US3133918A - Derivatives of - Google Patents

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US3133918A
US3133918A US3133918DA US3133918A US 3133918 A US3133918 A US 3133918A US 3133918D A US3133918D A US 3133918DA US 3133918 A US3133918 A US 3133918A
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lower alkyl
dihydro
benzothiadiazine
sulfamyl
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention concerns 2-substituted-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides. More particularly, it relates to compounds of the formula (S32 HzNOgS CHE-R1 R3 N/ 1 RBI] in which R represents hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon, carbocyclic aryl, carbocyclic aryl-lower aliphatic hydrocarbon, heterocyclic aryl or heterocyclic aryl-lower aliphatic hydrocarbon, R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members and advantageously have from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members, R represents hydrogen or lower alkyl, and R stands for halogen, lower alkyl or halogenolower alkyl or salts thereof, as well as process for the
  • 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.
  • 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
  • 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.
  • carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon primarily monocyclic carbocyclic aliphatic 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 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 cycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as ring members, e.g.
  • cyclopentylmethyl l-cyclopentylethyl, 2 cyclopentylethyl, 1 cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, 1 cyclohexylethyl, 2 cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, when con- 3,133,918 Patented May 19, 1964 ice tain from five to six ring carbon atoms, e.g.
  • These aliphatic hydrocarbon radicals may contain functional groups as additional substituents.
  • substituents are primarily attached to lower alkyl radicals, which may be represented by a lower alkylene radical containing from one to live carbon atoms, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, l,1-dimethyl-1,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3- propylene, 2,2propylene, 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, trifluorornethyl, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.
  • halogen atom e.g. fluorine, bromine, or particularly chlorine
  • halogeno-substituted lower alkyl radicals, representing R are, for example, trifluorornethyl, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like.
  • substituents are amino groups, such as primary amino groups, secondary amino groups, such as N-lower alkyl-amino, e.g. N-methylamino, 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.
  • l-piperazino 4-methyl 1 piperazino, 4 hydroxyethyl-lpiperazino, 4-acetoxyethyl-l-piperazino and the like.
  • the teritary amino group and the lower alkyl radical to which the amino group is attached may present 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-ethylene, with the 3-position of the 1,2,4-thiadiazine 1,1- dioxide portion.
  • Such radicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl 3 piperidinomethyl, 2-(l-methyl-2- piperidino)-ethyl, 1-methyl-4-piperidino and the like.
  • 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-carbonic 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, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
  • 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 carboxylic acids, e.g.
  • phenylacetic, diphenylacetic, dihydrocinnamic acid and the like which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower 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.
  • 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
  • halogeno-lower alkyl e.g. trifiuoromethyl.
  • 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-carbonic acid, benzyloxy-carbonic acid and the like, lower alkenoic acids, e.g. acrylic, methacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
  • 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 aryllower alkenyl carboxylic 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.
  • halogen e.g. fluorine, chlorine, bromine and the like, or halogenolower alkyl, e.g. trifiuoromethyl.
  • substituents attached to aliphatic hydrocarbon 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, methylaerylic acid and the like, lower aliphatic dicarboxylic acids, e.g.
  • 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 aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnarnic 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 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.
  • di-lower alkyl-amino e.g. N,N-dimethylamino, N,N-diethylamino and the like
  • halogen e.g. fluorine, chlorine, bromine and the like
  • halogeno-lower alkyl e.g. trifluoromethyl.
  • aliphatic hydrocarbon radicals particularly lower alkyl radicals
  • etherified hydroxyl groups which may be represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethox n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyioxy and the like, carbocyclic aryloxy, such as monocyclic carbocylic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g.
  • carbocyclic aryl-aliphatic 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.
  • 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
  • halogeno-lower alkyl e.g. trlfluoromethyl.
  • aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, e.g. methyl-mercapto, 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 substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g.
  • 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-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.
  • 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-diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl.
  • R may represent carbocyclic aryl groups, such as monocycle carbocyclic aryl, e.g. phenyl or substituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naplithyl or Z-naphthyl or substituted naphthyl radicals, or carbocyclic arylaliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g.
  • 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
  • halogeno-lower alkyl e.g. trifluoromethyl.
  • Substituents attached to carbocyclic aryl, particularly monocyclic carbocyclic aryl portions may be in any of the available positions, whereby one or more than one of the same or of diiferent 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. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, thienyl, e.g. 2-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.
  • 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.
  • 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.
  • the radical R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members. These groups have advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members.
  • the carbon atoms of the lower cycloalkyl nucleus may be unsubstituted or substituted by lower hydrocarbon, particularly lower alkyl, e.g. ethyl, n-propyl, isopropyl, or especially methyl and the like; other substituents may be, for example, lower cycloalkyl, e.g. cyclopentyl or cyclohexyl and the like, monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl, monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g.
  • Two of the carbon atoms of the lower cycloalkyl nucleus may also be part of a second carbocyclic ring system fused onto the lower cycloalkyl nucleus; such carbocyclic ring systems may be represented, for example, by lower cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl.
  • the cycloalkyl radical, R may, therefore, be represented primarily by cyclo-oxa-alkyl containing from four to six carbon atoms, such at tetrahydrofuranyl (cyclooxapentyl) radicals, such as Z-tetrahydrofuranyl (2-cyclooxapent-yl) radicals, e.g.
  • tetrahydropyranyl (cyclo-oxahexyl) radicals, such as Z-tetrahydropyranyl (Z-cyclo-oxahexyl) radicals, e.g.
  • dioxanyl cyclo-dioxahexyl radicals
  • 2-( 1,4-dioxanyl) (2-cyclo-dioxahexyl) radicals e.g. 2- (l,4-dioxanyl) (2-cyclo-l,4-dioxahexyl) and the like
  • tetrahydro-oxathiinyl cyclo-oxathiahexyl radicals, such as 2 tetrahydro oxathiinyl (2-cyclo-1,4-oxathiahexyl) radicals, e.g.
  • Z-tetrahydro-oxathiinyl (2-cyclo-l,4-oxathiahexyl) and the like
  • tetrahydrothienyl (cyclo-thiapentyl) radicals such as Z-tetrahydrothienyl (Z-cyclothiapentyl) radicals, e.g. Z-tetrahydrothienyl and the like
  • tetrahydro-thiapyranyl (cyclo-thiahexyl) radicals such as 2tetrahydro-thiapyranyl (2 cyclo thiahexyl) radicals, e.g. Z-tetrahydro-thiapyranyl (Z-cyclo-thiahexyl) and the like
  • tetrahydro-dithiinyl (cyclo-dithiahexyl) radicals such as Z-tetrahydro-dithiinyl (2-cyclo-1,4-dithiahexyl) radicals, e.g. Z-tetrahydro-dithiinyl (2-cyclo-l,4-dithiahexyl) and the like.
  • 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-2H-1,2,4-benzothiadiazine-1,1-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, particularly trifluoromethyl and the like.
  • 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 natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, caused by kidney or heart ailments. Coupled with the diuretic and saliuretic activities of the present compounds is a strong antihypertensive effect, 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.
  • R represents cyclo-oxa-alkyl (particularly, 2-cyclo-oxa-alkyl) containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members, R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g. trifluoromethyl, and sodium or potassium salts thereof.
  • halogen e.g. fluorine, bromine, or particularly chlorine
  • 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 s 2 mNo s R G H- (halogeno-lower alkyl) ⁇ N (/11- (phenyl-lower alkyl) in which compounds R stands for chlorine or trifluoromethyl, and lower alkyl contains from one to four carbon atoms, and R is defined as above.
  • Particularly active compounds are, for example,
  • each of which is substituted in the 3-position by a lower cyclo-alkyl group containing oxygen and/ or sulfur atoms as ring members and advantageously having from four to six carbon atoms and at most two hetero (S or O) ring members.
  • the new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 2-substituted-3,4-dihydro-2H-l,2, 4-benzothiadiazine-l,l-dioxide compounds or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration.
  • the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments.
  • 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 as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.
  • antihypertensive compounds such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum 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.
  • antihypertensive compounds such as Rauwolfia alkaloids, e.g. reserpine, rescinnamine or deserpidine, semisynthetic Rauwolfia alkaloids, e.g. syrosingopine and the like, Veratrum alkaloids, e.g. germine, protoveratrine and the like, synthetic antihypertensive compounds, e
  • the compounds of the present invention may be prepared according to methods which are known in themselves.
  • compounds of the formula z// in which R 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,l-dioxide of the in which R R and R have the previously-given meaning, or an alkali metal salt thereof, with a cycloalkene containing oxygen and/ or sulfur atoms as ring members, which is capable of introducing the radical R in the presence of a condensing agent, 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.
  • the above-mentioned lower cycloalkene reagents are more particularly Z-cycloalkenes containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members.
  • Such compounds are, for example, 2-cyclo-oxaalkenes containing from four to six carbon atoms as ring members, such as dihydrofurans (Z-cyclo-oxapentenes), e.g.
  • dihydrofuran Z-cyclo-oxapentene
  • 4-methyl-dihydrofuran (4-methyl-2-cyclo-oxapentene)
  • S-methyl-dihydrofuran (5-methyl-2cyclo-oxapentene) and the like
  • dihydropyrans (2-cyclo-oxahexenes), e.g.
  • dihydrodioxines (2-cyclo-dioxahexenes), such as dihydro-1,4- dioxines (2-cyclo-l,4-dioxahexenes), e.g. dihydro-1,4-dioxine (Z-cyclo-1,4-dioxahexene) and the like
  • dihydrooxathiins (2-cyclo-oxathiahexenes), such as dihydro-l,4- oxathiins (2-cyclo-1,4-oxathiahexenes), e.g.
  • dihydro-1,4- dioxathiin Z-cyclo-l,4-oxathiahexene
  • dihydrothiophenes Z-cyClo-thiapentene
  • dihydrothiophene (2-cyclo-thiapentene) and the like
  • dihydrothiapyrans (2-cyclo-thiahexenes), e.g.
  • reagents particularly the 2-cyclo-oxa-alkenes containing from four to six carbon atoms as ring members, such as dihydropyrans, e.g. dihydropyran, are reacted with the deserpidate compound in the presence of a condensing reagent, particularly an acidic condensing reagent represented by a Lewis acid.
  • a condensing reagent particularly an acidic condensing reagent represented by a Lewis acid.
  • Lewis acids are, for example, mineral acids, e.g.
  • hydrochloric, hydrobromic or sulfuric acid used in anhydrous form or as concentrated aqueous solutions
  • phosphoric acid for example, in the form of polyphosphoric acid
  • phosphorous oxychloride for example, in the form of polyphosphoric acid
  • fluoboric acid in the form of a highly concentrated aqueous solution
  • borontrifluoride in the form of its etherate, particularly with diethyl ether
  • carbocyclic aryl sulfonic acid such as a monocyclic carbocylic acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins.
  • the reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cycloalkene may serve as the solvent, or in the presence of an inert solvent.
  • solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene or toluene and the like, others, e.g. diethylether or tetrahydrofuran and the like, lower alkanoncs, e.g. acetone or ethyl methyl ketone and the like, formamides, e.g. formamide or N,N-dimethylformamide and the like.
  • 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.
  • the 3,4-dihydro-2H-1,4-benzothiadiazine-1,l-dioxides used as the starting materials are known or may be prepared according to procedures used for the known analogs.
  • 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-given meaning, or a reactive derivative thereof, to form the desired 3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide, which may then be condensed with the desired cyclo-oxa-alkene or cyclo-azaalkene to yield the R-R '-substituted product, R having the previously-given meaning.
  • the disulfamyhaniline 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, hydrobrornic 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.
  • aldehyde 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.
  • a base such as an alkali metal hydroxide, e.g lithium, sodium or potassium hydroxide
  • the aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ.
  • an acetal of an aldehyde R CHO with lower alkanols may be used in the presence of a mineral acid; such acetals are, for example, 1,1-dimethoxyethane, 1,l-dimethoxy-isobutane, 1,1-diethoxy-isobutane, 2,2-dichloro-1,l-dimethoxyethane, 2,2-dichlorol,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 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 alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide and the like, or an aqueous mixture of such solvents or water.
  • a solvent for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide and the like, or an aqueous mixture of such solvents or water.
  • a solvent for example, an ether, e.g. p-dioxane, diethyleneglycol dimethylether and the like, a lower alkanol, e.
  • 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 in which R R and R have the previously-given 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, carrying out the optional steps.
  • the above reaction may be performed according to the previously-described method for the preparation of 2-unsubstituted 3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxides used as the starting materials in the first modifimtion of the process of this invention.
  • the two reactants may be heated in a solution using one of the previously-described diluents, if desired, in the pres ence of a base as a condensing reagent.
  • the aldehyde may also be used in the form of an appropriate reactive derivative.
  • the 2 (N-R '-sulfamyl) 4 sulfamyl-5-R -N-R analine 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 formula R '--NH in which R has the above-given meaning, and reacting the resulting compound of the formula in which R R R and Hal have the previously-given meaning, with ammonia.
  • the first step in the above procedure may be carried out in a solvent; halogenated alkanes, particularly chloroform, 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 those in which the term R has the meaning given above.
  • 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.
  • 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 -sulfamyl)-aniline-4-sulfonyl halide compound may be recovered from the filtrate.
  • the resulting 2-(N-R '-sulfamyl)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.
  • 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 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 outstanding properties to relieve conditions of excessive water and salt retention, for example, those connected with kidney or heart ailments. Coupled with the diuretic and saliuretic activities of these compounds is a strong antihypertensive effect, 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.
  • R stands for lower cycloalkyl containing oxygen and/ or sulfur atoms as ring members and advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members and R stands for lower alkyl containing from one to four carbon atoms, e.g.
  • allylic lower alkenyl containmg 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 from three to five carbon atoms, e.g. allyl, Z-methyl- 13 like, and R stands for halogen, e.g. fluorine, bromine, or particularly chlorine, or halogeno-lower alkyl, e.g.
  • This group of compounds may be represented by the compounds of the formula aza eyeloalkyl in which formulae R represents chlorine or trifluoromethyl, 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.
  • 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 which R 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 previouslygiven 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, converting a free compound into a salt thereof.
  • 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-tolu- 14 ene sulfonic acid and the like; such esters are preferably reacted with a salt, particularly an alkali metal salt of the starting material.
  • an aldehyde of the formula R CHO may also be used in the form of an acetal with a lower alkanol, e.g. methanol, ethanol and the like.
  • a lower alkanol e.g. methanol, ethanol and the like.
  • Formaldehyde or acetaldehyde may be present as a polymeric form thereof, e.g. paraformaldehyde, metaldehyde and the like; other reactive forms furnishing formaldehyde are, for example, 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, e.g. hydrochloric acid and the like.
  • the reaction may be performed as previously shown; the desired product is separated from any simultaneously formed 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide containing an unsubstituted sulfamyl group in the 7-position, on the basis of differing solubilities 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, e.g. 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.
  • Monoor poly-salts may be obtained.
  • Any resulting racemate may be converted into the antipodes thereof according to methods used for resolving racemates.
  • Example 1 To 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamy1-l,2,4- benzothiadiazine-l,l-dioxide in 35-40 cc. of warm acetone is added 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight, then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals are obtained, yielding, when recrystallized from acetone, 600 mg.
  • Example 2 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 40 cc. of warm acetone is treated with 0.9 g. 4-methyl-dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight and then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals of the product, 6-chloro-3,4-dihydro 7 sulfamyl 2 (4 methyl-tetrahydro-2-pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide, are obtained.
  • 6-ethoxy-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo.
  • Example 6 3.2 g. of 6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfarnyl-l,2,4-benzothiadiazine-l,l-dioxide in cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain overnight at room temperature and then concentrated to dryness in vacuo. The residue thus obtained is recrystallized from ethanol-water to produce the pure 6-chloro-3-dichloromethyl 7 sulfamyl-Z-(tetrahydro-Z-pyranyl)-l,2,4-benzothiadiazine-1,l-dioxide.
  • R represents a member of the group consisting of hydrogen, lower alkyl, lower alkyl substituted by halo gen, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-rnercapto-lower alkyl, phenyl-lower alkyl-mercaptolower alkyl, lower alkenyl, cycloalkyl having from five to six ring carbon atoms and phenyl-lower alkyl, R stands for 2-cycloalkyl having four to six carbon atoms and at least one and at most two atoms of the group consisting of oxygen and sulfur as ring members, and R represents a member of the group consisting of halogen and halogen-lower alkyl, and alkali metal salts thereof.

Description

United States Patent 015 3,1l33fi18 DERIVATEVES F 3, l-DKHYDRQ-Zfi-1,2,4-BENZO- THIADIAZINE 1,1-Dl0XlDES Harold Balding Maelhillamy, Madison, and Geargc dc Stevens, Willow Kncll, New Providence, NJ, assignors to Cilea (forporation, a corporation of Delaware No Drawing. Filed Apr. 20, 1960, Ser. No. 23,373
Claims. (Cl. 260-243) The present invention concerns 2-substituted-3,4-dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxides. More particularly, it relates to compounds of the formula (S32 HzNOgS CHE-R1 R3 N/ 1 RBI] in which R represents hydrogen, aliphatic hydrocarbon, substituted aliphatic hydrocarbon, carbocyclic aryl, carbocyclic aryl-lower aliphatic hydrocarbon, heterocyclic aryl or heterocyclic aryl-lower aliphatic hydrocarbon, R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members and advantageously have from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members, R represents hydrogen or lower alkyl, and R stands for halogen, lower alkyl or halogenolower alkyl or salts thereof, as well as process for the preparation of such compounds.
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 lke, or carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon, primarily monocyclic carbocyclic aliphatic 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 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 cycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as ring members, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2 cyclopentylethyl, 1 cyclopentylpropyl, 3 cyclopentylpropyl, cyclohexylmethyl, 1 cyclohexylethyl, 2 cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, when con- 3,133,918 Patented May 19, 1964 ice tain from five to six ring carbon atoms, e.g. 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 2 (2 cyclopentenyl) ethyl, 2 cyclohexenylmethyl, 3 cyclohexenylmethyl, 1-(3-cyclol1exenyl) 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 live carbon atoms, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, l,1-dimethyl-1,2- ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3- propylene, 2,2propylene, 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, trifluorornethyl, 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-methylamino, 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-methyl-amino, N,N- diethylamino, 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, N carbocyclic aryl lower alkyl N lower alkyl amino, e.g. N- benzyl-N-rnethyl-amino, N-methy 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, Z-methyl-l-pyrrolidino and the like, l-piperidino, e.g. 1 piperidino, 2 methyl 1 piperidino, 3-methyl-1- piperidino, 4 methyl 1 piperidino, 3 hydroxy 1- piperidino, 3-acetoxy 1 piperidino, 3-hydroxymethyl-1 piperidino and the like, or l-N,N-hexamethylene-imi11o, l-N,N-lower oxa-a1kylene-imino, in which oxa-alkylene contains preferably four carbon atoms, e.g. l-morpholino and the like, or l-N,N-lower aza-alkylene-imino, in which aza-alkylene contains preferably four carbon atoms, e.g. l-piperazino, 4-methyl 1 piperazino, 4 hydroxyethyl-lpiperazino, 4-acetoxyethyl-l-piperazino and the like. The teritary amino group and the lower alkyl radical to which the amino group is attached may present 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-ethylene, with the 3-position of the 1,2,4-thiadiazine 1,1- dioxide portion. Such radicals are, for example, 1-methyl-3-pyrrolidinomethyl, l-methyl 3 piperidinomethyl, 2-(l-methyl-2- piperidino)-ethyl, 1-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-carbonic 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, 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, 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 carboxylic acids, e.g. phenylacetic, diphenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryllower 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. 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. trifiuoromethyl.
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-carbonic 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, 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 aryllower alkenyl carboxylic 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 halogenolower alkyl, e.g. trifiuoromethyl.
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, methylaerylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their haltesters 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 aryllower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnarnic 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 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.
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, ethox n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyioxy and the like, carbocyclic aryloxy, such as monocyclic carbocylic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g. l-naphthyloxy or Z-naphthyloxy or substituted naphthyloxy, or carbocyclic aryl-aliphatic 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. trlfluoromethyl.
in addition, aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, e.g. methyl-mercapto, 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 substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g. benzyl-mercapto, l-phenylethyl-mercapto, 2-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-diethylamino 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 monocycle carbocyclic aryl, e.g. phenyl or substituted phenyl, or monocyclic carbocyclic aryl, e.g. l-naplithyl or Z-naphthyl or substituted naphthyl radicals, or carbocyclic arylaliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, lphenylethyl, Z-phenylethyl, 3-pl1enylpropyl, l-naphylmethyl 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 any of the available positions, whereby one or more than one of the same or of diiferent 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. Z-pyridyl, 3-pyridyl, 4-pyridyl and the like, thienyl, e.g. 2-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. Z-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.
The radical R stands for lower cycloalkyl containing oxygen and/or sulfur atoms as ring members. These groups have advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members.
The carbon atoms of the lower cycloalkyl nucleus may be unsubstituted or substituted by lower hydrocarbon, particularly lower alkyl, e.g. ethyl, n-propyl, isopropyl, or especially methyl and the like; other substituents may be, for example, lower cycloalkyl, e.g. cyclopentyl or cyclohexyl and the like, monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl, monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl or Z-phenylethyl and the like. Two of the carbon atoms of the lower cycloalkyl nucleus may also be part of a second carbocyclic ring system fused onto the lower cycloalkyl nucleus; such carbocyclic ring systems may be represented, for example, by lower cycloalkyl containing from five to seven carbon atoms, e.g. cyclopentyl, cyclohexyl or cycloheptyl and the like, or carbocyclic aryl, such as monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or naphthyl.
The cycloalkyl radical, R may, therefore, be represented primarily by cyclo-oxa-alkyl containing from four to six carbon atoms, such at tetrahydrofuranyl (cyclooxapentyl) radicals, such as Z-tetrahydrofuranyl (2-cyclooxapent-yl) radicals, e.g. 2-tetrahydrofuranyl (2-cyclo oxapentyl), 4-methyI-Z-tetrahydrofuranyl (4 methyl 2- cyclo-oxapentyl) or S-methyl-Z-tetrahydrofuranyl (5- methyl-2-cyclo-oxapentyl) and the like, tetrahydropyranyl (cyclo-oxahexyl) radicals, such as Z-tetrahydropyranyl (Z-cyclo-oxahexyl) radicals, e.g. Z-tetrahydropyranyl (2- cyclo-oxahexyl), 2-methyl-2-tetrahydropyranyl (2-methyl 2-cyclo-oxahexyl), 4 methyl 2 tetrahydropyranyl (4- methyl-Z-cyclo-oxahexyl), 6-rnethyl-2-tetrahydropyranyl (6-methyl-2-cyclo-oxahexyl), 6 phenyl 2 tetrahydro pyranyl (6 phenyl 2 cyclo oxahexyl), 2-hexahydrobenz [e] tetrahydropyranyl (bicyclo [4,4,0] -2-oxa-3-decyl or 2 benz[e]tetrahydropyranyl (2 benz[e]cyclo oxahexyl) and the like, cyclo-oxaheptyl radicals, such as 2-cyclo-oxaheptyl radicals, e.g. Z-cyclo-oxaheptyl, and the like, dioxanyl (cyclo-dioxahexyl) radicals, such as 2-( 1,4-dioxanyl) (2-cyclo-dioxahexyl) radicals, e.g. 2- (l,4-dioxanyl) (2-cyclo-l,4-dioxahexyl) and the like, tetrahydro-oxathiinyl (cyclo-oxathiahexyl) radicals, such as 2 tetrahydro oxathiinyl (2-cyclo-1,4-oxathiahexyl) radicals, e.g. Z-tetrahydro-oxathiinyl (2-cyclo-l,4-oxathiahexyl) and the like, tetrahydrothienyl (cyclo-thiapentyl) radicals, such as Z-tetrahydrothienyl (Z-cyclothiapentyl) radicals, e.g. Z-tetrahydrothienyl and the like,
tetrahydro-thiapyranyl (cyclo-thiahexyl) radicals, such as 2tetrahydro-thiapyranyl (2 cyclo thiahexyl) radicals, e.g. Z-tetrahydro-thiapyranyl (Z-cyclo-thiahexyl) and the like, or tetrahydro-dithiinyl (cyclo-dithiahexyl) radicals, such as Z-tetrahydro-dithiinyl (2-cyclo-1,4-dithiahexyl) radicals, e.g. Z-tetrahydro-dithiinyl (2-cyclo-l,4-dithiahexyl) and the like.
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-2H-1,2,4-benzothiadiazine-1,1-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, particularly trifluoromethyl and the like.
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 natriuretic agents having improved and outstanding properties to relieve conditions of excessive water and salt retention, for example, caused by kidney or heart ailments. Coupled with the diuretic and saliuretic activities of the present compounds is a strong antihypertensive effect, 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, benzylmercaptoethyl and the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkyl containing from five to six ring carbon atoms, e.g. cyclo pentyl and the like, or phenyl-lower alkyl, e.g. benzyl, Z-phenylethyl and the like, R represents cyclo-oxa-alkyl (particularly, 2-cyclo-oxa-alkyl) containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members, 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 s 2 mNo s R G H- (halogeno-lower alkyl) \N (/11- (phenyl-lower alkyl) in which compounds R stands for chlorine or trifluoromethyl, and lower alkyl contains from one to four carbon atoms, and R is defined as above. Particularly active compounds are, for example,
6-chloro-2- (2-cyclo-oxapentyl) -3-methyl-7-sulfamyl-3 ,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl -3- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,
6-chloro-2- (Z-cyclo-oxapentyl -3-methyl-7-sulfamyl-3 ,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- (4-methyl-2-cyclo-oxapentyl) -3 -methyl-7-sulfarnyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1,1-dioxide,
6-chloro-2- 5-methyl-2-cyclo-oxapentyl) -3-isobutyl-2- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiaZine-1,1-dioxide,
6-trifiuoromethyl-2- (2-cyclo-oxahexyl) -3-isobutyl-2- methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine- 1 l-dioxide,
6-chloro-2- (2-methyl-Z-cyclo-oxahexyl) -3-dichloromethyl-2-methyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-l,1-dioxide,
3-dichloromethyl-6-trifluoromethyl-2- (4-methyl-2-cyclooxahexyl) -7-sulfamyl-3,4-dihydro-2H-l ,2,4-benzothiadiazine-l,1-dioxide,
3-benzyl-6-chloro-2- 6-methyl-2-cyclo-oxahexyl) -7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,
3-benzyl-2- 6-phenyl-2-cyclo-oxahexyl) -6-trifluoromethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,
2- (bicyclo [4,4,0] -2-oxa-3-decyl) -6-chloro-7-sulfamyl-3,4-
dihydro-ZH-l,2,4-benZothiadiaZine-1,l-dioxide,
2- (Z-benz [e] -cyclo-oxahexyl -3-ethyl-6-trifluoromethyl- 7-sulfamyl-3 ,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,
6-chloro-3-ethyl-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-
dihydro-2H-1,2,4-benzothiadiaZine-l,l-dioxide,
6-trifiuoromethyl-2-(2-cyclo-1,4-dioxahexyl)-7-sulfamyl- 3 ,4-dihydro-2I-I-1,2,4-benzothiadiaZine-1, l-dioxide,
6-chloro-3-ethyl-2-(Z-cyclo-1,4-oxathiahexyl) -7-sulfamyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-l,l-dioxide,
6-trifluoromethyl-2- (Z-cyclo-thiapentyl) -3-isobutyl-7- sulfamyl-3,4-dihydro-2H-l,2,4-benZothiadiaZine-1,1- dioxide,
6-chloro-2- (Z-cycIo-thiahexyl) -3-ethyl-7-sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide,
2- Z-cyclol ,4-dithiahexyl) -3-ethyl-6-trifluoromethyl-7- sulfamyl-3 ,4-dihydro-2H-l,2,4-benZothiadiazine-1,1- dioxide,
6-ehloro-2- (2-cyclo-oxapentyl) -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1, l-dioxide,
2- (4-methyl-2-cyclo-oxapentyl) -6-trifluoromethyl-7 sulfamyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1- dioxide,
6-chloro-2- (2-cyclo-oxahexyl) -7-sulfamyl-3 ,4-dihydro- 2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-trifluoromethyl-2- Z-cyclo-oxahexyl -7-sulfamyl-3,4-
dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide,
6-chloro-2- (2-cyclo-oxaheptyl -7-sulfamyl-3,4-dihydro- ZH-l,2,4-benzothiadiazine-1,l-dioxide,
-trifluoromethyl-Z- (Z-cyclo-oxaheptyl -7-sulfamyl-3,4-
dihydro-ZH-1,2,4-benzothiadiazi ne-1,1-dioxide,
2-(2-cyclo-1,4-dioxapentyl)-6-chloro-7-sulfamyl-3,4-dihydro-2H-l,2,4-benzothiadiazine-1,1-dioxide,
2- (Z-cyclo-1,4-oxathiahexyl) -6-trifluoromethyl-7-sulfamyl-B'A-dihydro-ZH-l,2,4,-benzothiadiazine-l,l-dioxide and the like,
each of which is substituted in the 3-position by a lower cyclo-alkyl group containing oxygen and/ or sulfur atoms as ring members and advantageously having from four to six carbon atoms and at most two hetero (S or O) ring members.
The new compounds of this invention may be used as medicaments in the form of pharmaceutical preparations, which contain the new 2-substituted-3,4-dihydro-2H-l,2, 4-benzothiadiazine-l,l-dioxide compounds or the salts thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenteral administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, waxes, propylene glycol, polyalkylene glycols or any other known carrier for medicaments. 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 as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain, in combination, other 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, Veratrum 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 z// 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,l-dioxide of the in which R R and R have the previously-given meaning, or an alkali metal salt thereof, with a cycloalkene containing oxygen and/ or sulfur atoms as ring members, which is capable of introducing the radical R in the presence of a condensing agent, 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.
The above-mentioned lower cycloalkene reagents are more particularly Z-cycloalkenes containing at most two atoms selected from the group consisting of oxygen and sulfur and from four to six carbon atoms as ring members. Such compounds are, for example, 2-cyclo-oxaalkenes containing from four to six carbon atoms as ring members, such as dihydrofurans (Z-cyclo-oxapentenes), e.g. dihydrofuran (Z-cyclo-oxapentene), 4-methyl-dihydrofuran (4-methyl-2-cyclo-oxapentene), or S-methyl-dihydrofuran (5-methyl-2cyclo-oxapentene) and the like, dihydropyrans (2-cyclo-oxahexenes), e.g. dihydropyran (2-cyclo-oxahexene), Z-methyl-dihydropyran (Z-methyl- 2-cyclo oxahexene), 4-methyl-dihydropyran (4-methyl-2- cyclo-oxahexene), 6-methyl-dihydropyran (6-methyl-2- cyclo-oxahexene), 6-phenyl-dihydropyran (6 phenyl 2- cyclo-oxahexene), hexahydro-benz[eJdihydropyran (bicyclo[4,4,0]-2-oxa-3-decene) or 2-benz[e]dihydr0pyran (2-benz[e]cyclo-oxahexene) and the like, 2-cyclo-oxaheptenes, e.g. 2-cyclo-oxaheptene and the like, dihydrodioxines (2-cyclo-dioxahexenes), such as dihydro-1,4- dioxines (2-cyclo-l,4-dioxahexenes), e.g. dihydro-1,4-dioxine (Z-cyclo-1,4-dioxahexene) and the like, dihydrooxathiins (2-cyclo-oxathiahexenes), such as dihydro-l,4- oxathiins (2-cyclo-1,4-oxathiahexenes), e.g. dihydro-1,4- dioxathiin (Z-cyclo-l,4-oxathiahexene) and the like, dihydrothiophenes (Z-cyClo-thiapentene), e.g. dihydrothiophene (2-cyclo-thiapentene) and the like, dihydrothiapyrans (2-cyclo-thiahexenes), e.g. dihydrothiapyran (2- cyclo-thiahexene) and the like, or dihydro-dithiins (2- cyclo-dithiahexenes), such as dihydro-l,4-dithiins (2- cyclo-l,4-dithi&exenes), e.g. dihydro-l,4-dithiin (2-eyclo- 1,4-dithiahexene) and the like.
These reagents, particularly the 2-cyclo-oxa-alkenes containing from four to six carbon atoms as ring members, such as dihydropyrans, e.g. dihydropyran, are reacted with the deserpidate compound in the presence of a condensing reagent, particularly an acidic condensing reagent represented by a Lewis acid. Such Lewis acids are, for example, mineral acids, e.g. hydrochloric, hydrobromic or sulfuric acid (used in anhydrous form or as concentrated aqueous solutions), phosphoric acid (for example, in the form of polyphosphoric acid), phosphorous oxychloride, fluoboric acid (in the form of a highly concentrated aqueous solution), borontrifluoride (in the form of its etherate, particularly with diethyl ether), or a carbocyclic aryl sulfonic acid, such as a monocyclic carbocylic acid, especially p-toluene sulfonic acid, or similar reagents having Lewis acid properties, such as, for example, cation exchange resins in acid form, e.g. sulfonic acid resins.
The reaction may be carried out in the absence of a solvent, whereby an excess of a liquid cycloalkene may serve as the solvent, or in the presence of an inert solvent. Such solvents are, for example, carbocyclic aryl hydrocarbons, such as monocyclic carbocyclic aryl hydrocarbons, e.g. benzene or toluene and the like, others, e.g. diethylether or tetrahydrofuran and the like, lower alkanoncs, e.g. acetone or ethyl methyl ketone and the like, formamides, e.g. formamide or N,N-dimethylformamide and the like.
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.
The 3,4-dihydro-2H-1,4-benzothiadiazine-1,l-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-given meaning, or a reactive derivative thereof, to form the desired 3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,l-dioxide, which may then be condensed with the desired cyclo-oxa-alkene or cyclo-azaalkene to yield the R-R '-substituted product, R having the previously-given meaning.
Although the disulfamyhaniline 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, hydrobrornic 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, f r 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-dimethoxyethane, 1,l-dimethoxy-isobutane, 1,1-diethoxy-isobutane, 2,2-dichloro-1,l-dimethoxyethane, 2,2-dichlorol,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 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 alkanol, e.g. methanol, ethanol and the like, a formamide, e.g. dirnethylformamide 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 sol vent 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 in which R R and R have the previously-given 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, carrying out the optional steps.
The above reaction may be performed according to the previously-described method for the preparation of 2-unsubstituted 3,4-dihydro-2H-l,2,4-benzothiadiazine-l,l-dioxides used as the starting materials in the first modifimtion 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 pres ence of a base as a condensing reagent. As pointed out, the aldehyde may also be used in the form of an appropriate reactive derivative.
The 2 (N-R '-sulfamyl) 4 sulfamyl-5-R -N-R analine 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 formula R '--NH in which R has the above-given meaning, and reacting the resulting compound of the formula in which R R R and Hal have the previously-given meaning, with ammonia.
The first step in the above procedure may be carried out in a solvent; halogenated alkanes, particularly chloroform, 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 those in which the term R has the meaning given above.
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 -sulfamyl)-aniline-4-sulfonyl halide compound may be recovered from the filtrate.
The resulting 2-(N-R '-sulfamyl)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-sulfonyl halide from any 2,4-bis-(N-R '-sulfamyl)-aniline compound simultaneously formed as a by-product; a resulting mixture may be reacted directly 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 NH:
members, as enumerated above.
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 and R have the meaning given above.
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 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 outstanding properties to relieve conditions of excessive water and salt retention, for example, those connected with kidney or heart ailments. Coupled with the diuretic and saliuretic activities of these compounds is a strong antihypertensive effect, 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, benzylmercaptoethyl and the like, lower alkenyl, e.g. l-propenyl and the like, cycloalkyl containing from five to six carbon atoms as ring members, e.g. cyclopentyl and the like, or phenyl-lower alkyl, e.g. benzyl, 2- phenylethyl and the like, the radical R stands for lower cycloalkyl containing oxygen and/ or sulfur atoms as ring members and advantageously from four to six carbon atoms and at most two atoms selected from the group consisting of sulfur and oxygen as ring members and R stands for lower alkyl containing from one to four carbon atoms, e.g. methyl, ethyl, n-propyl, isoproyl, nbutyl, isobutyl and the like, allylic lower alkenyl containmg 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 from three to five carbon atoms, e.g. allyl, Z-methyl- 13 like, and 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 formula aza eyeloalkyl in which formulae R represents chlorine or trifluoromethyl, 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.
Similarly, as with the previously-described compounds containing an N-unsubstituted 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 which R 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 previouslygiven 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, converting 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-tolu- 14 ene sulfonic 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 acetal with a lower alkanol, e.g. methanol, ethanol and the like. Formaldehyde or acetaldehyde may be present as a polymeric form thereof, e.g. paraformaldehyde, metaldehyde and the like; other reactive forms furnishing formaldehyde are, for example, 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, e.g. hydrochloric acid and the like.
Compounds of the formula in which R R R R and R have the previouslygiven meaning, and R and R stand for the identical group, may also be prepared by reacting a compound of the formula 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 as previously shown; the desired product is separated from any simultaneously formed 3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide containing an unsubstituted sulfamyl group in the 7-position, on the basis of differing solubilities 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, e.g. 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. Monoor poly-salts may be obtained.
Any resulting racemate may be converted into the antipodes 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 degrees centigrade.
Example 1 To 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamy1-l,2,4- benzothiadiazine-l,l-dioxide in 35-40 cc. of warm acetone is added 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight, then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals are obtained, yielding, when recrystallized from acetone, 600 mg. 6-chloro-3,4-dihydro- 7 sulfamyl Z-(tetrahydro-Z-pyranyl)-1,2,4-benzothiadizine-1,1-dioxide; M.P. 23 l232d.
[By substituting an equivalent amount of 6-trifluor0- methyl-3,4-dihydro 7 sulfamyl-l,2,4-be11zothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-l,l-dioxide and following the procedure 15 given above, the corresponding 6-trifluoromethyl compound may be obtained. Using the identical procedure and any of the other cyclooxa-alkyl or cyclo-aza-alkyl reactants named above, corresponding products may be obtained, as is evident below.]
Example 2 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 40 cc. of warm acetone is treated with 0.9 g. 4-methyl-dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight and then concentrated to dryness in vacuo. A small amount of ether is added to the residue and white crystals of the product, 6-chloro-3,4-dihydro 7 sulfamyl 2 (4 methyl-tetrahydro-2-pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide, are obtained.
[By substituting an equivalent amount of 6-trifluoromethyl-3,4-dihydro 7 sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sultamyl-l,2,4- benzothiadiazine-1,1-dioxide and following the procedure given above, the corresponding 6-trifluoromethyl compound may be obtained] Example 3 2.55 g. of 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide in 35 cc. of warm acetone is treated with 1 g. 6-ethoxy-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo. The product, 6-chloro-3,4-dihydro- 2-(6-ethoxy-tetrahydro 2 pyranyl) 7 sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide, is collected and recrystallized from acetone.
[By substituting an equivalent amount of 6-trifiuoromethyl-3,4-dihydro 7 sulfamyl-l,2,4-benzothiadiazine- 1,1-dioxide for the 6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide and following the procedure given above, the corresponding 6-trifluoromethyl compound may be obtained] Example 4 3.2 g. of 6-chloro-3-cyclopentylmethyl-3,4-dihydro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide in 40 cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain at room temperature overnight. The product is then collected and recrystallized from ethanol-Water to produce the pure 6-chloro-3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl-2 (tetrahydro-2-pyranyl)- 1 ,2,4-benzothiadiazine-1,l-dioxide.
[By substituting 6-trifluoromethyl-3-cyclopentylmeth yl-3,4-dihydro 7 sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the 6-chloro-3-cyclopentylmethyl-3,4-dihydro- 7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide reactant used in this example, the corresponding trifluoromethyl product may be obtained] Example 3.8 g. of 3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-l,2,4-benzothiadiazine-l,l-dioxide is dissolved in 50 cc. of warm acetone. This is treated with 1 g. 4,6-dimethyl-dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight at room temperature, the solution is concentrated to dryness in vacuo. The residue is recrystallized from ethanol to produce the pure 3-benzylmethyl-6-chloro 3,4 dihydro-7-sulfamyl-2- (4,6-dimethyl 2 pyranyl) 1,2,4 benzothiadiazine-1,ldioxide.
[By substituting 3-benzylmethyl-6-trifiuoromethyl-3,4- dihydro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide for the 3-benzylmethyl-6-chloro-3,4-dihydro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide used in this example, the corresponding trifluoromethyl compound may be obtained.]
15 Example 6 3.2 g. of 6-chloro-3-dichloromethyl-3,4-dihydro-7-sulfarnyl-l,2,4-benzothiadiazine-l,l-dioxide in cc. of warm acetone is treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. The solution is allowed to remain overnight at room temperature and then concentrated to dryness in vacuo. The residue thus obtained is recrystallized from ethanol-water to produce the pure 6-chloro-3-dichloromethyl 7 sulfamyl-Z-(tetrahydro-Z-pyranyl)-l,2,4-benzothiadiazine-1,l-dioxide.
[By substituting 6-trifluor0methy1-3-monochlorometl1 yl-3,4-dihydro 7 sulfamyl 1,2,4 benzothiadiazine-l,1- dioxide for the 6-chloro-3-dichloromethyl-3,4-dihydro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide used in this example, the corresponding 3-monochloromethyl compound may be obtained. Substitution of the 6-chloro-3- monochloromethyl (or 3-dichloromethyl) reactants for the one used in this example, will yield the corresponding trifluoromethyl derivatives] Example 7 2.75 g. of 3-cyclopentylmethyl-3,4-dihydro-7-sulfamyl- 6-trilluoromethyl-1,2,4-benzothiadiazine-1,l-dioxide is dissolved in cc. of warm acetone and then treated with 0.84 g. dihydropyran and two drops concentrated hydrochloric acid. After remaining overnight the solution is evaporated to one-half its volume, the crystals collected and recrystallized from ethanol-water to produce the pure 3-cyclopentylmethyl 3,4 dihydro-7-sulfamyl-6-trifiuoromethyl-2-(tetrahydro 2 pyranyl)-1,2,4-benzothiadiazine-1,1-dioxide.
1 What is claimed is:
l. A member of the group consisting of 3,4-dihydro- ZH-l,2,4-benzothiadiazine-1,l-dioxides of the formula in which R represents a member of the group consisting of hydrogen, lower alkyl, lower alkyl substituted by halo gen, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkyl-rnercapto-lower alkyl, phenyl-lower alkyl-mercaptolower alkyl, lower alkenyl, cycloalkyl having from five to six ring carbon atoms and phenyl-lower alkyl, R stands for 2-cycloalkyl having four to six carbon atoms and at least one and at most two atoms of the group consisting of oxygen and sulfur as ring members, and R represents a member of the group consisting of halogen and halogen-lower alkyl, and alkali metal salts thereof.
2. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-1,2,4- benzothiadiazine-l,l-dioxide, wherein R is 2-tetrahydro-2- pyranyl.
3. 6 chloro 2-R-7 sulfamyl-3,4-dihydro-2H-l,2,4- benzothiadiazine-1,1-dioxide, wherein R is 4-methyl-tetrahydro-Z-pyranyl.
4. 6 trifluoromethyl 2-R-7 sulfamyl-3,4-dihydro- ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which R is 2- cyclo-oxaalkyl having from four to six carbon atoms.
5. -chloro-3-halogeno-lower alkyl-2-R-7-sulfamyl-3,4- dihydro-ZH-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is 2-cyclooxaalkyl having from four to six carbon atoms.
6. 6 trifiuoromethyl-3-halogeno-lower alkyl 2-R-7- sulfamyl 3,4 dihydro-ZH-l,2,4-benzothiadiazine-1,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is 2-cyclo-oxaalkyl having from four to six carbon atoms.
7. 6-chloro-2-R-3-phenyl-lower alkyl-7-sulfamy hydro-2H-1,2,4-benzothiadiazine-l,l-dioxide, in which lower alkyl has from one to four carbon atoms and R is y -oxaalkyl having from four to six carbon atoms.
3,133,918 17 18 8. 6 trifiuoromethy1-2-R-3-phenyl-10wer alkyl 7 suI- References Cited in the file of this patent famyI-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 diOX- UNITED STATES PATENTS ide, in which lower alkyl has from one to four carbon atoms and R is zmrmhydmpyranyli 1,911,719 Schwefzer et a1 May 30, 1933 9. 6 chl0ro-2,3-bis-(tetrahydro-Z-pyranyl)-7-su1famy1- 5 g g et a 3,4- dihydro-2H-1,2,4-benzothiadiazine-1, 2809194 n i 5 10. 6 n-ifluoromethy1-2,3-bis-(tetrahydr -py y 2910475 oveno c 7 1959 7-sulfamyl 3,4 dihydm-ZH-l,2,4-benzothiadiazinel,1- Nove 2 dioxidi 2,910,4588 Novello Oct. 27, 1959

Claims (1)

1. A MEMBER OF THE GROUP CONSISTING OF 3,4-DIHYDRO2H-1,2,4-BENZOTHIADIAZINE-1,1-DIOXIDES OF THE FORMULA
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3356692A (en) * 1963-11-30 1967-12-05 Bayer Ag Tetrahydrofuryl-benzene sulfonamides
US3452020A (en) * 1967-11-09 1969-06-24 Wallace & Tiernan Inc 2-alkenyl and 2-alkynyl substituted - tetrahydro - halo-sulfamyl-quinazolinones
US3458513A (en) * 1967-11-02 1969-07-29 Wallace & Tiernan Inc 2-substituted-tetrahydro-halosulfamyl-quinazolinones
US3868379A (en) * 1972-04-28 1975-02-25 Warner Lambert Co Heterocyclic amides of 4-hydroxy-2H-1-benzothiopyran-3-carboxylic acid 1,1-dioxide
US3957769A (en) * 1973-11-23 1976-05-18 E. R. Squibb & Sons, Inc. 1,2,4-benzothiadiazines
US4029780A (en) * 1974-10-29 1977-06-14 Dainippon Pharmaceutical Co., Ltd. 3-Piperazinyl 1,2,4-benzothiadiazine 1,1-dioxide derivatives their compositions and method of use
US20040087577A1 (en) * 2002-11-01 2004-05-06 Pratt John K Anti-infective agents
US20040162285A1 (en) * 2002-11-01 2004-08-19 Pratt John K. Anti-infective agents
US20040167123A1 (en) * 2002-11-01 2004-08-26 Pratt John K Anti-infective agents
US20050075331A1 (en) * 2003-10-06 2005-04-07 Pratt John K. Anti-infective agents

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1911719A (en) * 1933-05-30 Aromatic aisino sitlphochlosides
US1939025A (en) * 1928-10-26 1933-12-12 Ig Farbenindustrie Ag Aromatic amino-sulpho chlorides, substituted in the amino-group
US2338106A (en) * 1937-02-13 1944-01-04 Foldi Zoltan Process for the production of new efficacious p-amino-benzene-sulphamide derivativessuitable for injection purposes
US2809194A (en) * 1957-10-08 Thiadiazine type natriuretic agents
US2910488A (en) * 1958-01-22 1959-10-27 Merck & Co Inc Aniline derivatives
US2910475A (en) * 1957-09-13 1959-10-27 Merck & Co Inc Process for preparing benzothiadiazine-1, 1-dioxides

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1911719A (en) * 1933-05-30 Aromatic aisino sitlphochlosides
US2809194A (en) * 1957-10-08 Thiadiazine type natriuretic agents
US1939025A (en) * 1928-10-26 1933-12-12 Ig Farbenindustrie Ag Aromatic amino-sulpho chlorides, substituted in the amino-group
US2338106A (en) * 1937-02-13 1944-01-04 Foldi Zoltan Process for the production of new efficacious p-amino-benzene-sulphamide derivativessuitable for injection purposes
US2910475A (en) * 1957-09-13 1959-10-27 Merck & Co Inc Process for preparing benzothiadiazine-1, 1-dioxides
US2910488A (en) * 1958-01-22 1959-10-27 Merck & Co Inc Aniline derivatives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3356692A (en) * 1963-11-30 1967-12-05 Bayer Ag Tetrahydrofuryl-benzene sulfonamides
US3458513A (en) * 1967-11-02 1969-07-29 Wallace & Tiernan Inc 2-substituted-tetrahydro-halosulfamyl-quinazolinones
US3452020A (en) * 1967-11-09 1969-06-24 Wallace & Tiernan Inc 2-alkenyl and 2-alkynyl substituted - tetrahydro - halo-sulfamyl-quinazolinones
US3868379A (en) * 1972-04-28 1975-02-25 Warner Lambert Co Heterocyclic amides of 4-hydroxy-2H-1-benzothiopyran-3-carboxylic acid 1,1-dioxide
US3957769A (en) * 1973-11-23 1976-05-18 E. R. Squibb & Sons, Inc. 1,2,4-benzothiadiazines
US4029780A (en) * 1974-10-29 1977-06-14 Dainippon Pharmaceutical Co., Ltd. 3-Piperazinyl 1,2,4-benzothiadiazine 1,1-dioxide derivatives their compositions and method of use
US20040087577A1 (en) * 2002-11-01 2004-05-06 Pratt John K Anti-infective agents
US20040097492A1 (en) * 2002-11-01 2004-05-20 Pratt John K Anti-infective agents
US20040162285A1 (en) * 2002-11-01 2004-08-19 Pratt John K. Anti-infective agents
US20040167123A1 (en) * 2002-11-01 2004-08-26 Pratt John K Anti-infective agents
US7902203B2 (en) 2002-11-01 2011-03-08 Abbott Laboratories, Inc. Anti-infective agents
US20050075331A1 (en) * 2003-10-06 2005-04-07 Pratt John K. Anti-infective agents

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