PYRIDO-1,2,4-THIADIAZINE AND PYRIDO-1,4-THIAZINE DERIVATIVES, THEIR PREPARATION AND USE

Abstract: Pyrido-1,2,4-thiadiazine and -1,4-thiazine derivatives represented by formula (I) wherein A, B, D, R<1>, R<2>, R<3> and R<4> are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, pulmonary system, the gastrointestinal system and the endocrinological system.

Description: TITLE Pyrido-1 ,2,4-Thiadiazine and Pyrido-1 ,4-Thiazine Derivatives, their Preparation and Use FIELD OF THE INVENTION The present invention relates to pyrido-1 ,2,4-thiadiazine and pyrido-1 ,4-thiazine 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 endocrinological 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 (KATP-) channels which are regulated by changes in the intracellular concentration of adenosine triphosphate. The K AT p-channels have been found in cells from various tissues such as cardiac cells, pancreatic-cells, skeletal muscles, smooth muscles, central 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 KAT p-channels have been found to be of importance for the treatment of various diseases. Certain sulfonylureas which have been used for the treatment of non-insulin-dependent diabetes mellitus act by stimulating insulin release through an inhibition of the K A . p -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 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 compounds can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia. 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 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 such compounds 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 compounds are claimed to be agonists at the AMPA- glutamate receptor. In Acta Crystallographica Section C, 1995, C51(9), 1903-1905 the crystal structure of 3-benzamido- 4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide is described. DESCRIPTION OF THE INVENTION The present invention relates to pyrido-1 ,2,4-thiadiazine and pyrido-1 ,4-thiazine derivatives of the ge¬ neral formula I: (I) wherein B represents >NR 5 or >CR 5 R 6 , wherein R 5 and R 6 independently can be hydrogen; hydroxy; d-ε- alkoxy; or Cι -6 -alkyl, C 2 -ralkenyl or C 2 _ε-alkynyl optionally mono- or polysubstituted with halogen; or R 5 and R 4 together represent one of the bonds in a double bond between the atom 2 and 3 of formula I; D represents - S(=0) 2 - or -S(=0)-; or D-B represents -S(=O)(R 10 )=N- wherein R 0 is C 1-6 -alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, aryloxy, arylalkoxy, nitro, amino, C t __-monoalkyl- or dialkylamiπo, cyano, acyl, or Cι. 6 -alkoxycarbonyl; R 1 is hydrogen; hydroxy; Cι._-alkoxy; or C 1-6 -alkyl, C 3 - 6 -cycloalkyl, C -6- alkenyl or C 2 . 6 -alkynyI optionally mono- or polysubstituted with halogen and R 4 is hydrogen 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; or R together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I; R 2 is hydrogen; hydroxy; Cι. 6 -alkoxy; or C 1-6 -alkyl, C 3 ^-cycIoalkyl, C 2 . 6 - alkenyl or C 2 ._-alkynyl optionally mono- or polysubstituted with halogen; R 3 is R 11 ; -OR 11 ; -C(=X)R 11 ; -NR 11 R 12 ; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, d-β-alkoxy, aryloxy, arylalkoxy, nitro, amino, Cι_s-monoalkyl- or dialkylamino, cyano, oxo, acyl or d-s-alkoxycarbonyl; or aryl substituted with d-β-alkyl; wherein R 11 is hydrogen; group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms; or straight or branched C 1-18 -alkyl optionally mono- or polysubstituted with halogen, hydroxy, C 1-6 -alkoxy, C 1 _ 6 -alkylthio, C 3 _ 6 -cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, d_ 5 - monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, Ci -β-alkoxycarbonyl, or carbamoyl; X is O or S; R 12 is hydrogen; C 1-6 -alkyl; C 2 _s-alkenyl; C3_s-cycloalkyl optionally mono- or polysubstituted with Cι_s- alkyl, halogen, hydroxy or d_s-alkoxy or R 11 and R 12 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, Ci._-all.yl, hydroxy, alkoxy, d-e-alkoxy-d-β-alkyl, nitro, amino, cyano, trifluoromethyl, d.6-monoalkyl- or dialkylamino, oxo; or R 3 is wherein n,m,p independently are 0,1 ,2,3 and R _13 : i,s hydrogen; hydroxy; d_6-alkoxy; optionally mono- or polysubstituted with C 1-s -alkyl, halogen, hydroxy or d-β-alkoxy; Cι.6-alkyl, C 2 - 5 - alkenyl or C 2 . 6 -alkynyl optionally mono- or polysubstituted with halogen; or R 2 and R 3 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, d._-alkyl, hydroxy, C,^- alkoxy, C .e-alkoxy-d.e-alkyl, nitro, amino, cyano, trifluoromethyl, Ci-rmonoalkyl- or dialkylamino or oxo; A together with carbon atoms 5 and 6 of formula I forms a pyridine ring selected from wherein R 7 , R 8 , R 9 independently are hydrogen; halogen; d. 12 -alkyl; C^e-cycloalkyl; hydroxy; C 1-6 - alkoxy; C . 6 -alkoxy-C 1 . 6 -alkyl; nitro; amino; cyano; cyanomethyl; perhalomethyl; Cι_6-monoalkyl- or dialkylamino; sulfamoyl; d-s-alkylthio; d-e-alkylsulfonyl; C 1-6 -alkylsulfinyl; d-e-alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C 1 - 6 - alkyl, halogen, hydroxy or Ci -β-alkoxy; C 1-s -alkoxycarbonyl; C 1 ^-alkoxycarbonyl-Cι^-alkyl; carbamyl; carbamylmethyl; Cι. 6 -monoalkyl- or dialkylaminocarbonyl; d^monoalkyl - or dialkylaminothiocarbo- nyl; ureido; d. 6 -monoalkyl- or dialkylaminocarbonylamino, thioureido; Cι. 6 -monoalkyl- or dialkylami- nothiocarbonylamino; Cι. 6 -monoalkyl- or dialkylaminosulfonyl; carboxy; carboxy-d- 6 -alkyl; acyl; aryl, arylalkyl, aryloxy, the aryl group optionally being mono- or polysubstituted with d._-alkyl, halogen, hydroxy or d._-alkoxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol-3-yl)-d. 6 -alkyl the oxadiazolyl group optionally being substituted with C 1-€ -alkyl or d^-cycloalkyl; or a 5 - 6 membered nitrogen con¬ taining ring, optionally substituted with phenyl or Cι__-alkyl; provided that when B represents NR 5 , D represents S0 2 and R 2 is hydrogen, d. 6 -alkyl or C^ cycloalkyl, then R 3 is not hydrogen, unsubstituted C 1-6 -alkyl, C 3 ._-cycloalkyl, pyrrolidine, piperidine, piperazine, moφholine, thiomoφholine or benzoyl, or a salt thereof with a pharmaceutically acceptable acid or base. 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 all 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, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, 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, mag¬ nesium and the like. The term "Cι. 6 -alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a d_s-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 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 _s-alkenyr 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^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 cyclohexyl. The term "C 2 - 6 -alkynyl" as used herein refers to unsaturated hydrocarbons which contain triple bonds, such as e.g. -CsCH, -C≡CCH 3 , -CH 2 C≡CH, -CHzCHjCsCH, -CH(CH 3 )C≡CH, and the like. The term "C 1-6 -alkoxy-Cι. 6 -alkyl" as used herein refers to a group of 2-12 carbon atoms interrupted by an O such as e.g. CH O-CH 3 , CH 2 -0-CH r CH 3 , CH 2 -0-CH(CH 3 ) 2 and the like. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl. The terms "Ci-s-alkyl", "Ci.i alkyl" and "d.^-alkyl" as used herein, alone or in combination, refer to a straight or branched, 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 "d_ 18 -alkyr as used herein also includes secondary C h alky! and tertiary C 4-6 -alkyl. The term "Cι. 6 -monoalkylamino" as used herein refers to an amino 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-methylbutylamino, n-hexylamino, 4- methylpentylamino, neopentylamino, n-hexylamino, 2,2-dimethylpropylamino and the like. The term "d-β-dialkylamino" as used herein refers to an amino 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-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 d-β-alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, and the like. The term "Ci. 6 -alkoxycarbonyl" as used herein refers to a monovalent substituent comprising a d_s- 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 term "3-12 membered mono- or bicyclic system" as used herein refers to a monovalent substituent of formula -NR 2 R 3 or -NR 11 R 12 where R 2 and R 3 , or R 11 and R 12 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, such as 1-pyrrolidyl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 7-azabicyclo[2.2.1]heptan-7-yl, tropanyl and the like. The term "3-6 membered saturated ring system" as used herein refers to a monovalent substituent comprising a monocyclic saturated system containing one ore 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-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 bicyclic structure made of 6-12 carbon atoms such as e.g. 2-norbornyl, 7-norbornyl, 2-bicyclo[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, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine. 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 car bohydride; 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-naphthyloxy or 2-naphthyloxy. -The term "arylalkoxy" as used herein refers to a 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- fury methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like. The term "Cι. 6 -alkylsulfonyl" as used herein refers to a monovalent substituent comprising a Cι-_-alkyl group linked through a sulfonyl group such as e.g. methylsulfonyl, ethylsulf onyl, 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 "Cι. 6 -monoalkylaminosulfonyl" as used herein refers to a monovalent substituent comprising a Cι_s-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-hexylaminosulfonyl, 4-methylpentylaminosulfonyl, neopentylaminosulfonyl, n-hexylaminosulfonyl and 2,2- dimethylpropylaminosulfonyl. The term "Ci - 6 -dialkylaminosuIfonyl" as used herein refers to a monovalent substituent comprising a Cι_e-dialkylamino group linked through a sulfonyl group such as dimethytaminosulfonyl, N-ethyl-N- methylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, N-(n-butyl)-N- methylaminosulfonyl, di(n-pentyl)aminosulfonyl, and the like. The term "C 1 _ 6 -alkylsulfinyl" 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, ethyisulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfmyl, and the like. The term "C L s-alkylcarbonylamino" as used herein refers to an amino group wherein one of the hy¬ drogen atoms is substituted with an acyl group, such as e.g. acetamido, propionamido, isopropylcar- bonylamino, and the like. The term "(C 3 . 6 -cycloalkyl)Cι_ 6 -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 Qj-s-cycloalkyl group, the cycloalkyl group optionally being mono- or polysubstituted with C h alky!, - halogen, hydroxy or d. 6 -alkoxy; such as e.g. cyclopropylmethyl, (l-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 C -6 -alkyl, halogen, hydroxy or Cι. 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(=0)-), the aryl group optionally being mono- or polysubstituted with d-e-alkyl, halogen, hydroxy or Cι_ 5 - alkoxy; such as e.g. phenylsulfinyl, (4-chlorophenyl)sulfιnyl, 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 1-6 -alkyl, halogen, hydroxy or such as e.g. phenylsulfonyl, tosyl, and the like. The term "C 1 . 6 -monoalkylaminocarboπyl" as used herein refers to a monovalent substituent compri¬ sing a C ._-monoalkylamino group linked through a carbonyl group such as e.g. methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec- butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, 2- methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, n-hexylaminocarbonyl, 4-methylpen- tylaminocarbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl and 2-2-dimethylpropylamino- carbonyl. The term "Cι_ 6 -dialkylaminoca. bonyl" as used herein refers to a monovalent substituent comprising a d-e-dialkylamino group linked through a carbonyl group such as dimethylaminocarbonyl, N-ethyl-N- methylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, N-(n-butyl)-N- methylaminocarbonyl, di(n-pentyl)aminocarbonyl, and the like. The term "Ci. 6 -monoalkylaminocarbonylan .ino" as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a Cι._-monoalkylaminocarbonyl group, e.g. methylamino- carbonylamino, ethylaminocarbonylamino, n-propylaminocarbonylamino, isopro- pylaminocarbonylamino, n-butylaminocarbonyiamino, sec-butylaminocarbonylamino, iso- butylaminocarbonylamino, tert-butylaminocarbonylamino, and 2-methylbutylaminocarbonylamino. The term "C 1-6 -dialkylaminocarbonylamino" as used herein refers to an amino group wherein one of the hydrogen atoms is substituted with a d-β-dialkylaminocarbonyl group, such as dimethylaminocar- bonylamino, N-ethyl-N-methylaminocarbonylamino, diethylaminocarbonylamino, dipro- pylaminocarbonylamino, N-(n-butyl)-N-methylaminocarbonylamino, di(n-pentyl)aminocarbonylamino, and the like. The term "5- or 6-membered nitrogen containing ring" as used herein refers to a monovalent substituent comprising a monocyclic unsaturated or saturated system containing one or more nitrogen atoms and having 5 or 6 members, e.g. pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyra- zolinyl, 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. 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. In a preferred embodiment of the invention the general formula of formula I is selected from wherein R 1 and R 5 independently are hydrogen; hydroxy; d^-alkoxy; or d-β-alkyl, d^-cycloalkyl, C . 6 -alkenyl or C 2 -β-alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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 9 is as defined above; D represents -S(=0) r or -S(=0)-. In another preferred embodiment of the invention the general formula of formula I is selected from wherein R 1 is hydrogen; hydroxy; d. 6 -alkoxy; or d-β-alkyl, d-e-cycloalkyl, C 2 -6-alkenyl or C 2 . 6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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; D represents -S(=O)R 10 = wherein R 10 is C 1 . 6 -alkyl; aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, d_s-alkoxy, aryloxy, arylalkoxy, nitro, amino, Cι. 6 -monoalkyl- or dialkylamino, cyano, acyl or C 1-6 - alkoxycarbonyl. In another preferred embodiment of the invention the general formula of formula l is selected from wherein RR 11 ,, RR 55 aand R 6 independently are hydrogen; hydroxy; d-β-alkoxy; or d-β-cycloalkyl, C 2-ε - alkenyl or C 2 .6-alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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 and R 6 are 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 and R 6 are as defined above; " D represents -S(=0) 2 - or S(=0). Preferably, the general formula of formula I is (la). In another preferred embodiment of the invention D is -S(=0) . In another preferred embodiment of the invention R 1 is selected from hydrogen, -β-alkyl, C 3-6 - cycloalkyl or C 2 ._-alkenyl. Preferably R 1 is hydrogen or C 1-6 -alkyL In another preferred embodiment of the invention R together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I. In another preferred embodiment of the invention R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I. In another preferred embodiment of the invention R 2 is selected from hydrogen, hydroxy, dialkyl, Cs-s-cycloalkyl or C 2 - 6 -alkenyl. In another preferred embodiment of the invention R 3 is selected from R 11 , -OR 11 , -NR 11 R 12 or aryl, the aryl group optionally being substituted with C -β-alkyl; wherein R 11 is hydrogen; Cs-s-cycloalkyl; (C 3 . 6 -cycloalkyl)d. 6 -alkyl; a 3-6 membered saturated ring system comprising one, two or three nitrogen-, oxygen- or sulfur atoms; or straight or branched d. 8 -alkyl optionally substituted with halogen, hydroxy, Ci-β-alkoxy, Cι._-alkyrthio, C_. 6 -cycloalkyl or aryl; R 12 is hydrogen, d_s-alkyl or Cs-β-cycloalkyl; or R 1 and R 12 together with the nitrogen atom form a 4 - 6 membered ring, preferably 1-pyrrolidyl, piperidine or morpholino. In yet another preferred embodiment of the invention R 3 is selected from secondary tertiary C+β-alkyl, optionally mono- or polysubstituted with C _s-alkyl, halo¬ gen, hydroxy or Preferably R 3 is selected from isopropyl, 1-methylpropyl, 2-methylpropyl, tert- butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, 2,3-dimethylbutyl, 1-ethylpropyl, 1-ethyl- 2-methylpropyl, 1-ethyl-2,2-dimethylpropyl, 2,3,3-trimethylbutyl, 2-methylbutyl, cyclopropyl, 1- methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1-(cyclopropyl)ethyl cyclobutyl- methyl, cyclopentylmethyl or cyclohexylmethyl. In a further preferred embodiment of the invention R 2 and R 3 together with the nitrogen atom forms a six membered ring, optionally substituted in the 2-position with a C,^-alkyl group, preferably selected from methyl, ethyl or isopropyl. Preferably the six membered ring is a piperidine, piperazine, morp¬ holine or thiomorpholine ring. - In another preferred embodiment of the invention R 10 is selected from d. 6 -alkyl, phenyl or pyridyl. in another preferred embodiment of the invention R 7 , R 8 , R 9 are independently hydrogen; halogen; d. 2 -alkyl; C 3 - 6 -cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; d- 6 -alkylthio; C 1-6 - alkylsulfonyl; d._-alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with Cι. 6 -alkyl, halogen, hydroxy or Cι- 6 -alkoxycarbonyl-C 1 . 6 -alkyl; carbamylmethyl; carboxy-C 1 _ s -alkyl; aryloxy; (1,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol-3-yl)C 1 _ s -alkyl, the oxadiazolyl group optionally being substituted with C 1-6 -alkyl or C^cycloalkyl; acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C 1-ε -alkyl. Preferred compounds of the invention are: 3-Hydrazino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Benzylamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(R)-(1-Phenylethylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(S)-(1 -Phenylethylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide; 3-Benzylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1 ,1 -dioxide; 7-Chloro-3-(R)-(1-phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 7-Chloro-3-(S)-(r-phenylethylamino)-4H-pyridot2,3-e]-1,2,4-thiadiazine 1,1-dioxide; 3-Benzylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1 ,1-dioxide; 3-(R)-(1-Phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(S)-(1 -PhenyIethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide; 3-Hexylamino-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1,1 -dioxide; 7-Chloro-3-hexylamino-4H- pyridoI2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Octylamino-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; - 7-Chloro-3-octylamino-4H- pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Allylamino-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Allylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1 ,1-dioxide; 7-Chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-Methoxy-1-methylethyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-Hydroxy-1-methylethyl)amino-4H-pyrido{4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Benzylamino-2-methyl-2H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 2-lsopropylamino-3,3-dimethoxy-3H-pyrido[2,3-b][1 ,4]thiazine 4,4-dioxide. 3-Methoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Ethoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1-1 -dioxide; 3-Cyclopropylmethoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-lsopropoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-lsobutoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Butoxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Cyclopentyloxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Allyloxyamino-4H-pyridol4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Benzyloxyamino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-Phenylethoxy)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Methylhydrazino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-Ethylhydrazino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-lsopropylhydrazino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Methyl-2-ethylhydrazino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Methyl-2-isopropylhydrazino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2,2,2-Trifluoroethyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(1 ,1 ,1 ,3,3,3-Hexafluoro-2-propyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(2-(1 ,1-Bis(trifluoromethyl)propyl))amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(1-Methyl-2,2,-difluoropropyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(1-Methyl-2,2-dicyanoethyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Bicyclo[2,2,2]octyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Adamantylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(1-Adamantylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(3-Quinuclidinyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(1 ,5-dimethylhexyl)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1-dioxide; 3-(3-methylhexyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(3-methylbutyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 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 pectoris and coronary heart diseases; the pulmonary system; the gastrointestinal system; the central nervous system and the endocrinological system. Since some K A ,p-openers are able to antagonize vasospasms in basiiar or cerebral arteries the compounds of the present invention can be used for the treatment of vasospastic disorders such as subarachnoid haemorrhage and migraine. Potassium channel openers hyperpolarizes neurons and inhibit neurotransmitter release and it is expected that the present 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. By acting on potassium channels of the central nervous system the compounds of the present invention can be used for treatment of various neurological and psychiatric diseases such as Alzheimer, epilepsia and cerebral ischemia. The compounds of the present invention may also be used for the treatment of diseases associated with decreased skelettal muscle blood flow such as Reynauds disease and intermittent ctaudication. 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 ureter. 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. 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 labor and dysmenorrhea. Further, potassium channel openers promote hairgrowth, therefore, the compounds of the present invention can be used for the treatment of baldness. In diseases such as nesidioblastosis and insulinoma in which a hypersecretion of insulin causes severe hypoglycemia the compounds of the present invention can be used to reduce insulin secretion. ln obesity hyperinsuiinemia 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 contracting the hyperinsuiinemia and thereby prevent diabetes and reduce obesity. In overt NIDDM treatment of hyperinsuiinemia 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. Compounds of the present invention which act as blockers of can be used for the treatment of NIDDM. Preferably, the compounds of the present invention may be used for treatment or prevention of di¬ seases 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 acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of hyperinsulinaemia 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 hyperinsulinaemia 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 A, B, D, R 1 and R are as defined above and Z is a leaving group such as imidazol-1-yl, alkoxy, alkylthio, halogen, preferentially chloro, bromo, iodo, trimethylamino, 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 l using procedures described by e.g. T. H. Cronon et al., J. Med. Chem. ϋ, 136 (1968); L. Raffa et al., Farmaco Ed. Sci. 29, 411 (1974); B. Pirotte et al., J. Med. Chem. 36, 3211 (1993). Another method comprises: b) reacting a compound of formula IV: wherein R 1 is hydrogen and A, B, D and X are as defined above, or B is NH and R 1 , A, D and X 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 amine 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 A, B, D and X are as defined above or B is NH and R , A, D and X are as defined above, with a compound of the formula III, or a suitable salt thereof in the presence of titanium tetrachloride 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. 2 725-731 (1979); or G. Roma et al. Eur.J. Med.Chem. 26. 489-496 (1991), to form a compound of the general formula I. d) reacting a compound of formula V wherein R 1 and A 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 Chem J.W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of the general formula I, wherein D is S0 2 , B is >NR 5 , 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 and A are as defined above, with a compound of formula VII R 3 NHC(=0)CI (VII) wherein R 3 is as defined above using the method described by Chem J.W. et al., J. Heterocycl. Chem., 27, 1909-1915 (1990), to form a compound of the general formula I, wherein D is S0 2 , B is >NR 5 , 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 and A are defined as above, with a compound of formula VIII wherein Y is NH or S, or a suitable salt thereof using procedures described 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 S0 2 , B is >NR 5 , R 4 and R 5 together form a bond, and R 2 and R 3 are H . 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 Huang B.-S., et al., J. Med. Chem., 23, 575-7 (1980), Ofitserov V. I. 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. Heterocycl. Chem., 6, 407-408 (1969) and Hattori M., Yoneda M., and Goto M., Bull. Chem. Soc. Jap., 46, 1890-1 (1973), Williams T.R. and Cram D.J., J. Org. Chem., 38, 20-26 (1973), Barnes A.C., Kennewell P.D. and Taylor J.B., J. Chem. Soc. Chem. Commun., 1973, 776-777, Stoss and Satzinger, Chem. Ber., 109, 2097 (1976), Kresze G., Hatjiissaak A., Phosphorus Sulfur, 29, 41-47 (1987), Dillard R.D., Yen T.T., Stark P., Pavey D.E., J. Med. Chem., 23, 717-722 (1980). 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., Nefer E., Sakman B. and Sigworth F.J., Plϋgers Arch., 391. 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 ai , Brit J. Pharmacol, m, 42-48 (1994). After a 45 min. equilibration period under a tension of 2 g, the preparations were contracted to achieve 80% of the maximum response using the required concentration of phenylephrine. 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 contracted tension. The potency of a compound was expressed as the concentration required to evoke a -50% relaxation of the tissue. In the pancreatic β-cell the opening of the l< A τp-channels can be determined by measuring the subsequent change in the concentration of cytoplasmic free Ca 2* concentration according to the method of Arkhammer 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 RPM1 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 cells 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 ml/well, and grown 24 hours before use in assay. The plates were washed 4 times with Ringer buffer (150 mM NaCl, 10 mM Hepes, 3.0 mM KCI, 1.0 mM CaCI 2 , 20 mM Sucrose, pH 7.1). Eighty ml Ringer buffer and 1 ml control- or test compound dissolved in DMSO was added. After incubation 1 h at room temperature with a lid, 50 ml of the supernatant was transferred to PicoPlates (Packard Instrument Company, CT, USA) and 100 ml MicroScint40 (Packard Instrument Company, CT, USA) added. The plates were counted in TopCount (Packard Instrument Company, CT, USA) for 1 min/well at the 32 P program. The calculation of EC 50 and Em a was done by SlideWrite (Advanced Graphics Software, Inc., CA, USA) using a four parameter logistic curve: y = (a-d)/ (1+(x c)Vd, 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 5 0 = c and E max = d, when the curve is turned of at infinite concentrations. Measurement of insulin release from incubated pancreatic islets isolated bv the collagenase method from fed female albino Wistar rats. Groups of 10 islets, each derived from the same batch of islets, are preincubated for 30 min at 37°C in 1 ml of a bicarbonate buffered solution (in mM : NaCl 115, KCI 5, CaCI 2 2.56, MgCl 2 1 , NaHC0 3 24) supplemented with 2.8 mM glucose, 0.5% (w/v) dialysed albumin (fraction V, Sigma Chemical Co and equilibrated against a mixture of 0 2 (95%) and C0 2 (5%). The groups of 10 islets are then incubated at 37°C for a further 90 min in 1 ml of the same bicarbonate buffered medium containing 16.7 mM glucose and, in addition, the selected test compounds. In this procedure 6 to 8 series of 10 beakers are incubated simultaneously. For each serie, 8 beakers contain groups of 10 islets and 2 beakers are considered as control beakers (treated in the same manner, containing physiological medium but no islets). In order to ensure homogeneous distribution of islets among the different series, the collected islets are placed in succession in one beaker of each serie. The first and last series of 10 beakers (8 beakers with islets, 2 beakers without islets in each series) are incubated in the presence of 16.7 mM glucose (no added pharmacological compound; these series are regarded as control series). The 4-6 other series of 10 beakers are incubated in a 16.7 mM glucose medium enriched with the selected pharmacological compound (either different compounds or 1 or 2 compounds tested at different concentrations). After incubation, the incubation medium is removed from the beaker with a Pasteur pipette and stored at -20°C. The release of insulin is measured radioimmunologically using rat insulin as a standard. Experiments are repeated 2-4 times, on different days (which means on 2-4 different sources of pancreatic islets). The islets-related variations (variations in the absolute values for insulin secretion from one to another immunoassay) led us to express the secretory rate with reference to a control value (100% = average of absolute values of the first and last series of beakers in each experiment : control series). Thus for each experimental series, the absolute values are expressed as % compared to the control condition within the same experiment. At a concentration of 50 μM several compounds potently inhibit insulin release: Compound No. % Residual insulin released 1 75 3 17.5 6 52.3 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 5 mg to about 200 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 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, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose 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 delayed release of the active ingredient after administration to the patient by employing procedures 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 compounds. 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 like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, com starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. A typical tablet, appropriate for use in this method, may be prepared by conventional tabletting techniques and contains: 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. Due to their high degree of activity, the compounds of the invention may be administered to an animal in need of such treatment, prevention, elimination, alleviation or amelioration of various diseases as mentioned above and especially of diseases of the endocrinological system such as hyperinsulinaemia and diabetes. Such animals include both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. Preferably the animal is a mammal especially a human. EXAMPLES The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples which, however, are not to be construed as limiting. EXAMPLE 1 Preparation of intermediates 3-Methylsulfanyl-4H-Pyrido[4.3-el-1.2.4-thiadiazine 1 ,1-dioxide monohydrate (Compound I), was prepared according to the published procedure ( B. Pirotte et al., J.Med.Chem.,1993, 36, 3211-3213. 7-Chloro-3-.imidazol-1-yl)-4H-pyrido[2.3-el-1.2.4-thiadiazine 1.1 -dioxide A solution of 2-amino-5-chloropyridine-3-sulfonamide (8.0 g) and thiocarbonyldiimidazole (20.5 g) in dioxane (80 mL) and DMF (20 mL) was refluxed for 3 h. The reaction was checked by t.l.c. When the reaction was complete, the solvents were removed under reduced pressure. The resi¬ due was dissolved in an aqueous solution of NaOH (4 g in 150 mL of water). The solution turns rapidly to a suspension of the sodium salt of the title compound. The salt was collected by filtrati- on and washed with a small volume of water. The salt was dissolved in hot water (200 mL), trea¬ ted with charcoal, filtered and the filtrate was adjusted to pH 5-6 with 1N HCl. The precipitate was collected by filtration, washed with water and dried (yield: 8.8 g); m.p. 330-331 β C. (Compound II). 3-(lmidazo.-1-yr_-4H-pyridθι2.3-el- .2.4-thiadiazine 1.1-dioxide The same procedure as described for Compound II was used starting from 2-aminopyridine-3- sulfonamide (5.0 g) and thiocarbonyldiimidazole (13 g) except that the sodium salt did not preci¬ pitate after the addition of NaOH. The alcaline solution was treated with charcoal, filtered and the " filtrate was adjusted to pH 5-6 with HCl 1 N. The precipitate was collected by filtration, washed with water and dried (yield: 4.8 g); m.p. 312-314 β C. (Compound III). 2-Methyl-3-thioxo-2.3-dihvdro-4H-Pyridof4.3-el-1.2.4-thiadiazine 1.1-dioxide A solution of N-methyl-4-aminopyridine-3-sulfonamide (de Tullio et al., Tetrahedron 1995, 3221- 3234) (5.0 g) and thiocarbonyldiimidazole (7.5 g) in dioxane (30 mL) and DMF (15 mL) was heated at 90 °C for 2 h. The solvents were removed by distillation under reduced pressure. The residue was dispersed in 0.6N NaOH (20 mL) and stirred for 30 min. The alkaline solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 4-5. The precipitate was collected by filtrati¬ on, washed with water and dried (yield: 4 g); m.p. 195-198 °C. (Compound IV). 2-Methyl-3-methylsulfanyl-2H-Pyridof4.3-e1-1.2.4-thiadiazine 1.1 -dioxide A solution of 2-methyl-3-thioxo-2.3-dihydro-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide (1.0 g) in acetonitrile (20 mL) was supplemented with potassium carbonate (1.0 g), then with methyl iodide (1 mL). After 1 h at room temperature, the solvent was removed by distillation under reduced pressure. The residue was dispersed in water (50 mL) and the suspension was adjusted to pH 5 with formic acid. The insoluble material was collected by filtration, washed with water and dried (yield: 0.8 g); m.p. 135-138 β C. (Compound V). 1 H-Pyridof2.3-blf 1.4.thiaziπ-2_3H)-thione Thionation of 1H-pyrido[2,3-b][1 ,4]thiazin-2(3H)-one (prepared according to Dunn and Norrie, J.Prakt.Chem. 1990,332 (4) 444-452) with phosphorous pentasulfide in toluene by standard procedu¬ res (see e.g. H. Tawada et al., Chem.Pharm.Bull. 1990, 38, 1238-1245) gave the title compound; m.p. 233-234 °C. (Compound VI). 2-lsoproρylamino-3H-pyridof2.3-b1f1.4_thiazine 1H-Pyrido[2,3-b][1 ,4]thiazin-2(3H)-thione (0.5 g) was dissolved in 10 ml of isopropylamine and al¬ lowed to stand for 45 min at room temperature. Then the excess of the amine was removed in vacu¬ um and the solid residue was dissolved in 25 ml of ethyl acetate / methanol (4:1), treated with char- coal and filtered through a pad of silica. The filter was eluted with 2 X 10 ml of ethyl acetate / metha¬ nol (4:1). The filtrate was evaporated and the slowly crystallizing residue was triturated with 5 ml of ethyl acetate and then with 3 ml of diethyl ether. The crystals were filtered off and dried to give the title compound; m.p. 135-139 °C. (Compound VII). EXAMPLE 2 3-Hvdrazino-4H-pyridθι4.3-e1-1.2.4-thiadiazine 1.1-dioxide 3-Methylsulfanyl-4H-pyrido[4,3-el-1,2,4-thiadiazine 1 ,1-dioxide monohydrate (1.0 g) was added to hydrazine hydrate (0.8 ml) and the mixture was heated to 70 β C for 30 min. After cooling, the reaction mixture was supplemented with methanol (10 ml) and the solvents were removed by distillation under reduced pressure. The residue was dissolved in NaOH 2M (20 ml), treated with charcoal, filtered, and the filtrate was adjusted to pH 6-7 with HCl 1 M. The precipitate so obtained was collected by filtration, washed with water an dried (yield: 0.8 g); m.p. 290-292 °C. (Compound 1). EXAMPLE 3 3-Aralkylamino-4H-1 ,2.4-pyridothiadiazine 1.1 -dioxides A mixture of the appropriate precursor (Compound I, II, or III) (0.5 g) and the appropriate aralky- lamine (2.5 mL) was refluxed for 30 min to 60 min (until completion of the reaction ; t.l.c). After cooling, the reaction mixture was distributed between 0.5% aqueous NaOH (200 mL) and di- ethylether (100 mL). The aqueous layer was separated and was treated with charcoal, then fil¬ tered. The filtrate was adjusted to pH 6-7 with formic acid. The resulting precipitate was collected by filtration, washed with water and dried (yield: 70-85 %). In this way the following compounds were prepared: 3-Benzylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1-dioxide; m.p. 198-201 °C. (Compound 2). 3-(R)-(1-Phenylethylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide; m.p. 236-238 β C. (Compound 3). 3-(S)-(1-Phenylethylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 233-235 β C. (Compound 4). 3-Benzylamino-7-chloro-4H-ρyrido[2,3-eJ-1,2,4-thiadiazine 1 ,1-dioxide; m.p. 244-245 "C. (Compound 5). 7-Chloro-3-(R)-(1-phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 261-262 β C. (Compound 6). 27 7-Chloro-3-(S)-(1-phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 262-265 °C. (Compound 7). 3-Benzylamino-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 232-233 °C. (Compound 8). 3-(R)-(1-Phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 207-210 β C. (Compound 9). 3-(S)-(1-Phenylethylamino)-4H-pyrido[2.3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 213-214 °C. (Compound 10). EXAMPLE 4 3-Hexylamino-4H- ρyrido.4.3-e,-1,2.4-thiadiazine 1 ,1-dioxide 3-Methylsulfanyl-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide monohydrate (0.5 g) and hexylami- ne (5.0 mL) were refluxed for 3-4 h (until completion of the reaction ; t.l.c). The amine was distil¬ led under reduced pressure. The residue was dissolved in 1N NaOH (150 mL), treated with char- coal, filtered, and the filtrate was adjusted to pH 5-6 with formic acid. The resulting precipitate was collected by filtration, washed with water and dried (yield: 0.38 g); m.p. 170-171 "C. (Compound 11). In a similar manner the following compound was prepared: 7-Chloro-3-hexylamino-4H- pyrido[2,3-e]-1,2,4-thiadiazine 1 ,1-dioxide; m.p. 176-179 °C; from 7- chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide and hexylamine. (Compound 12). EXAMPLE 5 3-Octylamino-4H- pyrido_4.3-e1-1.2.4-thiadiazine 1.1 -dioxide A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide monohydrate (0.5 g), octylamine (0.5 mL) and m-chlorotoluene (3 mL) was refluxed for 2-3 h (until completion of the re¬ action ; t.l.c). Most of the solvents were removed by distillation and the residue was dispersed in a mixture of water (30 L) and methanol (30 mL) and supplemented with NaOH 10 % w/v in water (2 mL). The mixture was treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried (yield: 0.29 g); m.p. 176-179 °C. (Compound ' 13). In a similar manner the following compound was prepared: 7-Chloro-3-octylamino-4H- pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 170-175 °C; from 7- chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and octylamine. (Compound 14). EXAMPLE 6 3-Allylamino-4H- pyrido_4.3-e1-1.2.4-thiadiaziπe 1.1-dioxide A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide monohydrate (0.5 g) and allylamine (4 mL) was heated in a sealed bumb for 4-5 h at 120 β C. After cooling, the amine was removed by distillation under reduced pressure. The residue was dissolved in 0.5N NaOH, treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a dihydrate (yield: 0.44 g); m.p. 206-208 β C . (Compound 15). in a similar manner the following compound was prepared: 3-Allylamino-7-chloro-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; m.p. 224-227 °C; from 7-chloro- 3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide and allylamine. (Compound 16). EXAMPLE 7 7-Chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido[2.3-el-1.2,4-thiadiazine 1.1 -dioxide A mixture of 7-chloro-3-(imidazol-1-yl)-4H-pyrido(2,3-e]-1 ,2,4-thiadiazine (0.5 g) and 2-amino-1- methoxypropane (5 mL) was refluxed for 24 h. The amine was removed by distillation under re¬ duced pressure. The residue was dissolved in a small volume of 0.1 N NaOH (20 mL), treated with charcoal, filtered and the filtrate was adjusted to pH 5-6. The suspension was conserved 24 h at +4 β C. The precipitate was collected by filtration, washed with the minimum of water and dried (yield: 0.25 g); m.p. 150-156 β C. (Compound 17). EXAMPLE 8 3-(2-Methoxy-1-methylethyl)amino-4H-pyridof4,3-e1-1.2,4-thiadiazine 1.1-dioxide The same procedure than above was used (except the starting material was 3-methylsulfanyl-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide monohydrate) up to the adjustement of the aqueous solution to pH 5-6. However, in this case, no precipitation occured. Then, the solvent was rem¬ oved by distillation under reduced pressure. The residue was dispersed in a small volume of water (4 mL). The insoluble material was collected by filtration. The solid was dispersed in acetone (30 mL). The insoluble material was eliminated by filtration. The filtrate was concentrated under re¬ duced pressure. The residue was solubilized in a small volume of acetone (3 mL). After a few minutes, a fine precipitate appears which was collected by filtration, washed with acetone and dried to give the title compound as a monohydrate (yield: 0.1 g); m.p. 174-178 °C. (Compound 18). EXAMPLE 9 3-.2-Hvdroxy-1-methylethyl.amino-4H-pyrido.4.3-e.-1 ,2.4-thiadiazine 1.1 -dioxide A suspension of 3-methylsulfanyl-4H-pyridol4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide monohydrate and 2-amino-1-propanol (0.75 mL) was refluxed for 90 min (until completion of the reaction; t.l.c). After cooling, the addition of diethylether (20 mL) gave rise to the separation of an oily residue. After decantation of the etheral solution, the residue was solubilized in methanol (1 mL) and then supplemented with diethylether (15 mL). An oily residue separated again. After decantation of the supematent, the oily residue was solubilized in acetone (6 mL). A fine precipitate readily appea¬ red. After 3 h at +4 "C, the resulting precipitate was collected by filtration, washed with acetone and dried (yield: 0.33 g); m.p. 213-216 °C. (Compound 19). EXAMPLE 10 3-Benzylamino-2-methyl-2H-pyridof4.3-el-1.2.4-thiadiazine 1.1-dioxide A solution of 2-methyl-3-methylsulfanyl-2H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide (0.5 g) and benzylamine (0.5 mL) in dioxane (2.5 mL) was refluxed until completion of the reaction (t.l.c). After cooling, the addition of ether gave rise to the precipitation of the title compound. The preci¬ pitate was collected by filtration, washed with ether and recrystallized from methanol-ether (yield: 0.4 g); m.p. 142-146 °C. (Compound 20). EXAMPLE 11 2-!sopropytamino-3.3-dimethoxy-3H-pyrido_2,3-b1ι1.41thiazine 4,4-dioxide To a stirred solution of 2-isopropylamino-3H-pyrido[2,3-b][1 ,4]thiaziπe (0.10 g) in 2 ml of methanol was added 2 ml of water. To the resulting turbid mixture oxone (0.59 g) was added over 10 min and stirring was continued for 1 h. Then 10 ml of water was added and the mixture was extracted 3 times with 5 ml of dichloromethane. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuum. The residue was purified on a silica column eluted with a 9:1 mixture of ethyl acetate and methanol to give the title compond; m.p. 123-126 "C; m/e 299 (M+); Η- NMR(CDCI 3 ), δ (ppm): 7.92 (m, 1H, 6-H), 7.39-7.23 (m, 7-H and residual chloroform), 7.16-7.07 (m, 1H, 8-H), 5.79 (br d, 1H, NH), 4.2-4.0 (m, 1H, CH), 3.66 (s, 3H, CH 3 0), 3.57 (s, 3H, CH 3 0), 1.35-1.26 (two d, 6H, (CH 3 ) 2 C). (Compound 21).

Claims: CLAIMS 1. A compound of the general formula I wherein B represents >NR 5 or >CR 5 R 6 , wherein R 5 and R 6 independently can be hydrogen; hydroxy; C 1-6 - alkoxy; or dialkyl, d^-cycloalkyl, C 2 . 6 -alkenyl or C 2 .β-alkynyl optionally mono- or polysubstituted with halogen; or R 5 and R 4 together represent one of the bonds in a double bond between the atom 2 and 3 of formula I; D represents - S(=0) 2 - or -S(=0)-; or D-B represents -S(=O)(R 10 )=N- wherein R 10 is C 1-6 -alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, Cι. 6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, d-β-monoalkyl- or dialkylamino, cyano, acyl, or C 1-6 -alkoxycarbonyl; R 1 is hydrogen; hydroxy; C -β-alkoxy; or d_s-alkyl, d-β-cycloalkyl, C 2 _s- alkenyl or C 2-6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen or R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula 1; or R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I; R 2 is hydrogen; hydroxy; C 2 _s- alkenyl or C 2-6 -alkynyl optionally mono- or polysubstituted with halogen; R 3 is R 11 ; -OR 11 ; -C(=X)R 11 ; -NR 1 R 12 ; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, C 1-6 -alkoxy, aryloxy, arylalkoxy, nitro, amino, d. 6 -monoalkyl- or dialkylamino, cyano, oxo, acyl or C 1-6 -alkoxycarbonyl; or aryl substituted with Cι. 6 -alkyl; -wherein R 1 is hydrogen; C 3 _s-cycloalkyl or the d.e-cycloalkyl group optionally being mono- or polysubstituted with d-β-alkyl, halogen, hydroxy or a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms; or straight or branched d. 18 -alkyl optionally mono- or polysubstituted with halogen, hydroxy, d. 6 -alkoxy, Cι_ δ -alkylthio, d-s-cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, d_ 5 - monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, Ci.e-alkoxycarbonyl, or carbamoyl; X is O or S; R 12 is hydrogen; d-β-alkyl; C 2 ^-alkenyl; Cs-6-cycloalkyl optionally mono- or polysubstituted with Ci- alkyl, halogen, hydroxy or Cι_ralkoxy or R 11 and R 12 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, d-β-alkyl, hydroxy, Cι._- alkoxy, nitro, amino, cyano, trifluoromethyl, d._-nrιonoalkyl- or dialkylamino, oxo; or wherein n.m.p independently are 0,1,2,3 and R ,1 1 3 J is hydrogen; hydroxy; C 1-6 -alkoxy; Cs^-cycloalkyl optionally mono- or polysubstituted with d-β-alkyl, halogen, hydroxy or C 1 ^-atkoxy; Cι. 6 -alkyl, C 2-6 - alkenyl or C 2-6 -alkynyl optionally mono- or polysubstituted with halogen; or R 2 and R 3 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, dialkyl, hydroxy, d- < r alkoxy, Cι. 6 -alkoxy-Cι. 6 -alkyl, nitro, amino, cyano, trifluoromethyl, d-e-monoalkyl- or dialkylamino or oxo; A together with carbon atoms 5 and 6 of formula I forms a pyridine ring selected from wherein R 7 , R 8 , R 9 independently are hydrogen; halogen; C 1-12 -alkyl; hydroxy; C 1-6 - alkoxy; d-e-alkoxy-d- t ralkyl; nitro; amino; cyano; cyanomethyl; perhalomethyl; d._-monoalkyl- or dialkylamino; sulfamoyl; C 1-6 -alkylthio; C 1-6 -alkylsulfonyI; C 1-6 -alkylsulfinyl; C 1-6 -alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with Cι._- alkyl, halogen, hydroxy or Cι -6 -alkoxy; Ci-β-alkoxycarbonyl; Cι -6 -alkoxycarbonyl-Cι. 6 -alkyl; carbamyl; carbamylmethyl; d^-monoalkyl- or dialkylaminocarbonyl; C 1 ^-monoalkyl - or dialkylaminothiocarbo- nyl; ureido; Cι- 6 -monoalkyl- or dialkylaminocarbonylamino, thioureido; d-β-monoalkyl- or dialkylami- nothiocarbonylamino; C 1 ^-monoalkyl- or dialkylaminosulfonyl; carboxy; carboxy-d-e-alkyl; acyl; aryl, arylalkyi, aryloxy, the aryl group optionally being mono- or polysubstituted with C 1-6 -alkyl, halogen, hydroxy or C 1-6 -alkoxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol-3-yl)-d^-alkyl the oxadiazolyl group optionally being substituted with d- 6 -alkyl or Cs-s-cycloalkyl; or a 5 - 6 membered nitrogen con¬ taining ring, optionally substituted with phenyl or C h al y!; provided that when B represents NR 5 , D represents S0 2 and R 2 is hydrogen, C 1-6 -alkyl or C^ cycloalkyl, then R 3 is not hydrogen, unsubstituted d-e-alkyl, Cs^cycloalkyl, (C 3 . 6 -cycloalkyl)C 1-6 -alkyl, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or benzoyl. 2. A compound according to claim 1 , wherein R 2 is hydrogen or d-_-alkyl. A compound according to claim 1 or 2 wherein R 3 is R 11 , -OR 11 , NR 11 R 12 or aryl, the aryl groups optionally being substituted with Cι_s-alkyl; wherein R 11 is hydrogen; 0 3 . 6 -cycloalkyl; (C«-cycloalkyl)C 1 _ 6 -alkyl; a 3 - 6 membered saturated ring system comprising one, two or three nitrogen-, oxygen- or sulfur atoms; or straight or branched d. 18 -alkyl optionally substituted with halogen, hydroxy, or aryl, R 12 is hydrogen, C h alky! or Qws-cycloalkyl; or R 11 and R 12 together with the nitrogen atom form a 4 - 6 membered ring. 4. A compound according to any one of the preceding claims wherein R _3 . i„s secondary C_^- alkyl, tertiary C 4 ^-alkyl, Qj-β-cycloalkyl or (Crws-cycloalkyr methyl. 5. A compound according to any one of the preceding claims wherein A together with carbon atoms 5 and 6 of formula I forms a pyπ ' dine ring selected from wherein R 7 , R 8 , R 9 independently are hydrogen; halogen; Ci.iralkyl; C_. 6 -cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; C,_s-alkylthio; d-e-alkylsulfonyl; d_s-alkylsulfιnyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with Cι_ 5 -alkyl, halogen, hydroxy or Cι_ 6 -alkoxy; d-e-alkoxycarbonyl-d-β-alkyl; carbamylmethyl; carboxy-d -e-alkyl; aryloxy; (1 ,2,4- oxadiazol-5-yl)- or (I .Σ^-oxadiazol-S-y d-s-alkyl, the oxadiazolyl group optionally being substituted with Cι_ 6 -alkyl or C^e-cycloalkyl; acyl or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or d-β-alkyl. ( A compound according to any one of the claims 1 - 5, wherein the general formula I is wherein R 1 and R 5 independently are hydrogen; hydroxy; or C 1 _ s -alkyl, Cs-6-cycloalkyl, C 2 .6-alkenyl or C 2-6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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(=0) 2 - or S(=0)-; and -A, R 2 and R 3 are as defined above. χ A compound according to claim 6 wherein R 1 and R 5 independently are hydrogen or d._- alkyl. Σ A compound according to claims 6 or 7 wherein R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I. 9. A compound according to any one of the claims 6 - 8, wherein R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I. 10. A compound according to any one of the claims 6 - 9 wherein D is -S(=0) 2 -. 11. A compound according to any one of the claims 1 - 5 wherein the general formula I is wherein R 1 is hydrogen; hydroxy; C 1-6 -alkoxy; or d.6-alkyl, C^cycloalkyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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; D represents -S(=O)R 10 = wherein R 10 is C .«-alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, d.e-alkoxy, aryloxy, arylalkoxy, nitro, amino, d.6-monoalkyl- or dialkylamino, cyano, acyl or C 1-6 -alkoxycarbonyl; and A, R 2 and R 3 are as defined above. 12. A compound according to claim 11 wherein R 1 is hydrogen or Cι.e-alkyl. - 13;, A compound according to claim 11 or 12 wherein R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I. 14. A compound according to any one of the claims 11 - 13 wherein R 10 is Cι_β-alkyl, phenyl or pyridyl. 15. A compound according to any one of the claims 1 - 5 wherein the general formula I is wherein R 1 , R 5 and R 6 independently are hydrogen; hydroxy; or C h alky!, C 3 . 6 -cycloalkyl, C 2-5 - alkenyl or C 2 - 6 -alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; 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 and R 6 are 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 and R 6 are as defined above; D represents -S(=0) 2 - or -S(=0)-; and A, R 2 , R 3 are as defined above. 16. A compound according to claim 15 wherein R 1 , R 5 and R 6 independently are hydrogen or d- β-alkyl. 17. A compound according claim 15 or 16 wherein R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I. ϋ A compound according to any one of the claims 15 - 17 wherein R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I. 19. A compound according to any one of the claims 15 - 18 wherein D is -S(=0) 2 -. - 20, A compound selected from the following: 3-Hydrazino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Benzylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1 -dioxide; 3-(R)-(1-Phenylethylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(S)-(1-Phenylethylamino)-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-Benzylamino-7-chloro-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 7-Chloro-3-(R)-(1-phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 7-Chloro-3-(S)-(1 '-phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Benzylamino-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(R)-(1-Phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(S)-(1-Phenylethylamino)-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-(Hexylamino)-4H- pyrido[4,3-e]-1 ,2,4-thiadiaziπe 1 ,1-dioxide; 7-Chloro-3-hexylamino-4H- pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Octylamιno-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 7-Chloro-3-octylamino-4H- pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Allylamino-4H- pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Allylamino-7-chloro-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 7-Chloro-3-(2-methoxy-1-methylethyl)amino-4H-pyrido[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Methoxy-1-methylethyl)amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1 ,1 -dioxide; 3-(2-Hydroxy-1-methylethyl)amino-4H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 3-Benzylamino-2-methyl-2H-pyrido[4,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide; 2-lsopropylamino-3,3-dimethoxy-3H-pyrido[2,3-b][1 ,4]thiazine 4,4-dioxide. Compounds according to any one of the preceding claims which acts as openers of the K A .p-regulated potassium channels. 22. A method of preparing a compound of formula I, characterized in a) reacting a compound of formula II: wherein A, B, D, R 1 and R 4 are as defined above and Z is a leaving group such as imidazol-1-yl, alkoxy, alkylthio, halogen, preferentially chloro, bromo, iodo, trimethylamino, 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; b) reacting a compound of formula IV: wherein R 1 is hydrogen and A, B, D and X are as defined above, or B is NH and R , A, D and X 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 amine or a suitable salt thereof, to form a compound of the general formula I; c) reacting a compound of the formula IV: wherein R 1 is hydrogen and A, B, D and X are as defined above or B is NH and R 1 , A, D and X are as defined above, with a compound of the formula III, or a suitable salt thereof in the presence of titanium tetrachloride and a solvent with which it may form a complex, like e.g. tetrahydrofuran, or a mixture of toluene and anisole, to form a compound of the general formula I; d) reacting a compound of formula V (V) wherein R 1 and A are as defined above, with a compound of formula VI R J NCO (VI) wherein R 3 is as defined above, to form a compound of the general formula I, wherein D is S0 2 , B is >NR 5 , 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 and A are as defined above, with a compound of fonmula VII R 3 NHC(=0)CI (VII) wherein R 3 is as defined, to form a compound of the general formula I, wherein D is S0 2 , B is >NR 5 R is H, and R" and R 3 together form a bond; or f) reacting a compound of the formula V (V) wherein R 1 and A are defined as above, with a compound of formula VIII Y H 2 N^ C ^NH 2 ( IM) wherein Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is S0 2 , B is >NR 5 , R 4 and R 5 together form a bond, and R 2 and R 3 are H. 23. A pharmaceutical composition comprising a compound according to any of the claims 1 - 21 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents. 24. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as hyperinsulinaemia and diabetes comprising a compound according to any of the claims 1 - 21 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents. 25. The pharmaceutical composition according to claim 23 or 24 in the form of an oral dosage unit or parenteral dosage unit. 26. A pharmaceutical composition according to claim 23 or 24 wherein said compound is administered as a dose in a range from about 0.05 to 1000, preferably from about 0.1 to 500 and especially in the range from 5 to 200 mg per day. 27. A compound according to any of the claims 1 - 21 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use. 2£ A compound according to any of the claims 1 - 21 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes. - 2SL The use of a compound according to any of the claims 1 - 21 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament. 3( The use of a compound according to any of the claims 1 - 21 for preparing a medicament. 31. The use of a compound according to any of the claims 1 - 21 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes. 32. A method of treating or preventing diseases of the endocrinological system, such as hyperinsulinaemia and diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims 1 - 21 to said subject. 33. A process for the manufacture of a medicament, particular to be used in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes which process comprising bringing a compound of formula I according to any of the claims 1 - 21 or a pharmaceutically acceptable salt thereof into a galenic dosage form. 34. Any novel feature or combination of features as described herein.

Inventors: DE TULLIO PASCAL, DELARGE JACQUES ELIE, HANSEN HOLGER CLAUS, HANSEN JOHN BONDO, LEBRUN PHILIPPE, NIELSEN FLEMMING ELMELUND, PIROTTE BERNARD, SOMERS FABIAN
Applicants: NOVONORDISK AS
Application year: 1997
Main classification: C07D513
IPC codes: A61K31, A61P1, A61P3, A61P5, A61P9, A61P11, A61P13, A61P15, A61P17, A61P25, C07D513