FIELD OF THE INVENTION

The present invention relates to 1 ,2,4-benzothιadιazιne derivatives, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and their use in therapy e g in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system the gastrointestinal system and the endocnnological system

BACKGROUND OF THE INVENTION

Potassium channels play an important role in membrane potential Among the different types of potassium channels are the ATP-sensitive (K _ATP -) channels which are regulated by changes in the intracellular concentration of adenosine tπphosphate The K _ATP -channels have been found in cells from various tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, central neurons and adenohypophysis ceils The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohy- pophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system

Modulators of the K _ATP -channels have been found to be of importance for the treatment of various diseases Certain sulphonylureas which have been used for the treatment of non- insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K _ATP -channels on pancreatic beta-cells

The potassium channel openers, which comprise a heterogeneous group of compounds, have been found to be able to relax vascular smooth muscles and have therefore been used for the treatment of hypertension

In addition, potassium channel openers can be used as bronchodiiators in the treatment of asthma and various other diseases

Furthermore, potassium channel openers have been shown to promote hairgrowth, and have been used for the treatment of baldness

Potassium channel openers are also able to relax urinary bladder smooth muscle and therefore, can be used for the treatment of urinary incontinence Potassium channel openers which relax smooth muscle of the uterus can be used for treatment of premature labor

By acting on potassium channels of the central nervous system these compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer epilepsia and cerebral ischemia

Further, the compounds are found to be useful in the treatment of benign prostatic hyperplasia, erectile dysfunction and in contraception

Compounds of the present invention, which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with compounds which reduce blood glucose levels. Examples of such compounds are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenciamide and glucagon like peptide ( GLP1 ), inhibitors of α- glucosidases and hepatic enzymes responsible for the biosynthesis of glucose, and glucagon.

Recently, it has been shown that Diazoxide (7-chloro-3-methyl-2H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde) and certain 3-(alkyiamιno)-4H-pyrιdo[4,3-e]-1 ,2,4-thιadιazιne 1 ,1 -dιoxιde derivatives inhibit insulin release by an activation of K _ATP -channels on pancreatic beta-cells (Pirotte B et al Biochem Pharmacol, 47, 1381-1386 (1994), Pirotte B et al., J Med Chem , 36, 3211-3213 (1993) Diazoxide has furthermore been shown to delay the onset of diabetes in BB-rats ( Vlahos WD et al. Metabolism 40, 39-46 (1991 ). In obese zucker rats diazoxide has been shown to decrease insulin secretion and increase insulin receptor binding and consequently improve glucose tolerance and decrease weight gain (Alemzadeh R et al Endocrinol 133, 705-712, 1993) It is expected that compounds

which activate K _ATP -channels can be used for treatment of diseases characterised by an overproduction of insulin and for the treatment and prevention of diabetes

The following compounds are known from the literature

3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-ιsobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (2-ethylhexylamιno)-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide cyclohexylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

7-chloro-3-(1 ,2,2-tπmethylpropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-chloro-3-(1 ,2-dιmethylpropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-chloro-3-(1-methylpropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 7-chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-chloro-3-cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-chloro-3-cyciohexylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6-chloro-3-cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 6,7-dιchloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-dιchloro-3-cyclopropyiamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-ιsobutylamtno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-cyclopentylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 3-cyclohexylamιno-6-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide (N-cyclohexyl-N-methylamιno)-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-cyclohexylamιno-4-methyl-4H-1,2,4-benzothιadιazιne 1 ,1-dιoxιde 3-cyclohexylamιno-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

DESCRIPTION OF THE INVENTION

The present invention relates to 1 ,2,4-benzothιadιazιne derivatives of the general formula I

wherein R ¹ and R ⁵ independently can be hydrogen, hydroxy, C _{1 6} -alkoxy, C _{3 6} -cycloalkyl optionally mono- or polysubstituted with C, ₆ -alkyl, halogen, hydroxy or C, ₆ -alkoxy, or C, ₆ -alkyl, C _{2 6} - alkenyl or C ₂ . ₆ -alkynyl optionally mono- or polysubstituted with halogen and R ⁴ is hydro¬ gen, or

R ⁴ together with R ⁵ represent one of the bonds in a double bond between the atoms 2 and

3 of formula I and R ¹ is as defined above, or

R ⁴ together with R ¹ represent one of the bonds in a double bond between the atoms 3 and

4 of formula I and R ⁵ is as defined above,

D represents -S(=O) ₂ - or -S(=O)-,

R ² is hydrogen, hydroxy, C^-alkoxy, C _{3 6} -cycloalkyl optionally mono- or polysubstituted with C, e-alkyl, halogen, hydroxy or C, ₆ -alkoxy, or d ₆ -alkyl, C ₂₆ - alkenyl or C ₂₆ -alkynyl optionally mono- or polysubstituted with halogen,

R ³ is R ⁸ , -OR ⁸ , -C(=X ¹ )R ^β , , bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, C^-alkyl, C, ₆ -alkoxy, aryloxy, arylalkoxy, nitro, ammo, C, ₆ -monoalkyl- or dialkylamino, cyano, oxo, acyl or C, ₆ - alkoxycarbonyl,

wherein R ⁸ is hydrogen, C _{3 6} -cycloalkyl or (Ca e-cycloalkyOCg-alkyl the C ₃ . ₆ -cycloalkyl

group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C _1-6 - alkoxy, a 3-6 membered saturated ring system comprising one or more nitrogen- oxygen- or sulfur atoms, optionally being mono- or polysubstituted with halogen, cyano, trifluoromethyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C,. ₆ -monoalkyl or dialkylamino; or straight or branched d.^-alkyl optionally mono- or polysubstituted with halogen, hydroxy, aryl, aryloxy, arylalkoxy, nitro, amino, C,. ₆ - monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, d.g-alkoxycarbonyl, carbamoyl, formylamino, or

R ³ ιs

wherein n,m,p independently can be 0,1 ,2,3 and R ¹⁰ is hydrogen, hydroxy, Cvg-alkoxy, C ₃ . _s -cycloalkyl optionally mono- or polysubstituted with C,. ₆ -alkyl, halogen, hydroxy or C,_ ₆ - alkoxy; or C _V6 -alkyl, C ₂ . ₆ -alkenyl or C ₂ . ₆ -alkynyl optionally mono- or polysubstituted with halogen;

R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ independently are hydrogen; halogen; C ₃ . ₆ -cycloalkyl; hydroxy, C,. ₆ -alkoxy; d.e-alkoxy-C _Lβ -alkyl; nitro; amino; cyano; cyanomethyl; pemalomethyl; C _1-6 - monoalkyl- or dialkylamino; sulfamoyl; C^-alkylthio; C _1-6 -alkyisulfonyl; C^e-alkylsulfinyl; C,. ₆ -alkylcarbonyiamino; formyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C, e-alkoxy, C _{1 6} - alkoxycarbonyl; C,. ₆ -alkoxycarbonyl-C _{1 6} -alkyl; carbamyl; carbamylmethyl; C, ₆ -monoaikyl- or dialkylaminocarbonyl; d.s-monoalkyl - or dialkylaminothiocarbonyl; ureido; C _v6 -

monoalkyl- or dialkylaminocarbonylamino, thioureido, d ₆ -monoalkyl- or dialkylaminothio- carbonylamino, d-e-monoalkyl- or dialkylaminosulfonyl, carboxy, carboxy-C, ₆ -alkyl, acyl, aryl, arylalkyl, aryloxy, the aryl group optionally being mono- or polysubstituted with C, ₆ - alkyl, halogen, hydroxy or C, ₆ -alkoxy, (1 ,2,4-oxadιazol-5-yl)- or (1 ,2,4-oxadιazol-3-yl)-d ₆ - alkyl the oxadiazolyl group optionally being substituted with C, ₆ -alkyl or C ₃₆ -cycloalkyl, or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C, ₆ -alkyl,

Within its scope the invention includes all optical isomers of compounds of formula I some of which are optically active, and also their mixtures including racemic mixture thereof

The scope of the invention also includes ail tautomeric forms of the compounds of formula I

The salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, tπfluoroacetic, tπchloroacetic oxalic, maleic, pyruvic, malonic, succinic, citric, tartaπc, fumaπc mandelic, benzoic, cinnamic, methane- sulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceuti¬ cally acceptable salts listed in Journal of Pharmaceutical Science, 66 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium magnesium and the like

The term "C, ₆ -alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e g methyl ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-peÏ€tyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 4-methylpentyl, neopentyl, n-hexyl, 1 ,2-dιmethylpropyl, 2,2- dimethylpropyl and 1 ,2,2-trιmethylpropyl

The term "C, ₆ -alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a d e-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e g methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy

The term "d ₆ -alkylthιo" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a lower alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having 1 to 6 carbon atoms e g methylthio ethylthio, propylthio, butylthio, pentylthio

The term "C _{2 6} -alkenyl" as used herein refers to an unsaturated hydrocarbon chain having 2-6 carbon atoms and one double bond such as e g vinyl, 1-propenyl, allyl isopropenyl, n-butenyl, n-pentenyl and n-hexenyl

The term "C ₃₆ -cycloalkyl" as used herein refers to a radical of a saturated cyclic hydrocar¬ bon with the indicated number of carbons such as cyclopropyl, cyclobutyl cyclopentyl or cyclohexyl

The term "C _{2 6} -alkynyl" as used herein refers to unsaturated hydrocarbons which contain triple bonds, such as e g -C≡CH, -C≡CCH ₃ , -CH ₂ C≡CH, -CH ₂ CH ₂ C≡CH, -CH(CH ₃ )C≡CH, and the like

The term "d ₆ -alkoxy-C, _s -alkyl" as used herein refers to a group of 2-12 carbon atoms interrupted by an O such as e g CH ₂ -O-CH ₃ , CH ₂ -0-CH ₂ -CH ₃ CH ₂ -O-CH(CH ₃ ) ₂ and the like

The term "halogen" means fluorine, chlorine, bromine or iodine

The term "perhalomethyl" means tπfluoromethyl tπchloromethyl, tπbromomethyl or tπiodomethyl

The term " C, ₁₈ -alkyl" as used herein refers to a straight or branched, saturated hydrocar¬ bon chain having the indicated number of carbon atoms such as e g methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3- methylbutyl, n-hexyl 4-methylpentyl, neopentyl, n-hexyl, 1 ,2-dιmethylpropyl, 2,2- dimethylpropyl, 1 ,2 2-tÏ€methylpropyl and the like The term " C, ₁₈ -alkyl" as used herein also includes secondary C _{3 6} -alkyl and tertiary C _{4 6} -alkyl

The term "d.e-monoalkylamino" as used herein refers to an ammo group wherein one of the hydrogen atoms is substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e g methylamino, ethylamino, propylamino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2-methylbutylamιno, n-hexylamino, 4-methylpentylamιno, neopentylamino, n-hexylamino, 2,2-dιmethylpropylamιno and the like

The term "C, ₆ -dιalkylamιno" as used herein refers to an ammo group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as dimethylamino, N-ethyl-N-methylamiÏ€o, diethylammo, dipropylamino, N-(n-butyl)-N-methylamιno, dι(n- pentyl)amιno, and the like

The term "acyl" as used herein refers to a monovalent substituent comprising a C,. ₆ -alkyl group linked through a carbonyl group, such as e g acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like

The term "C, ₆ -alkoxycarbonyl" as used herein refers to a monovalent substituent comprising a C, ₆ -alkoxy group linked through a carbonyl group, such as e g methoxycar- bonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec- butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the

The term "3-6 membered saturated ring system" as used herein refers to a monovalent substituent comprising a moπocyclic saturated system containing one or more hetero atoms selected from nitrogen, oxygen and sulfur and having 3-6 members and having its free valence from a carbon atom, e g 2-pyrrolιdyl, 4-pιperιdyl, 3-morpholιnyl, 1 ,4-dιoxan-2- yl, 5-oxazolιdιnyl, 4-ιsoxazolιdιnyl, or 2-thιomorpholιnyl

The term "bicycloalkyl" as used herein refers to a monovalent substituent comprising a bicyclic structure made of 6-12 carbon atoms such as e g 2-norbornyl, 7-norbornyl, 2-

bιcyclo[2.2.2]octyl, and 9-bicyclo[3.3.1]nonanyl.

The term "aryl" as used herein refers to phenyl, 1-naphthyl, or 2-naphthyl

The term "heteroaryl" as used herein, alone or in combination, refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g. pyrrole, imidazole, pyrazole, tπazole, pyridine, pyrazme, pyrimidine, pyπdazme, isothiazole, isoxazole, oxazoie, oxadiazole, thiadiazole, quinoline, isoquinoline, qumazolme, quinoxaline, indole, benzimidazole, benzofuran, ptendine, and puπne

The term "arylalkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydπde, such as benzyl, phenethyl, 3-phenylpropyl, 1 -naphtylmethyl, 2-(1-naphtyl)ethyl and the like.

The term "aryloxy" as used herein refers to phenoxy, 1-naphthyioxy or 2-naphthyloxy

The term "arylalkoxy" as used herein refers to a C, ₆ -alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1- naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.

The term "heteroarylalkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group, such as (2-furyl)methyl, (3-furyl)methyl, (2-thιenyl)methyl, (3-thienyl)methyl, (2-pyrιdyl)methyl, 1- methyl-1-(2-pyrimidyl)ethyl and the like.

The term "d-e-alkylsulfonyi" as used herein refers to a monovalent substituent comprising a C, e-alkyl group linked through a sulfonyl group such as e.g. methylsulfonyl, ethylsul- fonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3- methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n-

hexylsulfonyl and 2,2-dιmethylpropylsulfonyl

The term "d ₆ -monoalkylamιnosulfonyl" as used herein refers to a monovalent substituent comprising a d. ₆ -monoalkylamιno group linked through a suifonyl group such as e g methylammosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylammosulfonyl, n-butylaminosulfonyl, sec-butylamtnosulfonyl, isobutylaminosulfonyl, tert- butylammosulfonyl, n-pentylammosulfonyl, 2-methylbutylamιnosulfonyl, 3- methylbutylaminosulfoÏ€yl, n-hexylaminosulfonyl, 4-methylpentylamιnosulfonyl, neopenty- lammosulfonyl, n-hexylammosulfonyl and 2 2-dιmethylpropylamιnosulfonyl

The term "C, ₆ -dιalkylamιnosulfonyl" as used herein refers to a monovalent substituent comprising a d ₆ -dιalkylamιno group linked through a suifonyl group such as dimethylami- nosulfonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylammosulfonyl, N- (n-butyl)-N-methylamιnosulfonyl, dι(n-pentyl)amιnosulfonyl, and the like

The term "d ₆ -alkylsulfιnyl" as used herein refers to a monovalent substituent comprising a straight or branched d ₆ -alkyl group linked through a sulfinyl group (-S(=0)-), such as e g methylsulfinyl ethylsulfmyl isopropylsulfmyl, butylsulfinyl, peÏ€tylsulfinyl and the like

The term "d ₆ -alkylcarbonylamιno" as used herein refers to an ammo group wherein one of the hydrogen atoms is substituted with an acyl group, such as e g acetamido, propiona- mido, isopropylcarbonylamino and the like

The term "(C^-cycloalkyOd β-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubstituted with a C^-cycloalkyl group, the cycloalkyi group optionally being mono- or polysubstituted with C,. ₆ -alkyl, halogen, hydroxy or C, ₆ -alkoxy, such as e g cyclopropylme- thyl, (l-methylcyclopropyl)methyl, 1-(cyclopropyl)ethyl, cyclopentylmethyl, cyclohexylmethyl,

The term "arylthio" as used herein, alone or in combination, refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl

group optionally being mono- or polysubstituted with C, ₆ -alkyl, halogen, hydroxy or C _1-6 - alkoxy, e g phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thιo, and the like

The term "arylsulfinyl" as used herein refers to an aryl group linked through a sulfmyl group (- 5 S(=0)-), the aryl group optionally being mono- or polysubstituted with C, ₆ -alkyl, halogen, hydroxy or d e-alkoxy, such as e g phenylsulfmyl, (4-chlorophenyl)sulfιnyi and the like

The term "arylsulfonyl" as used herein refers to an aryl group linked through a suifonyl group, the aryl group optionally being mono- or polysubstituted with C,. ₆ -alkyl, halogen, o hydroxy or C, ₆ -alkoxy, such as e g phenylsulfonyl, tosyl, and the like

The term "C, ₆ -monoalkylamιnocarbonyl" as used herein refers to a monovalent substituent comprising a C, ₆ -monoalkylammo group linked through a carbonyl group such as e g methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylammocarbonyl, 5 n-butylammocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert- butylammocarbonyl, n-pentylammocarbonyl, 2-methylbutylamιnocarbonyl, 3- methylbutylamino-carbonyl, n-hexylammocarbonyl, 4-methylpentylamιnocarbonyi, neo- pentylaminocarbonyl n-hexylammocarbonyl and 2-2-dιmethylpropylamιnocarbonyl

0 The term "d ₆ -dιalkylamιnocarbonyl" as used herein refers to a monovalent substituent comprising a d ₆ -dιalkylamιno group linked through a carbonyl group such as dimethylami- nocarbonyl, N-ethyl-N-methylaminocarbonyl, diethylaminocarbonyl dipropylammocarbonyl, N-(n-butyl)-N-methylamιnocarbonyl, dι(n-pentyl)amιnocarbonyl, and the like

5 The term "C, ₆ -monoalkylamιnocarbonylamιno" as used herein refers to an ammo group wherein one of the hydrogen atoms is substituted with a C,. ₆ -monoalkylamιnocarbonyl group, e g methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopropylaminocarbonylamino, n-butylammocarbonylamino, sec-butylaminocarbonylammo, isobutylaminocarbonylamino, tert-butylammocarbonylamino, and 2- 0 methylbutylaminocarbonylammo

The term "d ₆ -dιalkylamιnocarbonylammo" as used herein refers to an ammo group wherein

one of the hydrogen atoms is substituted with a C, ₆ -dιalkylamιnocarbonyl group, such as dimethyiaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethyla- minocarbonylamino, dipropylammocarbonylamino, N-(n-butyl)-N- methylaminocarbonylamino, dι(n-pentyl)amιnocarbonylamιno, and the like

The term "5- or 6-membered nitrogen containing ring" as used herein refers to a monova¬ lent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, e g pyrrolidinyl, pyrrolinyl, imida- zohdmyl, pyrazolidmyl, pyrazolmyl, pipeπdyl, piperazinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, tπazolyl, pyndyl, pyrazmyl, pyπmidinyl, pyπdazmyl, morpholino, thiomorpholmo, isothiazolyl isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1 ,3-dιoxolanyl, and 1 4- dioxolanyl

In a preferred embodiment of the invention one of R ¹ and R ⁵ is hydrogen, hydroxy, d e- alkoxy, C ₃₆ -cycloalkyl optionally mono- or polysubstituted with d ₆ -alkyl, halogen hydroxy or d ₆ -alkoxy, C, ₆ -alkyl, C ₂₆ -alkenyl or C ₂₆ -alkynyl optionally mono- or polysubstituted with halogen, and the other of R ¹ and R ⁵ together with R ⁴ is a bond Preferably one of R ¹ and R ⁵ is hydrogen and the other of R ¹ and R ⁵ together with R ⁴ is a bond

In another preferred embodiment of the invention R ² is hydrogen or C, ₆ -alkyl Preferably R ² is hydrogen

In another preferred embodiment of the invention R ³ is R ⁸ , -OR ⁸ -C(=0)R ⁸ , wherein R ^B is hydrogen, C^-cycloalkyl or (C^-cycloalkyOd ₆ -alkyl, C^-cycloalkyl optionally being mono- or polysubstituted with d ₆ -alkyl, halogen, hydroxy or C,. ₆ -alkoxy, a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms, or straight or branched C, ₁₈ -alkyl optionally mono- or polysubstituted with halogen, Cj.e-cycloalkyl, hydroxy or C, ₆ -alkoxy,

In yet another preferred embodiment of the invention R ³ is selected from secondary C ₃₆ - alkyl, tertiary C ₄₆ -alkyl, C ₃₆ -cycloalkyl or (C ₃₆ -cycloalkyl)methyl optionally mono- or polysubstituted with C, ₆ -alkyl, halogen, hydroxy or d ₆ -alkoxy Preferably R ³ is selected from

isopropyl, 1 -methylpropyl, 2-methylpropyl, tert-butyl, 1 ,1-dιmethylpropyl, 1 ,2-dιmethylpropyl 1,2,2-tπmethylpropyl, 2,3-dιmethylbutyl, 1-ethylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-2,2- dimethylpropyl, 2,3,3-tπmethylbutyl, 2-methylbutyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1-(cyclopropyl)ethyl cyclobutylmethyl, 5 cyciopentylmethyl or cyclohexylmethyl

In another preferred embodiment of the invention R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ are selected from hydrogen, halogen, C, ₁₈ -alkyl, C ₃₆ -cycloalkyl, cyano, cyanomethyl, perhalomethyl, sulfa¬ moyl, C, ₆ -alkylthιo, d e-alkylsulfonyl, C, ₆ -alkylsulfιnyl, arylthio, arylsulfinyl, arylsulfonyl, the o aryl group optionally being mono- or polysubstituted with d ₆ -alkyl, halogen, hydroxy or C, ₆ - alkoxy, C, ₆ -alkoxycarbonyl-C, ₆ -alkyl, carbamylmethyl, carboxy-d ₆ -alkyl aryloxy, (1 ,2,4- oxadιazol-5-yl)- or (1 ,2,4-oxadιazol-3-yl)d ₆ -alkyl, the oxadiazolyl group optionally being substituted with d e-alkyl or C^-cycloalkyl, acyl, or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or d ₆ -alkyl 5

Preferred compounds of the invention are

3-Benzyloxyamιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-methoxyamιno-4H-1 ,2 4-benzothιadιazιne 1 ,1 -dioxide 7-Bromo-3-ιsopropylamιno-4H-1 ,2 4-benzothιadιazιne 1 ,1-dιoxιde 0 7-Chloro-3-(N- ethyl-N-methylamιno)-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6-Chloro-3-methoxyamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Chloro-3-(1 ,2,2-tπmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 7-Bromo-3-(1 ,2,2-tπmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιπe 1 ,1 -dioxide 6-Chloro-3-(N- ethyl-N-methylamιno)-4H-1,2,4-benzothιadιazιne 1 1 -dioxide 5 5-Amιno-7-chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-(1 ,3-dιmethylpentyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Chloro-3-(1 ,5-dιmethylhexyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-(1 ,4-dιmethylpentyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 5,7-Dιchloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 0 7-Bromo-6-tπfluoromethyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-(3,3-dιphenylpropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Chloro-3-(4-phenylbutylamιno)-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

-Chloro-3-(3-dιethylamιno-1-methylpropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide -lsopropylamιno-4H-1 ,2,4-benzothιadιazιne- 5-carboxaldehyde 1 ,1 -dioxide -lsopropylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxaldehyde 1 , 1 -dioxide -lsopropylamιno-4H-1 ,2,4-benzothιadιazιne-6-carboxylιc acid 1 , 1 -dioxide -Cyano-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-7-ιodo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-cyanomethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide ,7-Dιchloro-3-ιsopropylamιno-6-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-(3-(1 H-ιmιdazol-4-yl)propyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -lsopropylammo-6,7-dιmethoxy-4H-1 ,2,4-benzothιadιazιne 1 , 1-dιoxιde -(1-Azabιcycio[2 2 2]oct-3-yl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde -Chloro-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-(1 ,2-dιmethylpropyl)amιno-7-sulfamoyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Anιlιno-7-chioro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-(ιmιdazol-2-yl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-(4-pyrιdyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-ιsobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -sec-Butylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-cyclohexylmethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Fluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Cyclopentylamιno-6-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-ιsopropylamιno-5-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -tert-Butylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -lodo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde -Chloro-7-fluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -lsopropylamιno-6-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-cyclopropylmethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -lsopropylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide ,7-Dιbromo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Acetyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Allylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-(1-ethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

6-Chloro-3-butylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Chloro-3-hexylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6,7-Dιchloro-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6,7-Dιchloro-3-(1-methylbutyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 7-Chloro-3-(1 ,2-dιmethylpropyl)amιno-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 6,8-Dιchloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7- Chloro-3-ιsopropylamιno-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-lsopropylamιno-6-benzenesulfonyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-lsopropylamιno-6-methanesulfony I-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 5-Chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde 3-lsopropylamιno-6-methyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6-Chloro-3-ιsopropylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6-Ethoxycarbonylmethyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6-Carboxymethyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 8-Chloro-3-ιsopropylammo-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 6-lsopropyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-tert-Butyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 3-lsopropyiamιno-6-phenoxy-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6-Hexyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6-Cyclohexyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

2-(3-lsopropylamιno-1 1-dιoxo-1 ,4-dιhydro-1 λ ⁶ ,2,4-benzothιadιazιn-6-yl)-acetamιde 6-(3-Cyclopropyl-1 2 4-oxadιazol-5-yi)methyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Cyanomethyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-(2-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-sec-Butylamιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-lodo-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 7-lodo-3-( 1 ,2,2-tÏ€methylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Chloro-3-cyclohexylmethyiamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (R)-7-Chloro-3-(1 -cyclohexylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (S)-7-Chloro-3-(1-cyciohexylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (R)-7-Chloro-3-(1-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

(S)-7-Chloro-3-(1-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 3-Cyclohexylmethylamιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (R)-3-(1-Cyclohexylethyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (S)-3-(1-Cyclohexylethyl)amιno-7-ιodo-4H-1,2,4-benzothιad ιazιne 1 1 -dioxide 3-Benzylammo-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (R)-7-lodo-3-( 1 -phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (S)-7-lodo-3-( 1 -phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-sec-Butylamιno-7-bromo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Bromo-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde 7-Fluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-sec-Butylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Fluoro-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 7-Bromo-3-cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Chloro-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Chloro-3-(2 2,2-tÏ€fluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 3-lsopropylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-Allylammo-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Chloro-3-(2-methoxy-1 -methylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 7-Chloro-3-(1-ethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-(1-Ethylpropyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-sec-Butylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-(1 ,2-Dιmethylpropyl)amιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 7-Chloro-3-(2-hydroxypropyl)amιno-4H-1 ,2,4-benzothιadιazιπe 1 1 -dioxide 7-Chloro-3-(2-hydroxy-1-methylethyl)amιno-4H-1,2,4-benzothÎ ¹adιazιne 1 , 1 -dioxide 3-(2-Amιnoethyl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 7-Chloro-3-(2,2-dιethoxyethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 3-Ethylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Fluoro-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-Cyclopropylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 3-Cyclobutylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-Cyclopentylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 3-Cyclopropylmethylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

-Allylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Fluoro-3-(2-methoxy-1-methylethyl)amιno-4H-1,2,4-benzothι adιazιne 1 1 -dioxide -Chloro-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-(2,2,2-trιfluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Bromo-3-methylamιno-4H-1 ,2 ₎ 4-benzothιadιazιne 1 ,1 -dioxide -Bromo-3-ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Bromo-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Bromo-3-(2,2,2-tÏ€fluoroethyl)amιno-4H-1 ,2,4-benzothιadιazme 1 , 1 -dioxide -Fluoro-3-methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-hexyiamιno-4H-1 ,2 4-benzothιadιazιne 1 ,1 -dioxide 7-Dιchloro-3-hexylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -(2,2-Dιethoxyethyl)amιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide -Fluoro-3-(2,2,2-tÏ€fluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Bromo-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-cyclopropylmethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Cyclopropylmethylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Nιtro-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Cyclobutylammo-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Dιchioro-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide -Amιno-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Acetamιdo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide -Cyclobutylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -lsopropylamιno-7-methoxy-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Methoxy-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-(2-formylammoethyl)amιno-4H-1,2,4-benzothιadιaz ιne 1 , 1 -dioxide -(2-Acetylamιnoethyl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-hexyiamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-octylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3-(1 ,5-dιmethylhexyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde -lsopropylamιno-7-trιfluoromethyi-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

1 8

-sec-Butylamιno-7-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -lsopropylammo-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 ,1 -dioxide -sec-Butylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 , 1 -dioxide -Propylamιno-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Cyclopropylmethylamιno-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Propylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 , 1 -dioxide -Chloro-3-(pyrιdιn-2-yl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Ethylamιno-6,7-dιfluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Fluoro-3,6-dι(ιsopropylamιno)-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,8-Dιfluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,7-Dιfluoro-3-ιsopropyiamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,7,8-Trιfluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Fluoro-3-ιsopropylamιno-6-methyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3-ιsopropylamιno-6-methoxy-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide ,8-Dιchloro-3-ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide ,8-Dιchloro-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,8-Dιchloro-3-cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,8-Dιchloro-3-cyclopropylmethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide ,8-Dιchloro-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide ,8-Dιchloro-3-cyclopentylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (2-pyrιdyl)methyiamιno-4H-1 ,2,4-beπzothιadιazιne 1 ,1 -dioxide -Chloro-3 (3-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3- (4-pyπdyl)methyiamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3 (2-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (3-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide -Chloro-3 (4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (2-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (3-pyπdyl)methyiamtno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (4-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3- (2-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde -Chloro-3 (3-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide -Chloro-3 (4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

7-Fluoro-3- (2-pyπdyi)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 7-Fluoro-3- (3-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Fluoro-3-< (4-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Fluoro-3- (2-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 5 7-Fluoro-3-< (3-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 7-Fluoro-3 (4-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Fluoro-3 (2-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Fluoro-3- (3-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6-Fluoro-3 (4-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

10 6-Fiuoro-3 (2-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6-Fluoro-3- (3-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6-Fluoro-3 (4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιchloro-3- 2-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6,7-Dιchloro-3- 3-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

15 6,7-Dιchloro-3- 4-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιchloro-3- 2-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6,7-Dιchloro-3- 3-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιchloro-3- 4-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde 6,8-Dιchloro-3- 2-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

20 6 8-Dιchloro-3- 3-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6 8-Dιchloro-3- 4-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Dιchloro-3H 2-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6 8-Dιchloro -3- (3-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6,8-Dιchloro-3- 4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

25 6,7-Dιfluoro-3 2-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιfluoro-3 3-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιfluoro-3 4-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Dιfluoro-3 2-pyrιdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,7-Difluoro-3 3-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

30 6,7-Dιfluoro-3 4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Dιfluoro-3' 2-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazme 1 ,1 -dioxide 6,8-Dιfluoro-3- 3-pyπdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

6,8-Dιfluoro-3-(4-pyrιdyl)methylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide ,8-Dιfluoro-3-(2-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde 6,8-Dιfluoro-3-(3-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Dιfluoro-3-(4-pyπdyl)ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6,8-Bιs(trιfluoromethyl)-3-(1 ,4-dιmethylpentyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Bιs(tπfluoromethyl)-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Bιs(tπfluoromethyl)-3-cyclopentylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Bιs(tπfluoromethyl)-3-cyclopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 6,8-Bιs(trιfluoromethyl)-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 6,8-Bιs(trιfluoromethyl)-3-cyclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 6 8-Bιs(tπfluoromethyl)-3-ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

The compounds of the present invention interact with the potassium channels and hence act as openers or blockers of the ATP-regulated potassium channels, which make them useful in the treatment of various diseases of the cardiovascular system, e g cerebral ischemia, hypertension, ischemic heart diseases, angina pectons and coronary heart diseases, the pulmonary system, the gastrointestinal system the central nervous system and the endocnnological system

Since some K _ATP -openers are able to antagonize vasospasms in basilar or cerebral arteries the compounds of the present invention can be used for the treatment of vaso- spastic disorders such as vasospastic disorders, subarachnoid haemorrhage and migraine

The compounds of the present invention may also be used for the treatment of diseases associated with decreased skeletal muscle blood flow such as Raynauds disease and intermittent claudication

Further, the compounds of the invention may be used for the treatment of chronic airway diseases, including asthma, and for treatment of detrusor muscle instability secondary to bladder outflow obstruction and therefore for kidney stones by aiding their passage along the urethra

The present compounds could also be used for treatment of conditions associated with disturbances in gastrointestinal mobility such as irritable bowel syndrome Additionally these compounds can be used for the treatment of premature labour and dysmenorrhea

Potassium channel openers hyperpolaπzes neurons and inhibit neurotransmitter release and it is expected that such compounds can be used for the treatment of various diseases of the central nervous system, e g epilepsia, ischemia and neurodegenerative diseases, and for the management of pain

Further, potassium channel openers promote hairgrowth, therefore the compounds of the present invention can be used for the treatment of baldness

Potassium channel openers also relax urinary bladder smooth muscle, thus, the compounds of the present invention can be used for the treatment of urinary incontinence

In diseases such as nesidioblastosis and msuiinoma in which a hypersecretion of insulin causes severe hypoglycemia the compounds of the present invention can be used to reduce insulin secretion in obesity hypeπnsuiinemia and insulin resistance is very frequently encountered This condition could lead to the development of noninsulin dependent diabetes (NIDDM) It is expected that potassium channel openers and hence the compounds of the present invention can be used for reducing the hypeπnsuiinemia and thereby prevent diabetes and reduce obesity In overt NIDDM treatment of hypeπnsuhnemia with potassium channel openers, and hence the present compounds, can be of benefit in restoring glucose sensitivity and normal insulin secretions

In early cases of insulin dependent diabetes (IDDM) or in prediabetic cases, potassium channel openers and hence the present compounds can be used to induce betacell rest which may prevent the progression of the autoimmune disease

The potassium channel openers of the present invention can be administered in combination with an immunosuppressant or with an agent like nicotmamide, which will

reduce autoimmune degeneration of beta-cells

Combining beta-cell rest with a treatment protecting the beta-cells against cytokine mediated beta-cell impairment/cytotoxicity is another aspect of this invention Insulin requiring or Type 1 diabetes (IDDM) as well as late onset IDDM (also known as type 1 5 e g non-insulm-requiπng Type 2 (NIIDM) patients with autoreactivity against beta-cell epitopes that later turns insulin requiring) have circulating autoreactive mono- cytes/lymphocytes that homes to the islets/beta-cells and releases their cytokmes Some of these cytokmes (e g ιnterleukιn-1 b (IL-1b) , tumour necrosis factor a (TNFa) and mterferon g (IFNg)) are specifically toxic to the beta-cells, e g through the induction of nitric oxide (NO) and other free radicals Inhibition of this cytotoxicity, e g by co- admimstπng nicotmamide (NA), a derivative hereof or other cytokine protective com¬ pounds to the prediabetic/diabetic patients treated with the PCO compound is an example of this aspect Nicotmamide belongs to the B-vitamm family and is derived from nicotmic acid by amidation of the carboxyl group It processes none of nicotine's pharmacological properties NA is converted into NAD+, which acts as a coenzyme for proteins involved in tissue respiration NA has been proposed to influence several of the putative intracellular molecular events following immune attack on the beta-cells Animal experiments and early non-blinded experiments in humans have indicated a protective role of this compound against IDDM as well as in cytokme/immune mediated beta-cell destruction

Yet another aspect of this application concerns the use of a PCO compound alone or in combination with the inhibitor of cytokine/immune mediated beta-cell impairment , in transplantation, e g islet transplantation into diabetes patients The use of one or both of these treatments may reduce the risk of rejection of the transplanted islets/beta- cells/engineered beta-cells/pancreas

Compounds of the present invention which act as blockers of K _ATP -channels can be used for the treatment of NIDDM

Preferably, the compounds of the present invention may be used for treatment or prevention of diseases of the endocnnological system such as hypeπnsulinaemia and

diabetes

Accordingly, in another aspect the invention relates to a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hypeπnsulinaemia and treatment or prevention of diabetes

Furthermore, the invention also relates to the use of the inventive compounds of formula I as medicaments useful for treating hypeπnsuhnaemia and treating or preventing diabetes

In yet another aspect, the present invention relates to methods of preparing the above mentioned compounds The methods comprises

a) reacting a compound of formula II

wherein D, R ¹ , R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above and Z is a leaving group such as alkoxy, alkylthio, halogen, preferentially chloro, bromo, lodo, amino, tnmethylami- no, ιmιdazol-1-yl, methylsulfmyl or methylsulfonyl with a compound of formula III

wherein R ² and R ³ are defined above to form a compound of the general formula I using e g procedures described by T H Cronon et al , J Med Chem 1J., 136 (1968), L Raffa et al , Farmaco Ed Sei. 29, 411 (1974), B Pirotte et al , J Med Chem 36, 3211 (1993), H J Petersen Acta Chem Scand 27, 2655(1973)

Another method comprises

b) reacting a compound of formula IV

wherein R ¹ is hydrogen and D, R ⁵ , R ¹² , R ¹³ , R ¹⁴ , and R ¹⁵ are as defined above, or R ⁵ is H and R ¹ , R ¹² R ¹³ , R ¹⁴ , R ¹⁵ and D are as defined above, with the compound of formula III, or a suitable salt thereof in the presence of P ₂ 0 ₅ and a high boiling tertiary amme or a suitable salt therof using a procedure described by Jensen K G and Pedersen E B , Chem Ser 20, 248-250 (1988) and Andersen L , Nielsen F E and Pedersen E B , Chem Ser , 29, 45-49 (1989), to form a compound of the general formula I

c) reacting a compound of the formula IV

wherein R ¹ is hydrogen and D, R ⁵ R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above or R ⁵ is H and R ¹ R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and D are as defined above, with a compound of the formula III, or a suitable salt thereof in the presence of titanium tetrachloÏ€de and a solvent with which it may form a complex like e g tetrahydrofuran, or a mixture of toluene and anisole, according to the methods described in R I Fryer, J V Earley, G F Field, W Zally, and L H Sternbach, J Org Chem 34, 1143-1145 (1969), J B Press et al , J Med Chem 22, 725-731 (1979), or G Roma et al EurJ Med Chem _26, 489-496 (1991 ) to form a compound of the general formula I

d) reacting a compound of formula V

(V)

wherein R ¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above, with a compound of formula VI

R ³ NCO (VI)

wherein R ³ is as defined above using the method described by Chern J.W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of the general formula I, wherein D is SO ₂ , R ² is H. and R ⁴ and R ⁵ together form a bond.

e) reacting a compound of the formula V

wherein R ¹ , R , R , R ¹⁴ and R ¹⁵ are as defined above, with a compound of formula VII

R ³ NHC(=O)CI (VII)

wherein R ³ is as defined above using the method descÏ€bed by Chern J.W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of the general formula I, wherein D is SO ₂ , R ² is H, and R ⁴ and R ⁵ together form a bond.

f) reacting a compound of the formula V

wherein R ¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are defined as above, with a compound of formula VIII

C .

H ₂ N ^' NH.

(VIII)

wherein Y is NH or S, or a suitable salt thereof using procedures descÏ€bed by Kotovskaya S.K. et al., Khim.-Farm Zh., 13, 54-57 (russ.) (1979) and Topliss J.G. et al., J. Org. Chem., 28, 2313 (1963), to form a compound of the general formula I, wherein D is SO ₂ , R ⁴ and R ⁵ together form a bond, and R ² and R ³ are H.

g) reacting a compound of the formula V

wherein R ¹ , R , R ¹³ R ¹⁴ and R ⁵ are as defined above, with a compound of formula IX

R ³ -N=C=S (IX)

wherein R ³ is as defined above, using e g the procedures described by Topliss et al , J Org Chem , 28, 2313 (1963), to form a compound of the general formula I, wherein D is S0 ₂ , R ² is H, and R ⁴ and R ⁵ together form a bond,

h) reacting in the presence of a base a compound of formula X

or a suitable salt thereof, wherein R ¹¹ is R ¹ or EtOC(=0), wherein R ¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above, with a compound of formula IX

R ³ N=C=S (IX)

wherein R ³ is as defined above, to form an adduct which may have either of the two structures XI or XII or be a mixture of the two

either of which by ring-closure, e.g. by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if R ¹¹ is R ¹ , wherein D is S0 ₂ , R ² is H, and R ⁴ and R ⁵ together form a bond, and a compound of the general formula XIII if R ¹¹ is EtOC(=0);

(XIII)

i) hydrolyzmg and subsequently decarboxylating a compound of the general formula XIII

e.g. by heating the compound in aqueous base and subsequently neutralizing with an acid, to form a compound of the general formula I, wherein D is SO ₂ , R ¹ and R ² are H, and R ⁴ and R ⁵ together form a bond, and R ³ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above.

j) reacting a compound of formula

wherein R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above with thiocarbonyldiimidazole in a suitable solvent, like e.g. dioxane, to form a compound of formula

which by treatment with an amme of formula

^ R ³

(III)

forms a compound of the general formula I, wherein D is SO ₂ , R ¹ is H, R ⁴ and R ⁵ together form a bond, and R ² R ³ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above The reaction may take place with or without a solvent and preferentially at elevated temperatures, e g in the range 100 - 150 °C For volatile amines, the reaction may be carried out in a sealed vessel

Compounds of the general formula I may also undergo chemical transformations in one or more steps by conventional methods to form other compounds of the general formula I wherein D, R\ R ² , R ³ R ⁴ , R ⁵ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined above, e g by transfor¬ mation of functional groups of (I) or by direct introduction of new substituents, e g on an aromatic ring Such chemical transformations may consist of e g electrophihc substitution, nucleophilic substitution, nitration, alkylation, acylation, metalation followed by reaction with electrophiies, halogenation, reduction, oxidation, diazotization, and dehydration

The starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of known compounds or in analogy with known methods as described by e g Y Girard et al , J Chem. Soc Perkm I, 1043, 1979, D F Hayman et al , J Pharm Pharmacol , 522, 1962 (3-oxo-2,3-dιhydro-4H-1 ,2,4- benzothiadiazme 1 ,1 -dioxides), DiBella et al , II Farmaco Ed. Sei 21 , 829, 1966 (3-thιoxo-

2, 3-dιhydro-4/-/-1 , 2, 4-benzothιadιazιne 1 ,1 -dioxides), DiBella et al II Farmaco Ed Sei 27 990, 1972 (3-methyJsulfanyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxides), Szabo, Bull Soc Chim Fr , 1953, 771 , Bιerbaum,B A et al , J Med Chem 6, 1963 272-275 (4- amιno-3-sulfamoylbenzoιc acid), Patent, Farbwerke Hoechst, FR 1381634 1962 (2- chloro-5-trιfluoromethyl-benzenesulfonamιde and 2-benzylamιno-5-tπfluoromethyl- benzenesulfonamide), Short, J H , Biermacher.U , J Amer Chem Soc , 82 1960, 1135- 1138 (2-amιno-4,5-dιchlorobenzenesulfonamιde), Patent, Aktieselskabet Ferrosan, Ger 1 135,483, 1962, (2-amιno-4,6-dιchlorobenzenesulfonamιde), H J Petersen, Acta Chem Scand 27, 2655(1973)

PHARMACOLOGICAL METHODS

The ability of the compounds to interact with potassium channels can be determined by various methods When patch-clamp techniques (Hamill O P , Marty A Neher E , Sakmann B and Sigworth F J , Plugers Arch , 39J., 85-100 (1981)) are used the ionic current through a single channel of a cell can be recorded

The activity of the compounds as potassium channel openers can also be measured as relaxation of rat aortas rings according to the following procedure

A section of rat thoracic aorta between the aortic arch and the diaphragm was dissected out and mounted as ring preparations as described by Taylor P D et al , Bπt J Pharma¬ col, HI, 42-48 (1994)

After a 45 mm equilibration period under a tension of 2 g, the preparations were con¬ tracted to achieve 80% of the maximum response using the required concentration of phenylephπne When the pheπylephπne response reached a plateau, potential vasodila¬ tor/ agents were added cumulatively to the bath in small volumes using half log molar increments at 2 mm intervals Relaxation was expressed at the percentage of the contracted tension The potency of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue

Relaxation of rat aorta rings

Example EC50 micro M

50 5.2 101 14.1

88 32.7

94 4.8

In the pancreatic b-cell the opening of the K _ATP -channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca ²⁺ concentration according to the method of Arkhammar P et al. , J Biol Chem , 262, 5448-5454 (1987)

-Rb ^* efflux from a β-cell line

The RIN 5F cell line was grown in RPMI 1640 with Glutamax I, supplemented with 10 % fetal calf serum (from GibcoBRL, Scotland, UK) and maintained in an atmosphere of 5 % C0 ₂ / 95 % air at 37°C The ceils were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/ml ⁸⁶ Rb ⁺ and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 μl/well, and grown 24 hours before use in assay

The plates were washed 4 times with Ringer buffer (150 mM NaCI, 10 mM Hepes, 3 0 mM KCI, 1 0 mM CaCI ₂ , 20 mM Sucrose, pH 7 1 ) Eighty μl Ringer buffer and 1 μl control- or test compound dissolved in DMSO was added After incubation 1 h at room temperature with a lid, 50 μl of the supernatant was transferred to PicoPlates (Packard instrument Company, CT, USA) and 100 μl MιcroScint40 (Packard Instrument Company, CT, USA) added The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 mm/well at the ³² P program

The calculation of EC ₅₀ and E _max was done by SlideWÏ€te (Advanced Graphics Software, Inc , CA, USA) using a four parameter logistic curve y = (a-d)/(1 +(x/c) ^b )+d, where a = the activity estimated at concentration zero, b = a slope factor, c = the concentration at the middle of the curve and, d = the activity estimated at infinite concentration EC ₅₀ = c and

E _max = d, when the curve is turned of at infinite concentrations

Increased Rb-efflux in nn 5F cells

Example EC50 micro M

26 12 9

66 9 4

86 13.0

The compounds according to the invention are effective over a wide dosage range In general satisfactory results are obtained with dosages from about 0 05 to about 1000 mg, preferably from about 0 1 to about 500 mg, per day A most preferable dosage is about 1 mg to about 100 mg per day The exact dosage will depend upon the mode of administra¬ tion, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e g rectal transdermal, subcutaneous, intravenous intramuscular or intranasal the oral route being preferred

Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound The active compound can be adsorbed on a granular solid container for

example in a sachet Some examples of suitable carriers are water, salt solutions, alco¬ hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglyceπdes and diglyceπdes, pentaerythπtol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrohdone The 5 formulations may also include wetting agents, emulsifying and suspending agents, preser¬ ving agents, sweetening agents or flavouring agents The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art

10

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring sub¬ stances and the like, which do not deletenously react with the active compounds

15 For parenteral application, particularly suitable are injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the 20 like are particularly suitable for oral application Preferable carriers for tablets, dragees, or capsules include lactose, corn starch and/or potato starch A syrup or elixir can be used in cases where a sweetened vehicle can be employed

Generally, the compounds are dispensed in unit form comprising from about 1 to about 25 100 mg in a pharmaceutically acceptable carrier per unit dosage

A typical tablet, appropriate for use in this method, may be prepared by conventional tablettmg techniques and contains

30 Active compound 5 0 mg

Lactosum 67 8 mg Ph Eur

Avicel® 31 4 mg

Amberlite® 1 0 mg

Magnesn stearas 0 25 mg Ph Eur

EXAMPLES

The process of preparing the compounds of formula I is further illustrated in the following examples which, however, are not to be construed as limiting

General procedures for the preparation of the 3-alkylamιno-4/-/-1 2 4-benzothιadιazιne 1 ,1- dioxides

Method A

A mixture of the appropriate 3-methylsulfanyl-substιtuted or 3-(ιmιdazol-1-yl)-substιtuted benzothiadiazine 1 ,1-dιoxιde (0 5 g) and the appropriate alkylamme (5 mL) was heated in a sealed vessel at 120-150°C for 4-8 h (until completion of the reaction monitored by t i c ) The excess of amme was removed by distillation under reduced pressure and the oily residue was dispersed in water The suspension was supplemented with 2 5N NaOH until complete dissolution The resulting solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 5-6 with 6N HCl The precipitate was collected by filtration washed with water and recrystallized from methanol-water (yields 60-90%)

Method B

A mixture of the appropπate 3-methylsulfanyl-substιtuted or 3-(ιmιdazol-1-yl)-substιtuted benzothiadiazine 1 ,1 -dioxide (0 5 g) and the appropriate alkylamme (5 mL) was refluxed for 2-120 h (until completion of the reaction monitored by 1 1 c ) The final compound was then isolated and purified as reported in method A (yields 60-90%)

Method C

A mixture of the appropriate 3-methylsulfanyl-substιtuted or 3-(ιmιdazol-1-yl)-substιtuted benzothiadiazine 1 ,1 -dioxide (0 5 g) and the appropriate alkylamme (1 mL) in 3- chlorotoluene (5 mL) was refluxed for 1-3 h (until completion of the reaction monitored by t i c ) Most of the solvent and the excess of amine was removed by distillation, and the oily residue was dispersed in a 1 1 mixture of methanol and water (50-100 mL) A 10% aqueous solution of NaOH was added dropwise until dissolution of most of the insoluble material The alkaline medium was treated with charcoal, filtered, and the filtrate was adjusted to pH 5-6 The precipitate was collected by filtration, washed with water and recrystallized from methanol-water (yields 60-90%)

Method D

A mixture of the appropriate 3-methylsulfanyl-substιtuted or 3-(ιmιdazol-1-yl)-substιtuted benzothiadiazine 1 ,1 -dioxide (0 6 g) and the appropriate alkylamme (1 mL) in dioxane (5 mL) was heated in a sealed vessel at 120-150°C for 4-8 h (until completion of the reaction monitored by 1 1 c ) The final compound was then isolated and purified as reported in method A (yields 60-90%)

EXAMPLE 1

7-Chloro-3-(2-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

2-Phenylethyl isothiocyanate (0 36 g) was added to a stirred slurry of 2-amιno-5- chlorobenzenesulfonamide sodium salt (0 50 g) in 5 ml of acetonitrile at 60 °C After 2V ₂ h an additional amount of 2-phenylethyl isothiocyanate (0 18 g) was added, and the temperature was raised to 90 °C for VA h The reaction mixture was treated with 1 ml of 4M acetic acid, 5 ml of ethanol and 0 1 g of charcoal and filtered through celite The solvent was evaporated and the residue extracted with 10 ml of ethyl acetate The solvent was evaporated and the oily residue was purified on a silica column eluted with ethyl acetate The title compound was obtained as white crystals, m p. 250-252 °C

EXAMPLE 2

7-Bromo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

To a suspension of 2-amιno-5-bromobenzenesulfonamιde (0 8 g, 3 2 mmol) and potas¬ sium carbonate (0 54 g, 3 9 mmol) in acetone (20 ml) was added isopropyl isothiocyanate (0 387 g, 3 84 mmol) The mixture was heated to 60 °C and after 16 hr cooled, concen¬ trated in vacuo and the crude residue was taken up in tetrahydrofuran (50 ml) and cooled to 0 °C To the cooled mixture was added triethylamine (0 648 g, 6 4 mmol) followed by the addition of phosgene in toluene 1 9 M (1 82 ml) over 2 mm After 1 hr at 0 °C the mixture was concentrated in vacuo The crude product was taken up in water (10 ml) and pH was adjusted to 6 with sodium bicarbonate The precipitated product was collected by filtration and dried in vacuo at 50 °C for 16 hr giving 390 mg (38 3 %) of the title com¬ pound, m p >220 °C

Η-NMR (DMSO-d6) ppm, 10 49 (br s,1 H, NH), 7 75 (m, 2H, H-6 and H-8), 7 21 (s 1 H, H- 5), 7 15 (s, 1 H, NH), 3 97 (m, 1 H, CH) 1 19 (d, 6H, 2xCH ₃ )

EXAMPLE 3

6,8-Dιchloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

A mixture of 2-amιno-4,6-dιchlorobenzenesulfonamιde (1 0 g), isopropyl isothiocyanate (0 84 g), copper(l) chloride (0 4 g), and DMF (1 5 ml) was heated at 100 °C for 2 h Then 5 ml of methanol was added and the precipitated material was removed by filtration Evaporation of the solvent in vacuo and subsequent treatment of the residue with 25 ml of ethyl acetate gave a yellow precipitate, which was collected by filtration and recrystallized from ethanol to give the title compound as white crystals, m p 291-293 °C

EXAMPLE 4

3-lsopropylamιno-6-methanesulfonyl-4H-1 ,2.4-benzothιadιazιne 1 , 1 -dioxide

a) N-(2-amιno-4-(methanesulfonyl)benzenesulfonyl)-N'-ιsopropy lthιourea

A mixture of 2-amιno-4-methanesulfonylbenzenesulfonamιde (2 5 g), potassium carbonate (1 66 g) and isopropyl isothiocyanate (1 22 g) in 20 ml of dry acetone was heated at 50°C for 18 h Then the reaction mixture was evaporated in vacuo and the residue was dissolved in 25 ml of water Then the solution was adjusted to pH 2 by dropwise addition of 4 M HCl at 0 °C with stirring After stirring for 2 h the product was filtered off and dried yielding the title compound as white crystals, m p 151-153 °C

b) 3-lsopropylamιno-6-methanesulfonyl-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

To a stirred mixture of N-(2-amιno-4-(methanesulfonyl)benzenesulfonyl)-N - isopropylthiourea (3 0 g) and triethylamine (1 7 g) in 30 ml of dry THF at 0 °C was added 5 2 ml of a 20% solution of phosgene in toluene during 5 mm The mixture was stirred at 0 °C for 1 h and then evaporated in vacuo The white, solid residue was triturated with 50 ml of water for 45 mm and then the product was isolated by filtration The filter cake was rinsed on the filter with water and dried to give the title compound as white crystals, m p > 300 °C

Η-NMR(d ₆ -DMSO)), δ (ppm) 10 7 (br, 1 H NH), 7 98-7 72 (m, 3H, arom ), 7 43 (br, 1 H NH), 4 07-3 87 (m, 1 H CH) 3 29 (s, 3H, CH ₃ ), 1 20 (d, 6H, CH ₃ )

EXAMPLE 5

3-lsopropylamιno-6-benzenesulfonyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Starting from 2-amιno-4-(benzenesulfonyl)benzenesulfonamιde and isopropyl isothiocy¬ anate, and following a procedure analogous to the one descπbed in Example 4a, N-(2-amιno-4- (benzenesulfonyl)benzenesulfonyl)-N ^' -isopropylthiourea was prepared, m p 178-180 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 308-310 °C

EXAMPLE 6

5-Chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Starting from 2-amιno-4-methylbenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-3- chlorobenzenesulfonyl)-N ^' -isopropylthiourea was prepared, m p 124-125 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 204-206 °C

EXAMPLE 7

3-lsopropylamιno-6-methyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Starting from 2-amιno-4-methylbenzenesulfonamιde and isopropyl isothiocyanate and following a procedure analogous to the one described in Example 4a N-(2-amιno-4- methylbenzenesulfonyl)-N ^' -ιsopropylthιourea was prepared m p 137-139 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 309-311 °C

EXAMPLE 8

6-Chloro-3-ιsopropylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Starting from 2-amιno-4-chloro-5-methylbenzenesulfonamιde and isopropyl isothiocy- anate and following a procedure analogous to the one described in Example 4a, N-(2- amιno-4-chloro-5-methylbenzenesulfonyl)-N ^' -isopropylthiourea was prepared, m p 120- 122 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, ¹ H-NMR (d ₆ -DMSO), δ (ppm) 10 3 (br, 1 H, NH), 7 68 (1H, arom ), 7 29 (1 H, arom), 7 2 (br, 1 H, NH), 4 0-3 8(m, 1 H, CH), 2 37 (s, 3H, CH ₃ ), 1 20 (d, 6H, CH ₃ )

EXAMPLE 9

Ethyl (3-lsopropylamιno-1 , 1-dιoxo-1 ,4-dιhvdro-1λ ^β ,2,4-benzothιadιazιn-6-yl)acetate

Starting from ethyl 3-amιno-4-sulfamoylphenylacetate and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-3- 5 (ethoxycarbonylmethyl)benzenesulfonyl)-N ^' -ιsopropylthιourea was prepared, m p 111-112 °C

Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 182-184 °C, Η-NMR (d ₆ -DMSO), δ (ppm) 10 4 (s, 1 H, NH), 7 65-7 57 (1H, arom ), 7 2-7 03 (m, 3H, arom ), 7 03-6 9 (br, 1 H NH), 4 18- 10 4 01 (q, 2H, CH ₂ ), 4 01-3 8 (m, 1 H, CH), 3 77 (s, 2H, CH ₂ ), 1 25-1 1 (t+d, 9H CH ₃ )

EXAMPLE 10

8-Chloro-3-ιsopropytamιno-4H-1 ,2.4-benzothιadιazιne 1.1 -dioxide

1 5

Starting from 2-amιno-6-chlorobenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-6- chlorobenzenesulfonyl)-N ^' -ιsopropylthιourea was prepared, m p 144-146 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in

20 Example 4b gave the title compound, m p 273-275 °C

EXAMPLE 11

6-lsopropyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

25

Starting from 2-amιno-4-ιsopropylbenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-4- ιsopropylbenzenesulfonyl)-N ^' -isopropylthiourea was prepared The crude product containing approx 16 % starting material (by ¹ H-nmr) was used without purification for the

30 next step Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 237-239 °C

EXAMPLE 12

7-tert-Butyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Starting from 2-amιno-5-tert-butylbeπzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a N-(2-amιno-5-tert- butylbenzenesulfonyl)-N -isopropylthiourea was prepared, m p 128-130 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 290-293 °C

EXAMPLE 13

3-lsopropylamιno-6-phenoxy-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Starting from 2-amιno-4-phenoxybenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-4- phenoxybenzenesulfonyl)-N ^' -isopropylthiourea was prepared The impure crude product was used without purification Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 250-252 °C

EXAMPLE 14

6-Hexyl-3-ιsopropylamιno-4H-1 ,2.4-benzothιadιazιne 1 ,1 -dioxide

Starting from 2-amιno-4-hexylbenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-4- hexylbenzenesulfonyl)-N ^' -isopropylthiourea was prepared The crude product was obtained as an oil and used without purification Subsequent ring closure with phosgene by a procedure analogous to the one descπbed in Example 4b gave the title compound, m p 319-321 °C

EXAMPLE 15

6-Cyclohexyl-3-ιsopropylamιno-4H-1 ,2,4-beπzothιadιazιne 1 , 1 -dioxide

Starting from 2-amιno-4-cyclohexylbenzenesulfonamιde and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amιno-4- cyclohexylbenzenesulfonyl)-N -isopropylthiourea was prepared, m p 131-133 °C Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m p 264-266 °C

EXAMPLE 16

6-Chloro-3-(1-ethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

The title compound was prepared from 2-amιno-4-chlorobenzenesulfonamιde and 3-pentyl isothiocyanate by a method analogous to the one described in Example 4 m p 224-226°C (ethyl acetate) Η-NMR (DMSO-d ₆ ) δ 0 88 (t, 6H, 2 x CH,), 1 33-1 66 (m 4H, 2 x CH ₂ ), 3 65 (m, 1 H CH), 7 1 (br s, 1 H, NH), 7 21-7 32 (m, 2H, ArH), 7 68 (d, 1 H, ArH), 10 30 (br s, 1 H, NH), MS m/e 301-303 (M+), (C ₁₂ H ₁₆ N ₃ CI,O ₂ S _l ) calc C 47 76 H 5 34 N 13 92 found C 47 74 H 5 49 N 13 93

EXAMPLE 17

(3-lsopropylamιno-1 , 1 -dιoxo-1 4-dιhvdro-1 λ ⁶ ,2,4-benzothιadιazιn-6-yl)acetιc acid

Ethyl (3-ιsopropylamιno-1 ,1-dιoxo-1 ,4-dιhydro-1 λ ⁶ ,2 4-benzothιadιazιn-6-yl)acetate (0 22 g) was stirred in 5 ml of 4M aqueous sodium hydroxide at room temperature for 1 h The reaction mixture was then acidified with 4M hydrochloric acid The resulting precipitate was collected by filtration, the filter cake was rinsed with a small amount of water and dried to give 0 17 g of the title compound, m p 262-264 °C

EXAMPLE 18

6-(3-Cvclopropyl-1 ,2,4-oxadιazol-5-yl)methyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

A mixture of ethyl (3-ιsopropylamιno-1 ,1-dιoxo-1 ,4-dιhydro-1λ ⁶ ,2,4-benzothιadιazιn-6- yl)acetate (0.20 g), crushed 4A molecular sieves (0 6 g), cyclopropanecarboxamide oxime (0 30 g), and sodium hydride (40 mg of a 60 % oil dispersion) in 5 ml of dry dimethylfor- mamide was stirred at room temperature for 45 mm Two drops of glacial acetic acid and 20 ml of dichloromethane were added and the mixture was stirred for 10 mm and filtered througn celite The solvents were removed in vacuo from the filtrate The remaining oil was stirred with 5 ml of water for 15 mm and the resulting precipitate was collected by filtration and dried to give the title compound, m p 255-259°C

EXAMPLE 19

2-(3-lsopropylamιno-1 1 -dιoxo-1 ,4-dιhydro-1λ ⁶ 2,4-benzothιadιazιn-6-yl)acetamιde

Ammonia gas was passed through a solution of ethyl (3-ιsopropylamιno-1 ,1-dιoxo-1 ,4- dιhydro-1λ ⁶ ,2,4-benzothιadιazιn-6-yl)acetate (0 20 g) and sodium cyanide (20 mg) in 10 ml of methanol at room temperature for 5 mm The solution was heated at 55-60 °C in a sealed flask overnight The solvent was removed in vacuo and the residue was treated with 25 ml of water On standing, a crystalline precipitate was formed The crystals were filtered off and dried to give the title compound, m p 321-325 °C

EXAMPLE 20

(3-lsopropylamιno-1 1 -dιoxo-1 ,4-dιhvdro-1 λ ⁶ ,2,4-benzothιadιazιn-6-yl)acetonιtrιle

A slurry of 2-(3-ιsopropylamιno-1 , 1-dιoxo-1 4-dιhydro-1λ ⁶ ,2,4-benzothιadιazιn-6- yl)acetamιde (50 mg) in a mixture of 0 8 ml of acetonitrile, 0 2 ml of formic acid and 25 mg of paraformaldehyde was heated at reflux for 16 h, and then evaporated to dryness The residue was purified on a silica column eluted with dichloromethane-methanol (95 5) to give the title compound, m p 195-203 °C

EXAMPLE 21

3-Benzyloxyamιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

To a solution of O-benzylhydroxylamine hydrochloride (500 mg ) and triethylamine (200 mg) in ethanol (10 ml) was added 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (500 mg) The mixture was stirred for 3 h and concentrated in vacuo The crude product was taken up in hot ethyl acetate (50 ml) and cooled to room temperature and the precipitate was collected by filtration to give the title compound (200 mg, 59 %), m p >220 °C, ¹ H- NMR (DMSO-d6) ppm, 11 2 (br s,1 H, NH), 7 7-7 35(m, 9H,arom and NH), 4 49 (s, 2H, CH ₂ ) Analysis C ₁₄ H ₁₂ CIN ₃ 0 ₃ S requires C 49 78 H 3 58 , N 12 44 (found C 49 49 , H 3 80 N 12 09)

EXAMPLE 22

7-Chloro-3-methoxyamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Starting from 3 7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (502 mg, 2 mmol) and O- methylhydroxylamine hydrochloride (300 mg) and with the use of the same procedure as in example 21 280 mg (57 %) of the title compound was prepared, m p >220 °C, ¹ H-NMR (DMSO-dδ) ppm 11 35 (s,1 H, NH),11 28 (s,1 H,NH), 7 78 (d, 1 H,H-8) 7 63 (dd, 2H, H-6 and H-5) 3 80 (s, 3H, CH ₃ ), ¹³ C-NMR (DMSO-d6) ppm 151 19, 132 79, 131 26, 127 10, 123 00 120 83, 118 78, 63 25

EXAMPLE 23

6-Chloro-3-butylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

The title compound was prepared from 2-amιno-4-chlorobenzenesulfonamιde and butyl isothiocyanate by a method analogous to the one described in Example 4, m p 267-269°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 0 90 (t, 3H, CH ₃ ), 1 24-1 60 (m, 4H, CH ₂ CH ₂ ), 3 21 (q, 2H, NHCH ₂ ), 7 2-7 4 (m, 3H, ArH +NH), 7 68 (d, 1 H, ArH),10 55 (br s, 1 H, NH), MS m/e 287-289 (M+), (CH^CIASO calc C 45 91 H 4 91 N 14 60, found C 45 92 H 5 12 N 14 46

EXAMPLE 24

6-Chloro-3-hexylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

The title compound was prepared from 2-amιno-4-chlorobenzenesulfonamιde and hexyl isothiocyanate by a method analogous to the one described in Example 4, m.p 244-247°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 0 88 (distorted t 3H, CH ₃ ), 1 31 (m, 6H, 3 x CH ₂ ), 1 53 (m, 2H, CH ₂ ), 3 22 (q, 2H, NHCH ₂ ), 7 2-7 4 (m, 3H, ArH +NH), 7 68 (d, 1 H, ArH), 10 55 (br s, 1H, NH), MS m/e 315/317 (M+), calc C 49 44 H 5 74 N 13 31 , found C 49 59 H 6 01 N 13 25

EXAMPLE 25

7-Bromo-3-ιsopropylamιno-6-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

A solution of 3-ιsopropyiamιno-6-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (307 mg, 1 mmol) in water (5ml) was added 40% hydrobromic acid (0 44 ml, 3 mmol) The solution was then heated to 70 °C and 30% hydrogen peroxide (0 33 g, 3 mmol) was added After 30 mm the reaction mixture was cooled and extracted with ethyl acetate (20 ml) and purified by column chromatograpy (ethyl acetate ethanol 9 1) Concentration of the appropiate fractions produced the title compound (22 mg), 'H-NMR (DMSO-d6) ppm, 7 60 (s, 1H), 7 10 (s, 1H), 6 65 (s, 1H), 3.95 (m, 1H) 1 11 (d, 6H)

EXAMPLE 26

6,7-Dιchloro-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

The title compound was prepared from 2-amιno-4,5-dιchlorobenzenesulfonamιde and 1 ,2- dimethylpropyl isothiocyanate by a method analogous to the one described in Example 4, m p 242-250°C (ethyl acetate), ¹ H-NMR (DMSO-d ₆ ) δ 0 90 (d, 3H, CH ₃ ), 0 91 (d, 3H, CH ₃ ), 1 10 (d, 1 H, CH ₃ ), 1 77 (m, 1 H, CH(CH ₃ ) ₂ ), 3 71 (m, 1 H, NHCH), 7 29 (br , 1 H, NH),

7 49 (br s, 1 H, ArH), 7 89 (s, 1 H ArH), 10 41 (br s, 1 H, NH), MS m/e 335/337/339 (M+), calc C 42 87 H 4 50 N 12 50, found C 42 94 H 4 68 N 12 45

EXAMPLE 27

6-Chloro-3-(1 ,2,2-trιmethylpropyl)ammo-4H-1 ,2,4-benzothιadιazιne 1.1-dιoxιde

Starting from 3,6-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (500 mg, 1 99 mmol) and 1 ,2,2-tÏ€methylpropylamιne (500 mg, 5 62 mmol) with the use of same procedure as in example 21 250 mg (39 8 %) of the title compound was prepared m p >220 °C Η-NMR (DMSO-d6) ppm, 10 3 (s,1 H, NH), 7 70 (d, 1 H, H-8), 7 31 (dd, 1 H, H-7), 7 25 (br d, 1 H H- 5), 7 15 (br, 1 H, NH), 3 75 (q, 1 H, CH), 1 10 (d, 3H CH ₃ ), 0 9 (s, 9H, 3xCH ₃ ) Analysis C ₁₃ H _1β CIN ₃ 0 ₂ S requires C 49 44 H 5 74 , N 13 3 (found C 49 37 H 6 04 , N 13 11 )

EXAMPLE 28

7-Bromo-3-(1 ,2,2-trιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Starting from 7-bromo-3-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde (300 mg, 1 01 mmol) and 1 ,2,2-tÏ€methylpropylamιne (359 mg, 4 04 mmol) with the use of same procedure as in example 21 200 mg (54 9 %) of the title compound was prepared, m p >220 °C, 'H-NMR (DMSO-d6) ppm, 10 35 (s, 1H, NH), 7 78 (d, 1 H, H-8), 7 6 (dd, 1 H H-6), 7 12 (br d, 1 H, H-5), 6 95 (br, 1 H, NH), 3 72 (q, 1 H, CH), 1 10 (d, 3H, CH ₃ ), 0 92 (s, 9H, 3xCH ₃ ), MS EI/70eV 361 (M+1 ), 304, 277, 236, 170, 116, 90, 44

EXAMPLE 29

6,7-Dιchloro-3-(1-methylbutyl)amιno-4H-1.2,4-benzothιa dιazιne 1 ,1 -dioxide

The title compound was prepared from 2-amιno-4,5-dιchlorobenzenesulfonamιde and 2- pentyl isothiocyanate by a method analogous to the one descÏ€bed in Example 4, m p 217- 220°C (ethyl acetate), ¹ H-NMR (DMSO-d ₆ ) δ 0 90 (t, 3H, CH ₃ ), 1 14 (d, 3H, CH ₃ ), 1 20- 1 55 (m, 4H, CH ₂ CH ₂ „ 3 83 (m, 1 H, NHCH), 7 33 (br , 1 H, NH), 7 49 (br s, 1H, ArH), 7 89

(s, 1H, ArH), 1048 (br s, 1H, NH), MS m/e 335/337/339 (M+)

EXAMPLE 30

5-Amιno-7-chloro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

To a stirred suspension of 7-chloro-3-ιsopropylamιno-5-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (200 mg, 0 63 mmol) and zmk (200 mg, 3 06 mmol) in acetic acid (20 ml) was added 36 % hydrochloric acid (0 3 ml) The mixture was stirred for 12 hr After filtration and concentation in vacuo the crude product was purified by column chromatography eluting with ethyl acetate ethanol (9 1) Concentration of the appropriate fractions produced 90 mg of the title compound, m p > 230 °C

EXAMPLE 31

7-Chloro-3-(1.3-dιmethylpentyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Starting from 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (500 mg, 1 99 mmol) and 1 ,3-dιmethyipentylamιne (1 g, 8 68 mmol) and with the use of same procedure as in example 21 230 mg (35 1 %) of the title compound was prepared, m p >220 °C, Η-NMR (DMSO-d6) ppm, 10 41 (s,1 H, NH), 7 68 (d, 1 H, H-8), 7 60 (dd 1 H H-5), 7 2 (d, 1 H, H-7), 7 0 (br, 1 H, NH), 3 95 (m, 1 H, CH), 1 5 (m, 8H ), 0 9 (m, 6H, 2xCH ₃ ), MS EI/70eV 329 (Ml 301 , 258, 231 , 190, 126, 69, 44 Analysis C ₁₄ H ₂₀ CIN ₃ O ₂ S requires C 50 98 , H 6 1 1 N 12 74 (found C 51 23 , H 6 42 , N 12.53)

EXAMPLE 32

7-Chloro-3-(1 ,5-dιmethylhexyl)amιno-4H-1.2,4-benzothιadιazιne 1 ,1-dιoxιde

Starting from 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde (300 mg, 1 19 mmol) and 1 ,5-dιmethylhexylamιne (1 g, 7 73 mmol) and with the use of same procedure as in example 21 260 mg (63 5 %) of the title compound was prepared, m p >220 °C ¹ H-NMR (DMSO-d6) ppm, 10 50 (s,1 H, NH), 7 68 (d, 1 H, H-8), 7 63 (dd, 1 H H-5), 7 25 (d, 1 H, H-

7) 7 1 (br, 1 H, NH), 3 85 (q, 1 H, CH), 1 5 (m, 4H ), 1 35 (m, 3H ), 1 15 (d, 3H CH ₃ ), 0 85

(d, 6H, 2xCH ₃ )

MS EI/70eV 343 (M ⁺ ) 300, 258, 231 , 190, 126, 69, 44

EXAMPLE 33

7-Chloro-3-(1 ,4-dιmethylpentyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde

Starting from 3 7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (300 mg, 1 19 mmol) and 1 ,4-dιmethylpentylamιne (1 0 g, 8 68 mmol) with the use of same procedure as in example 21 210 mg (53 5 %) of the title compound was prepared, m p >220 °C, Η-NMR (DMSO- d6) ppm 10 4 (s,1 H, NH), 7 7 (d, 1 H, H-8), 7 6 (dd, 1H, H-5), 7 25 (d, 1 H, H-7), 7 1 (br, 1 H, NH), 3 88 (q 1 H CH ₂ ), 1 55 (m, 3H),1 21 (m, 2H), 1 1 (d, 3H CH ₃ ), 0 9 (d, 6H, 2xCH ₃ ) MS EI/70eV 330 (M ^* ), 258, 231 , 190, 126, 69, 55, 44 Analysis C ₁₀ H ₁₂ CIN ₃ O ₂ S requires C 50 98 , H 6 1 1 , N 12 74 (found C 51 14 , H 6 43 N 12 64)

EXAMPLE 34

5,7-Dιchloro-3-isopropylamιno-4H-1 ,2.4-benzothιadιazιne 1.1-dιoxιde

Starting from 2-amιno-3,5-dιchlorobenzenesulfonamιde (0 5 g, 2 07 mmol) and isopropyl isothiocyanate (251 mg, 2 48 mmol) with the use of the procedure described in example 4, 100 mg (17 4 %) of the title compound was isolated, m p >230 °C

EXAMPLE 35

7-Chloro-3-(3,3-diphenylpropylamιno)-4H-1.2 4-benzothιadιazιne 1 1-dιoxιde

Starting from 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (300 mg,1 19 mmol) and 3,3-dιphenylpropylamιne (1 5 g, 7 1 mmol) with the use of same procedure as in example

21 300 mg (59 %) of the title compound was prepared, Η-NMR (DMSO-d6) ppm, 10 7 (s,1 H, NH), 7 68 (d, 1 H, H-8), 7 60 (dd, 1 H, H-5), 7 25 (m, 11H, ), 4 1 (t, 1 H, CH) 3 11 (q, 2H, CH ₂ ), 2 35 (q, 2H, CH ₂ ), MS E!/70eV 425 (M ⁺ ), 245, 193, 180, 165, 152, 115

EXAMPLE 36

7-Chloro-3-(4-phenylbutylamιno)-4H-1.2,4-benzothιadιaz ιne 1 ,1 -dioxide

Starting from 3,7-dιchloro-4H-1 ,2,4-beÏ€zothιadιazιne 1 , 1 -dioxide (300 mg, 1 19 mmol) and 4-phenylbutylamιne (1 5 g, 4 12 mmol) and with the use of same procedure as in example 21 120 mg (27 7 %) of the title compound was prepared , ¹ H-NMR (DMSO-d6) ppm, 10 8 (s,1 H, NH), 7 75 (d, 1 H, H-8), 7 60 (dd, 1 H, H-5), 7 2 (m, 7H), 3 29 (t, 2H, CH ₂ ), 2 66 (t, 2H, CH ₂ ), 1 5 (m, 4H, 2xCH ₂ ), MS EI/70eV 363 (M ⁺ ), 272, 259, 231 , 180, 91 44

EXAMPLE 37

6-Chloro-3-(1.2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1.1 -dioxide

Phosphorus pentoxide (7 55 g, 53 2 mmol), N,N-dιmethylcyclohexyiamιne (17 ml, 113 mmol) and 1 ,2-dιmethylpropyiamιne hydrochloride (12 4 g, 100 4 mmol) were carefully mixed and heated with mechanical stirring on an oil bath at 190-200°C for about 15 mm To the homogeneous mass was added 6-chloro-3,4-dιhydro-3-oxo-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (5 84 g, 25 1 mmol) and the mixture was stirred at 235°C for 2 h After cooling to about 100°C, water (200 ml) was added and the dark mixture was hydrolysed by stirring over night at room temperature The precipitate was isolated by filtration and recrystallised from ethanol with decolorising charcoal to give 2,83 g (37%) of the pure title compound, m p.(DSC) 264 7°C, ¹ H-NMR (DMSO-d ₆ ) δ 0 90 (dd, 6H, CH(CH ₃ ) ₂ ), 1 09 (d, 3H, NCHCH ₃ ), 1 76 (m, 1 H, CH(CH ₃ ) ₂ ), 3 70 (m, 1 H, NHCH), 7 15 (br , 1 H, NH), 7 28 (m, 2H, ArH), 7 68 (d, 1 H,ArH), 10 3 (br s, 1 H, NH), (C^H^^C^O.S,) calc C 47 76 H 5 34 N 13 92, found C 47 66 H 5 47 N 13 91

EXAMPLE 38

6-Chloro-3-(1 ,2-dιmethylpropyl)amιno-7-sulfamoyl-4H-1.2,4-benzothιadι azιne 1 , 1 -dioxide

The title compound was prepared from 6-chloro-2,3-dιhydro-3-oxo-7-sulfamoyl-1 ,2 4- benzothiadiazine 1 ,1 -dioxide (4 94 g, 15 84 mmol) and 1 ,2-dιmethylpropylamιne hydro¬ chloride (8 0 g, 65 0 mmol) by a method analogous to the method described in example 37, except that the product was purified by column chromatography affording 143 mg (2 4%) of pure product, m p (DSC) 244°C (methanol), ¹ H-NMR (DMSO-d ₆ ) δ 0 90 (dd, 6H, CH(CH ₃ ) ₂ ), 1 11 (d, 3H, NCHCH ₃ ), 1 76 (m, 1 H, CH(CH ₃ ) ₂ ), 3 71 (m, 1 H, NHCH) 7 34 (br 1 H, NH), 7 41 (br s, 1H ArH), 7 80 (br s, 2H, S0 ₂ NH ₂ ) 8 18 (s, 1 H, ArH) 10 58 (br s 1 H NH), MS (FAB) m/e 381/383 (MH+), (C _l2 H ₁₇ N ₄ CI,0 ₄ S ₂ ) calc C 37 84 H 4 50 N 14 71 found C 37 66 H 4 65 N 14 52

EXAMPLE 39

3-Anιlιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

The title compound was prepared from 6-chloro-2,3-dιhydro-3-oxo-1 2,4-benzothιadιazιne 1 ,1-dιoxιde (3 0 g, 12 9 mmol) and aniline (4 8 g 52 0 mmol) by a method analogous to the method described in example 37 except that triethylamine hydrochloride (7 1 g 52 0 mmol) was used instead of N,N-dιmethylcyclohexylamιne Yield 1 68 g (44 %) of pure product, m p (DSC) >350°C (ethanol^H-NMR (DMSO-d ₆ ) δ 7 1-7 8 (m, 8H, ArH) 9 5 (br s, 1H, NH), 11 05 (br s, 1 H NH), MS m/e 307/309 (M+), (C^H^CI^S,) calc C 50 74 H 3 28 N 13 65, found C 50 31 H 3 24 N 13 59

EXAMPLE 40

7-Chloro-3-(4-pyrιdyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

The title compound was prepared from 6-chloro-2,3-dιhydro-3-oxo-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde (3 0 g, 12 9 mmol) and 4-amιnopyπdιne (4 9 g, 52 0 mmol) by a method analogous to the method described in example 39, except that the hydrolysed mixture was adjusted to pH 7 and extracted with ethyl acetate (5 x 50 ml) The organic phase was

evaporated to dryness and the residue was purified by column chromatography affording 34 mg (0 9%) of product; ¹ H-NMR (DMSO-d ₆ ) δ 7 32 (d, 1H, ArH), 7 40-7 52 (m, 4H, ArH), 7 68 (dd, 1 H, ArH), 7 76 (dd, 1 H, ArH), 9 6 (br s, 1 H, NH), 11 05 (br s, 1 H, NH)

EXAMPLE 41

6-Chloro-3-ιsobutylammo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

A mixture of 2-ammo-4-chlorobenzenesulfonamιde (5.0 g, 24 18 mmol) and isobutyl isothiocyanate (10 ml, 83 6 mmol) was heated at 150°C for 3 h The mixture was allowed to cool and then stirred with 50 ml of ethyl acetate for 30 mm The precipitate was isolated by filtration and recrystallised from ethanol to give 2 9 g (42 %) of the pure title compound, m p 298-301 °C, Η-NMR (DMSO-d ₆ ) δ 0 91 (d, 6H, CH(CH ₃ ) ₂ ), 1 83 (m, 1 H, CH(CH ₃ ) ₂ ), 3 05 (t, 2H, CH ₂ ), 7 2-7 4 (m, 3H, ArH + NH), 7 67 (d, 1 H, ArH), 10 5 (br s, 1 H, NH) MS m/e 287/289 (M+), (CHwNaCIAS,) calc C 45 91 H 4 90 N 14 60, found C 45 90 H 5 04 N 14 66

EXAMPLE 42

3-sec-Butylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

A mixture of 2-amιno-4-chlorobenzenesulfonamιde (2 1 g, 10 16 mmol) and sec-butyl isothiocyanate (5 0 ml, 40 9 mmol) was heated at 150°C for 4 h The mixture was allowed to cool and then stirred with 25 ml of ethyl acetate for 1 h The precipitate was isolated by filtration and recrystallised from ethanol to give 201 mg (7 %) of the title compound as white crystals, m p 242-245°C, Η-NMR (DMSO-d ₆ ) δ 0 89 (t, 3H, CH ₂ CH ₃ ), 1 15 (d, 3H, CHCH ₃ ), 1 50 (m, 2H, CH ₂ ), 3 76 (m, 1 H, CH),7.19 (br s, 1H, NH), 7 29 (m, 2H, ArH), 7 68 (d, 1H, ArH), 10.35 (br s, 1H, NH), MS" m/e 287/289 (M+), (C ₁₁ H ₁₄ N ₃ CI ₁ 0 ₂ S ₁ ) calc C 45 91 H 4 90 N 14 60, found C 46 42 H 5 08 N 14 65

EXAMPLE 43

6-Chloro-3-cvclohexylmethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

A mixture of 2-amιno-4-chlorobenzenesulfonamιde (2 1 g, 10 16 mmol) and cyclohexyl- methyl isothiocyanate (6 31 g, 40.6 mmol) was heated at 150°C for 4 h The mixture was allowed to cool and then stirred with 25 ml of ethyl acetate for 1 h The precipitate was isolated by filtration and recrystallised from ethanol to give 867 mg (26 %) of the title compound, m p 317-323°C, ¹ H-NMR (DMSO-d ₆ ) δ 0 8-1 8 (m, 11 H cyclohexyl), 3 08 (t, 2H, CH ₂ ), 7 78 (m, 3H, ArH + NH), 7 68 (d, 1H, ArH), 10 52 (br s, 1 H NH), MS m/e 327/329 (M+), (dAβNaCIASi) calc C 51 29 H 5 53 N 12 82, found C 51 21 H 5 72 N 12 81

EXAMPLE 44

6-Fluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

A mixture of 2-amιno-4-fluorobenzenesulfonamιde (1 9 g, 10 mmol) and isopropyl isothiocyanate (6 4 ml, 60 mmol) was heated at 140°C for 2 5 h The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate for 20 mm The precipitate was isolated by filtration and washed with ethyl acetate to give 355 mg (14 %) of the title compound m p 266-269X, Η-NMR (DMSO-d ₆ ) δ 1 18 (d, 6H, CH(CH ₃ ) ₂ ), 3 91 (m, 1 H, CH(CH ₃ ) ₂ ) 7 00-7 13 (m, 2H, ArH), 7 16 (br s, 1 H, NH), 7 73 (dd, 1 H ArH), 10 4 (br s 1H, NH), MS m/e 257 (M+, 25%), (C ₁₀ H _l2 N ₃ FASι) calc C 46 68 H 4 70 N 16 33, found C 46 84 H 4 88 N 16 13

EXAMPLE 45

3-Cyclopentylamιno-6-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

A mixture of 2-amιno-4-fluorobenzenesulfonamιde (1 71 g, 9 mmol) and cyclopentyl isothiocyanate (4 6 ml, 36 mmol) was heated at 140 ^β C for 4 h The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate The precipitate was isolated by filtration and recrystallised from ethanol to give 591 mg (23 %) of the title compound m p 295-298°C, ¹ H-NMR (DMSO-d ₆ ) δ 1 37-2 02 (m, 8H, cyclopentyl), 4 05 (sext, 1 H, CH),

6 97-715 (m, 2H, ArH), 7 32 (br s, 1 H, NH), 7 72 (dd, 1 H, ArH), 10 35 (br s, 1 H, NH), MS m/e 283 (M+, 21%), (C _l2 H ₁₄ N ₃ FASι) calc C 50 87 H 4 98 N 14 83, found C 50 75 H 5 12 N 14 93

EXAMPLE 46

7-Chloro-3-ιsopropylamιno-5-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

The title compound was prepared from 2-amιno-5-chloro-3-nιtrobenzenesulfonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4, m p 266-267°C ¹ H-NMR (DMSO-d ₆ ) δ 1 20 (d, 6H, CH(CH ₃ ) ₂ ), 3 92 (m, 1 H CH(CH ₃ ) ₂ ), 8 19 (d, 1H, ArH), 8 48 (d, 1H, ArH), 8 72 (br s, 1H, NH), 10 57 (br s, 1 H, NH), MS m/e 318/320 (M+), (C ₁₀ H _{l 1} N ₄ CI ₁ O ₄ S ₁ ) calc C 37 68 H 3 48 N 17 58, found C 37 82 H 3 54 N 17 58

EXAMPLE 47

3-tert-Butylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

The title compound was prepared from 2-amιno-4-chlorobenzenesulfonamιde and tert- butyl isothiocyanate by a method analogous to the one described in Example 4 except that the mixture was heated at 60°C for 6 days The intermediate N-(2-amιno-4- chlorobenzenesulfonyl)-N ^' -tert-butylthιourea and the ring closed product were both purified by column chromatography , m p 291 -294°C (light petroleum/ ethyl acetate), Η- NMR (DMSO-d ₆ ) δ 1 39 (s, 9H, C(CH ₃ ) ₃ ), 6 92 (br s, 1 H, NH), 7 17 (d, 1 H ArH), 7 28 (dd, 1H, ArH), 7 68 (d, 1 H, ArH), 10 25 (br s, 1H, NH), MS m/e 287/289 (M+)

EXAMPLE 48

7-lodo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

The title compound was prepared from 2-amιno-5-ιodobenzenesulfonamιde and isopropyl

isothiocyanate by a method analogous to the one described in Example 4, m p 305-307°C dec, Η-NMR (DMSO-d ₆ ) δ 1 17 (d, 6H, CH(CH ₃ ) ₂ ), 3 91 (m, 1H, CH(CH ₃ ) ₂ ), 7 02 (d, 1 H, ArH), 7 15 (br , 1 H, NH), 7 8-7 9 (m, 2H, ArH), 10 43 (br s, 1 H, NH), MS m/e 365 (M+, 27%), (C ₁₀ H ₁₂ N ₃ l ₁ O ₂ S ₁ ) calc C 32 89 H 3 31 N 11 51 , found C 32 79 H 3 41 N 11 27 5

EXAMPLE 49

6-Chloro-7-fluoro-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

1 o The title compound was prepared from 2-amιno-4-ch!oro-5-fluorobenzenesu!fonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4 m p 282-285°C (ethyl acetate), ¹ H-NMR (DMSO-d ₆ ) δ 1 17 (d, 6H, CH(CH ₃ ) ₂ ), 3 92 (m, 1 H, CH(CH ₃ ) ₂ ), 7 34 (br , 1 H, NH), 7 45 (d, 1H, ArH), 7 76 (d, 1H, ArH), 10 44 (br s, 1 H, NH), MS m/e 291/293 (M+), (C ₁₀ HιιN ₃ CI,FASι) calc C 41 17 H 3 80 N 14 40, found C

1 5 41 3 H 3 8 N 14 4

EXAMPLE 50

20 3-lsopropylamιno-6-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

The title compound was prepared from 2-amιno-4-tÏ€fluoromethylbenzenesulfonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4, m p 294-297°C (ethyl acetate), ¹ H-NMR (DMSO-d ₆ ) δ 1 20 (d, 6H, CH(CH ₃ ) ₂ ), 3 95 (m, 25 1 H, CH(CH ₃ ) ₂ ), 7 42 (br , 1H, NH), 7 56 (m, 2H, ArH), 7 99 (d, 1 H, ArH), 10 55 (br s, 1 H, NH), MS- m/e 307 (M+, 33%), H ₂ O) calc C 40 6 H 4 3 N 12 9, found C 41 0 H 4 1 N 13 1

EXAMPLE 51 30

7-Chloro-3-cvclopropylmethylamιno-4H-1.2.4-benzothιadι azιne 1 , 1 -dioxide

The title compound was prepared from 2-amιno-5-chlorobenzenesulfonamιde and

cyclopropylmethyl isothiocyanate by a method analogous to the one described in Example 4, m p 288-290°C (ethyl acetate), ¹ H-NMR (DMSO-d ₆ ) δ 0 20-0 54 (m, 4H, CH ₂ CH ₂ ), 1 05 (m, 1 H, CH), 3 10 (distorted t, 1 H, NHCH ₂ ), 7 22 (d, 1 H, ArH ),7 31 (br , 1 H, NH), 7 55- 7 69 (m, 2H, ArH), 10 7 (br s, 1 H, NH), MS m/e 285/287 (M+), calc C 5 46 24 H 4 23 N 14 71 found C 46 48 H 4 32 N 14 72

EXAMPLE 52

3-lsopropylamιno-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 0

The title compound was prepared from 2-amιno-5-methylbenzenesulfonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4, m p 266-268°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 1 16 (d, 6H, CH(CH ₃ ) ₂ ), 3 91 (m, 1H, CH(CH ₃ ) ₂ ) 6 92 (br d, 1 H, NH), 7 06 (d, 1 H, ArH), 7 35 (dd, 1 H, ArH), 7 45 (d, 1 H, 5 ArH),10 20 (br s, 1 H, NH), MS m/e 253 (M+ 44%), (CH _I NAS,) calc C 52 16 H 5 97 N 16 59, found C 52 28 H 6 19 N 16 49

EXAMPLE 53 0

5,7-Dιbromo-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

The title compound was prepared from 2-amιno-3,5-dιbromobenzenesulfonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4, 5 m p 306-311°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 1 19 (d, 6H, CH(CH ₃ ) ₂ ), 3 90 (m, 1H, CH(CH ₃ ) ₂ ), 7 82 (d 1 H, ArH), 7 92 (br d, 1 H, NH), 8 16 (d, 1H, ArH), 9 65 (br s, 1H, NH), MS m/e 395/397/399 (M+), calc C 30 25 H 2 79 N 10 58, found C 30 34 H 2 77 N 1048

0 EXAMPLE 54

6-Acetyl-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazme 1 1 -dioxide

The title compound was prepared from 4-acetyl-2-amιnobenzenesulfonamιde and isopropyl isothiocyanate by a method analogous to the one described in Example 4, m p.305-308°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 1 19 (d, 6H, CH(CH ₃ ) ₂ ), 3 95 (m, 1 H, CH(CH ₃ ) ₂ ), 7 25 (br , 1H, NH), 7 70-7 85 (m, 3H, ArH), 10 5 (br s, 1H, NH), MS m/e 281 (M+, 39%), (C ₁₂ H ₁₅ N ₃ O ₃ S,) calc C 51.23 H 5.37 N 14 94, found C 51 15 H 5 50 N 14 69

EXAMPLE 55

3-Allylamιno-6-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

The title compound was prepared from 2-amιno-4-chlorobenzenesulfonamιde and ally! isothiocyanate by a method analogous to the one described in Example 4, m p 284-286°C (ethyl acetate), Η-NMR (DMSO-d ₆ ) δ 3 88 (distorted t, 2H, NHCH ₂ ), 5 1-5 3 (m, 2H, =CH ₂ ), 5 78-6 0 (m, 1 H, =CH), 7 22-7 35 (m, 2H, ArH), 7 50 (br t, 1 H, NH), 7 69 (d, 1 H, ArH), 10 73 (br s, 1 H, NH), MS m/e 271/273 (M+), (C ₁₀ H ₁₀ N ₃ C ^] AS,) calc C 44 20 H 3 71 N 15 46, found C 44 10 H 3 79 N 15 32

EXAMPLE 56

3-lsopropylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

a) 2-Chloro-5-nιtrobenzenesulfonamιde

Glacial acetic acid (160 mL) was saturated with gaseous sulfur dioxide and then supple¬ mented with an aqueous solution of cupπc chlortde (7 g/20 mL)

A solution of 2-chloro-5-nιtroanιlιne (10 g) in glacial acetic acid (160 mL) and 12N HCl (40 mL) was cooled to -5°C A solution of sodium nitrite (4 g) in water (20 mL) was then added dropwise under stirring to the cold solution of 2-chloro-5-nιtroanιlιne The diazonium salt formed was added under stirring to the cold solution of sulfur dioxide in acetic acid previously prepared After 10 mm , the mixture was poured on ice (200 g) The

resulting precipitate was collected by filtration, washed with water and suspended in a 10% aqueous solution of ammonia (200 mL) After stirring at room temperature for 30 mm , the mixture was concentrated to the half volume by evaporation under reduced pressure The resulting suspension was adjusted to pH 1 with 12N HCl The insoluble material was collected by filtration, washed with water and crystallized from methanol- water to give 8 8 g of the title compound, m p 174-176°C

b) 2-Amιno-5-nιtrobenzenesulfonamιde

A suspension of 2-chloro-5-nιtrobenzenesulfonamιde (8 g) in concentrated aqueous ammonia (80 mL) was saturated with ammonia just before its introduction into a sealed vessel The former was placed in an autoclave and heated at 120°C for 5 h The reaction mixture was then concentrated to the half volume by evaporation under reduced pressure and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (yield 6 1 g), m p 202-204°C

c) 3-(lmιdazol-1-yl)-7-nιtro-4H-1 2,4-benzothιadιazιne 1 ,1 -dioxide imidazohum salt

To a hot solution of 2-amιno-5-nιtrobenzenesulfonamιde (5 g) in dioxane (150 mL) was added thiocarbonyldnmidazole (14 g) and the reaction mixture was refluxed for 5 h After cooling, the precipitate of the title compound was collected by filtration washed with dioxane and dried to give the title compound (yield 5 7 g ), m p 246-248°C

d) 3-lsopropylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

3-(lmιdazol-1-yl)-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde imidazolium salt was treated with isopropylamme according to the general procedure Method A to give the title compound, m p 311-313 °C, IR (KBr) 3363, 3221 , 2980, 1657, 1646, 1615, 1601 , 1572, 1532, 1494, 1339, 1284, 1267, 1155, 1106 cm \ Η-NMR (DMSO-d ₆ , HMDS, d ppm) 1 10 (d, 6H, 2 x

CH ₃ ), 3 90 (m, 1 H, NH-CH), 7 35 (m, 2H, 5-H + NH-CH), 8 35 (m, 2H, 6-H + 8-H), 10 90 (bs, 1 H, NH)

EXAMPLE 57

3-sec-Butylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1.1-dιoxιde

3-(lmιdazol-1-yl)-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde imidazohum salt was treated with sec-butylamine according to the general procedure Method A to give the title compound m p 287-288°C

EXAMPLE 58

3-(1 ,2-Dιmethylpropyl)arnιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

3-(lmιdazol-1-yl)-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide imidazohum salt was treated with 1 ,2-dιmethylpropyiamιne according to the general procedure Method B to give the title compound, m p 308-311 °C, IR (KBr) 3294, 3199, 3101 , 2965, 1636, 1600, 1566, 1538 1497, 1485 1349 1252 1166, 1153, 1 107 cm ¹

EXAMPLE 59

3-(Cvclopropylmethyl)arnιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

3-(lmιdazol-1 -yl)-7-nιtro-4H-1 2,4-benzothιadιazιne 1 ,1-dιoxιde imidazohum salt was treated with cyctopropylmethylamine according to the general procedure Method D to give the title compound, m p 276-278°C, IR (KBr) 3290, 3193, 3104, 2994, 1635, 1603, 1564, 1539, 1499, 1486, 1347 1276, 1251 , 1153, 11 11 cm ¹

EXAMPLE 60

7-Nιtro-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

60

3-(lmιdazol-1-yl)-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde imidazohum salt was treated with propylamine according to the general procedure Method A to give the title compound, m p 268-270°C

EXAMPLE 61

3-Cvclobutylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

3-(lmιdazol-1-yl)-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide imidazohum salt was treated with cyclobutylamine according to the general procedure Method D to give the title compound, m p 298-301 °C

EXAMPLE 62

7-Amιno-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

A solution of 3-ιsopropylamιno-7-nιtro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (0 6 g) in hot methanol (25 mL) was supplemented with 10% Pd/C (0 06 g) and submitted to hydrogen under pressure (4 bars) for 1 h at 40°C The insoluble mateÏ€al was removed by filtration and the filtrate was concentrated to dryness by evaporation under reduced pressure The residue of the crude title compound was recrystallized from methanol-water (yield 0 45 g), m p 278-283°C, IR (KBr) 3455, 3363, 3216, 2972, 1618, 1575, 1510, 1298 1255, 1 174, 1146, 11 13 cm ¹ , Η-NMR (DMSO-d ₆ , HMDS, d ppm) 1 10 (d, 6H, 2 x CH ₃ ), 3 85 (m, 1 H, NH-CH), 5 15 (bs, 2H, NH ₂ ), 6 50-6 95 (bm, 4H, 5-H + 6-H + 8-H + NH-CH), 9 75 (bs, 1 H

NH)

EXAMPLE 63

7-Acetylamιno-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

A mixture of 7-amιno-3-ιsopropylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (0 18 g) and

acetic anhydride (0 6 mL) in dioxane (2 mL) was stirred for 1 h at room temperature The medium was then mixed with water (5 mL) and stirred for 1 h The solvents were removed by distillation under reduced pressure and the residue of the crude title compound was recrystallized from methanol-water to give the title compound (yield 0 16 g) m p 260- 5 262°C, IR (KBr) 3353, 3316, 3240, 3101 , 3069, 2974, 1672, 1624 1608 1581 1546, 1497, 1467, 1391 , 1279, 1159, 1142 1123, 1104 cm \ ¹ H-NMR (DMSO-d ₆ , HMDS, d ppm) 1 10 (d, 6H, 2 x CH ₃ ), 2 00 (s, 3H, COCH ₃ ), 3 90 (m, 1 H, NH-CH) 6 85 (bd, 1 H,

NH-CH), 7 05 (d, 1 H, 5-H), 7 60 (bd, 1 H, 6-H), 8 00 (bs, 1 H, 8-H), 10 00 (bs, 1 H, CONH), 10 10 (bs 1H NH) 0

EXAMPLE 64

6,7-Dιchloro-3-hexylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

5 a) 6,7-Dιchloro-3-(ιmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide monohydrate

A mixture of 2-amιno-4,5-dιchlorobenzenesulfonamιde (10 g) and thiocarbonyldnmidazole (22 g) in dioxane (160 mL) was refluxed for 2-3 h The solvent was removed by distillation 0 under reduced pressure and the residue was dispersed in water (100 mL) The addition of an aqueous solution of NaOH (16 g/160 mL) gave a solution which after cooling, abundantly precipitated the crystalline sodium salt of the title compound The salt was collected by filtration and dissolved in a 1 2 mixture of methanol and water (300 mL), treated with charcoal filtered, and the filtrate was adjusted to pH 2 with 12N HCl The 5 precipitate was collected by filtration, washed with water and dried (yield 11 3 g), m p 312-315°C

b) 6,7-Dιchloro-3-hexylamιno-4H-1 ,2.4-benzothιadιazιne 1 , 1 -dioxide

0 6,7-Dιchloro-3-(ιmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde monohydrate was treated with hexylamme according to the general procedure Method B to give the title compound, m p 282-286°C, IR (KBr) 3332, 3173, 3074, 2956 2930, 2854, 1637, 1580,

1562, 1464, 1241, 1168, 1143, 1132 cm ¹

EXAMPLE 65

3-Cvclobutylamιno-6,7-dιchloro-4H-1,2,4-benzothιadιaz ιne 1,1 -dioxide

6,7-Dιchloro-3-(ιmιdazol-1-yl)-4H-1,2,4-benzothιadιa zιne 1,1 -dioxide monohydrate was treated with cyclobutylamme according to the general procedure Method D to give the title compound, m p 320-326°C, IR (KBr) 3290, 3163, 3068, 2979 2952, 1631, 1580 1556 1460 1331, 1251 1166, 1152, 1137 1128cm'

In the following, EXAMPLE 66 to 122, the 3-alkylamιno-1,2,4-benzothιadιazιne 1,1- dioxides were prepared from the appropriate 3-methylsulfanyl-1,2,4-benzothιadιazιne 1,1- dioxides and the appropriate alkylammes according to the general procedure described above For each compound the applied method and data for the compound are given

EXAMPLE 66

7-Chloro-3-(cvclohexyimethyl)amιno-4H-1 ,2,4-benzothιadιazιne 11 -dioxide

Method C, m p 277-279°C

EXAMPLE 67

7-Chloro-3-(R)-(1-cvclohexylethyl)amιno-4H-1,2,4-benzoth ιadιazιne 1,1 -dioxide

Method C, m p 177-182 °C, IR (KBr) 3300, 3187, 3085, 2927, 2853, 1631, 1581, 1483, 1251 1162, 1105 cm ¹

EXAMPLE 68

7-Chloro-3-(S)-(1-cvclohexylethyl)amιno-4H-1,2,4-benzothιa dιazιne 1,1-dιoxιde

Method C, m p 177-182 °C, IR (KBr) 3300, 3185 3084, 2927, 2853, 1632, 1578, 1483,

1243, 1162, 1105 cm- ¹ 5

EXAMPLE 69

7-Chloro-3-(R)-(1-phenylethyl)amιno-4H-12,4-benzothιadÎ ¹azιne 11-dιoxιde

10 Method C, m p 178-181°C IR (KBr) 3299, 3183 3085, 2977, 1631, 1568, 1482, 1251, 1163, 1105 cm ¹

EXAMPLE 70

157-Chloro-3-(S)-(1-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Method C, m p 178-181°C, IR (KBr) 3299, 3186 3086, 2977, 1631, 1568, 1482, 1251, 1163, 1105 cm ¹

20 EXAMPLE 71

7-Chloro-3-cyclobutylamιno-4H-1.2,4-benzothιadιazιne 1,1 -dioxide

Method D, m p 275-278°C, IR (KBr) 3284, 3180, 3087, 2983, 1633, 1575, 1494, 1479, 25 1238, 1155, 1125, 1102 cm ¹ NMR (DMSO-d ₆ , HMDS, d ppm) 120-230 (m, 6H,

(CH ₂ )3), 415 (m, 1H, NH-CH), 715 (d, 1H, 5-H), 750 (m, 2H, 6-H + NH-CH), 760 (s, 1H,

8-H), 1025(bs, 1H, NH)

EXAMPLE 72 30

7-Chloro-3-(2,2,2-tÏ€fluoroethyl)amιno-4H-1,2,4-benzothÎ ¹adιazιne 1,1 -dioxide

Method A, m p 302-304°C, IR (KBr) 3283, 3186, 3120, 3087 1627, 1582 1483 1265, 1240 1 181 , 1161 1 136, 1107 cm '

EXAMPLE 73 5 3-Allylanruno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Method A, m p 220-222°C, IR (KBr) 3310, 3185, 3089, 2988 1651 , 1630, 1584, 1483, 1239 1 164, 1138, 1105 cm ¹ 10

EXAMPLE 74

7-Chloro-3-(2-methoxy-1 -methylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

15

Method B, m p 150-153°C, IR(KBr) 3294, 3186, 3118, 3084 2983, 2932, 2880, 1631, 1582 1480, 1250, 1162, 1105 cm ^"1

EXAMPLE 75

20

7-Chloro-3-(1-ethylpropyl)amιno-4H-1.2,4-benzothιadιaz ιne 1 1 -dioxide

Method B, m p 233-236°C, IR (KBr) 3290 3191 , 31 19, 3087, 2968, 2934, 2879, 2859 1627 1582, 1482, 1242, 1158, 1 146, 1121 , 1102 cm ¹ , NMR (DMSO-d ₆ , HMDS d ppm)

25 0 75 (t, 6H, 2 x CH3), 1 40 (quint , 4H, 2 x CH ₂ ), 3 55 (m, 1H NH-CH), 6 95 (b, 1 H, NH- CH), 7 10 (d, 1 H, 5-H), 7 50 (d, 1H, 6-H), 7 55 (s, 1H, 8-H), 10 30 (bs, 1H, NH)

EXAMPLE 76

30 7-Chloro-3-(2-hvdroxypropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

Method B, m p 248-250°C, IR (KBr) 3365, 3174, 3068, 2968 1636, 1587, 1566, 1481

1274 1175 1149 cm ¹

EXAMPLE 77

7-Chloro-3-(2-hvdroxy-1-methylethv!)amιno-4H-1,2,4-benzo thιadιazιne 1,1 -dioxide Method B, m p 216-217°C, IR (KBr) 3428, 3286, 3102, 1626, 1582, 1483, 1272, 1163, 1122 1105 cm ¹ , NMR (DMSO-d ₆ , HMDS, d ppm) 105 (d, 3H, CH ₃ ), 330 (bd, 2H, CH ₂ ), 380 (m, 1H NH-CH), 485 (b, 1H, OH), 690 (bd, 1H, NH-CH), 710 (d, 1H, 5-H), 750 (d, 1H 6-H), 755 (s, 1H, 8-H), 1050 (bs, 1H, NH)

EXAMPLE 78

7-Chloro-3-(2,2-dιethoxyethyl)amιno-4H-1 ,2.4-benzothιadιazιne 11 -dioxide Method B, m p 219-220°C, IR(KBr) 3367, 3194, 3092, 2978, 1627, 1611, 1585, 1570, 1486 1251 1169, 1135 1105 cm ¹ , NMR (DMSO-d ₆ , HMDS, d ppm) 105 (t, 6H, 2 x

CH ₃ ) 325 (bd, 2H, NH-CH ₂ -CH), 355 (q, 4H, 2 x CH ₂ ), 455 (t, 1H, NH-CH ₂ -CH), 700

(b, 1H, NH-CH ₂ -CH), 710 (d, 1H, 5-H), 755 (d, 1H, 6-H), 760 (s 1H, 8-H), 1065 (b, 1H,

NH)

EXAMPLE 79

7-Chloro-3-hexylamιno-4H-1,2,4-benzothιadιazιne 1.1 -dioxide

Method B, mp 218-220X

EXAMPLE 80

3-(2-Butv0amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method A, m p .253-254°C, IR (KBr) 3318, 2969, 1618, 1573, 1476, 1274, 1247 1149, 1114cm ¹

EXAMPLE 81

7-lodo-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method B, m p 267-270°C, IR (KBr) 3317, 2961 , 1616, 1573, 1475, 1276 1248, 1 156, 1115 cm ¹

EXAMPLE 82

7-lodo-3-(1 ,2,2-trιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method B, m p 309-310°C, IR (KBr) 3336, 2961 1620, 1573, 1559 1475 1277, 1253, 1148, 1114 cm ¹

EXAMPLE 83

3-(Cvclohexy!methyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method C m p 285-287°C, IR (KBr) 3312, 2922 2850 1614, 1574 1563 1474 1280 1254, 1148, 1117 cm ¹

EXAMPLE 84

3-(R)-(1-Cvclohexylethyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method C , m p 281-284°C, IR(KBr) 3361 , 3288, 3200, 2921 , 2849, 1629, 1600, 1573, 1475, 1279, 1256, 1 162, 1122 cm ¹

EXAMPLE 85

3-(S)-(1-Cvclohexylethyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 , 1-dιoxιde

Method C, m p. 288-290°C, IR(KBr).3361, 3289, 3201, 2922, 2848, 1628, 1600, 1573, 1475, 1279, 1256, 1161, 1123 cm ^"1

5 EXAMPLE 86

3-Benzylamιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

Method C, m p 254-257°C, IR (KBr) 3289, 3183, 3087, 1626, 1575, 1477, 1268, 1260 10 1235, 1 152, 1 127 cm ¹

EXAMPLE 87

7-lodo-3-(R)-(1-phenylethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide 1 5

Method C, m p 234-236°C, IR (KBr) 3360, 3281 , 3191 , 3077, 1627, 1600, 1567, 1473, 1281 1255, 1 162, 1 132 cm ¹

EXAMPLE 88

20

7-lodo-3-(S)-(1-phenylethyl)amιno-4H-1 2,4-benzothιadιazιne 1 1 -dioxide

Method C, m p 236-239°C, IR (KBr) 3360, 3281 , 3191 , 3076, 1626, 1600, 1567, 1473, 1280, 1255, 1 162, 1 132 cm

25

EXAMPLE 89

3-(3-Pentyl)amιno-7-ιodo-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

30 Method B, m p. 210-220°C, IR (KBr) 3314, 2966, 2938, 2876, 1617, 1574, 1475, 1277, 1250, 1151, 1118 cm ¹ , NMR (DMSO-dβ, HMDS; d ppm) 080 (t, 6H, 2 x C/ήj), 140 (quint , 4H, 2 x CH ₂ ), 360 (m, 1H, NH-CH), 695 (bm, 2H, 5-H + NH-CH), 775 (d, 1H, 6-

H), 785 (s, 1H, 8-H) 1025 (bs, 1H, NH)

EXAMPLE 90

57-Bromo-3-sec-butylamιno-4H-1,2,4-benzothιadιazιne 11-dιoxιde

Method A, m p 224-226°C, IR(KBr).3320, 3105, 2971, 2933, 2879, 1622, 1579, 1480, 1277, 1253, 1158, 1150, 1115cm ¹

10 EXAMPLE 91

7-Bromo-3-(1,2-dιmethylpropyl)amιno-4H-1,2,4-benzothιa dιazιne 1,1-dιoxιde

Method B, m p 254-256°C, IR(KBr) 3319, 2963, 2876, 1618, 1578, 1562, 1478, 1282, 15 1252, 1160, 1151, 1116, 1101 cm ¹

EXAMPLE 92

7-Bromo-3-cvclopropylamιno-4H-1 ,2,4-benzothιadιazιne 11 -dioxide

20

Method A, m p 248-253°C, IR(KBr) 3274, 3198, 3140, 1621, 1588, 1528, 1483, 1445, 1342, 1251, 1158 1147, 1101 cm ¹

EXAMPLE 93

25

7-Bromo-3-methylamιno-4H-1,2,4-benzothιadιazιne 11 -dioxide monohydrate

Method A (using a 40% w/v solution of methylamine in water) mp 305-307°C 30

EXAMPLE 94

7-Bromo-3-ethylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method A (using a 70% w/v solution of ethylamme in water) m.p..267-268°C IR(KBr) 3305,3189,3123,2972, 1630, 1583, 1478, 1249, 1159, 1122 cm- ¹

EXAMPLE 95

7-Bromo-3-cyclobutylamιno-4H-1,2.4-benzothιadιazιne 1,1 -dioxide

Method D mp 279-281 °C

IR(KBr) 3288, 3175, 3081,2984, 1631, 1580, 1563, 1480, 1258, 1242, 1153, 1123 cm- ¹

EXAMPLE 96

7-Bromo-3-(2,2,2-tπfluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method A m p 298-301 °C

EXAMPLE 97

7-Bromo-3-propylamιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method A m.p. 234-235X

EXAMPLE 98

7-Fluoro-3-ιsopropylamιno-4H-1,24-benzothιadιazιne 1,1-dιoxιde

Method A m.p . 242-244°C

IR (KBr) 3304, 3177, 3084, 2986, 1639, 1619, 1594, 1568, 1509, 1493 1267, 1258,

1242, 1178, 1148, 1119, 1108 cm- ¹ 5 NMR (DMSO-d ₆ , HMDS, d ppm) 1 10 (d, 6H, 2 x CH ₃ ), 3 90 (m, 1 H, NH-CH), 7 00 (bd,

1 H, NH-CH), 7 10-7 50 (m, 3H, 5-H + 6-H + 8-H), 10.25 (bs, 1 H, NH)

EXAMPLE 99

10 3-(2-Butyl)amιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde monohydrate

Method A m p 203-205°C

IR (KBr) 3545, 3492, 3348, 3080, 2974 1651 , 1636, 1618, 1595, 1568, 1498, 1267,

15 1180, 1159, 11 15 cm- ¹

EXAMPLE 100

7-Fluoro-3-(1 ,2-dιmethylpropyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 20

Method B m p - 193-198°C

IR (KBr) 3298, 3189, 3089, 2968, 1636, 1616, 1593, 1572, 1504, 1494, 1258 1 168,

1147, 1110 cm- ¹

25

EXAMPLE 101

3-Ethylamιno-7-fluoro-4H-1 ,2.4-benzothιadιazιne 1 , 1 -dioxide

30 Method A (using a 70% w/v aqueous solution of ethylamine) m.p 235-237°C IR (KBr) 3289, 3194, 3127, 3086, 2987, 2891 , 1636, 1620, 1593, 1579, 1505, 1491 ,

1260, 1240 1159, 1 145, 1 112 cm- ¹

EXAMPLE 102

7-Fluoro-3-propylamιno-4H-1 ,2 4-benzothιadιazιne 1 ,1 -dioxide

Method A m p 199-202°C

EXAMPLE 103

3-Cyclopropylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

Method A m p 242-245°C

EXAMPLE 104

3-Cyclobutylamιno-7-fluoro-4H-1 2,4-benzothιadιazιne 1 ,1 -dioxide

Method D m p 252-253°C

IR (KBr) 3303, 3176 3085, 2983, 1640, 1619, 1595, 1566, 1508, 1493, 1260, 1245,

1169, 1 151 , 1138, 1 1 17 cm ^'1

EXAMPLE 105

3-Cyclopentylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Method B m p 237-239°C

IR (KBr) 3299, 3176, 3084, 3008, 2982, 2874, 1640, 1619, 1593, 1569, 1509, 1493,

1266, 1258, 1241 , 1160, 1137, 1112 cÏ€r ¹

EXAMPLE 106

5 3-(Cvclopropylmethyl)amιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method D m p 221-222°C

IR (KBr) 3295 3187 3086, 3008, 2884, 1641 , 1620, 1592 1508, 1496, 1270, 1256 10 1240, 1 155, 1137, 1 1 15 cm- ¹

EXAMPLE 107

3-Allylamιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide 1 5

Method A m p 209-210°C

IR (KBr) 3353 3312, 3187, 3087, 2989, (1636), 1615, 1595, 1569, 1493 1259, 1 164

1 141 , 1 1 19 cm- ¹

20

EXAMPLE 108

7-Fluoro-3-(3-methoxy-2-propyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (or 7-Fluoro-3-(2-methoxy-1-methylethyl)amιno-4H-1 2,4-benzothιadιazιne 1.1 -dioxide) 25

Method B m p 148-149°C

IR (KBr) 3309 3201 , 3137, 3099, 2986, 2934, 2900, 1636, 1618, 1594, 1580, 1507

1494, 1260, 1 149, 1111 cm" ¹ 30 EXAMPLE 109

7-Fluoro-3-methylamιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide monohydrate

Method A (using a 40% w/v aqueous solution of methylamine) m p 275-277°C

EXAMPLE 110

3-(2,2-Dιethoxyethyl)amιno-7-fluoro-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method B m p 202-203X EXAMPLE 11 1

7-Fluoro-3-(2.2,2-tπfluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method A m p 269-271 °C

EXAMPLE 112

3-Cyclobutylamino-7-methyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

Method D m p 289-290°C

IR(KBr) 3285, 3179, 3088, 2986, 2947, 1631, 1587, 1568, 1500, 1269, 1239, 1149, 1122 cm" ¹ EXAMPLE 113

3-lsopropylamιno-7-methoxy-4H-1 ,2.4-benzothιadιazιne 1.1 -dioxide

Method A m p 227-233°C

IR(KBr) 3285, 3128, 2969, 2925, 1628, 1609, 1580, 1505, 1273, 1254, 1147, 1 121 , 1109 cm ^-1

NMR (DMSO-d6, HMDS, d ppm) 1 10 (d, 6H, 2 x CH ₃ ), 3 70 (s, 3H, OCH ₃ ), 3 90 (m, 1H, NH-CH), 6.85 (bd, 1 H, NH-CH), 7 10 (s, 3H, 5-H + 6-H + 8-H), 10 05 (bs, 1 H, NH)

EXAMPLE 1 14

7-Methoxy-3-propylamιno-4H-1 ,2,4-benzothiadiazιne 1 , 1 -dioxide monohydrate

Method A m p 194-199°C

EXAMPLE 115

6-Chloro-3-cvclobutylamιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method D m.p. 306-307°C

IR (KBr) 3333, 3285, 3181 , 3079, 2993, 2951 , 1631 , 1583, 1549, 1470, 1245, 1 167,

1149, 1 124 cm ^"1

EXAMPLE 1 16

6-Chloro-3-(2,2,2-trιfluoroethyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Method A m p . 320-323°C

IR (KBr). 3298, 3185, 3122, 3082, 3023, 2977, 1636, 1586, 1574, 1473, 1257, 1245, 1188, 1167, 1152, 1134 cm ^"1

EXAMPLE 117

6-Chloro-3-cvclopropylmethylamιno-4H-1 ,2,4-benzothiadiazιne 1 , 1 -dioxide

Method D m p 278-280°C

IR (KBr) 3304, 3173, 3071, 3009, 2979, 1636, 1584, 1560, 1473, 1242, 1164, 1124 cm" ¹

EXAMPLE 118

5-Chloro-3-cvclobutylamιno-4H-1,2.4-benzothιadιazιne 1,1 -dioxide

Method D mp 222-224°C

EXAMPLE 119

5-Chloro-3-propylamιno-4H-1,2,4-benzothιadιazιne 1,1 -dioxide

Method A mp 196-197°C

EXAMPLE 120

5-Chloro-3-hexylamιno-4H-1,2,4-benzothιadιazιne 1,1 -dioxide

Method B mp 164-165°C

EXAMPLE 121

6-Chloro-3-octylamιno-4H-1 ,2,4-beπzothιadιazιne 1 ,1 -dioxide

Method C mp 231-232°C

EXAMPLE 122

6-Chloro-3-(1 ,5-dιmethylhexyl)amιno-4H-1 ,2,4-benzothιadιazιne 1.1 -dioxide

Method C m p 207-208°C

5

EXAMPLE 123

7-Chloro-4-methyl-3-methylsulfanyl-4H-1 ,2 4-benzothιadιazιne 1 , 1 -dioxide

0 A solution of 7-chloro-3-methylsulfanyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (0 8 g) in acetonitrile (24 mL) and methanol (0 5 mL) was supplemented with potassium carbonate (0 96 g), then with methyl iodide (3 mL), and stirred at room temperature for 10 h The solvent was removed by distillation under reduced pressure The residue was suspended in water (40 mL) and the pH was adjusted to pH 2 with formic acid The precipitate of the

1 5 title compound was collected by filtration, washed with water and dried The compound was used without further purification in the next step (yield 0 53 g)

7-Chloro-3-ιsopropylamιno-4-methyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide hemi-hydrate

20 A mixture of 7-chloro-4-methyl-3-methylsulfanyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (0 4 g) in isopropylamine (4 mL) was refluxed for 90 mm The amme was removed by distillation under reduced pressure, and the residue was suspended in water (20 mL) After stirring for 1 h at room temperature the precipitate of the crude title compound was collected by filtration, washed with water and recrystallized from methanol water (yield

25 0 27 g), m p 176-183 °C,

EXAMPLE 124

3-(2-Amιnoethyl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide monohydrate 30

A solution of 7-chloro-3-methylsulfanyl-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde (1 g) in ethylenediamine (2 5 mL) was refluxed for 45 mm Most of the excess of amine was

removed by distillation under reduced pressure and the resulting oily residue was dissolved in methanol (10 mL) Addition of diethylether (40 mL) gave rise to the precipita¬ tion of an oil which turned to a white solid after a stirring of 30 mm at 0°C The precipitate was collected by filtration, washed with diethylether and dried The solid was dissolved in boiling water (40 mL) and traces of insoluble material were removed by filtration The filtrate was concentrated to the half volume by distillation under reduced pressure and placed at +4°C for 2 h The crystalline precipitate of the title compound was collected by filtration washed with a small volume of water and dried to give the title compound (yield 0 62 g) m p 200-204°C IR (KBr) 3498, 3372, 2932, 1637, 1560 1481 , 1264, 1 163 cm ¹ Η-NMR (DMSO-d ₆ , HMDS, δ ppm) 2 70 (t, 2H, NH-CH ₂ -CH ₂ -NH ₂ ), 3 20 (t, 2H, NH- CH ₂ -CH ₂ -NH ₂ ), 5 25 (b, 6H, 2 x NH + H ₂ 0 + NH ₂ ) 6 95 (d, 1 H 5-H), 7 30 (d, 1 H, 6-H), 7 45 (s, 1H, 8-H)

EXAMPLE 125

3-lsopropylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 1 -dioxide

a) 3-Oxo-2 3-dιhydro-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 1 -dioxide monohy¬ drate

7-Methyl-3-oxo-2,3-dιhydro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (20 g) was suspended in hot water (2000 mL) and supplemented dropwise with a 10 % aqueous solution of NaOH until complete dissolution Potassium permanganate (60 g) was added portionwise and the reaction mixture was stirred for 3 h at 70°C After cooling the insoluble material was removed by filtration and the purple filtrate was treated with sodium hydrogen sulfite until complete discolouration of the excess of permanganate The solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 12N HCl The resulting suspension was placed at +4°C during 2 h and the crystalline precipitate was collected by filtration washed with water and dried (yield 14 5 g), m p 305-308°C

b) 4-Amιno-3-sulfamoylbenzoιc acid

A suspension of 3-oxo-2,3-dιhydro-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 1- dioxide monohydrate (10 g) in a mixture of concentrated sulfuric acid (150 mL) and water (150 mL) was refluxed until complete dissolution of the starting mateπal (1-2 h) The resulting solution was placed on an ice bath and supplemented dropwise with a 20% aqueous solution of NaOH under stirring and cooling until pH 1-2 The precipitate was collected by filtration, washed with water and dried (yield 6 6 g), m p 214-219 °C

c) 3-(lmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 ,1-dιoxιde

4-Amιno-3-sulfamoylbenzoιc acid (6 g) and thiocarbonyldiimidazole (23 2g) in dioxane (60 mL) was refluxed for 2 h The solvent was removed by distillation under reduced pressure The residue was dispersed in water (200 mL) and supplemented with a 10% aqueous solution of NaOH (40 mL) After stirring for 30 mm at room temperature the solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 2 with 12N HCl The resulting precipitate was collected by filtration washed with water and dried to give the title compound (yield 4 5 g), m p >300°C

d) 3-lsopropylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 , 1 -dioxide

3-(lmιdazol-1-yl)-4H-1 2,4-benzothιadιazιne-7-carboxyiιc acid 1 1 -dioxide was treated with isopropylamme according to the general procedure Method A to give the title compound m p >310 °C

EXAMPLE 126

3-sec-Butylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 ,1 -dioxide

3-(lmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 ,1 -dioxide was treated with sec-butylamme according to the general procedure Method A to give the title compound m p >310 °C

EXAMPLE 127

3-Propylamιno-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 1 -dioxide

3-(lmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazme-7-carboxylιc acid 1 , 1 -dioxide was treated with propylamine according to the general procedure Method A to give the title compound, m p >310°C

EXAMPLE 128

3-lsopropylamιno-7-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

a) 2-Amιno-5-trιfluoromethylbenzenesulfonamιde

A solution of 2-benzylamιπo-5-tπfluoromethylbenzenesulfonamιde (7 3 g) in methanol (80 mL) was supplemented with 10% Pd/C (0 73 g) and submitted to hydrogen under pressure (4 bars) during 90 mm at room temperature The insoluble material was removed by filtration and the filtrate was concentrated to dryness The residue was crystallized in methanol-water to give the title compound (yield 5 g), m p 142-143°C

b) 3-(lmιdazol-1-yl)-7-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

The procedure described for 3-(ιmιdazol-1-yl)-4H-1 ,2,4-benzothιadιazιne-7-carboxylιc acid 1 , 1 -dioxide was used for the preparation of the title compound starting from 2-amιno-5- tπfluoromethylbenzenesulfonamide (4 5 g) and using a refluxing time of 4 h The crude compound was recrystallized from methanol-diethylether (yield 1 9 g), m p 211-214°C

c) 3-lsopropylamιno-7-trιfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

3-(lmιdazol-1-yl)-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide was treated with isopropylamine according to the general procedure Method A to give the title compound, m p 287-289 °C

EXAMPLE 129

3-sec-Butylamιno-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

3-(lmιdazol-1-yl)-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde was treated with sec-butylamme according to the general procedure Method A to give the title compound, m p 234-236 °C

EXAMPLE 130

3-Propylamιno-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

3-(lmιdazol-1-yl)-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide was treated with propylamine according to the general procedure Method A to give the title compound, m p 241-243 °C

EXAMPLE 131

3-Cyclopropylmethylamιno-7-trιfluoromethyl-4H-1 ,2 4-benzothιadιazιne 1 ,1 -dioxide

3-(lmιdazol-1-yl)-7-tπfluoromethyl-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde was treated with cyclopropylmethylamine according to the general procedure Method D to give the title compound, m p 266-268 °C

EXAMPLE 132

7-Fluoro-3,6-dι(ιsopropylamιno)-4H-1 ,2.4-benzothιadιazιne 1 1 -dioxide

a) 2-Amιno-4,5-dιfluorobenzenesulfonamιde

3,4-Dιfluoroanιhne (20 g) in chlorosulfonic acid (60 mL) was heated for 1 h at 140°C After cooling at 70°C, the reaction mixture was supplemented with thionyl chloride (30 mL) and

refluxed for 2 h. After cooling, the mixture was poored on ice water (200 g) and extracted three times with diethyl ether (3 x 100 mL). The combined organic layers were dried over MgS0 ₄ , filtered and concentrated to dryness under reduced pressure. The oily residue was dissolved in dioxane (100 mL) and added under stirring to a 10% w/v aqueous solution of ammonia (300 mL). After 1 h, the resulting solution was treated with charcoal, filtered and concentrated to a volume of 100 mL, then adjusted to pH 3. After standing overnight at +4 ^C C, the precipitate was collected by filtration and washed with the minimum of water (first part) The filtrate was extracted three times with ethyl acetate (3 x 100 mL) The combined organic layers were dried over MgS0 ₄ , filtered, and the filtrate was concentrated to dryness The residue was suspended in a small volume of water, and the insoluble material was collected by filtration, washed with a minimum of water and dried (second part) (total yield of crude compound 5.5 g); m.p 137-142X (methanol- diethylether)

b) 6,7-Difluoro-3-(imιdazol-1-yl)-4H-1.2,4-benzothiadiazιne 1 ,1 -dioxide

The procedure described for 3-(imιdazol-1-yl)-4H-1 ,2,4-benzothιadiazιne-7-carboxylic acid 1 ,1 -dioxide was used for the preparation of the title compound starting from 2-amιno-4,5- difluorobenzenesuifonamide (5 g) and using a refluxmg time of 4 h The crude compound was recrystallized from acetone-diethyiether (yield 2.6 g); m p. 264-266°C

c) 7-Fluoro-3.6-di(ιsopropylamιno)-4H-1 ,2.4-benzothiadiazine 1.1 -dioxide

6,7-Difluoro-3-(imιdazol-1-yl)-4H-1 ,2,4-benzothιadiazine 1 ,1-dioxιde was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. 234-237°C.

EXAMPLE 133

3-Ethylamιno-6,7-difluoro-4H-1 ,2,4-benzothiadiazιne 1 ,1 -dioxide

Starting from 2-amιno-4,5-difluorobenzenesulfonamide and ethyl isothiocyanate, and

following a procedure analogous to the one described in Example 4a, N-(2-amιno-4,5- dιfluorobenzenesulfonyl)-N'-ethylthιourea was prepared The crude compound was used without further purification in a cychsation step analogous to the one described in Example 4b to give the title compound, m p 246-252 °C

EXAMPLE 134

7-Chloro-3-(pyπdιn-2-yl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

a) 7-Chloro-3-methylsulfιnyl-4H-1 2.4-benzothιadιazιne 1 1 -dioxide

A suspension of 7-chloro-3-methylsulfanyl-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (0 5 g) in an aqueous solution of sodium hydrogen carbonate (0 22 g/25 mL) was supplemented dropwise with 2M NaOH until complete dissolution Liquid bromine (0 1 mL) was added under stirring at room temperature After 10 mm , the resulting suspension was adjusted to pH 2-3 with 6N HCl and the insoluble material was collected by filtration and washed with water The white precipitate was suspended in methanol (20 mL), stirred for 1 h and then collected by filtration, washed with methanol and dried (yield 0 45 g), m p 260-261 °C

b) 7-Chloro-3-(pyrιd-2-yl)amιno-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide

7-Chloro-3-methylsulfιnyl-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide (0 25 g) and 2- ammopyπdine (0 25 g) in 3-chlorotoluene (5 mL) was heated at 150°C for 1 h After cooling, the white precipitate was collected by filtration and washed with diethylether The insoluble material was dissolved in 1 M NaOH (20 mL), treated with charcoal, filtered, and the filtrate was adjusted to pH 3 with 6N HCl The precipitate was collected by filtration, washed with water, dissolved in hot DMF (15 mL), mixed with an equal volume of distilled water and cooled The white precipitate was collected by filtration washed with water and dried (yield 0 12 g), m p >310°C

EXAMPLE 135

7-Chloro-3-(2-formylamιnoethyl)amιno-4H-1 ,2,4-benzothιadιaztne 1 , 1 -dioxide A mixture of formic acid (1 mL) and acetic anhydride (2 mL) was heated at 50°C for 20 mm After cooling at room temperature, 3-(2-amιnoethyl)amιno-7-chloro-4H-1 ,2 4- benzothiadiazine 1 ,1 -dioxide monohydrate (0 5 g) was added, and the reaction mixture was stirred for 2 h, then supplemented with water (20 mL) and stirred for 20 mm The precipitate was collected by filtration, washed with water and dried (yield 0 3 g), m p 245-247 °C

EXAMPLE 136

3-(2-Acetylamιnoethyl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 , 1-dιoxιde

The same process as described in the preceding example was used for the synthesis of the title compound using 3-(2-amιnoethyl)amιno-7-chloro-4H-1 ,2,4-benzothιadιazιne 1 ,1- dioxide monohydrate (0 5 g) and acetic anhydride (3 mL) instead of the mixture of formic acid and acetic anhydride (yield 0 25 g), m p 295-297 °C

EXAMPLE 137

7-Chloro-3-(1 ,2-dιmethylpropyl)amιno-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde

To 10 ml of dry tetrahydrofuran stirred under nitrogen was added successively titanium tetrachloÏ€de (0 2 ml), anisole (0 5 ml), 1 ,2-dιmethylpropylamιne (0 8 ml), and then a slurry of 7-chloro-2,3-dιhydro-2-methyl-3-oxo-4H-1 ,2,4-benzothιadιazιne 1 1-dιoxιde (400 mg) in a mixture of 1 ,2-dιmethyipropylamιne (0 4 ml) and 5 ml of dry toluene The mixture was heated at 120 °C After VA h an additional amount of 1 ,2-dιmethylpropylamιne (0 4 ml) was added After 2 ¹ / ₂ h the reaction mixture was cooled to room temperature Isopropyl alcohol (1 ml) concentrated ammonium hydroxide (1 ml) and diatomaceous earth (0 5 g) was added and stirring was continued for 15 mm The insoluble material was removed by filtration and the filter cake rinsed with two portions of 25 ml of ethyl acetate The organic phases were combined and shaken with 25 ml of water, then with 25 ml of saturated

aqueous sodium chloride, dried over sodium sulfate and the solvent was removed in vacuo The residue was dissolved in 50 ml of ethyl acetate and extracted with 2x 50 ml of 4 M hydrochloric acid The aqueous extracts were made alkaline with concentrated ammonium hydroxide and then extracted with 2 x 50 ml of ethyl acetate The organic phase was dried over sodium sulfate and the solvent removed in vacuo The residue was purified on a silica gel column with a 7 3 mixture of n-heptane and ethyl acetate as solvent to give the title compound as white crystals, m p 102-105 °C

EXAMPLE 138

7-Chloro-3-ιsopropylamιno-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Tπethyloxonium tetrafluoroborate (0 95 g) in 10 ml of dry dichloromethane was added under nitrogen to a stirred suspension of 7-chloro-2,3-dιhydro-2-methyl-3-oxo-4H-1 ,2,4- benzothiadiazine 1 1 -dioxide (0 5 g) in 25 ml of dichloromethane at room temperature, and stirred overnight Then the mixture was poured into 50 ml of a stirred saturated aqueous sodium bicarbonate solution The organic layer was dried over sodium sulfate and the solvent was removed in vacuo The residue consisting of 0 47 g of crude 7-chloro-3- ethoxy-2-methyl-2H-1 2 4-benzothιadιazιne 1 ,1 -dioxide was processed further without purification

A mixture of crude 7-chloro-3-ethoxy-2-methyl-2H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide (0 45 g) and isopropylamine (4 ml) in an ethanohc sodium ethoxide solution, prepared by dissolving 0 4 g of sodium in 10 ml of ethanol, was refluxed for 3 hours and then neutral- ized with 4M acetic acid The mixture was evaporated to dryness and partitioned between 25 mi of water and 25 ml of dichloromethane The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo The residue was purified by chromatog¬ raphy on a silica gel column with a 7 3 mixture of n-heptane and ethyl acetate as solvent to give the title compound, Η-NMR (CDCy, δ (ppm) 7 7 (d, 1H), 7 47 (dd, 1H), 7 25 (d, 1 H), 4 45 (br, 1 H, NH), 4 38- 4 18 (m, 1 H, CH), 3 31 (s, 3H, CH ₃ ), 1 29 (d, 6H, CH ₃ ), m p 139-141°C

EXAMPLE 139

7-Chloro-3-(N-ethyl-N-methylamιno)-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide 5 Starting from 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (753 mg, 3 mmol) and N- ethyl-N-methylamine (708 mg, 12 mmol) and with the use of same procedure as in example 21 650 mg (79 %) of the title compound was prepared, m p >220 °C Η-NMR (DMSO-d6) ppm, 10 4 (s 1 H, NH), 7 69 (d, 1 H, H-8), 7 61 (dd, 1 H H-6), 7 55 (d, 1 H H-5), 10 3 5 (q, 2H CH ₂ ), 3 09 (s, 3H, CH ₃ ), 1 10 (t, 3H, CH ₃ ), ¹³ C-NMR (DMSO-d6) ppm, 150 21 , 134 69, 131 81 , 127 27 123 98, 121 42, 1 19 54, 44 2, 34 69, 1 1 91 Analysis C ₁₀ H ₁₂ CIN ₃ O ₂ S requires C 43 88 , H 4 42 , N 15 35 (found C 43 52 , H 4 55 , N 15.30)

EXAMPLE 140 15

6-Chloro-3-(N-ethyl-N-methylamιno)-4H-1 ,2,4-benzothιadιazιne 1 1 -dioxide

Starting from 3,6-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (500 mg, 1 99 mmol) and N-ethyl-N-methylamine (500 mg, 8 47 mmol) and with the use of same procedure as in 20 example 21 200mg (36 7 %) of the title compound was prepared m p >220 °C Η-NMR (DMSO-d6) ppm 10 35 (s,1 H NH), 7 65 (d, 1 H, H-8), 7 58 (dd, 1 H, H-5) 7 3 (d, 1 H, H-7) 3 5 (q, 2H CH ₂ ), 3 1 1 (s, 3H, CH ₃ ), 1 14 (t, 3H CH ₃ ) Analysis C ₁₀ H _l2 CIN ₃ O ₂ S requires C 43 88 H 4 42 , N 15 35 (found C 43 78 , H 4 51 , N 15 24)

25 EXAMPLE 141

7-Chloro-3-(3-(1 H-ιmιdazol-4-yl)propyl)amιno-4H-1 ,2,4-benzothιadιazιne 1 , 1 -dioxide

A suspension of 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1 -dioxide (200 mg, 0 8 mmol) 30 and 3-(1-tπtyl-1 H-ιmιdazo-4(5)-yl)-propylamιne (339 mg, 1 2 mmol) in ethanol (3 ml) was stirred at 90 °C in a sealed flask for 16 h The reaction mixture was concentrated in vacu To the residue was added 6N HCl and extracted with dichloromethane The aqueous phase was brought to pH 10 with 10N NaOH and extracted with dichloromethane The

aqueous phase was concentrated The residue was purified by flash chromatography using ethanol / 25% aqueous ammoniumhydroxide 10 1 as eluent to give the title compound (133 mg, 49%)

Η-NMR (DMSO-d ₆ ), δ(ppm) 7 6 (m, 3H), 7 25 (br, 1H, NH), 6 80 (s, 1H) 3 4 (br, NH + HDO), 3 25 (q, 2H, CH ₂ ), 2 48 (m, 2H + DMSO, CH ₂ ), 1 78 (m, 2H, CH ₂ ), MS EI/70eV 339, 341 ( ³⁵ CI, ³⁷ CI) [M+]

EXAMPLE 142

3-(1 -Benzylpyrrolιdιn-3-ylamιno)-7-chloro-4H-1 ,2,4-benzothιadιazιne 1.1 -dioxide

A suspension of 3,7-dιchloro-4H-1 ,2,4-benzothιadιazιne 1 ,1-dιoxιde (100 mg, 0 4 mmol) 1- benzyl-3-amιnopyrrolιdιne (0 35 ml, 2 0 mmol) was stirred at 110 °C for 72 h The reaction mixture was concentrated in vacu and the residue was purified by flash chromatography using ethyl acetate / methanol 10 1 to give oily crystals (114 mg) These were recrystal¬ lised from ethyl acetate to give the title compound as white crystals (83 mg, 53%), m p 208 5-209 5 °C,

¹ H-NMR (DMSO-d ₆ ), δ(ppm) 10 6 (br, 1 H NH), 7 65 (d, 1 H), 7 50 (dd, 1 H) 7 4 (br, 1 H, NH), 7 3 (m, 5H,Ph), 7 20 (d, 1 H) 4 25 (m, 1 H), 3 60 (s, 2H , CH ₂ Ph), 2 7 (m 2H), 2 5 (m, 1 H + DMSO) 2 32 (m, 1 H), 2 22 (m, 1 H) 1 68 (m 1H), MS EI/70eV 389 [M-1]

Analysis calc For C ₁₈ H, ₉ CIN ₄ O ₂ S x 0 25 H ₂ 0 C 54 68 H 4 97 N 14 17 found C 54 79 H 4 96 N 13 95