BACKGROUND OF THE INVENTION Potassium channels play an important role in the physiological and pharmacological control of cellular membrane potential. Amongst the different types of potassium channels are the ATP-sensitive (KATP-) channels which are regulated by changes in the intracellular con- centration of adenosine triphosphate. The KATP-channels have been found in cells from vari- ous tissues such as cardiac cells, pancreatic cells, skeletal muscles, smooth muscles, cen- tral neurons and adenohypophysis cells. The channels have been associated with diverse cellular functions for example hormone secretion (insulin from pancreatic beta-cells, growth hormone and prolactin from adenohypophysis cells), vasodilation (in smooth muscle cells), cardiac action potential duration, neurotransmitter release in the central nervous system.

Modulators of the KATp-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 KATP-channels on pancreatic beta-cells.

The potassium channel openers, which comprise a heterogeneous group of compound, ha- ve 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 bronchodilators 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 compound can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia.

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

Compound of the present invention, which inhibit insulin secretion by activating potassium channels of the beta-cell can be used in combination with other compound which may be used to treat non-insulin dependent diabetes mellitus and insulin dependent diabetes mellitus. Examples of such compound are insulin, insulin sensitizers, such as thiazolidinediones, insulin secretagogues, such as repaglinide, tolbutamide, glibenciamide and glucagon like peptide (GLP1), inhibitors of a-glucosidases and hepatic enzymes responsible for the biosynthesis of glucose.

Recently, it has been shown that Diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide) and certain 3- (alkylamino)-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide derivatives inhibit insulin release by an activation of KATp-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 compound which activate KATP- channels can be used for treatment of diseases characterised by an overproduction of insulin and for the treatment and prevention of diabetes.

EP 618 209 discloses a class of pyridothiadiazine derivatives having an alkyl or an alkylamino group in position 3 of the thiadiazine ring. These compound are claimed to be agonists at the AMPA-glutamate receptor.

In J. Med. Chem. 1980,23,575-577 the synthesis of 4 (5)-amino-and formylaminoimidazo- 5 (4) carboxamide and their properties as agents of chemotherapeutic value are described.

Especially, the compound 3-aminoimidazo [4, 5-e]-1, 2,4-thiadiazine 1,1-dioxide and N- benzoylaminoimidazo [4,5-e]-1,2,4-thiadiazine 1,1-dioxide are shown.

DESCRIPTION OF THE INVENTION The present invention relates to pyrido 1,2,4-thiadiazine derivatives of the general formula l: wherein Z is O, S, S (=O), S (=O) 2, S (=NR), S (=O) (=NR) or S (=NR) 2 wherein R is hydrogen; C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally mono-or polysubsti- tuted with halogen, hydroxy or C, 6-alkoxy; or C3-6-cycloalkyl optionally mono-or polysubsti- tuted with C, _6-alkyl, halogen, hydroxy or C1 6-alkoxy; R3 is C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl the C3 6-cycloalkyl group optionally being mo- no-or polysubstituted with C, _6-alkyl, halogen, hydroxy or C, _6-alkoxy; a 3-6 membered satu- rated ring system comprising one or more nitrogen-, oxygen-or sulfur atoms, optionally be- ing mono-or polysubstituted with halogen, cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, C1-6- alkoxy-C, _s-alkyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C1-6-monoalkyl or dialkylamino; or straight or branche C1-18-alkyl, C2-18-alkenyl or C2-18-alkynyl, each of the groups being optio- nally mono-or polysubstituted with halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-

cycloalkyl, nitro, amino, C1 6-monoalkyl-or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C1-6-alkoxycarbonyl, carbamoyl, formylamino, or C1-6-alkylcarbonylamino, aryl, aryloxy, a- rylalkoxy, the aryl group optionally being mono-or polysubstituted with C, _6-alkyl, perhalo- methyl, halogen, hydroxy or C1 6-alkoxy; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroa- rylalkyl, each of the groups being optionally mono-or polysubstituted with halogen, hydroxy, C1-6-alkyl, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C1 6-monoalkyl-or dialkylamino, cya- no, oxo, acyl or C1-6-alkoxycarbonyl ; or R3 is

wherein n, m, p independently are 0,1,2,3 and R10 is hydrogen; hydroxy; C1-6-alkoxy ; C3-6- cycloalkyl optionally mono-or polysubstituted with C1 6-alkyl, halogen, hydroxy or C, _6-alkoxy; C1-6-alkyl, C2-6-alkenyl or C2 6-alkynyl optionally mono-or polysubstituted with halogen; A together with the carbon atoms forming bond e of formula I forms a pyridine ring selected from

the pyridine ring optionally being mono-or polysubstituted with halogen; C1-18-alkyl ; C3 6- cycloalkyl; hydroxy; C1-6-alkoxy ; C1-6-alkoxy-C1-6-alkyl ; nitro; amino; cyano; cyanomethyl; per- halomethyl; C, 6-monoalkyl-or dialkylamino; sulfamoyl; C1-6-alkylthio ; C1-6-alkylsulfonyl ; C1-6- alkylsulfinyl; C1-6-alkylcarbonylamino ; arylthio, arylsulfinyl, arylsulfonyl, aryl, arylalkyl, aryloxy, the aryl group optionally being mono-or polysubstituted with C, _6-alkyl, perhalomethyl, halo- gen, hydroxy or C, _6-alkoxy; C1-6-alkoxycarbonyl ; C1 6-alkoxycarbonyl-C1 6-alkyl; carbamyl; carbamylmethyl; C1-6-monoalkyl- or dialkylaminocarbonyl ; C1 6-monoalkyl-or dialkylaminothi-

ocarbonyl; ureido; C1 6-monoalkyl-or dialkylaminocarbonylamino, thiocarbamyl; thioureido; C1 6-monoalkyl-or dialkylaminothiocarbonyl-amino; C1 6-monoalkyl-or dialkylaminosulfonyl; carboxy; carboxy-C1 6-alkyl; acyl; formyl; or a 5-6 membered nitrogen, oxygen or sulfur con- taining ring, optionally substituted with C, _6-alkyl or phenyl, the phenyl group optionally being mono-or polysubstituted with C1 6-alkyl, perhalomethyl, halogen, hydroxy or C, _6-alkoxy; or a salt thereof with a pharmaceutically acceptable acid or base.

Within its scope the invention inclues all optical isomers of compound of formula 1, some of which are optically active, and also their mixtures including racemic mixture thereof.

The scope of the invention also inclues all tautomeric forms of the compound of formula 1.

The salts include pharmaceutically acceptable acid addition salts, pharmaceutically accepta- ble metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malo- nic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically 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"C1 6-alkoxy"as used herein, alone or in combination, refers to a straight or bran- ched monovalent substituent comprising a C, _6-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"C1 6-alkylthio"as used herein, alone or in combination, refers to a straight or bran- ched 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 terms"C2 6-alkenyl","C2 18-alkenyl"and"C8 18-alkenyl"as used herein refers to an unsaturated hydrocarbon chain having 2-6,2-18 or 8-18 carbon atoms, respectively, and

one double bond such as e. g. vinyl, 1-propenyl, ailyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.

The term "C3-6-cycloalkyl" as used herein refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclo- hexyl.

The terms"C2 6-alkynyl","C2 18-alkynyl"and"C8, 8-alkynyl"as used herein refers to unsatu- rated hydrocarbons which contain triple bonds, such as e. g. -C#CH, -C#CCH3, -CH2C#CH, - CH2CH2C#CH, -CH (CH3) C---CH, and the like.

The term"C, 6-alkoxy-C, 6-alkyl"as used herein refers to a group of 2-12 carbon atoms in- terrupted by an O such as e. g. CH2-O-CH3, CH2-O-CH2-CH3, CH2-O-CH (CH3) 2 and the like.

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

The term"perhalomethyl"means trifluoromethyl, trichloromethyl, tribromomethyl or triiodo- methyl.

The terms "C1-6-alkyl", "C1-12-alkyl" and "C1-18-alkyl" as used herein, alone or in combination, refers to a straight or branche, saturated hydrocarbon 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, 4-methylpentyl, neopentyl, n-hexyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term "C1-18-alkyl" as used herein also inclues secondary C3-6-alkyl and tertiary C4 6-alkyl.

The term"C1 6-monoalkylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a straight or branche, saturated hydrocarbon chain ha- ving the indicated number of carbon atoms such as e. g. methylamino, ethylamino, propyla- mino, n-butylamino, sec-butylamino, isobutylamino, tert-butylamino, n-pentylamino, 2- methylbutylamino, n-hexylamino, 4-methylpentylamino, neopentylamino, n-hexylamino, 2,2- dimethylpropylamino and the like.

The term"C, _6-dialkylamino"as used herein refers to an amino group wherein the two hy- drogen atoms independently are substituted with a straight or branche, saturated hydrocar- bon chain having the indicated number of carbon atoms; such as dimethylamino, N-ethyl-N- methylamino, diethylamino, dipropylamino, N- (n-butyl)-N-methylamino, di (n-pentyl) amino, and the like.

The term"acyl"as used herein refers to a monovalent substituent comprising a C1 6-alkyl group linked through a carbonyl group; such as e. g. acetyl, propionyl, butyryl, isobutyryl, pi- valoyl, valeryl, and the like.

The term"C1 6-alkoxycarbonyl"as used herein refers to a monovalent substituent compri- sing a C, _6-alkoxy group linked through a carbonyl group; such as e. g. methoxycarbonyl, carbethoxy, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.

The ter"3-6 membered saturated ring system"as used herein refers to a monovalent sub- situent comprising a monocyclic saturated system containing one or more hetero atoms se- lected from nitrogen, oxygen and sulfur and having 3-6 members and having its free valence from a carbon atom, e. g. 2-pyrrolidyl, 4-piperidyl, 3-morpholinyl, 1,4-dioxan-2-yl, 5- oxazolidinyl, 4-isoxazolidinyl, or 2-thiomorpholinyl.

The term"bicycloalkyl"as used herein refers to a monovalent substituent comprising a bicy- clic structure made of 6-12 carbon atoms such as e. g. 2-norbornyl, 7-norbornyl, 2- bicyclo [2.2.2joctyl, 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 sub- situent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicy- clic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e. g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazi- ne, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazo- line, quinoxaline, indole, benzimidazole, benzofuran, pteridine, and purine.

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

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

The term"arylalkoxy"as used herein refers to a C, _6-alkoxy group substituted with an aro- matic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2- (l-naphtyl) ethoxy and the like.

The term"C1 6-alkylsulfonyl"as used herein refers to a monovalent substituent comprising a C, _6-alkyl group linked through a sulfonyl group such as e. g. methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert- butylsulfonyl, n-pentylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, neopentylsulfonyl, n-hexylsulfonyl and 2,2-dimethylpropylsulfonyl.

The term"C, _6-monoalkylaminosulfonyl"as used herein refers to a monovalent substituent comprising a C, 6-monoalkylamino group linked through a sulfonyl group such as e. g. methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n- butylaminosulfonyl, sec-butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, n- pentylaminosulfonyl, 2-methylbutylaminosulfonyl, 3-methylbutylaminosulfonyl, n-hexylamino- sulfonyl, 4-methylpentylaminosulfonyl, neopentylaminosulfonyl, n-hexylaminosulfonyl and 2,2-dimethylpropylaminosulfonyl.

The term"C, _6-dialkylaminosulfonyl"as used herein refers to a monovalent substituent com- prising a C1 6-dialkylamino group linked through a sulfonyl group such as dimethylaminosul- fonyl, N-ethyl-N-methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N- (n- butyl)-N-methylaminosulfonyl, di (n-pentyl) aminosulfonyl, and the like.

The term"C, _6-alkylsulfinyl"as used herein refers to a monovalent substituent comprising a straight or branche C, _6-alkyl group linked through a sulfinyl group (-S (=O)-); such as e. g. methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, and the like.

The term"C, _6-alkylcarbonylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with an acyl group, such as e. g. acetamido, propionamido, iso- propylcarbonylamino, and the like.

The term "(C3-6-cycloalkyl)C1-6-alkyl" as used herein, alone or in combination, refers to a straight or branche, saturated hydrocarbon chain having 1 to 6 carbon atoms and being monosubsti- tuted with a C6-cycloalkyl group, the cycloalkyl group optionally being mono-or polysubstitu- ted with C, _6-alkyl, halogen, hydroxy or C, _6-alkoxy; such as e. g. cyclopropylmethyl, (1- methylcyclopropyl) methyl, 1- (cyclopropyl) ethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

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 C1 6-alkyl, haiogen, hydroxy or C, _6-alkoxy; e. g. phenylthio, (4-methylphenyl)-thio, (2-chlorophenyl) thio, and the like.

The term"arylsulfinyl"as used herein refers to an aryl group linked through a sulfinyl group (- S (=O)-), the aryl group optionally being mono-or polysubstituted with C, _6-alkyl, halogen, hy- droxy or C1 6-alkoxy; such as e. g. phenylsulfinyl, (4-chlorophenyl) sulfinyl, and the like.

The term"arylsulfonyl"as used herein refers to an aryl group linked through a sulfonyl group, the aryl group optionally being mono-or polysubstituted with C, _6-alkyl, halogen, hydroxy or C 6-alkoxy; such as e. g. phenylsulfonyl, tosyl, and the like.

The term"C, _6-monoalkylaminocarbonyl"as used herein refers to a monovalent substituent comprising a C, 4-monoalkylamino group linked through a carbonyl group such as e. g. methy- laminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n- butylaminocarbonyl, sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylamino-carbonyl, n- hexylaminocarbonyl, 4-methylpentylaminocarbonyl, neopentylaminocarbonyl, n-hexylamino- carbonyl and 2-2-dimethylpropylaminocarbonyl.

The term"C, _6-dialkylaminocarbonyl"as used herein refers to a monovalent substituent com- prising a C1-6-dialkylamino group linked through a carbonyl group such as dimethylaminocarbo-

nyl, N-ethyl-N-methyZaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N- (n-butyl)- N-methylaminocarbonyl, di (n-pentyl) aminocarbonyl, and the like.

The term"C, _6-monoalkylaminocarbonylamino"as used herein refers to an amino group whe- rein one of the hydrogen atoms is substituted with a C1 6-monoalkylaminocarbonyl group, e. g. methylaminocarbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopro- pylaminocarbonylamino, n-butylaminocarbonylamino, sec-butylaminocarbonylamino, iso- butylaminocarbonylamino, tert-butylaminocarbonylamino, and 2- methylbutylaminocarbonylamino.

The term"C, _6-dialkylaminocarbonylamino"as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a C1-6-dialkylaminocarbonyl group, such as di- methylaminocarbonylamino, N-ethyl-N-methylaminocarbonylamino, diethyla- minocarbonylamino, dipropylaminocarbonylamino, N- (n-butyl)-N-methylaminocarbonylamino, di (n-pentyl) aminocarbonylamino, and the like.

The term"5-or 6-membered nitrogen, oxygen or sulfur containing ring"as used herein refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system con- taining one or more nitrogen, oxygen or sulfur atoms and having 5 or 6 members, e. g. pyrro- lidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl, 2H- pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholino, thiomorpholino, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1,3-dioxolanyl, and 1,4-dioxolanyl.

Preferred compound of the invention are: 3-cyclopropylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclohexylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclohexylmethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-(1-phenylethyl)(1-phenylethyl) sulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfinyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide

3-ethylsulfinimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfonimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfinimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfinyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopropylsulfanyl-4H-pyrido [4,3-ex-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclobutylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopropylmethylsulfanyl-4H-pyrido [4,3-ex- 1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclohexylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclohexylmethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-(1-phenylethyl)(1-phenylethyl) sulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-ethylsulfinyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-ethylsulfinimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-ethylsulfonimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-isopropylsulfinimidoyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-isopropylsulfinyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopropoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopropylmethoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclobutoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 6-chloro-3-cyclopentoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclohexylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclohexylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3- (l-phenylethyl) sulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfinyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfinimidoyl-4H-pyrido (2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfonimidoyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide

3-isopropylsulfinimidoyl-4H-pyrido (2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfinyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropoxy-4H-pyrido (2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclobutoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopentoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopropylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopentylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopropylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclohexylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclohexylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-(1-phenylethyl)(1-phenylethyl) sulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-ethylsulfinyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-ethylsulfinimidoyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-ethylsulfonimidoyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-isopropylsulfinimidoyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-isopropylsulfinyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopropoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopropylmethoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclobutoxy-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopentoxy-4H-pyrido (2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-propylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3- (1,2-dimethylpropyl) sulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isobutylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-propoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3- (1,2-dimethylpropoxy)-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isobutoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropoxy-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropoxy-4H-pyrido [4,3-ex-1,2,4-thiadiazine 1,1-dioxide

3-ethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-ethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfanyl-7-methyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-ethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-isopropylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfanyl-7-methyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-isopropylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 7-chloro-3-cyclopropylmethylsulfanyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-7-methyl-4H-pyrido [2,3-e]-1,2,4-thiadiazine 1,1-dioxide 3-cyclopropylmethylsulfanyl-4H-pyrido [4,3-e]-1,2,4-thiadiazine 1,1-dioxide The compound 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, hy- pertension, ischemic heart diseases, angina pectoris and coronary heart diseases; the pul- monary system; the gastrointestinal system; the central nervous system and the endocrino- logicalsystem.

Since some KATp-openers are able to antagonize vasospasms in basilar or cerebral arteries the compound of the present invention can be used for the treatment of vasospastic disor- ders such as subarachnoid haemorrhage and migraine.

The compound of the present invention may also be used for the treatment of diseases as- sociated with decreased skeletal muscle blood flow such as Raynauds disease and inter- mittent claudication.

Further, the compound 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 compound could also be used for treatment of conditions associated with dis- turbances in gastrointestinal mobility such as irritable bowel syndrome. Additionally these compound can be used for the treatment of premature labour and dysmenorrhea.

Potassium channel openers hyperpolarize neurons and inhibit neurotransmitter release and it is expected that such compound 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 compound of the present invention can be used for the treatment of baldness.

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

In diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compound of the present invention can be used to reduce insulin secretion. In obesity hyperinsulinemia 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 compound of the present invention, can be used for reducing the hyperinsulinemia and thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of hyperinsulinemia with potassium channel openers, and hence the present compound, 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 compound can be used to induce pancreatic cell 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 nicotinamide, 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-insulin-requiring Type 2 (NIIDM) patients with autoreactivity against beta-cell epitopes that later turns insulin requiring) have circulating autoreactive monocy- tes/lymphocytes that homes to the islets/beta-cells and releases their cytokines. Some of these cytokines (e. g. interieukin-1 b (IL-1 b), tumour necrosis factor a (TNFa) and interferon 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-administring nicotinamide (NA), a derivative hereof or other cytokine protective compound to the prediabetic/diabetic patients treated with the PCO compound is an example of this aspect. Nicotinamide belongs to the B-vitamin family and is derived from nicotinic 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 propose 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 indi- cated a protective role of this compound against IDDM as well as in cytokine/immune medi- ated 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 trans- plantation, 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.

Compound of the present invention which act as blockers of KATP-channels can be used for the treatment of NIDDM.

Preferably, the compound of the present invention may be used for treatment or prevention of diseases of the endocrinological system such as hyperinsulinaemia 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 ac- ceptable substance, preferably for use as a therapeutically acceptable substance in the tre- atment of hyperinsulinaemia and treatment or prevention of diabetes.

Furthermore, the invention also relates to the use of the inventive compound of formula I as medicaments useful for treating hyperinsulinaemia and treating or preventing diabetes Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combine with one or more other pharmacologically active compound, e. g. an an- tidiabetic or other pharmacologically active material, including compound for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabetics comprise insulin as well as orally ac- tive hypoglycaemic agents such as sulphonylureas, e. g. glibenclamide and glipizide; bigua- nides, e. g. metformin; benzoic acid derivatives, e. g. repaglinide; and thiazolidinediones, e. g. troglitazone and ciglitazone.

In yet another aspect, the present invention relates to methods of preparing the above men- tioned compound. The methods comprises: a) reacting a compound of formula 11: wherein Y is O or S and A is as defined above with a compound of formula III R3-X (I I I) wherein R3 is as defined above and X is a leaving group such as halogen or sulfate, prefe- rentially chloro, bromo or iodo to form a compound of the general formula I wherein Z is O or S. The rection may be carried out in a suitable solvent and in the presence of a base, or b) reacting a compound of formula 11:

wherein Y is O and A is as defined above with a diazo compound of formula IV R'R"CN2 (IV) wherein R'and R"together as two substituents on methyl form a group R'R"CH meeting the criteria defined above for R3, to form a compound of the general formula I wherein Z is O and R3 is R'R"CH, or c) reacting a compound of formula V: wherein Q is a leaving group such as halogen, preferentially chloro, bromo, iodo; amino, trimethylamino, imidazol-1-yl, methylsulfanyl, methylsulfinyl or methylsulfonyl with a com- pound of formula VI : R3YH (VI) wherein R3 is as defined above and Y is O or S to form a compound of the general formula I wherein Z is O or S. The rection may be carried out in a suitable solvent and in the pre- sence of a base, or d) reacting a compound of formula VII :

wherein A and R3 are as defined above with an oxidizing agent to form a compound of the general formula I wherein Z is S (=O) or S (=O) 2, or e) reacting a compound of formula VII : wherein A and R3 are as defined above with an aminating agent according to known proce- dures, see e. g. P. D. Kennenwell, J. B. Taylor, Chem. Soc. Rev. (1980) 477-498 and P. D.

Kennenwell, J. B. Taylor, Chem. Soc. Rev. (1975) 189-209, to form a compound of the gene- ral formula VIII wherein n is 1 or 2, or f) reacting a compound of formula Vil:

wherein A and R3 are as defined above with an aminating agent and subsequently an oxidi- zing agent, or vice versa, according to known procedures, see e. g. P. D. Kennenwell, J. B.

Taylor, Chem. Soc. Rev. (1980) 477-498 and P. D. Kennenwell, J. B. Taylor, Chem. Soc. Rev.

(1975) 189-209, to form a compound of the general formula I wherein Z is S (=O) (=NR), or g) reacting a compound of formula IX

wherein A is as defined above with CS2 in the presence of a base to give the corresponding sulfonylimino carbodithioate which in turn is treated with an alkylating agent of formula III R3-X(III) wherein R3 is as defined above and X is a leaving group such as halogen or sulfate, prefe- rentially chloro, bromo or iodo to form a compound of formula X

which by ring-closure, e. g. by treatment with phosgene in a suitable solvent, forms a com- pound of the general formula 1, or h) reacting a compound of formula XI wherein A and R3 are as defined above and PG is a protecting group, e. g. substituted ben- zyl, with chlorosulfonyl isocyanate (CI-S02-NCO) and subsequent ring closure followed by removal of the protecting group to form a compound of formula 1.

The starting materials are either known compound or compound which may be prepared in analogy with the preparation of known compound or in analogy with known methods as described by e. g. Huang B.-S., et al., J. Med. Chem., 23,575-7 (1980), Ofitserov V. 1. et al., Khim. Geterotsikl. Soedin., 1119-22 (russ.) (1976), Topliss J. G., U. S. 3,641,017 (1972), Kotovskaya S. K. et al., Khim.-Farm. Zh., 13,54-57 (russ.) (1979), Meyer R. F., J. Hetero- cycl. Chem., 6,407-408 (1969), Hattori M., Yoneda M., Goto M., Bull. Chem. Soc. Jap., 46, 1890-1 (1973), Williams T. R. and Cram D. J., J. Org. Chem., 38,20-26 (1973), T. Iwakawa, H. Tamura, Y. Hayase, Chem. Pharm. Bull. 38 (4), 1075-6 (1990), F. E. Nielsen, H. C. Hansen, J. B. Hansen, T. M. Tagmose, PCT Int. Appui. WO 97/26265, M. E. Arranz, S. Vega, Hetero- cycles 45,1767-1774 (1997).

PHARMACOLOGICALMETHODS The ability of the compound to interact with potassium channels can be determined by vari- ous methods. When patch-clamp techniques (Hamill O. P., Marty A., Neher E., Sakmann B. and Sigworth F. J., Plages Arch., 391,85-100 (1981)) are used the ionic current through a single channel of a cell can be recorde.

The activity of the compound as potassium channel openers can also be measured as rela- xation of rat aorta 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, Brit J. Pharmacol, 111, 42-48 (1994).

After a 45 min. equilibration period under a tension of 2 g, the preparations were contracte to achieve 80% of the maximum response using the required concentration of phenylephri- ne. When the phenylephrine response reached a plateau, potential vasodilatory agents were added cumulatively to the bath in small volumes using half log molar increments at 2 min intervals. Relaxation was expressed at the percentage of the contracte tension. The poten- cy of a compound was expressed as the concentration required to evoke a 50% relaxation of the tissue.

In the pancreatic b-cell the opening of the KATp-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Cl 21 concentration accor- ding to the method of Arkhammar P. et al., J. Biol. Chem., 262,5448-5454 (1987).

86Rb+ efflux from a ß-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 % CO2 / 95 % air at 37°C. The cells were detached with a Trypsin-EDTA solution (from GibcoBRL, Scotland, UK), resuspended in medium, added 1 mCi/ml 86Rb+ and replated into microtiter plates (96 well cluster 3596, sterile, from Costar Corporation, MA, USA) at a density of 50000 cells/well in 100 pI/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 Cal2,20 mM Sucrose, pH 7.1). Eighty pI Ringer buffer and 1 ti control-or test compound dissolve in DMSO was added. After incubation 1 h at room temperature with a lid, 50 pl of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 pI MicroScint40 (Packard Instrument Company, CT, USA) added. The

plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32p program.

The calculation of EC50 and EmaX was done by SlideWrite (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 infinie concentration. EC50 = c and EmaX= d, when the curve is turned of at infinie concentrations.

The compound according to the invention are effective over a wide dose 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 administration, form in which administered, the subject to be treated and the body weight of the subject to be trea- ted, 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 com- pound 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 enclose within a carrier which can be in form of a capsule, sachet, paper or other container. In making the compositions, conventio- nal techniques for the preparation of pharmaceutical compositions may be used. For exam- ple, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclo- sed 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 com- pound can be adsorbe on a granular solid container for example in a sachet. Some exam- ples of suitable carriers are water, salt solutions, alcools, polyethylene glycols, polyhydroxy- ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulo-

se and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delay- ed release of the active ingredient after administration to the patient by employing procedu- res well known in the art.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compound.

For parenteral application, particularly suitable are injectable solutions or suspensions, prefe- rably aqueous solutions with the active compound dissolve in polyhydroxylated castor oil.

Tables, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tables, dragees, or cap- sules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in ca- ses where a sweetened vehicle can be employed.

Generally, the compound are dispense in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.

A typical tablet, appropriate for use in this method, may be prepared by conventional tablet- ting techniques and coritains: Active compound 5.0 mg Lactosum 67.8 mg Ph. Eur.

Avicel 31.4 mg Amberlite 1.0 mg Magnesii stearas 0.25 mg Ph. Eur.

EXAMPLES The process of preparing the compound of formula I is further illustrated in the following e- xamples which, however, are not to be construed as limiting.

General procedures for the preparation of 3-alkylsulfanyl-4H-pyrido[4,3-e]-1,2 4-thiadiazine 1 1-dioxides Method A The appropriate 2,3-dihydro-3-thioxo-4H-pyrido-1,2,4-thiadiazine 1,1-dioxide (0.6 g) was dis- solved in a solution of sodium hydrogen carbonate (0.44 g) in water (18 mL) and methanol (12 mL) and supplemented with an excess of the appropriate alkyl halide (1.0-1.5 mL). The mixture was stirred at room temperature for a few hours (until completion of the rection checked by t. l. c.). Methanol and the excess of the reagent were removed by distillation un- der reduced pressure. The aqueous suspension of the crude compound was supplemented with 4N NaOH until dissolution. The alkaline solution was treated with charcoal, filtered off, and the filtrate was adjusted to pH 4-5 with formic acid. The resulting precipitate was col- lected by filtration, washed with water and dried (yields: 45-50 %).

Method B The appropriate 2,3-dihydro-3-thioxo-4H-pyrido-1,2,4-thiadiazine 1,1-dioxide (0.5 g) and an- hydrous potassium carbonate (0.32 g) were introduced in a mixture of acetonitrile (20 mL) and DMF (5 mL). The suspension was supplemented with an excess of the appropriate alkyl halide (1-1.5 mL) and then heated at 50°C for 2 h. The completion of the rection was controled by t. l. c. The solvents were removed by distillation under reduced pressure and the residue was dissolve in 2N NaOH (30-50 mL). The alkaline solution was treated with char- coal, filtered off, and the filtrate was adjusted to pH 2-3 with 6N HCI. The resulting precipi- tate was collecte by filtration, washed with water and dried (yields: 45-50 %).

EXAMPLE 1 3-Isopropylsulfanyl-4H-pyrido[4,3-e]-1,2 4-thiadiazine 1.1-dioxide monohydrate The title compound was obtained from 2,3-dihydro-3-thioxo-4H-pyrido [4,3-e]-1,2,4- thiadiazine 1,1-dioxide monohydrate (B. Pirotte et al, J. Med. Chem. 36,1993,3211) and

isopropyl iodide as described in method A; mp 80-82 °C; IR (KBr): 3490,3227,2927,1600, 1550,1475,1315,1296,1204,1183,1165, 1104 cm-1.

EXAMPLE 2 3-Isopropylsulfanyl-7-methyl-4H-pyrido[2,3-e]-1,2,4-thiadiaz ine1,1-dioxide The title compound was obtained from 2,3-dihydro-7-methyl-3-thioxo-4H-pyrido [2,3-e]-1,2,4- thiadiazine 1,1-dioxide (C. G. Neill et al, Tetrahedron. 54,1998,13645) and isopropyl iodide as described in method A. The crude compound was recrystallized from methanol; mp 226- 228 °C ; IR (KBr): 3128,2967,1603,1553,1500,1456,1320,1300,1217,1204,1162,1083 cm-1.

EXAMPLE 3 3-Cyclopropylmethylsulfanyl-7-methyl-4H-pyrido[23-e]-1, 2.4-thiadiazine 1.1-dioxide The title compound was obtained from 2,3-dihydro-7-methyl-3-thioxo-4H-pyrido [2,3-e]-1,2,4- thiadiazine 1,1-dioxide and cyclopropylmethyl bromide as described in method B; mp 254- 255 °C ; IR (KBr): 3128,2936,2794,1604,1554,1498,1456,1317,1301,1216,1203,1157, 1082 cm~1.