MXPA00008128A - Novel compounds and their use as positive ampa receptor modulators - Google Patents

Abstract

The invention provides novel compounds represented by general formula (I) wherein the bond represented by the broken line may be a single, double bond or absent;and if the bond is absent, then the nitrogen is substituted with a hydrogen and R2;X represents SO2 or C=O of CH2;Y represents -CH(R4)-, -N(R4)- or -N(R4)-CH2-, O;and the meaning of R2, R3, R4, R5, R6, R7, and R8 are as defined in the application. The compounds are useful as positive modulators of the AMPA-receptor.

Description

NOVEDOUS COMPOUNDS AND THEIR USE AS POSITIVE AMPA RECEIVER MODULATORS This invention relates to novel compounds, useful as modulators of AMPA sensitive glutamate receptors, to pharmaceutical compositions comprising said compounds and to their use in therapy.

BACKGROUND OF THE INVENTION L-glutamate is the main excitatory neurotransmitter in the central nervous system of mammals, which activates several subtypes of ionotropic and metabotropic receptors. The ionotropic receptors can be divided into three subtypes: NMDA, AMPA and kainate receptors, based on structural and pharmacological differences. Glutamatergic impairment in learning and memory loss observed in numerous neurological disorders, such as, for example, death by Alzheimer's, senile dementia, attacks (McEntee and Crook, Psycopharmacology 11 1: 391-401 (1993)) has been implicated. . It is widely accepted that learning and memory are related to the induction of long-term potentiation (LTP, acronym for its English designation: Long-Term Potentiation), which is a stable increase in synaptic potency after high repetitive stimulation. frequency.

Experimental studies have shown that increasing the synaptic response mediated by AMPA receptors increases the induction of LTP (Arai and Lynch, Brain Research, 598: 173-184 (1992)). For the reasons stated above, compounds that stimulate the AMPA receptor response in the brain can induce improvements in intellectual behavior and intellectual functioning. The activation of the AMPA receptors with L-glutamate or with the selective agonist of AMPA leads to a rapid sensitization of the receptor, that is, the receptor channels can not be opened, despite the continuous presence of the agonist. Therefore, it is possible to obtain an increase in synaptic potency by attenuating the desensitization of the AMPA receptor normally triggered by the endogenous neurotransmitter L-glutamate. In 19090 Ito and coauthors reported (J. Physiol, 424: 533-543) that the nootropic drug Aniracetam (N-anisoyl-2-pyrrolidinone) increased currents induced by AMPA in oocytes injected with rat brain mRNA. In another study, it has been shown that 1- (1,3-benzodioxol-5-ylcarbonyl) -1, 2,3,6-tetrahydropyridine, a compound that promotes synaptic transmission mediated by AMPA receptors, is effective in improving memory in experimental animals at a very high dose of 120 mg / kg (Staubli and co-authors, Proc. Nati, Acad. Sci. USA, 91: 11158-1,162 (1994)). Benzothiadiazide cyclothiazide is a more potent and effective modulator of the AMPA receptor current in vitro than aniracetam (Johansen and co-authors, Mol.Pharmacol., 48: 946-955 (1995)). The effect of cyclothiazide on the kinetic properties of AMPA receptor currents appears to be by a mechanism different from that of aniracetam (Partin and co-authors, J. Neuroscience, 16: 6634-6647 (1996)). However, cyclothiazide has no therapeutic potential for modulation of the AMPA receptor, since it can not cross the blood-brain barrier after peripheral administration. The low potency of the known compounds also meets higher demands for high solubility, due to the higher doses used for administration ..}.

TECHNICAL BACKGROUND US 5,488,049 describes the use of benzothiadiazide derivatives to treat memory and learning disorders. The compounds are intimately related in a structural sense with the compounds of the present invention. However, the compounds of the present invention show greater potentiation at lower concentrations (Figure 3 of US 5,488,049). US 4,184,039 describes benzothiadiazides for use in the promotion of hair growth. DE 1470316 describes a method for producing some benzothiadiazides, for use as additives in galvanization baths. In Synthesis (10), 183, page 851, a method for preparing 1,1-benzothiadiazine dioxides is described. The compounds useful as antihypertensive agents and antimicrobial reagents are described. In J. Med. Chem. (15, No. 4, 1972, pages 400-403, the 1, 1-dioxides of benzothiadiazine are investigated by their constants of p substituents, as a study of structural activity for hypertensive activity. No. 9812185 describes benzothiadiazines of different structure than the compounds of the present invention.

OBJECTIVES OF THE INVENTION It is an object of the present invention to provide modulators AMPA which are useful in the treatment of disorders or diseases in mammals, including humans, and especially in the treatment of diseases and disorders that respond to the modulation of receptors AMPA in the brain. It is another object of the present invention to provide a method for treating disorders or diseases of a mammal, including a human, that respond to modulators of the AMPA receptor, which comprises administering to a mammal in need thereof, a compound of the invention. It is a third objective of the present invention to provide novel pharmaceutical compositions for the treatment of disorders or diseases of mammals, including humans, that respond to AMPA modulators. Other objects of the present invention will be apparent to the skilled person, in what follows.

BRIEF DESCRIPTION OF THE INVENTION Among others, the invention comprises the following, alone or in combination: A compound represented by the general formula: I in which: the ligature represented by the interrupted line can be a simple ligature, a double ligature or be absent; and if the ligature is absent, the nitrogen is substituted with a hydrogen and R2; X represents SO2 or C = O or CH2; Y represents -CH (R4) -, -N (R4) - or -N (R4) -CH2-, O; R 2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R9, wherein: R9 represents alkyl, cycloalkyl, benzyl, aryl, or R2, together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, alkyl-S-R13, where: R13 and R14 independently represent hydrogen, alkyl, cycloalkyl, or R13 and R14, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members. A carbocyclic ring of 7 to 12 members, optionally substituted by halogen, alkyl, hydroxy or alkoxy; or a 3- to 8-membered heterocyclic ring, optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally, the heterocyclic ring is fused to an aryl; benzyl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; aryl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio; halogenoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino, or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl , alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10 or CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times, with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or uncle; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -SO2-NR11R12; wherein: R 11 and R 2 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl or R 11 and R 12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, hydroxy , alkoxy, amino or thio, aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR15R16, NHSO2-R15, NHSO2-aryl, where the aryl is optionally substituted one or more times with selected substituents of halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, aryl NO2; aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino; HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy; - (alkyl) mS-R15, - (alkyl) m-SO-R15, - (alkyl) m-SO2-R15, - (alkyl) m- SO2OR15, - (alkyl) m-SO2-NR15R16, - (alkyl) m-NHCOR15, - (alkyl) m-CONR15 R16, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R15, - (alkyl) m-CO2-R15; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16 together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an arjle; R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl; -NR17R18, NHSO2-R17, NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2, aryl; - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m- SO2OR17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, - (alkyl) m-CO2-R17; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with nitrogen at which are fixed, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl , SO2-aryl, SO2NR17R18; aryl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, where n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; wherein n is 1, 2 or 3; R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nyroalkyl; aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; - (alkyl) mS-R19, - (alkyl) m-SO-R19, - (alkyl) m-SO2-R19, - (alkyl) ™ - SO2OR19, - (alkyl) m-SO2-NR19R20, - ( alkyl) m-NHCOR19, - (alkyl) m-CONR19 R20, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R19, - (alkyl) m-CO2-R19; where: m is 0 or 1, and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic ring structure, of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; provided that, when the interrupted line in formula I represents a double bond and X represents SO2 and Y represents NH and the compound is monosubstituted, then it is not monosubstituted with R3 representing OCH3, methyl, pentyl, terbutyl, aminophenyl, 2- phenylethylene, phenethyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornene, benzyl, thienyl, furyl, aryl, aryl substituted with 4-methyl, 4-methoxy, 4-chloro, 4-nitro or 3-nitro; and when the compound is disubstituted with R3 methyl, then R5 is not Cl, CH3 or then R3 is F, Cl, Br, I, CH3, CF3, nitro, SO2N (CH3) 2; or then R6 is not Cl, Br, CH3, CF3 > ethyl, methoxy; or when R7 is chloro, then R3 is not ethyl, butyl, secondary butyl, tertiary butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl; and when the compound is disubstituted, then it is not with R6 = Ome, R3 = ethyl, R6 = methyl, R3 = propyl, R7 = SO2NH2, R6 = CI, R7 = SO2NH2) R3 = phenyl; R7 = Br, R3 = phenyl. and conditioned that, when the compound is trisubstituted, then it is not R3 = CH3, R5 = NO2, R7 = Cl, R3 = CH3, R6 = NO2, R7 = Cl, R3 = CH3, R5 = NH2, R7 = Cl; and provided that, when the interrupted line in formula I represents a simple bond, and X represents SO2 and Y represents NH: then the compound is not a disubstituted compound in which R7 and R8 are chloro and R3 is alkyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclohexenyl, norbornenyl, norbornylnyl, ethylthiomethyl, ethylxymethyl, ethyloxyethyl, methyloxymethyl, methylamino, 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, amino; and the compound is not a compound trisubstituted with R3 = CH3 and R5 = isopropyl, R7 = F, R7 = F, R5 = ethyl, R7 = Cl, R5 = propyl, R7 = Cl, R5 = ethyl, R7 = F, R5 = methyl, R7 = Cl, R5 = ethyl, R7 = methyl; R5 = Cl, R7 = methyl; R5 = methyl, R7 = Cl; R 4 = methyl, R 5 = ethyl; or trisubstituted with R 4 = methyl, R 5 = methyl, R 7 = F. A pharmaceutical composition comprising a therapeutically effective amount of a compound as above, together with pharmaceutically acceptable carriers or excipients. The use of a compound represented by the general formula: wherein: the ligature represented by the interrupted line may be a simple ligature, a double ligature or be absent; and if the ligature is absent, the nitrogen is substituted with a hydrogen and R2; X represents SO2 or C = O or CH2; Y represents -CH (R4) -, -N (R4) - or -N (R4) -CH2-, O; R 2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R9, wherein: R9 represents alkyl, cycloalkyl, benzyl, aryl, or R2, together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, alkyl-S-R13, where: R13 and R14 independently represent hydrogen, alkyl, cycloalkyl, or R13 and R14, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members. A carbocyclic ring of 7 to 12 members, optionally substituted by halogen, alkyl, hydroxy or alkoxy; or a 3 to 8 membered heterocyclic ring, optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally, the heterocyclic ring is fused to an aryl; Benzyl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Aryl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio; halogenoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino, or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl , alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10 or CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times, with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or uncle; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -SO2-NR11R12; wherein: R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl or R 1 and R 12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, hydroxy , alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -NR15R16, NHSO2-R15, NHSO2-aryl, where the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, aryl NO2; aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino; HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy; - (alkyl) m-S-R15, - (alkyl) m-SO-R15, - (alkyl) m-SO2-R15, - (alkyl) ™ - SO2OR15, - (alkyl) m-SO2-NR15R16, - (alkyl) m-NHCOR15, - (alkyl) m-CONR15 R16, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R15 , - (alkyl) m-CO2-R15, where: m is 0 or 1, and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16 together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl , benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl; -NR17R18, NHSO2-R17, NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2, aryl; - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m- SO2OR17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, - (alkyl) m-CO2-R17; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R 7 and R 18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18, together with nitrogen to which they are fixed, they form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl , SO2-aryl, SO2NR17R18; aryl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; wherein n is 1, 2 or 3; R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, niroalkion; aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; - (alkyl) mS-R19, - (alkyl) m-SO-R19, - (alkyl) m-SO2-R19, - (alkyl) m- SO2OR19, - (alkyl) m-SO2-NR19R20, - (alkyl) m-NHCOR19, - (alkyl) m-CONR19 R20, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R19, - (alkyl) m-CO2-R19; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic ring structure, of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; for the manufacture of a medicament for the treatment of disorders or diseases that respond to the modulation of the AMPA receptor complex. A method for the treatment of disorders or diseases that respond to modulation of the AMPA receptor complex, wherein a therapeutically effective amount of a compound represented by the general formula is administered: wherein: the ligature represented by the interrupted line may be a simple ligature, a double ligature or be absent; and if the ligature is absent, the nitrogen is substituted with a hydrogen and R2; X represents SO2 or C = O or CH2; Y represents -CH (R4) -, -N (R4) - or -N (R4) -CH2-, O; R 2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; CO-R9, wherein: R9 represents alkyl, cycloalkyl, benzyl, aryl, or R2, together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, alkyl-S-R13, where: R13 and R14 independently represent hydrogen, alkyl, cycloalkyl, or R13 and R14, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members. A carbocyclic ring of 7 to 12 members, optionally substituted by halogen, alkyl, hydroxy or alkoxy; or a 3 to 8 membered heterocyclic ring, optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally, the heterocyclic ring is fused to an aryl; Benzyl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; Aryl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio; halogenoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino, or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl , alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10 or CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, optionally substituted one or more times, with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or uncle; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -SO2-NR11R12; wherein: R 11 and R 12 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl or R 11 and R 2, together with the nitrogen to which they are attached, form a 3 to 8-membered heterocyclic ring structure, optionally substituted with halogen, alkyl, hydroxy , alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; Rβ represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl, -NR15R16, NHSO2-R15, NHSO2-aryl, where the aryl is optionally substituted one or more times with selected substituents of halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, aryl NO2; aryl optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino; HET optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy; - (alkyl) mS-R15, - (alkyl) m-SO-R15, - (alkyl) m-SO2-R15, - (alkyl) m- SO2OR15, - (alkyl) m-SO2-NR15R16, - ( alkyl) m-NHCOR15, - (alkyl) m-CONR15 R16, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R15, - (alkyl) m-CO2-R15; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16 together with the nitrogen to which they are fixed, they form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl; -NR17R18, NHSO2-R17, NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2, aryl; - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) ™ - SO2OR17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, - (alkyl) m-CO2-R17; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with nitrogen at which are fixed, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl , SO2-aryl, SO2NR17R18; aryl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; wherein n is 1, 2 or 3; R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nyroalkyl; aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, alkoxy; - (alkyl) mS-R19, - (alkyl) m-SO-R19, - (alkyl) m-SO2-R19, - (alkyl) ™ - SO2OR19, - (alkyl) m-SO2-NR19R20, - (alkyl) m-NHCOR19, - (alkyl) m-CONR19 R20, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R19, - (alkyl) m-CO2-R19; where: m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic ring structure, of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl.

DETAILED DESCRIPTION OF THE INVENTION The invention provides novel compounds of the formula I that was shown further back. Preferred embodiments of the invention are the compounds of formula I above, wherein: R 2 represents: hydrogen, alkyl, cycloalkyl, phenyl, benzyl; or R2 together with R3 and together with the atoms to which they are attached, form a ring of 5 to 6 members, optionally substituted one or more times with substituents selected from halogen, alkyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms, and optionally containing carbonyl groups; R3 represents: hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic ring of 7 to 10 members, a heterocyclic ring of 5 to 6 members; benzyl, aryl; or R3 together with R2 or R4 forms a ring of 5 to 6 members; R4 represents hydrogen, alkyl, or R4, together with R3 and together with the atoms to which they are attached, forms a ring of 5 to 6 members; optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, -SO2-NR11R12, where: R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 5 to 6 members; R6 represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, alkoxyalkyl; phenyl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkoxy; HET; -S-R15, -SO-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR '= NOR ", -CO-R15, -CO2R15, where: R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; R7 represents hydrogen, Br, F, I, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, halogenoalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl, - (alkyl) m-NR17R18, NHSO2-R17, -S-R17, - SO-R17, -SO2-R17, -SO2-NHR17R18, NHCOR17, CONR17R18, CR '= NOR ", -CO-R17, -CO2-R17; where R 'and R "independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl and R 7 and R 18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R 17 and R 18, together with the nitrogen to which they are attached, form a 3- to 8-membered heterocyclic ring structure, optionally substituted with alkyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl, and the heterocyclic ring optionally fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, SO2NR17R18; phenyl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18, wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8. members, optionally substituted with halogen, alkyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; where n is 1, 2 or 3; -SO2-NR- (CH2) n-, where n is 1 or 2; -SO-NR (CH2) n-, where n is 1 or 2; -SO2- (CH2) n-, where n is 2 or 3; -SO- (CH2) n- where n is 2 or 3; -CO-CH = CH-NH-, -CO-CH = CH-O-, -CO- (CH2) n- where n is 1 or 2, -CO-NH- (CH2) n, where n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; where n is 1, 2 or 3; R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, halogenalkyl, CN, cyanoalkyl, nitro, nitroalkyl; phenyl, optionally substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl, alkoxy; HET; -S-R19, -SO-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR '= NOR ", -CO-R19, -CO2R19, where: R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO2-alkyl , SO2-aryl, SO2-benzyl, and the heterocyclic ring is optionally fused to an aryl; conditioned that, when X represents SO2 and Y represents N and the interrupted line represents a single bond, then neither R7 nor R6 are chlorinated when R2, R4, R5, R8 and the remainder of R6 and R7 are all hydrogen; and conditioned that R3 can represent CH3 only when R5 is hydrogen or R7 is not sulphamoyl; and conditioned that, when X represents SO2 and Y represents N and the interrupted line represents a double bond, then neither R7 nor R8 are chlorinated when R2, R4, R5, R8 and the remaining R6 and R7 are all hydrogen; and provided that R2, R4, R5, R6, R7 and R8 are not all hydrogen; and conditioned that the compound is not disubstituted with R3 which is CH3 when R7 is fluorine, bromine, iodine, CF3, CH3, NO2, SO2N (CH3) 2, or R6 is bromine, CF3, CH3, ethyl, methoxy: or R5 it is chloro- CH3 > or R8 is chlorine; and conditioned to the compound not being: 1, 1-dioxide of 3-ethyl-6-methoxy-1, 2,4-benzothiadiazine, 1,1-dioxide of 3-propyl-6-methyl-1, 2,4 -benzothiadiazine, 1, 1-dioxide, 3-ethyl-6-methoxy-1, 2,4-benzothiadiazine, 1,1-3-phenyl-7-bromo-1 dioxide, 2,4-benzothiadiazine, 1, 1 3-phenyl-7-sulfamoyl-1, 2,4-benzothiadiazine dioxide, 5-bromo-7-chloro-3-methyl-1, 2,4-benzothiadiazine 1,1-dioxide, 1 1-dioxide 5-iodo-7-chloro-3-methyl-1, 2,4-benzothiadiazine, 1,1-dioxide 5-nitro-7-chloro-3-methyl-1, 2,4-benzothiadiazine, 1, 1-dioxide 6-nitro-7-chloro-3-methyl-1, 2,4-benzothiazine, or 1,1-dioxide 6-amino-7-chloro-3-methyl-1 , 2,4-benzothiadiazine. A more preferred embodiment of the invention is a compound of formula I, as above, wherein: R 2 represents hydrogen, alkyl, cycloalkyl; or R2 together with R3 forms a 5- to 6-membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and which optionally contains carbonyl groups; and a preferred embodiment is one in which: R3 represents hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic ring of 7 to 10 members, a heterocyclic ring of 5 to 6 members; benzyl, aryl, or R3 together with R2 or R4 forms a 5-6 membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups. And another preferred embodiment is one in which: R4 represents hydrogen, alkyl, or R4, together with R3 and together with the atoms to which they are attached, form a 5-6 membered ring, optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups. And another preferred embodiment is one in which: R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, -SO2-NR11R12, wherein R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R1 and R12, together with the nitrogen to which they are attached, forms a heterocyclic structure of 3 to 8 members. And another preferred embodiment is one in which: R6 represents hydrogen, halogen, cycloalkyl, alkyl, alkoxy, alkoxyalkyl; aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, alkoxy; HET; -S-R15, -SO-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR '= NOR ", -CO-R15, -CO2R15, where: R' and R" independently represent hydrogen, alkyl, cycloaikyl, phenyl, benzyl; and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl, and optionally the heterocyclic ring is fused to an aryl. And another preferred embodiment is one in which: R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, - (alkyl) m-NR17R18, NHSO2-R17, -S -R17, -SO-R17, -SO2-R17, -SO2-NHR17R18, NHCOR17, CONR17R18, CR '= NOR ", -CO-R17, where R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with alkyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and the heterocyclic ring optionally is fused to an aryl; HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, SO2NR17R18; phenyl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18, where R17 and R18 independently represent hydrogen, alkyl , cycloalkyl, benzyl, aryl; or R17 and R18 together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; where n is 1, 2 or 3; -SO2-NR- (CH2) n-, where n is 1 or 2; -SO-NR (CH2) n-, where n is 1 or 2; -SO2- (CH2) n-, where n is 2 or 3; -SO- (CH2) n- where n is 2 or 3; -CO-CH = CH-NH-, -CO-CH = CH-O-, -CO- (CH2) n- where n is 1 or 2, -CO-NH- (CH2) n, where n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; where n is 1, 2 or 3. And another preferred embodiment is one in which: R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, nitroalkyl; phenyl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy; HET; -S-R19, -SO-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR '= NOR ", -CO-R19, -CO2R19, where: R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20 together with the nitrogen to which they are attached form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO2-alkyl , SO2-aryl, SO2-benzyl, and the heterocyclic ring is optionally fused to an aryl. An especially preferred embodiment is a compound of formula I above, wherein: X represents SO2; Y represents N and the interrupted line represents a simple ligature; R2 represents H; R3 represents cycloalkyl, a carbocyclic ring of 7 to 10 members; a heterocyclic ring of 5 to 6 members; R4 represents H; R 5 represents H R 6 represents hydrogen, alkyl or halogen; R7 represents: cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) m-SO-R17, - (alkyl) m-SO2R17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-CONR > 1p7'DR1'8 °, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO2-R17, where: m is 0 or 1; R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, benzyl and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with alkyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and the heterocyclic ring is optionally fused to aryl; or HET; or R7 together with R6 or together with R8 forms a ring of 5 to 7 members, having one of the following structures: -O- (CH2) n-O-; where n is 1, 2 or 3; -SO2-NR- (CH2) n-, where n is 1 or 2; -SO-NR (CH2) n-, where n is 1 or 2; -SO2- (CH2) n-, where n is 2 or 3; -SO- (CH2) n- where n is 2 or 3; -CO-CH = CH-NH-, -CO-CH = CH-O-, -CO- (CH2) n-where n is 1 or 2, -CO-NH- (CH2) n, where n is 1 or 2; -CO- (CH2) 2-O-, -O- (CH2) n-O-; where n is 1, 2 or 3; R8 represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) m-SO-R17, - (alkyl) m-SO2R17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-CONR17R18, - ( alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, - (alkyl) m-CO2-R17, where: m is 0 or 1; R' and R" independently represent hydrogen, alkyl, cycloalkyl , phenyl, benzyl and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with alkyl, S? 2-alkyl, S? 2-aryl, S? 2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or HET. The special embodiments of the invention are the following; they all refer to formula I above. One embodiment of the invention is one in which: R3 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbornene, norbornane, adamantane, benzyl, phenyl; or R3 together with R2 or R4 and together with the atoms to which they are attached, form a five-membered ring. Another embodiment of the invention is one in which: R4 represents hydrogen, methyl, ethyl; or R4 together with R3 and together with the atoms to which they are attached, form a 5-membered ring. And another embodiment of the invention is one in which: R5 represents hydrogen, chlorine, bromine, methyl, phenyl, -SO2NH2; And another embodiment of the invention is one in which: R6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chlorine or bromine. And another embodiment of the invention is one in which: R7 represents hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, - (CH3) C = N-OH, CONH2, CO2-ethyl, cyano, phenyl, 2- N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2- pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-thienyl, 2- (N-methyl) imidazolyl, 5-thiozolyl, 4-phenyl-triazol-5-yl, 5-methyl-1 , 2,4-oxadiazol-3-yl, CH3CONH-, CH3SO2NH-, NO2, SO2OH, phenyl-SO2-, sulfamoyl, N, N-dimethylsulphamoyl, N, N-diethylsulphamoyl, N-phenyl-N-methyl-sulfamoyl, N-cyclohexyl-sulfamoyl, -SO2-heterocyclic ring; wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1, 2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethylpiperazine, morpholine. And another embodiment is one in which: R8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy. Especially preferred embodiments are the compounds represented by formula I above, wherein: X is SO2 and Y is N and the interrupted line represents a simple ligation; and R2 represents hydrogen or CH3; and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane, phenyl, ethoxy; and R 4 represents hydrogen or CH 3; and R 5 represents hydrogen, CH 3, phenyl, sulfamoyl, chlorine, bromine; and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl, 3-pyridyl; and R7 represents hydrogen, chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, - (CH3) C = N-OH, CONH2, CO2-ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl , 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl , 3-furyl, 2-thienyl, 2- (N-methyl) imidazolyl, 5-thiozolyl, 4-phenyl-triazol-5-yl, 5-methyl-1, 2,4-oxadiazol-3-yl, CH3CONH- , CH3SO2NH-, NO2, SO2OH phenyl-SO2-, sulfamoyl, N, N-dimethylsulphamoyl, N, N-diethylsulphamoyl, N-phenyl-N-methyl-sulphamoyl, N-cyclohexyl-sulphamoyl, -SO2-heterocyclic ring; wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1, 2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethylpiperazine, morpholine. R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy. Another especially preferred embodiment of the invention is a compound of the formula I as illustrated above, wherein X is SO2 and Y is N, and the interrupted line represents a double ligation; and R3 represents CH3 O CF3, or R3 together with R4 and together with the atoms to which and R4, R6 and R8 are all hydrogen; and R5 is hydrogen or halogen; and R7 is N-methylsulphamoyl, N, N-dimethylsulphamoyl, N-cyclohexyl sulphamoyl, tetrahydropyridyl-sulfonyl; SO2OH, sulfamoyl. Another especially preferred embodiment of the invention is a compound of formula I as illustrated above, wherein X is C = O and Y is N, O or CH; and R2 represents hydrogen; and R3 represents hydrogen, CH3, CF3, cyclohexyl, norbornene, phenyl, ethyl, and R7 represents hydrogen, N, N-dimethylsulphamoyl, N-cyclohexylsulfamoyl, tetrahydropyridylsulfonyl, morpholino-sulfonyl sulphamoyl, bromine; and R5 represents hydrogen or bromine; and R4, R6 and R8 all represent hydrogen. Another especially preferred embodiment of the invention is a compound of formula I as illustrated above, wherein X represents CH2 and Y is N; and R3 represents cyclohexyl or norbornene; and R5 represents hydrogen or bromine; and R7 represents bromine or sulphamoyl; and R2, R4, R5 and R8 all represent hydrogen. Another especially preferred embodiment of the invention is a compound of formula I as illustrated above, wherein X represents SO2 and Y represents NH; and the interrupted line is absent and R2, R4, R5 and R8 all represent hydrogen; R4, R5 and R8 all represent hydrogen; R3 represents cyclohexyl, methyl or hydrogen; and R7 represents N, N-dimethylsulphamoyl, tetrahydropyridylsulfonyl, bromine; and R represents bromine or hydrogen. Another especially preferred embodiment of the invention is a compound of formula I as illustrated above, wherein X is SO2 and N is -NHCH2-; and R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R7 represents 1-piperidino-sulfonyl. The most preferred embodiment of the invention is that of the compounds of the formula I as illustrated above, in which the compounds are the following: 2-cyclohexyl-4-oxo-1, 2,3,4- tetrahydroquinazoline, 2-phenyl-4-oxo-1, 2,3,4-tetrahydroquinazoline, 2-methyl-3,4-dihydro-1,3-benzoxazin-4-one, 2-phenyl-3,4-dihydro- 1,3-benzoxazin-4-one, 1,1-dioxide, 3-bicyclo [2.2.1] hept-5'-en-2'-yl-1, 2,3,4-tetrahydro-1,2, 4-benzo-thiadiazine, 1, 1-3-phenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 1, 2,3,5,10, 10a-hexahydrobenzo [e] pyrrolo [1,2-b] -1,4-thiadiazine, 2-ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one, , 1-3-cyclohexyl-6- (2-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzo-thiadiazine, 1,1-dioxide-3-cyclohexyl-6- ( 2-pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-6- (3-pyridyl) -1, 2,3,4-tetrahydro dioxide -1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1-hydroxyethyl) -1, 2,3, 4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-7-acetyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1, 1 - 3-cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,4-benzo-thiadiazine 1,1-dioxide-3-cyclohexyl-7-carbamoyl-1,2-dioxide , 3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7-ethoxycarbonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1-dioxide, 1 , 1-dioxide 3-cyclohexyl-7-cyano-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-bicyclo [2.2.1] hept-5'- dioxide en-2'-yl-7-phenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-7- (2'-acetamidophenyl) - 1, 2,3,4-tetrahydro-1, 2,4-benzo-thiadiazine, 1,1-3-cyclohexyl-7- (2'-nitrophenyl) -1, 2,3,4-tetrahydro-1 dioxide , 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1, 1-3-cyclohexyl-7- (2'-methoxy-4'-trifluoromethylphenyl9-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1, 1- 3-cyclohexyl-7- (2 ', 4'-dimethoxyphenyl) -1,2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide, 1,1-cyclohexyl-7-dioxide (2 '- (N, N-dimethylsulfamoyl) phenyl) -1,2,4,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl-7- (2'-chlorophenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-fluorophenyl) -1, 2,3,4-tetrahydro-1 dioxide, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (3'-hydroxyphenyl) -1,2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3 -cyclohexyl-7- (2'-pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (3'-) dioxide pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-pyrimidinyl) -1 dioxide, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-furyl) -1, 2,3,4-tetrahydro-1,2, 4-benzothiadiazine, 1,1-3-cyclohexyl-7- (3'-furyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-cyclohexyl dioxide -7- (2'-thienyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1 -methyl-1H-2-dioxide imidazolyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiazoline, 1,1-3-cyclohexyl-7-dioxide (r, 2 ', 3'-tr! azol-4'-yl) -1, 2,3,4-tetrahydro-1, 2,4-benzo-thiadiazine, 1,1-3-cyclohexyl-7- (5'-phenyl-1 ', 2'-3'-triazol-4'-yl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (5'-methyl-) dioxide 1 ', 2'-4'-oxadiazol-3-yl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7-acetamido-1 dioxide, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxy-7-methylsulfonylamino-1, 2,3-tetrahydro-1,4-benzothiadiazine, 1,1-dioxide, 1, 1-dioxide 3-cyclohexyl-7-nitro-1, 2,3,4-tetrahydro-1, 2,4- benzothiadiazine, 1, 1-3-cyclohexyl-7-phenylsulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 2-cyclohexyl-1, 2,3,4-tetrahydro-6-dioxide quinazoline-sulfonamide, 1,1-3-cyclohexyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1,1-3-cyclohexyl-7-sulfamoyl-dioxide 1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dimethyl-7-dimethylsulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-dioxide benzothiadiazine, 2-cyclohexyl-1, 2,3,4-tetrahydro-6-quinazolin-N, N-dimethylsulfonamide, 1,1-3-cyclohexyl-7-dimethylaminosulfonyl-1, 2,3,4-tetrahydroxydioxide 1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (N, N-diethylamino) sulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1-dioxide, 1 , 1-3-cyclohexyl-7-pyrrolidinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothia-diazine dioxide, 3-methyl-7-piperidinosulfonyl-1,2-dioxide , 3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclopropyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide , 1, 1-3-isopropyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1,1-3-propyl-7-piperidinesulfonyl-1 dioxide, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1-l-dioxide 3-benzyl-7-p-peridynesulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclopentyl-7-p-peridinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1,1-dioxide dioxide cyclohexyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 3-bicyclo [2.2.1] hept-5'-en-2'- il-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino dioxide) ) sulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1-l-3-cyclohexyl-7- (N-methyl-N-phenylamino) sulfonyl-1,3, 4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1 '- (1', 2'-3 ', 4'-tetrahydroquinolinyl)) sulfonyl-1, 2, 3,4-tetrahydro-1, 2,4-benzothiazine, 1,1-3-cyclohexyl-7-dioxide (4'-methylpiperazino) sulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiazoline, 1,1-3-cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl- 1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7-morpholinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1, 1-3-bicyclo [2.2.1] hept-5'-en-2'-yl-7-bromo-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide, 2- methyl-4-oxo-3,4-dihydro-6-quinazolin-N, N-dimethylsulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin-suifonamide 2-trifluoromethyl-4-oxo -3,4-dihydro-6-quinazolin-N, N-dimethylsulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin-1 ', 2', 3 ', 6'-tetrahydropiperidino-sulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin-N-cyclohexylsulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin -morpholinosulfonamide, 2-cyclohexyl-4-oxo-3,4-dihydro-6-quinazolin-N, N-dimethylsulfonamide, 1,1-dioxide-3-methyl-7-sulfamoyl-1,2-dihydro-1,2. , 4-benzothiadiazine, 1, 1-dioxide 3-methyl-7-dimethylsulphamoyl-1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-3-methyl-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1,2-dihydro-1,4-benzothiadiazine dioxide, 1,1-dioxide 3-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-3-trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,4-benzothiadia- dioxide zina, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinsulfonic acid, 1,1-cyclohexyl-8-methyl-1, 2,3,4-tetrahydro-1,4-dioxide -benzothiadiazine, 1, 1-3-cyclohexyl-8-hydroxymethyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl-8- ( 2-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-8- (3-methoxyphenyl) -1, 2,3,4 -tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-8- (2-pyridyl) -1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1 , 1-dioxide, 3-cyclohexyl-8-methoxy-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 5,7-dibromo-1,2-dihydro-1 , 2,4-benzothiazine, 1,1-cyclohexy dioxide l-2-methyl-7-morpholinesulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2-dioxide, 3,4-tetrahydro-1, 2,4-benzothiadiazine, 5-methylsulfonylamino-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,5, 5,5-dioxide , 4-thiadiazine, 5,5-dioxamido-7-sulfamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5, 5-methylsulfamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5-cyclohexylsulfamoyl 5,5-dioxide -1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5-dimethyl-7-dimethylsulfamoyl-2,3, 3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5,5-dioxide 7-methylsulfamoyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,4-thiadiazine, 5-dimethylsulfamoyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,5,5-dioxide , 4-thiadiazine, 5-cyclohexylsulfamoyl-1, 5,5-dioxide, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5,5-dioxide 7- (r, 2 ', 3 ', 6'-tetrahydropiperidino) sulfonyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 1,1-dioxide 3-bicyclo [2.2 .1] hept-5'-en-2'-l-5,7-dimethyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl dioxide 7- (N, N-diethylsulfamoyl) -5-methyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-bicyclo [2.2.1] hept-5 'dioxide -in-2'-il-5,7-diphenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-bicyclo [2.2.1] heptide dioxide 5'-en-2-yl-5,7-disulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 3-bicyclo [2.2.1] hept-5 '-en-2'-il-5,7-dichloro-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1, 1-5-bromo-3-cyclohexyl-7-suIamoamoyl dioxide -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 2-bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-1, 2,3 , 4-tetrahydroquinazoline, 2-bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-4-oxo-1, 2,3,4-tetrahydroquinazoline, 1,1-dioxide of 3-bicicio [2.2.1] hept-5'-en-2'-il-5,7-dibromo-1, 2,3,4-tetrahydro-1, 2,4-benzothiad iazine, 1, 1-5,7-dibromo-3-bicyclo [2.2.1] heptan-2'-iI-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide, 1, 1 -3-cyclohexyl-5,7-dibromo-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1,1-adamantyl-5,7-dibromo-1,2-dioxide , 3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 3-phenyl-5,7-dibromo-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1 , 1-dioxide of 3-ethoxy-5,7-dibromo1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3-methyl-5,7-dibromo- 1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-6-methyl-7- (2'-pyridyl) -1,2,4,4-dioxide -tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-6-methyl-7- (4'-triazolyl) -1, 2, 2,4-tetrahydro-1,2,4-dioxide benzothiadiazine, 1, 1-3-cyclohexyl-6-methyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclopentyl-6-dioxide methyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-6-methyl-7-morpholinosulfonyl-1, 2,3 dioxide, 4-tetrahydro-1, 2,4-benzothiadiazin, 1,1-3-cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1 dioxide, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-6-methoxy-7-piperidinosulfoni-1, 2,3,4-tetrahydro-1,2-dioxide , 4-benzothiadiazine, 1,1-cyclohexyl-7,8-ethene-1-dioxido, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-6-dioxide , 7-ethylendioxy1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-6-chloro-7-sulfamoyl-1, 2,3,4-tetrahydro-1 , 2,4-benzothia-diazine, 1,1-3-phenyl-6-chloro-7-sulfamoyl-1, 2,3,4-tetrahydro-1,4-benzothia-diazine dioxide, 1, 1 3-cyclohexyl-6-bromo-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide, 2-cyclohexylmethylamino-5-N, N-dimethyl-sulphonylbenzenesulfonamide, 2-ethylamino-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonylbenzenesulfonamide, 1,1-dioxide 3-isobutyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1 , 2,5-benzothia-diazepine, 1,1-3-cyclohexyl-7-cyclopentylsulfinyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl -7-cyclopentylsulfinyl-1, 2,3,4-tetrahydro-1, 2,4-benzothia-diazine, 1,1-3-cyclohexyl-7-cyclopentylsulfinyl-1, 2,3,4-tetrahydro-1,2-dioxide , 4-benzothia-diazine, or 1,1-3-cyclohexyl-7-cyclopentylsulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothia-diazine; or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts The chemical compound of the invention can be provided in any suitable form for the intended administration. Suitable forms include the pharmaceutically (ie, physiologically) acceptable salts, and the prodrug or prodrug forms of the chemical compound of the invention. Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic, inorganic and organic acid addition salts, such as acetate, acetic acid derivative; the aconate, aconitic acid derivative; ascorbate, derived from ascorbic acid; benzenesulfonate, benzenesulfonic acid derivative; benzoate, benzoic acid derivative; cinnamate, derived from cinnamic acid; citrate, citric acid derivative; the embonate, derived from embonic acid; the enanthate, derived from enanthic acid; formate, formic acid derivative; fumarate, derivative of fumaric acid; glutamate, a glutamic acid derivative; the glycolate, derived from glycolic acid; the hydrochloride, hydrochloric acid derivative; the hydrobromide, hydrobromic acid derivative; lactate, a lactic acid derivative; maleate, maleic acid derivative; malonate, derived from malonic acid; the mandelate, derived from mandelic acid; methanesulfonate, methanesulfonic acid derivative; Naphthalene-2-sulfonate, naphthalene-2-sulfonic acid derivative; nitrate, nitric acid derivative; perchlorate, perchloric acid derivative; phosphate, phosphoric acid derivative; phthalate, derivative of phthalic acid; salicylate, derivative of salicylic acid; sorbate, derived from sorbic acid; stearate, stearic acid derivative; succinate, succinic acid derivative; sulfate, derived from sulfuric acid; tartrate, tartaric acid derivative; p-toluenesulfonate, p-toluenesulfonic acid derivative, and the like. Said salts can be formed by methods well known and described in the art. Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates for obtaining the chemical compound of the invention and its pharmaceutically acceptable acid addition salt. The metal salts of a chemical compound of the invention include the alkali metal salts, such as the sodium salt of a chemical compound of the invention which contains a carboxy group. The chemical compound of the invention may be provided in dissolvable or indissoluble forms, together with a pharmaceutically acceptable solvent, such as water, ethanol and the like. Dissolvable forms can also include hydrated forms, such as the monohydrate, the dihydrate, the hemihydrate, the trihydrate, the tetrahydrate and the like. In general, dissolvable forms are considered to be equivalent to indissoluble forms, for the purposes of this invention.

Definitions of substituents Halogen is fluorine, chlorine, bromine or iodine. "Alkyl" means a straight chain or a branched chain of one to six carbon atoms, or cyclic alkyl of three to seven carbon atoms, including, but not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, methyl, ethyl, propyl and isopropyl. Halogenoalkyl means alkyl as above, substituted one or more times with halogen, as defined above. Preferred embodiments are CF3, C2F3, CH2CI, CHCI2, -CHFCH2F, -CHCICH2CI. Cycloalkyl means cyclic alkyl of three to seven carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Cycloalkylalkyl means cyclic alkyl, as above, and alkyl as above, where alkyl can be considered as a substituent on cycloalkyl, and vice versa. Preferred groups are cycloalkyl of 3 to 6 carbon atoms and alkyl of 1 to 4 carbon atoms, such as - (CH 2) -cyclopropyl, -cyclopropyl- (alkyl of 1 to 4 carbon atoms), - (CH 2) n- cyclohexyl, -cyclohexyl- (alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms) -cyclobutyl, -cyclobutyl (alkyl of 1 to 4 carbon atoms), - (alkyl of 1 to 4 carbon atoms) carbon) cyclopentyl, -cyclopentyl (alkyl of 1 to 4 carbon atoms), - (alkyl of 1 to 4 carbon atoms) cyclohexyl, cyclohexyl (alkyl of 1 to 4 carbon atoms) Halogenocycloalkyl means cyclic alkyl, as before, which is substituted with one or more halogens, as further back, including, but not limited to: chlorocyclopropyl, fluorocyclopropyl, yo-cyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl, fluorocyclopentyl, iodocyclopentyl, chlorocyclohexyl, fluorocyclohexyl, dichlorocyclohexyl, difluorocyclohexyl, dicyclohexyl Preferred embodiments are monosubstituted and disubstituted cycloalkyl of 3 to 6 carbon atoms, such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iodocyclohexyl, chlorocyclopentyl, fluorocyclopentyl. "Alkenyl" means a straight chain or a branched chain of two to six carbon atoms, containing a double bond, including, but not limited to: ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and -butenyl. Alkynyl means a straight chain or a branched chain of two to six carbon atoms containing a triple ligation, including, but not limited to: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3- Butynyl Alkoxy is O-alkyl, where alkyl is as defined above. Alkoxyalkyl is -alkyl-O-alkyl, where alkyl is as defined above. Hydroxyalkyl is alkyl as defined above, substituted with OH. Amino is NH2 or NH-alkyl or N- (alkyl) 2, where alkyl is as defined above. Alkylamino is alkyl as defined above, which is substituted with amino, as defined above. Preferred embodiments are: -CH2-N (aikyl) 2, -CH-N (alkyl) 2CH3, -CH2CH2N (alkyl) 2, -CH2-NH2, -CH- (NH2) -CH3, -CH2CH2NH2.

Ciano is CN; Cyanoalkyl is alkyl as defined above, with CN. Nitro is -NO2. Nitroalkyl is alkyl as defined above, substituted with nitro, as defined above. Tio is SH or S-alkyl, where the alkyl is as defined above. Alkylthio is alkyl as defined above, substituted with a thio group, which is as defined above. Acyl is (C = O) -R ° or (C = S) -R °, where R ° is alkyl; phenyl, which may be substituted one or more times with substituents selected from the group consisting of halogen; CF3) NO2, amino, alkyl, alkoxy, phenyl and SO2NR'R ", where R 'and R" are independently, each hydrogen or alkyl, or where R' and R "together are (CH2) m, where m is 2, 3, 4, 5 or 6, or R ° is benzyl, or where each of R1"and R? V is independently hydrogen or alkyl, and where R1" and R? V together are (CH2) P, where p is 2, 3, 4, 5 or 6. Acylamino is acyl-NH-, where acyl is as defined above, Aryl is an aromatic carbocycle, such as phenyl or biphenyl, and fused carbocycles, such as naphthyl, HET is a cyclic heteroaryl of 5 to 6 members, and includes, for example: oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazole-2 -yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,4-oxadiazol-3-yl, 1, 2,4 -oxadiazol-5-yl, 1, 2,4-thiadiazol-3-yl, 1, 2,4-thiadiazol-5-yl, 1, 2,5-oxadiazol-3-yl, 1, 2,5-oxadiazole -4-yl, 1, 2,5-thiadiazol-3-yl, 1, 2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidaz olyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl, furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thienyl, isooxazolyl, pyrimidyl, pyrazole, triazolyl. Particularly preferred heteroaryls of the invention are: pyridyl, pyrimidyl, triazole, furyl, thienyl, oxadiazolyl, imidazolyl. A carbocyclic ring structure of 7 to 12 members includes monocyclic, bicyclic and tricyclic structures. The preferred modalities are the annular structures of 7 to 10 members, such as: a heterocyclic ring structure of 3 to 8 members includes a partially or fully saturated heterocyclic ring structure, such as aziridine, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene , morpholino, tetrahydropyridine, and compounds such as: Preferred embodiments are rings of 5 to 6 members containing at least one nitrogen, such as pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine. The rings of 4 to 7 members described, fused to the ring structure of the formula I, formed between the substituents R 2 and R 3, or R 3 and R 4, or R 5 and R 6, or R 6 and R 7, or R 7 and R 8 are carbocyclic rings which optionally contain a heteroatom and optionally contain a carbonyl group. Preferred rings are 5 and 6 membered carbocyclic rings. The rings formed between the substituents R7 and R6 or R8 are 5 or 6 members and contain O, C = O, SOO or SO2 groups and, optionally, contain nitrogen. Preferred rings are -O- (CH2) n-O-, where n is 1, 2 or 3; -SO2-NR- (CH2) n-, where n is 1 or 2; -SO-NR- (CH2) n-, where n is 1 or 2; -SO2- (CH2) n-, where n is 2 or 3; -SO- (CH2) n-, where n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O, -CO- (CH2) n-NH-, where n is 1 or 2; -CO-NH- (CH2) n, where n is 1 or 2; -CO (CH2) 2-O-. The compounds of this invention can exist in unsolvated form as well as in solvated forms, with pharmaceutically acceptable solvents, such as water, ethanol and the like. In general, solvated forms are considered as equivalents of unsolvated forms, for the purposes of the present invention.

The steric isomers The chemical compounds of the present invention can exist in (+) and (-) forms, as well as in racemic forms. The racemates of these isomers and the individual isomers, by themselves, are within the scope of the present invention. The racemic forms can be resolved to the optical antipodes by means of known methods and known techniques. One way of separating the diastereomeric salts is by using an optically active acid and releasing the optically active amine compound by treatment with a base. Another method for resolving the racemates to optical antipodes is based on chromatography on an optically active matrix. In this way, the racemic compounds of the present invention can be resolved to their antipodes, for example, by fractional crystallization of the salts d- or I- (tartrates, mandelates or camphor sulfonates). The chemical compounds of the present invention can also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid, such as the derivative of (+) or (-) - phenylalanine. , (+) or (-) phenylglycine, (+) or (-) canfánico acid or by the formation of diastereomeric carbamates, by reaction of the chemical compound of the present invention with an optically active chloroformate, or the like. Additional methods for resolving the optical isomers are known in the art. Such methods include those described by Jaques J. Collet A and Wilen S in Enantiomers, Racemates and Resolutions, John Wiley and Sons, New York, (1981). Furthermore, since oximes are some of the chemical compounds of the invention, they can exist in two forms: "without" and "anti" forms (Z and E forms), depending on the arrangement of the substituents around the double bond -C = N-. Thus, a chemical compound of the present invention may be in the "sin" or "anti" forms (forms Z and E), or may be a mixture thereof. A compound of the invention includes endo and exo forms and tautomers, when this is possible.

Pharmaceutical Compositions One aspect of the invention provides pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention and the use of compounds of the invention for the manufacture of a medicament for the treatment of specific diseases or disorders.

While a chemical compound of the invention can be administered for use in therapy, in the form of a crude chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptasalt, into a pharmaceutical composition, together with a or more usual adjuvants, excipients, carriers, regulators, diluents and / or other auxiliaries. In a preferred embodiment the invention provides pharmaceutical compositions comprising the chemical compound of the present invention, or a pharmaceutically acceptasalt or a derivative thereof, together with one or more pharmaceutically acceptacarriers therefor; and optionally, other therapeutic and / or prophylactic ingredients. The carrier or carriers must be "accepta in the sense of being compatiwith the other ingredients of the formulation, and not harmful to the recipient. The pharmaceutical compositions of the invention may be those which are suitafor oral, rectal, bronchial, nasal, topical administration (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular and intravenous injection), or in a form suitafor administration by inhalation or insufflation. The chemical compound of the invention, together with a conventional adjuvant, carrier or diluent, can thus be placed in the form of pharmaceutical compositions and their unit doses. Said forms include solids, and in particular tas, filled capsules, powder and pellet and liquid forms, in particular solutions, suspensions, emulsions, aqueous and non-aqueous elixirs, and capsules filled therewith; all for oral use; suppositories for rectal administration, and sterile injectasolutions for parenteral use. Said pharmaceutical compositions and their unit dosage forms may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and said unit dosage forms may contain any suitaeffective amount of the active ingredient that is compatiwith the daily dose scale. intended to be used. The chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as an active component, a chemical compound of the invention or a pharmaceutically acceptasalt or a chemical compound of the invention. To prepare pharmaceutical compositions from a chemical compound of the present invention, pharmaceutically acceptacarriers can be solid or liquid. Solid form preparations include: powders, tas, pills, capsules, seals, suppositories and dispersigranules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, ta disintegrating agents or encapsulating material.

In the powders, the carrier is a finely divided solid, which is a mixture with the finely divided active component. In tas, the active component is mixed with the carrier, which has the necessary binding capacity, in suitaproportions, and is compacted to the desired shape and size. The powders and tas preferably contain from five to ten to about seventy percent of the active compound. Suitacarriers are: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, which provides a capsule in which the active component, with or without carriers, is surrounded by a carrier which is thus in association with the. Similarly, stamps and candies are included. Tablets, powders, capsules, pills, seals and candies can be used as solid forms suitable for oral administration. To prepare suppositories, a low-melting wax, such as a mixture of fatty acid glyceride or cocoa butter, is first melted and the active component is dispersed therein homogeneously, for example, by stirring. The homogeneous molten mixture is then poured into molds of suitable size and allowed to dry, so that it solidifies in this way.

Suitable compositions for vaginal administration may be presented as diaphragms, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, carriers that are known in the art to be appropriate. Liquid preparations include: solutions, suspensions and emulsions; for example, water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in aqueous-polyethylene glycol solution. The chemical compound according to the present invention, in such a manner, can be formulated for parenteral administration (for example, by injection, such as bolus injection or continuous infusion), and can be presented in unit dose form in ampoules, syringes previously filled, low volume or multi-dose infusion containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the powder form, obtained by aseptic isolation of sterile solid or by lyophilization from the solution, to be constituted with a suitable vehicle, eg, sterile, pyrogen-free water, before use. Aqueous solutions for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners, when desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component, in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations, for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. For topical administration to the epidermis, the chemical compound according to the invention can be formulated, such as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be formulated, for example, with an aqueous or oily base, with the addition of suitable thickeners and / or gelling agents. The lotions can be formulated with an aqueous or oily base and, in general, will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents or coloring agents. Compositions suitable for topical administration in the mouth include candies comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth gum; pills, comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia gum; and mouth rinses, which comprise the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, a pipette or a sprayer. The compositions can be provided in single dose or multiple dose form. In the case of a dropper or pipette, this can be achieved by administering to the patient a predetermined, appropriate volume of the solution or suspension. In the case of a sprayer, this can be achieved, for example, by means of a spraying and dosing spray pump. Administration to the respiratory tract can also be achieved by means of an aerosol formulation, in which the active ingredient is provided in a pressure package, with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant, such as lecithin. The dose of drug can be controlled by the provision of a metering valve. Alternatively, the active ingredients can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in the form of unit doses, for example, in capsules or cartridges, for example, gelatin, or in ampoule packages from which the powder can be administered by means of an inhaler. In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size, for example, of the order of 5 microns or less. Said particle size can be obtained by means known in the art, for example, by micronization. When desired, compositions adapted to give sustained release of the active ingredient can be employed. It is preferred that the pharmaceutical preparations be in unit dosage forms. In that form the preparation is subdivided into unit doses containing the appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, packaged capsules and powders in ampoules or flasks. Also the unit dosage form can be a capsule, a tablet, a stamp, or the candy itself; or it may be the appropriate number of any of these forms of packaging.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are the preferred compositions. Of course, the dose administered can be carefully adjusted to the age, weight and condition of the individual being treated, as well as to the route of administration, the dosage form and regimen and the desired result. The active ingredient can be administered in one or several doses per day. In some cases, a satisfactory result can be obtained at a dose of only 0.1 μg / kg intravenously, and 1 μg / kg orally. The upper limit of the dose scale is currently considered around 10 mg / kg intravenously and 100 mg / kg orally. Preferred scales are approximately 0.1 μg / kg to 10 mg / kg / day, intravenously, and approximately 1 μg / kg to 100 mg / kg / day, orally.

The method of treatment The compounds of the present invention are stimulators of the AMPA receptor and, therefore, are useful for the treatment of a variety of disorders or diseases that respond to AMPA receptor modulators. As one embodiment of the invention, the diseases respond to the positive modulation of the AMPA receptor. The compounds can be used in the treatment, prevention, prophylaxis or alleviation of a disease, disorder or condition of the central nervous system, for example, neurodegenerative disorders, cognitive or memory dysfunction, memory and learning disorders, disorders of attention, learning disorders and memory that are the result of age, traumas, attacks, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, AIDS dementia, senile dementia, learning difficulty, knowledge difficulty, sexual dysfunctions, psychotic disorders, sexual dysfunction, intellectual damage disorders, schizophrenia, depression or autism; lack of attention or a disorder or disease that is the result of neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia. The appropriate dose scales with 0.1-500 mg per day, and especially from 10 to 70 mg per day, administered once or twice a day, depending, as usual, on the exact mode of administration, the way in which which is administered, the indication to which the administration is directed, the subject involved and the weight of the body of the subject involved, and also, the preference and experience of the doctor or veterinarian in charge. The abbreviation i. p. means intraperitoneally, which is a well-known route of administration; p. or. it means orally, which is a well-known route of administration. The invention then comprises the following, alone or in combination: The use of a compound as indicated above, wherein the disease to be treated responds to modulation of the AMPA receptor.

The use of a compound as indicated above, for the manufacture of a medicament for the treatment of a disease that responds to AMPA receptor modulation. The use as indicated above, where the disease is a memory and learning disorder, psychotic disorder, sexual dysfunction, intellectual damage disorders, schizophrenia, depression or autism; Alzheimer's disease, learning deficiencies, attention deficits, memory loss or senile dementia; or a disorder or disease that is the result of trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, age, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia. biology In vitro inhibition of 3h-ampa binding L-glutamate (GLU) is the main excitatory neurotransmitter in the central nervous system of mammals. From electrophysiological and binding studies, it seems that there are three subtypes of GLU receptors, tentatively named N-methyl-D-aspartate (NMDA) receptors, quiscalate and kainate. The GLU receptor subtypes sensitive to quiscalate and kainate, as a group, are often referred to as non-NMDA receptors. Receptor binding studies, using the labeled agonists 3H-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) (for the quiscalate receptors) and 3H-kainate (for kainate receptors) have shown different antagonistic selectivities and different regional distribution. It has been known for several years that AMPA is a potent and selective agonist in quiscalato receivers traditionally named. The activation of the quiscalate receptors by AMPA is associated with the influx of Na + and the efflux of K +, which lead to depolarization. Non-NMDA receptors have recently been reclassified to include the type of metabotropic receptor activated by quiscalate, linked to the metabolism of inositol triphosphate and diacyl glycerate. AMPA does not interact with the metabotropic receptor of quiscalate, but only with the ionotropic quisquat receptor. Selective activation of the metabotropic type has been attributed to trans-ACPD. Recently, antagonists of the receptor that are not NMDA, CNQX and NBQX have been described, potent and competitive, and it has been reported that CNQX does not block the effect of quiscalate in the metabotropic receptor subtype. 3H-AMPA is a selective radioligand for labeling the quisquat ionotropic receptors (AMPA).

The tissue preparation The preparations are carried out at 0-4 ° C, unless otherwise indicated. Brain cortex of male Wistar rats is homogenized (150-200 g) for 5 to 10 seconds in 20 ml of Tris-HCl (30 mM, pH 7.4), using an Ultra-Turrax homogenizer. The suspension is centrifuged at 27,000 x g for 15 minutes and the pellet is washed three times with a regulator (centrifuged at 27,000 x g for 10 minutes). The washed pellet is homogenized in 20 ml of regulator and incubated in a water bath at 37 ° C for 30 minutes, to remove the endogenous glutamate and then centrifuged for 10 minutes at 27,000 x g. The pellet is then homogenized in regulator and centrifuged for 10 minutes at 27,000 x g. The final pellet is resuspended in 30 ml of regulator and the preparation is frozen and stored at -20 ° C.

The analysis The membrane preparation is thawed and centrifuged at 2 ° C for 10 minutes at 27,000 x g for 10 minutes. The pellet is washed twice with 20 ml of 30 mM Tris-HCl containing 2.5 mM CaCl 2, pH 7.4, using an Ultra-Turrax homogenizer and centrifuged for 10 minutes at 27,000 x g. The final pellet is resuspended in 30 mM Tris-HCl, which contains 2.5 mM CaCl2 and 100 mM KSCN, pH 7.4 (100 ml per g of original tissue) and is used for binding analysis. Aliquots of 0.5 (0.2 ml) are added to 25 (20) μl of the test solution and 25 (20 μl of 3H-AMPA (5 nM final concentration), mix and incubate for 30 minutes at 2 ° C. The non-specific binding is determined using L-glutamate (0.6 mM final concentration). After incubation the 550 μl samples are added to 5 ml of ice-cold buffer and poured directly into Whatman GF / C glass fiber filters, under suction, and immediately washed with 5 ml of ice-cold buffer. Filter the 240 μl samples onto a glass fiber filter using a Skatron cell harvester. The filters are washed with 3 ml of ice-cold regulator. The radioactivity of the filters is determined by means of conventional liquid flash counting. The specific binding is the total union minus the non-specific binding.

The results The compound numbers refer to the following table: Enhancement of AMPA-induced I3H1GABA release from cultured cortical neurons. Neurons expressing receptors for excitatory amino acids can be depolarized by means of said compounds; and this depolarization will eventually lead to the release of a transmitting substance from the neurons. The cultured neurons, obtained from 16-day mouse embryo cortex, are mainly GABAergic and express all types of excitatory amino acid receptors. This means that they can be stimulated by high potassium concentration (55 mM) or by the NMDA of excitatory amino acids (20 μM), AMPA (5 μM) and kaonate (5 μM) to release their neurotransmitter GABA. 3H-GABA can be used to mark the deposit of GABA transmitter in neurons and the release of 3H-GABA from neurons can be used as a simple functional model for studies of the effects of excitatory amino acid receptor agonists, their antagonists and its modulators.

Methods The cell cultures were chopped from NMRI mouse embryos from 15-16 days, to 0.4 x 0.4 mm dices and the tissue was dissociated by moderate trypsinization (0.1% (w / v) trypsin, 37 ° C, 10 minutes). Subsequently, the cell suspension (3 million / ml) is inoculated into 30 ml Petri dishes, coated with poly-L-lysine (3 ml / dish) containing a slightly modified DMEM (24.5 mM KCl), supplemented with 7 μM. D.E.P. aminobenzoate, 100 mU / L insulin and 10% (volume / volume) of horse serum. The cells are maintained in culture for 5 to 7 days, adding the cytosine-arabinoside antimitotic agent (5 μM) from day 2 in vitro, to prevent the proliferation of glial. For more details and references, see Drejer and co-authors, (Exp. Brain Res., 47, 259 (1982)).

Release experiments Release experiments are carried out using the model described by Drejer and coauthors (Life Sci, 38 2077 (1986)). Brain cortex neurons, cultured in Petri dishes (30 mm), are added to 100 mM gamma-vinyl-GABA one hour before the experiment, in order to inhibit the degradation of GABA in neurons. Thirty minutes before the experiment, 5 μCi of 3H-GABA is added to each culture. After this preload period, the monolayer of cells at the bottom of the dish is covered with a piece of nylon mesh to protect the cells against mechanical damage and to facilitate the dispersion of the medium on the cell layer. The preloading medium is removed and the Petri dishes are placed in a superfusion system consisting of a peristaltic pump that continuously supplies controlled superfusion medium at 37 ° C per thermostat (saline regulated with HEPES (HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO, 1.0 mM CaCl2 and 6 mM D-glucose, pH 7.4), from a deposit to the upper part of the slightly inclined Petri dish. The medium is continuously collected from the bottom of the plate and supplied to a fraction collector. Initially the cells are superfused with HBS for 30 minutes (flow rate 2 ml / min). The cells are then stimulated for thirty seconds, every four minutes, by changing the superfusion medium of HBS to a corresponding medium containing 5 μM of AMP, in the absence or in the presence of modulators. The test substances are dissolved in 50% DMSO, 48% ethanol. The final concentration of DMSO and ethanol in the analysis should not exceed 0.1%.

The results The induced release of 3H-GABA (cpm) is corrected for the mean baseline release (cpm) before and after the stimulation, and used to calculate the value of the test. The enhancement of the AMPA response is expressed by means of a test substance, with respect to the enhancement of the AMPA response induced by cyclothiazide (30 μM).

Results The result of the test is shown in figures 1 and 2. The results show a significant increase. Figure 1 shows the potentiation of the release of [3 H] GABA from cultured cortical neurons, by the compound 115. The potentiation is expressed in relation to the potentiation induced by 30 μM of cyclothiazide. Figure 2 shows the potentiation of the [3H] GABA release induced by AMPA, from cultured cortical neurons, by compound 114. Potentiation is expressed in relation to the potentiation induced by 30 μM of cyclothiazide.

Fixation to voltage The methods Voltage-setting experiments were carried out, using conventional methods of whole-cell patch fixation (Hamill and co-authors, 1981), essentially as previously described (Mathiesen and co-authors, 1998). The following salt solutions (mM) were used: NaCl (140), KCl (4), CaCl2 (2), MgCl2 (1), sucrose (30), tetradotoxin (0.0003), bicuculline methoiodide (0.005) and HEPES ( 10, pH 7.4). Intracellular solution (mM): CsCI (120), CsF (20), MgCl 2 (2), EGTA (10), HEPES (10, pH = 7.2).

Cell cultures Neocortical mouse neurons were cultured essentially as described by Drejer and coauthors (1987). Briefly, the antecerebros of embryonic NMRI mice (E17) were extracted under sterile conditions. The tissue was shredded to 0.4 mm cubes and triturated with trypsin (12.5 μg / ml) and DNase (2.5 μg / ml) for 15 minutes at 37 ° C. The cells were suspended in concentration of 1 x 106 cells / ml in a slightly modified DMEM containing horse serum (10% (volume / volume)), penicillin (333 U / ml), acid-para-aminobenzoic acid (1 mg / ml) , L-glutamine (0.5 mM), insulin (0.08 U / ml) and KCl (23.8 mM). Subsequently, the cell suspension was inoculated in 35 mm Petri dishes, coated with poly-L-lysine (2 ml / dish). Glass coverslips (3.5 mm) were placed on the plates, before coating. After 24 hours of culture, the medium was replaced by fresh medium, which contained 1% N2 supplement, instead of serum. The cells were kept in culture for 7-14 days at 37 ° C (5% C? 2/95% O2) before carrying out the experiments.

Electronic elements, programs and acquisition data: The amplifier used was EPC-9 (HEKA Electronics, Lambrect, Germany), operated by a Power Macintosh G3 computer, through an ITC-16 interface. The experimental conditions were set with the Pulse application program, which accompanies the amplifier. It was filtered in a low pass filter and sampled directly to the hard disk, at a rate of 3 times the cutoff frequency.

Pipettes and electrodes: Borosilicate glass pipettes were formed (Modulohm, Copenhagen, Denmark), using a horizontal electrode stretcher (Zeitz-Instrumente, Augsburg, Germany). The pipette resistances were 1.7-2.4 MW in the saline solutions used in these experiments. The pipette electrode was chlorided with silver wire, and the reference was a silver chloride pellet electrode (In Vivo Metric, Healdsburg, E.U.A.), fixed to the experimental chamber. The electrodes were zeroed with the pipette open in the bath, just before sealing.

Experimental procedure: The coverslips were transferred to a 15 ml experimental chamber, mounted on the microscope slide of an inverted microscope (IMT-2, Olympus) provided with Nomarski optics. The neurons were continuously superfused with extracellular saline at a rate of 2.5 ml / minute. After the formation of the giga-seal (1-5 GW, success rate = 90%), the complete cell configuration was achieved by suction. The cells were maintained at a fixation voltage of -60 mV and at the start of each experiment the current was continuously measured for at least 30 seconds to ensure a stable leakage current. Solutions containing AMPA were supplied to the chamber, through the custom-made gravity-operated flow tube, the tip of which was placed approximately 50 μm from the cell. The application was triggered when the tube connected to the flow tube was compressed by means of a valve controlled by the Pulse application program. AMPA (30 μM) was applied for one second every 45 seconds. After obtaining the responses of a repeatable amplitude, the compound to be tested was included both in the chamber and in the solution containing AMPA. The compound was present until responses of a new repetition were obtained. The sampling interval in all the experiments was 310 μsec. All the experiments were carried out at room temperature (20-25 ° C).

Materials Obtained NMRI mice (9 days) from Bomholgaard were obtained Breeding and Research Center, Ry, Denmark. Horse serum, with N2 supplement and culture media, was purchased from Life Technologies (GIBCO), Roskilde, Denmark. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) was synthesized in NeuroSearch A / S. Tetrodotoxin was purchased from Alomone Labs, Jerusalem, Israel, and bicuculline methoiodide from RBl, MA, E. U. A., sucrose, from Fluka Chemie, Buchs, Switzerland. All other reagents were obtained from SIGMA, E. U. A.

The results The results are shown in figures 3-7. The compounds 56 (figure 3), 63 (figure 4), 1 1 1 (figure 6), 114 (figure 7) and 1 15 (figure 5) all boosted the current induced by the application of 30 μM of AMPA. An example is shown below for each compound. It is seen that the potentiation, in each case, is reversible, even though the effect of 56 and 63 persists for several minutes after the compounds were washed off. The time between AMPA stimuli was 45 seconds. Scale bars: 63: 200 pA / 2 seconds; 56: 500 pA / 5 seconds, 1 15: 50 pA / 2 seconds, 1 1 1: 400 pH / 3 seconds; 114 (40 pA / 3 seconds) In the experiments shown, the concentration of the compounds was 3 μM (56, 63 and 14) or 10 μM (11 11 and 15) .The effect of the compounds depended on the concentration, as exemplified for 1 14 below (scale bars 200 pA / 5 seconds) (figure 8).

References Drejer, J., Honoré T. and Schousboe A. (987) Excitatory amino acid-induced reagent of 3H-GABA from cultured mouse cerebral cortex interneurons. J. Neurosci., 7: 2910-2916. Hamill O. P., Marty A., Neher E., Sakmann B. and Sigworth F. J. (1981): Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches, Pflügers Arch., 39, 85-100. Mathiesen C, Varming T and Jensen L. H. (1998) In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurons and cultured mouse cortical neurons, Eur. J. Pharmacol., 353: 159-167.

Iontophoretic application Purpose Evaluation of the in vivo effects of AMPA-positive modulators (PAM) on peak activity evoked by AMPA in the rat hippocampus.

Principle The peak activity of a single hippocampal neuron is strongly influenced by the input of excitation and the iontophoretic application of AMPA induces peak activity in vivo in a dose-dependent manner (Mathiesen and coauthors, 1998). Peak activity evoked by AMPA is inhibited by the intravenous (i.v.) administration of a wide variety of AMPA receptor antagonists (Mathiesen and coauthors, 1998), which indicate that excitation is mediated primarily by means of AMPA receptors. PAM potentiates AMPA receptor activation in vitro, and if this mechanism also operates in vivo, i.v. of a PAM should increase the peak activity evoked by AMPA. Thus, the purpose of this study was to test the in vivo effect of a group of active PAM in vitro. This has been done by studying its ability to increase the peak activity evoked by AMPA after i.v. administration.

The preparation Experiments were carried out on male Wistar rats (M &B, Denmark), weighing 280-380 g, housed in two per cage, with free access to food and water. The rats were anesthetized with mebumal (50 mg / kg "1, ip) and the femoral artery was catheterized for the purpose of monitoring blood pressure and vein for intravenous injection of drugs and continuous injection of 0.9% NaCl (0.5 -1.0 ml / hr "1) and mebumal (5-10 mg / hr" 1) iv additional anesthetic was administered if the rat responded to a puncture in the hind paw, the trachea cannulated and the rats were placed in a frame stereotactic and ventilated using a rodent ventilator (Ugo Basile, Comerio-Varese, Italy) The central body temperature was maintained at 37.5 ° C by a DC heating pad.The dorsal left part of the parietal bone was removed by craniotomy, and the dura was extracted exposing the pia mater, and the underlying brain was covered with 0.9% NaCl.

Compounds / reagents AMPA (Sigma, E.U.A.) was dissolved at 10 mM in 0.2 M NaCl. NMDA (Sigma, E.U.A.) was dissolved at 100 mM in 100 mM NaCl. Both solutions were adjusted to pH 7.5-8.0 with NaOH. Compound 61 was dissolved in 200 mM of CH3SO3"Na +, at a concentration of 10 mM for iontophoretic application (pH 5.7) and in 278 mM of isotonic glucose for iv administration Cyclothiazide, compound 63, compound 56, compound 115 and compound 114 were dissolved in a 5% solution. % cremophorus at a concentration of 5 mg / ml "1.

The parameters The neuronal peak activity evoked was analyzed, online, by means of a computer, saving the individual peaks and the time of the event. The neuronal peak activity (number of action potentials _1) was monitored in a pulse velocity histogram, together with indicators for AMPA, compound 61 and vehicle application.

The procedure Extracellular recordings of individual hippocampal neurone peaks were made, with five glass microelectrodes, cylinder shaped (5B120F-6, World Precision Instruments, Inc., Sarasota, Florida, USA), with a tip diameter of 10 -12 μm. The individual cylinders were filled with 5M NaCl (log), 400 mM NaCl (current equilibrium), 10 mM Compound 61 in 200 mM CH3SO3"Na + (pH 4.7, 200 mM CH3SO3" Na + (pH 4.7, vehicle ) and the last cylinder with AMPA was filled in. Experiments were performed on hippocampal neurons (A = . 5-6.5 mm; L = 1.5-2.0 mm; H = 2.0-3.0 mm), according to Paxinos and Watson, 1986). The activity of neuronal peak was evoked by the iontophoretic application of AMPA during periods of 10 to 15 seconds, with intervals of 1.5 minutes. The peak activity of a single neuron was amplified 5,000 times, with a bandwidth of 0.3 to 3 kHz (CyberAmp 320, with intelligent probe A1 402 x 50, Axon Instruments, California, E. U. A.). On-line and off-line analyzes were carried out using the Spike2 program, with a 1401 plus interface (Cambridge Electronic Design Limited, England). He also recorded the computer program's mean arterial blood pressure and monitored and controlled the iontophoretic application. AMPA was ejected into the hippocampus in regular cycles of 100-105 seconds. When the neuronal responses were stable (when the AMPA responses did not vary by more than 10%, measured over a period of 10 seconds) for at least half an hour, then a single dose of cyclothiazide was injected into the femoral vein. 63, compound 56, compound 1 15, compound 61 or compound 1 14 (10 mg / kg "1) The recording of neuronal peak activity was continued for at least 45 minutes after intravenous injection. by the microiontophoretic application of compound 61 (20 nA, figure).

The results Figure 8 shows that the iontophoretic application of compound 61 increased the peak activity evoked by AMPA, while the vehicle did not influence the peak activity evoked. Intravenous administration of 10 mg / kg "1 of cyclothiazide did not increase the peak activity evoked by AMPA (Figure 10).

Figure 9 shows that the ontophoretic application of compound 61 increased the peak activity of a single neuron, evoked by AMPA. The ontophoretic application of the vehicle did not influence the peak activity evoked by AMPA. Figure 10 shows that 10 mg / kg "1 of cyclothiazide does not affect the peak activity evoked by AMPA in the hippocampus.The shaded area above the trace AMPA1 indicates the time of administration (1500 s after the start of recording). in vivo of the PAMs on the peak activity evoked by AMPA depended on the level of activity of the control peak.The compound 63 increased the small responses of AMPA, evoked by stimulation with AMPA of low intensity, but only had marginal effect on the responses large AMPA, evoked by stimulation with AMPA of high intensity (Figure 11) There was an initial inhibition of AMPA responses and the onset of the increase occurs 15 to 30 minutes after iv administration (figure 11). an example of increased AMPA responses by compound 56 (10 mg / kg "1). The onset occurred approximately 10 minutes after the administration (Figure 12). Figure 11 shows that 10 mg / kg "1 i.v. of compound 63 increased low intensity AMPA responses (12 nA), but only had a marginal effect on high intensity AMPA responses (17 nA). 10 mg / kg "1 of compound 63 1500 s was administered after the start of the recording The injection time was marked by the shaded area on top of the AMPA2 trace Figure 12 shows that 10 mg / kg" 1 i.v. of compound 56 increased the peak activity evoked by AMPA. The compound was injected 1250 seconds after the start of registration. The injection time is marked with a shaded area on top of the AMPA trace. Figure 13 shows an example of increased AMPA peak activity after i.v. administration. of 10 mg / kg "1 of compound 115. The effect was initiated 2 minutes after i.v. administration and lasted more than two hours.Compound 61 (10 mg / kg" 1) also increased AMPA responses in the hippocampus. The threefold increase in peak activity evoked by AMPA induced by compound 61 was initiated 20 minutes after the administration and lasted more than two hours (Figure 14). Compound 114 (10 mg / kg "1) induced a ten-fold increase in AMPA responses when the level of AMPA responses was low (from 21 to 209 spike peaks" 1, mean response, Figure 15), while only a minor increase was observed with larger control responses (from 124 to 204 response peaks "1, Figure 16) Figure 13 shows that (10 mg / kg" 1 iv) of compound 115 increased peak activity evoked by AMPA in the hippocampus. The shaded area indicates the injection time i.v. 1900 seconds after the start of registration. The effect of compound 1 15 lasted more than two hours. Figure 14 shows that compound 61 increased AMPA responses in the hippocampus. I.v. 10 mg / kg "1 1, 000 seconds after the start of registration (marked by a shaded area above the trace) The effect of compound 61 lasted more than 2.5 hours Figure 15 shows that (10 mg / kg" 1 iv ) of compound 1 14 increased the peak activity evoked by AMPA. The compound was given 1730 seconds after the start of registration, which is marked by a shaded area on top of the AMPA trace. Figure 16 shows that compound 14 (10 mg / kg "1 iv) approximately doubled AMPA responses, iv administration occurred at 3900 seconds, and indicated by the shaded area on top of the AMPA trace. results show that cyclothiazide showed no effect in vivo after iv administration. However, compound 63, compound 56, compound 1 15, compound 61 and compound 1 14 increased the peak activity evoked by AMPA, a way that depends on the activity.

References: MATHIESEN, C, VARMING, T and JENSEN, L. H. (1998). In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurons and cultured mouse cortical neurons. European Journal of Pharmacology 353, 159-167. PAXINOS, G. and WATSON, C (1986): The rat brain in stereotactic coordinates. Second edition.

Passive cancellation Purpose: To test the pharmacological effect of the compounds on association memory.

Principle: A mouse is placed in a clear compartment with access to a dark compartment. If you enter the dark compartment you will receive a shock on the leg (0.4 mA). After a delay (24 hours) the association is tested with the risk of receiving an unpleasant discharge in the leg when re-entering the dark compartment.

Animals: Female NMRI mice (Bromholdtgaard, DK) weighing 22-25 g were used. The mice were kept in Macrolon plastic cages with free access to food (Altromin, DK) and tap water. The mice were habituated to the laboratory for at least three days before the test (light on at 7:00 a.m./light off at 7:00 p.m.).

Equipment: The passive bypass apparatus consisted of a modular test chamber (ENV-307, MED-Associates, E. U. A.). The clear compartment and the dark compartment consisted of Plexiglas boxes of equal size (15 x 17 x 13 cm, width x length x height) with metallic grid floors. A sliding guillotine door was placed in the opening (4 x 4 cm) connecting the two compartments. A manual grid stirrer (ENV-412, MED-Associates, E.U.A.) was used to provide the 0.4 mA discharge in the leg.

Parameters The input latency (in seconds) was measured to re-enter the dark compartment.

Procedure: The mice were pretreated (usually for thirty minutes) before training, with the test compound. Training: A mouse was placed in the clear compartment and the guillotine door was opened to the dark compartment. When the mouse had entered the dark compartment with all four legs, it received a shock on the leg (0.4 mA) and will be returned to the original cage. Test: After a delay (24 hours) the mouse will be reintroduced to the clear compartment and the latency in time to enter the dark compartment is measured, with a time limit of two minutes. The latency is recorded in time as 2 minutes if the mouse has not entered the dark compartment with a maximum test time (2 minutes). Vehicle: 10% Tween 80. Volume of doses: 10 ml / kg. n = 10. The results show in figure 17 the memory enhancing effect of different concentrations of compound 61.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 and Figure 2 show the enhancement of the release of [3H [] GABA induced by AMPA, from cultured cortical neurons, by the compounds of the invention. Figures 3 to 8 show the voltage-setting experiments in the compounds of the invention. The compounds 56 (FIG. 3), 63 (FIG. 4), 11 (FIG. 6), 114 (FIG. 7) and FIG. 5 (FIG. 5) all enhance the current induced by the application of 30 .mu.M AMPA. Figure 8 shows the concentration dependent effect of a compound of the invention (1 14). Figures 9 to 16 are iontophoresis experiments. Figure 9 is an iontophoretic application of compound 61 and the iontophoretic application of the vehicle. Figure 10 is cyclothiazide applied in the hippocampus. Figure 11 is the application of compound 63.

Figure 12 is the application of compound 56. Figure 13 is the application of compound 1 15 to the hippocampus. Figure 14 is the application of compound 61 to the hippocampus. Figure 15 is compound 114. Figure 16 is compound 1 14. Figure 17 is the passive nullification test of compound 61.

EXAMPLES General methods of transformation Method A.- Sulfamoilation in general 32.5 mmol of the compound to be chlorosulfonated was dissolved in 75 ml of chlorosulfonic acid, and was heated in an oil bath at 110 ° C until the TLC indicated that the reaction had proceeded to completion. [A small aliquot was taken, added to ice in a test tube, neutralized with sodium bicarbonate and then extracted with EtOAc. The aqueous phase was separated and piperidine (xs) was added to the organic phase and left for some time. TLC was taken from this small-scale reaction mixture]. The reaction mixture was poured into ice and the formed precipitate was filtered off. The isolated solid was washed with a small amount of water and dried on the filter. The solid was dissolved in 200 ml of THF and an excess of the amine (230 mmol) was added and the reaction mixture was left overnight, with stirring, at room temperature. The reaction mixture was evaporated to dryness, then stirred with water to give a solid which was isolated by filtration and washed with EtOAc in the filter. Further purification was possible either by column chromatography or by recrystallization from EtOAc / hexane. The yield was typically 60-90%.

Method B O-Sulfamoylation of anilines (see also Girard et al., Atkinson J. G. and Rokach J. J. Chem. Soc. Perkin I (1979) 1043) To a stirred solution of 250 mmol of the aminobenzene derivative in 100 ml of nitroethane or nitromethane, at -50 ° C, a solution of 275 mmol of CISO2NCO in 75 ml of nitroethane or nitromethane was added, so that the temperature of the reaction was not will exceed -30 ° C. The cooling bath was removed and the thick reaction mixture was allowed to warm to 0 ° C. 300 mmol of solid AICI3 was added in one portion. The clear brown reaction mixture was heated in an oil bath at 120 ° C for 20 minutes; then it was cooled to room temperature and poured into a beaker with 1 liter of ice water, agitated. The formed precipitate was isolated by filtration. [The meta-substituted anilines give rise to a mixture of the two possible isomers, which in the urea intermediate step can be separated by crystallization in MeOH, or in the final product stage, by crystallization from EtOAc / hexane or chromatography] . 98 mmol of the urea intermediate was suspended in a mixture of 250 ml of dioxane and 500 ml of 6M sulfuric acid (or concentrated hydrochloric acid only) and heated to efflux overnight. The reaction mixture was cooled to room temperature, filtered and the dioxane was removed from the filtrate, by evaporation. The aqueous residue was neutralized to pH 7-8 using 4M NaOH. The precipitate formed was filtered off and washed with water and with EtOAc. The total yield varied from 10% to 75%.

Method C Protection with trifluoroacetyl To a stirred solution of 27 mmol of the 2-aminobenzenesulfonamide derivative in 75 ml of dry THF, at 0 ° C, trifluoroacetic anhydride was added, so that the reaction mixture did not exceed + 10 ° C. The reaction mixture was stirred at room temperature until all the starting material was consumed. The reaction mixture was evaporated to dryness, stirred with water, filtered and washed with hexane. 250 g of PPA was added to the isolated solid and heated in an oil bath at 140 ° C for 2.5 hours. The reaction mixture was cooled to 60-70 ° C and poured into an ice water solution, mechanically stirred. The formed precipitate was isolated by filtration and air dried. The total yield was typically d85-90%.

Method D Deprotection of trifluoroacetyl A stirred solution of 3.6 mmol of trifluoroacetyl protected compound, dissolved in 1 M KOH (30 ml), was heated at 80 ° C for one hour. The reaction mixture was cooled to room temperature and the pH adjusted to 7, using aqueous concentrated HCl. The reaction mixture was cooled to 0 ° C and filtered. The isolated solid was washed with water and air dried. The yields typically ranged from 85 to 95%.

Method E Foraction of 1, 1-dihydrobenzothiadiazine dioxide from 2-aminobenzenesulfonamides To a stirred solution of 148 mmol of the 2-aminobenzenesulfonamide derivative, 150 mmol of triethylamine, 7.5 mmol of 4- (N, N-dimethylamino) pyridine in 600 ml of THF at 5 ° C, the carboxylic acid chloride was added. The reaction mixture was allowed to stir overnight and then evaporated to dryness. The crude material was stirred with water and filtered. The isolated solid was dissolved in 250 ml of 1 M NaOH and heated at 80 ° C for three hours. The reaction mixture was cooled to room temperature and the pH adjusted to 7, using concentrated HCl. The formed precipitate was isolated and recrystallized from i-PrOH. The total returns varied from 80 to 90%.

Method F Reduction of 1, 1-dioxide dihydrobenzothiadiazines to 1,1-tetrahydrobenzothiadiazine dioxide To a stirred solution of 19.4 mmol of 1,1-dihydrobenzothiadiazine dioxide in 200 ml of THF at -70 ° C, a solution of 1.5 M DIBALH in 33 ml of toluene (50 mmol) was added. The reaction mixture was allowed to stir overnight, while slowly increasing the temperature from -70 ° C to -15 ° C. [The aminal product is further reduced to the open ring alkylamine, if the temperature is not carefully controlled]. 10 ml of water was added to the reaction mixture, followed by 5 ml of 1 M NaOH. The reaction mixture was then warmed to room temperature and extracted with EtOAc. The combined organic fractions were dried with magnesium sulfate and evaporated to dryness. In some cases the product was further purified by column chromatography. The yields ranged from 45 to 85%.

Method G Formation of 1, 1-dioxides of tetrahydrobenzothiadiazines from 2-aminobenzenesulfonamides A stirred solution of 7 mmol of the 2-aminobenzenesulfonamide derivative, 10 mol of an aldehyde and 20 mmol of MgSO in 40 ml of dry THF or dry dioxane was put under reflux, under nitrogen, until the TLC indicated that the consumption of the 2-aminobenzenesulfonamide derivative (typically 12-36 hours). The reaction mixture was filtered and the precipitate was washed thoroughly with THF or with dioxane. The filtrate was evaporated to dryness, water was added and extracted with EtOAc. The combined organic fractions were dried with magnesium sulfate and evaporated to dryness. Column chromatography (EtOAc / hexane) yielded the pure product. Yields typically ranged from 25 to 75%.

Method H Formation of aryl- or hetaryl-substituted compounds through the use of pd-catalyzed cross coupling P.S. cat. Hetaryl / Aryl Areno Metalated / Hetarene x = Br, i Suzuki coupling: A stirred mixture of 2 mmol of aryl haiogenide, an arylboronic or hetarylboronic acid, a boronic acid ester or dialkylborane was heated at 70 ° C for three hours ( 6 mmol), 10 ml of K2CO3, 30 mg of Pd (PPh3), 10 mmol of 1,3-propanediol, 50 ml of dimethoxyethane and 25 ml of water, under nitrogen. The reaction mixture was cooled to room temperature. More water was added and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried with magnesium sulfate and evaporated to dryness. Column chromatography yielded the pure product. The yields ranged from 40 to 100%.

Method Formation of compounds containing triazolyl substitution Sonogashira Coupling: A mixture of an aryl iodide or aryl bromide (2 mmol), acetylene (10 mmol) was stirred at room temperature; Pd (PPh3) 2 Cl2 (140 mg, 0.2 mmol); Cul (40 mg, 0.1 mmol) and 10 ml of triethylamine, under nitrogen, overnight (in case of the aryl bromides it was necessary to prolong the heating to 60 ° C). THF was added and the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. Column chromatography gave the ethynylated arene. Yields ranged from 40 to 53% for aryl bromides to 97% for aryl iodides. Destrimethylsilylation for R '- = TMS: A solution of 1.7 mmol of ethynylated arene in 8 ml of MeOH was added to a solution of 2 ml of 1 M KOH in 2 mmol of MeOH, and stirred at room temperature for two hours . The reaction mixture was diluted with THF, adsorbed onto silica and chromatographed to give the disilylated ethynylarene. Yields ranged from 61% to 73%.

Trizite formation: Ethynylarene (0.7 mmol) and 2 ml (15 mmol) of TMS-N3 were heated at 70 ° C in an ampoule for 50 hours. The reaction mixture was cooled to room temperature and evaporated almost to dryness. (CAUTION: Evaporation to dryness may lead to explosion, due to the presence of some HN3) and MeOH was added. The reaction mixture was stirred for one hour (to remove the TMS group in the TMS-triazole), then adsorbed onto silica and purified by chromatography. Yields ranged from 20 to 72%.

SYNTHESIS OF INDIVIDUAL COMPOUNDS COMPOUND 1 2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline Anthranilamide was transformed by the G method (using cyclohexanecarboxyaldehyde). Melting point 172-174 ° C.

COMPOUND 2 2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline Anthranilamide was transformed by the G method (using benzaldehyde); p.f. 221-222 ° C.

COMPOUND 3 2-Methyl-3,4-dihydro-1,3-benzoxazin-4-one 2-hydroxybenzamide was transformed by the G method (using paraldehyde); p.f. 124-126 ° C.

COMPOUND 4 2-Phenyl-3,4-dihydro-1,3-benzoxazin-4-one 2-Hydroxybenzamide was transformed by the G method (using benzaldehyde); p. F. 157-160 ° C.

COMPOUND 5 1.1.-3-bicyclo2.2.nhept-5'-en-2'-yl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-aminobenzenesulfonamide was transformed by the method G (using a racemic endo / exo mixture of 2-norbornecarboxaldehyde); p. F. 206-209 ° C.

COMPOUND 6 1.1-3-Phenyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was transformed by the method G (using benzaldehyde); p. F. 125.5-128.5 ° C.

COMPOUND 7 5.5-Dioxide of 1.2.3.5.10.1 Oa-hexahydrobenzoFelpirroloH .2-b1-1.2.4- thiadiazine 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride) The reaction mixture was not subjected to ring closure catalyzed with NaOH, but was dissolved in sulfuric acid and heated at 100 ° C for 72 hours and precipitated on ice); p. F. 149-154 ° C.

COMPOUND 8 5-Etii-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one 2-Hydroxybenzamide was transformed by the G method (using 2-butanone), p. F. 76-78 ° C.

COMPOUND 9 1.1-3-Cyclohexyl-6- (2-methoxyphenyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 3-Bromoaniline was transformed by method B (see compound 121) to give 4-bromo-2-aminobenzenesulfonamide. A mixture of 140 mg (0.56 mmol) of 4-bromo-2-aminobenzenesulfonamide, 106 mg (0.70 mmol) of 2-methoxyphenylboronic acid, 20 mg (5 mol%) of Pd was left under reflux for four hours. (PPh3) 2Cl2 in 30 ml of 1,2-dimethoxyethane and 2M, 3, ml (6 mmol) of Na2CO3. The solvents were removed under reduced pressure and the residue was treated with 20 ml of sodium bicarbonate and extracted with 2 x 40 ml of EtOAc. The organic layer was washed with 20 ml of brine, dried (over sodium sulfate) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica, using EtOAc: n-hexane (1: 1 v / v) as eluent, which yielded 155 mg (100%) of 2-amino-4- (2-methoxyphenyl) benzenesulfonamide , as a colorless powder. The product was further transformed by the method G (using cyclohexanecarboxaldehyde), m.p. 219-221 ° C.

COMPOUND 10 1.1-3-Cyclohexyl-6- (2-pyridyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide .58 g (30 mmol) of 3-aminophenylboronic acid semisulfate, 2.7 ml (28 mmol) of 2-bromopyridine, 100 mg (0.5 mol%) of Pd (PPh3) 2Cl2, 50 ml of 3M carbonate were allowed to reflux. potassium, in 50 ml of dimethoxyethane for 24 hours, under nitrogen. The mixture was diluted with 100 ml of methylene chloride and washed with 50 ml of saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. Flash chromatography with methylene chloride as eluent gave 3- (2-pyridyl) aniline, as a yellow oil, 1.0 g (21%). The 3- (2-pyridyl) aniline was transformed by method B and method G (using cyclohexanecarboxaldehyde), p. F. 213-216 ° C.

COMPOUND 11 1.1-3-Cyclohexyl-6- (3-pyridyl) -1.2.3.4-tetrahydro-1,2,4-benzothiadiazine dioxide 3-Bromoaniline was transformed by method B (see compound 121) to give 4-bromo-2-aminobenzenesulfonamide. A mixture of 250 mg (1.0 mmol) of 4-bromo-2-aminobenzenesulfonamide, 225 mg (1.5 mmol) of diethyl-3-pyridylborane, 35 mg (5% molar) of nitrogen was left under reflux for 4 hours. Pd (PPh3) 2Cl2 in 30 ml of 1,2-dimethoxyethane and 2M, 3 ml (6 mmol) of sodium carbonate. The solvents were removed under reduced pressure and the residue was treated with 20 ml of sodium bicarbonate and extracted with 2 x 40 ml of EtOAc. The organic layer was washed with 20 ml of brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The product was purified by chromatography on silica using EtOAc: n-hexane (1: 1 v / v) as eluent, which yielded 240 mg (96%) of 2-amino-4- (3-pyridyl) -benzenesulfonamide, as a colorless powder. The product was further transformed by the method G (using cyclohexanecarboxaldehyde), p. F. 240-243 ° C.

COMPOUND 12 1.1-3-Cyclohexyl-7- (1-hydroxyethyl), 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-amino-5- (1-hydroxyethyl) benzenesulfonamide: 0.95 g (4.4 mmol) of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) was suspended in 50 ml of 96% EtOH and added in one portion 0.46 g (12 mmol) of NaBH. The mixture was stirred at 25 ° C for four hours and filtered through Celite and the solvent was removed under reduced pressure. The residue was treated with 50 ml of saturated sodium bicarbonate and extracted with 2 x 50 ml of EtOAc, dried over sodium sulfate and evaporated to dryness. Flash chromatography with EtOAc: n-hexane: Et N (200: 100: 4 by volume / volume / volume), as eluent, gave 0.35 g (37%) of 2-amino-5- (1-hydroxyethyl) benzenesulfonamide, as a light brown powder, p. F. 160-162 ° C.

COMPOUND 13 1.1-3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide To a solution of 5.8 ml (60 mmol) of ethyl vinyl ether in 50 ml of dry THF at -78 ° C, 25 ml (40 mmol) of 1.7 M t-BuLi in pentane was added, and the yellow mixture was stirred for one hour. hour at -78 ° C. The cooling bath was removed and the mixture was slowly warmed to 0 ° C and stirred for another 30 minutes. The mixture was again cooled to -78 ° C and 20 ml (40 mmol) of a solution of ZnCl2 (2M in THF) was slowly added, and the cooling bath was removed and heated to 20 ° C. 1.8 g (6 mmol) of 5-iodo-2-aminobenzenesulfonamide (see example 37) and 0.2 g (3 mol%) of Pd (PPh3) were added, and the mixture was refluxed for six hours. The THF was evaporated and the residue was boiled in 30 ml of 1 M hydrochloric acid and 30 ml of MeOH for 30 minutes. 14.6 g (50 mmol) of EDTA was added and made slightly basic (pH = 8-9) with 1 M NaOH, after which it was extracted with 3 x 150 mL EtOAc; Drying over sodium sulfate and evaporation of the solvent gave a brown solid. Trituration with n-hexane gave 0.95 g (74%) of 5-acetyl-2-aminobenzenesulfonamide, as a white matte powder. The product was further transformed by the method G (using cyclohexanecarboxaldehyde), p. F. 224-226 ° C (with decomposition).

COMPOUND 14 1.1-3-Cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide To a suspension of 0.45 g (2.1 mmol) of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) in 40 ml of 96% EtOH, 0.28 g (4 mmol) of H2NOH-CHI and 2 ml of 2M were added. of NaOH. The mixture was boiled for two hours and the solvent was evaporated. The residue was triturated with 25 ml of water and the product was filtered off and dried, which yielded 0.39 g (81%) of 2-amino-5- (1-hydroxy-aminoethyl) benzenesulfonamide as a yellow powder. . The product was further transformed by the method G (using cyclohexanecarboxaldehyde), p. F. 230-233 ° C.

COMPOUND 15 1.1-3-Cyclohexyl-7-carbamoyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide A mixture of 2 g (10 mol) of 5-cyano-2-aminobenzenesulfonamide (see compound 37), 4 ml of concentrated sulfuric acid and 4 ml of the mixture were heated at 80 ° C for 5 hours and overnight at 50 ° C. ml of absolute ethanol. The reaction mixture was poured into ice and extracted with 1 x EtOAc. [The first extraction contains the nitrile (starting material) and another by-product]. The organic phase was discarded and the aqueous phase was neutralized with sodium carbonate and extracted with 3 x EtOAc. The organic phase was evaporated to dryness and subjected to column chromatography (EtOAc / hexane = 2/1) to give 200 mg (9%) of the carboxamide. The carboxamide was further transformed by the use of the G method (using cyclohexanecarboxaldehyde), e.g. F. 235-237 ° C.

COMPOUND 16 1, 3-3-Cyclohexyl-7-ethoxycarbonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide A mixture of 3 g (15 mmol) of 5-cyano-2-aminobenzenesulfonamide (see compound 37), 5 ml of concentrated sulfuric acid and 15 ml of absolute ethanol was heated at 80 ° C overnight. The reaction mixture was poured onto ice. The formed precipitate was isolated by filtration. The precipitate was washed with EtOAc to give 2.01 g (55% pure ethyl ester) The ester was transformed by using method G (using cyclohexanecarboxaldehyde), mp 234-236 ° C.

COMPOUND 17 1.1-3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -Cyano-2-aminobenzenesulfonamide (see compound 37) was transformed by the method G (using cyclohexanecarboxaldehyde), p. F. 234-237 ° C.

COMPOUND 18 1.1-3-bicyclic2.2.phept-5'-en-2'-yl-7-phenyl-1.2.3.4-tetrahydro-1,4-benzothiadiazine dioxide -bromo-2-aminobenzenesulfonamide: To a stirred solution of 1.72 g (10 mmol) of 2-aminobenzenesulfonamide in 15 ml of AcOH, a solution of 0.55 ml, (10.5 mmol) of Br2 in 5 ml of AcOH was added. The reaction mixture was poured into 100 ml of water and filtered. The isolated solid was adsorbed on silica and subjected to chromatography to give 1.428 g (57%) of product (and 650 mg (20%) of the derivative 3,5-dibromo). 1, 1-3-bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (18) : 5-Bromo-2-aminobenzenesulfonamide was transformed by method H (using phenylboronic acid) and method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-en-2-carboxaldehyde); p. F. 190.5-195.0 ° C.

COMPOUND 19 1.1-3-Cyclohexyl-7- (2'-acetamidophenyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Nitrophenylboronic Acid: To a solution of 10 g (82 mmol) of phenylboronic acid in 100 ml of acetic anhydride at -15 ° C, 5 ml (120 mmol) of fuming nitric acid was added for thirty minutes, so that the temperature of the reaction was maintained below -10 ° C. The reaction mixture was allowed to warm to room temperature and was allowed to stir overnight. The reaction mixture was poured onto ice and concentrated to 50 ml. The residue was then evaporated five times, in another 100 ml of water and finally filtered to give 7.1 g of crude product, as a mixture of isomers. Column chromatography (methylene chloride / EtOH = 10 / 0.5) gave 4.8 g (35%) of pure product, as oil. and 2-acetamidophenylboronic acid: A mixture of 2 g (12 mmol) of 2-nitrophenylboronic acid and 100 mg of 5% Pd / C in 100 ml of EtOH was hydrogenated at 1 bar until the TLC indicated the conversion complete of the starting material. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was washed with hexane and filtered to give 900 mg of 2-aminophenylboronic acid (55%). A mixture of 900 mg of 2-aminophenitrichloronic acid (6 mmol), 0.57 ml (7 mmol) of triethylamine and 0.5 ml (7 mmol) of acetyl chloride was stirred at room temperature for one hour. The reaction mixture was evaporated to dryness, stirred with water and filtered to give 750 mg (63%) of product. 1,1-3-cyclohexyl-7- (2'-acetamidophenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (19): 5-iodo-2-aminobenzenesulfonamide ( see compound 37) by method H (using 2-acetamidophenylboronic acid) and method G (using cyclohexancarboxaldehyde), p. F. 245-249 ° C.

COMPOUND 20 1.1-3-Cyclohexyl-7- (2'-nitrophenyl, -1.2.3.4-tetrahydro-1,2,4- benzothiadiazine dioxide) -iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using 2-nitrophenylboronic acid (see compound 19)) and method G (using cyclohexanecarboxaldehyde); p.f. 204-207 ° C.

COMPOUND 21 1.1-3-Cyclohexyl-7- (2'-methoxypheniD-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide) -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by the method H (using 2-methoxyphenylboronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 219-222 ° C.

COMPOUND 22 1.1-3-Cyclohexyl-7- (2'-methoxy-4'-trifluoromethylphenyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 4-trifluoromethylanisole: 12.78 g (555 mmol) of sodium was added to 100 ml of dry MeOH. When the evolution of gas ceased, the reaction mixture was evaporated to dryness and dried in 250 ml of NMP, and then 35.3 (555 mmol) of Cu (S), and 25 g (11.1 mmol) of 4-7% were added. bromine-trifluoromethyl-benzene. The reaction mixture was heated at 130 ° C for four hours, cooled to room temperature and filtered. 500 ml of water was added to the filtrate and extracted with 2 x 200 ml of diethyl ether. The combined organic fractions were washed with 2 x 100 ml of water and dried over magnesium sulfate and evaporated to dryness. Column chromatography gave 8.05 g (41%) of the product. 2-Methoxy-5-trifluoromethylphenylboronic acid: To a solution of 8 g (45 mmol) of 4-trifluoromethylanisole in 80 ml of THF, at -30 ° C, under nitrogen, was added a solution of 20 ml (50 mmol) of 2.5 M n-BuLi in hexane. The reaction mixture was stirred for one hour at -30 ° C, then cooled to -70 ° C and 14.1 ml (64 mmol9 of B (Oi-Pr) 3 was added. The reaction mixture was slowly allowed to warm to room temperature. At room temperature overnight, 40 ml, 2M HCl was added to the reaction mixture and the THF was removed by evaporation, the aqueous residue was extracted with 4 x 20 ml of diethyl ether and the combined organic fractions were extracted with 5 x. 17 ml of 1 M NaOH The combined aqueous fractions were neutralized with 10 M HCl The precipitate formed was isolated by filtration and washed with 1 M HCl to give 8.1 g (81%) of product. 3-cyclohexyl-7- (2'-methoxy-4'-trifluoromethylphenol) -1, 2,3,4-tetrahydro-1,4-benzothiadiazine (22): 5-iodo-2 was transformed -aminobenzenesulfonamide (see compound 37) by the H method (using 2-methoxy-5-trifluoromethylphenylboronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 255-257 ° C.

COMPOUND 23 1.1-3-Cyclohexyl-7- (2'4'-dimethoxyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide) -iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using 2,4-dimethoxyphenylboronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 208-213 ° C.

COMPOUND 24 1.1 - 3-Cyclohexyl-7- (2 '- (n.n-dimethylsulfamoyl) phenyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2- (N, N-Dimethylsulfamoyl) phenylboronic acid: To a solution of 10 ml (78 mmol) of benzenesulfonyl chloride in 100 ml of THF, a 40% solution of dimethylamine in 20 ml of water (160 mmol) was added. , so as to keep the reaction temperature below 50 ° C. The reaction mixture was stirred for one hour at room temperature. Water was added to the reaction mixture and the THF was removed by evaporation. The formed precipitate was isolated by filtration and dried in the air to give 14 g (97%) of N, N-dimethylbenzenesulfonamide. A solution of 9.25 g (50 mmol) of N, N-dimethylbenzenesulfonamide in 150 ml of dry diethyl ether was cooled to -70 ° C under nitrogen, and a solution of 2.5 M n-BuLi in 24 ml of hexane was added. (60 mmol), so as to keep the reaction temperature below -60 ° C. The cooling bath was removed and the reaction mixture was allowed to warm to + 20 ° C. The reaction mixture was again cooled to -70 ° C and 16.1 ml (70 mmol) of B (Oi-Pr) 3 was added. The reaction mixture was allowed to cool and allowed to warm overnight. Then 100 ml of 1 M HCl was added and stirring was continued at room temperature for one hour. The reaction mixture was then extracted with 2 x 50 ml of ethyl ether and the combined organic fractions were extracted with 4 x 50 ml of 1 M NaOH.

The combined aqueous fractions were neutralized with 1 M HCl and extracted with 4 x 100 ml of ether. The combined organic fractions were dried over sodium sulfate and evaporated to dryness and washed with ether / hexane to give 3.4 g (30%) of product. 1,1-cyclohexyl-7- (2 '- (N, N-dimethylsulfamoyl) phenyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (24): -iodo-2-aminobenzenesulfonamide (see compound 37) by method H (using 2- (N, N-dimethylsulfamoyl) phenylboronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 290-300 ° C.

COMPOUND 25 1, 1-3-Cyclohexyl-7- (2'-chlorophenin-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using 2-chlorophenylboronic acid) and method G (using cyclohexanecarboxaldehyde), m.p. 233-236 ° C.

COMPOUND 26 1, 1-3-Cyclohexyl-7- (2'-fluorophenyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -Iodo-2-aminobenzenesphonamide (see compound 37) was transformed by method H (using 2-fluorophenylboronic acid and method G (using cyclohexanecarboxaldehyde), mp 249-250 ° C.

COMPOUND 27 1.1-3-Cyclohexyl-7- (3 * -hydroxyphenyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 3-hydroxyphenylboronic acid: To a stirred solution of 6.2 g (33.3 mmol) of 3-aminophenylboronic acid semisulfate and 3.7 ml (33.3 mmol) of 50% sulfuric acid in 100 ml of water at -2 ° C was added. a solution of 2.5 g (36.3 mmol) of NaNO2 (2.5 g (36.3 mmol) in 20 ml of water for one hour.) The reaction mixture was slowly added to a stirred solution of 25 ml of concentrated sulfuric acid in 20 ml of water. After refluxing, the reaction mixture was refluxed for 30 minutes, cooled, activated charcoal was added, it was heated to reflux, cooled and filtered through Celite. with NaCl (s), filtered and extracted with 5 x 100 ml of ether, the combined organic fractions were dried over sodium sulfate and evaporated to dryness to give 4.3 g (94%) of the product.1,1-dioxide of 3-cyclohexyl-7- (3'-hydroxyphenyl) -1,2,3,4-tetrahydro-1, 2,4-benzothiadiazine (27): It was converted to 3-hydroxyphenylboronic acid by method H and method G (using cyclohexanecarboxaldehyde), p. F. 238-246 ° C.

COMPOUND 28 1.1 -3-Cyclohexyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 4- (2'-pyridyl) -2-aminobenzenesulfonamide: A stirred mixture of 1 g (3.3 mmol) of 5-iodo-2-aminobenzenesulfonamide was heated at 100 ° C for six hours, and overnight at room temperature. , 5.5 g (15 mmol) of 2-tributylstanilpyridine, 240 mg (0.34 mmol) of Pd (PPh3) 4 and 780 mg (3.36 mmol) of Ag2O in 50 ml of DMF, under nitrogen. The reaction mixture was evaporated to dryness and resuspended and stirred in water / EtOAc and finally filtered. The organic phase was isolated and the aqueous phase was extracted with 2 x aqueous volume of ethyl acetate. The combined organic fractions were dried over sodium sulfate, evaporated to dryness and subjected to column chromatography to give 200 mg (24%) of the product. 1,1-3-cyclohexyl-7 - (2'-pyridyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (28): 4- (2'-pyridyl) was transformed -2-aminobenzenesulfonamide by the method G (using cyclohexanecarboxaldehyde), p. F. 222-224 ° C.

COMPOUND 29 1.1-3-Cyclohexyl-7- (3'-pyridyl, -1.2.3.4-tetrahydro-1,2,4- benzothiadiazine dioxide -iodo-2-aminobenzenesulfonamide was transformed by method H (using diethyl-3-pyridylborane) and method G (using cyclohexanecarboxaldehyde), p. F. 240-242 ° C.

COMPOUND 30 1.1 -3-Cyclohexyl-7- (2 * -pyr8midinin-1, 2.3.4-tetrahydro-1.2.4-benzothiadiazine dioxide y4c / 'oO 4 - ((2,2-dimethylpropanoyl) amino) phenylboronic acid: To a solution at 1.56 g (6 mmol) of 4-bromo-N-pivaloylaniline in 50 ml of dry THF, at -78 ° C, added 13.3 ml (20 mmol) of 1.5M t-BuL1 in pentane, and the yellow mixture was stirred for one hour at -78 ° C, under nitrogen. The reaction was quenched with 1.7 ml (15 mmol) of B (OCH3) 3 and stirred for another hour at -78 ° C. The reaction mixture was then warmed to room temperature and hydrolyzed with 50 ml of 0.5M hydrochloric acid and extracted with 3 x 80 ml EtOAc, dried over sodium sulfate and concentrated to about 40 ml. 120 ml of n-hexane was added slowly and the colorless crystalline product was filtered off and dried, yielding 1.26 g (95%). N- (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide: A mixture of 2.0 g (9 mmol) of 4 - ((2,2-dimethylpropanoyl) acid was allowed to reflux under nitrogen for five hours. ) amino) phenylboronic, 0.8 g (7 mmol) of 2-chloropyrimidine, 100 mg (2 mol%) of Pd (PPh3) 2CI2, 40 ml of 1,2-dimethoxyethane and 7 ml (14 mmol) of 2M carbonate of sodium. The mixture was diluted with 20 ml of 10% sodium carbonate and extracted with 3 x 50 ml of ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The crude product was recrystallized from methanol / water (1: 1), which afforded 0.52 g (85%) of N- (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide, as colorless crystals. 4- (2-pyrimidinyl) aniline: 1.41 g (5.48 mmol) of N- (4- (2-pyrimidinyl) phenyl) -2,2-dimethylpropanamide in 40 ml of 6M hydrochloric acid was left to boil for two hours . The mixture was cooled and made strongly basic with NaOH (s) and extracted with 2 x 50 ml of methylene chloride, dried over sodium sulfate and the solvent was removed in vacuo. Trituration with n-hexane gave 0.83 g (88%) of 4- (2-pyrimidinyl) aniline, as a light yellow powder. The product was transformed by method B and method G (using cyclohexanecarboxaldehyde), p. F. 236-238 ° C.

COMPOUND 31 1.1-3-Cyclohexyl-7- (2'-furyl, -1, 2,3,4-tetrahydro-1,2,4- benzothiadiazine dioxide -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using furyl-2-boronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 226-228 ° C.

COMPOUND 32 1.1-3-Cyclohexyl-7- 3'-furyl dioxide) -1.2.3.4-tetrahydro-1.2.4-benzothiadiazine -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using furyl-3-boronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 204-205 ° C.

COMPOUND 33 1.1-3-Cyclohexyl-7- (2'-thienyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method H (using furyl-2-boronic acid) and method G (using cyclohexanecarboxaldehyde), p. F. 234-236 ° c COMPOUND 34 1.1-3-Cyclohexyl-7- (1-methyl-1 h-2-imidazolyl) -1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide To a solution of 4.8 ml (60 mmol) of 1-methylimidazole in 120 ml of dry THF, at -78 ° C, 26 ml (65 mmol) of N-BuLi (2.5 M in hexane) was added, and the yellow mixture for 45 minutes at -78 ° C. A solution of 75 ml (150 mmol) of zinc chloride (2M in THF) was added slowly, and the cooling bath was removed. The colorless solution was stirred for another 10 minutes at 0 ° C. 2.1 g (7 mmol) of 5-iodo-2-aminobenzenesulfonamide (see compound 37) (2.1 g (7 mmol) and 0.5 g (5 mol%) of Pd (PPh3) 4 were added and the mixture was refluxed. mixture for six hours The THF was evaporated and the residue was treated with 53 g (0.18 mol) of EDTA and made slightly basic (pH = 8-9) with 1 M NaOH, followed by extraction with 3 x 150 ml of EtOAc, drying over sodium sulfate and evaporation of the solvent gave a dark oil.Short chromatography with 5% MeOH in methylene chloride, as eluent, gave 1.33 g (75%) of 2-amino-5- ( 1-methyl-1 H-2-imidazolyl) -1-benzenesulfonamide, as colorless crystals The product was further transformed by method G (using cyclohexanecarboxaldehyde), mp> 250 ° C (with decomposition).

COMPOUND 35 1.1 -3-Cyclohexyl-7- (1"'. S'-triazoM'-il .2.3.4-tetrahydro-1.2.4- benzothiadiazine dioxide -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method I (using trimethylsilylacetylene) and method G (using cyclohexanecarboxaldehyde), p. F. 230-234 ° C (with decomposition).

COMPOUND 36 1.1 -3-Cyclohexyl-7- (5'-phenyl-1 '.2'.3'-trilazole-4'yl) -1.2.3.4-tetrahydro-1,4-benzothiadiazine dioxide -Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by method I (using phenylacetylene) and method G (using cyclohexanecarboxaldehyde), p. F. 231-232 ° C (decomposition).

COMPOUND 37 1.1-3-Cyclohexyl-7- (5'-methyl-1 •, 2 *, 4'-oxadiazol-3-ylM .2.3.4- tetrahydro-1,2,4-benzothiadiazine dioxide -iodo-2-aminobenzenesulfonamide: To a stirred, cold (0 ° C) solution of 17.2 g (100 mmol) of 2-aminobenzenesulfonamide in 200 g of chloroform chloride was added a solution of 17.1 g (105 mmol) of iodine monochloride in 50 ml of chloroform, for 1 hour. The reaction mixture was slowly warmed to room temperature and left stirring overnight. The reaction mixture was filtered and the isolated solid was washed on the filter with 3 x 20 ml of chloroform, 1 x 20 ml of saturated aqueous sodium bicarbonate and 4 x 50 ml of water. The isolated solid was air dried to give 27.3 g (92%) of 5-cyano-2-aminobenzenesulfonamide product: A mixture of 17.9 g (60 mmol) of 5-iodine was heated at 80 ° C for 2 hours. 2-aminobenzenesulfonamide, 4.9 g (41.9 mmol) of Zn (CN) 2 and 2.5 G (2.2 MMOL) of Pd (PPh3) 4 in 150 ml of DMF, under nitrogen. The reaction mixture was poured into 600 ml of saturated aqueous sodium bicarbonate, and extracted with 9 x 200 ml EtOAc. The combined organic fractions and saturated aqueous NaCl were washed with saturated aqueous sodium bicarbonate; dried over sodium sulfate, filtered and evaporated to dryness. The residue was washed with water and with hexane, and filtered to give 10.9 g (92%) of product. 5- (N-hydroxyamidino) -2-aminobenzenesulfonamide: A mixture of 764 mg (11 mmol) of hydroxylamine hydrochloride and 616 mg (1.4 mmol) of NaOMe in 10 ml of MeOH was stirred at room temperature for one hour.; and then 1 g (5 mmol) of 5-cyano-2-aminobenzenesulfonamide was added. The reaction mixture was then left stirring for 48 hours and poured into water and extracted with 2 x 50 ml of EtOAc. The combined organic fractions were dried over sodium sulfate, evaporated to dryness and purified by column chromatography to give 200 mg (17%) of product. 7,1-3-cyclohexyl-7- (5'-methyl-1 ', 2', 4'-oxadiazol-3-yl) -1,2,3,4-tetrahydro-1,4- dioxide benzothiadiazine (37): A mixture of 200 mg (0.9 mmol) of 5- (N-hydroxyamidino) -2-aminobenzenesulfonamide, 50 mg (1 mmol) of NaOMe, 5 ml of EtOAc, was heated overnight at 70 ° C. 2 g of MS3A crushed in 20 ml of anhydrous EtOH. The combined organic fractions were dried over sodium sulfate and evaporated to dryness, to a brown oil, which was subjected to transformation by method G (using cyclohexancarboxaldehyde), to give 8 mg of product, after chromatography; p.f. 249-251 ° C.

COMPOUND 38 1.1-3-Cyclohexyl-7-acetamido-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 1, 1-7-amino-3-cyclohexyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide: To a stirred solution of 0.5 g (2 mmol) of 1,1-dioxide 7-amino-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazine in 10 ml of dry THF at -70 ° C was added a solution of 1.5M DIBALH in 2.7 ml (4 mmol) of toluene , under nitrogen. The reaction mixture was stirred for two hours at -70 ° C, 2 hours at -40 ° C and then warmed to 0 ° C. The reaction was quenched with water and stirred for 30 minutes at 0 ° C and left overnight without stirring at + 5 ° C. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed well with MeOH and filtered. The combined filtrates were adsorbed on silica gel. Column chromatography (EtOAc) gave 200 mg of the product. 1, 1-7-acetylamino-3-cyclohexyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (38): A mixture of 100 mg was stirred for two hours at room temperature. 0.26 mmol) of 1,1-amino-3-cyclohexyl-1, 1-dioxide, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 20 μl (0.29 mol) of acetyl chloride, and 42 μl (0.3 mmol) of triethylamine. The reaction mixture was resuspended in water and filtered. The isolated solid was purified by column chromatography (EtOAc) to give 22 mg of 27a; p.f. 202-206 ° C.

COMPOUND 39 1, 1-3-Cyclohexyl-7-methylsulfonylamino-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 1, 1-3-cyclohexyl-1,2-dihydro-1,4-benzothiadiazine dioxide: 2-aminobenzenesulfonamide was transformed by the method E (using cyclohexanecarbonyl chloride). 1,1-cyclohexyl-7-nitro-1,2-dihydro-1,4-benzothiadiazine dioxide: To a stirred solution of 1.2 g (1 1.5 mmol) of KNO 3 and 8 ml of concentrated sulfuric acid, at 5 ° C, a solution of 1,1-dioxide of 3-cyclohexyl-1,2-dihydro-1,4-benzothiadiazine in 8 ml of concentrated sulfuric acid was added. The reaction mixture was allowed to warm to room temperature and then allowed to stir overnight. The product was precipitated by slowly adding ice and isolated by filtration. 4.3 g of crude product was used without further purification. 1, 1-7-amino-3-cyclohexyl-1,2-dihydro-1,4-benzothiadiazine dioxide: A stirred suspension of 4.2 g (14 mmol) of 1,1-cyclohex dioxide was hydrogenated. L-7-nitro-1,2-dihydro-1, 2,4-benzothiadiazine and 400 mg of 10% Pd / C in 100 ml of absolute ethanol, at 1 bar. After consuming the calculated amount of hydrogen, the reaction mixture was filtered through Celite. The Celite was washed twice with 75 ml of DMF and then the combined organic fractions were evaporated to dryness. The residue was resuspended in EtOAc / i-PrOH and the formed precipitate was isolated by filtration. The isolated solid was dissolved in 0.5M NaOH (aqueous) and re-precipitated with 4M HCl (aqueous). The filtration gave 1.6 g of product. 1,1-di-deoxy-7-methylsulfonyl-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine: was added to a stirred solution of 1 g (3.6 mmol) of 1.1. 7-amino-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazine dioxide and 1.2 ml (8 mmol) of triethylamine in 25 ml of dry THF, 0.6 ml (8 mmol) of methanesulfonyl chloride , and stirred at room temperature for two hours. The reaction mixture was evaporated to dryness, resuspended in water / ethyl acetate and filtered. The filtrate was adsorbed on silica gel. Column chromatography (methylene chloride: acetone = 9.19 gave 210 mg of product 7, 1-dioxide of 3-cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,4-benzothiadiazine ( 39): 1,1-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1,4-benzothiadiazine was converted by the method F, mp 255-258 ° C.

COMPOUND 40 1.1-3-Cyclohexyl-7-nitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 1, 1-3-trifluoromethyl-1,2,4-benzothiadiazine dioxide: Protected with trifluoroacetyl 2-aminobenzenesulfonamide, using method C. To 1 g (4 mmol) of a solution of this in 16 ml of sulfuric acid at 0 ° C, 4.4 mmol of KNO3 was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into 150 ml of water, filtered and air dried to give 1.11 g (94%) of pure product as a yellow solid. 1, 1-3-cyclohexyl-7-nitro-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (40): 1,1-trifluoromethyl-1,2-dioxide was subjected , 4-benzothiadiazine to the following transformation scheme: method D and method F (using ciciohexancarboxaldehyde), mp 209-211 °.

COMPOUND 41 1.1-Dioxides of 3-cyclohexyl-7-phenylsulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine 4-Phenylsulfonylaniline was used as the starting material for the following transformation sequence: method B and method G (using cyclohexanecarboxaldehyde), m.p. 243-245 ° C.

COMPOUND 42 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoiinsulfonamide To a solution of 3 g (25 mmol) of 2-aminobenzylamine in 50 ml of THF, 3.8 ml (27 mmol) of trifluoroacetic anhydride was added and stirred at room temperature for two hours. The reaction mixture was evaporated to dryness, stirred with water and filtered. The crude product was transformed by method A (using 25% NH3 (aqueous) as amine) and method G (using cyclohexanecarboxaldehyde), m.p. 178-180 ° C.

COMPOUND 43 1.1-3-Cyclohexyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 4-Sulfamoylantranilamide: Added to a stirred solution of ml of CISO3H 7.5 g (55 mmol) of anthranilamide in small portions. The reaction mixture was heated at 100 ° C for one hour and then poured into 300 ml of ice water. A precipitate formed, which was isolated by filtration and dried on the filter. The isolated solid was dissolved in 25% aqueous ammonia and stirred at room temperature overnight. The aqueous phase was washed with EtOAc and concentrated to 20 ml. The aqueous phase was saturated with NaCl (s) and extracted with 3 x 50 ml of THF. The combined organic fractions were evaporated to dryness and subjected to column chromatography to yield 13 mg of product. 1, 1-3-cyclohexyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide (43): 4-Sulfamoylantranilamide was transformed by method G (using cyclohexancarboxaldehyde. NMR with 1H (DMSO-de) 8.1 (1 H, br), 8.0, 1 H, d), 7.58 (1 H, dd), 7.3 (1 H, br), 7.05 (2H, br), 6.79 ( 1 H, d), 4.5 (1 H, m), 1.8-1.5 (6H, m), 1.2-1.0 (5H, m).

COMPOUND 44 1, 1-3-Cyclohexyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Amino-5-sulfamoylbenzenesulfonamide was transformed (see compound 1019 by the method G (using cyclohexanecarboxaldehyde), mp 252-254 ° C.

COMPOUND 45 1, 1-3-Methyl-7-dimethylsulfamoyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 1,1-Dioxy-3-methyl-7-dimethylsulphamoyl-1,2-dihydro-1,4-benzothiadiazine 1,1-dioxide was reduced by using the F method; p.f. 210-212 ° C.

COMPOUND 46 2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazolin-n.n-dimethylsulfonamide To a solution of 3 g (25 mmol) of 2-aminobenzylamine in 50 ml of THF, 3.8 ml (27 mmol) of trifluoroacetic acid anhydride was added and stirred at room temperature for two hours. The reaction mixture was evaporated to dryness, stirred with water and filtered.

The crude product was transformed by method A (using dimethylamine as amine), method D and method G (using cyclohexanecarboxaldehyde); p.f. > 300 ° C. MS (electrospray) M + 323. 1 H NMR (DMSO-d 6): 7.2 (1 H, dd), 7.1 (1 H, d), 6.68 (1 H, br), 6.62 (1 H, d), 3.85 ( 1 H, s), 3.8 (2 H, s), 2.2 (1 H, br), 1.8-1.0 (11 H, m).

COMPOUND 47 1, 1-3-Cyclohexyl-7-dimethylaminosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material, for the following transformation sequence: E method (using cyclohexanecarbonyl chloride), method A (using dimethylamine as amine), method F; p.f. 243-245 ° C. v COMPOUND 48 1.1 -3-Cyclohexyl-7- (n.n-diethylamino) sulfonyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material, for the following transformation sequence: method E (using cyclohexanecarbonyl chloride), method A (using diethylamine as amine), method F; p.f. 207-209 ° C.

COMPOSITE 49 * 1, 1-3-Cyclohexyl-7-pyrrolidinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method E (using cyclohexanecarbonyl chloride), method A (using pyrrolidine as the amine); method F; p.f. 244-246 ° C.

COMPOUND 50 1, 1-3-Methyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material, for the following transformation sequence: method C, method A (using piperidine as amine), method D, method G [using para-aldehyde and a catalytic amount of TsOH]; p.f. 255-256 ° C.

COMPOUND 51 1, 1-3-Cyclopropyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material, for the following transformation sequence: method C, method A (using piperidine as amine), method D, method G [using cyclopropancarboxaldehyde]; p.f. 228-231 ° C.

COMPOUND 52 1, 1-3-Isopropyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method C, method A (using piperidine as the amine), method D, method G [using isobutyraldehyde], m.p. 237-239 ° C.

COMPOUND 53 1.1-3-Propyl-7-piperidinesulfonyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method C, method A (using piperidine as the amine), method D, method G [using butyraldehyde], m.p. 147.4-151.2 ° C.

COMPOUND 54 1.1 -3-Benzyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method C, method A (using piperidine as the amine), method D, method G [using phenylacetaldehyde], p. F. 242-244 ° C.

COMPOUND 55 1.1-3-Cyclopentyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide Cyclopentanecarboxaldehyde: To a stirred solution of 2.16 ml (20 mmol) of cyclopentanecarboxylic acid in 50 ml of dry THF, at room temperature, under nitrogen, was added 2.28 g (60 mmol) of NaBH and was allowed to stir for 20 minutes. The reaction mixture was cooled to 0 ° C and 10 ml (80 mmol) of BF3OEt2 was added during one hour, while maintaining the reaction temperature below + 3 ° C. The reaction mixture was allowed to warm to room temperature and was left stirring overnight. To the reaction mixture was added saturated aqueous sodium bicarbonate, water and extracted with ethyl acetate. It was washed with saturated aqueous sodium chloride, the combined organic fractions, dried over sodium sulfate and evaporated to dryness to give 1.4 g of an oil which was used without further purification. 1.4 g of the oil was dissolved in 75 ml of methylene chloride and 30 g (30 mmol) of PCC was added to AI2O3 [see Cheng YS Liu, WL and Chen SH, Synthesis, 1980), 223], and the Ambient temperature with stirring for one hour. The reaction mixture was filtered and the filtrate was evaporated on silica. Column chromatography yielded the pure aldehyde, which was used as a solution in methylene chloride. 1, 1-3-cyclopentyl-7-piperidinesulfonyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (55): 2-aminobenzenesulfonamide was used as the starting material for the following transformation sequence : method C, method A (using piperidine as the amine), method D, method G [using cyclopentancarcoxaldehyde], mp 258-260 ° C.

COMPOUND 56 1, 1-3-Cyclohexyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method E, (using cyclohexanecarbonyl chloride), method A (using piperidine as the amine), method F; p. F. 262-264 ° C.

COMPOUND 57 1.1 -3-bichloride2.2.1lhept-5'-en-2'-yl-7-piperidinosulfonyl-1,2.3.4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method C, method A (using piperidine as the amine), method D, method G (using a racemic endo / exo mixture of 2-norbornecarboxaldehyde). Two separate diastereomeric mixtures were isolated, with m.p. (A) 240-242 ° C and p. F. (B) of 234-238 ° C.

COMPOUND 58 1.1-3-Cyclohexyl-7- (1 '.2'.3'.6'-tetrahydropiperidino) sulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method E (using cyclohexanecarbonyl chloride), method A (using 1, 2,3,6-tetrahydropyridine as the amine), method F; p. F. 237-239 ° C.

COMPUJEST 59 1, 1-3-Cyclohexyl-7- (n-methyl-n-phenylamino) sulfonyl-1, 2,3,4-tetrahydro-1,4-benzodiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method E (using cyclohexanecarbonyl chloride), method A (using N-methylaniline as the amine), method F (mp 210-212 ° C.

COMPOUND 60 1.1 -3-Cyclohexyl-7- (.2'.3'-4'-tetrahydroquinolinyl)) sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: method E (using cyclohexanecarbonyl chloride), method A (using 1, 2,3,4-tetrahydroquinoline as the amine), method F; p.f. 218-220 ° C.

COMPOUND 61 3-Cyclohexyl-7- (4'-methylpiperazino) sulfonyl-1,2,3,4-tetrahydro-1,2,4- benzothiadiazine 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method C, method A (using N-methylpiperazine as the amine), method D, method G (using cyclohexanecarboxaldehyde), m.p. 227-229 ° C. Methanesulfonate salt of (61): 0.6 g (1.4 mmol) of 61 was dissolved in 30 ml of 99% EtOH and a solution of 1 M of CH3SO3H in 99% EtOH was added. The mixture was left for precipitation for two hours and the salt was isolated by filtration. The composition of the salt was checked by HPLC for stability, compared to the free base. The salt was found to be stable to hydrolysis under these conditions and had a solubility in water of 10 mg / ml.

COMPOUND 62 1.1 -3-Cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl-1,2.3.4- tetrahydro-1,2,4-benzothiadiazine dioxide N-mesylpiperazinium chloride.- To a stirred solution of 4.3 g (50 mmol) of piperazine in 50 ml of methylene chloride, at + 5 ° C, a solution of 4.25 ml (55 mmol) of CH3CH2CI in 15 ml was added. of methylene chloride. The reaction mixture was stirred at room temperature for 12 hours, 100 ml of methylene chloride was added and extracted with 300 ml of 1M HCl. A precipitate formed in the aqueous phase, which was filtered to give 2.66. g of N-mesylpiperazinium chloride (32%). 1, 1-3-cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (62): 2-aminobenzenesulfonamide was used as starting material for the following transformation sequence: E method (using cyclohexanecarbonyl chloride), method A (using N-mesylpiperazinium chloride (1.5 eq), 3 equivalents of potassium carbonate was used for neutralization); method F, p. F. 272-274 ° C.

COMPOUND 63 1.1 -3-Cyclohexyl-7-morpholinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: E method (using cyclohexanecarbonyl chloride), method A (using morpholine as the amine), method F (p.p. 262-264 ° C.

COMPOUND 64 1.1 -3-bicyclochloride.2.2.nhept-5'-en-2'-yl-7-bromo-1.2.3.4-tetrahydro-1,2,4-benzothiadiazine dioxide -Bromo-2-aminobenzenesulfonamide (see compound 18) was transformed by method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-en-2-carboxaldehyde), p. F. 200-204 ° C.

COMPOUND 65 2-Methyl-4-oxo-3,4-dihydro-6-quinazolin-n.n-dimethylsulfonamide 2-methyl-4-oxo-3,4-dihydroquinazoline: A solution of 13.6 g (100 mmol) of anthranilamide in 100 ml of acetic acid was allowed to reflux for 60 hours. The reaction mixture was evaporated to dryness, suspended in water, filtered and washed thoroughly with sodium bicarbonate until the filtrate had a pH of 8-8.5. 2-methyl-4-oxo-3,4-dihydro-6-quinazolin-N, N-dimethylsulfonamide. 2-Methyl-4-oxo-3,4-dihydroquinazoline was transformed by method A (using dimethylamine as the amine), m.p. 264-266 ° C COMPOUND 66 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinesulfonamide 2-Trifluoroacetamidobenzamide (see compound 68) was transformed by method A (using 0.5 M NH3 in THF as the amine), p. F. 311-314 ° C.

COMPOUND 67 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin-n.n-dimethyl-sulfonamide 2-Trifluoroacetamidobenzamide (see compound 68) was transformed by method A (using dimethylamine as the amine), p. F. 257-258 ° C.

COMPOUND 68 2-Trifluoromethyl-4-oxo-3,4-dirtidro-6-quinazolin-1 ', 2 *, 3', 6'- tetrahydropiperidinosulfonamide To a stirred mixture of 13.6 g (100 mmol) of anthranilamide in 100 ml of THF at 0 ° C was added 15.2 ml (110) mmol of trifluoroacetic acid anhydride and allowed to warm to room temperature, and then left Waving during the night. The reaction mixture was evaporated to dryness; it was suspended in water and filtered. The isolated solid was air dried to give 21.6 g (93%) of 2-trifluoroacetamidobenzamide. The 2-trifluoroacetamidobenzamide was transformed by method A (using 1, 2,3,6-tetrahydropyridine as the amine), p. F. 227-230 ° C.

COMPOUND 69 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoln-n-cyclohexyl-sulfonamide 2-Trifluoroacetamidobenzamide (see compound 68) was transformed by method A (using cyclohexylamine as the amine), p. F. 261-263 ° C.

COMPOUND 70 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinmorpholino sulfonamide 2-Trifluoroacetamidobenzamide (see compound 68) was transformed by method A (using morpholine as the amine), p. F. 282-285 ° C.

COMPOUND 71 2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazolin-n.n-dimethyl-sulfonamide Anthranilamide was used as the starting material for the following transformation sequence: method A (using 25% NH3 (aqueous) as the amine). The reaction mixture contained both 5-mono- and 5,7-disulfonamide, which were separated by chromatography); G method (using cyclohexanecarboxaldehyde, the amine is autooxidated to the aromatic hydroxyquinazoline), p. F. 306-310 ° C.

COMPOUND 72 1.1-3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiazine-zine dioxide 1, 1-3-Methyl-1,2-dihydro-1,4-benzothiadiazine dioxide (see compound 73) was transformed by method A (using 0.5M NH 3 in THF, as the amine), . F. 295-297 ° C.

COMPOUND 73 1,1-3-Methyl-7-dimethylsulfamoyl-1,2-dithiazole-1,2,4-benzothiadiazine dioxide Refluxing in AcOH for 5 days was 17.2 g (100 mmol) of 2-aminobenzenesulfonamide. The formed precipitate was isolated by filtration and washed with water to give 17.8 g (91%) of 1,1-3-methyl-1,2-dihydro-1,4-benzothiadiazine dioxide. The 1,1-methyl-1,2-dihydro-1,4-benzothiadiazine 1,1-dioxide was transformed by method A (using dimethylamine as the amine), p. F. 260-261 ° C.

COMPOUND 74 1.1 -3-Methyl-7-1 *, 2 * .3 * .6'-tetrahydropiperidino) sulfonyl-1,2-dihydro-1, 2,4-benzothiadiazine dioxide 1, 1-dioxide of 3-methyl-1,2-dihydro-1, 2,4-benzothiadiazine (see compound 73) was transformed by method A (using 1, 2,3,6-tetrahydropiperidine as the amine) , p. F. 265-268 ° C.

COMPOUND 75 1.1-3-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-1,4-benzothiadiazine dioxide 1, 1-Dioxide of 3-methyl-1,2-dihydro-1, 2,4-benzothiadiazine (see compound 73) was transformed by method A (using cyclohexylamine as the amine), p. F. 239-242 ° C.

COMPOUND 76 1.1-3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method C and method A (using dimethylamine as the amine), p. F. 240-242 ° C.

COMPOUND 77 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-sulfonic acid 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method C and method A (using NaOH instead of an amine), p. F. > 330 ° C.

COMPOUND 78 1.1-3-Cyclohexyl-8-methyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide M-toluidine was used as the starting material for the following transformation sequence: method B [2-amino-6-methylbenzenesulfonamide from 2-amino-4-methylbenzenesulfonamide was removed by recrystallization (from ethyl acetate / hexane)]. 2-Amino-6-methylbenzenesulfonamide was further purified by means of column chromatography and transformed by the method G (using cyclohexanecarboxaldehyde), p. F. 228-230 ° C.

COMPOUND 79 1.1-3-Cyclohexyl-8-hydroxymethyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -chloro-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazin-1,1-dioxide-8-carboxylic acid. To a solution of 1,1-dioxide of 0.30 g (1.0 mmol) of 5-chloro-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazine (see compound 80) in 15 ml of dry THF , at -78 ° C, 1.3M of s-BuLi was added in 1.6 ml (2.1 mmol) of cyclohexane, under nitrogen. The yellow mixture was stirred for 15 minutes at -78 ° C and dry gaseous CO2 was bubbled through the solution for 30 minutes. The cooling bath was removed and the mixture allowed to warm to 0 ° C. The solvent was removed under reduced pressure and the residue was triturated with hydrochloric acid (0.2M, 12 ml). The crude product was recrystallized from 50% MeOH, which yielded 300 mg (82%) of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazin-1,1-dioxide- 8-carboxylic acid, as colorless crystals. 3-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazin-1,1-dioxide-8-carboxylic acid: 160 mg (0.47 mmol) of 5-chloro-3-cyclohexyl-1 acid was dissolved, 2-dihydro-1, 2,4-benzothiadiazin-1,1-dioxide-8-carboxylic acid in 50 ml of 99% EtOH and hydrogenated using 10 mg of 10% Pd / C under 1 baria pressure for 24 hours . 12 ml of 1 M NaOH was added and the mixture was filtered through a pad of Celite ™ and concentrated to 10 ml and concentrated hydrochloric acid was added slowly to precipitate the product, yielding 10 mg (76%). ) of 3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazin-1,1-dioxide-8-carboxylic acid, as a colorless powder. 1,1-cyclohexyl-8-hydroxymethyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (79): 2M NaBH4 was dissolved in 0.75 ml (1.5 mmol) of triglyme in 20 ml of dry tetrahydrofuran, and cooled to -50 ° C, under nitrogen. 0.25 ml (2.0 mmol) of BF3 etherate was added and the mixture was stirred for 10 minutes at -50 ° C. 170 mg (0.55 mmol) of solid 3-cyclohexyl-1,2-dihydro-1,4-benzothiadiazin-1,1-dioxide-8-carboxylic acid was added in one portion and the suspension was stirred for six hours. hours at -50 ° C and overnight at 20 ° C. The mixture was hydrolysed with 1 M, 2 ml of hydrochloric acid and the solvent was removed under reduced pressure. The residue was extracted with 50 ml of EtOAc and the organic layer was washed with 10 ml of brine, dried over sodium sulfate and evaporated to dryness. The product was purified by flash chromatography on silica, using ethyl acetate / n-hexane (2: 1 v / v) as eluent, which yielded 100 mg (62%) of 1,1-dioxide of 3-cyclohexyl- 8-hydroxymethyl-1,2-dihydro-1,4-benzothiadiazine. The product was further transformed by the method F, p. F. 220-223 ° C.

COMPOUND 80 1.1-3-Cyclohexyl-8- (2-methoxyphenyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 1, 1-5-chloro-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazine dioxide: 3-Chloroaniline was used as the starting material for the following transformation sequence: method B, followed by the Method E (using cyclohexylcarbonyl chloride). 1, 1-dioxide 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1, 2,4-benzothiadiazine: To a solution of 596 mg (2 mmol) of 1,1-dioxide of 5 -chloro-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiadiazine in 20 ml of dry THF, at -78 ° C, 1.3M of s-BuLi was added in 3.8 ml (5 mmol) of cyclohexane , under nitrogen. The yellow mixture was stirred for 15 minutes at -78 ° C and a solution of 1.27 g (5 mmol) of iodine in 5 ml of dry THF was added. The cooling bath was removed and the mixture allowed to warm to 0 ° C. 20 ml of 5% sodium bisulfate was added and extracted with 2 c 30 ml of ethyl acetate, dried over sodium sulfate and evaporated to dryness, to give 0.76 g (90%) of 1,1-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2-dioxide, 4-benzothiadiazine. 7,1-5-chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1, 2,4-benzothiadiazine dioxide: A mixture of nitrogen was allowed to reflux under nitrogen for two hours. 290 mg (0.68 mmol) of 1,1-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1, 2,4-benzothiadiazine 1,1-dioxide, 122 mg (0.80 mmol) of 2-methoxyphenylboronic acid , 10 mg (2 mol%) of Pd (PPh3) 2Cl2 in 50 ml of 1,2-dimethoxyethane and 2M sodium carbonate (2 ml, 4 mmol). The solvents were removed under reduced pressure and the residue was extracted with 2 x 40 ml of EtOAc and the organic layer was washed with 20 ml of saturated sodium bicarbonate, dried over sodium sulfate and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica, using ethyl acetate / n-hexane (1: 2 v / v) as eluent, which yielded 200 mg (73%) of 5-chloro-1,1-dioxide. 3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1, 2,4-benzothiadiazine, as colorless crystals. 1,1-3-cyclohexyl-8- (2-methoxyphenyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (80): 190 mg (0.47 mmol) of 1 was dissolved 1-5-chloro-3-cyclohexyl-8- (2-methoxyphenyl) -1,2-dihydro-1, 2,4-benzothiadiazine dioxide in 30 ml of 99% EtOH and hydrogenated using 10 mg of Pd / C (at 10%) at a pressure of 1 bar. The mixture was filtered through a pad of Celite ™ and the solvent was removed under reduced pressure, which yielded 174 mg (100%) of 1,1-chloro-3-cyclohexyl-8- (2-1-dioxide) meoxyphenyl) -1,2-dihydro-1, 2,4-benzothiadiazine, as colorless crystals. The product was transformed by the F method; p.f. 100-105 ° C.

COMPOUND 81 1.1-3-Cyclohexyl-8- (3-methoxyphenyl) -1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide Synthesis as for compound 870 (using 3-methoxyphenylboronic acid for cross coupling catalysed with Pd), p. F. 108-115 ° C.

COMPOUND 82 1.1-3-Cyclohexyl-8- (2-pyridiD-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide) 1, 1-5-chloro-3-cyclohexyl-8- (dihydroxyboron) -1,2-dihydro-1, 2,4-benzothiadiazine dioxide: To a solution of 0.60 g (2.0 mmol) of 1,1-dioxide of 5-chloro-3-cyclohexyl-1,2-dihydro-1, 2,4-benzothiazine (see compound 80) in 15 ml of THF at -78 ° C, 1.3M of s-BuLi was added to 3.8 ml (5 mmol) of cyclohexane, under nitrogen. The yellow mixture was stirred for 15 minutes at -78 ° C and 0.57 ml (5 mmol) of B (OCH3) 3 was added. The cooling bath was removed and the mixture was allowed to warm to 0 ° C and stirred for another hour. The mixture was hydrolyzed with 0.5M, 12 ml of hydrochloric acid and extracted with 2 x 50 ml of EtOAc, dried over sodium sulfate and evaporated to dryness to give 0.65 g (95%) of 1,1-dioxide. of 5-chloro-3-cyclohexyl-8- (dihydroxyboronyl) -1,2-dihydro-1, 2,4-benzothiadiazine. 1, 1-5-chloro-3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1, 2,4-benzothiadiazine dioxide: A mixture of nitrogen was left under reflux for 24 hours. 440 mg (1.28 mmol) of 1,1-chloro-3-cyclohexyl-8- (dihydroxyboronyl) -1,2-dihydro-1,4-benzothiazine, 1, 1 dioxide, 0.14 ml (1.50 mmol) ) of 2-bromopyridine, 10 mg (2 mol%) of Pd (PPh3) 2CI2 in 30 ml of 1,2-dimethoxyethane and 2M, 3 mol (6 mmol) of sodium carbonate. The solvents were removed under reduced pressure and the residue was treated with 10 ml of saturated NH 4 Cl and extracted with 2 x 40 ml of EtOAc. The organic layer was washed with 20 ml of water, dried over sodium sulfate and the solvent was removed under reduced pressure. The product was purified by flash chromatography on silica, using ethyl acetate / n-hexane (2: 1 v / v) as eluent, which yielded 280 mg (58%) of 1,1-chloro-1-dioxide. 3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1, 2,4-benzothiadiazine as colorless crystals. 3-cyclohexyl-8- (2-pyridyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine (82): 0.268 g (0.713 mmol) of 1,1-dioxide of 5- was dissolved. chloro-3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1, 2,4-benzothiadiazine in 50 ml of 99% EtOH and hydrogenated using 10 mg of 10% Pd / C, a pressure at 4 bars, for 24 hours. The mixture was filtered through a pad of Celite ™ and the solvent was removed under reduced pressure. The residue was dissolved in 50 ml of EtOAc and washed with phosphate buffer (pH = 7.10 ml), dried over sodium sulfate and the solvent was removed under reduced pressure, yielding 200 mg (82%) of 1 , 3-cyclohexyl-8- (2-pyridyl) -1,2-dihydro-1, 2,4-benzothiadiazine 1-dioxide, as colorless crystals. The product was further transformed by the method F, p. F. 200-203 ° C.

COMPOUND 83 1.1-3-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide M-Anisidine was used as the starting material for the following transformation sequence: Method B [2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc / hexane)] and then method G ( using cyclohexanecarboxyaldehyde), p. F. 221-223 ° C.

COMPOUND 84 1.1-5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine dioxide 2-Amino-3,5-dibromobenzenesulfonamide was transformed by the method G (using ethyl formate and a catalytic amount of triethylamine), p. F. 289-292 ° C.

COMPOSITE 85 AND COMPOUND 86 1.1-3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine (85) dioxide and 1,1-cyclohexyl-3-dioxide 4-methyl-7- morpholinosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine (86) 1,1-3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,4-benzothiadiazine dioxide: 2-aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method E (using cyclohexancarbonyl chloride) and method A (using morpholine as the amine), which gave 1, 1-dioxide of 3-cyclohexyl-7-morpholinesulfonyl-1,2-dihydro-1, 2,4-benzothiadiazine. 1, 1-3-cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2-dihydro-1, 2,4-benzothiadiazine dioxide and 1,1-cyclohexyl-4-methyl-7-morpholinosulfonyl dioxide 1,2-dihydro-1, 2,4-benzothiadiazine A mixture of 2 g (5 mmol) of 1,1-dioxo-3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro was cooled to 0 ° C. -1, 2,4-benzothiadiazine, 2.35 ml (15 mmol) of DEAD, 4 g (15 mmol) of PPh3 in 30 ml of dry THF, and 1.25 ml (30 mmol) of MeOH were added. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, stirred with EtOAc and filtered. The isolated precipitate was stirred with methylene chloride and filtered to give the methyl 2-isomer in the filtrate and the 4-methyl isomer as a precipitate. The 4-methyl isomer was purified by recrystallization from DMSO / water. The 2-methyl isomer was purified by column chromatography (EtOAc). 1, 1-dioxide, 3-cyclohexyl-2-methyl-7-morpholinesulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine (85): 1,1-3-cyclohexyl dioxide was reduced -2-methyl-7-morpholinesulfonyl-1,2-dihydro-1,4-benzothiadiazine by using method F, p. F. 243-245 ° C. 7, 1-3-cyclohexyl-4-methyl-7-morpholinesulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (86): 1,1-3-cyclohexyl dioxide was reduced -4-methyl-7-morpholinesulfonyl-1,2-dihydro-1,4-benzothiadiazine by using method F, p. F. 207-210 ° C.

COMPOUND 87 5.5-7-Methylsulfonylamino-1.2.3.3.4.4-hexahydrobenzo dioxide relpirrolof2.1 -c11, 2,4-thiadiazine dioxide 1,2,3,5-tetrahydrobenzo [e] pyrrolo [2, 1-c] -1,2,4-thiadiazine 5,5-dioxide: 2-aminobenzenesulfonamide was transformed by the E method (using 4-chloride) chlorobutanoyl). 5, 5-dioxide of 7-nitro-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2, 1-c] -1, 2,4-thiadiazine: It was added to a stirred solution of 222 mg (1 mmol) of 1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1,5, 2,4-thiadiazine-5-dioxide in 2 ml of sulfuric acid at 5 ° C, a solution of 122 mg (1.2 mmol) of KNO3 in 2 ml of sulfuric acid. The reaction mixture was allowed to warm to room temperature and was stirred for two hours. The reaction mixture was poured into ice water, filtered and air dried to give 190 g of product (71%). 5, 5-amino-1,2,3,5-tetrahydrobenzo [e] pyrrolo [2, 1-c] -1, 2,4-thiadiazine: It was added to a stirred solution of 167 mg (0.6 mmol) of 5-nitro-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,5,4-thiadiazine 5,5-dioxide in 2 ml of THF dry, at -50 ° C, 115 mg (3 mmol) of L1AIH4 in a single portion. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched by adding water and 10M NaOH, stirred, filtered through Celite and evaporated to dryness, to give 150 mg of product. 5, 5-dimethyl-7-methylsulfonylamine-1, 2, 3, 3a, 4, 5-hexahydro-benzo [e] pyrrolo [2,1-c] -1,2,4-thiadiazine (87): added to a stirred solution of 150 mg (0.5 mmol) of 5-amino-1, 2,3,3a,5,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,5,5-dioxide, 2,4-thiadiazine and 70 μl (0.5 mmol) of triethylamine in 1 ml of THF, a solution of 40 μl (0.5 mmol) of CH3SO2CI in 1 ml of THF, and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, suspended in water and extracted with EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg of product, e.g. F. 177-180 ° C.

COMPOUND 88 5.5-7-Slfamoyl-1,2,3,3a, 4,5-hexahydrobenzore-1-pyrrolo f2,1-c1- 1,2,4-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using 0.5M NH3 in THF, as the amine), method F (using LiAIH4 and temperature environment), p. F. 260-262 ° C.

COMPOUND 89 5.5-7-Methylsulfamoyl-1,2,3,3a, 4,5-hexahydrobenzore-1-pyrrolor-2,1-cl-1,2,4-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using methylamine as the amine, method F (using LiAIH4 h at room temperature), mp 244-245 ° C.

COMPOUND 90 5.5-7-Cyclohexylsulfamoyl-1, 2,3.3a.4.5- hexahydrobenzore] pyrrolof2,1 -cl-1, 2,4-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using cyclohexylamine as the amine), method F (using L¡AIH4 and room temperature), p. F. 195-197 ° C.

COMPOUND 91 5,5-7-Dimethylsulfamoyl-1, 2,3,3a.4.5-hexahydrobenzore-1-pyrrolof2,1-cl-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using dimethylamine as the amine), method F (using LiAIH4 and room temperature), p. F. 240-243 ° C.

COMPOUND 92 5.5-7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzore1 pyrrolor2,1-c1- 1.2.4-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using methylamine as the amine), p. F. 244-247 ° C.

COMPOUND 93 5.5-7-Dimethyl-sulphamoyl-1, 2,3,5-tetrahydrobenzofel pyrrolor-2-c * | - 1.2.4-thiadiazine dioxide 2-Aminobenzenesulfonamide was transformed by the method E (using 4-chlorobutanoyl chloride) and method A (using dimethylamine), p. F. 251-253 ° C.

COMPOUND 94 5.5-7-Cyclohexylsulfamoyl-1, 2,3,5-tetrahydrobenzo pyrroloß.l-cl-1, 2,4-thiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using cyclohexylamine as the amine), m.p. 151-153 ° C.

COMPOUND 95 5.5-Dioxide of 7- (1 '.2'.3'.6'-tetrahydropiperidino) sulfonyl-1.2.3.5- tetrahydro-benzolepyrrolor2.1-cl-1, 2,4-thiadiazine 2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride), method A (using 1, 2,3,6-tetrahydropyridine, as the amine), p. F. 204-206 ° C.

COMPOUND 96 1.1 -3-bicyclochloride.2.2phept-5'-en-2 * -il-5,7-dimethyl-1.2.3.4- tetrahydro-1, 2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: Method B, method G [using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-en-2-carboxaldehyde. Column chromatography gave two diastereomeric fractions, each of which is a mixture of two diastereomers]. Isomeric mixture A, p. F. 160-165 ° C; isomeric mixture B, m.p. 182-187 ° C.

COMPOUND 97 1.1-3-Cyclohexyl-7- (n.n-diethylsulfamoyl) -5-methyl-1,2.3.4-tetrahydro-1, 2,4-benzothiadiazine dioxide 1, 1-3-cyclohexyl-7- (N, N-diethylsulfamoyl) -5-formyl-1,2-dihydro-1, 2,4-benzothiadiazine dioxide: 2-aminobenzenesulfonamide was used as starting material for the following Transformation sequence: Method E (using cyclohexanecarbonyl chloride) and method A (using diethylamine as the amine). To 0.60 g (1.5 mmol) of the transformation product, dissolved in 15 ml of dry THF, at -78 ° C, 1.3 M of s-BuLi in 2.5 ml (3.2 mmol) of cyclohexane) was added under nitrogen. The yellow mixture was stirred for 25 minutes at -78 ° C. The reaction was quenched with 0.3 ml (4 mmol) of dry DMF and the mixture was stirred for 20 minutes at -78 ° C. The cooling bath was removed and the mixture allowed to warm to 0 ° C. 0.5M, 10 ml of hydrochloric acid was added and the mixture was extracted with 40 ml of EtOAc. The organic layer was washed with 10 ml of brine, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in 8 ml of acetone. 30 ml of Et2O was added and in a few minutes the product crystallized, which produced 0.41 g (64%) of 1,1-cyclohexyl-7- (N, N-diethylsulfamoyl) -5-formyl-1-dioxide, 2-dihydro-1, 2,4-benzothiadiazine, as colorless crystals. 1, 1-3-cyclohexyl-7- (N, N-diethylsulfamoyl) -5-methyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (97): 0.20 g was dissolved ( 0.46 mmol) of 1,1-cyclohexyl-7- (N, N-diethylsulfamoyl) -5-formyl-1,2-dihydro-1, 2,4-benzothiadiazine 1,1-dioxide in 60 ml of 99% EtOH %. A small drop of concentrated hydrochloric acid was added to ensure full hydrogenation. The mixture was hydrogenated using 10 mg of 10% Pd / C, under pressure of 4 bar, for 24 hours. The mixture was filtered through a pad of Celite ™ and evaporated to dryness. The residue was dissolved in 50 ml of EtOAc and washed with 10 ml of water, dried over sodium sulfate and evaporated to dryness, which yielded 0.18 mg (95% of 1,1-cyclohexyl-7-dioxide). - (N, N-diethylsulfamoyl) -5-methyl-1,2-dihydro-1, 2,4-benzothiadiazine, as a colorless powder The product was further transformed by the method F.p.p. 206-208 ° C.

COMPOUND 98 1.1-3-bicyclic2.2.phept-5 * -en-2'-yl-5,7-diphenyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 3,5-Dibromo-2-aminobenzenesulfonamide (see compound 125) was transformed by method H (using phenylboronic acid) and method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-ene- 2-carboxaldehyde (mp 222-225 ° C.

COMPOUND 99 1.1-3-Bicyclochloride.2.2n-5'-en-2'-yl-5,7-disulfamoyl-1.2.3.4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Aminobenzenesulfonamide was transformed by method A (using 25% aqueous NH3 as the amine) and method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-en-2-carboxaldehyde), p. F. 172-180 ° C.

COMPUEST0 100 1.1 -3-bicyclic2.2.nhept-5'-en-2'-yl-5,7-dichloro-1.2.3.4-tetrahydro-1,2,4-benzothiadiazine dioxide 2,4-Dichloroaniline was transformed by method B and method G (using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-ene-2-carboxaldehyde) The product was isolated as a diastereomeric mixture), p. F. 149-151 ° C.

COMPOUND 101 1.1-5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-amino-5-sulfamoylbenzenesulfonamide: A stirred suspension of 11.4 g (40 mmol) of 2-amino-4-chlorosulfamoylbenzenesulfonamide and 750 mg of 10% Pd / C in 300 ml of EtOH was hydrogenated to a baria, until the consumption of hydrogen ceased (24 hours). The reaction mixture was evaporated to dryness; was re-suspended in THF and filtered through Celite. The filtrate was evaporated to dryness and the isolated solid was washed with 2 x 150 ml of EtOAc to give 9.58 g (95%) of product. 2-amino-3-bromo-5-sulfamoylbenzenesulfonamide: To a stirred solution of 3.77 g (15 mmol) of 2-amino-5-sulfamoylbenzenesulfonamide in 50 ml of AcOH was added a solution of 0.78 ml (15 mmol) of Br 2 in 10 ml of AcOH. The reaction mixture was heated at 70 ° C for six days, evaporated to dryness, resuspended in 85 ml of MeOH and 3.8 g (68 mmol) of solid KOH was added. The reaction mixture was heated at 60 ° C for 2.5 hours (hydrolysis of the isomers 3-methyl-, 3-bromomethyl-, 3-dibromomethyl- and 3-tribromomethyl-1,2-dihydro-1, 2,4-benzodthiadiazine. , formed in situ), filtered, neutralized and evaporated to dryness. Column chromatography gave 3.1 g (63%) of product 1.1-5-bromo-3-cyclohexyl-7-sulfamino-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide ( 101): The 2-amino-3-bromo-5-sulfamoylbenzenesulfonamide was transformed by the method G (using cyclohexancarboxaldehyde), p. F. 254-258 ° C.

COMPOUND 102 2-Biciclor2.2.nhept-5'-en-2 -'- l-6.8-dibromo-1.2.3.4-tetrahydroquinoline 2-Amino-3,5-dibromobenzylamine: To a mixture of 6.1 g (50 mmol) of 2-aminobenzylamine in 100 ml of CHCl3, at 5.1 ° C, 5.1 ml of a solution of Br2 (100 mmol) was added at 45 ° C. ml of chloroform, so as to keep the reaction temperature below + 2 ° C. The cooling was then removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the precipitate was washed with EtOAc and purified by column chromatography. 2-bicyclo [2.2.1] hept-5'-en-2'-1-6, 8-dibromo-1 , 2, 3, 4-tetrahydroquinoline (102): 2-Amino-3,5-dibromobenzylamine was transformed, by the method G (using a racemic endo / exo mixture of 2-norbornecarboxaldehyde, mp 240 ° C .

COMPOUND 103 2-Biciclor2.2.nhept-5'-en-2'-il-6.8-dibromo-4-oxo-1.2.3.4- tetrahydroquinazoline 3,5-dibromoantranilamide: A solution of 10.3 ml of Br2 (0.2 mol) was added to a stirred suspension of 13.6 g (0.1 mol) of anthranilamide in 350 ml of AcOH. The reaction mixture was stirred at 45 ° C for 120 hours, poured into 1.5 liters of water and filtered. Recrystallization, (including hot filtration) from 96% ethanol (approximately 1 liter) gave 23.6 g (80%) of product. 2-bicyclo [2.2.1] hept-5'-en-2'-yl-6,8-dibromo-4-oxo-1, 2,3,4-tetrahydro-quinazoline (103): Transformed 3.5 -dibromoantranilamide by the method G, using a racemic endo / exo mixture of bicyclo [2.2.1] hept-5-en-2-carboxal-dehyde). The product was separated to individual diastereomeric mixtures; p.f. (A) 213-215 ° C; p.f. (B) 209-210 ° C.

COMPOUND 104 1.1-3-bicyclic2.2.nhept-5'-en-2'-yl-5,7-dibromo-1.2.3.4-tetrahydro-1,2,4-benzodiadiazine dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by the method G (using a racemic endo / exo mixture of bicyclo [2.2.1 [hept-5-en-2-carboxaldehyde]. The diastereomeric mixture was purified by column chromatography to give three of the four theoretically possible diastereomers; p.f. (a) 202-206 ° C; p.f. (b9 196-199 ° C, p.f. (C): 180-184 ° C.

COMPOUND 105 1.1-5,7-Dibromo-3-bicyclic dioxide 2,1-lheptan-2'-yl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide Bicyclo [2.2.1] heptan-2-carboxaldehyde: stirred at 2-3 ° C for one hour, a stirred suspension of 0.5 ml (5.8 mmol) of 2-norbomilmethanol and PCC on AI2O3 [see Cheng Y., S. Liu, W. L and Chen SH, Synthesis (1980) 223], in 25 ml of methylene chloride; and then allowed to warm slowly to room temperature. The reaction mixture was filtered and the solid material was washed with 2 x 25 ml of methylene chloride. The combined organic fractions were adsorbed on silica and chromatographed to give 300 mg (42%) of the product, as an oil. 1, 1-5, 7-dibromo-3-norbornyanil-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (105): 2-Amino-3,5-dibromobenzenesulfonamide was converted (see compound 125) by the method G (using bicyclo [2.2.1] heptane-2-carboxaldehyde), p. F. 182-183 ° C.

COMPOUND 106 1.1-3-Cyclohexyl-5,7-dibromo-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by the method G (using cyclohexanecarboxaldehyde), m.p. 166-167 ° C.

COMPOUND 107 1.1-3-Adamantyl-5,7-dibromo-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 1 - . 1-adamantanecarboxaldehyde: 1-adamantylmethanol was oxidized by the method used for 2-norbomilmethanol (see compound 105) [see Cheng Y., S. Liu, W.L and Chen S.H., Synthesis (1980) 223]. 1,1-adamantyl-5,7-dibromo-1, 2,3,4-tetrahydro-1,4-benzothiadiazine 1,1-dioxide: 2-Amino-3,5-dibromobenzenesulfonamide was transformed by the Method G (using 1-adamantylcarboxaldehyde), p. F. 270-273 ° C.

COMPOUND 108 1,1-3-Phenyl-5,7-dibromo-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by the method G (using benzaldehyde), m.p. 186-189 ° C.

COMPOUND 109 1.1-3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide A stirred mixture of 666 mg (2 mmol) of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125), 15 ml (90 mmol) of ethyl orthoformate and 0.05 ml of sulfuric acid was allowed to reflux overnight. . The reaction mixture was evaporated to dryness and subjected to column chromatography, m.p. 96-98 ° C.

COMPOUND 110 1.1-3-Methyl-5,7-dibromo-1,2-dihydro-1, 2,4-benzothiadia-zine dioxide A stirred solution of 660 mg (2 mmol) of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) in 25 ml (265 mmol) of Ac 2 O was left at reflux overnight. The reaction mixture was poured into ice and filtered. The isolated solid was washed with ether; p. F. 287-289 ° C.

COMPOUND 111 1.1-3-Cyclohexyl-6-methyl-7- (2'-pyridyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide To a 1.7M solution of t-BuLi in 25 ml (42 mmol) of pentane, in dry THF, at -78 ° C, 1.9 ml (20 mmol) of bromopyridine was added, at a rate such that the temperature did not exceed -70 ° C. The mixture was stirred for another 30 minutes at -78 ° C. A 2M solution of ZnC'2 in 30 ml (60 mmol) of THF was slowly added; and the cooling bath was removed and heated to 20 ° C. 1.0 g (3.2 mmol) of 5-iodo-2-aminobenzenesulfonamide and 0.3 g (8 mol%) of Pd (PPh3) 4 were added and the mixture was refluxed for six hours. THF was evaporated and the residue was treated with 53 g (0.18 mol) of EDTA and made slightly basic (pH = 8-9) with 1 M NaOH, followed by extraction with 3 x 100 ml) of EtOAc, drying over sulfate of sodium. The organic layer was concentrated to approximately 40 ml and n-hexane was slowly added. The product was filtered off, which yielded 0.72 g (87%) of 2-amino-4-methyl-5- (2-pyridyl) -1-benzenesulfonamide, as light yellow crystals. The product was further transformed by the method G (using cyclohexanecarboxaldehyde), m.p. 229-231 ° C.

COMPOUND 112 1.1 -3-Cyclo [ohexyl-6-methyl-7- (4'-triazolyl) -1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide -iodo-4-methyl-2-aminobenzenesulfonamide: m-toluidine was transformed by method B and the two isomers were separated by column chromatography to give 4-methyl-2-aminobenzenesulfonamide. To a stirred suspension of 620 mg (3.3 mmol) of 4-methyl-2-aminobenzenesulfonamide in 7 ml of chloroform was added a solution of 1.6 g (9.9 mmol) of iodine monochloride in 7 ml of chloroform. The reaction mixture was stirred at 0 ° C until the 1 H NMR spectrum indicated full conversion of the starting material. The reaction mixture was filtered and the isolated solid was washed with small volumes of chloroform, sodium bicarbonate (saturated aqueous), water and air dried to give 640 mg (62%) of product. 1,1-cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (112): 5-iodo- 4-methyl-2-aminobenzenesulfonamide by method I (using trimethylsilylacetylene) and method G (using cyclohexanecarboxaldehyde). FAB + 348; NMR with 1 H (DMSO-d6) 8.0 (1 H, br), 7.65 (1 H, br), 7.25 (1 H, s), 7.22 (1 H, s), 6.95 (1 H, br), 6.8 (1 H, s), 4.45 (1 H, dd), 2.35 (3H, s), 1.95-1.8 (2H, m), 1.8-1.6 (3H, m), 1.3-1.0 (6H, m).

COMPOUND 113 1.1-3-Cyclohexyl-6-methyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide N-acetyl-3-methylaniline: 10 ml (93 mmol) of m-toluidine was added to a stirred solution of 30 ml of acetic anhydride. The reaction mixture was stirred for 1.5 hours at room temperature, evaporated to dryness, stirred with water and filtered to give 13 g of product (94%). 1,1-cyclohexyl-6-methyl-7-sulfamyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide: N-acetyl-3-methylaniline was converted by method A (using 25% aqueous NH3 as amine, deacetylation completed) and method G (using cyclohexancarboxaldehyde), mp 231-233 ° C.

COMPOUND 114 1.1 -3-Cyclopentyl-6-methyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide Cyclopentanecarbonyl chloride: 0.55 ml (5 mmol) of cyclopentanecarboxylic acid was allowed to reflux in 1 ml of thionyl chloride for three hours. The reaction mixture was cooled to room temperature, evaporated to dryness and used directly without purification. 1, 1-3-cyclopentyl-6-methyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide (114): m-toluidine was used as the starting material for the following transformation sequence: Method B [2-Amino-6-methylbenzenesulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by means of recrystallization (ethyl acetate / hexane)]; E method (using cyclopentanecarbonyl chloride), method A (using piperidine as the amine), method F, p. F. 229-230 ° C.

COMPOUND 115 1.1-3-Cyclohexyl-6-methyl-7-morpholinesulfonyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide M-toluidine was used as starting material for the next transformation sequence. Method B [2-amino-6-methylbenzenesulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc / hexane)], method E (using cyclohexanecarbonyl chloride), method A (using morpholine as the amine), method F , p. F. 268-271 ° C.

COMPOUND 116 1.1-3-Cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 3-Bromo-4-methylaniline was transformed by method B. (The isomers were separated by fractional crystallization from MeOH) to give 2-amino-4-bromo-5-methylbenzenesulfonamide. A mixture of 100 mg (0.38 mmol) of 2-amino-4-bromo-5-methylbenzenesulfonamide, 76 mg (0.50 mmol) of 2-methoxyphenylboronic acid, (13 mg (5 mg) was allowed to reflux under nitrogen for four hours. % molar) of Pd (PPh3) 2Cl2 in 20 ml of 1,2-dimethoxyethane and 2M of Na2CO3 (1 ml, 2 mmol) The solvents were removed under reduced pressure and the residue was treated with 10 ml of sodium bicarbonate and extracted with 2 x 25 ml of EtOAc The organic layer was washed with 20 ml of brine, dried over sodium sulfate and the solvent was removed under reduced pressure The product was purified by flash chromatography on silica, using EtOAc: n -hexane (1: 1 in volume / volume) as eluent, which yielded 100 mg (90% of 2-amino-4- (2-methoxypheni) -5-methylbenzenesulfonamide as a colorless powder.) The product was transformed by the method G (using cyclohexancarboxaldehyde), m.p. 172-175 ° C.

COMPOUND 117 1.1-3-Cyclohexyl-6-methoxy-7-piperidinesulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide M-Anisidine was used as the starting material for the following transformation sequence: method B [2-amino-6-methoxybenzenesulfonamide was separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (ethyl acetate / hexane)] , method C, method A (using piperidine as the amine), method D, method G (using cyclohexancarboxaldehyde), p. F. 237-240 ° C COMPOUND 118 AND COMPOUND 122 1, 1-3-Cyclohexyl-7.8-ethylenedioxy-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine (122) and 1,1-dioxide dioxide of 3-cyclohexyl-6.7- ethylendioxy-1.2.3.4- tetrahydro-1, 2,4-benzothiadiazine (118) 6-Amino-1,4-benzodioxane was used as the starting material and it was transformed into a mixture of isomers of ethylene-2-aminobenzenesulfonamide, by using method B. The two isomers were separated by column chromatography. 1,1-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,4-benzothiadiazine 1,1-dioxide: 2-Amino-5,6-ethylenedioxybenzenesulfonamide was transformed by the Use of the G method (using cyclohexanecarboxyaldehyde, mp 196-200 ° C.1, 1-3-cyclohexyl-7,8-ethylenedioxy-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (122 ): 2-Amino-7,8-ethylenedioxybenzenesulfonamide was transformed using the method G (using cyclohexanecarboxyaldehyde), mp 268-270 ° C.

COMPOUND 119 1.1-3-Cyclohexyl-6-chloro-7-sulfamoyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-Amino-4-cyoro-5-sulfamoylbenzenesulfonamide was transformed by the method G (using benzaldehyde), p. F. 274-276 ° C.

COMPOUND 120 1, 1-3-phenyl-6-chloro-7-sulfamoyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide 2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide was transformed by the method G (using benzaldehyde), p. F. 235-238 ° C.

COMPOUND 121 1.1-3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide M-bromoaniline was used as the starting material for the following transformation sequence: method B [2-amino-6-bromobenzenesulfonamide, 2-amino-4-bromobenzenesulfonamide was separated by recrystallization (EtOAc / hexane)], method C, method A, (using piperidine as the amine), method D, method G (using cyclohexanecarboxaidehyde); p. F. 238-241 ° C.

COMPOSITE 122 See compound 118.

COMPOUND 123 2-Cyclohexylmethylamino-5-n, n-dimethylsulfamoylbenzenesulfon-amide 2-Aminobenzenesulfonamide was used as the starting material for the following transformation sequence: method E (using cyclohexanecarbonyl chloride), method A (using dimethylamine as amine), method F (The reaction mixture was left overnight with DIBALH at room temperature, with stirring); p. F. 123-125 ° C.

COMPOUND 124 2-Ethylamino-7- (1 ', 2'.3'.6'-tetrahydropiper8dino) sulfonylbenzenesulfonamide 1, 1-dioxide of 3-methyl-1,2-dihydro-1, 2,4-benzothiadiazine (see compound 73) was transformed by method A (using 1, 2,3,6-tetrahydropyridine as the amine), followed by method F (using L¡AIH4 and room temperature), p. F. 175-177 ° C.

COMPOUND 125 2-Amino-3,5-dibromobenzenesulfonamide It was added slowly to a stirred solution of 8.6 g (50 mmol) of 2-aminobenzenesulfonamide to a solution of 5.13 ml (100 mmol) of Br2 in 20 ml of AcOH. The reaction mixture was heated at 55 ° C for 60 hours, poured into 800 ml of ice water, filtered, adsorbed on silica and purified by column chromatography to give 1.1 g (67%) of product, p. F. 165-169 ° C.

COMPOUND 126 2-Acetamidobenzenesulfonamide To a stirred solution of 1.72 g (10 mmol) of 2-aminobenzenesulfonamide and 1.53 ml (11 mmol) of triethylamine in 25 ml of HF, at 0 ° C, 0.85 ml (12 mmol) of AcCl was added and allowed to stir at room temperature overnight. The reaction mixture was filtered and adsorbed on silica. Column chromatography gave 1.7 g (79%) of product, e.g. F. 153.5-155.5 ° C.

COMPOUND 127 1.1 - 3-Isobutyl-8- (piperidinosulfonyl) -2.3.4,5-tetrahydro-1,2,5-benzothiadiazepine dioxide N- (3'-methyl-1'-carboxybutyl) -2-nitrobenzenesulfonamide: It was added to a solution of 11 g (50 mmol) of 2-nitrobenzenesulfonyl chloride and 2.1 g (53 mmol) of NaOH in 100 ml of water , 6.55 g (50 mmol) of DL-leucine and left overnight, with stirring, at room temperature. To the reaction mixture was added 4M (12.5 ml) of NaOH and filtered. The filtrate was acidified with 50 ml of 1 M HCl and extracted with EtOAc. The combined organic fractions were dried over sodium sulfate and evaporated to dryness to give 6.7 g (42%) of product. 1, 1-dioxide of 3-isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazine: A stirred suspension of 6.7 g (21.2 mmol) of N- was hydrogenated at 1 bar. (3'-methyl-1'-carboxybutyl) -2-n-tetrabenzenesulfonamide and 200 mg of 10% Pd / C in absolute ethanol. The reaction mixture was filtered through Celite and evaporated to dryness. To a solution of the crude product in 50 ml of dry THF was added at 0 ° C N-hydroxysuccinimide (2.53 g (22 mmol) and 4.54 g (22 mmol) of DCC.The reaction mixture was slowly heated to room temperature and The reaction mixture was filtered and the solid material was washed with THF.The combined organic fractions were evaporated to dryness and water was added to the residue and extracted with EtOAc. The combined organic fractions were evaporated to dryness to give 3 g (53%) of the product.1,1-3-isobutyl-8-piperidinesulfonyl-2,3,4,5-tetrahydro-1, 2,5- dioxide. benzothiadiazepine To a solution of 500 mg (1.8 mmol) of 1,1-dioxido-3-isobutyl-4-oxo-2,3,4,5-tetrahydro-1, 2,5-benzothiadiazepine in 20 ml of dry THF, under nitrogen, at 0 ° C, a solution of 9.2 ml (18 mmol) of 2M of BH3.Sme in THF was added.After the addition was complete, the reaction mixture was heated to room temperature. ura environment and then at reflux for two hours. The reaction mixture was cooled to room temperature and carefully quenched by the addition of 15 ml of 5M HCl. The reaction mixture was made strongly alkaline by adding 7.5 M aqueous NaOH and extracted with EtOAc. The combined organic fractions were dried over sodium sulfate and evaporated to dryness to yield 320 mg (70%) of product. The product was transformed by method A (using piperidine as the amine), m.p. 209-21 1 ° C.

COMPOUND 128 1.1-3-Cyclohexyl-8- (piperidinosulfonyl) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine dioxide DL-cyclohexylglycine: To a solution of 15.9 g (0.32 mol) of NaCN, 17 g (0.32 mol) of NH 4 Cl was added followed by a solution of 37 ml (0.31 mol) of cyclohexanecarboxaldehyde in 60 ml of MeOH. The reaction mixture was stirred vigorously for two hours at room temperature. The reaction mixture was diluted with 100 ml of water and extracted with 2 x 70 ml of toluene. The combined organic phases were washed with 2 x 50 ml of water and extracted with 2 x 90 ml of 6M HCl. The acidic aqueous phase and the precipitate which was formed by acidification were combined and refluxed for 24 hours. The reaction mixture was cooled to room temperature and made slightly alkaline (using 25% NH3 (aqueous)). The precipitate formed, was isolated by filtration, washed with cold water and dried in air to give 13 g (26%) of the free amino acid. Compound 128 was synthesized by the method used for compound 127 (using as amino acid DL-cyclohexylglycine).

COMPOUND 129 1.1-3-Cyclohexyl-7-cyclopentylsulfinyl-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine dioxide 2-amino-5-cyclopentylthiobenzenesulfonamide: A mixture of 1192 g (4 mmol) of 5-iodo-2-aminobenzenesulfonamide, 750 μl (10 mmol) of triethylamine, 76 mg (0.4 mmol) of Cul, 590 μl (6 mol) was stirred. mmol) of cyclopentylmercaptan and 462 mg (0.4 mmol) of Pd (PPh3) 4 in 10 ml of dry dioxane, under nitrogen, in a bottle with a screw cap, at 130 ° C, overnight. The reaction mixture was cooled to room temperature, diluted with water, made alkaline (using 4M NaOH) and filtered through Celite. The filtrate was neutralized to pH 8.5 and evaporated to dryness. Column chromatography gave 327 mg (30%) of product. 1, 1-3-cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide (129): Bromine in the ring (3-position) 2-amino-5- cyclopentylthiobenzenesulfonamide and S-oxidized under the conditions described in Ali and Bohnert (Synthesis, (1998) 1238), using two equivalents of Br2. The product was reduced to 1 bar using 5% Pd / C in 95% EtOH and transformed by the G method (using cyclohexanecarboxaldehyde). The following table summarizes the described compounds: fifteen fifteen WHAT fifteen fifteen fifteen WHAT

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound, characterized in that it is represented by the general formula (I): wherein: X represents SO2 or C = O or CH2; Y represents -CH (R4) -, -N (R4) - or -N (R4) -CH2-, O; and R2 represents hydrogen, alkyl, cycloalkyl, aryl, benzyl; or CO-R9, wherein: R9 represents alkyl, cycloalkyl, benzyl, or aryl, or R2, together with R3 and together with the atoms to which they are attached, forms a ring of 4 to 7 members, said ring is optionally substituted or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, acyl, alkyl-NR13R14, or alkyl-S-R13, where: R13 and R14 independently represent hydrogen, alkyl, or cycloalkyl, or R13 and R14, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, or R3 represents a carbocyclic ring of 7 to 12 members, said ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a 3- to 8-membered heterocyclic ring, said ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally, the heterocyclic ring is fused to an aryl; or R3 represents benzyl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and aicylamino; or R3 represents aryl, which is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio; halogenalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino, or R3 together with R2 or R4 and together with the atoms to which they are attached, forms a 4- to 7-membered ring, said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R10 or CO2R10, wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3 and together with the atoms to which they are attached, forms a 4 to 7 membered ring, said ring is optionally substituted one or more times, with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy , amino or thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, or aryl, or R5 represents -SO2-NR11R12; wherein: R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenoalkyl, or R6 represents -NR15R16, NHSO2-R15, NHSO2-aryl, where the aryl is optionally substituted with one or more sometimes with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2 and aryl; wherein R15 and R6 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R15 and R16, together with the nitrogen to which they are attached, form an annular structure of 3 to 8 members; said structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl; said aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy alkyl, alkoxyl and amino; or R6 represents HET; Said HET is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and haloalkoxy; or R6 represents - (alkyl) mS-R15, - (alkyl) m-SO-R15, - (alkyl) m-SO2-R15, - (alkyl) m- SO2OR15, - (alkyl) m-SO2-NR15R16, - (alkyl) m-NHCOR15, - (alkyl) m-CONR15 R 6, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R15, - (alkyl) m-CO2-R15; : m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl, and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R15 and R16 together with the nitrogen to which they are fixed, they form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; and R7 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyl, cycloalkyl, cyclohaloalkyl; or R7 represents -NR17R18, NHSO2-R17, NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2, aryl; or R7 represents - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m- SO2OR17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, - (alkyl) m-CO2-R17; m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl, and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R17 and R18, together with the nitrogen to which they are fixed form a heterocyclic ring structure of 3 to 8 members, optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, S? 2-aryl , SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl, SO-aryl, or SO2NR17R18; or R7 represents aryl; said aryl is optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, S 2 -alkyl, S 2 -aryl, S 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO- CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, or -O- (CH2) n-O-; wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl; said aryl is optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl and alkoxy; or R8 represents HET; said HET is optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl and alkoxy; or R8 represents - (alkyl) mS-R19, - (alkyl) m-SO-R19, - (alkyl) m-S02-R19, - (alkyl) m-S02OR19, - (alkyl) m-SO2-NR19R20, - (alqull) m-NHCOR19, - (alkyl) m-CONR19 R20, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R19, or - (alkyl) m-CO2-R19; m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl, and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO 2 -alkyl, S 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or a compound represented by the general formula (I) wherein X represents SO2 and Y represents CH (R4), N (R4), N (R4) -CH2 or O; and R2 represents hydrogen; and R3 represents hydrogen, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy, haloalkoxy, -alkyl-NR13R14, or -alkyl-S-R13; wherein R13 and R14 independently represent hydrogen, alkyl or cycloalkyl; or R13 and R14, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; or R3 represents a carbocyclic ring of 7 to 12 members, said carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R3 represents a heterocyclic ring of 3 to 8 members; said heterocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy and optionally the heterocyclic ring is fused to an aryl; or R3 represents benzyl; said benzyl is optionally substituted one or more times with substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R3 together with R4 and together with the atoms to which they are attached, form a ring of 4 to 7 members; said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio; and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R 4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R 10 or -CO 2 R 10; wherein R10 represents hydrogen, cycloalkyl, alkyl, aryl or benzyl; or R4 together with R3 and together with the atoms to which they are attached, form a ring of 4 to 7 members; said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio; and said ring optionally contains one or more heteroatoms and optionally contains carbonyl groups; and R 5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl or -SO 2 -NR 11 R 12; wherein R11 and R12 independently represents hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; and R6 represents hydrogen, halogen, alkyl, cyano, cyanoalkyl, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R6 represents -NR15R16, -NHSO2-R15 or -NHSO2-aryl; wherein the aryl is optionally substituted, one or more times, with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO2 and aryl; wherein R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R15 and R16, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO 2 -alkyla, -SO 2 -aryl or -SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R6 represents aryl, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R6 represents HET, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl and haloalkoxy; or R6 represents - (alkyl) mS-R15, - (alkyl) m-SO-R15, - (alkyl) m-SO2-R15, - (alkyl) m- SO2OR15, - (alkyl) m-SO2-NR15R16, - (alkyl) m-NHCOR15, - (alkyl) m-CONR15 R1é, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R15, or - (alkyl) m-CO2-R15; : m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl, and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R15 and R16 together with the nitrogen to which they are fixed form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl, SO2 -aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; and R7 represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, or cyclohaloalkyl; or R7 represents -NR17R18, NHSO2-R17, NHSO2-aryl, wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF3, OCF3, NO2, and aryl; or R7 represents - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m- SO2OR17, - (alkyl) m-SO2-NR17R18 , - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, or - (alkyl) m-CO2-R17 wherein: m is 0 or 1, and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl, and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2 -alkyl, SO 2 -aryl, or S 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents - (alkyl) m-SO2-NR17R18, where m is 0 or 1; and R17 and R18, independently of each other, represent alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -S? 2 -alkyl, -S? 2 -aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NR17R18; or R7 represents aryl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R8, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio; aryl, benzyl, SO2-alkyl, SO-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH) 2-O-, or -O- (CH 2) n-O-; wherein n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents aryl optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, and alkoxy; or R8 represents HET optionally substituted one or more times with substituents selected from the group consisting of halogen, CF3, OCF3, NO2, alkyl, cycloalkyl, and alkoxy; or R8 represents - (alkyl) mS-R19, - (alkyl) m-SO-R19, - (alkyl) m-SO2-R19, - (alkyl) m-SO2OR19, - (alkyl) m-SO2-NR19R20, - (alkyl) m-NHCOR19, - (alkyl) m-CONR19 R20, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R19, or - (alkyl) m-CO2-R19; : m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl, and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R19 and R20, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio; aryl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; provided, however, that if X represents SO2 and Y represents NR4; and if one of R5, R6, R7 or R8 is halogen or alkyl or alkoxy; then one or more of one of the remaining R5, R6, R7 or R8 is not / are also halogen or alkyl; and then one or more of the remaining R5, R6, R7 and R8 is not / are hydrogen.

2. The compound according to claim 1, which is a 1,4-benzothiadiazine derivative having the general formula (II): wherein R3 represents hydrogen, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic ring of 7 to 10 members, a 5-6 membered heterocyclic ring or benzyl; or R3 together with R4 forms a ring of 5 to 6 members; and R4 represents hydrogen or alkyl, or R4, together with R3 and together with the atoms to which they are attached, forms a 5-6 membered ring; said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl, or -SO2-NR11R12, wherein: R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 5 to 6 members; R6 represents hydrogen, Br, F, I, cycloalkyl, alkyl, alkoxy, or alkoxyalkyl; or R6 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkoxy; or R6 represents HET; or -S-R15, -SO-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR '= NOR ", -CO-R15, or -CO2R15, where: R' and R" represent independently hydrogen, alkyl, cycloalkyl, phenyl, benzyl; and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO 2 -alkyl, SO 2 -aryl, S 2 -benzyl, and optionally the heterocyclic ring is fused to an aryl; and R7 represents hydrogen, Br, F, Ul, alkyl, cyano, cyanoalkyl, nitro, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, - (alkyl) m-NR17R18, NHSO2-R17, -S-R17, -SO-R17, -SO2-R17, -SO2-NHR17R18, NHCOR17, CONR 7R18, CR '= NOR ", -CO-R17, or -CO2-R17, where R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, or benzyl and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with alkyl , SO2-alkyl, SO2-aryl, SO2-benzyl; and the heterocyclic ring optionally is fused to an aryl; or R7 represents - (alkyl) m-SO2NR17R18, where m is 0 or 1 and R17 and R18, independently of each other, represent alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, S? 2NR17R18; or R7 represents phenyl, said phenyl is optionally substituted one or more times with substituents selected from the group consisting of: alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, or -SO2-NR 7R18, wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18 together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, SO2-alkyl, SO2-aryl, SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; where n is 1, 2 or 3; -SO2-NR- (CH2) n-, where n is 1 or 2; -SO-NR (CH2) n-, where n is 1 or 2; -SO2- (CH2) n-, where n is 2 or 3; -SO- (CH2) n- where n is 2 or 3; -CO-CH = CH-NH-, -CO-CH = CH-O-, -CO- (CH2) n- where n is 1 or 2, -CO-NH- (CH2) n, where n is 1 or 2; -CO- (CH2) 2-O-, or -O- (CH2) n-O-; where n is 1, 2 or 3; and R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro, or nitroalkyl; or R8 represents phenyl, said phenyl is optionally substituted one or more times with substituents selected from the group consisting of: alkyl, cycloalkyl and alkoxy; or R8 represents HET; or R8 represents -S-R19, -SO-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR '= NOR ", -CO-R19, or -CO2R19, where: R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R19 and R20 together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl , SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl, and the heterocyclic ring is optionally fused to an aryl.

3. The compound of the formula (I) according to claim 1, further characterized in that: R2 represents hydrogen, alkyl, cycloalkyl, phenyl or benzyl.

4. The compound according to any of the preceding claims, further characterized in that R3 represents hydrogen, cycloalkyl, alkyl, haloalkyl, alkoxy, a carbocyclic ring of 7 to 10 member, a heterocyclic ring of 5 to 6 members; or R3, together with R4, form a ring of 5 to 6 members; said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio; and optionally contains one or more heteroatoms and optionally contains carbonyl groups.

5. The compound according to any of the preceding claims, further characterized in that R4 represents hydrogen or alkyl; or R4, together with R3 and together with the atoms to which they are attached, form a ring of 5 to 6 members; said ring is optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio; and optionally contains one or more heteroatoms and optionally contains carbonyl groups.

6. The compound according to any of the preceding claims, further characterized in that R5 represents hydrogen, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO2-NR11R12: wherein R11 and R12 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aril; or R11 and R12, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members.

7. The compound according to any of the preceding claims, further characterized in that R6 represents hydrogen, halogen, cycloalkyl, alkyl, alkoxy or alkoxyalkyl; or R6 represents aryl; said aryl is optionally substituted one or more times with substituents selected from the group consisting of alkyl and alkoxy; or R6 represents HET; or R6 represents -S-R15, -SO-R15, -SO2OR15, -SO2-NR15R16, -NHCOR15, -CONR15R16, -CR '= NOR ", -CO-R15, or -CO2R15, where: R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R15 and R16 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl, or R15 and R16, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SO2-alkyl, SO2-aryl, SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl.

8. The compound according to any of the preceding claims, further characterized in that R7 represents halogen, alkyl, cyano, cyanoalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, - (alkyl) m-NR17R18, NHSO2-R17 , -S-R17, -SO-R17, -SO2-R17, -SO2-NHR17R18, NHCOR17, CONR17R18, CR '= NOR ", -CO-R17, or -CO2-R17, wherein R' and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl, or benzyl and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl, or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with alkyl, S 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and the heterocyclic ring optionally is fused to an aryl; or R7 represents - (alkyl) m-S02NR17R18, where m is 0 or 1 and R17 and R18, independently of each other, represent alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -S? 2 -alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET optionally substituted one or more times with substituents selected from halogen, alkyl, phenyl, or SO2NR17R18; wherein R17 and R8 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; ring structure which is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7 represents phenyl optionally substituted one or more times with substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R17 and R8, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; structure which is optionally substituted with halogen, alkyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl, and optionally the heterocyclic ring is fused to an aryl; or R7, together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein n is 1 or 2; -SO-NR- (CH2) n-, wherein n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, or -O- (CH2) n-O-; wherein n is 1, 2 or 3.

The compound according to any of the preceding claims, further characterized in that R8 represents hydrogen, alkyl, alkoxy, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R8 represents phenyl; said phenyl is optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl and alkoxy; or R8 represents HET, or R8 represents S-R19, -SO-R19, -SO2OR19, -SO2-NR19R20, -NHCOR19, -CONR19R20, -CR '= NOR ", -CO-R19, or -CO2R19, where: R 'and R' independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R19 and R20 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R19 and R20 together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl , SO 2 -alkyl, SO -aryl, SO 2 -benzyl, and the heterocyclic ring is optionally fused to an aryl.

10. - The compound according to any of the preceding claims, further characterized in that X represents SO2 and Y represents N; and R2 represents H; and R3 represents cycloalkyl, a carbocyclic ring of 7 to 10 members, a heterocyclic ring of 5 to 6 members; and R4 represents H; and R5 represents H; and R6 represents hydrogen, alkyl or halogen; and R7 represents cyanoalkyl, nitroalkyl, haloalkyl or (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, or - (alkyl) m-CO2-R17, where m is 0 or 1 and R and R "independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents - (alkyl) m-SO2-NR17R18, where m is 0 or 1 and R17 and R18, independently, represents alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl and n is 1 or 2; -SO-NR- (CH2) n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl, and n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, or -O- (CH2) n-O-; wherein n is 1, 2 or 3; and R8 represents halogen, cyanoalkyl, nitroalkyl, haloalkyl, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m-SO2-R17R18, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, or - (alkyl) m-CO2-R17, where m is O and R and R" independently represent hydrogen, alkyl, cycloalkyl, phenyl or benzyl; and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with alkyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R8 represents HET.

11. The compound according to any of the preceding claims, further characterized in that R3 represents hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF3, ethoxy, norbornene, norbornane, adamantane or benzyl; or R3, together with R4, and together with the atoms to which they are attached, form a 5-membered ring.

12. The compound according to any of the preceding claims, further characterized in that R represents hydrogen, methyl or ethyl; or R4, together with R3 and together with the atoms to which they are fixed, forms a 5-membered ring.

13. The compound according to any of the preceding claims, further characterized in that R5 represents hydrogen, chlorine, bromine, methyl or phenyl.

14. The compound of formula I, according to any of the preceding claims, further characterized in that R6 represents hydrogen, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy, chlorine or bromine.

15. The compound of the formula I, according to any of the preceding claims, further characterized in that: R7 represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH3) C = N-OH, -CONH2 , -CO2-, ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenol, 2-NN-dimethylsulfamoylphenyl, 2-chlorophenyl, 2 -fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-thienyl, 2- (N-methyl) -imidazolyl, 5-triazolyl, 4-phenyl-triazole -5-yl, 5-methyl-1, 2,4-oxadiazol-3-yl, CH3CONH-, CH3SO2NH.-, -SO2OH, phenyl-SO2-, N, N-dimethylsulphamoyl, N, N-diethylsufamoyl, N- phenyl-N-methylsulphamoyl or S? 2-heterocyclic ring; wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1, 2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethyl-piperazine and morpholine.

16. The compound of the formula I according to any of the preceding claims, further characterized in that R8 represents hydrogen, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy.

17. The compound of formula II according to claim 2, further characterized in that R2 represents hydrogen or CH3; and R3 represents cyclohexyl, cyclopentyl, norbornene, norbornane, adamantane or ethoxy; and R 4 represents hydrogen or CH 3; and R5 represents hydrogen, CH3, phenyl, sulfamoyl, chlorine or bromine; and R6 represents hydrogen, CH3, 2-methoxyphenyl, methoxy, chloro, bromo, 2-pyridyl or 3-pyridyl; and R7 represents chloro, bromo, methyl, 1-hydroxyethyl, acetyl, - (CH3) C = N-OH, -CONH2, -CO2-ethyl, cyano, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl , 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N, N-dimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl , 3-furyl, 2-thienyl, 2- (N-methyl) imidazolyl, 5-triazoyl, 4-phenyl-triazol-5-yl, 3-methyl-1, 2,4-oxadiazol-3-yl, -CH3CONH -, CH3SO2NH-, SO2OH, phenyl-SO2-, N, N-dimethylsulphamoyl, N, N-diethylsulphamoyl, N-phenyl-N-methylsulphamoyl or -SO2-heterocyclic ring; wherein the heterocyclic rings are selected from the group of piperidine, pyrrolidine, 1, 2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethylpiperazine and morpholine; and R8 represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy.

18. The compound of the formula I according to claim 1, further characterized in that X is C = O; And it is N, O or CH; R2 represents hydrogen; and R3 represents hydrogen, CH3, CF3, cyclohexyl, norbornene, phenyl or ethyl; and R7 represents hydrogen, N, N-dimethylsulphamoyl, N-cyclohexyl sulfamoyl, tetrahydropyrid-1-yl-sulfuric acid, morpholin-4-yl-sulfuric acid, sulfamoyl, bromine; and R5 represents hydrogen or bromine; and R4, R6 and R8 all represent hydrogen.

19. The compound of formula I according to claim 1, further characterized in that X represents CH2; And it's N; R3 represents cyclohexyl or norbornene; and R5 represents hydrogen or bromine; R7 represents bromine or sulphamoyl; and R2, R4, R6 and R8 all represent hydrogen.

20. The compound of the formula I according to claim 1, further characterized in that X is SO2; N is -NHCH2-, R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R7 represents 1-piperidinyl sulfuric acid.

21. The compound of formula I according to claim 1, further characterized in that said compound is: 2-cyclohexyl-4-oxo-1, 2,3,4-tetrahydroquinazoline, 2-phenyl-4-oxo-1 , 2,3,4-tetrahydro-quinazoline, 2-methyl-3,4-dihydro-1,3-benzoxazin-4-one, 2-phenyl-3,4-dihydro-1,3-benzoxazin-4 -one, 2-ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one, 2-methyl-4-oxo-3,4-dihydro-6-quinazolin-N, N-dimethylsulfonamide , 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinesulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolnn, N-dimethylsulfonamide, 2-trifluoromethyl-4-oxo -3,4-dihydro-6-quinazolin-1 ', 2', 3 ', 6'-tetrahydropiperidinesulfonamide, 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolin-N-cyclohexylsulfonamide, 2-trifluoromethyl -4-oxo-3,4-dihydro-6-quinazolin-morpholinosulfonamide, 2-cyclohexyl-4-oxo-3,4-dihydro-6-quinazolin-N, N-dimethyl-sulfonamide, 2-trifluoromethyl-4-acid oxo-3,4-dihydro-6-quinazolinesulfonic acid, 2-cyclohexylmethylamino-5-N, N-dimethylsulfamoylbenzenesulfonamide; or 2-ethylamino-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonylbenzenesulfonamide; or their pharmaceutically acceptable salts.

22. The derivative of 1,2,4-benzothiadiazine according to claim 2, further characterized in that said compound is: 1,1-dioxide of 3-bicyclo [2.2.1] hept-5'-en-2 ' -yl-1, 2,3,4-tetrahydro-1, 2,4-benzo-thiadiazine, 5,5-dioxide of 1, 2,3,5, 10,10a-hexahydrobenzo [e] pyrrolo [1, 2 -b] -1, 2,4-thiadiazine, 1,1-cyclohexyl-6- (2-methoxyphenyl) -1, 2,3,4-tetrahydro-1,4-benzo-thiadiazine dioxide, 1, 1-dioxide of 3-cyclohexyl-6- (2-pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3-cyclohexyl-6- (3-pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (1-hydroxyethyl) -1, 2,3-dioxide 4-tetrahydro-1, 2,4-benzothiadipazine, 1,1-cyclohexyl-7-acetyl-1, 2,3-tetrahydro-1-dioxide, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (1-hydroxyiminoethyl) -1,2,3,4-tetrahydro-1,4-benzo-thiadiazine, 1,1-dioxide of 3-cyclohexyl-7-carbamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7-ethoxycarbonyl-1, 2,3,4-dioxide -tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7-cyano-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3-bicyclo [2.2.1] hept-5'-en-2'-yl-7-phenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3 -cyclohexyl-7- (2'-acetamidophenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzo-thiadiazine, 1,1-dioxide-3-cyclohexyl-7- (2'-nitrophenyl) - 1, 2,3,4-tetrahydro-1, 2,4-benzothiadhylazine, 1,1-dioxide-3-cyclohexyl-7- (2'-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (2'-methoxy-4'-trifluoromethylphenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 1, 1 -3-cyclohexyl-7- (2 ', 4'-dimethoxyphenyl) -1,2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1,1-dioxide-3-ci-dioxide clohexyl-7- (2 '- (N, N-dimethylsulfamoyl) phenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2-dioxide '-chlorophenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-7- (2'-fluorophenyl) -1, 2,3,4- tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (3'-hydroxyphenyl) -1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1,1-dioxide, 1, 1 -3-cyclohexyl-7- (2'-pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine dioxide, 1,1-cyclohexyl-7- (3'-) dioxide pyridyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (2'-pyrimidinyl) -1,2,3,4-tetrahydro- 1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-furyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 3-cyclohexyl-7- (3'-furyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (2'-thienyl) dioxide -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1-methyl-1 H-2-imidazolyl) -1, 2,3-dioxide 4-tetrahydro-1, 2,4-benzothiad iazine, 1, 1-3-cyclohexyl-7- (1 ', 2', 3'-triazole-4'-ii) -1, 2,3,4-tetrahydro-1, 2,4-benzoyl dioxide thiadiazine, 3-cyclohexyl-7- (5'-phenyl-1 ', 2'-3'-triazol-4'-yl) -1,2,3,4-tetrahydro-1,2-dioxide , 4-benzothiadiazine, 1,1-cyclohexyl-7- (5'-methyl-1 ', 2'-4'-oxadiazol-3-yl) -1, 2,3,4-tetrahydro-1-dioxide , 2,4-benzothiadiazine, 1,1-3-cyclohexy-7-acetamido-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7-dioxide -methyl-sulfonylamino-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl-7-nitro-1, 2,3,4-tetrahydro-1, 2,4 -benzothiadiazine, 1,1-dioxido-3-cyclohexyl-7-phenylsulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 2-cyclohexyl-1, 2,3,4-tetrahydro-6 3-cyclohexyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7-sulfamoyl dioxide -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-methyl-7-dimethylsulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothia dioxide diazine, 2-cyclohexyl-1, 2,3,4-tetrahydro-6-quinazolin-N, N-dimethylsulfonamide, 1,1-dioxide-3-cyclohexyl-7-dimethylaminosulfonyl-1, 2,3,4- tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (N, N-diethylamino) sulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1 , 1-3-cyclohexyl-7-pyrrolidinosulfoniI-1, 2,3,4-tetrahydro-1, 2,4-benzothia-diazine, 1,1-3-methyl-7-piperidinesulfonyl-1 dioxide , 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclopropyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,2-dioxide, 2,4 -benzothiadiazine, 1, 1-dioxide 3-isopropyl-7-piperidinosulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide 3-propyl-7-piperidinosulfonyl-1 , 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-benzyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1 , 1-3-cyclopentyl-7-piperidinesulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 3-cyclohexyl-7-piperidinosulfonyl-1,2-dioxide , 3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 3-bicyclo [2.2.1] hept-5'-en-2'-yl-7-piperidinosuIfonil-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-cyclohexyl-7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1,2, 3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (N-methyl-N-phenylamino) sulfonyl-1, 2,3,4-tetrahydro-1,2-dioxide , 4-benzothiadiazine, 1,1-cyclohexyl-7- (1 '- (1', 2'-3 ', 4'-tetrahydroquinolinyl)) sulfonyl-1, 2,3,4-tetrahydro-1-dioxide , 2,4-benzothiadiazine, 1,1-cyclohexyl-7- (4'-methylpiperazino) sulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1,1-dioxide of 3-cyclohexyl-7- (4'-methylsulfonylpiperazino) sulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl-7-morpholinesulfonyl -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide, 3-bicyclo [2.2.1] hept-5'-en-2'-yl-7-bromo-1 , 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine, 1,1-dioxide of 3-methyl-7-dimethylsulphamoyl-1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-methyl-3-dioxide 7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-methyl-7-cyclohexyl-sulphamoyl-1, 2 -dihydro-1, 2,4-benzothiadiazine, 1,1-trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl - 8-methyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine, 1,1-cyclohexyl-8-hydroxymethyl-1, 2,3-tetrahydro-1,2-dioxide , 4-benzothiadiazine, 1,1-cyclohexyl-8- (2-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-cyclohexyl dioxide -8- (3-methoxyphenyl) -1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-cyclohexyl-8- (2-pyridyl) -1, 2,3 , 4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-8-methoxy-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide of 5,7-dibromo-1, 2-dihydro-1, 2,4-benzothiadiazine, 1,1-dioxido-3-cyclohexyl-2-methyl-7-morpholinosulfoniI-1, 2,3,4-tetrahydro -1, 2,4-benzothiadiazine, 1,1-cyclohexyl-4-methyl-dioxide 7-morpholinosulfonyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 5-methylsulfonylamino-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo 5-dioxide 2.1-c] -1, 2,4-thiadiazine, 5,5-dioxido of 7-sulfamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 7,5-methylsuicamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1,5,4-thiadiazine 5,5-dioxide , 7-cyclohexylsulfamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2, 1-c] -1, 2,4-thiadiazine, 5,5-dioxide-7-dioxide dimethylsulfamoyl-1, 2,3,3a, 4,5-hexahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5,5-dioxide, 7-methylsulfamoyl-1, 2,3 , 5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 5,5-dioxido of 7-dimethylsulfamoyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2, 1-c] -1, 2,4-thiadiazine, 5-cyclohexylsulfamoyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-dioxide thiadiazine, 5,5-dioxide 7- (1 ', 2', 3 ', 6'-tetrahydropiperidino) sulfonyl-1, 2,3,5-tetrahydrobenzo [e] pyrrolo [2,1-c] -1, 2,4-thiadiazine, 1, 1-3-bicic dioxide [2.2.1] hept-5'-en-2'-yl-5,7-dimethyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-dioxide Cyclohexyl-7- (N, N-diethylsulfamoyl) -5-methyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-3-bicyclo [2.2.1] heptide dioxide 5'-en-2'-il-5,7-diphenyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-bicyclo [2.2.1] hept-5'-en-2-yl-5,7-disulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-bicyclo [2.2.1] hept -5'-en-2'-yl-5,7-dichloro-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido-5-bromo-3-cyclohexyl-7 -sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxide-3-bicyclo [2.2.1] hept-5'-en-2'-yl-5 , 7-dibromo-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine, 1,1-dioxido of 5,7-dibromo-3-bicyclo [2.2.1] heptan-2'-il- 1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine, 3-cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,1-dioxide, 4-benzothiadiazine, 3-adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide, 3-f-1,1-dioxide enyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine, 3-ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiazine, 1,1-dioxide, 3-methyl-5,7-dioxide -dibromo-1,2-dihydro-1,2,4-benzothiadiazine, 3-cyclohexyl-6-methyl-7- (2'-pyridyl) -1,2,3,4-tetrahydro-1,1-dioxide 1,2,4-benzothiadiazine, 3-cyclohexyl-6-methyl-7- (4'-triazolyl) -1,2,4,4-tetrahydro-1,4-benzothiadiazine 1,1-dioxide , 3-cyclohexyl-6-methyl-7-sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothiadiazine 1-dioxide, 3-cyclopentyl-6-methyl-1,1-dioxide -7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine, 3-cyclohexyl-6-methyl-7-morfoiinosulfonyl-1,2,3,4-tetrahydro 1,1-dioxide -1,2,4-benzothiadiazine, 3-cyclohexyl-6- (2-methoxyphenyl) -7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide, , 1-3-cyclohexyl-6-methoxy-7-piperidnosulfonyl-1, 2,3,4-tetrahydro-1,4-benzothiadiazine dioxide, 1,1-cyclohexyl-3-dioxide 7,8-ethylenedioxy-1, 2,3,4-tetrahydro-1,2,4-benzothiadiazine, 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,1,1-dioxide, 2,4-benzothiadiazine, 3-cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide, 3-phenyl-1,1-dioxide 6-chloro-7-sulfamoyl-1, 2,3,4-tetrahydro-1, 2,4-benzothia-diazine, 1,1-dioxido of 3-cyclohexyl-6-bromo-7-p-peridinosulfonyl 1,2, 3,4-tetrahydro-1, 2,4-benzothiadiazine, 3-isobutyl-8- (p.peridinosulfonyl) -2, 3,4,5-tetrahydro-1,2,5-benzothia- 1,1-dioxide diazepine, or its pharmaceutically acceptable salt.

23. A compound having the general formula (III): wherein Y represents CH (R4), N (R4) or N (R4) -CH2 or O; and R3 represents a carbocyclic ring of 7 to 12 members; said carbocyclic ring is optionally substituted with halogen, alkyl, hydroxy or alkoxy; and R6 represents halogenoalkyl; and R7 represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R7 represents -NR17R18, -NHSO2-R17 or -NHSO2-aryl; wherein the aryl is optionally substituted one or more times with substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3-, -OCF3, -NO2 and aryl; or R7 represents - (alkyl) mS-R17, - (alkyl) m-SO-R17, - (alkyl) m-SO2-R17, - (alkyl) m- SO2OR17, - (alkyl) m-SO2-NR17R18, - (alkyl) m-NHCOR17, - (alkyl) m-CONR17 R18, - (alkyl) m-CR '= NOR ", - (alkyl) m-CO-R17, or - (alkyl) m-CO2-R17; : m is 0 or 1; and R and R "independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or benzyl, and R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, aryl, or R17 and R18, together with the nitrogen to which they are fixed, they form a heterocyclic ring structure of 3 to 8 members, said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO2-alkyl , SO2-aryl, or SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents - (alkyl) m-SO2-NR17R18, where m is 0 or 1; and R17 and R18, independently of each other, represent alkyl, cycloalkyl, benzyl or aryl; or R17 and R18, together with the nitrogen to which they are fixed, form a heterocyclic ring structure of 3 to 8 members; said ring structure is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amine, thio, aryl, benzyl, -SO2-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 represents HET optionally substituted one or more times with substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO2-alkyl, SO2-aryl, SO2NR17R18; or R7 represents aryl optionally substituted one or more times with substituents selected from the group consisting of: alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF3, -SO2-NR17R18; wherein R17 and R18 independently represent hydrogen, alkyl, cycloalkyl, benzyl, or aryl; or R17 and R18, together with the nitrogen to which they are attached, form a heterocyclic ring structure of 3 to 8 members, said ring structure being optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio; aryl, benzyl, SO 2 -alkyl, SO 2 -aryl, SO 2 -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R7 together with R6 or together with R8 forms a 5- to 7-membered ring having one of the following structures: -O- (CH2) n-O-; wherein n is 1, 2 or 3; -SO2-NR- (CH2) n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl and n is 1 or 2; -SO-NR- (CH2) n-, wherein R is hydrogen, alkyl, cycloalkyl, benzyl or aryl and n is 1 or 2; -SO2 (CH2) n-, wherein n is 2 or 3; -SO (CH2) n-, wherein n is 2 or 3; -CO-CH = CH-NH-, CO-CH = CH-O-, -CO- (CH2) n-NH-, where n is 1 or 2; CO-NH- (CH2) n, wherein n is 1 or 2; -CO- (CH2) 2-O-, or -O- (CH2) n-O-; wherein n is 1, 2 or 3.

24.- A pharmaceutical composition, characterized in that it comprises an effective amount of a chemical compound according to any of claims 1 to 23, or its pharmaceutically acceptable salt, and an excipient, carrier or pharmaceutically acceptable diluent.

25. The use of a compound according to any of claims 1 to 23, for the preparation of a medicament for the treatment of a disorder or a disease in a living animal body, including a human; said disorder or said disease responding to modulation of the AMPA receptor complex of the central nervous system.

26. The use according to claim 25 for the preparation of a medicament for treating a disorder or disease in a living animal body, including a human; disorder or disease that respond to modulation of the AMPA receptor complex of the central nervous system.

27. The use according to any of claims 25 and 26, further characterized in that the disorders or diseases are selected from disorders of memory and learning, psychotic disorders, sexual dysfunction, disorders of intellectual damage, schizophrenia, depression, autism, Alzheimer's disease, learning deficiency, poor attention, memory loss and senile dementia; or are selected from a disorder or disease that are the result of trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery and cerebral ischemia.