydro 2H 1,2,4- benzothiadiazine-l,l-dioxide, M.P. 203-205 can be recovered.

A sodium salt may be prepared, for example, by evaporating the solution of 6-chloro-2-methyl-7-sulfamyl-3,4- dihydro-ZH-l,2,4-benzothiadiazine-l,l-dioxide in an equimolar amount of aqueous sodium hydroxide.

The starting material may be prepared as follows: A mixture of 2.9 g. of S-chloro-2,4-disulfamyl-aniline in ml. of anhydrous diethyleneglycol dimethylether, 015 ml. of an ethyl acetate solution (containing 109.5 g. of hydrogen chloride per 1000 ml.) and 0.33 g. of paraformaldehyde is heated to 80-90" and maintained at that temperature for 1 hour. The resulting mixture is cooled to room temperature and concentrated to one third of its volume under reduced pressure, diluted with water, and the product is then allowed to crystallize. recrytsallized from water to yield the desired 6-chloro- 7 sulfamyl 3,4-dihydro-2H-l,'2,4-oenzothiadiazine-1,1- dioxide, M.P. 266-268"; yield: 1.4 g.

By replacing paraformaldehyde by 0.84 g. of 1,1-dimethoxymethane and proceeding as above, the same compound is obtained.

Example 2 By treating a cold solution of the 6-chloro-2-methyl-7- sulfamyl-3,4-dihydro-2H-l,2,4 benzothiadiazine-Ll dioxide in dilute sodium hydroxide with dimethyl sulfate according to the procedure of Example 1, the 6-chloro-2- methyl-7-(N-methyl-sulfamyl)-3,4 -dihydro 2H 1,2,4- benzothiadiazine-1,1-dioxide, M.P. 203-205", is formed, which is identical with the product described in Example 1.

Example 3 A mixture of 2.0 g. of 5-chloro-2,4-di-(N-methyl-sulfamyD-aniline, ml. of diethyleneglycol dimethylether, 0.18 g. of paraformaldehyde and 0.5 ml. of a saturated solution of hydrogen chloride in anhydrous ethyl acetate is heated for one hour to about '8090, then cooled, evaporated under reduced pressure, and the residue is diluted with water. The Water is decanted, ethanol and water are added, whereupon a crystalline material is formed, which is filtered off. The resulting 6-chloro-2- methyl-7-(N-methyl sulfamyl) -3,4-dihydro 2H 1,2,4- benzothiadiazine-1,1dioxide is dissolved in ethanol and water is added to precipitate the desired product, which is filtered oif, M.P. 203-206"; yield: about 0.5 g. It is identical with the product obtained according to the proce dures of Examples 1 and 2.

The starting material used in the above reaction may be prepared as follows: 3.25 g. of 5-chloro-aniline-2,4- disulfonyl chloride is treated with 20 ml. of a percent aqueous solution of methylamine at room temperature for minutes and then on the steam bath for an additional 15 minutes. The reaction mixture is cooled, filtered, and the isolated 5-chloro-2,4-di-(N-methyl-sulfa myl)-aniline is twice recrystallized from a lzl-mixture of ethanol and Water, M.P. 186-190".

Example 4 To a solution of 5.9 g. of 6-chloro-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxide in a mixture of 30 ml. of water, 10 ml. of ethanol and 1.2 g. of sodium It is filtered oif and hydroxide is added 2.8 g. of methyl iodide and the reaction mixture heated in a sealed tube for one hour at After cooling the crystalline material is filtered off and recrystallized from a mixture of dimethylformamide and water. The 6 chloro-2-methyl-7-(N-methyl-sulfamyl) 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,1-dioxide crystallizes; it is identical with the product described in Examples 1, 2 and 3.

The filtrate of the reaction mixture is neutralized with 2 N aqueous hydrochloric acid; the resulting crystalline material is recrystallized from aqueous ethanol to yield 6-chloro-2-methyl-7-sulfamyl 3,4 dihydro 2H 1,2,4- benzothiadiazine-1,1-dioxide, M.P. 253-254", identical with the product described in Example 1.

Example 5 To a solution of 5-chloro-2-(N-methyl-sulfamyl)-4- sulfamyl-aniline in 50 ml. of diethyleneglycol dimethylother are added 0.14 g. of paraformaldehyde and 0.25 ml. of ethyl acetate saturated with hydrogen chloride. The reaction mixture is heated to 80-90 for one hour, concentrated to dryness, and water is added to the residue. The crystalline material is filtered off and recrystallized once from water and once from a lzl-mixture of water and ethanol. 0.7 g. of 6-chloro-2-methyl-7-sulfamyl-3,4- dihydro-2H-l,2,4-benzothiadiazine-1,l-dioxide is recovered, M.P. 248-251"; the compound is identical with the one obtained according to the procedures of Examples 1 and 4.

The starting material may be prepared as follows: To a solution of 17.7 g. of 5-chloro-aniline-2,4-disulfonyl chloride in 250 ml. of chloroform is added 3.1 g. of methylamine (as a 25 percent aqueous solution); the reaction mixture is stirred at room temperature for 1% hours and the solid material, consisting mainly of 5-chloro-2,4-di- (N-methyl-sulfamyl)-aniline, is filtered ofi and discarded. The filtrate is evaporated to dryness, hexane is added and the desired 5-chloro-2-(N-methyl-sulfamyl)-aniline-4-sulfonyl chloride precipitates and is filtered oil. It melts at 158-162 after being recrystallized from a mixture of ethyl acetate and hexane.

A total of 3.6 g. of 5-chloro-2-(N-methyl-sulfamyl)- aniline-4-sulfonyl chloride is added to 25 ml. of liquid ammonia; the mixture is allowed to stand until the ammonia is evaporated. The residue is taken into water, the crystalline material is filtered off and recrystallized from a lzl-mixture of water and ethanol to yield S-chloro-2-(N-methyl-sulfamyl)-4--sulfamyl-aniline, M.P.

In the preparation of the starting material the methylamine may be replaced by other amines, such as ethylamine, allylamine, benzylarnine and the like, and reacted With 6-chloro-aniline-2,4-disulfonyl chloride to form other 5 -chloro-2-(N-substituted sulfamyl) aniline-4-sulfonyl chlorides, such as 5chloro-2-(N-ethyl-sulfamyl)-aniline- 4-sulfonyl chloride, 2-(N-allyl-sulfamyl)-5-chloro-aniline- 4-sulfonyl chloride, 2-(N-benzyl-sulfamyl) -5-chloro-ani- 1,2,4-benzothiadiazine-1,l-dioxide -198 6-ch1oro-3 isobutyl-Z-methyl 7 sulfamyl-3,4- dihydro 2H 1,2,4 benzothiadiazine-1,ldioxide 6 chloro-3-chloromethyl-2-methyl-7-sulfamyl- 3,4 dihydro 2H 1,2,4 'bcnzothiadiazine- 1,1-di6xide 6 chloro 3 dichloromethyl-Z-methyl-7-sulfamyl-3,4-dihydro 2H 1,2,4-benzothiadiazine-Ll-dioxide 6 chloro-3-dichloromethyl 2-ethyl-7-sulfamyl- 3,4 dihydro 2H 1,2,4 benzothiadiazine- 1,1-dioxide Q. 2-allyl-6-chloro 7-sulfamyl 3,4 dihydro-Zl-l- 1,2,4-benzothiadiazine-1,1-dioxide 188-193 2 allyl-6-chloro-3-dichloromthylJ-sulfamyl- 3,4 dihydro 2H 1,2,4 benzothiadiazine- 1,1- dioxide 210-212 2-benzyl-6-chloro-7-sulfamyl-3,4-dihydro 2H- 'l,2,4-benzothiadiazine-1,1-dioxide 2-benz-yl 6 chloro 3 dichloromethylJ-sulfamyl 3,4 dihydro-2H-1,2,4-benzothiadia zine-1,1-dioxide 268-270 Example 6 9.4 -g. of 6-chloro-3-rnethyl-7-sulfarnyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dio1dde is dissolved in a mixture of 33 ml. of 1N aqueous sodium hydroxide and 120 ml. of Water; undissolved material is filtered err. After cooling to 10, 4.2 g. of dimethyl sulfate is added and kept at that temperature forone hour and for an additional hour at room temperature. The reaction mixture is filtered and the crystalline material is recrystallized twice from a 1:1-mixture of ethanol and water to yield "6-chloro- 2,3-dimethyl-7-sulfamyl-3,4-dihydro 2H 1,2,4-benzothiadiazine-1,1-dioxide, M.P. 274-276, yield: 0.9 g.

The solvents of the recrystallization mother liquor are evaporated, the residue solidifies and is recrystallized from methanol, followed by an additional recrystallization from aqueous. ethanol to yield 6-chloro-2,3-dimethyl-7-(N- methy'l-su'lfamyl)-3,4=dihydro 2H 1,2,4 benzothiadiazine-1,1-dioxide, M.P. 248-251"; yield: 0.2 g.

The starting material may be prepared as follows: A mixture of 2.9 g. of 5-chloro-2,4-disulfamyl-ani1ine, ml. of anhydrous diethyleneglycol dime thylet-her, 0.44 g. acetaldehyde and 0.5 ml. of a solution of hydrogen chloride in ethylacetate (109.5 g. hydrogen chloride per 1000 nil.) is heated to 80-90" and maintained at this temperature for 1 hour. The reaction mixtureis concentrated under reduced pressure; on addition of water, the crystalline product separates and is then recrystallized from 1 ethanol and aqueous ethanol to yield 1.2 g. of the desired 6-chloro-3-mcthyl-7-sulfamyl 3,4 dihydro 2H 1,2,4- benzothiadiazine-l,l dioxide, MEP. 25 8-260".

The same product is obtained by' replacing the 0.44 'g..

acetaldehyde by 019 g. 1,1-dime'thoxyethane or by 1.2 g. 1,1-diethoxyethane. I

Example 7 By reacting 3.14 g. of 5-chloro-2,4-di-(N-methylsulfamyl)-aniline with 0.9 g. of 1,1-dimethoxyethane in 25 ml. of diethyleneglycol dimethylether and a small amount of anhydrous hydrogen chloride at 80-90 for one.

Example 8 A mixture of 10.6 g. of 6-chloro-3-isobutyl-7-sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 dioxide in 66 ml. of 1 N aqueous sodium hydroxide and 120 ml. of water is cooled to 10; 3.85 g. of dimethyl sulfate is added The desired 6-chloro-3-isobutyl-2-methyl-7-sulfamyl-3,4-

dihydro-ZH-l,2,4-benzothiadiazine-l,l-dioxide is obtained by extraction from the solid material with a small amount of ethanol and evaporation of the solvent, MP. 241-244"; yield: 0.15 g.

The starting material used in the above reaction may be prepared as follows: To a solution of 2.9 g. of 5-chl0ro- 2,4-disulfamy -aniline in 15 ml. of diethyleneglycol dimethylether are added 0.9 g. of isovaleraldehyde and 0.5 ml. of a saturated solution of hydrogen chloride in ethyl acetate. The reaction mixture is heated for one hour to -90, then concentrated under reduced pressure. An oily material precipitates on the addition of water; the latter is decanted and ethanol is added. The 6-chloro-3- isobutyl-7-sulfamyl 3,4 dihydro 2H 1,2,4-benzotl1iadiazine-l,1-dioxide crystallizes and is filtered off and recrystallized from a mixture of dimethylformamide and water, MP. 241-245"; yield: 1.1 g.

Example 9 A solution of 10.6 g. of 3-n-butyl-6-chloro-7-sulfamyl- 3,4-dihydro 2H 1,2,4 benzothiadiazine-l,l-dioxide in 66 m1. of 1 N aqueous sodium hydroxide and 120 ml. of Water is cooled to below 20 and 4.2 g.'or dimethyl sulfate is added dropwise. The reaction mixture is stirred at that temperature for one hour, then at room temperature for an additional hour, and is extracted with three portions of ethyl acetate. The organic layer is dried over sodium sulfate, the solvent is evaporated to leave an amorphous mixture consisting of 3-n-butyl-6-chloro-2- methyl-7-sulfamyl-3,4-dihydro-2H 1,2,4 benzo thiadiazine-1,1-dioxide and 3-n-butyl-6-chloro-2-methyl-7-(N- methyl sulfamyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide contaminated with unreacted starting material; it melts at -95 (with decomposition and foaming).

The starting material may be prepared as follows: A mixture of 2.9 g. of 5-chloro-2,4-disulfarnyl-aniline, 15 ml. of diethyleneglycol dimethylether, 1.1 g. of n-valeraldehyde and 0.5 ml of a saturated solution of hydrogen chloride in anhydrous ethyl acetate is heated to 80-90" for two hours. The reaction mixture is concentrated under reduced pressure, Water is added to the residue and then decanted from the oily precipitate. Upon addition of ethanol and standing at room temperature some unre acted 5-chloro-2,4-disulfamyl-aniline separates; the filtrate is then evaporated to dryness. The residue is treated with benzene and then with aqueous ethanol to yield 1.3 g. of 3-n-butyl-6-chloro-7-sulfamyl 3,4 dihydro- 2H 1,2,4- benzothiadiazine-1,1-dioxide, which after recrystallization from aqueous ethanol melts at 176-179".

hydro 2H 1,2,4-benzothiadiazine-l,lrdioxide with dimethylsulfate according to the procedure of Example 1, a mixture of N-methylated derivatives is formed, which can be separated into the single compounds 6-chloro-3- isopropyl 2 methyl 7 sulfamyl-3,4-dihydro-2H-1,2,4-.

benzothiadiazine-l,l-dioxide and 6-chloro-3-isop1'oyl-2- methyl 7 (N-methyl-sulfamyl)-3,4-dihydro-2I-I-1,2,4- benzothiadiazine-1,1-dioxide by fractionated crystallization.

The starting material may be prepared as follows: The reaction of 2.9 g. of 5-chloro-2,4-disulfamyl-aniline in 15 ml. of diethyleneglycol dime'thyle-ther with 0.75 g. of isobutyraldehyde in the presence of 0.5 ml. of a saturated 23 solution of hydrogen chloride in ethyl acetate at 8090 yields the crystalline 6-chloro-3-isopropyl-7-sulfamyl-3,4- dihydro-ZH-1,2,4-benzothiadiazine-1,l-dioxide as a precipitate after about ten minutes. The latter is recrystallized from dimethylformamide by adding hot water to the solution, M.P. 304306; yield: 2.6 g.

Example 11 Upon reaction of 6-chloro-3-ethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide with dimethyl sulfate according to the procedure of Example 1, the mixture of 6-cl1loro-3-ethyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide and 6-chloro-3- ethyl 2 methyl-7-(N-methyl-sulfamyl)-3,4-dihydro-2H- 1,2,4-benzothiadiazine-l,l-dioxide can be obtained and separated into the single compounds by fractionated crystallization.

The starting material may be prepared by treating 5- chloro-2,4-disulfamyl-aniline with propionaldehyde or 1,1- dimethoxypropane according to the procedure given in Example 1.

Example 12 When 6 chloro-4-methyl-7-sulfamyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide is reacted with dimethyl sulfate according to the procedure of Example 1 a mixture of two products is obtained which is separated into the single compounds 6-chloro-2,4-dimethyl-7-sulfarnyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide and 6- chloro 2,4-dimethyl-7-(N-methyl-sulfamyl)-3,4-dihydro- 2H-1,2,4-benzothiadiazine-l,l-dioxide by fractionated recrystalliaztion.

The starting material in the above reaction may be prepared as follows: A mixture of 1.0 g. of S-chloro- 2,4-disulfamyl-N-methyl-aniline, 10 ml. of diethyleneglycol dimethylether, 0.09 g. of paraformaldehyde and 0.25 ml. of a saturated solution of hydrogen chloride in anhydrous ethyl acetate is heated to 80100 for one hour. fter cooling the reaction mixture is concentrated under reduced pressure, water is added to the residue and the resulting crystalline 6-chloro-4-methyl-7-sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized from aqueous ethanol, M.P. 225-227; yield: 0.5 g.

Example 13 To a solution of 1.0 g. of 5-chloro-2,4-di-(N-methylsulfamyl)-N-methyl-aniline in 15 ml. of diethyleneglycol dimethylether are added 0.24 ml. of ethyl acetate, saturated With hydro-gen chloride, and 0.09 g. of paraformaldehyde; the reaction mixture is heated to 60-70 for thirty minutes. The solvent is evaporated, ml. of water is added, and the crystalline material is filtered off and taken up in ethanol. The insoluble material is removed, the filtrate is concentrated, diluted with Water and the crystalline precipitate is filtered off. The 6-chloro- 2,4 dimethyl-7-(N-methyl-sulfamyl)-3,4-dihydro-2Hl,2, 4-benzothiadiazine-l,l-dioxide is recrystallized from ethyl acetate, M.P. 180183; yield: 0.8 g.

The starting material may be prepared as follows: 61 g. of 3-chloro-N-methyl-aniline is added to 325 ml. of chlorosulfonic acid and 310 g. of sodium chloride and the mixture is heated to 120140 for three hours. After cooling, the mixture is diluted with water, the solution is extracted with benzene and the benzene layer is evaporated to leave 46 g. of S-chloro-N-methyl-aniline-Z,4-disulfonyl chloride, which is used without further purification.

A solution of 23 g. of the S-chloro-N-methyl-analine- 2,4-disulfonyl chloride in 50 ml. of toluene is added dorpwise to 142 ml. of a 25 percent aquenous solution of methylamine while stirring. The reaction mixture is kept at room temperature for twenty-five minutes and is then heated on the steam bath for thirty minutes. On standing and cooling, the 5-chloro-2,4-di-(N-methyl-sulfamyl)-N-methyl-aniline crystallizes from the aqueous layer and is recrystallized from ethanol and water, M.P. 210212; yield: 2 g.

24 Example 14 A mixture of 1.0 g. of 5-chloro-2,4-di-(N-methylsulfamyl)-N-methyl-aniline, 25 ml. of diethyleneglycol dimethylether, 0.24 ml. of ethyl acetate, saturated With hydrogen chloride, and 0.33 ml. of 1,1-dimethoxyethane is heated to 80 for one hour. The reaction mixture is concentrated under reduced pressure, water is added, the crystalline product is filtered oil and recrystallized from a lzl-mixture of ethanol and water. The desired 6 chloro 2,3,4-trimethyl-7-(N-methyl-sulfamyl-3,4-dihydro-Zl-I-1,2,4-benzothiadiazine-1,l-dioxide melts at 196- 198"; yield: 0.5 g.

Example 15 The reaction of 6-chloro-3,4-dimethyl-7-sulfamyl-3,4- d'ihydrO-ZH-I,2,4-benzothiadiazine-l,1 dioxide with dimethyl sulfate according to the procedure of Example 1 or with methyl iodide according to the procedure of Example 4 furnishes a mixture of 6-chloro-7-sulfamyl-2,3,4- trimethyl-3,4-dihydro-2H-1,2,4=benzothiadiazine-1,1 dioxide and 6-chloro-2,3,4-trimethyl-7-(N methyl sulfamyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1 dioxide, the latter being identical with the product obtained according to the procedure of Example 14. The mixture may be separated into the single compounds by repeated recrystallization.

The starting material may be prepared according to the procedure given in Example 12 by substituting acetaldehyde or 1,1-dimethoxyethane for the paraformaldehyde.

Example 16 A solution of 6-trifiuoromethyl-7-sulfamyl-3,4-dihydro- 2H-l,2,4-benzothiadiazine-1,1-dioxide in aqueous sodium hydroxide is treated with dimethyl sulfate at about 10; the resulting crystalline mixture may be separated into the 6-trifluoromethyl-2-methyl7-sulfamy1 3,4 dihydro- 2H-1,2,4-benzothiadiazin-1,1-dioxide and the 6-trifiuor0- methyl-Z-methyl 7 (N-methyl-sulfamyl)-3,4-dihydro- 2H-1,2,4-benzothiadiazine 1,1 dioxide by fractionated crystallization.

The starting material may be prepared as follows: To a solution of 0.85 g. of S-trifluoromethyl-2,4-disulfamylaniline in 20 ml. of diethyleneglycol dimethylether are added 0.08 g. paraformaldehyde and 0.5 ml. of a sat urated solution of hydrogen chloride in ethyl acetate and the reaction mixture is heated to for two hours. The volume is brought to one-half by removal of the solvent, water is added, and the crystalline material is recrystallized from aqueous ethanol to yield the desired 6-trifluoromethyl 7 sulfamyl-3,4-dihydro-2Hl,2,4-benzothiadiazine-l,l-dioxide, M.P. 198-200.

Example 1 7 To a mixture of 13.8 g. of 6-chloro-3-chloromethyl-7- sulfamyl-3,4-dihydro-2H 1,2,4 benzothiadiazine-1,l-dioxide in 50 ml. of water containing 2.0 g. of sodium hydroxide is added ml. of Water. The mixture is stirred until complete solution is obtained; under cooling to 10- 20 is added 6 g. of dimethyl sulfate while stirring. The reaction mixture is agitated for one hour at room temperature, the crystalline material is filtered otf, Washed with water and recrystallized from a mixture of methanol and water to yield the 6-chloro-3-chloromethyl-2-methyl- 7-(N-methyl-sulfamyl) 3,4 dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxide, M.P. 228230. A second crop obtained from the filtrate isrecrystallized from an ethanol-water mixture to yield the 6-chloro-3-chloromethyl- 2-methyl-7-sulfamyl 3,4 dihydro-ZH-1,2,4-benzothiadiazine-1,1-dioxide, M.P. 208210.

The starting material may be prepared as follows: A mixture of 2.9 g. of S-chloro-2,4-disu1famyl-aniline, 1.53 g. of chloroacetaldehyde diethylacetal and 0.5 ml. of a saturated solution of hydrogen chloride in ethyl acetate in 15 ml. of diethyleneglycol dimethylether is heated to 80-90 for one hour and then concentrated under re- Examp'le 18 A mixture of 15.3 g. of 6-chloro-3-dichloromethyl-7- sulfamyl-3,4-dihydro 2H 1,2,4-benzothiadiazine-1,1- dioxide, a solution of 2 g. of sodium hydroxide in 40 ml. or" water and 160 ml. of water is stirred until complete solution is achieved. 6.2 g. of dimethyl sulfate is added w'hile cooling to -210" and stirring. Cooling is continued for one hour and stirring is maintained for an additional hour at room temperature. The precipitate is filtered ofi", washed with water and recrystallized from a mixture of 6 ml. of water, 5 ml. of acetone and m1. of methanol. The solid material is filtered off; the desired 6-chloro-3-dichloromethyl-2-methyl-7-sulfamyl 3,4-dillydro-2H-1,2,4-benzothiadiazine-1,l-dioxide precipitates as a second crop from the filtrate, M.P. 234-236.

The starting material used in the above reaction may be prepared as follows: A mixture of 5.6 g. of S-chloro- 2,4-disulfamyl-aniline, 2.2 g. or" dichloroacetaldehyde, 2 ml. of a saturated solution of hydrogen chloride in ethyl acetate and ml. of diethyleneglycol dimethylether is heated at 90 for 1 /2 hours. The reaction mixture is chilled, then added to 200 ml. of water. and the water is decanted. The residue is triturated with Water, the resulting viscous material is dissolved in a minimum amount of ethanol, and the solution is allowed to stand overnight.

The crystalline 6-cl1loro-3-dichloromethyl-7-sulfamyl-3,4 dihydro-ZH-1,2,4-benzothiadiazine-l,l dioxide is filtered off and recrystallized from a mixture of ethanol and water, M.P. 261262 (with decomposition).

Example 19 A mixture of 5-chloro-2,4-di-(N-methyl-sulfainyl)- arliline in 120 ml. of diethyleneglycol dimethylether, 0.12 ml. of ethyl acetate, saturated With'hydrogen chloride, and 0.4 g. of 3-phenyl-propionaldehyde is heated to 60- 70 for one hour. The sole'vnt is removed under reduced pressure, the residue is washed with water, triturated with hexane and recrystallized from ethylacetate. The desired 6-chloro-2-met hyl-7-(N-methyl sulfamyl)-3-(2-phen'ylethyl) -3,4-dihydro-2H-l,2,4 benzothiadiazine-l, l-dioxide melts at 165l68; yield: 0.4 g.

Example 20 Dimethyl sulfate is added to a solution of 6-chloro-3- ethoxymethyl 7 sul-famyl -S,4-dihydro-2H-l,2,4 b ehzothiadiazine-l,1-dioxide in 1 N aqueous sodium hydroxide, held at about 10; the residue obtained after evaporating the solvent represents a'rnixture of '6-chloro-3-ethoxymethyl 2 methyl-7-sulfamyl-3,4-dihydro 2H 1,2,4- benzothiadiazine-l,l-dioxide and 6-chloro-3-ethoxymethyl-2-methyl-7-(N-methyl') 3,4 dihydro-ZH-LZA-benzothiadiazine-1,1-dioxide, which may be separated into the single compounds by repeated recrystallization.

The'starting material may be prepared as follows: To a so'lution of 5.9 g. of 5-chloro-2,4-disulfamyl-aniline in 30 ml. of diethyleneglycol dimethylether are added 1 ml. of a 2 N solution of hydrogen chloride inethylacetate and 3.2 g. ofethoxyacetaldehyd'e diethyl acetal and the mixture is heated to 80-90" for one hour and then cooled.

Upon concentration under reduced pressure and addition of water an oily product is formed; the'wateris decanted and on addition of ether a crystalline material precipi tates, which is filtered (id. The 6-chloro-3 ethoxymethyl- 7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1- dioxide is recrystallized three times from a lzl-mixture of ethanol and water, M.P. 186-190.

Example 21 26 in 1 N aqueous sodium hydroxide, kept at 10, is treated with dimethyl sulfate according to the procedure of Example 1 and the resulting mixture of 6-chloro-3(2-ethylmercaptoethyl) 2 methyl-7-sulfamyl-3,4-dihydro-2H- 1,2,4 benzothiadiazine-l,l-dioxide and 6 chloro-3-(2- ethylmercaptoethyl) 2 methyl-7-(N-methyl-sulfamyl)- 3,4 dihydro-2H-1,2,4-benzothiadiazine 1,1 dioxide is separated into its components by repeated recrystallization.

The starting material may be prepared as follows: To a solution of 5.9 g. of 5-chloro-2,4-disulfamyl-aniline and 0.5 ml. of ethyl acetate, saturated with hydrogen chloride,

A solution of 6-chlor'o-3-('2-ethylmercaptoethyl)-7-sulf- ,amyl-3,4-dihydro-2H-1,2,4 benzothiadiazine 1,1 dioxide recrystallization and elimination of in 30 ml. of diethyleneglycol dimethyle-ther is added 2.3 g. of 3-ethy1mercaptopropionaldehyde. The mixture is heated to -90 for one hour, the solvent is removed under reduced pressure and the residue is triturated with Water. The water is decanted, hexane is added and the re sulting crystalline 6-chloro-3-(2-ethylmercaptoethyl)-7- sulfarhyl 3,4 dihydro-2H-l,2,4-benzothiadiazine-1,1- dioxide is recrystallized from a mixture of ethanol and Water, M.P. (with decomposition); yield: 3.1 g;

Example 22 To a solution of 3-(2 benzylmercaptoethyl)-6-chloro- 7-sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,1- dioxide in 1 N aqueous sodium hydroxide is'added dimethyl sulfate while cooling and a mixture of 3(2-benzylmercaptoethyl)-6-chloro-2-methyl 7 sulfa1nyl-3,4-dihydro-2H1,2,4-benzothiadiazine l,l-dioxide and 3 g (2- benzylmercaptoethyl) 6 -chloro-2-methy l-7-(N-methyh sulfamyl) 3,4 dihydro-2H-1,2,4-benzothiadiazine-1,1 dioxide can be obtained according to the procedure of Example 1. Upon repeated recrystallization such mixture can be separated into the two components.

The starting material may be prepared as follows: A mixture of 5.9 g. of 5-chloro-2,4-disulfamyl-aniline, 0.5 ml. of ethyl acetate, saturated with hydrogen chloride, and 3.6 g. of 3-benzylmercaptopropionaldehyde' in 30 ml.

or" diethyleneglycol dimethylether is heated to 8090 for 7 three hours. The solution is evaporated to dryness; under reduced pressure, the residue is t-r'iturated' with water, the

water is decanted and hexane is added. The crystalline 3-(2-benzylmercaptoet-hyl) 6 chloro-7-sulfarnyl 3,4- dihydro-ZH-l,2,4=benzothiadiazine-1,1-dioxide is collected and recrystallized from methanol, M.P. 20'72l'0 yield:

Example 23 -chloro 2 methyl-7-(N-methyl sulfamyl)-3-(l-propenyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 -dioxide may be separated into the components by recrystallization and enrichment of one of the compounds.

The starting material may be prepared by treating 5- chloro-2,4-disulfamyl-aniline with crotonalde'hyde according 'to the procedure of Example Example 24] A solution of 6-chloro-3-cyclopentyl-7-sulfamyl-3,4 dihydro 2H 1,2,4-benzothiadiazin -1,1-dioxide in dilute aqueou sodium hydroxide, when reacted with dimethyl sulfate according to the procedure of Example 1, yields a mlxture of 6-chloro-3-cyclopentyl-2-methyl-7-sulfamyl- 3,4-dihydro 2H-1,2,4-benzothiadiazine-l,l-dioxide and 1 o-chloro 3-cyclopentyl-2-me'thyl-7-(N-mthyl-sulfamyD- 3,4-dihydr'o-2H-1,2,4-benzothiadiazine-1,1=dioxide, which may be separated into the single compounds by repeated he component.

The starting material may be prepared by reacting S-chloro-2,4-disuIfamyl-aniline with cyclopentyl aldehyde diethyl acetal according to the procedure given in Example 1.

Example 25 A cold mixture of 3-benzyl-6-trifluoromethyl-7-sulfamyl-3,4-dihydro 2H-1,2,4-benzothiadiazine-1,l-dioxide in 1 N aqueous sodium hydroxide and dimethyl sulfate, when reacted and worked up as shown in Example 1, yields a mixture of 3-benzyl-6-trifluoromethyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide and 3 benzyl-6-trifiuoromethyl-2-rnethyl-7-(N-methyl-sulfamyl) 3,4 dihydro-ZH-1,2,4-benzothiadiazine-1,l-dioxide, which may be separated into the two components by re crystallization.

The starting material may be prepared as follows: A mixture of 0.01 mol of 5-trifluoromethyl-2,4-disulfamylaniline, 20 ml. of diethyleneglycol dimethylether, 0.01 mol of phenylacetaldehyde dimethyl acetal and 2 ml. of ethyl acetate (saturated with hydrogen chloride) is heated on the steam bath for three hours. The volume of the reaction mixture is brought to about one-half by evaporation under reduced pressure; upon chilling and adding 100 ml. of water while stirring, a precipitate is formed which is filtered off, washed with water and taken up in ethanol. The ethanol is evaporated, the residue is triturated with 15 ml. of ethanol and the solid material is filtered off. The 3 benzyl 6 trifiuoromethyl-7-sulfamyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide is recrystallized from methanol, M.P. 228-230.

Example 26 To a solution of 12.2 g. of 6-chloro-7-sulfamyl-3,4- dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide in a mixture of 55 ml. of 1 N aqeous sodium hydroxide and 200 ml. of water is added 6.9 ml. of diethyl sulfate. The reaction mixture is stirred at 10-20 for about 5 /2 hours and then allowed to stand at room temperature overnight. A viscous material is separated from the solution, dissolved in a small amount of ethanol; unreacted starting material is filtered oil. After standing at room temperature for some time, the crystalline 6-chloro-2-ethyl-7-sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioidde is filtered oil? and recrystallized from aqueous ethanol, M.P. 195198; yield: 1.2 g.

, Example 27 24 g. of 6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4benzothiadiazine-1,1-dioxide is dissolved in a solution of 4.0 g. of sodium hydroxide in 80 ml. of ethanol and 80 ml. of water while warming. After cooling to room temperature, 12.5 g. of ethyl iodide is added rapidly while stirring. The reaction mixture is kept at 50 for eleven hours and at 25 for another 10 hours, and is then neutralized with 2 N aqeuous hydrochloric acid. The organic solvent is removed under reduced pressure, the aqueous phase is decanted from the resulting precipitate, which is then dissolved in a small volume of methanol and allowed to crystallize. The resulting 6-chloro-2-ethyl-7-sulfamyl-3,4- dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide melts at 191-193 after several recrystallizations from methanol and a methanol-water mixture; yield: 2.0 g. The compound is identical with the one obtained according to the procedure of Example 26.

Example 28 To a solution of 7.6 g. of 6-chloro-3-dichloromethyl-7- sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide in 100 ml. of diethyleneglycol dimethylether is added 0.48 g. of sodium hydride. The reaction mixture is heated to 90 for six hours, 3.1 g. of ethyl iodide is added and heating is continued for six hours. After filtration, the solvent is removed from the filtrate under reduced pressure, the residue is taken up in ethanol and water is added while stirring. The resulting 6-chloro-3-dichlorornethyl 2 ethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide is filtered off and melts at 176.

Example 29 To a solution of 3.42 g. of 5-chl0ro-2,3-di-(N-ethylsulfamyl)-aniline in ml. of diethyleneglycol dimethylether are added 0.3 g. of paraformaldehyde and 0.5 ml. of a saturated solution of hydrogen chloride in ethyl acetate. The mixture is heated to 80-90 for one hour, the solvent is removed and water is added to the syrupy residue. The water is decanted, the residue is dissolved in a small volume of warm ethanol and crystallizes upon cooling to yield the 6-chloro-2-ethyl-7-(N-ethyl-sulfamyl)-3,4- dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide; it melts at 163166 after recrystallization from aqueous ethanol, yield: 2.55 g.

The starting material can be prepared according to the procedure given in Example 3, by substituting ethylamine for methylamine.

Example 30 By reacting 4.0 g. of 5-chloro-2,4-di-(N-n-butylsulfamyl)-aniline in 20 ml. diethyleneglycol dimethylether with 0.3 g. of paratormaldehyde in the presence of 0.5 ml. of a saturated solution of hydrogen chloride in ethyl acetate according to the procedure described in Example 29 the 2 n butyl-7-(N-n-butylsulfarnyl)-6-ch1oro-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l-dioxide is obtained, M.P. l70l7l; yield: 2.4 g.

The starting material can be prepared by substituting n-butylamine for methylamine in the procedure described in Example 3.

Example 31 To a solution of 24.0 g. of 6-chloro-7-sulfamyl-3,4- dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide in 120 ml. of water, ml. of ethanol and 4 g. of sodium hydroxide is added 9.7 g. of allyl bromide in 10 ml. of ethanol. The allyl bromide is given very rapidly to the solution, held at 30 to 35, and the reaction mixture is stirred for three hours. Stirring is continued at room temperature for an additional twelve hours. The crystalline precipitate is filtered off, washed with ml. of methanol and recrystallized once from methanol and once from a mixture of methanol and water to yield the desired 2-allyl-6-chloro- 7 sulfamyl 3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1- dioxide, M.P. 188-193".

The allyl bromide in the above reaction may be replaced by Z-methyl-allyl bromide, 3-rnethyl-allyl bromide,

2-pentene bromide and the like and reacted with the 6- chloro 7 sultamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide according to the previously given procedure to form 6-chloro-2-(2-methyl-allyl)-7-sulfamyl- 3,4 dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide, 6- chloro 2 (methyl-allyl)-7-sulfamyl-3,4-dihydro-2H- 1,2,4-benzothi adiazine-1,1-dioxide, 6-ch1oro-2-(2-pentenyl -7-su.lfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-l,1- dioxide and the like.

Instead of 6-clrloro-7-sulfamyl-3,4-dihydro-2H-l,2,4- benzothiadiazine-l,l-dioxide, other 3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxides, such as 6-chloro-3-methyl- 7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, 6 chloro-3-isobutyl-7-sulfamyl-3,4-dihydro-2H- 1,2,4 benzothiadiazine-l,l-dioxide, 3-benzyl-6-chloro-7- sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide, 6-chloro-3-(Z-phenylethyl)-7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l-dioxide, 3-(benzylmercaptomethyl) 6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide and the like, may be reacted with an allyl halide, e.g. allyl bromide and the like, according to the above-given procedure to form 2-allyl-6-chloro-3- methyl 7 sulfamyl 3,4-dihydro-2H-l,2,4-benzothiadiazine 1,1-dioxide, 2-allyl-6-chloro-3-isobutyl-7-sulfamyl- 3,4 dihydro-2H-l,2,4-benzothiadiazine-1,l-dioxide, 2-allyl 3 benzyl-6-chloro-7-sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l l-dioxide, 2-allyl-3- (2-phenylethy] -7- sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide, 2 allyl-3-benzylmercaptomethyl-6-chloro-7-sul- 29 famyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide, and the like. p

Example 32 A mixture of 7.6 g. of 6 chloro-3-d.ichloromethyl-7-sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide in 80 ml. of water and a solution of 1.1 g. of sodium hydroxide in 20 ml. of Water is stirred until complete solution is obtained. 2.8 g. of allyl bromide is added; stirring is continued for six hours at room temperature, and the reaction mixture is allowed to stand overnight. The de sired 2 allyl-6-chloro-3-dichloromethyl-7-sulfamyl-3,4- dihydro-ZH- l ,2,4-benzothi-adiazine-1, l-dioxide is recrystallized from ethanol, M.P. 210-212".

Example 33 A mixture of 6-triiluoromethyl-7-sulfamyl-3,4-dihydro- 2H-1,2,4-benzothiadiazine-1,l dioxide and sodium hydroxide in water, when reacted with ally-l bromide as shown in Example 32, yields the desired 24allyl-6-trifluoromethyl 7-sulfamyl-3,4-dil1ydro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

The starting material may be prepared by replacing in the procedure for the preparation of 6'-chloro-7-sulfamyl- 3,4 dihydro-ZH-1,2,4-benzotl1iadiazine-1,1-dioxide (see Example 1), the -chloro-2,4-disulfamyl-aniline by S-trifluoromethyl-2,4-disulfamyl-aniline.

Example 34 A mixture of 3.7 g. of 2,4-di'-(N-allylsulfamyl)-5- Chloro aniline, ml. of diethyleneglycol dimethylether,

0.3 g. of paraformaldehyde and 0.5 ml. of ethyl acetate, saturated with hydrogen chloride'is heated to 80-90 for one hour. The reaction mixture is concentrated under reduced pressure, ethanol is added and the 2aallyl-7- (N allyl sulfamyl) 6-chloro -3,4-dihydro=2H 1,2,4-benzothiadiazine-1,1-dioxide crystallizes. It melts at 195-197 after recrystallization from ethanol; yield: 2.3 g.

The starting material may be prepared according to the following procedure: 9.7 g. of 5-chloro-aniline-2,4-disulfonyl chloride is added slowly to a solution of 20.6 g. of allylarnine in 100 ml. of water. The reaction mixture is heated on the steam bath for twenty minutes and then cooled; the precipitate is filtered off and recr stallized from a 1:1-mixture of ethanol and water to yield 8.7 g. of the 2,4-di-(N-allyl-sulfamyl)-5-chloro-a.uiline, M.P. 139-142.

Example 35 I To a solution of '6-chloro-7-sulfamyl-3,4 dihydro-2H- 1,2,4-benzothiadiazine-l,l-dioxide in a mixture of 60 m1.

of water, 20 ml. of ethanol and 2 g. of sodium hydroxide is added 7.3 'g. of benzyl bromide in 5 ml. of ethanol. The reagent is added dropwise over a period of ten minutes while vigorously stirring; the temperature is maintained at for an additional 1 /2 hours. After cooling, the resulting 2 benzyl-6-chloro-7-sulfiamyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine 1, I-dioxide precipitates, is filtered (iii and recrystallized twice from ethanol, M.P. 238-244.

By replacing in the above reaction the benzyl bromide by l-phenylethyl bromide, 2-phenylethy1 bromide, 4- chlorobenzyl bromide, 3,4-di-methoxy-benzy'l bromide and the like, and reacting the latter with 6-chloro-7-sulfamyl- 3,4 dihy'drO-ZH-1,2,4 benzothiadiazine-1,l-dioxide, the 6 ch1oro-2-(l-phenylethyl)-7-sulfaniyl-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide, 6-chloro-2-(2-phenylethyl) 7 sulfamyl-3 ,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, 6 chloro-2-(4-chlorobenzyl)-7-sulfamyl 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide, 6- chloro 2-(3,4-dimethoxybenzyl)-7 sulfamyl-3,4-dihydro- 2H-1,2,4-benzothi adiazine-1,1-dioxide, and the like, may

be formed. 7

The 6 Lhloro 7 sulfamyl-3,4=dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxide may be replaced by 6'-chloro- 3 methyl ,7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide, 6 chloro 3 isobutyl-7-sulfamso yl 3,4 dihyd'ro 2H 1,2,4- benzothiadiazine-Lldioxide, 3 benzyl 6 chloro 7 'sulfamyl 3,4 dihydro 2H 1,2,4 benzothiadiazine 1,1 dioxide and the like and upon treament with benzyl bromide the 2 benzyl 6 chloro 3 methyl 7 sulfamyl 3,4 dihydro 2H 1,2,4 benzothiadiazine 1,1 dioxide, 2 benzyl 6 chloro 3 isobutyl 7-sulfamyl-3,4-dihydro 2H 1,2,4 benzothiadiazine 1,1 dioxide, 2,3- di-benzyl 6 chloro 7 sulfamyl 3,4 dihydro 2H- 1,2,4 benzothiad-iazine 1,1 dioxide and the like may be prepared.

Example 36 V 7 To a mixture of 7.6 g. of 6-chloro-3-dichloromethyl- 7 sulfamyl 3,4 dihydro 2H -1,2,4-benz0thiadiazine- 1,1-'dioxide in ml. of water is added a solution of 1.1 g. of sodium hydroxide in water; the reaction mixture is stirred until a clear solution is obtained. A total of 3.6

g. of benzyl bromide is added dropwise at room temperature while stirring. The reaction mixture is stirred for an additional four hours at room temeprature; a precipitate is formed, which is filtered off. The resulting 2 benzyl 6; chloro 3 dichloromethyl-7-sulfamyl- 3,4 dihydro 2H 1,2,4 benzothiadiazine 1,1 dioxide of paraformaldehyde and 0.5 ml. of hydrogen chloridesaturated ethyl acetate is heated to 80-90 for one hour and then evaporated under reduced pressure. The residue is recrystallized from ethanol to yield 4.0 g. of 2-benzyl- 7 (N-benzyl-sulfamyl) 6 chloro-3,4-dihydro-2H- 1,2,4 benzothiadiazine 1,1 dioxide, M.P. 236-238".

The starting material may be prepared as follows: 9.7 g. of 5 cbloro aniline 2,4 disulfonyl chloride is added slowly while stirring and cooling to a solution of 16.0 g. of benzylamine in 30 ml. of chloroform. After thirty minutes, the reaction mixture is heated on the steam bath for fifteen minutes; the solution is cooled, the precipitate is filtered off and the filtrate is evaporated. Ethanol is added and the 2,4 di (N benzyl sulfamyl).-5- chloro aniline crystallizes and is recrystallized from ethanol, M.P. 149-152"; yield: 7.7 g.

A further useful process for the preparation of certain compounds of this invention having the formula:

lower alkyl containing from one to three carbon atoms,

e.g. methyl, ethyl, n-pr'opyl or iso'propyl, for vinylic lower alkenyl, containing from three to four carbon atoms, e.g. vinyl, l-rrrethyl-vinyl, 2-methyl-viny1 and the like, or for phenyl, benzyl and the like, or salts thereof, comprises converting in compounds of the formula:

in which R R R and R have the previously given meaning, the group R CO into the group R CH having the previously given meaning, by reduction, and, if desired, carrying out the optional steps.

The reduction may be performed by using reducing reagents capable of converting an acyl radical attached to a nitrogen atom into a hydrocarbon group. Preferred reagents are aluminum hydrides, particularly lithium aluminum hydride. Ethers, such as diethylether, or more especially polyalkylene glycol ethers, e.g. diethyleneglycol dimethylether and the like, or cyclic ethers, e. g. tetrahydrofuran and the like, or formamide, e.g. N,N-dimethylformamide and the like, may serve as diluents; the reaction may be completed at an elevated temperature.

The starting material used in the above procedure may be prepared, for example, by reacting a compound of the formula:

in which R R and R have the previously given meaning with a reactive derivative of an aliphatic hydrocarbon carboxylic acid, a substituted aliphatic hydrocarbon carboxylic acid or a carbocyclic aryl-aliphatic hydrocarbon carboxylic acid, and isolating the desired compound of the formula:

in which R R R and R have the previously given meaning. The reaction may be carried out, for example, by treatment with an acid halide, e.g. chloride and the like, of an aliphatic hydrocarbon carboxylic acid, a substituted aliphatic hydrocarbon carboxylic acid or a carbocyclic aryl-aliphatic hydrocarbon carboxylic acid, in the presence of a diluent, for example, acetone and the like. Corresponding anhydrides and ketenesmay be used as well, together with solvents inert towards such reagents. The desired compounds may be obtained by crystallization, recrystallization, adsorption and elution and the like.

The above procedure may also serve for the preparation of compounds of the formula:

in which R R R and R have the previously given meaning and R represents aliphatic hydrocarbon or substituted aliphatic hydrocarbon having an a-methylene group less than the corresponding homo-radical R carbocyclic aryl or carbocyclic aryl-lower aliphatic hydrocarbon having an u-methylene group less than the corresponding homo-radical R particularly lower alkyl conin which R R R R and R have the previously given meaning, the group of the formula R CO into the desired group R -CH by reduction and, if desired, carrying out the optional steps.

The reaction may be carried out as previously shown; the starting material is prepared by acylation of compounds of the formula:

in which R R R and R have the previously given meaning, with a reactive derivative of an aliphatic hydrocarbon carboxylic acid, a substituted aliphatic carboxylic acid or a carbocyclic aryl aliphatic hydrocarbon carboxylic acid, such as a halide, e.g. chloride, as previously shown and isolating the desired compound.

Compounds of the formula:

in which R R and R have the previously given meaning, and R and R are identical and have the previously given meaning, may be obtained by converting in compounds of the formula:

02 s 122 -0 o-nums- (PR2,

R3 H-Rl in which R R R and R have the previously given meaning, the groups R CO into the groups R CH by reduction, and, if desired, carrying out the optional steps.

the starting materials may be prepared according to methods previously described, for example, by reacting compounds of the formula:

in which R R and R have the previously given meaning, with a reactive derivative, e.g. chloride and the like,

of an appropriate carboxylic acid and isolating the desired compound,

The reaction may be carried out as shown hereinabove;

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 163,644 December 29, 1964 George de Stevens et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent "should read as corrected below.

Column 5, line 19, strike out "an"; column 6, line- 48,

for "those" read these line 64, for "-benzothiodiazine-"-. read -benzothiadiazine column 7, line 9, for "ous-tan'din'gff read outstanding line 29, for "atoms,

read atoms, same column 7, lines 60 to 66, the formula should appear as shown below instead of as in the patent:

H NO S Y -(lower alkyl R3 l-l t-phenyl lower alkyl) column 8, line 21, for "7methyl-sulfamy1-" read -7 sulfamylline 35, for "-2n" read -2-n column 10,

lines 69 to 75, the formula should appear as shown below instead of as in the patent:

column 11, line 1, strike out "11' line 2, for "ing" read meaning line 17, after "amides" insert a comma; line. 52, for "roomide" read bromide column 16, line 23, for "cycloakyl" read cycloalkyl column '18, line 75, for "degress centigrade read degrees Centigrade column 19, line 12, for "6chloro-2" read 6'chloro2- line 80, for "recrytsallized" read recrystallized same column 19, line 57, for "l,ldioxide" read -l,ldioxide column 23, lines 30 and 31, for "recrystalliaztion" read recrystallization line 68, for "dorpwise" read dropwise same line 68, for "aquenous" read. aqueous column 24, line 10, for -"-sulfamyl-3,4-" read -Sulfamyl) -3,4-

column 25, line 42, for "solevnt" read --solvent column 27, line 31, for "aqeous" read aq'ue'ous-'; line 51, for "aqeuous'fread aqueous column-30, line 21, for "temeprature" read temperature same column 30, lines 56 to 63, the formula should appear as shown below instead of as in the patent:

column 32, line 56, for "11' read "-11% lines 64' .to 71 the formula should appear as shown below instead cl as in the patent:

column 34, line 27, after "phenyl-lower alkylflf insert R" is a member selected from the group consisting of hydrogen and lower alkyl Signed and sealed this 6th day of April 1965.

(SEAL) Attest:

ERNEST w. SWIDER EDWARD J.-.-'5'BRENNER Attesting Officer Commissioner of Patents

Claims

1. A MEMBER OF THE GROUP CONSISTING OF 3,4-DIHYDRO2H-1,2,4-BENSOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA: