CZ20002896A3 - New compounds and their use as AMPA receptor positive modulators - Google Patents

Abstract

Novel compounds of general formula I, where the bond represented by the dashed line may be single, double or absent and if the bond is absent, then the nitrogen is substituted by a hydrogen atom and a substituent R2; X represents SO2, C=O or CH2; Y represents -CH(R4)-, -N(R4)- or -N(R4)-CH2-, O; and the other substituents R2, R3, R4, R5, R6, R7 and R8 have specific meanings. The compounds are effective as positive modulators of the AMPA receptor, for example in the treatment of memory or learning disorders, psychotic disorders, sexual dysfunctions, intellectual disorders, schizophrenia, depression or autism.

Description

NEW COMPOUNDS AND THEIR USE AS POSITIVE MODULATORS

AMPA RECEPTOR

This invention relates to novel compounds useful as modulators of AMPA-sensitive glutamate receptors, pharmaceutical compositions containing such compounds and their use in therapies.

State of the art

L-Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system, activating several subtypes of ionotropic and metabotropic receptors. Ionotropic receptors can be divided into three subtypes, NMDA, AMPA, and kainate receptors, based on structural and pharmacological differences.

Impairment of glutamatergic neurotransmission has been demonstrated in the learning and memory loss observed in many neurological diseases such as Alzheimer's disease, senile dementia, stroke (McEntee and Crook, Psychopharmacology 111:391-401 (1993)). It is widely accepted that learning and memory involve the induction of long-term potentiation (LTP), which is a stable increase in synaptic strength following repetitive high-frequency stimulation. Experimental studies have shown that an increase in synaptic responsiveness mediated by AMPA receptors enhances the induction of LTP (Arai and Lynch, Brain Research, 598:173-184 (1992)). For the above reasons, compounds that stimulate AMPA receptor responses in the brain may induce improvements in intellectual behavior and performance.

Activation of AMPA receptors by L-glutamate or a selective AMPA agonist leads to a rapid desensitization of the receptor; i.e. the receptor channel does not resist the continuous presence of the agonist. This makes it possible to obtain an increase in synaptic strength by attenuating the desensitization of the AMPA receptor normally induced by the endogenous neurotransmitter L-glutamate.

In 1990, Ito et al. reported (J. Physiol., 424:533-543) that the nootropic drug aniracetam (γ-anisoyl-2-pyrrolidine) increases AMPA-induced currents in oocytes injected with rat brain mRNA. In another study, it was reported that 1-(1,3-benzodioxol-5ylcarbonyl)-1,2,3,6-tetrahydropyridine, a compound that increases synaptic transmission mediated by AMPA receptors, is effective in improving memory in experimental animals at very high doses of 120 mg/kg (Staubli et al., Proc. Natl. Acad. Sci.

USA, 91:11158-11162 (1994)).

• ·

Cyclothiazide benzothiadiazide is a more potent and effective modulator of AMPA receptor flux in vitro than aniracetam (Johansen et al., Mol. Pharmacol. 48:946-955 (1995)). The effect of cyclothiazide on the kinetic properties of AMPA receptor fluxes is thought to be due to a different mechanism than aniracetam (Partin et al., J. Neuroscience 16:6634-6647 (1996)). However, cyclothiazide has no therapeutic efficacy for modulating AMPA receptors because it cannot cross the blood-brain barrier and is administered peripherally. Known compounds have lower efficacy because of their high solubility requirements at higher doses.

State of the art

US Patent No. 5,488,049 discloses the use of benzothiadiazide derivatives for the treatment of memory and learning disorders. The compounds are structurally very similar to the compounds of the present invention. However, the compounds of the present invention exhibit greater potentiation at lower concentrations. (Fig. 3 of US Patent No. 5,488,049)

U.S. Patent No. 4,184,039 discloses benzothiadiazides for use in promoting hair growth.

DE patent number 1470316 discloses a process for the production of certain benzothiadiazides for use as additives in galvanic zinc plating baths.

A method for preparing benzothiadiazine-1,1-dioxides is described in Synthesis (10), 183, p. 851. The compounds are described as effective antihypertensive and antimicrobial agents.

In J. Med. Chem. (15, No.4), 1972. pp. 400 - 403 benzothiadiazine-1,1-dioxides are examined for their π-substituent constants as a structure activity study for antihypertensive activity.

WO 9812185 describes benzothiadiazines of different structures than the compounds of the present invention.

It is an object of the present invention to provide positive AMPA modulators that are effective in treating diseases or disorders in mammals, including humans, and particularly in treating diseases and disorders that are responsive to modulation of AMPA receptors in the brain.

• ·

AND

It is another object of the present invention to provide a method of treating diseases or disorders in mammals, including humans, responsive to AMPA receptor modulators, which comprises administering to the mammal in need of such treatment a compound of the present invention.

A third object of the present invention is to provide novel pharmaceutical compositions for the treatment of diseases or disorders in mammals, including humans, responsive to AMPA modulators.

Other objects of the present invention will become apparent to those skilled in the art from the following description.

The essence of the invention

The invention includes, among others, the following alone or in combination:

The compound represented by the general formula:

wherein the bond represented by the dashed line may be a single bond, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen atom and a substituent R ² ;

X represents SO ₂ or C=O or CH ₂ ;

Y represents -CH(R ⁴ )-, -N(R ⁴ )- or -N(R ⁴ )-CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ , where

the substituent R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

a 4-membered to 7-membered ring optionally substituted with one or more 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 ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy group, haloalkoxy group, acyl, alkyl-NR ¹³ R ¹⁴ , alkyl-SR ¹³ where the substituents R ¹³ and R ¹⁴ independently represent a hydrogen atom, alkyl, cycloalkyl; or the substituents R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure;

A carbocyclic 7- to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

A heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;

Benzyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy group, alkoxy group, amino group or thio group, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio group, alkylamino group;

Aryl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted with one or more 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 ⁴ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO2R ¹⁰ , where the substituent R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 4-membered or 7-membered ring optionally substituted with one or more 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 ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ -NR ⁿ R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure 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 aryl;

R ⁶ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy groups, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁵ R ¹⁶ , NHSO2-R ¹⁵ , NHSO2-aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy group, alkoxy group, amino group, thio group, CF3, OCF3, _NO2 , aryl;

• ·

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;

-(alkyl) _m -SR ¹⁵ ; -(alkyl)m-SO-R ¹⁵ ; -(alkyl)m-SO ₂ -R ¹⁵ ; -(alkyl)m-SO2OR ¹⁵ ; -(alkyl)mSO ₂ -NR ¹⁵ R ¹⁶ ; -(alkyl)m-NHCOR ¹⁵ ; -(alkyl)m-CONR ¹⁵ R ¹⁶ ; -(alkyl)m-CR'=NOR; (alkyl)m-CO-R ¹⁵ ; -(alkyl)m-CO ₂ -R ¹⁵ , where the index m is 0 or 1; and the substituents R' and R" independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

R ⁷ represents a hydrogen atom, halogen, alkyl, cyano group, nitro group, nitroalkyl; alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO ₂ , aryl;

Ί ·· 9· • 99 9

9 99 • · · 9

9 9

9999 99 ·

-(alkyl) _m -SR ¹⁷ ; -(alkyl) m -SO-R ¹⁷ ; -(alkyl) m -SO ₂ -R ¹⁷ ; -(alkyl) m -SO2OR ¹⁷ ; -(alkyl) m SO ₂ -NR ¹⁷ R ¹⁸ ; -(alkyl) m -NHCOR ¹⁷ ; -(alkyl) m -CONR ¹⁷ R ¹⁸ ; -(alkyl) m -CR'=NOR; (alkyl) m -CO-R ¹⁷ ; -(alkyl) m -CO ₂ -R ¹⁷ , where the index m is 0 or 1; and the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy group, alkoxy group, amino group, thio group, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ NR ¹⁷ R ¹⁸ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO ₂ -NR' ⁷ R ¹⁸ , wherein the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or ·« φφ • · · • · φφ

ΦΦΦ φφφφ φφ φ φφ e · φ φ • ΦΦΦ · · φ ·

ΦΦΦ φ Φ 9 · ·· ΦΦΦ Φφ φ

ΦΦΦΦΦΦΦ

ΦΦΦΦΦΦ ΦΦΦ

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ )„-, where the index n is 1 or 2; -SO-NR-(CH ₂ )„-, where the index n is 1 or 2; -SO ₂ -(CH ₂ )„-, where the index n is 2 or 3; -SO-(CH ₂ )„-, where the index n is 2 or 3; CO-CH=CH-NH; -CO-CH=CH-O-; -CO-(CH ₂ ) _n -NH-, where the index n is 1 or 2; -CONH-(CH ₂ ) _n , where the index n is 1 or 2; -CO-(CH ₂ ) ₂ -O-; -O-(CH ₂ )„-O-; where the index n is 1, 2 or 3;

R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF3, OCF3, _NO2 , alkyl, cycloalkyl, alkoxy groups;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF3, OCF3, _NO2 , alkyl, cycloalkyl, alkoxy;

-(alkyl) _m -SR ¹⁹ ; -(alkyl)m-SO-R ¹⁹ ;-(alkyl)m-SO ₂ -R ¹⁹ ; -(alkyl)m-SO2O-R ¹⁹ ; -(alkyl)mSO ₂ -NR ¹⁹ R ²⁰ ; -(alkyl)m-NHCOR ¹⁹ ; -(alkyl)m-CONR ¹⁹ R ²⁰ ; -(alkyl)m-CR =NOR; (alkyl)m-CO-R ¹⁹ ; -(alkyl)m-CO ₂ -R ¹⁹ , where the index m is 0 or I; and the substituents Ra and R" independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

if the dashed line in formula I represents a double bond and X represents SO ₂ and Y represents NH and the compound is monosubstituted, then the compound is not

• 0 0 • 0 0 ·· 00 • 0 0

0 00 monosubstituted with a substituent R ³ representing OCH ₃ , methyl, pentyl, t-butyl, aminophenyl, 2-phenylethylene, phenethyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornylene, benzyl, thienyl, furyl, aryl, aryl substituted with 4-methyl, 4-methoxy, 4-chloro, 4-nitro or 3-nitro;

and if the compound is disubstituted by R ³ which is methyl, then R ⁵ is not Cl, CH 3 ; or R ⁷ is not F, Cl, Br, I, CH 3 , CF ₃ , nitro, SO ₂ N(CH ₃ ) ₂ ; or R ⁶ is not Cl, Br, CH ₃ , CF ₃ , ethyl, methoxy; or R ⁷ is chlorine, then R ³ is not ethyl, butyl, sec-butyl, t-butyl, cyclobutyl, 2,2-dimethylpropyl, phenyl;

and if the compound is disubstituted, then it is not disubstituted by the substituent R ⁶ =

OMe, R ³ = ethyl; R ⁶ = methyl, R ³ = propyl; R ⁷ = SO 2 NH 2 , R ⁶ = Cl; R ⁷ = SO 2 NH ₂ , R ³ = phenyl; R ⁷ = Br, R ³ = phenyl;

And if the compound is trisubstituted, then R ³ = CH3, R ⁵ = NO2, R ⁷ = Cl; R ³ = CH3, R ⁶ = NO2, R ⁷ = Cl; R ³ = CH3, R ⁵ = NH2, R ⁷ = Cl;

And if the dashed line in formula I represents a single bond and X represents SO ₂ and Y represents NH

Then the compound is not disubstituted by substituents R ⁷ or R ⁶ which are chlorine and a substituent R which is alkyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclohexene, norbornylene, norbornanyl, ethylthiomethyl, ethyloxymethyl, ethyloxyethyl, methyloxymethyl, methylamino group, 2-chloroethyl, chloromethyl, dichloromethyl, trifluoromethyl, amino group;

and the compound is not trisubstituted by R ³ , which is CH ₃ and R ⁵ = isopropyl, R ⁷ = F; R ⁵ = ethyl, R ⁷ = Cl; R ⁵ = propyl, R ⁷ = Cl; R ⁵ = ethyl, R ⁷ = F; R ⁵ = methyl, R ⁷ = Cl; R ⁵ = ethyl, R ⁷ = methyl; R ⁵ = Cl, R ⁷ = methyl; R ⁵ = methyl, R ⁷ = Cl; R ⁴ = methyl, R ⁵ = ethyl; or trisubstituted by R ⁴ = methyl, R ⁵ = methyl, R ⁷ = F;

A pharmaceutical composition comprising a therapeutically effective amount of the above compound together with pharmaceutically acceptable carriers or excipients;

Use of a compound represented by the general formula

*· ·· φφ ··

wherein the bond represented by the dashed line may be a single bond, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen atom and a substituent R ² ;

X represents SO ₂ or C=O or CH ₂ ;

Y represents -CH(R ⁴ )-, -N(R ⁴ )- or -N(R ⁴ )-CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ , where the substituent R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

a 4-membered to 7-membered ring optionally substituted with one or more 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 ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy group, haloalkoxy group, acyl, alkyl-NR. ¹³ R ¹⁴ , alkyl-SR ¹³ where the substituents R ¹³ and R ¹⁴ independently represent a hydrogen atom, alkyl, cycloalkyl; or the substituents R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure;

A carbocyclic 7- to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

A heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;

Benzyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy group, alkoxy group, amino group or thio group, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio group, alkylamino group;

Aryl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted with one or more 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 ⁴ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO2R ¹⁰ , where the substituent R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 4-membered or 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

• ·· # · · · • · · ·· ·« • 9 9 • · ·« • · · ···· ··

9 9

9 9 9

9 9 9

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ -NR ⁿ R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R and R together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure 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 aryl;

R ⁶ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁵ R ¹⁶ , NHSO 2 -R ¹⁵ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy group, alkoxy group, amino group, thio group, CF ₃ , OCF 3 , NO ₂ , aryl;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;

-(alkyl) _m -SR ¹⁵ ; -(alkyl) m -SO-R ¹⁵ ; -(alkyl) m -SO ₂ -R ¹⁵ ; -(alkyl^-SOjO-R ¹⁵ ; -(alkyl) m SO2-NR ¹⁵ R ¹⁶ ; -(alkyl) m -NHCO-R ¹⁵ ; -(alkyl) _m -CONR ¹⁵ R ¹⁶ ; -(alkyl) m -CR'=NOR; (alkyl) m -CO-R ¹⁵ ; -(alkyl) m -CO ₂ -R ¹⁵ , where the index m is 0 or 1; and the substituents R and R" independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and

»« ·· • · · ·· ·· • · • * · « « • « • · • • ·· • · • • • • · • • · • · • • • • · • ·· · • · • · · ·· • · ··

R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

R ⁷ represents a hydrogen atom, halogen, alkyl, cyano group, nitro group, nitroalkyl; alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSO 2 -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO ₂ , aryl;

-(alkyl) _m -SR ¹⁷ ; -(alkyl) m -SO-R ¹⁷ ; -(alkyl) m -SO ₂ -R ¹⁷ ; -(alkyl) m -SO2O-R ¹⁷ ; -(alkyl) m SO ₂ -NR ¹⁷ R ¹⁸ ; -(alkyl) m -NHCOR ¹⁷ ; -(alkyl) m -CONR ¹⁷ R ¹⁸ ; -(alkyl) m -CR'=NOR; (alkyl) m -CO-R ¹⁷ ; -(alkyl) m -CO ₂ -R ¹⁷ , where the index m is 0 or 1; and the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio ·· φφ > · φ

ΦΦΦ· φφφφ ··

Φ· φφ φ φ φ φ φ φ φ · φ φ φ φ φφ ·Φ group, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SOi-alkyl, SO ₂ -aryl, SO ₂ NR ¹⁷ R ¹⁸ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SCh-benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; -SO2-NR-(CH ₂ ) _n -, where the index n is 1 or 2; -SO-NR-(CH ₂ ) _n , where the index n is 1 or 2; -SO ₂ -(CH2) _n -, where the index n is 2 or 3; -SO-(CH2)n-> where the index n is 2 or 3; CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ ) ₁₁ -NH-, where the index n is 1 or 2; -CONH-(CH ₂ ) _n , where the index n is 1 or 2; -CO-(CH ₂ )2-O-; -O-(CH ₂ ) n O-; where the index n is 1, 2 or 3;

R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy groups;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , OCF ₃ , NO ₂ , alkyl, cycloalkyl, alkoxy group;

«0

0

0 *0 ·· • 000 • · 0

0 0

0000 00

0*0 • 0 00 • 0 0 0

0 0 0

0 0 0

0 0 0

0 0·

-(alkyl) _m -SR ¹⁹ ; -(alkyl) m -SO-R ¹⁹ ; -(alkyl) r a -SO ₂ -R ¹⁹ ; -(alkyl) m -SO2O-R ¹⁹ ; -(alkyl) m SO ₂ -NR ¹⁹ R ²⁰ ; -(alkyl) m -NHCOR ¹⁹ ; -(alkyl) m -CONR ¹⁹ R ²⁰ ; -(alkyl) m -CR'=NOR; (alkyl) m -CO-R ¹⁹ ; -(alkyl) m -CO ₂ -R ¹⁹ , where the index m is 0 or 1; and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

for the manufacture of a medicinal product for the treatment of disorders and diseases responsible for the modulation of the AMPA receptor complex.

A method for treating disorders and diseases responsive to modulation of the AMPA receptor complex, comprising administering a therapeutically effective amount of a compound represented by the general formula

R ³ where the bond represented by the dashed line may be a single bond, a double bond or absent; and if the bond is absent, then the nitrogen is substituted with a hydrogen atom and a substituent R ² ;

Φ· Φ· φ · V φφφφ φφφ φφφ φφφφ φφ

X represents SO ₂ or C=O or CH ₂ ;

Y represents -CH(R ⁴ )-, -N(R ⁴ )- or -N(R ⁴ )-CH ₂ -, O;

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl;

CO-R ⁹ , where the substituent R ⁹ represents alkyl, cycloalkyl, benzyl, aryl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

a 4-membered to 7-membered ring optionally substituted with one or more 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 ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy group, haloalkoxy group, acyl, alkyl-NR ¹³ R ¹⁴ , alkyl-SR ¹³ where the substituents R ¹³ and R ¹⁴ independently represent a hydrogen atom, alkyl, cycloalkyl; or the substituents R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure;

A carbocyclic 7- to 12-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; or

A heterocyclic 3-membered to 8-membered ring optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl;

Benzyl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy group, alkoxy group, amino group or thio group, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio group, alkylamino group;

ΦΦ ·· • * · • φφφ • φ • · φφφφ φφ φφ • · • φ φ · φ • φ φ φφ «φ φ« φ φ φ φ φ φφφ φ φ φ φ φ φ φ *♦ φφ

Aryl, which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino or thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, alkylamino; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4-membered to 7-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing a carbonyl group.

R ⁴ represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or CO2R ¹⁰ , where the substituent R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or

R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 4-membered or 7-membered ring optionally substituted with one or more 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 ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl,

-SO ₂ -NR ⁿ R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure 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 aryl;

• · • · • ·

R ⁶ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁵ R ¹⁶ , NHSO 2 -R ¹⁵ , NHSO ₂ -aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO ₂ , aryl;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl or amino;

HET optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy;

-(alkyl) _m -SR ¹⁵ ; -(alkyl)m-SO-R ¹⁵ ; -(alkyl)ra-SO ₂ -R ¹⁵ ; -(alkyl)M-SO2O-R ¹⁵ ; -(alkyl)mSO ₂ -NR ¹⁵ R ¹⁶ ; -(alkyl) _m -NHCO-R ¹⁵ ; -(alkyl)m-CONR ¹⁵ R ¹⁶ ; -(alkyl)m-CR'=NOR”; (alkyl) _m -CO- ^R15 ; -(alkyl) _m - _CO2 - ^R15 , where the index m is 0 or 1; and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents ^R15 and ^R16 independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents ^R15 and ^R16 together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, _aryl , benzyl, SO2alkyl, _SO2aryl , _SO2benzyl ; and optionally a heterocyclic ring fused to aryl;

• · · • · · • · ·· • · · · · • · · · · · · <2 ,

R represents a hydrogen atom, halogen, alkyl, cyano group, nitro group, nitroalkyl; alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl,

-NR ¹⁷ R ¹⁸ , NHSO 2 -R ¹⁷ , NHSCh-aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, CF ₃ , OCF ₃ , NO 2 , aryl;

-(alkyl) _m -SR ¹⁷ ; -(alkyl) m -SO-R ¹⁷ ;-(alkyl)]n-SO ₂ -R ¹⁷ ; -(alkyl) m -SO2O-R ¹⁷ ; -(alkyl) m SO ₂ -NR ¹⁷ R ¹⁸ ; -(alkyl) m -NHCOR ¹⁷ ; -(alkyl) m -CONR ¹⁷ R ¹⁸ ; -(alkyl) m -CR =NOR ; (alkyl) m -CO-R ¹⁷ ; -(alkyl) m -CO ₂ -R ¹⁷ , where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy group, alkoxy group, amino group, thio group, aryl, -S-alkyl, -S-aryl, SO-alkyl, SO-aryl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ NR ¹⁷ R ¹⁸ ;

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , SO2-NR R , where the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen, ·· ·· • · · · · · ♦ · · · · 9 to which they are attached, form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl;

or

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH ₂ ) n O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) n -, where the index n is 1 or 2; -SO-NR-(CH ₂ )„, where the index n is 1 or 2; -SO ₂ -(CH ₂ ) _n -, where the index n is 2 or 3; -SO-(CH ₂ )„-, where the index n is 2 or 3; CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ ) _n -NH-, where the index n is 1 or 2; -CONH-(CH ₂ )„, where the index n is 1 or 2; -CO-(CH ₂ ) ₂ -O-; -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3;

R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group, nitroalkyl;

Aryl optionally substituted with one or more substituents selected from the group consisting of halogen, CF3, OCF3, _NO2 , alkyl, cycloalkyl, alkoxy groups;

HET optionally substituted with one or more substituents selected from the group consisting of halogen, CF3, _OCF3 , _NO2 , alkyl, cycloalkyl, alkoxy;

-(alkyl) _m -SR ¹⁹ ; -(alkyl) m -SO-R ^I9 ;-(alkyl) m -SO ₂ -R ¹⁹ ; -(alkyl) m -SO2O-R ¹⁹ ; -(alkyl) m SO ₂ -NR ¹⁹ R ²⁰ ; -(alkyl) m -NHCOR ¹⁹ ; -(alkyl) m -CONR ^I9 R ²⁰ ; -(alkyl) m -CR'=NOR; (alkyl) m -CO-R ¹⁹ ; -(alkyl) m -CO ₂ -R ¹⁹ , where the index m is 0 or 1; and the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally ·· » · · • · 4 • · • · >··· « • ·· substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

Detailed description of the invention

The invention provides novel compounds of the above formula I.

Preferred embodiments of the invention are compounds of the above formula I, wherein

R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl; or

R ² together with the substituent R ³ and together with the atoms to which they are attached form

a 5-membered to 6-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups;

R ³ represents a hydrogen atom, cycloalkyl, cycloalkylalkyl, alkyl, haloalkyl, alkoxy group, and a carbocyclic 7- to 10-membered ring; a heterocyclic 5- to 6-membered ring; benzyl; aryl;

or the substituent R ³ together with the substituent R ² or R ⁴ forms a 5-membered to

6-member circle;

R ⁴ represents a hydrogen atom, alkyl, or the substituent R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 5- to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy group, alkoxy group, amino » 00 • 0

0 00 • · 0 groups or thio groups and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

0 0 00

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, phenyl,

-SO ₂ -NR ⁿ R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 5- to 6-membered ring structure;

R ⁶ represents a hydrogen atom, Br, F, I, cycloalkyl, alkyl, alkoxy group, alkoxyalkyl, phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy group;

HET;

-SR ¹⁵ ; -SO-R ¹⁵ ; -SO2-R ¹⁵ ; -SO2O-R ¹⁵ ; -SO2-NR ¹⁵ R ¹⁶ ; -NHCO-R ¹⁵ ; CONR ¹⁵ R ¹⁶ ; CR'=NOR; -CO-R ¹⁵ ; -CO2-R ¹⁵ , where the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure 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 a heterocyclic ring fused to aryl;

R ⁷ represents φ φ · φ φ φ φ φ φ φ φ φ φ • · · • · φ« • · • φ · hydrogen atom, Br, F, I, alkyl, cyano group, cyanoalkyl, nitro group, nitroalkyl; alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohalogenalkyl, -(alkyl) _m -NR ¹⁷ R ¹⁸ , NHSO2-R ¹⁷ , -SR ¹⁷ ; -SO-R ¹⁷ ; -SO2-R ¹⁷ ; SO2O-R 17 ; -SO2-NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR'=NOR ; -CO-R ¹⁷ ; -CO ₂ R ¹⁷ , where ^the substituents Ra and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl, SO ₂ NR ¹⁷ R ¹⁸ ;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ benzyl; and optionally the heterocyclic ring is fused to aryl; or

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5-membered to

A 7-membered ring having one of the following structures -O-(CH ₂ )„-O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ )„-, where the index n is 1 or 2; -SO-NR-(CH ₂ )„, where the index n is 1 or 2; -SO ₂ -(CH ₂ )„-, where the index n is 2 or 3; -SO-(CH ₂ ) _n -, where the index n is 2 or 3; CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ )„-NH-, where the index n is 1 or 2; -CO• Β Β Β > · Β

B B B B

NH-(CH ₂ ) _n , where the index η is 1 or 2; -CO-(CH ₂ ) ₂ -O-; -O-(CH ₂ )„-O-; where the index n is 1, 2 or 3;

R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group, nitroalkyl;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;

HET;

-SR ¹⁹ ; -SO-R ¹⁹ ;-SO2-R ¹⁹ ; -SO2O-R ¹⁹ ; -SO2-NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; CR -NOK ; -CO-R ¹⁹ ; -CO2-R ¹⁹ , where the substituents Ra and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure 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 a heterocyclic ring fused to aryl;

if X represents SO ₂ and Y represents N and the dashed line represents a single bond, then either R ⁷ or R ⁶ is chlorine if R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R ⁶ and R ⁷ are all hydrogen; and provided that R ³ can only represent CH 3 if R ⁵ is hydrogen or R ⁷ is not sulfamoyl;

and if X is SO ₂ and Y is N and the dashed line represents a double bond, then either R ⁷ or R ⁶ is chloro, when R ² , R ⁴ , R ⁵ , R ⁸ and the remaining R ⁶ and R ⁷ are all hydrogen; and provided that R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are not all hydrogen; and provided that the compound is not disubstituted by R ³ which is CH3, when R ⁷ is fluorine, bromine, iodine, CF3, _CH3 , NO ₂ , SO ₂ N(CH ₃ ) ₂ or R ⁶ is bromine, CF3, CH3, ethyl, methoxy; or R ⁵ is chlorine, CH3; or R ⁸ is chlorine; and provided that the compound is not

3-ethyl-6-methoxy-1,2,4-benzothiadiazine-1,1-dioxide;

-propyl-6-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

-ethyl-6-methoxy-1,2,4-benzothiadiazine-1,1-dioxide;

3-phenyl-7-bromo-1,2,4-benzothiadiazine-1,1-dioxide; 3-phenyl-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide;

5-bromo-7-chloro-3-methyl-1,2,4-benzothiadiazine-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-benzothiadiazine-1,1-dioxide; or

6-amino-7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide;

A more preferred embodiment of the invention is a compound of the above formula I, wherein

R ² represents a hydrogen atom, alkyl, cycloalkyl; or

R ² together with the substituent R ³ forms

a 5- to 6-membered ring; optionally substituted with one or more 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 ³ represents a hydrogen atom, cycloalkyl, alkyl, haloalkyl, alkoxy group, and a carbocyclic 7- to 10-membered ring; a heterocyclic 5- to 6-membered ring; benzyl; aryl; or

R ³ together with R ² or R ⁴ forms a 5- to 6-membered ring; optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups.

9

9 • · • ·

999 9

99 • 9 9 9

9 9 9

9 9 9

9 9 ·

And another advantageous embodiment is where

R ⁴ represents a hydrogen atom, alkyl, or together with the substituent R ³ and together with the atoms to which they are attached, form a 5- to 6-membered ring; optionally substituted with one or more 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 advantageous embodiment is where

R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, phenyl,

-SO ₂ -NR ^H R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure;

And another advantageous embodiment is where

R ⁶ represents a hydrogen atom, halogen, cycloalkyl, alkyl, alkoxy group, alkoxyalkyl,

Aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy;

HET;

-SR ¹⁵ ; -SO-R ¹⁵ ; -SO2-R ¹⁵ ; -SO2O-R ¹⁵ ; -SO2-NR ¹⁵ R ¹⁶ ; -NHCO-R ¹⁵ ; CONR ¹⁵ R ¹⁶ ; CR-NOR '; -CO-R ¹⁵ ; -CO2-R ¹⁵ , where the substituents R' and R” independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl, aryl, or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl,

• · • · • · ·

φφ φφ • φ * φ • · φ φ φ φ φ · • φ φ ·

SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to an aryl;

And another preferred embodiment is where R ⁷ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl) _ra -NR ¹⁷ R ¹⁸ , NHSO2-R ¹⁷ , -SR ¹⁷ ; -SO-R ¹⁷ ; -SO2-R ¹⁷ ; SO2O-R ¹⁷ ; -SO2-NR ¹⁷ R ¹⁸ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR'=NOR ; -CO-R ¹⁷ ; -CO ₂ where the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl, SO ₂ NR ¹⁷ R ¹⁸ ;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, NHCO-alkyl, nitro, OCF ₃ , -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ benzyl; and optionally the heterocyclic ring is fused to aryl; or

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5-membered to

A 7-membered ring having one of the following structures -O-(CH ₂ ) _n -O-; where the index n is 1, 2

ΦΦ φφ • φ φ • φφφ φφφ φφφ ΦΦ· φ φφ φφ φφ φ · φ « • · « φ φ φ φ φ • φ φ φ φφ φφ or 3; -SO ₂ -NR-(CH ₂ )„-, where the index n is 1 or 2; -SO-NR-(CH ₂ ) _n , where the index n is 1 or 2; -SO ₂ -(CH ₂ )„-, where the index n is 2 or 3; -SO-(CH ₂ )„-, where the index n is 2 or 3; CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ )„-NH-, where the index n is 1 or 2; -CONH-(CH ₂ ) _n , where the index n is 1 or 2; -CO-(CH ₂ ) ₂ -O-; -O-(CH ₂ )„-O-; where the index n is 1, 2 or 3;

And another advantageous embodiment is where

R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group, nitroalkyl;

Phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy;

HET;

-SR ¹⁹ ; -SO-R ¹⁹ ;-SO2-R ¹⁹ ; -SO2O-R ¹⁹ ; -SO2-NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; CR =NOR; -CO-R ¹⁹ ; -CO2-R ¹⁹ , where the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure 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 a heterocyclic ring fused to aryl;

Particularly preferred embodiments are compounds of the above formula I, wherein X represents SO ₂ ; Y represents N and the dashed line represents a single bond;

R ² represents H;

«* * 9 9 ·♦· • · 9

9 9

9999 »«

999

• 9 9 • 9 9

9 « • 9 9

R ³ represents a cycloalkyl, carbocyclic 7-membered to 10-membered ring; heterocyclic 5- to 6-membered ring;

R ⁴ represents H;

R ⁵ represents H;

R ⁶ represents a hydrogen atom, alkyl or halogen;

R ⁷ represents cyanoalkyl, nitroalkyl, haloalkyl, -(alkyl) _m -SO-R ¹⁷ ; -(alkyl) m -SO2-R ¹⁷ ; -(alkyl) m SO ₂ -NR ^,7 R ¹⁸ ; -(alkyl) m -CONR ¹⁷ R ¹⁸ ; -(alkyl) m -CR-NOR; -(alkyl) _m -CO-R ¹⁷ ; (alkyl) _m -CO ₂ -R ¹⁷ , where the index m is 0 or 1 and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl;

HET or

R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5-membered to

A 7-membered ring having one of the following structures

-O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ )„-, where the index n is 1 or 2; SO-NR-(CH ₂ ) _n , where the index n is 1 or 2; -SO ₂ -(CH ₂ )„-, where the index n is 2 or 3; -SO(CH ₂ )„-, where the index n is 2 or 3; -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ )„NH-, where the index n is 1 or 2; -CO-NH-(CH ₂ )„, where the index n is 1 or 2; -CO-(CH ₂ ) ₂ O-; -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3;

R ⁸ represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl,

-(alkyl) _m -SO-R ¹⁷ ;-(alkyl)m-SO2-R ¹⁷ ; -(alkyl)m-SO ₂ -NR ¹⁷ R ¹⁸ ; -(alkyl)m-CONR ^,7 R ¹⁸ ; (alkyl)m-CR-NOR'; -(alkyl) _m -CO-R ¹⁷ ; -(alkyl) _m -CO ₂ -R ¹⁷ , where the index m is 0 or 1;

»» ·«

Φ · ♦ * ♦ · • · • V

Φ * * ♦) • ΦΦ« • 9 · • · ···· Φφ ®· »·· • · · • · • 9 • 9 the substituents Ra R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl, benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl, or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, SO ₂ -alkyl, SO ₂ -aryl, SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; or

HET;

Special embodiments of the present invention are all of the following which relate to the above formula I.

An embodiment of the invention is where R ³ represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl,

CF ₃ , ethoxy group, norbomylene, norbornane, adamantane, benzyl; phenyl; or

R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 5-membered ring;

Another embodiment of the invention is where R ⁴ represents a hydrogen atom, methyl, ethyl; or the substituent R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 5-membered ring;

Another embodiment of the invention is, wherein

R ⁵ represents a hydrogen atom, chlorine, bromine, methyl, phenyl, -SO ₂ NH ₂ ;

Another embodiment of the invention is where R ⁶ represents a hydrogen atom, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy group, chlorine or bromine;

Another embodiment of the invention is where

R ⁷ represents a hydrogen atom, chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, -(CH ₃ )C=N-OH, CONH ₂ ,

CO ₂ -ethyl, cyano group, phenyl, 2-7V-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl, » · φ φ φ φφφφ

4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-AjjV-dimethylsulfamoylphenyl,

2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-thuryl,

3- furyl, 2-thienyl, 2-(γ-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl1.2.4- oxadiazol-3-yl, CH ₃ CONH-, CH ₃ SO ₂ NH-, NO ₂ , SO ₂ OH, phenyl-SO ₂ -, sulfamoyl, Λζ TV-dimethylsulfamoyl, Λζ/V-diethylsulfamoyl, γV-phenyl-γ-methyl-sulfamoyl, Ncyclohexyl-sulfamoyl, -SO ₂ -heterocyclic ring, wherein the heterocyclic rings are selected from the group piperidine, pyrrolidine, 1,2,5,6-tetrahydropyridine, tetrahydroquinoline, N-methylpiperazine, N-sulfonylmethylpiperazine, morpholine;

And another embodiment of the invention is where

R ⁸ represents a hydrogen atom, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy group;

Particularly preferred embodiments are compounds represented by the above formula I, wherein X is SO ₂ and Y is N and the dashed line represents a single bond and the substituent R ² represents a hydrogen atom or CH ₃ ;

and the substituent R ³ represents a cyclohexyl, cyclopentyl, norbomylene, norbomane, adamantane, phenyl, ethoxy group;

and the substituent R ⁴ represents a hydrogen atom or CH ₃ ;

and the substituent R ⁵ represents a hydrogen atom, CH ₃ , phenyl, sulfamoyl, chlorine, bromine, and the substituent R ⁶ represents a hydrogen atom, CH ₃ , 2-methoxyphenyl, methoxy group, chlorine, bromine, 2-pyridyl, 3-pyridyl; and the substituent R ⁷ represents a hydrogen atom, chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, -(CH ₃ )C=N-OH, CONH ₂ , CO ₂ -ethyl, cyano group, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2-methoxyphenyl,

4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-Y _> A-dimethylsuliamoylphenyl,

2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl,

3- furyl, 2-thienyl, 2-(Y-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl1.2.4- oxadiazol-3-yl, CH ₃ CONH-, CH ₃ SO ₂ NH-, NO ₂ , SO ₂ OH, phenyl-SO ₂ -, sulfamoyl, N,N-dimethylsulfamoyl, AζA-diethylsulfamoyl, A-phenyl-N-methyl-sulfamoyl, Ncyclohexyl-sulfamoyl, -SO ₂ -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;

R ⁸ represents methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl, methoxy group, • · · • · · ···

Another particularly preferred embodiment of the invention are compounds of the above formula I, wherein X is _SO2 and Y is N and the dashed line represents a double bond and the substituent ^R3 represents CH3 or _CF3 or the substituent ^R3 together with the substituent ^R4 and together with the atoms to which they are attached form and the substituents ^R4 , ^R6 and ^R8 are all hydrogen;

and R ⁵ is hydrogen or halogen;

and the substituent R ⁷ is 7V-methylsulfamoyl, Λζ/V-dimethylsulfamoyl, 7V-cyclohexyl sulfamoyl, tetrahydropyridyl-sulfonyl; SO ₂ OH, sulfamoyl;

Another particularly preferred embodiment of the invention are compounds of the above formula I, wherein X is C=O and Y is N, O or CH; and R ² represents a hydrogen atom; and

R ³ represents a hydrogen atom, CH ₃ , CF ₃ , cyclohexyl, norbornylene, phenyl, ethyl; and

R ⁷ represents a hydrogen atom, ΛζΥ-dimethylsulfamoyl, Γ-cyclohexylsulfamoyl, tetrahydropyridyl-sulfonyl, morpholinosulfonyl, sulfamoyl, bromine; and

R ⁵ represents a hydrogen atom or bromine; and

R ⁴ , R ⁶ and R ⁸ are hydrogen;

Another particularly preferred embodiment of the invention are compounds of the above formula I, wherein X represents CH2 and Y is N; and

R ³ represents cyclohexyl or norbornylene; and

R ⁵ represents a hydrogen atom or bromine; and

R ⁷ represents bromo or sulfamoyl; and

R ² , R ⁴ , R ⁶ and R ⁸ are hydrogen;

Another particularly preferred embodiment of the invention are compounds of the above formula I, wherein X represents SO ₂ and Y represents NH; and the dashed line is absent and R ² , R ⁴ , R ⁵ and R ⁸ are hydrogen;

R ³ represents cyclohexyl, methyl or hydrogen; and

R ⁷ represents N-dimethylsulfamoyl, tetrahydropyridylsulfonyl, bromo; and

R ⁶ represents bromine or hydrogen;

Another particularly preferred embodiment of the invention are compounds of the above formula I, wherein X is SO2 and N is _-NHCH2- ; and the substituent ^R3 represents 3-methylbut-2-yl, phenyl or cyclohexyl; and the substituent ^R7 represents 1-piperidino-sulfonyl.

• · · · • « · • · · ·

The most preferred embodiments of the invention are compounds of the above formula I, wherein the compounds are selected from the group consisting of:

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;

-Bicyclo[2,2,1]hept-5'-en-2'-yl-1-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3- Phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

1,2,3,5,10,10α-Hexahydrobenzo[e]pyrrolo[1,2-α]-1,2,4-thiadiazine-5,5-dioxide;

2- Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one;

-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(2'-nitrophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(2'-(N,N-dimethyl sulfamoylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl 1-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

·· · 0 ·

0 0 0

-Cyclohexyl-7-(3'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(3-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(1-methyl-177-2-imidazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

3-Cyclohexyl-7-(5'-methyl-r,2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cycohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-methylsulfonylamino-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-dioxide;

3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

2- Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide;

-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3- Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline- ^R ,7N-dimethylsulfonamide;

-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazi-7N-1,1dioxide;

3- Cyclohexyl-7-(N/V-diethylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 dioxide;

-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Methyl-7-piperidinosulfone 1-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Propyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Benzyl-7-piperidinosulfone 1-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

• · ·* • · · • · ·· • ·· ·· ·· ··· · · « · · • · · « · · · • · · · · · in · • · · · · · · ··· ·* ·· ··

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-(r ^, 2,3,6'-tetrahydropiperidino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide ^;

3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-7-(r-(r, ^2,3 ',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-(4'-methylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-7-(4'-methylsulfonypiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-bromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-r,2',3',5'-tetrahydropiperidinosulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-N-cyclohexylsulfonamide;

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-morpholinosulfonamide;

2- Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide;

-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Methyl-7-dirnthylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

3- Methyl-7-(r,2',3',6 ^, -tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

2- Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acids;

-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-8-hydroxy methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-8-(2-methoxy phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

• · φ φ · φ φ ·· φ · • · φ · · · · · · · · • ··· φ φ φ · φ · » • · φ φ · φ ··· · · · • · φ ΦΦΦ ΦΦ·· φφφφ φφ ΦΦΦ φφ ·Φ ··

3-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-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-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-2-methyl-7-morpholinesulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide;

7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide; 7-Methylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide;

7-Cyclohexylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide;

7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide;

7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;

7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide;

7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide;

7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4thiadiazine-5,5-dioxide;

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

3-Cyclohexyl-7-(γN,nN-diethylsulfamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-disulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine1,1-dioxide;

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

• · · · φ φφ φφ φφφ φφφφ φφφ· ···· · φ φ · φφ · ·· φφ φφ φφφ φφ φ φ · φ «φφ φφφφ

...... ··· ·· ·♦ ··

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;

3- Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

5,7-Dibromo-3-bicyclo[2,2,1]heptan-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Phenyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Methyl-5,7-dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl 1-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1dioxide;

3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide;

-Cyclohexyl-7,8-ethyldioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-cyclohexyl-6,7-ethyldioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

3-Phenyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1dioxide;

2-cyclohexylmethylamino-5-N,N-dimethylsulfamoylbenzenesulfonamide;

2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzenesulfonamide;

3-isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide;

-Cyclohexyl-7-cyclopentylsulfmyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexy 1-7-cyclopentysulfomyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide;

-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide or pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts

The chemical compound of the invention may be prepared in any form suitable for the intended application. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts and prodrugs of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from enanthic acid, formate derived from formic acid, fumarate derived from filmaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid. acids, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from orthophosphoric acid, phthalate derived from violet acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulfate derived from sulfuric acid, tartrate derived from tartaric acid, toluene-psulfonate derived from p-toluenesulfonic acid, etc. Such salts can be prepared by methods known and described in the prior 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 in obtaining the chemical compound of the invention and its pharmaceutically acceptable acid addition salt.

Metal salts of the chemical compounds of the invention include alkali metal salts such as the sodium salt of the chemical compound of the invention containing a carboxy group.

The chemical compound of the invention may be prepared in soluble or insoluble forms together with pharmaceutically acceptable solvents such as, for example, water, ethanol, etc. Soluble forms may also include hydrated forms such as, for example, monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc. Generally, for the purposes of this invention, soluble forms are considered equivalent to insoluble forms.

Definition of substituents

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means a straight or branched chain having 1 to 6 carbon atoms or a cyclic alkyl having 1 to 7 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl; methyl, ethyl, propyl and isopropyl are preferred groups.

Haloalkyl means the above alkyl substituted one or more times with halogen as defined above. Preferred embodiments are CF ₃ , C 2 F 5 , CH 2 Cl, CHCl 2 , -CHFCH 2 F, CHClCH 2 Cl;

Cycloalkyl means a cyclic alkyl having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Cycloalkylalkyl means the above cyclic alkyl and the above alkyl, wherein the alkyl may be considered as a substituent on the cycloalkyl and vice versa. Preferred groups are C ₃ .

6-cycloalkyl and Ci. _4- alkyl such as -(CH ₂ )-cyclopropyl, -cyclopropyl-(Ci-4-alkyl), -(CH ₂ )cyclohexyl, -cyclohexyl-(Ci- _4- alkyl), (Ci- _4- alkyl)-cyclobutyl, -cyclobutyl(Ci- _4- alkyl) -(C1.4alkyl)cyclopentyl, -cyclopentyl(Ci- _4- alkyl), -(Ci- ₄ -alkyl)cyclohexyl, cyclohexyl(C _1-4 alkyl);

Halocycloalkyl means the above cyclic alkyl which is substituted one or more times with the above halogen including, but not limited to, chlorocyclopropyl, fluorocyclopropyl, iodocyclopropyl, dichlorocyclopropyl, difluorocyclopropyl, chlorocyclobutyl, fluorocyclobutyl, chlorocyclopentyl, fluorocyclopentyl, iodocyclopenyl, φφ • · φ • φ ♦· • · · φφφ φ φ φ * φ φ * φ φ φ φ φ • φ φ φφφ · φ φ φφφ φφφ φφφ φφ φφφ φφφ φφφ φφφ φφφ φφφ φφφ chlorocyclohexyl, fluorocyclohexyl, dichlorocyclohexyl, difluorocyclohexyl, iodocyclohexyl. Preferred embodiments are monosubstituted and disubstituted cycloalkyl having 3 to 6 carbon atoms such as dichlorocyclopropyl, difluorocyclopropyl, chlorocyclohexyl, fluorocyclohexyl, iodocyclohexyl, chlorocyclopentyl, fluorocyclopentyl.

Alkenyl means a straight or branched chain having 2 to 6 carbon atoms containing one triple bond including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

Alkynyl means a straight or branched chain having 2 to 6 carbon atoms containing one triple bond and including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

An alkoxy group is O-alkyl, where alkyl is defined above.

Alkoxyalkyl is -alkyl-O-alkyl, where alkyl is as defined above.

Hydroxyalkyl is alkyl as defined above substituted with an OH group;

The amino group is NH ₂ or NH-alkyl or N-(alkyl) ₂ , where alkyl is defined above.

An alkylamino group is an alkyl as defined above which is substituted with an amino group as defined above. Preferred embodiments are -CH ₂ -N(alkyl) ₂ , -CH-N(alkyl) ₂ CH ₃ , CH ₂ CH ₂ N(alkyl) ₂ , -CH ₂ -NH ₂ , -CH-(NH ₂ )-CH ₃ , -CH ₂ CH ₂ NH ₂ ;

The cyano group is CN;

Cyanoalkyl is an alkyl as defined above substituted with a CN group;

The nitro group is -NO ₂ ;

Nitroalkyl is an alkyl as defined above substituted with a nitro group as defined above.

Β · · · · Β Β < · « * » Μ· ΒΒΒ i * * · • > ·· · Β Β · Β · · « • · · Β · Β · * · »

ΒΒΒ· ·Β ΒΒΒ ·· ·· ««

The thio group is SH or S-alkyl, where alkyl is defined above;

An alkylthio group is an alkyl as defined above substituted with a thio group as defined above.

Acyl is (C=O)-R° or (C=S)-R°, where R° is alkyl; phenyl, which may be substituted with one or more substituents selected from the group consisting of halogen, CF ₃ , NO2 , amino, alkyl, alkoxy, phenyl and SO ₂ NR'R, where R' and R are each independently hydrogen or alkyl or where R' and R are together with (CH ₂ ) _m , where m is 2, 3, 4, 5, or 6; or R° is benzyl; or NR ⁱⁿ R ^IV are each independently hydrogen or alkyl or where R ⁿⁱ and R ^IV are together with (CH ₂ ) p , where p is 2, 3, 4, 5, or 6.

An acylamino group is acyl-ΝΗ-, where acyl is defined above.

Aryl is an aromatic carbocyclic ring such as phenyl or biphenyl and a fused carbocyclic ring such as naphthyl;

HET is a 5- to 6-membered cyclic heteroaryl and includes, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-foranyl, 3-foranyl, 2-thienyl, 3-thienyl, 2pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl and 4-pyrazolyl, furanyl, tetrahydrofuranyl, pyrrolyl, pyrrolidyl, imidazolyl, oxadiazolyl, pyridyl, thienyl, isoxazolyl, pyrimidyl, pyrazole, triazolyl. Particularly preferred heteroaryls of the invention are pyridyl, pyrimidyl, triazole, phoryl, thienyl, oxadiazolyl, imidazolyl;

Carbocyclic 7- to 12-membered ring structures include monocyclic, bicyclic, and tricyclic structures. Preferred embodiments are 7- to 10-membered ring structures such as

ΏΌΌ • Φ «φ φ φ φ • φφφ • φ φ φφφφ φ φ φφ Φ· φφ • ΦΦΦ φφφφ φφφ φ φ φ φ • ΦΦ φφ φφ heterocyclic 3-membered to 8-membered ring structure includes partially or fully saturated heterocyclic ring structure such as aziridine, pyrrolidine, piperidine, piperazine, homopiperidine, homopiperazine, azacyclooctane, 1,3-diazacyclooctane, 1,4-diazacyclooctane, tetrahydrofuran, tetrahydrothiophene, morpholine, tetrahydropyridine and compounds such as e.g.

Preferred embodiments are 5-membered to 6-membered rings containing at least one nitrogen such as pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine.

The described 4-membered to 7-membered rings fused to the ring structures of 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 optionally containing a heteroatom and optionally containing a carbonyl group. Preferred rings are 5-membered and 6-membered carbocyclic rings;

The rings formed between the substituents R ⁷ and R ⁶ or R ⁸ are 5-membered or 6-membered and contain O, C=O, S=O or SO ₂ groups and optionally contain nitrogen.

Preferred rings are -O-(CH ₂ ) n -O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) n -, where the index n is 1 or 2; -SO-NR-(CH ₂ ) n -, where the index n is 1 or 2; -SO ₂ -(CH ₂ ) n -, where the index n is 2 or 3; -SO-(CH ₂ ) n -, where the index n is 2 or 3; -CO-CH=CH-NH-; -CO-(CH ₂ ) n -NH-, where the index n is 1 or 2; -CO-NH-(CH ₂ ) _{n -} , where the index n is 1 or 2; -CO-(CH ₂ ) ₂ O-;

The compounds of this invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water,

• · 9 99 99 99 • 9 • 99 9 9 9 ♦ • • • 9 9 9 • • » « « • 9 9 9 9 9 • • • • 9 9 999 99 99 ··

ethanol, etc. In general, for the purposes of this invention, solvated forms are considered equivalent to unsolvated forms.

Steric isomers

The chemical compounds of the present invention may exist in (+) and (-) forms, as well as in racemic forms. Racemates of these isomers and individual isomers are within the scope of the present invention.

The racemic forms can be resolved into their optical antipodes by known methods and techniques. One method of separating diastereoisomeric salts is to use an optically active acid and release the optically active amine compound by reaction with a base. Another method for resolving racemates into their optical antipodes is based on chromatography on an optically active matrix. The racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallization of the d- or 1- (tartrates, mandelates, or camphorsulfonate) salts.

The chemical compounds of the present invention can also be distinguished by forming diastereomeric amides by reacting the chemical compounds of the present invention with an optically active activated carboxylic acid such as those derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid, or by forming diastereomeric carbamates by reacting the chemical compounds of the present invention with an optically active chloroformate, etc.

Other methods for resolving optically active isomers are known in the art. Such methods are described in Jaques J, Collet A, & Wilen S in Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York (1981).

Furthermore, some of the chemical compounds of the invention which are oximes can thereby exist in two forms, syn- and anti-form (Z-form and E-form), depending on the arrangement of the substituents on the -C=N- double bond. The chemical compound of the present invention can thus be syn-form or anti-form (Z-form and E-form) or can be a mixture thereof.

The compound of the invention includes, where possible, endo-forms and exo-forms and tautomers.

Pharmaceutical preparations ·· Φ· • · · • φφφ φφφ Φ·ΦΦ ΦΦ

ΦΦ

ΦΦΦΦ • ·

ΦΦ

Φ Φ Φ

ΦΦ

An aspect of the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of a chemical compound of the invention and the use of the compounds of the invention for the manufacture of a medicament directed to the treatment of specific diseases and disorders;

While the chemical compound of the invention for use in therapy may be administered in the form of the unmodified chemical compound, it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical preparation together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceutical compositions comprising a chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient.

The pharmaceutical compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular and intravenous injections) administration or those in a form suitable for administration by inhalation or insufflation.

The chemical compound of the invention together with a conventional adjuvant, carrier or diluent may thus be incorporated into the form of pharmaceutical preparations and their unit dosages. Such forms include solids and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled in the same manner, all for oral use, rectal suppositories for rectal administration, and sterile injectable solutions for parenteral use. Such pharmaceutical preparations and their unit dosage forms may contain conventional ingredients in conventional doses with or without other active compounds or ingredients, and such unit dosage forms may contain any effective amount of the active ingredient commensurate with the intended use and daily dosage range.

The chemical compound of the present invention can be administered in a wide range of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as the active ingredient, either the chemical compound of the invention or a pharmaceutically acceptable salt of the chemical compound of the invention.

For the preparation of pharmaceutical compositions from the chemical compound of the present invention, the carriers may be either liquid or solid. Solid forms of compositions include

* «0 0 00 00 00 0 0 00 0 0 0 0 0 0 • 000 0 0 0 0 0 0 0 • Φ 0 0 00 0 0 0 0 0 00 0 0 00 0 0 0 00

powders, tablets, pills, capsules, cachets, rectal suppositories and dispersible granules. The solid carrier may be one or more substances which may function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, disintegrants or microencapsulating agents.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having the necessary binding capacity in suitable doses and compressed in the desired shape and size.

Powders and tablets preferably contain from 5% or 10% up to about 70% of the active ingredient. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter, etc. The term formulation refers to the association of the active ingredient with a microencapsulating agent as a carrier providing a capsule in which the active ingredient, with or without carriers, is surrounded by the carrier which is thus bound thereto. Similarly, capsules and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.

To prepare rectal suppositories, low melting waxes, such as fatty acid glycerides or cocoa butter, are first dissolved and the active ingredient is homogeneously dispersed by stirring. The liquid homogeneous mixture is then poured into a mold of suitable size, allowed to cool and thereby solidify.

Preparations suitable for vaginal application may be pessaries, tampons, creams, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be suitable.

Liquid preparations include solutions, suspensions and emulsions, e.g., water or water-propylene glycol solutions. For example, parenteral injectable liquid preparations may be prepared as solutions in an aqueous polyethylene glycol solution.

The chemical compound of the present invention may thus be prepared for parenteral administration (e.g., by injection, e.g., by bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, prefilled syringes, slow infusions, or in multi-dose containers with an added preservative. The formulations may be in such forms as, e.g., suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain agents for formulation such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in the form of

4· ΦΦ • Φ Φ

Φ ΦΦΦ

Φ Φ ΦΦΦΦ φφ

Φ ΦΦ Φ Φ Φ

ΦΦΦ

Φ

ΦΦΦΦ

Φ Φ φ ·

Φ Φ Φ Φ

Φ Φ φ Φ

Φ Φ Φ Φ

ΦΦΦ powder for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, obtained by aseptic isolation of a sterile solid or lyophilization from a solution.

Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding, as desired, a suitable colorant, flavoring, stabilizing agent, and thickening agent.

Aqueous suspensions suitable for oral use can be formed by dispersing the finely divided active ingredient in water with a viscous substance 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, into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizing agents, buffers, artificial and natural sweeteners, dispersants, thickening agents, solubilizing agents, etc.

For topical application to the epidermis, the chemical compound of the invention may be formulated as ointments, creams or lotions or as a transdermal patch. Ointments and creams may be formulated, for example, with an aqueous or oily base with the addition of a suitable thickening agent and/or gelling additives. Lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants.

Preparations suitable for topical administration in the mouth include tablets containing the active ingredient in a flavored base, usually sucrose and gum tragacanth or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerol or sucrose and gum tragacanth; and mouthwashes containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applicable directly to the nasal cavity by conventional means, e.g., by dropper, pipette or spray. The preparations may be provided in single-dose or multi-dose forms. Later, in the case of drops or pipettes, dosing may be effected by application of a suitable, predetermined volume of solution or suspension. In the case of a spray, dosing may be effected by means of a spray pump with a metered spray.

Application to the respiratory tract can also be achieved by means of aerosol delivery, in which the active ingredient is provided in a pressurized package with a suitable propellant such as a freon (CFC), e.g. dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane,

*♦ « 00 • 0 00 • « 0 0« « 0 0 • 0 « • 00« 0 0 0 0 « * « 0 • 0 0 0 0 0 0 0 0 0000 0 0 • 0 0 00 00 00

carbon dioxide or other suitable gases. The aerosol may also suitably contain a surfactant such as lecithin. The dose of the drug may be controlled by providing a metered dose closure.

In another method, the active ingredients may be provided in dry powder form, e.g., a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). A suitable powder carrier forms a gel in the nasal cavity. The powder preparation may be presented in unit dosage form, e.g., in capsules or cartridges, e.g., gelatin, or soft transparent packs, from which the powder may be administered by means of an inhalation device.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compounds will generally have a small particle size, e.g., on the order of 5 microns or less. Such particle size may be obtained by means known in the art, e.g., by grinding the fine particle.

If desired, formulations adapted to provide sustained release of the active ingredient may be used.

Pharmaceutical preparations are preferably in unit dosage forms. In such forms, the preparation is divided into unit doses containing a corresponding quantity of the active ingredient. A unit dosage form may be a packaged preparation, a package containing a small quantity of the preparation, e.g., tablets, capsules, and powders in tubes or ampoules. A unit dosage form may also be a capsule, tablet, cachet, or lozenge, or may be an appropriate number of any of these forms in a packaged form.

Preferred formulations are tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion.

The dose administered must, of course, be carefully adjusted according to the age, weight and condition of the patient being treated, as well as the route of administration, dosage form and regimen, and the desired result.

The active ingredient may be administered at one time or in several doses daily. A satisfactory result may in certain cases be obtained at a dose as low as 0.1 pg/kg i.v. and 1 pg/kg p.o. The upper limit of the dose range is considered to be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from about 0.1 pg/kg to about 10 mg/kg/day i.v. and from about 1pg/kg to about 100 mg/kg/day p.o.

Treatment method

·· « ·* ·· ·· * · • • Φ · • • • • 4 • ♦ · • • • • · • • · « · • · · ·♦ • • • · • • · ··

The compounds of the present invention are AMPA receptor stimulators and therefore useful in the treatment of a range of disorders and diseases responsive to AMPA receptor modulators. In an embodiment of the invention, the diseases are responsive to positive modulation of the AMPA receptor. The compounds can be used in the treatment, prevention, prophylaxis or alleviation of diseases, disorders or conditions of the central nervous system such as: neurodegenerative disorders, cognitive or memory dysfunctions, memory and learning disorders, attention deficit disorder, memory or learning disorders due to age, trauma, stroke, epilepsy; Alzheimer's disease, depression, schizophrenia, memory loss, dementia due to AIDS, senile dementia, learning deficit, cognitive deficit, sexual dysfunction, psychotic disorders, sexual dysfunction, intellectual disability, schizophrenia, depression or autism, attention deficit, or diseases or disorders due to neurotoxic agents, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia; A suitable dosage range is 0.1-500 milligrams per day and especially 10-70 milligrams per day, administered once or twice daily, depending generally on the proper route of administration, the form of administration, the indication for the route of administration chosen, the subject and the body weight of the subject, and other priorities and practice of the physician or veterinarian.

I.p. means intraperitoneally, which is a very well-known route of administration.

P.o. means orally, which is also a very well-known route of administration.

The invention then includes the following alone or in combination:

Use of the above compound for the manufacture of a medicinal product intended for the treatment of diseases that are responsible for the modulation of the AMPA receptor.

The above uses, wherein the disorders are memory or learning disorders, psychotic disorders, sexual dysfunction, intellectual disorders, schizophrenia, depression or autism; Alzheimer's disease, learning deficit, attention deficit, memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance misuse, heart bypass surgery or cerebral ischemia;

Biology

·· *· • ·· *· • · « • · · • • • • • ··· • · • • • « • • • • · • · • • • • 9 • · * * »· ·· · ·· • · ··

In vitro determination of ³ H-AMPA binding inhibition

L-glutamate (GLU) is the major excitatory neurotransmitter in the mammalian central nervous system. Electrophysiological and binding studies have revealed at least three subtypes of GLU receptors, tentatively designated N-methyl-D-aspartate (NMDA), chischalate, and kainate receptors. The chischalate- and kainate-sensitive GLU receptor subtypes are often collectively referred to as nonNMDA receptors. Receptor binding studies of the labeled agonists ³ H-AMPA (α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid) (for chischalate receptors) and ³ H-kainate (for kainate receptors) have shown different antagonist selectivities and local occurrences. AMPA has been known for several years to be a potent and selective agonist at the traditionally labeled chischalate receptors. Activation of chischalate receptors by AMPA is associated with Na ⁺ influx and K ⁺ efflux, leading to depolarization.

Non-NMDA receptors have recently been reclassified to include the activated metabotropic type of chischalate receptors, associated with the metabolism of inositol triphosphate and diacylglycerate. AMPA does not interact with the metabotropic chischalate receptor, but only the ionotropic chischalate receptor. The selective activation of the metabotropic type has been claimed for trans-ACPD. Potent and competitive antagonists of non-NMDA receptors CNQX and NBQX have now been described, and CNQX has been reported not to block the action of chischalate on the metabotropic subtype of receptors. ³ H-AMPA is a selective radioligand for labeling ionotropic chischalate (AMPA) receptors.

Tissue preparation

Preparations were performed at 0-4°C unless otherwise stated. Cerebral cortex from male Wistar rats (150-200 g) was homogenized for 5-10 seconds in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-Turrax homogenizer. The suspension was centrifuged at 27,000 x g for 15 minutes and the pellets were washed three times with buffer (centrifuged at 27,000 x g for 10 minutes). The washed pellets were homogenized in 20 ml buffer and incubated in a water bath (37°C) for 30 minutes to remove endogenous glutamate and then centrifuged for 10 minutes at 27,000 x g. The pellets were then resuspended in 30 ml buffer and the preparation was frozen and stored at -20°C.

φφ φφ φ

• φ

φ ·· ·· • · » • φφφ • · • · ΦΦΦΦ «0

φφ • Φ • φ φ • · · φ φ φ φ φ φ

Determination

The membrane preparation is thawed and centrifuged at 2°C for 10 minutes at 27,000 xg for 10 minutes. The pellets are 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 xg. The final pellets are resuspended in 30 mM Tris-HCl containing 2.5 mM CaCl ₂ and 100 mM KSCN, pH 7.4 (100 ml per g of original tissue) and used for binding assays. Aliquots of 0.5(0.2) ml are added to 25(20) μΐ of the test solution and 25(20) μΐ of ³ H-AMPA (5nM, final concentration), mixed and incubated for 30 minutes at 2°C. Non-specific binding is determined using L-glutamate (0.6 mM, final concentration). After incubation, 5 ml of ice-cold buffer is added to 550 μΐ samples and poured directly onto Whatman GF/C glass fiber filters with suction turned on and immediately washed with 5 ml of ice-cold buffer. The filters are washed with 3 ml of ice-cold buffer. The amount of radioactivity on the filters is determined by standard liquid scintillation counting. Specific binding is total binding minus non-specific binding.

Results

Test results will be reported as IC50 (concentration (μΜ) of the control substance that inhibits the specific binding of ³ H-AMPA by 50%)

Test results

The compound numbers correspond to the numbers in the table below.

Compound _IC50 (pM) 13 22.0 14 45.0 15 39.0 44 3.5 47 5.3 48 4.4 49 17.0 57 26.0

00 • 00 • 0 00 • 0 • 00 0 • 0 0 € 0 • 000 • 0 • • 0 • • 0 • • 0 • 0 • 0 0 0 0 ···· ·< ··· ·· 00 00

58 3.4 61 8.5 62 6.0 63 6.0 113 13.0 114 33.0 115 7.0

Potentiation of AMPA-induced release of [ ³ H]GABA from cultured cortical neurons

Neurons that express excitatory amino acid receptors can be depolarized by such compounds, and this depolarization actually leads to the release of the mediator from the neurons. Cultured neurons obtained from the cortex of 16-day-old mouse embryos are mainly GABAergic and express all types of excitatory amino acid receptors. That is, they can be stimulated by potassium (55 mM) or the excitatory amino acids NMDA (μΜ), AMPA (5 μΜ), and kainate (5 μΜ) to release their neurotransmitter GABA.

³ H-GABA can be used to label the GABA mediator pool in neurons, and the release of ³ H-GAB A from neurons can be used as a simple functional model for studying the effects of agonists, antagonists, and modulators of excitatory amino acid receptors.

Ways

Cell culture

Cerebral cortices from 15-16 day old NMRI mouse embryos are prepared by cutting into 0.4 x 0.4 mm cubes and the tissue is dissociated by mild trypsinization (0.1% (wt/vol) trypsin, 37°C, 10 min). Another cell suspension (3 mill/ml) is seeded into 30 mm poly-L-lysine-coated Petri dishes (3 ml/dish) containing slightly modified DMEM (24.5 mM KCl) supplemented with p-aminobenzoate (7 μΜ, insulin (100 mU/L) and 10% (v/v) horse serum. The cells are maintained in the culture medium for 5-7 days in vitro with the addition of the antimitotic agent cytosine arbinoside (5 μΜ) from day 2 to prevent glial proliferation. For further details and references see Drejer et. al. (Exp. Brain Res. 47, 259 (1982)).

Experiments to determine release

Release experiments are performed using the model described by Drejer et al. (Life Sci. 38, 2077 (1986)). To neurons of the cerebral cortex cultured in Petri dishes (30 mm) 10 mM γ-vinyl-GABA is added one hour before the experiment to inhibit the degradation of GABA in the neurons. 5 µCi ³ H-GABA is added to each culture 30 minutes before the experiment. After this pre-introduction, the cell monolayer at the bottom of the vessel is covered with pieces of nylon mesh to prevent mechanical damage and to facilitate the dispersion of the medium over the cell layer. The pre-loading medium is removed and the Petri dishes are placed in a superfusion system containing a peristaltic pump continuously feeding thermostated 37°C superfusion medium (HEPES buffered solution (HBS): 10 mM HEPES, 135 mM NaCl, 5 mM KCl, 0.6 mM MgSO ₄ , 1.0 mM CaCl ₂ and 6 mM D-glucose; pH 7.4) from the stock solution into the upper part of the slightly tilted Petri dishes. The medium is continuously ^concentrated from the lower part of the dish and fed into a fraction collector. Initially, the cells are superfused with HBS for 30 minutes (flow rate 2 ml/min), then stimulated for 30 seconds every 4 minutes by changing the superfusion medium from HBS to the corresponding medium containing 5 μΜ AMP A in the presence or absence of modulators.

The test substances are dissolved in 50% DMSO, 48% ethanol. The final concentration of DMSO and ethanol in the determination must not exceed 0.1%.

Results

The induced release of ³ H-GABA (cpm) is corrected for the mean basal release (cpm) before and after stimulation and used to calculate the assay value.

The potentiation of the AMP A response by the test substance is expressed as a ratio to the potentiation of the AMP A response induced by cyclothiazide (30 μΜ).

Results

The results of the assay are shown in Figures 1 and 2. The results show a significant increase, Figure 1 shows the potentiation of AMPA-induced [H ³ ]GABA release from cultured cortical neurons by compound 115. The potentiation is expressed as a ratio to the potentiation induced by 30 μΜ cyclothiazide.

Figure 2 shows the potentiation of AMPA-induced [ ³ H]GABA release from cultured cortical neurons by compound 11. The potentiation is expressed as a ratio to the potentiation induced by 30 μΜ cyclothiazide.

Artificially maintaining the membrane potential at a certain level

Ways

The experiments are performed in a membrane potential clamp apparatus using standard methods for these experiments (Hamill et al., 1981) essentially as described above (Mathiesen et al., 1998). The following salt solutions are used: NaCl (140), KC1 (4), CaCl ₂ (2), MgCl ₂ (1), sucrose (30), tetrodotoxin (0.0003), bicuculline iodomethylate (0.005) and HEPES (10, pH 7.4). Intracellular solution (mM): CsCl (120), CsF (20), MgCl ₂ (2), EGTA (10), HEPES (10, pH = 7.2).

Cell cultures

Mouse neocortical neurons are cultured essentially as described by Drejer et al. (1987). Briefly, forebrains from embryonic (E 17) NMRI mice are removed under sterile conditions. The tissue is prepared by cutting into 0.4 mm cubes and triturated with trypsin (12.5 pg/ml) and DNAse (2.5 μg/ml), 15 min, 37°C. The cells are suspended at a concentration of 1 x 10 ⁶ cells/ml in slightly modified DMEM containing horse serum (10% (v/v)), penicillin (333 U/ml), para-aminobenzoic acid (1 mg/ml), L-glutamine (0.5 mM), insulin (0.08 U/ml) and KCl (23.8 mM). The cell suspension is then inoculated into Petri dishes (2 ml/dish) coated with poly-L-lysine. Glass coverslips (3.5 mm) are placed in the dishes before plating. After 24 hours of cultivation, the medium is replaced with freshly prepared medium containing 1% N ₂ as a supplement instead of serum.

Before performing the experiment, the cells are maintained in culture for 7-14 days at 37°C (5% CO ₂ /95% O ₂ ).

Electronics, programs and data acquisition: An EPC-9 amplifier (HEKA-electronics,

Lambrect, Germany) running on a Power Macintosh G3 computer via an ITC-16 interface. Experimental conditions were set by Pulse software connected to the amplifier. Data were slowly passed and directly taken to the hard disk at a rate of 3 x the cutoff frequency.

Pipettes and electrodes: Pipettes were made of borosilicate glass (Modulohm, Copenhagen, Denmark) using a horizontal electrode puller (Zeitz-Instrumente, Augsburg, • · · · > · · • · · ·

Germany). In the salt solutions used in these experiments, the pipette resistance was 1.7 - 2.4 MW. The pipette electrode was a chlorinated silver wire and the reference electrode was a silver chloride pellet electrode (In Vivo Metric, Healdsburg, USA) fixed at the experimental site. Just before sealing, the electrodes were zeroed with an open pipette in the bath.

Experimental procedure: Coverslips were transferred to a 15 ml experimental chamber attached to an inverted microscope frame (IMT-2, Olympus) supplied by Nomarski. Neurons were continuously superfused with extracellular saline at a rate of 2.5 ml/min. After creating a giga seal (1-5GW, success rate of 90%), the entire cell cluster was reached with suction.

Cells were held at a holding voltage of -60 mV and current was measured continuously for at least 30 seconds at the start of each experiment to ensure stable current leakage. AMPA-containing solutions were fed into the chamber via a custom-made weight-driven feed line, the tip of which was positioned approximately 50 μm from the cell. Application was initiated when the tubing connected to the feed line was depressed by a valve controlled by Pulse software. AMPA (30 μM) was applied for 1 second every 45 seconds. After repeatable amplitude responses were obtained, the compound to be tested was included in both the chamber and the AMPA-containing solution. The compound was present until responses of new repeatable amplitudes were obtained.

The sampling interval in all experiments was 310 pseconds.

All experiments were performed at room temperature (20 - 25°C).

Substances

Pregnant (9 days) NMRO mice were obtained from Bomhlotgaard Breeding and Research Center, Ry, Denmark.

Horse serum, N2 supplement and culture medium were purchased from Life Technologies (GIBCO), Roskilde, Denmark.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolylpropionic acid) was synthesized at NeuroSearch A/S. Tetrodotoxin was purchased from Alomone Labs, Jerusalem, Israel and bicuculline iodomethylate from RBI, MA, USA. Sucrose was from Fluka Chemie, Buchs, Switzerland. All other reagents were from SIGMA, USA.

• · · ·

Results

The results are shown in Fig. 3-7.

Compounds 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114 (Fig. 7) and 115 (Fig. 5) potentiated the current induced by the addition of 30 μΜ AMPA. An example for each compound is given below. It can be seen that the potentiation in each case is reversible, although the effect of compounds 56 and 63 persisted for several minutes after the compounds were washed out. The time between AMPA stimulations was 45 seconds. Bars in the graph: 63: 200 pA/2 sec; 56: 500 pA/5 sec; 115: 50 pA/2 sec; 111: 400 pA/3 sec; 114: 40 pA/sec. In the experiments mentioned, the concentration of the compounds was 3 μΜ (56, 63 and 114) or 10 μΜ (111 and 115). The effect of the compounds was concentration-dependent as shown in the example of compound 114 below (bar in the graph 200 pA/5 sec). (Fig. 8)

Links

Drejer J., Honoře T. and Schousboe A. (1987) Excitatory amino acid-induced release of ³ HGABA from cultured fly cerebral cortex intemeurons. J. Neurosci. 7: 2910–2916.

Hamill OP, Marty A, Neher E, Sakmann B and Sigworth FJ. (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pluggers 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 neurones and cultured fly cortical neurones. Eur. J Pharmacol. 353: 159–157.

Iontophoretic applications

Purpose

In vivo evaluation of the effects of positive AMPA modulators (PAMs) on AMPA-evoked impulse activity in the rat hippocampus.

Principle

The firing activity of a single hippocampal neuron is strongly influenced by excitatory input, and iontophoretic application of AMPA induces firing activity in vivo in a dose-dependent manner (Mathiesen et al. 1998). The firing activity induced by AMPA is

inhibited by intravenous (i.v.) administration of a broad spectrum of AMP A receptor antagonists (Mathiesen et al. 1998), indicating that excitation is primarily mediated through AMP A receptors. PAM potentiates AMPA receptor activation in vitro and if this mechanism also operates in vivo, i.v. injection of PAM should increase the activity of AMPA-evoked impulses. Thus, the aim of this study was to test the in vivo effect of a group of in vitro active PAMs. This was done by studying their ability to increase the activity of AMPA-evoked impulses after i.v. administration.

Preparation

The experiments were performed on male Wistar rats (Μ & B, Denmark) weighing 280 - 380 g, housed in two cages 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 blood pressure monitoring and vein for intravenous drug injection and regular injections of 0.9% NaCl (0.5 - 1.0 ml h ¹ ) and mebumal (5 - 10 mg h' ¹ ). If the rat responded to hindpaw pressure, additional anesthetic was administered. The trachea was cannulated and the rats were placed in a stereotaxic frame and ventilated with a rodent ventilator (Ugo Basile, Comerio-Varese, Italy). Core body temperature was maintained at 37.5°C using an electric pad. The left and dorsal part of the parietal bone was removed by craniotomy and the dura mater was retracted exposing the choroid and underlying brain, covered with 0.9% NaCl.

Compounds/reagent

AMPA (Sigma, USA) was dissolved to 10 mM in 0.2 M NaCl. NMDA (Sigma, USA) was dissolved to 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 CH ₃ SO ₃ 'Na ⁺ to a concentration of 10 mM for iontophoretic applications (pH 5.7) and in isotonic glucose (278 mM) for iv application. Cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 56, COMPOUND 115 and COMPOUND 114 were dissolved in 5% chromophore solution to a concentration of 5 mg ml' ¹ .

Parameters

The evoked neuronal activity of the pulses was analyzed on-line by a computer, with individual pulse values and the duration of the event being recorded. The neuronal activity of the pulse (number of action potentials per second) was monitored on a pulse rate histogram together with indicators for AMPA, COMPOUND 61 and transmitter application.

·· ··

I · · 4 » · · 1 • · · · » · 9

9 44

Procedure

Extracellular recordings of single-pulse hippocampal neurons were obtained using five-cylinder glass electrodes (5B120F-6, World Precision Instruments Inc., Sarasota, Florida, USA) with a tip diameter of 10-12 pm. Individual cylinders were filled with 5 M NaCl (recording), 400 mM NaCl (buffering), 10 mM COMPOUND 61 in 200 mM _CH3SO3'Na (pH _4.7 ), ₂₀₀ mM _CH3SO3Na ⁺ (pH 4.7, transmitter), and the last cylinder was filled with AMPA.

Experiments were performed on hippocampal neurons (A = 5.5 - 6.5 mm, L = 1.5-2.0 mm, H = 2.0 - 3.0 mm, according to Paxinos and Watson, 1986). Neuronal impulse activity was evoked by iontophoretic application of AMPA for 10 to 15 s with 1.5 min intervals. Single neuron impulse activity was amplified 500 times with a waveband of 0.3 and 3 kHz (CyberAmp 320 with Al 402 x 50 with intelligent probe, Axon Instruments, California, USA). On-line and off-line analyses were performed using the Spike2 program with a 1401p/ws interface (Cambridge Electronic Design Limited, England). The computer program also recorded mean arterial blood pressure and monitored and regulated the iontophoretic application.

AMPA was released into the hippocampus in standard cycles of 100-105 s. After neuronal responses were stable (i.e., no more than 10% variation in AMPA responses measured over a 10-s period) for at least 30 min, a single dose of either cyclothiazide, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61, or COMPOUND 114 (10 mg kg- ¹ ) was injected into the femoral vein. Recording of neuronal firing activity was continued for at least 45 min after intravenous injection. PAM reactivity was assayed by microiontophoretic application of COMPOUND 61 (20 nA, Fig.).

Results

Fig. 8 shows that iontophoretic application of COMPOUND 61 increases the activity of AMPA-evoked impulses, since the transmitter does not affect the evoked impulse activity. Intravenous application of cyclothiazide (10 mg kg ^-1 ) does not increase the activity of AMPA-evoked impulses.

Fig. 9. Iontophoretic application of COMPOUND 61 increases the activity of single neuron impulses evoked by pooled AMPA.

Φ Φ · ·

I · · • ΦΦΦ φ φ φ φ φφ φφ

Fig. 10. Cyclothiazide (10 mg kg ¹ iv) does not affect the activity of AMPA-evoked impulses in the hippocampus. The shaded box above the AMPA1 recording line indicates the time of application (1500 s after the start of the recording).

The in vivo effects of PAM on AMPA-evoked impulse activity were dependent on the level of control impulse activity. COMPOUND 63 enhances small AMPA responses elicited by low-intensity AMPA stimulation but has only a marginal effect on large AMPA responses elicited by high-intensity AMPA stimulation (Fig. 11). Initial inhibition of AMPA responses and onset of enhancement occur 15 to 30 minutes after iv administration (Fig. 11). The figure shows the enhancement of AMPA responses by COMPOUND 56 (10 mg kg ¹ ). The onset occurs approximately 10 minutes after administration (Fig. 12).

Fig. 11. COMPOUND 63 (10 mg kg ¹ iv) increases low-intensity AMPA responses (12 nA) but has only a marginal effect on high-intensity AMPA responses (17 nA). 1500 s after the start of recording, 10 mg kg ¹ COMPOUND 63 was administered. The injection time is indicated by the shaded box above the AMPA2 recording line.

Fig. 12. COMPOUND 56 (10 mg kg- ¹ iv) increases the activity of AMPA-evoked impulses. The compound is injected 1250 s after the start of the recording. The injection time is indicated by the shaded box above the AMPA recording line.

Fig. 13. Shows an example of the increase in AMPA spike activity after iv administration of COMPOUND 115 (10 mg kg' ¹ ). The effect began 2 min. after iv administration and lasted for more than 2 hours. COMPOUND 61 (10 mg kg ¹ ) also increases AMPA responses in the hippocampus. The threefold increase in AMPA spike activity induced by COMPOUND 61 begins 20 min after administration and lasts for more than 2 hours (Fig. 14). COMPOUND 114 (10 mg kg ¹ ) induces a tenfold increase in AMPA responses, the control level of AMPA responses is low (from 21 to 209 responses in the form of pulses' ¹ , medium response, Fig. 15 ), while only a smaller increase is observed with the higher control response (from 124 to 204 responses in the form of pulses' ¹ , Fig. 16 .).

• · · * • ♦ · • · ·· « · · ♦· ·· « · • · · * « 9 · · • · ·

9 9 9

99

Fig. 13. COMPOUND 115 (10 mg kg- ¹ iv) increases the activity of AMPA-evoked impulses in the hippocampus. The shaded box indicates the time of iv injection, 1990 s after the start of recording. The effect of COMPOUND 115 lasted for more than 2 hours.

Fig. 14. COMPOUND 61 increases AMPA responses in the hippocampus. The compound (10 mg kg' ¹ ) is applied 1000 s after the start of recording (the time of application is indicated by the shaded box above the recording line). The effect of COMPOUND 61 lasted for more than 2.5 hours.

Fig. 15. COMPOUND 114 (10 mg kg- ¹ iv) increases the activity of AMPA-evoked impulses. The compound (10 mg kg- ¹ ) is applied 1730 s after the start of the recording, which is indicated by the shaded box above the AMPA recording line.

Fig. 16. COMPOUND 114 (10 mg kg ¹ ) approximately doubles AMPA responses. The compound is applied 3900 s after the start of the recording, which is indicated by the shaded box above the AMPA Recording Line.

The results show that cyclothiazide does not show any in vivo effects after i.v. administration. However, COMPOUND 63, COMPOUND 56, COMPOUND 115, COMPOUND 61 and COMPOUND 114 increase the activity of AMPA-evoked impulses in an activity-dependent manner.

Links

Mathiesen, C., Varming, T. & Jensen, L.H. (1998). In vivo and in vitro evaluation of AMPA receptor antagonists in rat hippocampal neurones and cultured fly cortical neurones. European Journal of Pharmacology 353, 159-167.

Paxinos, G. & Watson, C. (1986). The rat brain in stereotaxic coordinates. Second Edition.

Passive inefficiency

Purpose: To test the pharmacological effect of compounds on associative memory.

Principle: Mice are placed in a light chamber with access to a dark chamber. If they enter the dark chamber, they receive an electric shock to the foot (0.4 mA). After a 24-hour delay, the test is performed • · <

• · ι • t ··

• ♦ * • · ♦♦ • · · • · · · • · « I • · · • · · · · · • « · ··· •

association to risking an unpleasant electric shock to the leg by re-entering the dark chamber.

Animals: Female NMRI mice (Bomholdgaard, DK) weighing 22 - 25 g were used. Mice were housed in Macrolon plastic cages with free access to food (Altromin, DK) and tap water. Mice were allowed to acclimate to laboratory temperature for at least 3 days before testing (light 7:00/dark 19:00).

Apparatus: The passive incapacitating apparatus consisted of modular test chambers (ENV-307, MED-Associates, US). The light and dark chambers consisted of Plexiglas boxes of uniform size (15 x 17 x 13 cm; width x length x depth) with metal grid floors. A movable guillotine door was placed in the opening connecting the two chambers. A manual scrambler net (ENV-412, MED-Associates, US) was used to deliver a 0.4 raA foot shock.

Parameters: Entry latency (sec) to re-enter the dark chamber was measured.

Procedure: Mice were pre-conditioned (typically 30 minutes) before challenge with test compound.

Preparation: One mouse is placed in a light chamber and the guillotine door to the dark chamber is opened. When the mouse enters the dark chamber with all four paws, it receives one elec. shock to the paw (0.4 mA) and is removed to its home cage. Test. After a 24-hour delay, the mouse re-enters the light chamber and the waiting time to enter the dark chamber is measured with a time limit of 2 minutes. If the mouse does not enter the dark chamber within the time limit for the test (2 minutes), it is assigned a waiting time value of 2 minutes.

Carrier: 10%Tween80.

Dose volume: 10 ml/kg

N = 10;

Results; Mean (±SEM) input latency for each group is shown.

The results in Fig. 17 show the effect of different concentrations of compound 61 on memory improvement;

» t • ♦♦ φφ φφ • φ · « φ. r · φ φφφ φφφφ φ * φφφ φφ φ φφφ φφφφ • φφ φφ ·· ΦΦ

Brief description of the images

Fig. 1 and Fig. 2 show the potentiation of AMP A-induced [ ³ H]GABA release from cultured cortical neurons by compounds of the invention.

Fig. 3-8 show experiments with artificially maintaining the membrane potential at a certain level on the compounds of the invention. Compounds 56 (Fig. 3), 63 (Fig. 4), 111 (Fig. 6), 114 (Fig. 7) and 115 (Fig. 5) potentiate the current induced by the application of 30 μΜ of the substance AMP A.

Fig. 8 shows the concentration-dependent effect of the compounds of the invention (114).

Fig. 9 -16 are iontophoresis experiments.

Fig. 9. Iontophoretic application of COMPOUND 61a iontophoretic application of the carrier;

Fig. 10. Cyclothiazide is applied in the hippocampus.

Fig. 11. Application of COMPOUND 63;

Fig. 12. Application of COMPOUND 56.

Fig. 13. Application of COMPOUND 115.;

Fig. 13. COMPOUND 115 in the hippocampus.

Fig. 14. COMPOUND 61 in the hippocampus.

Fig. 15. COMPOUND 114;

Fig. 16. COMPOUND 114;

Fig. 17. Passive deactivation assay for compound 61.

·· φφ • ♦ · • · ·« ·« φφ • · « · • · φ « φ · · φ φ φ · ·

Φ· φφ

General synthesis methods

Method A

General sulfamoylation

i. CISQjH Δ «. HNR' _{2 R} . in ^R y ^s >

X ' NR _Z NR ₂ • φφ φφ · · • · ·

The compound (32.5 mmol) to be chlorosulfonated is dissolved in chlorosulfonic acid (75 mL) and heated in an oil bath at 110°C until TLC indicates the end of the reaction*. The reaction mixture is poured onto ice and the precipitate formed is isolated by filtration. The isolated solid is washed with a small amount of water and dried on the filter. The solid is dissolved in dry THF (200 mL) and excess amine (230 mmol) is added and the reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is evaporated to dryness, then stirred with water to give a solid which is isolated by filtration and washed with EtOAc on the filter. Further purification is possible either by column chromatography or by recrystallization from EtOAc/hexanes. Yields are usually: 60 - 90%.

*[A small aliquot is taken, added to ice in a test tube, neutralized with Na2CO3 and then extracted with EtOAc. The aqueous phase is removed and piperidine (xs) is added to the organic phase and allowed to stand for some time. TLC is done on this small reaction mixture as a standard].

Method B o-Sulfamoylation of anilines^

i. CISOjNCO θν® Τ/θ etc. AICl, A IfeSO, (6 M, aq.)

NHR ^Δ _r A^NHR

R

To a stirred solution of an aminobenzene derivative (250 mmol) in nitroethane or nitromethane (100 mL) at -50°C is added a solution of C1SO ₂ NCO (275 mmol) in nitroethane or nitromethane (75 mL) such that the reaction temperature does not exceed -30°C. The cooling bath is removed and the thick reaction mixture is warmed to 0°C. Solid AlCl 2 (300 mmol) is added all at once. The clear brown reaction mixture is heated in an oil bath at 120°C for 20 min, then cooled to room temperature and poured into a beaker of stirred ice water (1 L). The precipitate formed is isolated by filtration*. The urea intermediate (98 mmol) is suspended in a mixture of dioxane (250 mL) and 6 M H ₂ SO ₄ (or just concentrated HCl) (500 mL) and heated to reflux overnight.

0· 00 » 9 9

9 9 9

9999 99

00 • * ř « • · · · ι * · «

0» ·0

The reaction mixture is cooled to room temperature, filtered and the dioxane is removed from the filtrate by evaporation. The aqueous residue is neutralized to pH = 7 - 8 using 4 M NaOH. The precipitate formed is isolated by filtration and washed with water and EtOAc? Yields range from 10% to 75%.

t see also Girard Y., Atkinson J.G. and Rokách J., J. Chem. Soc., Perkinl, (1979) 1043.

*[Meta substituted anilines will give a mixture of two possible isomers, which at the urea intermediate stage can be separated by crystallization from MeOH or at the final product stage by crystallization from EtOAc/hexanes or chromatography.]

Method C

Application of the trifluoroacetyl protecting group

To a stirred solution of the 2-aminobenzenesulfonamide derivative (27 mmol) in dry THF (75 mL) at 0°C is added trifluoroacetic anhydride such that the reaction mixture does not exceed +10°C. The reaction mixture is stirred at room temperature until all the starting material has reacted. The reaction mixture is evaporated to dryness, stirred with water, filtered and washed with hexanes. PPA (250 g) is added to the isolated solid and heated in an oil bath at 140°C for 2.5 hours. The reaction mixture is cooled to 60 - 70°C and poured into a mechanically stirred solution of ice water. The precipitate formed is isolated by filtration and air dried. All yields are usually between 85 - 90%.

Method D

Removal of the trifluoroacetyl protecting group

A stirred solution of the trifluoroacetyl-protected compound (3.6 mmol) dissolved in 1 M KOH (30 mL) was heated at 80°C for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 using concentrated HCl (aq). The reaction mixture was

•« ♦ ·· ·· ·· • « • • * · • ♦ ♦ • « • ··* • fl • • • • • • • « · • · • • • • • ···· · ·· ·« • Φ

cooled to 0°C and filtered. The isolated solid is washed with water and air dried. Yields are usually in the range of 85 - 95%.

Method E

Formation of dihydrobenzothiadiazines-1,1-dioxide from 2-aminobenzenesulfonamides

i. R'-COCI, DMAP, TEA li. 1 M NaOH, Δ

IN

N{H)

A, (H)

To a stirred solution of 2-aminobenzenesulfonamide derivative (148 mmol), triethylamine (150 mmol), 4-(7N,N-dimethylamino)pyridine (7.5 mmol) in 600 mL THF at 5°C was added carboxylic acid chloride. 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 1 M NaOH (250 mL) and heated at 80°C for 3 h. The reaction mixture was cooled to room temperature and the pH was adjusted to 7 using concentrated HCl. The precipitate formed was isolated and recrystallized from z-PrOH. All yields were in the range of 80-90%.

Method F

Reduction of dihydrobenzothiadiazines-1,1-dioxide to tetrahydrobenzothiadiazines-1,1-dioxides in v a ,N(H) DIBALH 'NH

N-^R· ^M (H) ^R H

To a stirred solution of dihydrobenzothiadiazine-1,1-dioxide (19.4 mmol) in dry THF (200 mL) at -70°C was added a 1.5 M solution of DIBALH in toluene (33 mL; 50 mmol). The reaction mixture was allowed to stir overnight while the temperature slowly increased from -70°C to -15°C*. Water (10 mL), 1 M NaOH (5 mL) were added to the reaction mixture. The reaction mixture was then warmed to room temperature and extracted with EtOAc. The combined organic fractions were dried over MgSO ₄ and evaporated to dryness. In some cases, the product was further purified by column chromatography. Yields ranged from 45 - 85%.

*[If the temperature is not carefully controlled, the aminal product is further reduced to a ring-opened alkylamine].

Method G

Formation of tetrahydrobenzothiadiazines-1,1-dioxides from 2-aminobenzenesulfonamides

00

00 ·0

0 00

0 0

0· 0000 00

0

0

0 0 t 0

00

0 0 ·0 0 *0 0 0 0 00

A stirred solution of the 2-aminobenzenesulfonamide derivative (7 mmol), the aldehyde (10 mmol) and MgSO ₄ (20 mmol) in dry THF or dry dioxane (40 mL) is refluxed under N 2 until TLC indicates complete reaction of the 2-aminobenzenesulfonamide derivative (usually 12 - 36 hours). The reaction mixture is filtered, the precipitate is washed with THF or dioxane. The filtrate is evaporated to dryness, water is added and EtOAc is extracted. The combined organic fractions are dried over MgSO ₄ and evaporated to dryness. Column chromatography (EtOAc/hexanes) provides the pure product. Yields range from 25 - 75%.

Method H

Formation of substituted aryls or hetaryls using Pd-catalyzed cross-coupling + Metalated areyl/hetarene catalyzed - Pd additives

Helaryl/Aryt

R

Suzuki coupling: A stirred mixture of an aryl halide (2 mmol), an aryl or hetaryl boronic acid, a boronic acid ester or a dialkyl borane (6 mmol), K2CO3 (10 mmol), Pd( _PPh3 ) ₄ (30 mg), 1,3-propanediol (10 mmol), dimethoxyethane (50 mL) and H2O (25 mL) under N2 is heated at 70°C for 3 h. The reaction mixture is cooled to room temperature. Additional water is added and the reaction mixture is extracted with EtOAc. The combined organic fractions are dried over _MgSO4 and evaporated to dryness. Column chromatography affords the pure product. Yields range from 40 - 100%.

Method I

Formation of compounds having triazolyl substitution

X = Br, I

·· 99 • 99 99 ·« • 9 9 99 9 9 • · • 9 9 999 9 9 9 • 9 • 9 « • 9 9 9 9 9 9 9 • « 999· 99 999 99 99 99

Sonogashira coupling, a mixture of aryl iodide or aryl bromide (2 mmol); acetylene (10 mmol); Pd(PPh3)2Cl2 (140 mg; 0.2 mmol); Cul (40 mg; 0.1 mmol) and triethylamine (10 ml) under _N2 is stirred at room temperature overnight (in the case of aryl bromides, prolonged heating at 60°C is necessary). THF is added and the reaction mixture is filtered through Celite and the filtrate is evaporated to dryness. Column chromatography gives the ethynylated arene. Yields range from 40-53% for aryl bromides to 97% for aryl iodides.

Detrimethylsilylation for R' TMS: To a solution of the ethynylated arene (1.7 mmol) in MeOH (8 mL) was added 1 M KOH in MeOH (2 mL; 2 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with THF, adsorbed onto silica gel, and chromatographed to afford the desilylated ethynyl arene. Yields ranged from 61% to 73%.

Formation of triazolyl. Ethynylarene (0.7 mmol) and TMS-N3 (2 ml; 15 mmol) are heated at 170°C in a vial for 50 hours. The reaction mixture is cooled to room temperature and evaporated almost to dryness (caution! Evaporation to dryness can lead to an explosion due to the presence of HN3) and MeOH is added. The reaction mixture is stirred for 1 hour (to remove the TMS-group in the TMS-triazole), then adsorbed onto silica gel and purified by chromatography. Yields range from 20 - 72%.

44 » · • ··· ·· 9 9

4 ·

4494 94 • ·· 44 4 9

9 4

4

9 9

494 44

4 9

4 4

4 ·

4 ·

Examples of embodiments of the invention

Compound 1

2-Cyclohexyl-4-oxo-1,2,3,4-tetrahydroquinazoline

Anthranilamide is processed by method G (using cyclohexanecarboxaldehyde). Melting point 172-174°C.

Compound 2

2-Phenyl-4-oxo-1,2,3,4-tetrahydroquinazoline

Anthranilamide is processed by method G (using benzaldehyde). Melting point 221-222 °C.

Compound 3

2-Methyl-3,4-dihydro-1,3-benzoxazin-4-one

2-Hydroxybenzamide is processed by method G (using paraldehyde). Melting point 124-126°C.

Compound 4

2-Phenyl-3,4-dihydro-1,3-benzoxazin-4-one

2-Hydroxybenzamide is processed by method G (using benzaldehyde). Melting point 157-160°C.

Compound 5

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is prepared by method G (using an endo/exo racemic mixture of 2-norbornylenecarboxaldehyde). Melting point 206-209 °C.

Compound 6

-Phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is processed by method G (using benzaldehyde). Melting point 125.5-128.5 °C.

Compound 7

1,2,3,5,10,1 Oa-Hexahydrobenzo[e]pyrrolo[1,2-b]-1,2,4-thiadiazine-5,5-dioxide

• and ·· 9 99 99 99 • · • 9 9 9 9 9 • • and • 9 99 9 9 9 9 • • 9 • and • 9 9 9 9 • 9 • • • * · · · 99 999 99 ·· ··

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method E (using 4-chlorobutanoyl chloride. The reaction mixture is not subjected to NaOH-catalyzed ring closure, but is dissolved in H2SO4, heated at 100 °C for 72 hours and precipitated on ice). Melting point 149-154 °C.

Compound 8

2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one

2-Hydroxybenzamide is processed by method G (using 2-butanone). Melting point 7678°C.

Compound 9

-Cyclohexyl-6-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Bromoaniline is treated by method B (see compound 121) to give 4-bromo-2-aminobenzenesulfonamide.

A mixture of 4-bromo-2-aminobenzenesulfonamide (140 mg, 0.56 mmol), 2-methoxyphenylboronic acid (106 mg _, 0.70 mmol), Pd( _PPh3 ) _{2Cl2 (} 20 mg, 5 mol%) in 1,2-dimethoxyethane (30 mL) and _Na2CO3 (2M, 3 mL, 6 mmol) was refluxed under _N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated _NaHCO3 (20 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (20 mL), dried ( _Na2SO4 ) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a silica gel column using EtOAc: n-hexane (1:1, v/v) as eluent to give 155 mg (100%) of 2-amino-4-(2-methoxyphenyl)-benzenesulfonamide as a colorless powder. The product was further worked up by method G (using cyclohexanecarboxaldehyde). Melting point 219-221 °C.

Compound 10

-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Aminophenylboronic acid hemisulphate (5.58 g, 30 mmol), 2-bromopyridine (2.7 ml, 28 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (100 mg, 0.5 mol %), 2M K ₂ CO ₃ (50 ml) were refluxed in 1,2-dimethoxyethane (50 ml) for 24 h under N ₂ atmosphere. The mixture was diluted with CH ₂ Cl ₂ (100 ml) and washed with saturated NaHCO ₃ (50 ml). The organic layer was dried (Na ₂ SO 4 ) and the solvent was removed under reduced pressure. Flash chromatography with CH ₂ C1 ₂ as eluent affords 3-(2-pyridyl)aniline as a yellow oil, 1.0 g (21%). 3-(2• · • · · · • · • *·

·· ·· • 9 9 9

9 9 9 • · 9 » • · · · · · ·

Pyridyl)aniline is processed by method B and method G (using cyclohexanecarboxaldehyde). Melting point 213-216 °C.

Compound 11

-Cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Bromo-aniline is treated by method B (see Compound 121 ) to give 4-bromo-2-aminobenzenesulfonamide.

A mixture of 4-bromo-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3-pyridylborane (225 mg, 1.5 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (35 mg, 5 mol %) in 1,2-dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) was refluxed under N ₂ for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO ₃ (20 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a silica gel column using EtOAc; n-hexane (1; 1, v/v) as eluent, giving 240 mg (96%) of 2-amino-4-(3-pyridyl)-benzenesulfonamide as a colorless powder. The product was further worked up by method G (using cyclohexanecarboxaldehyde). Melting point 240-243°C.

Compound 12

-Cyclohexyl 1-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-(1-hydroxyethyl)benzenesulfonamide: 5-Acetyl-2-aminobenzenesulfonamide (see Compound 13) (0.95 g, 4.4 mmol) was suspended in 96% EtOH (50 mL) and NaBH ₄ (0.46 g, 1.2 mmol) was added in one portion. The mixture was stirred at 25°C for 4 h and filtered through Celite and the solvent was removed under reduced pressure. The residue was treated with saturated NaHCO ₃ (50 mL) and extracted with EtOAc (2 x 50 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness. Flash chromatography using EtOAc:n-hexane:Et ₃ N (200:100:4, v/w) as eluent afforded 0.35 g (37%) of 2-amino-5-(1-hydroxyethyl)benzenesulfonamide as a light brown powder. Melting point 160-162 °C.

Compound 13

-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

To a solution of ethyl vinyl ether (5.8 mL, 60 mmol) in dry THF (50 mL) at -78°C was added t-BuLi (1.7 M in pentane, 25 mL, 40 mmol) and the yellow mixture was stirred for 1 h at

9» » Φ » » 9 9· • 9* ·· ·· • 9 · 9 9 9 9 9

9 · · · · · *9 999 «9 * • 9 9 «999 • •9 99 ·· ·· at -78°C. The cooling bath was removed and the mixture was slowly warmed to 0°C and stirred for another 30 min. The mixture was cooled again to -78°C and a solution of ZnCl ₂ (2 M in THF, 20 mL, 40 mmol) was slowly added and the cooling bath was removed and warmed to 20°C.

5-iodo-2-aminobenzenesulfonamide (see compound 37) (1.8 g, 6 mmol) and Pd(PPh ₃ ) ₄ (0.2 g, 3 mol%) and the mixture was refluxed for 6 h. The THF was evaporated and the residue was boiled in 1 M hydrochloric acid (30 ml) and MeOH (30 ml) for 30 min. EDTA (14.6 g, 50 mmol) was added and made slightly basic (pH = 8-9) with 1 M NaOH followed by extraction with EtOAc (3 x 150 ml), drying (Na ₂ SO ₄ ) and evaporation of the solvent to give a brown solid. Trituration with n-hexanes gave 0.95 g (74%) of 5-acetyl-2-aminobenzenesulfonamide as an off-white powder. The product was further worked up by method G (using cyclohexanecarboxaldehyde). Melting point 224-226 °C (decomposition).

Compound 14

-Cyclohexyl 1-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide To a suspension of 5-acetyl-2-aminobenzenesulfonamide (see compound 13) (0.45 g, 2.1 mmol) in 96% EtOH (40 ml) was added H ₂ NOH*HCl (0.28 g, 4 mmol) and 2 M NaOH (2 ml). The mixture was boiled for 2 hours and the solvent was evaporated. The residue was triturated with water (25 ml) and the product was filtered off and dried to give 0.39 g (81%) of 2-amino-5-(1-hydroxyiminoethyl)benzenesulfonamide as a yellow powder. The product was further processed by method G (using cyclohexanecarboxaldehyde). Melting point 230-233°C.

Compound 15

3-Cyclohexyl-7-carbamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

A mixture of 5-cyano-2-aminobenzenesulfonamide (see compound 37) (2 g, 10 mmol), concentrated H ₂ SO ₄ (4 mL) and absolute EtOH (4 mL) was heated at 80 °C for 5 h and overnight at 50 °C. The reaction mixture was poured onto ice and extracted with EtOAc (1 x)*. The organic phase was removed and the aqueous phase was neutralized with Na ₂ CO ₃ and extracted with EtOAc (3x). The organic phase was evaporated to dryness and column chromatographed (EtOAc/hexane=2/L) to give 200 mg (9%) of the carboxamide. The carboxamide was further processed using method G (using cyclohexanecarboxaldehyde). Melting point 235-237 °C.

*[The first extraction contains the nitrile (starting substance) and the others contain the by-product]

Compound 16 ·♦ ·· « · · • ··« • · « • · · • · • · • * a»

··· ·« ·· ··

-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide A mixture of 5-cyano-2-aminobenzenesulfonamide (see compound 37) (3 g, 15 mmol), concentrated H2SO4 (5 mL) and absolute EtOH (15 mL) was heated at 80°C overnight. The reaction mixture was poured onto ice. The precipitate formed was isolated by filtration. The precipitate was washed with EtOAc to give 2.01 g (55%) of pure ethyl ester. The ester was further worked up using method G (using cyclohexanecarboxaldehyde). Melting point 234-236 °C.

Compound 17

3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Cyano-2-aminobenzenesulfonamide (see compound 37) is processed by method G (using cyclohexanecarboxaldehyde). Melting point 234-237°C.

Compound 18

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo-2-aminobenzenesulfonamide: To a stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) in AcOH (15 mL) was added a solution of Br ₂ (0.55 mL; 10.5 mmol) in AcOH (5 mL). The reaction mixture was poured into H ₂ O (100 mL) and filtered. The isolated solid was adsorbed onto silica gel and flash chromatographed to give 1.428 g (57%) of the product (and 650 mg (20%) of the 3,5-dibromo derivative).

-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (18): 5-Bromo-2-aminobenzenesulfonamide is prepared by method H (using phenylboronic acid) and method G (using endo/exo racemic mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). Melting point 190.5-195.0°C.

Compound 19

-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 -dioxide 2-Nitrophenylboronic acid: To a solution of phenylboronic acid (10 g; 82 mmol) in acetic anhydride (100 ml) at -15°C, fuming HNO3 (5 ml; 120 mmol) was added over 30 min to maintain the reaction temperature below -10°C. The reaction mixture was warmed to room temperature. The reaction mixture was poured onto ice and concentrated to 50 ml. The residue was then re-evaporated 5 times from another 100 ml of H ₂ O and finally filtered to obtain 7.1 g of crude product as a mixture of isomers. Column chromatography (CH ₂ Cl ₂ /EtOH=10/0.5) gave 4.8 g (35%) of pure product as an oil.

9 9

9 9

9 9

9 9 ·· ··

9 • 9 9 • ··· • 9

9

9999 99

99

9 9 • 9 · • 9 9 9 • 9 9

999 99

2- Acetamidophenylboronic acid: A mixture of 2-nitrophenylboronic acid (2 g; 12 mmol) and 5% Pd/C (100 mg) in EtOH (100 mL) was hydrogenated at 1 bar until TLC indicated complete reaction of the starting material. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was washed with hexanes and filtered to give 900 mg (55%) of 2-aminophenylboronic acid. A mixture of 2-aminophenylboronic acid (900 mg; 6.6 mmol), triethylamine (0.57 mL; 7 mmol) and acetyl chloride (0.5 mL; 7 mmol) was stirred at reflux temperature for 1 h. The reaction mixture was evaporated to dryness, stirred with H ₂ O and filtered to give 750 mg (63%) of product.

3- Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-7,2,4-benzothiadiazine-1,1-dioxide (19): 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using 2-acetamidophenylboronic acid) and method G (using cyclohexanecarboxaldehyde).

Melting point 245-249°C.

Compound 20

3-Cyclohexyl-7-(2'-nitrophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using 2nitrophenylboronic acid (see compound 19) and method G (using cyclohexanecarboxaldehyde). Melting point 204-207°C.

Compound 21

3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is prepared by method H (using 2methoxyphenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 219-222°C.

Compound 22

3- Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide

4- Trifluoromethylanisole: Sodium (12.78 g; 555 mmol) was added to dry MeOH (100 mL). After gas evolution had ceased, the reaction mixture was evaporated to dryness and dry NMP (250 mL), Cu(s) (35.3; 555 mmol) and 4-bromo-trifluoromethylbenzene (25 g; 111 mmol) were added. The reaction mixture was heated at 130°C for 4 h, cooled to room temperature and filtered. Water (500 mL) was added to the filtrate and extracted with _Et2O (2x 200 mL). The combined organic fractions were washed with _H2O (2x 100 mL), dried (MgSO4) and evaporated to dryness. Column chromatography gave 8.05 g (41%) of the product.

2- Methoxy-5-trifluoromethylphenylboronic acid: To a solution of 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 ml) at -30°C under N ₂ was added a solution of 2.5 M nBuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at -30°C, then cooled to -70°C and B(Oz-Pr) ₃ (14.1 ml; 64 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature overnight. 2 M HCl (40 ml) was added to the reaction mixture and the THF was removed by evaporation. The aqueous residue was extracted with Et ₂ O (4x 20 ml) and the combined organic fractions were extracted with 1 M NaOH (5x 17 ml). The combined organic 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'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (22):

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using 2methoxy-5-trifluoromethylphenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 255-257 °C.

Compound 23

3-Cyclohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is prepared by method H (using 2,4-dimethoxyphenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 208-213 °C.

Compound 24

3-Cyclohexyl-7-(2'-( N -dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1-dioxide

2-(N,N-Dimethylsulfamoyl)phenylboronic acid: To a solution of benzenesulfonyl chloride (10 mL; 78 mmol) in THF (100 mL) was added a 40% solution of dimethylamine in H ₂ O (20 mL; 160 mmol) such that the reaction temperature was maintained below 50 °C. The reaction mixture was stirred for 1 h at room temperature. H ₂ O was added to the reaction mixture and the THF was removed by evaporation. The precipitate formed was isolated by filtration and dried to give 14 g (97%) of N-dimethylbenzenesulfonamide.

A solution of Αζ/N-dimethylbenzenesulfonamide (9.25 g; 50 mmol) in dry Et2O (150 mL) under N2 was cooled to -70 °C and a solution of 2.5 M n-BuLi in hexane (24 mL; 60 mmol) was added to maintain the reaction temperature below -60 °C. The cooling bath was removed and the reaction mixture was slowly warmed to +20 °C. The reaction mixture was cooled again to -70 °C and B(O/-Pr) ₃ (16.1 mL; 70 mmol) was added. The reaction mixture was allowed to cool and warm overnight, 1 M HCl (100 mL) was added and stirring was continued at room temperature for 1 h. The reaction mixture was then extracted with Et2O (2 x 50 mL) and the combined organic fractions were extracted with 1 M NaOH (4 x 50 mL). The combined aqueous fractions were neutralized with 1 M HCl and extracted with Et2O (4 x 100 mL). The combined organic fractions were dried ( _Na2SO4 ) and evaporated to dryness, washed with Et2O/hexanes to give 3.4 g (30%) of product.

3-Cyclohexyl-7-(2'-(N,7N-dimethylsulfamoyl)phenyl)-1,2,3,4-tetrahydro-1,2,4-benzathiadiazine1,1-dioxide (24): 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is prepared by method H (using 2-(N,7N-dimethylsulfamoyl)phenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 290-300 °C.

Compound 25

-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using 2chlorophenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 233-236 °C.

Compound 26

-Cyclohexyl-7-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using 2fluorophenylboronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 249-250 °C.

Compound 27

-Cyclohexyl-7-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-hydroxyphenylboronic acid: To a stirred solution of 3-aminophenylboronic acid hemisulfate (6.2 g; 33.3 mmol) and 50% _H2SO4 (3.7 ml; 33.3 mmol) in H2O (100 ml) at -2°C, a solution of NaNCE (2.5 g; 36.3 mmol) in _H2O (20 ml) is added over 1 hour.

The reaction mixture is slowly added to a stirred solution of concentrated H2SCE (25 mL) in ft · · · · ·

H ₂ 0 (20 ml) at reflux. After the addition was complete, the reaction mixture was refluxed for 30 min, cooled, activated charcoal was added, heated to reflux, cooled and filtered through Celite. The filtrate was saturated with NaCl (s), filtered and extracted with Et ₂ O (5 x 100 ml). The combined organic fractions were dried (Na ₂ SO ₄ ) and evaporated to dryness to give 4.3 g (94%) of product.

-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (27): 3-Hydroxyphenylboronic acid is prepared by method H and method G (using cyclohexanecarboxaldehyde). Melting point 238-246 °C.

Compound 28

-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4-(2'-Pyridyl)-2-aminobenzenesulfonamide: A stirred mixture of 5-iodo-2-aminobenzenesulfonamide (1 g; 3.3 mmol), 2-tributylstannylpyridine (5.5 g; 15 mmol), Pd(PPh ₃ ) ₄ (240 mg, 0.34 mmol) and Ag ₂ O (780 mg; 3.36 mmol) in DMF (50 mL) under N ₂ was heated at 100°C for 6 h to overnight at room temperature. The reaction mixture was evaporated to dryness and resuspended and stirred in H ₂ O/EtOAc and finally filtered. The organic phase was isolated and the aqueous phase was extracted with EtOAc (2 x volume of water). The combined organic fractions were dried (Na ₂ SO ₄ ), evaporated to dryness and subjected to column chromatography to give 200 mg (24%) of product.

3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,7-dioxide (28): 4-(2'-Pyridyl)-2-aminobenzenesulfonamide is prepared by method G (using cyclohexanecarboxaldehyde). Melting point 222-224 °C.

Compound 29

3- Cyclohexyl-7-(3-Pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5- Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using diethyl-3-pyridylborane) and method G (using cyclohexanecarboxaldehyde). Melting point 240-242 °C.

Compound 30

-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4-((2,2-Dimethylpropanoyl)amino)phenylboronic acid: To a solution of 4-bromo-TV-pivaloylaniline (1.56 g, 6 mmol) in dry THF (50 mL) at -78°C was added t-BuLi (1.5 M in pentane, 13.3 mL, 20 mmol) and the yellow mixture was stirred for 1 h at -78°C under an atmosphere of • · · · · · · · · · · · · · · » ♦ · · · · · · • φ · · * · · · · · · · · · · · ·

Ν ₂ . The reaction was quenched with B(OCH ₃ ) ₃ (1.7 mL, 15 mmol) and stirred for an additional 1 h at -78°C. The reaction mixture was then warmed to room temperature, hydrolyzed with 0.5 M hydrochloric acid (50 mL), extracted with EtOAc (3 x 80 mL), dried (Na ₂ SO ₄ ) and concentrated to approximately 40 mL. n-Hexane (120 mL) was added slowly and the colorless crystalline product was filtered off and dried to give 1.26 g (95%).

N-(4-(2 pyrimidinyl)phenyl)-2,2-dimethylpropanamide: A mixture of 4-((2,2-dimethylpropanoyl)amino)phenylboronic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd( _PPh3 ) _{2Cl2 (} 100 mg, 2 mol%), 1,2-dimethoxyethane (40 mL) _{and Na2CO3} (2 M, 7 mL, 14 mmol) was refluxed under _N2 for 5 h. The mixture was diluted with 10% _Na2CO3 (20 mL ₎ and extracted with EtOAc (3 x 50 mL). The organic layer was dried ( _Na2SO4 ) and the solvent was _removed in vacuo. The crude product was recrystallized from MeOH/water (1:1) to give 0.52 g (85%) of N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide as colorless crystals.

4-(2-Pyrimidinyl)aniline: N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 M hydrochloric acid (40 ml) for 2 h. The mixture was cooled and made strongly basic with NaOEl (s) and extracted _{with CH2Cl2} (2 x 50 ml), dried ( _Na2SO4 ) and the solvent _was removed in vacuo. Trituration with n-hexanes gave 0.83 g (88%) of 4-(2-pyrimidinyl)aniline as a pale yellow powder. The product was further worked up by method B and method G (using cyclohexanecarboxaldehyde). Melting point 236-238°C.

Compound 31

-Cyclohexyl-7-(2'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5- Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using furyl-2-boronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 226-228 °C.

Compound 32

3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using furyl-3-boronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 204-205 °C.

Compound 33 • · · · · <

• ·· ·· ·· «·· · ··

3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method H (using thienyl-2-boronic acid) and method G (using cyclohexanecarboxaldehyde). Melting point 234-236 °C.

Compound 34

-Cyclohexyl-7-(1-methyl-1/f-2-imidazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide)

To a solution of 1-methylimidazole (4.8 mL, 60 mmol) in dry THF (120 mL) at -78°C was added n-BuLi (2.5 M in hexanes, 26 mL, 65 mmol) and the yellow mixture was stirred for 45 min at -78°C. A solution of ZnCl ₂ (2 M in THF, 75 mL, 150 mmol) was added slowly and the cooling bath was removed. The colorless solution was stirred for an additional 10 min at 0°C. 5-Iodo2-aminobenzenesulfonamide (see compound 37) (2.1 g, 7 mmol) and Pd(PPh ₃ ) ₄ (0.5 g, 5 mol%) were added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and slightly basified (pH = 8 - 9) with 1 M NaOH, then extracted with EtOAc (3 x 150 ml), dried (Na ₂ SO ₄ ) and evaporated to give a dark oil. Flash chromatography with 5% MeOH in CH ₂ Cl ₂ as eluent gave 1.33 g (75%) of 2-amino-5-(1-methyl-1/7-2imidazolyl)-1-benzenesulfonamide as colorless crystals. The product was further worked up by method G (using cyclohexanecarboxaldehyde). Melting point >250 °C (dec.).

Compound 35

-Cyclohexyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method I (using trimethylsilylacetylene) and method G (using cyclohexanecarboxaldehyde). Melting point 230-234°C (dec.).

Compound 36

-Cyclohexyl 1-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

5-Iodo-2-aminobenzenesulfonamide (see compound 37) is processed by method I (using phenylacetylene) and method G (using cyclohexanecarboxaldehyde). Melting point 231-232°C (dec.).

Compound 37 • » • ·· 00 ·· ·· · · · · · · • 00 · · · · · · · 0 0 · 0·· · · 00 «0

-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Iodo-2-aminobenzenesulfonamide: To a cold (0 °C) stirred solution of 2aminobenzenesulfonamide (17.2 g; 100 mmol) in CHCl ₃ (200 mL) was added a solution of iodine trichloride (17.1 g; 105 mmol) in CHCl 3 (50 mL) over 1 h. The reaction mixture was slowly warmed to room temperature and allowed to stir overnight. The reaction mixture was filtered and the isolated solid was washed on the filter with CHCl ₃ (3x 20 mL), NaHCO ₃ (sat. aq. solution, x 20 mL), H ₂ O (4x 50 mL). The isolated solid was dried to give 27.3 g (92%) of product.

5-Cyano-2-aminobenzenesulfonamide: A mixture of 5-iodo-2-aminobenzenesulfonamide (17.9 g; 60 mmol), Zn(CN) ₂ (4.9 g; 41.9 mmol), and Pd(PPh ₃ ) ₄ (2.5 g; 2.2 mmol) in DMF (150 mL) under N ₂ was heated at 80°C for 2 h. The reaction mixture was poured into NaHCO 3 (sat. aq. solution, 600 mL) and extracted with EtOAc (9x 200 mL). The combined organic fractions were washed with NaHCO ₃ (sat. aq. solution) and NaCl (sat. aq. solution), dried (Na ₂ SO 4 ), filtered, and evaporated to dryness. The residue was washed with water and hexanes and filtered to give 10.9 g (92%) of product.

5-(2N-Hydroxyamidino)-2-aminobenzenesulfonamide: A mixture of hydroxylamine hydrochloride (764 mg; 11 mmol) and NaOMe (616 mg; 11.4 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h, then 5-cyano-2-aminobenzenesulfonamide (1 g; 5 mmol) was added. The reaction mixture was allowed to stir for 48 h and poured into water and extracted with EtOAc (2x 50 mL). The combined organic fractions were dried (Na ₂ SO 4 ), evaporated to dryness and purified by column chromatography to give 200 mg (17%) of product.

3-Cyclohexyl-7-(5'-methyl-1',2',4'-axadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine1,1-dioxide (37): A mixture of 5-(A ^r -hydroxyamidino)-2-aminobenzenesulfonamide (200 mg; 0.9 mmol), NaOMe (50 mg; 1 mmol), EtOAc (5 mL), triturated MS3 A (2 g) in anhydrous EtOH (20 mL) was heated at 70 °C overnight. The reaction mixture was evaporated to dryness, stirred with water and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO ₄ ) and evaporated to dryness to give a brown oil which was worked up by method G (using cyclohexanecarboxaldehyde) to give 8 mg of product after chromatography. Melting point 249-251 °C.

Compound 38 • · · · · · · * · * · ··· ···· · ♦ · ♦ • · «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·* «·· ·· ·* ··

3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

7-Amino-3-cyclohexyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.5 g; 2 mmol) in dry THF (10 mL) at -70°C was added a 1.5 M solution of DIBALH in toluene (2.7 mL; 4 mmol) under N ₂ . The reaction mixture was stirred for 2 h at -70°C; 2 h at -40°C and then warmed to 0°C. The reaction was quenched with H2O and stirred for 30 min at 0°C and allowed to stand overnight at +5°C without stirring. The mixture was evaporated to dryness, resuspended in MeOH and filtered. The isolated solid was washed with MeOH and filtered. The combined filtrates were adsorbed onto silica gel. Column chromatography (EtOAc) gave 200 mg of product.

7-Acetylamino-3-cyclohexyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (38): A mixture of 7-amino-3-cyclohexyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (100 mg; 0.26 mmol), acetyl chloride (20 μΐ; 0.29 mol) and triethylamine (42 μΐ; 0.3 mmol) was stirred for 2 h at room temperature. The reaction mixture was resuspended in H2O and filtered. The isolated solid was purified by column chromatography (EtOAc) to give 22 mg of 27a. Melting point 202-206°C.

Compound 39

3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3 -Cyclohexyl-1,2-dihydro-1,2,4-benzathiadiazine-1,1 -dioxide: 2-Aminobenzenesulfonamide is processed by method E (using cyclohexanecarbonyl chloride),

3-Cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of KNO3 (1.2 g; 11.5 mmol) and concentrated H2SO4 (8 mL) at 5°C was added a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in concentrated H2SO4 (8 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The product was precipitated by slow addition of ice and isolated by filtration. The crude product (4.3 g) was used without further purification.

7-Amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A stirred suspension of 3cyclohexyl-7-nitro-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (4.2 g; 14 mmol) and 10%

Pd/C (400 mg) in absolute EtOH (100 mL) was hydrogenated at 1 bar. After the calculated amount of H 2 had been reacted, the reaction mixture was filtered through Celite. The Celite was washed with DMF (2 x 75 mL) and the combined organic fractions were evaporated to dryness. The residue was resuspended in EtOAc/iPrOH and the precipitate formed was isolated by filtration. The isolated solid was dissolved in 0.5 M NaOH (aq) and reprecipitated with 4 M HCl (aq). Filtration gave _1.6 g of product.

7-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a stirred solution of 7-amino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (1 g; 3.6 mmol) and triethylamine (1.2 mL; 8 mmol) in dry THF (25 mL) was added methanesulfonyl chloride (0.6 mL; 8 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness, resuspended in H ₂ O/EtOAc and filtered. The filtrate was adsorbed onto silica gel. Column chromatography (CH ₂ Cl ₂ :acetone = 9:1) gave 210 mg of product.

-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (3 9): 7-Methylsulfonylamino-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is processed by method F. Melting point 255-258 °C.

Compound 40

-Cyclohexyl-7-nitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide:

The 2-aminobenzenesulfonamide was protected with a trifluoroacetyl group using method C. To this solution (1 g; 4 mmol) in H ₂ SO 4 (16 mL) at 0°C was added solid KNO 3 (4.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into ice water (150 mL), filtered, and dried to give 1.11 g (94%) of pure product as a yellow solid.

3-Cyclohexyl-7-nitro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (40):

3-Trifluoromethyl-1,2,4-benzothiadiazine-1,1-dioxide is processed according to the following scheme: method D and method F (using cyclohexanecarboxaldehyde). Melting point 209-211°C.

Compound 41

3- Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4-Phenylsulfonylaniline is used as a starting material for the following work-up procedure: method B and method G (using cyclohexanecarboxaldehyde). Melting point 243-245°C.

• · · · • · · • · · · • · · • · · · ·

Compound 42

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide

To a solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 mL) was added trifluoroacetic anhydride (3.8 mL; 27 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness, stirred with H ₂ O and filtered. The crude product was worked up by method A (using 25% NH ₃ (aq) as the amine) and method G (using cyclohexanecarboxaldehyde). Melting point 178-180°C.

Compound 43

-Cyclohexy 1-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

4-Sulfamoylanthranilamide: To a stirred solution of ClSO ₃ H (20 mL) was added anthranilamide (7.5 g; 55 mmol) in small portions. The reaction mixture was heated to 100 °C for 1 h and then poured into ice water (300 mL). The precipitate formed was isolated by filtration and dried on the filter. The isolated solid was dissolved in 25% NH ₃ (aq) 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 THF (3 x 50 mL). The combined organic fractions were evaporated to dryness and subjected to column chromatography to give 13 mg of product.

3- Cyclohexyl-7-sulfamoyl-7,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (43):

4- Sulfamoylanthranilamide is prepared by method G (using cyclohexanecarboxaldehyde), Fab+ 310, ^! HNMR (DMSO-d6): 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 (1H; d), 4.5 (1H; m), 1.8-1.5 (6H; m), 1.2-1.0 (5H; m).

Compound 44

-Cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-5-sulfamoylbenzenesulfonamide (see compound 101) is processed by method G (using cyclohexanecarboxaldehyde). Melting point 252-254°C.

Compound 45

3-Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is reduced using method F. Melting point 210-212°C.

• 0 · · • ♦♦

0 00

0 ·

0 0

0000 00

00

0 0 f « · · ·

0 0 0 0

0 0 0

0« 0·

Compound 46

2-Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline N-dimethylsulfonamide

To a solution of 2-aminobenzylamine (3 g; 25 mmol) in THF (50 mL) was added trifluoroacetic anhydride (3.8 mL; 27 mmol) and stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness, stirred with H ₂ O and filtered. The crude product was worked up by method A (using dimethylamine as the amine), method D and method G (using cyclohexanecarboxaldehyde). Melting point > 300 °C. MS (electrospray) M ⁺ 323, '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

-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: method E (using cyclohexanecarbonyl chloride), method A (using dimethylamine as the amine), method F. Melting point 243-245°C.

Compound 48

3- Cyclohexyl-7-(N,N-diethylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: method E (using cyclohexanecarbonyl chloride), method A (using diethylamine as the amine), method F. Melting point 207-209°C.

Compound 49

3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method E (using cyclohexanecarbonyl chloride), method A (using pyrrolidine as the amine), method F. Melting point 244-246°C.

Compound 50

-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

• · « · • ♦ · * · ♦· • · · • · · · ♦ · · ·· * « · • · · • · · • · · · · · • « · « · · · · • · · ·♦

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method C, method A (using piperidine as the amine), method D, method G [using paraldehyde and catalytic amount of TsOH], Melting point 255-256°C.

Compound 51

-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method C, method A (using piperidine as amine), method D, method G [using cyclopropanecarboxaldehyde], Melting point 228-231°C.

Compound 52

-Isopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method G, method A (using piperidine as amine), method D, method G [using isobutyraldehyde]. Melting point 237-239°C.

Compound 53

-Propyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method C, method A (using piperidine as amine), method D, method G [using butyraldehyde]. Melting point 147.4-151.2°C.

Compound 54

-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as starting material for the following processing steps: method C, method A (using piperidine as amine), method D, method G [using phenylacetaldehyde]. Melting point 242-244°C.

Compound 55

-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 -dioxide Cyclopentanecarboxaldehyde: To a stirred solution of cyclopentanecarboxylic acid (2.16 ml; 20 mmol) in dry THF (50 ml) at room temperature under N ₂ atmosphere was added NaBH ₄ (2.28 g; 60 mmol) and allowed to stir for 20 min. The reaction mixture was cooled to 0°C • Φ · · φ φ φ φ φ φ φ φ φ • « · · φ * · φ · • φ φφ φ φ φφφ φφ φφφ φφ φφφ φ φ I φφφφφφ φφφφ «φφφφ φφ Φ· and BF ₃ OEt ₂ (10 ml; 80 mmol) was added over 1 h, while the reaction temperature was maintained below +3°C. The reaction mixture was treated with NaHCO ₃ (sat. aq. solution), H ₂ O and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. solution), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 1.4 g of an oil which was used without further purification.

The oil (1.4 g) was dissolved in CH ₂ Cl ₂ (75 ml) and PCC on Al ₂ O ₃ (30 g; 30 mmol)* was added and allowed to stir for 1 h at room temperature. The reaction mixture was filtered and the evaporated filtrate was applied to silica gel. Column chromatography gave the pure aldehyde which was used as a solution in CH ₂ Cl ₂ .

*[see Cheng Y.-S., Liu W.-L. and Chen S.-H., Synthesis, (1980) 223.]

3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (55): 2-Aminobenzenesulfonamide is used as starting material for the following work-up procedure: Method C, Method A (using piperidine as amine), Method D, Method G [using cyclopentanecarboxaldehyde]. Melting point 258-260°C.

Compound 56

3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method E (using cyclohexanecarbonyl chloride), method A (using piperidine as the amine), method F. Melting point 262-264°C.

Compound 57

3- Bicyclo[2,2,1]hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method C, method A (using piperidine as amine), method D, method G [using an endo/exo racemic mixture of 2-norbornylenecarboxaldehyde]. Two separate diastereoisomeric mixtures are isolated with melting point (A) 240-242°C and melting point (B) 234-238°C.

Compound 58

-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2,3,4-tetrahydro-1,2,4benzothiadiazine-1,1-dioxide

Φ ΦΦ ΦΦ ΦΦ

ΦΦΦ Φ ΦΦΦ Φ

ΦΦΦΦΦΦΦ

ΦΦΦΦΦ ΦΦΦ 9

ΦΦΦΦΦΦΦ

ΦΦΦ ·Φ Φ« ΦΦ • · φ φ * · • ΦΦΦ

Φ ΦΦ

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: method E (using cyclohexanecarbonyl chloride), method A (using 1,2,3,6-tetrahydropyridine as the amine), method F. Melting point: 237-239°C.

Compound 59

3- Cyclohexyl-7-(X-methyl-X-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: method E (using cyclohexanecarbonyl chloride), method A (using X-methylaniline as the amine), method F. Melting point 210-212°C.

Compound 60

3- Cyclohexyl-7-(r-(r,2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: method E (using cyclohexanecarbonyl chloride), method A (using 1,2,3,4-tetrahydroquinoline as the amine), method F. Melting point 218-220°C.

Compound 61

-Cyclohexyl-7-(4'-methylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: Method C, Method A (using N-methylpiperazine as the amine), Method D, Method G (using cyclohexanecarboxaldehyde). Melting point 227-229°C.

methanesulfonate salt: 61 (0.6 g; 1.4 mmol) was dissolved in 99% EtOH (30 mL) and a solution of 1 M CH3SO3H in 99% EtOH was added. The mixture was allowed to stand for 2 h to precipitate and the salt was isolated by filtration. The salt composition was checked for stability compared to the free base by HPLC. Under these conditions, the salt was found to be stable to hydrolysis and had a water solubility of 10 mg/mL.

Compound 62

3- Cyclohexyl-7-(4'-methylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4benzothiadiazine-1,1-dioxide

9φ 99

9 9 9 • 9 9 9

9 9 9 9

9 9 9

99 *9 • 9

9

9 · *9 • »·« • 9 • 9

99· ·*

9

9

N-Mesylpiperazinium chloride: To a stirred solution _{of piperazine (4.3 g; 50 mmol) in CH2Cl2 (50 mL) at +5 °C was added a solution of CH3SO2Cl (} 4.25 mL; 55 mmol) in _CH2Cl2 ( ₁₅ mL). The thick reaction mixture was stirred at room temperature for 12 h, _CH2Cl2 ( ₁₀₀ mL) was added and extracted with 1 M HCl (300 mL). The precipitate formed in the aqueous phase was filtered off to give 2.66 g of N-mesylpiperazinium chloride (32%).

3-Cyclohexyl-7-(4'-methylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4benzothiadiazine-1,1-dioxide (62): 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: method E (using cyclohexanecarbonyl chloride), method A (using N-Mesylpiperazinium chloride as the amine (1.5 equiv.), 3 equiv. K ₂ CO ₃ were used for neutralization), method F. Melting point 272-274°C.

Compound 63

-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method E (using cyclohexanecarbonyl chloride), method A (using morpholine as the amine), method F. Melting point 262-264°C.

Compound 64

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-bromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Bromo-2-aminobenzenesulfonamide (see compound 18) is prepared by method G (using endo/exo racemic mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). Melting point 200204°C.

Compound 65

2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide

2-Methyl-4-oxo-3,4-dihydroquinazoline: A solution of anthranilamide (13.6 g; 100 mmol) in acetic acid (100 mL) was refluxed for 60 h. The reaction mixture was evaporated to dryness, suspended in H ₂ O, filtered, and washed with NaHCO ₃ until the filtrate had a pH of 8-8.5.

2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide: 2-Methyl-4-oxo-3,4-dihydroquinazoline is prepared by method A (using dimethylamine as the amine). Melting point 264-266°C.

»9 9 9 9 9 9 • ·· 99 9 * 99 • 9 99 9 9 • 999 9 9 9 9 9 9 9 • 9 9 · 9 9 • • • 9 9 99 9 9 *9 999 99 • * 9 9

Compound 66

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide

2-Trilfluoroacetamidobenzamide (see compound 68) is prepared by method A (using 0.5 M NH ₃ in THF as the amine). Melting point 311-314°C.

Compound 67

Ν,Ν-dimethylsulfonamide 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline

2-Trilfluoroacetamidobenzamide (see compound 68) is processed by method A (using dimethylamine as the amine). Melting point 257-258°C.

Compound 68

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline-1,2',3',6'-tetrahydropiperidinosulfonamide To a stirred mixture of anthranilamide (13.6 g; 100 mmol) in THF (100 mL) at 0°C was added trifluoroacetic anhydride (15.2 mL; 110 mmol), allowed to warm to room temperature and stirred overnight. The reaction mixture was evaporated to dryness, suspended in H ₂ O and filtered. The isolated solid was air dried to give 21.6 g (93%) of 2-trifluoroacetamidobenzamide. 2-trifluoroacetamidobenzamide was worked up by method A (using 1,2,3,6tetrahydropyridine as the amine). Melting point 227-230°C.

Compound 69

N-cyclohexylsulfonamide 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline

2-Trilfluoroacetamidobenzamide (see compound 68) is processed by method A (using cyclohexylamine as the amine). Melting point 261-263°C.

Compound 70

2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazolinemorpholinosulfonamide

2-Trilfluoroacetamidobenzamide (see compound 68) is processed by method A (using morpholine as the amine). Melting point 282-285°C.

Compound 71

2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide

Anthranilamide is used as a starting material for the following work-up procedure: method A (using 25% NH ₃ (aq.) as the amine. The reaction mixture contains both 5-monosulfonamide and

ΦΦ • ♦ * φ φ φφ φφ • · φ φ· φ φ • κ φ • φφφ φ · φ φ • φ • φ φ φ φ φ φ φ φ φ φ·φ« φφ φφφ φφ φφ φφ

5,7-disulfonamide, which is separated by chromatography) method G (using cyclohexanecarboxaldehyde. The aminal autoxidizes to atomic hydroxy quinazoline). Melting point 306-310°C.

Compound 72

3-Methyl-7-sulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) is processed by method A (using 0.5M NH3 in THF as the amine). Melting point 295-297°C.

Compound 73

-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

2- Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was processed by method A (using dimethylamine as the amine). Melting point 260-261°C.

Compound 74

-Methyl -7-(1',2',36'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1dioxide

3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) is processed by method A (using 1,2,3,6-tetrahydropiperidine as the amine). Melting point 265-268°C.

Compound 75

3-Methyl-7-cyclohexylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) is processed by method A (using cyclohexylamine as the amine). Melting point 239-242°C.

Compound 76

-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method C and method A (using dimethylamine as the amine). Melting point 240-242°C.

Compound 77

99 9 ·· ·· ·· • · · ·· · « ·««· • · ·« · · · * I · ·

9 · » · · · · · · · 9

9 9 9 9 9 9 9 9 9

9999 99 999 99 99 99

2-Τ rifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acid

2-Aminobenzenesulfonamide is used as a starting material for the following processing steps: Method C and Method A (using NaOH instead of amine). Melting point >330 °C.

Compound 78

-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide zw-Toluidine is used as starting material for the following work-up procedure: method B [2amino-6-methylbenzenesulfonamide is separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc/hexane)], 2-Amino-6-methylbenzenesulfonamide is further purified by column chromatography and worked up by method G (using cyclohexanecarboxaldehyde). Melting point 228-230°C.

Compound 79

-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 -dioxide 5-Chloro-3-cyclohexyl-7,2-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide-8-carboxylic acid: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide (see compound 80) (0.30 g, 1.0 mmol) in dry THF (15 mL) at -78 °C was added s-BuLi in cyclohexane (1.3 M, 1.6 mL, 2.1 mmol) under N ₂ . The yellow mixture was stirred for 15 min at -78 °C and dry CO ₂ gas was bubbled through the solution for 30 min. The cooling bath was removed and the mixture was warmed to 0°C. The solvent was removed under reduced pressure and the residue was triturated with hydrochloric acid (0.2 M, 12 mL). The crude product was recrystallized from 50% MeOH to give 300 mg (82%) of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as colorless crystals.

-Cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid: 5-chloro3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid (160 mg, 0.47 mmol) was dissolved in 99% EtOH (50 mL) and hydrogenated for 24 h using Pd/C (10%, 10 mg) at 1 bar. NaOH (1 M, 12 mL) was added and the mixture was filtered through a pad of Celite™ and concentrated to 10 mL and concentrated hydrochloric acid was slowly added to the precipitate to give 110 mg (76%) of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-8-carboxylic acid as a colorless powder.

• 0 0

000

0 0 0000 00

0* 00 00 00 0 0 0 0 0 0

0 0 0 0 0 0

000 00 · 0 0 0 0 0 0 0

000 00 00 00

-Cyclohexyl-8-hydroxymethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (79): _NaBH4 in triglyme (2 M, 0.75 mL, 1.5 mmol) was dissolved in dry THF (20 mL) and cooled to -50°C under _N2 , _BF3- etherate (0.25 mL, 2.0 mmol) was added and the mixture was stirred for 10 min at -50°C. Solid 3-cyclohexyl-1,2-dihydro-1,2,4benzothiadiazine-1,1-dioxide-8-carboxylic acid (170 mg, 0.55 mmol) was added in one portion and the suspension was stirred for 6 h at -50°C and overnight at 20°C. The mixture was hydrolyzed with hydrochloric acid (1 M, 2 ml) and the solvent was removed under reduced pressure. The residue was extracted with EtOAc (50 ml) and the organic layer was washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness. The product was purified by flash chromatography on a silica gel column using EtOAc:n-hexane (2.T, v/v) as eluent to give 100 mg (62%) of 3-cyclohexyl-8-hydroxymethyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless needles. The product was further worked up according to method F. Melting point 220-223°C.

Compound 80

-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Chloro-3-cyclohexyl-7,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 3-Chloroaniline is used as the starting material for the following processing procedure: method B followed by method E (using cyclohexylcarbonyl chloride).

5-Chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (596 mg, 2 mmol) in dry THF (20 mL) at -78°C was added s-BuLi in cyclohexane (1.3 M, 3.8 mL, 5 mmol) under N ₂ . The yellow mixture was stirred for 15 min at -78°C and a solution of I ₂ (1.27 g, 5 mmol) in dry THF (5 mL) was added. The cooling bath was removed and the mixture was warmed to 0°C. NaHSO ₃ (5%, 20 mL) was added and extracted with EtOAc (2 x 30 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 0.76 g (90%) of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide:

A mixture of 5-chloro-3-cyclohexyl-8-iodo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (290 mg, 0.68 mmol), 2-methoxyphenylboronic acid (122 mg, 0.80 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (10 mg, 2 mol %) in 1,2-dimethoxyethane (50 mL) and Na ₂ CO ₃ (2M, 2 mL, 4 mmol) was refluxed under N ₂ for 2 h. The solvents were removed under reduced pressure and the residue was extracted • 0 ·· • « ♦ · • · · · · ·· ·« • · « • · · ·· • · f ♦ · · t ·♦ • ·» • · · · • · · * ·· ·

EtOAc (2 x 40 ml) and the organic layer was washed with saturated NaHCO ₃ (20 ml), dried (Na ₂ SO 4 ) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a silica gel column using EtOAc:n-hexane (1:2, v/v) as eluent to give 200 mg (73%) of 5-chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4benzothiadiazine-1,1-dioxide as colorless crystals.

3-Cyclohexyl-8-(2-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-7,7-dioxide (80): 5-Chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (190 mg, 0.47 mmol) was dissolved in 99% EtOH (30 mL) and hydrogenated using Pd/C (10%, 10 mg) at 1 bar. The mixture was filtered through a pad of Celite™ and the solvent was removed under reduced pressure to give 174 mg (100%) of 5-chloro-3-cyclohexyl-8-(2-methoxyphenyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product is processed by method F. Melting point 100-105°C.

Compound 81

-Cyclohexyl-8-(3-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

Same synthesis as for compound 80 (using 3-methoxyphenylboronic acid for cross-coupling with Pd catalyst). Melting point 108-115°C.

Compound 82

-Cyclohexyl-8-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

5-Chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: To a solution of 5-chloro-3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 80) (0.60 g, 2.0 mmol) in dry THF (15 mL) at -78°C under _N2 was added sBuLi in cyclohexane (1.3 M, 3.8 mL, 5 mmol). The yellow mixture was stirred for 15 min at -78°C and B( _OCH3 ) ₃ (0.57 mL, 5 mmol) was added. The cooling bath was removed and the mixture was warmed to 0°C and stirred for an additional 1 h. The mixture was hydrolyzed with hydrochloric acid (0.5 M, 12 mL) and extracted with EtOAc (2 x 50 mL), dried (Na ₂ SO 4 ) and evaporated to dryness to give 0.65 g (95%) of 5-chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

5-Chloro-3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: A mixture of 5chloro-3-cyclohexyl-8-(dihydroxyboryl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (440 mg, 1.28 mmol), 2-bromopyridine (0.14 ml, 1.50 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (10 mg, 2 mol %) at 1.292

·· ·» 9 44 44 44 • · Φ 44 4 4 4 4 • « • 4 4 4 9 4 • « 4 • • 41 4 4 9 4 4 • • » »· · • » 49 4 44 44 ··

dimethoxyethane (30 mL) and Na ₂ CO ₃ (2M, 3 mL, 6 mmol) were refluxed under N ₂ for 24 h. The solvents were removed under reduced pressure and the residue was treated with saturated NH ₄ Cl (10 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with water (20 mL), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a silica gel column using EtOAc:n-hexane (2:1, v/v) as eluent to give 280 mg (58%) of 5-chloro-3-cyclohexyl-8-(2-pyridyl)1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals.

3-Cyclohexyl-8-(2 pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (82): 5-Chloro3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (0.268 g, 0.713 mmol) was dissolved in 99% EtOH (50 mL) and hydrogenated using Pd/C (10%, 10 mg) at 4 bar for 24 h. The mixture was filtered through a pad of Celite™ and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with phosphate buffer (pH = 7, 10 mL), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure to give 200 mg (82%) of 3-cyclohexyl-8-(2-pyridyl)-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as colorless crystals. The product was further processed according to method F. Melting point 200-203°C.

Compound 83

-Cyclohexyl-8-methoxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide /«-Anisidine is used as starting material for the following work-up procedure: method B [2amino-6-methoxybenzenesulfonamide is separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc/hexane)] and then by method G (using cyclohexanecarboxaldehyde). Melting point 221-223°C.

Compound 84

5,7-Dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is processed by method G (using ethyl formate and catalytic amount of triethylamine). Melting point 289-292°C.

Compound 85 and compound 86

-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85) and 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (8 6) * * 99 9 ·» ·«> ·· • 99 99 9 9 9 999 * *♦· · * · » ♦ · Β

9 9 9 9 9 9 9 9 9

9999 99 999 9 9 9 9 9 99

3-Cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: 2-Aminobenzenesulfonamide is used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride) and Method A (using morpholine as the amine), which will provide 3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and

3-cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; Mixture of 3-cyclohexyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (2 g;

mmol), DEAD (2.35 mL; 15 mmol), PPh ₃ (4 g; 15 mmol) in dry THF (30 mL) was cooled to 0°C and MeOH (1.25 mL; 30 mmol) was added. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, stirred with EtOAc and filtered. The isolated precipitate was stirred with CH2Cl2 and filtered to give the 2-methyl isomers in the filtrate and the 4-methyl isomers as the precipitate.

The 4-methyl is purified by recrystallization from DMSO/H ₂ O. The 2-methyl isomer is purified by column chromatography (EtOAc).

3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (85): 3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is reduced according to method F. Melting point 243-245°C.

3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (86): 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is reduced according to method F. Melting point 207-210°C.

Compound 87

7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide: 2-Aminobenzenesulfonamide is prepared by method E (using 4-chlorobutanoyl chloride).

7-Nitro-1,2,3,5-tetrahydrobenza[e]pyrrolo[2,1c]-1,2,4-thiadiazine-5,5-dioxide: To a stirred solution of 1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1c]-1,2,4-thiadiazine-5,5-dioxide (222 mg; 1 mmol) in H2SO4 (2 ml) at 5°C was added a solution of _KNO3 (122 mg; 1.2 mmol) in H2SO4 (2

·* ·· 9 ·· • 9 ·· • * ·· · • 9 9 • 4 • *·· « · • ♦ · • • 4 • • · « · • • · • 4 «1·» ·· ·· · ·· ·· **

The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice water, filtered and air dried to give 190 mg (71%) of product.

7-Amino-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1c]-7,2,4-thiadiazine-5,5-dioxide: To a stirred solution of 7-nitro-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1c]-1,2,4-thiadiazine-5,5-dioxide (167 mg; 0.6 mmol) in dry THF (2 mL) at -50°C was added LiAflU (115 mg; 3 mmol) in one portion. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched by addition of H ₂ O and 10 M NaOH, stirred, filtered through celite, and evaporated to dryness to give 150 mg of product.

7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1c]-1,2,4-thiadiazine-5,5-dioxide (87): To a stirred solution of 7-amino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1c]1,2,4-thiadiazine-5,5-dioxide (150 mg; 0.5 mmol) and triethylamine (70 μΐ; 0.5 mmol) in THF (1 mL) was added a solution of CH ₃ SO ₂ Cl (40 μΐ; 0.5 mmol) in THF (1 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness, suspended in H ₂ O and extracted with EtOAc. The combined organic fractions were evaporated to dryness. Column chromatography gave 40 mg of product. Melting point 177-180°C.

Compound 88

7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is used as starting material for the following work-up procedure: method E (using 4-chlorobutanoyl chloride), method A (using 0.5 M NH ₃ in THF as amine), method F (using L1AlH4 and at room temperature). Melting point 260-262°C.

Compound 89

7-Methylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method E (using 4-chlorobutanoyl chloride), method A (using methylamine as the amine), method F (using L1AlH4 and at room temperature). Melting point 244-245°C.

Compound 90

7-Cyclohexylsulfamoyl-t,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,l-c]-l,2,4-thiadiazine-5,5dioxide «I ΦΦ * · * • ·«· ·· φφ «· » φ φ φ φ » · φ · · · φ ΦΦ · φ φ • φ φφ φφ φφ φφ

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: Method E (using 4-chlorobutanoyl chloride), Method A (using cyclohexylamine as the amine), Method F (using LiAlH4 and at room temperature). Melting point 195-197°C.

Compound 91

7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method E (using 4-chlorobutanoyl chloride), method A (using dimethylamine as the amine), method F (using L1AlH4 and at room temperature). Melting point 240-243°C.

Compound 92

7-Methylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is used as a starting material for the following processing procedure: method E (using 4-chlorobutanoyl chloride), method A (using methylamine as the amine). Melting point 244-247°C.

Compound 93

7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is processed by method E (using 4-chlorobutanoyl chloride) and method A (using dimethylamine). Melting point 251-253°C.

Compound 94

7-Cyclohexylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide 2-Aminobenzenesulfonamide is used as starting material for the following processing procedure: method E (using 4-chlorobutanoyl chloride), method A (using cyclohexylamine as amine). Melting point 151-153°C.

Compound 95

7-(1',2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-cj-1,2,4thiadiazine-5,5-dioxide tt

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: method E (using 4-chlorobutanoyl chloride), method A (using 1,2,3,6-tetrahydropyridine as the amine). Melting point 204-206°C.

Compound 96

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

2,4-Dimethylaniline is used as a starting material for the following work-up procedure: Method B, Method G [using a racemic endo/exo mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde, column chromatography yields two diastereoisomeric fractions, each a mixture of diastereoisomers]. Isomeric mixture A, melting point 160-165°C; Isomeric mixture B, melting point 182-187°C.

Compound 97

3-Cyclohexyl-7-(N/N-diethylsulfamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

3-Cyclohexyl-7-(N,N-diethylsulfamoyl)-5-formyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1dioxide: 2-Aminobenzenesulfonamide was used as the starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride) and Method A (using diethylamine as the amine). To the product from this work-up (0.60 g, 1.5 mmol) dissolved in dry THF (15 mL) at -78°C was added s-BuLi in cyclohexane (1.3 M, 2.5 mL, 3.2 mmol) under _N2 atmosphere. The yellow mixture was stirred for 25 min at -78°C. The reaction was quenched with dry DMF (0.3 mL, 4 mmol) and the mixture was stirred for 20 min at -78°C. The cooling bath was removed and the mixture was warmed to 0 °C. Hydrochloric acid (0.5 M, 10 mL) was added and the mixture was extracted with EtOAc (40 mL). The organic layer was washed with brine (10 mL), dried (Na ₂ SO 4 ) and evaporated to dryness. The residue was dissolved in acetone (8 mL), Et ₂ O (30 mL) was added and the product crystallized within a few minutes to give 0.41 g (64%) of 3-cyclohexyl-7( N / / N -diethylsulfamoyl)-5-form 1-1,2-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide as colorless crystals.

3-Cyclohexyl-7-(N,N-diethylsulfamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (97): 3-Cyclohexyl-7-(N,N-diethylsulfamoyl)-5-formyl-1,2-dihydro-1,2,4benzothiadiazine-1,1-dioxide (0.20 g, 0.46 mmol) was dissolved in 99% EtOH (60 ml). Hydrochloric acid was added dropwise to complete hydrogenation. The mixture was hydrogenated using Pd/C (10%, 10 mg) at 4 bar for 24 h. The mixture was filtered through Celite™ and evaporated to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (10 mL), dried (Na ₂ SO ₄ ) and evaporated to dryness to give 0.18 mg (95%) of 3-cyclohexyl-7-(N,N-diethylsulfamoyl)-5-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide as a colorless powder. The product was further worked up according to Method F. Melting point 206-208°C.

Compound 98

3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

3,5-Dibromo-2-aminobenzenesulfonamide (see compound 125) is prepared by method H (using phenylboronic acid) and method G (using endo/exo racemic mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). Melting point 222-225°C.

Compound 99

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

2-Aminobenzenesulfonamide is prepared by method A (using 25% NH3 (aq) as the amine) and method G (using an endo/exo racemic mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). Melting point 172-180°C.

Compound 100

3- Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dichloro-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

2,4-Dichloroaniline is processed by method B and method G (using a racemic endo/exo mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde. The product is isolated as a mixture of diastereoisomers). Melting point 149-151°C.

Compound 101

5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-sulfamoylbenzenesulfonamide: A stirred suspension of 2-amino-4-chloro-5sulfamoylbenzenesulfonamide (11.4 g; 40 mmol) and 10% Pd/C (750 mg) in EtOH (300 mL) was hydrogenated at 1 bar until hydrogen was consumed (24 h). The reaction mixture was evaporated to dryness, resuspended in THF and filtered through celite. The filtrate was evaporated to dryness ·· ·· ·· • · · · · · · · · · · · · · · · · · · · ···« and the isolated solid was washed with boiling EtOAc (2 x 150 mL) to give 9.58 g (95%) of product.

2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide: To a stirred solution of 2-amino-5sulfamoylbenzenesulfonamide (3.77 g; 15 mmol) in AcOH (50 mL) was added a solution of Br ₂ (0.78 mL; 15 mmol) in AcOH (10 mL). The reaction mixture was heated at 70°C for 6 days, evaporated to dryness, resuspended in MeOH (85 mL) and solid KOH (3.8 g; 68 mmol) was added. The reaction mixture was heated at 60°C for 2.5 h (hydrolysis of 3-methyl-, 3-bromomethyl-, 3-dibromomethyl and 3-tribromomethyl-1,2-dihydro-1,2,4-benzothiadiazine isomers formed in situ), filtered, neutralized and evaporated to dryness, column chromatography afforded 3.1 g (63%) of product.

5-Bromo-3-cyclohexyl-7-sulfamoyl-1,2,3,4-tetrahydro~7,2,4-benzothiadiazine-1,1 -dioxide (101): 2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide is prepared by method G (using cyclohexanecarboxaldehyde). Melting point 254-258°C.

Compound 102

2-Bicyclo[2,2,1]hept-5'-en-2'-yl-6,8-dibromo-1,2,3,4-tetrahydroquinazoline

2-Amino-3,5-dibromobenzylamine: To a mixture of 2-aminobenzylamine (6.1 g; 50 mmol) in CHCl ₃ (100 mL) at 0°C was added a solution of Br ₂ (5.1 mL; 100 mmol) in CHCl 3 (45 mL) such that the temperature was maintained below +2°C. The cooling bath was then removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, the precipitate was washed with EtOAc and purified by column chromatography.

2-Bicyclo[2,2,1]hept-5'en-2'-yl-6,8-dibromo-1,2,3,4-tetrahydroquinazoline (102)

2-Amino-3,5-dibromobenzylamine is prepared by method G (using an endo/exo racemic mixture of 2-norbornylenecarboxaldehyde). Melting point 240°C.

Compound 103

2-Bicyclo[2,2,1]hept-5'-en-2'-yl-6,8-dibromo-4-oxo-1,2,3,4-tetrahydroquinazoline

3,5-Dibromanthranilamide: To a stirred suspension of anthranilamide (13.6 g; 0.1 mol) in AcOH (350 mL) was added a Br ₂ solution (10.3 mL; 0.2 mol). The reaction mixture was stirred at 45°C to 120°C, poured into H ₂ O (1.5 L), and filtered. Recrystallization (including hot filtration) from 96% EtOH (approx. 1 L) 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-tetrahydroquinazoline (103): 3,5-Dibromanthranilamide is prepared by method G (using a racemic endo/exo mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). The product is separated into two separate mixtures of diastereoisomers. Melting point (A) 213-215°C. Melting point (B) 209-210°C.

Compound 104

3- Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is prepared by method G (using an endo/exo racemic mixture of bicyclo[2,2,1]hept-5-ene-2-carboxaldehyde). The mixture of diastereomers is purified by column chromatography to give three of the theoretically four possible diastereomers. Melting point (A) 202-206°C. Melting point (B) 196-199°C. Melting point (C) 180-184°C.

Compound 105

5.7- Dibromo-3-Bicyclo[2,2,1 ]heptan-2’-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 -dioxide Bicyclo[2,2,1]heptane-2-carboxaldehyde: To a stirred suspension of 2-norbornylenemethanol (0.5 mL; 5.8 mmol) and PCC on Al2O3* in CH2Cl2 (25 mL) was added and stirred at 2-3°C for 1 h, then allowed to slowly warm to room temperature. The reaction mixture was filtered and the solid was washed with CH2Cl2 (2 x 25 mL). The combined organic fractions were adsorbed onto silica gel and chromatographed to give 300 mg (42%) of the product as an oil.

*[see Gheng Y.-S, Liu W.-L. and Chen S.-H., Synthesis, (1980) 223.]

5.7- Dibromo-3-norbornanyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (105): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is prepared by method G (using bicyclo[2,2,1]heptane-2-carboxaldehyde). Melting point 182-183°C.

Compound 106

-Cyclohexyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide • · • · · • · · • · ·

100

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is processed by method G (using cyclohexanecarboxaldehyde). Melting point 166-167°C.

Compound 107

3- Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

1- Adamantanecarboxaldehyde: 1-Adamantylmethanol is oxidized according to the method used for 2-norbornylmethanol (see compound 105).

*[see Cheng Y.-S, Liu W.-L, and Chen S.-H., Synthesis, (1980) 223.]

3-Adamantyl-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (107): 2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is prepared by method G (using 1-adamantylcarboxaldehyde). Melting point 270-273°C.

Compound 108

-Pheny 1-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) is processed by method G (using benzaldehyde). Melting point 186-189°C.

Compound 109

3-Ethoxy-5,7-dibromo-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

A stirred mixture of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (666 mg; 2 mmol), ethyl orthoformate (15 mL; 90 mmol) and H ₂ SO ₄ (0.05 mL) was refluxed overnight. The reaction mixture was evaporated to dryness and subjected to column chromatography. Melting point 9698°C.

Compound 110

3-Methyl-5,7-dibromo-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

A stirred solution of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (660 mg; 2 mmol) was refluxed in Ac ₂ O (25 mL; 265 mmol) overnight. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et ₂ O. Melting point 287-289°C.

Compound 111

-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

To a solution of t-BuLi (1.7 M in pentane, 25 mL, 42 mmol) in dry THF at -78°C was added 2-bromopyridine (1.9 mL, 20 mmol) in such an amount that the temperature did not exceed -70°C. The mixture was stirred for another 30 min at -78°C. A solution of ZnCl ₂ (2 M in THF, 30 mL, 60 mmol) was added slowly, the cooling bath was removed and the mixture was warmed to 20°C. 5-iodo-2-aminobenzenesulfonamide (see compound 37) (1.0 g, 3.2 mmol) and Pd(PPh ₃ ) ₄ (0.3 g, 8 mol%) were added and the mixture was refluxed for 6 h. The THF was evaporated and the residue was treated with EDTA (53 g, 0.18 mol) and slightly basified (pH = 8-9) with 1 M NaOH, then extracted with EtOAc (3 x 100 ml), dried (Na ₂ SO 4 ). The organic layer was concentrated to approx. 40 ml and n-hexane was added slowly. The product was filtered off to give 0.72 g (87%) of 2-amino-4-methyl-5-(2-pyridyl)-1-benzenesulfonamide as light yellow crystals. The product was further worked up according to method G (using cyclohexanecarboxaldehyde). Melting point 229-231°C.

Compound 112

3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 5-Iodo-4-methyl-2-aminobenzenesulfonamide: w-Toluidine is treated by method B and the two isomers separated by column chromatography give 4-methyl-2aminobenzenesulfonamide.

To a stirred suspension of 4-methyl-2-aminobenzenesulfonamide (620 mg; 3.3 mmol) in CHCl ₃ (7 mL) at 0°C was added a solution of iodine trichloride (1.6 g; 9.9 mmol) in CHCl ₃ (7 mL). The reaction mixture was stirred at 0°C until 1H NMR indicated complete consumption of the starting material. The reaction mixture was filtered and the isolated solid was washed with a small volume of CHCl ₃ , NaHCO ₃ (saturated aqueous solution), H ₂ O and air dried to give 640 mg (62%) of product.

-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (112): 5-iodo-4-methyl-2-aminobenzenesulfonamide is processed according to method I (using trimethylsilylacetylene) and method G (using cyclohexanecarboxaldehyde), FAB ⁺ 348, *H NMR (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 (3 H; s); 1.95-1.8 (2 H; m); 1.8-1.6 (3 H; m); 1.3-1.0 (6H; m),

Compound 113

3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide N-Acetyl-3-methylaniline: w-Toluidine (10 mL; 93 mmol) was added to a stirred solution of acetic anhydride (30 mL). The reaction mixture was stirred for 1.5 h at room temperature, evaporated to dryness, stirred with H ₂ O and filtered to give 13 g of product (94%).

102 • · · ♦ • · · · • · · · · • · · · • 0 • ··

3-Cyclohexyl-6-methyl-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide: N-acetyl-3-methylaniline is processed by method A (using 25% NH ₃ (aq) as amine, complete deacetylation) and method G (using cyclohexanecarboxaldehyde). Melting point 231233°C.

Compound 114

3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

Cyclopentanecarbonyl chloride: Cyclopentanecarboxylic acid (0.55 mL; 5 mmol) was refluxed in thionyl chloride (1 mL) for 3 h. The reaction mixture was cooled to room temperature, evaporated to dryness, and used without further purification.

-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide (114): m-Toluidine was used as starting material for the following work-up procedure: Method B [2-amino-6-methylbenzenesulfonamide was separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc/hexane)], Method E (using cyclopentanecarbonyl chloride), Method A (using piperidine as amine), Method F. Melting point 229-230°C.

Compound 115

3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide /«-Toluidine is used as starting material for the following work-up procedure: Method B [2amino-6-methylbenzenesulfonamide is separated from 2-amino-4-methylbenzenesulfonamide by recrystallization (EtOAc/hexane)], Method E (using cyclohexanecarbonyl chloride), Method A (using morpholine as amine), Method F. Melting point 268-271°C.

Compound 116

-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide

3-Bromo-4-methylaniline is processed by method B (Isomers are separated by fractional crystallization from MeOH) to give 2-amino-4-bromo-5-methylbenzenesulfonamide. A mixture of 2-amino-4-bromo-5-methylbenzenesulfonamide (100 mg, 0.38 mmol), 2-methoxyphenylboronic acid (76 mg, 0.50 • 4 44

103

4444 49

44 44 44

9 4 4 4 9 4 4

4 4 9 4 4 9 • 4 9 4 4 4 4 4

4 4 4 4 4 4

444 44 49 44 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (13 mg, 5 mol %) in 1,2-dimethoxyethane (20 mL) and Na ₂ CO ₃ (2 M, 1 mL, 2 mmol) were refluxed under N ₂ for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO ₃ (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was washed with brine (20 mL), dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on a silica gel column using EtOAc:n-hexane (1:1, v/v) as eluent to give 100 mg (90%) of 2-amino-4-(2-methoxyphenyl)-5methylbenzenesulfonamide as a colorless powder. The product is further processed by method G (using cyclohexanecarboxaldehyde). Melting point 172-175°C.

Compound 117

-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide zw-Anisidine is used as starting material for the following work-up procedure: Method B [2amino-6-methoxybenzenesulfonamide is separated from 2-amino-4-methoxybenzenesulfonamide by flash chromatography (EtOAc/hexane)], Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). Melting point 237-240°C.

Compound 118 and compound 122

-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122) and 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118)

6-Amino-1,4-benzodioxane is used as the starting material and processed to a mixture of ethylenedioxy-2-aminobenzenesulfonamide isomers using method B. The two isomers are separated by column chromatography.

3-Cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (118): 2amino-5,6-ethylenedioxybenzenesulfonamide is prepared according to method G (using cyclohexanecarboxyaldehyde). Melting point 196-200°C.

-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (122): 2-amino-7,8-ethylenedioxybenzenesulfonamide is prepared according to method G (using cyclohexanecarboxyaldehyde). Melting point 268-270°C.

Compound 119 • 0 00 ·· • 0 9 9 0 0

0 0 0 0 0 « 0· 0 0 0 >

0 0 0 0 9

00 00

104 • 9 9

000 • · • · • · « 9 9·

-Cyclohexyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide is prepared by method G (using cyclohexanecarboxaldehyde). Melting point 274-276°C.

Compound 120

3- Phenyl-6-chloro-7-sulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide

2-Amino-4-chloro-5-sulfamoylbenzenesulfonamide is prepared by method G (using benzaldehyde). Melting point 235-238°C.

Compound 121

3-Cyclohexyl-6-bromo-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1 dioxide /w-Bromoaniline is used as starting material for the following work-up procedure: Method B [2amino-6-bromobenzenesulfonamide is separated from 2-amino-4-bromobenzenesulfonamide by recrystallization (EtOAc/hexane), Method C, Method A (using piperidine as amine), Method D, Method G (using cyclohexanecarboxaldehyde). Melting point 238-241°C.

Compound 122

See Compound 118.

Compound 123

2-Cyclohexylmethylamino-5-V,V-dimethylsulfamoylbenzenesulfonamide

2-Aminobenzenesulfonamide is used as a starting material for the following work-up procedure: Method E (using cyclohexanecarbonyl chloride), Method A (using dimethylamine as the amine), Method F (the reaction mixture is allowed to stir overnight with DIBALH at room temperature). Melting point 123-125°C.

Compound 124

2- Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzenesulfonamide

3- Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide (see compound 73) is processed by method A (using 1,2,3,6-tetrahydropyridine as the amine) followed by method F (using LiAlH4 and at room temperature). Melting point 175-177°C.

Compound 125 • ·

105

9» ·

• ··· * ·· ·· ·· ··· · · 9 9 · • · · · · · · t · ··· ·· · * · · · · · ♦ ··· ·· ·· ··

2-Amino-3,5-dibromobenzenesulfonamide

To a stirred solution of 2-aminobenzenesulfonamide (8.6 g; 50 mmol) in AcOH (100 mL) was slowly added a solution of Br ₂ (5.13 mL; 100 mmol) in AcOH (20 mL). The reaction mixture was heated to 55°C for 60 h, poured into ice water (800 mL), filtered, adsorbed onto silica gel, and purified by column chromatography to give 11.1 g (67%) of product. Melting point 165-169°C.

Compound 126

2-Acetamidobenzenesulfonamide

To a stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 mL; 11 mmol) in THF (25 mL) at 0°C was added AcCl (0.85 mL; 12 mmol) and allowed to stir at room temperature overnight. The reaction mixture was filtered and adsorbed onto silica gel. Column chromatography gave 1.7 g (79%) of the product. Melting point 153.5-155.5°C.

Compound 127

3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide N-(3-Methyl-1'-carboxybutyl)-2-nitrobenzenesulfonamide: To a solution of 2nitrobenzenesulfonyl chloride (11g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H ₂ O (100 mL) was added DL-leucine (6.55 g; 50 mmol) and allowed to stir overnight at room temperature. 4 M NaOH (12.5 mL) was added to the reaction mixture and filtered. The filtrate was acidified with 1 M HCl (50 mL) and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO 4 ) and evaporated to dryness to give 6.7 g (42%) of product.

3-Isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide: Stirred suspensions of N-(3'-methyl-1'-carboxybutyl)-2-nitrobenzenesulfonamide (6.7 g; 21.2 mmol) and 10% Pd/C (200 mg) in absolute EtOH were hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. To a solution of the crude product in dry THF (50 ml) at 0°C were added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warmed to room temperature and allowed to stir overnight. The reaction mixture was filtered and the solid was washed with THF. The combined organic fractions were evaporated to dryness and H ₂ O was added to the residue and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO 4 ) and evaporated to dryness to give 3 g (53%) of product.

« · 9 9 • 9 9

9 99

106

99 ··

999 · 9 99 9

9 9 9 9 9 9

999 99 9

9 9 9 9 9 9

999 ·« 99 99

3-Isobutyl-8-piperidinosulfonyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide: To a solution of 3-isobutyl-4-oxo-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide (500 mg; 1.8 mmol) in dry THF (20 mL) under _N2 at 0°C was added a solution of 2 M _BH3 « _SMe2 (9.2 mL; 18 mmol) in THF. After complete reaction, the reaction mixture was warmed to room temperature and then refluxed for 2 h. The reaction mixture was cooled to room temperature, carefully quenched by adding 6 M HCl (15 mL). The reaction mixture was made strongly basic by adding 7.5 M NaOH (aq) and extracted with EtOAc. The combined organic fractions were dried (Na ₂ SO 4 ) and evaporated to dryness to give 320 mg (70%) of product. The product was worked up according to method A (using piperidine as the amine). Melting point 209-211°C.

Compound 128

3-Cyclohexyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide DL-Cyclohexylglycine: To a solution of NaCN (15.9 g; 0.32 mol) in H ₂ O (60 ml) was added NH 4 Cl (17 g; 0.32 mol) followed by a solution of cyclohexanecarboxaldehyde (37 ml; 0.31 mol) in MeOH (60 ml). The reaction mixture was stirred vigorously for 2 h at room temperature. The reaction mixture was diluted with H ₂ O (100 ml) and extracted with toluene (2x 70 ml). The combined organic phases were washed with H ₂ O (2x 50 ml) and extracted with 6 M HCl (2x 90 ml). The acidic aqueous phases and the precipitate formed after acidification were combined and refluxed for 24 h. The reaction mixture was cooled to room temperature and gently basified (using 25% NH ₃ (aq.)). The precipitate formed was isolated by filtration, washed with cold H ₂ O and air dried to yield 13 g (26%) of the free amino acid.

Compound 128 is synthesized by the method used for compound 127 (using dlcyclohexylglycine as the amino acid).

Compound 129

-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide 2-Amino-5-cyclopentylthiobenzenesulfonamide: A mixture of 5-iodo-2-aminobenzenesulfonamide (1.192 g; 4 mmol), triethylamine (750 μΐ; 10 mmol), CUI (76 mg; 0.4 mmol); cyclopentyl mercaptan (590 μΐ; 6 mmol) and Pd(Ph ₃ ) 4 (462 mg; 0.4 mmol) in dry dioxane (10 ml) under N ₂ atmosphere in a sealed ampoule at 130°C overnight. The reaction mixture was cooled to room temperature, diluted with H ₂ O, basified (using 4 M NaOH) and filtered through Celite. Filter • Φ φφ ♦ · · φφφφ • φ φ · φφφ φφφφ φ φ φφ φ φ · φ φ φ φ φ φ φ φ φ φφ

107

φφ φ

ί φ

neutralized to pH 8.5 and evaporated to dryness. Column chromatography gave 327 mg (30%) of product.

3-Cyclohexyl-7-cyclopentylsulfinyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide (129): 2-Amino-5-cyclopentylthiobenzenesulfonamide was brominated at position 3 and A-oxidized under the conditions described by Ali and Bohnert (Synthesis, (1998) 1238), using 2 equivalents of Br ₂ . The product was reduced at 1 bar using 5% Pd/C in 96% EtOH and worked up according to method G (using cyclohexanecarboxaldehyde).

The following tables summarize the compounds described:

« φ φ φ

108

ΦΦΦ

ΦΦΦΦ φφ • φ φ

• φ Φ» φ · φ ί ::

Φ φ φ φφ φφ

109

« * • *· ·· 99 * * • • · · 9 9 9 9 ♦ « « · · • · 9 9 9 • « • • • ♦ • · b 9 • • « ··«· 99 ♦ · 9 99 99 ·♦

tO u> this this that this about 3 00 3 Lh 4a. w that O< ΙΛ O bJ LO O sj LO bP LO O SJ LO O SJ LO P> WHAT OF THIS LO O it WHAT OF SJ WHAT OF SJ LO O what About about From . from from from from from from from from from From from o s> Unit. sr ř G. Ct í Cu r CL ě- o G- oT ¹ f G- f G- {? r o- ir r O- r G. about ⁴ ø CL about ¹ §" about G- type of binding X X X X X X X X X X X 50 s> cyclohexyl cyclohexyl i §· δ cyclohexyl cyclohexyl 'ir cyclohexyl cyclohexyl o & • a> x <<* cyclohexyl cyclohexyl n *< π c π X % X X X X X X X X X X X X » X X X X X X X X X X X X W tzi X X X X X X X X X X X X w OX I 6 o <? J ¹ 8 i? R <j P P / 21 o=^ o ř (? □ o z m >° cf About <ř γ « pa % X X X X X X X X X X X X

9 · 9

9 9

9 99 · ·· · · •999 99

110 • 99

9 9 · 9 • 9 9 9 » 9

9 9 99

99 • 9 9 · • · · 9 • 9 9 · • 9 9 9 «9 99

LU lu LU LU M o LU O tO kD bU oo řO bU O\ bU LA that Q< LO Ο here tO O tU tO kP 00 o tu it O JU this about this it O tU this about this this about this it O IU this about this 0 from from from from from From From from from from from 0 kU Unit. Unit. Unit. Unit. Unit. t CD O. 3 O p. Unit i Unit. Unit. Unit. Unit. type of binding X X X X X X X X X X X cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyl cyclohexyls! cyclohexyl cyclohexyl cyclohexyl X Cm X X X X X X X X X X X x X X X X X X X X X X X X U) X X X X X X X X X X X X f ^w \^] P /^1 about Ί About P P P P P ' CA O ro Z O I X X X X X X X X X X X X 09

112

• · • · • 99 « • ·· 9 9· 99 9 9 ·· • • 9 9 9 9 9 • • • • 9 • • • · 9 · • * • • • 99·9 9 9 99 * ·· 99 ··

LA O\ CA CA About 45w CA U> CA Ni CA CA O 4^ kQ -fa. 00 o< (Λ (Z) O N) ω κΡ what Oh oh WHAT O Ν» WHAT OF IQ WHAT O it WHAT about S) what O sj about From From from from From From from from from o Ν» Unit. (X CD o Q. c CD Q. □ O p. c CD Q. 3 O Q. c. CD Q. 3 O Q. c. CD Q. 3 O p. C- CD Q. 3 O Q. c_ CD Q. 3 O Q. c_ CD Q. 3 O p. X and and and and and and and and P.O.K.> cyclohexyl cyclopentyl o a K> ►3 sr ό 3 Ό 55’ o *3 3 cyclopropyl ......... o X UJ cyclohexyl cyclohexyl w w and and and and and and and and and FRIDAY A. and and and and and and and and and PUT T and and and and and and and and and * O _o \ χ,Ο <ňď O C0< O y^o o \<P cn< y»>o Q, wr Q _o \ xP tni y^o Q _o \ XO y7o Q _o CD< y7o m / rn—z \ xP ω< and and and and and and and and and %

• φ

Φφφ φ φ φφφφφ φ φ φ φφφ φφφφ φφ

113 φ φφ φφφ φ

Φφφφ φφφ φφφ φφφ φφ φφ φφ φ φ · φ φ φ · φ φ φ φ φ « φ φ · φφ φφ

3,4,7-free substituted compounds with single bonds Single ~H 1~ cyclohexyl I CH, I Η H

116 • Φ φφ • * * • ··· • · · • · · • ·· · ··

φ· ♦· φ · φ φ • · · « • · · φ • φ · · φφ ··

\c ο 3,5,7-trisubstituted compounds with single bonds \o <-Λ in? •U \c ca in 3,4,7-trisubstituted compounds with double bonds VO M5 O oc VC 00 oc OO -u Q< ιη S> WHAT what ,P what about this what about this WHAT O here CO sP what about this what 0 here what 0 here About Ζ from from from from from from from from from O Κ» Unit. Q. - ¹ ° è Q)« ^ω □' Q)« -g ^w 3' Ol· Q. o 0)' c CD Q. 3 o· Q. c_ CD CL □ o· Q. c_ CD Q. □ o· Q. c CD Q. □ O Q. c- CD O. 3 O CL you X 1 t 1 and X X ►Τ’ »-ht X X » here Ρ & & & & & ¢/ Cy % X this JL Γ5 X X X X X X X X X X X «Λ X X X X X X X X X X 50 O\ ο X u> Q _o \ <.0 tni P 12 „ \ 0° tnť 54¾ š o—z ^Z I \ 02 “ 5^o X 'o / ^X2 \ 5?*o X % QZ _Λ <? 54¾ P ¹² Z, \ / tZli 54¾ X o / xz _Λ 54¾ X here of what ,P Π X LU CO 0 fj z X with you X X X X X X X X X X ?o 00

• · • · «

• 0

9

0 «

• *

117 *· ·· • 0 · ·0« • « · • · 0 • · · e 9 · ♦ · • 0 ·

• ·

9 ··

118 ·* • · · • ·>>

• · « • « « • *· · ·♦ ·

• · • · «· • · • · 9 9 • ·

3,7,8-trisubstituted compounds with single bonds 120 ^0 00 ^4 116 115 £ OJ here 3,6,7-trisubstituted compounds with single bonds Q< this P this O this this O KJ LO O KJ 00 O t-j ta O t-a 00 P what C ts> what P 00 0 No 00 0 here About From from From from from from from from from from from That c. CD CL 3 O p. t_ co Q. 3 O Q. c_ (0 a. 3 0 p. c_ CD Q. 3 O Q. c^ CD a. 3 8. c_ CD Q. 3 O p. c_ CD a. 3 a c. CD Q. 3 O p. c_ CD CL 3 p. C_ c_ CD Q. ? b *< and X X X X X X X X X » N> cyclohexyl c? 3 << 22 a 2T cd X cyclohexyl 0 Uí 3Γ o 3- cd X *<_ C5 E 0 3* cd X 0 *< E 0 3Γ η» X Π *< 0 3 CD X *<. <0 3Γ O 3Γ CD X *< E O 3” 8 n << E 0 3- CD X X w I X X X X X X X X X X X «. X tfl X X X X X X X X X what *» q and r~\ 0 o X o X w o *T* 0 ,x UJ n X Uí Ci X % o UJ< ν-Ασ X IU 2 00 0 it X w 2 co 0 tu 0 0 X UJ 0 ^λ —z _Λ \ <P cn< Q _about γΛο X ba 2 CZ5 P P X U X X X X X X X X X X X

• · • · ···· ·<

·· • · • · • · · • · · · • · • · • · · • · · • · · • · · • · · · ·· · • · ·«

119 ··

μ it o< what O NJ about from about Unit. type of binding X w cyclohexyl » Ul X 73 <u X % X oQ •>c y. 73 oc

·· ·· · ·· ··

Claims (30)

PATENT CLAIMS 1. A compound represented by the general formula (I): where X represents C=O or CH ₂ ; and Y represents CH(R ⁴ ), N(R ⁴ ) or N(R ⁴ )-CH ₂ or O; and R ² represents a hydrogen atom, alkyl, cycloalkyl, aryl, benzyl, or -CO-R ⁹ , where the substituent R ⁹ represents alkyl, cycloalkyl, benzyl or aryl; or R ² together with the substituent R ³ and together with the atoms to which they are attached form a 4- to 7-membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups; and R ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy group, haloalkoxy group, acyl, alkyl-NR ¹³ R ¹⁴ or alkyl-SR ¹³ , where the substituents R ¹³ and R ¹⁴ independently represent a hydrogen atom, alkyl or cycloalkyl; or the substituents R ¹³ and R ¹⁴ together with the nitrogen to which they are attached 121 attached, form a 3-membered to 8-membered heterocyclic ring structure; or R ³ represents a carbocyclic 7- to 12-membered ring which is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or R ³ represents a heterocyclic 3- to 8-membered ring which is optionally substituted with halogen, alkyl, hydroxy or alkoxy and optionally the heterocyclic ring is fused to aryl; or R ³ represents benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ³ represents aryl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ³ together with the substituent R ² or R ⁴ and together with the atoms to which they are attached form a 4- to 7-membered ring which is optionally substituted with one or more 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 a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or -CO2R ¹⁰ , where the substituent R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or 122 • · · · φ • · · ·· • · ·· · • · · · · • · · · ···· ·· ··· R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 4-membered or 7-membered ring which is optionally substituted with one or more 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 ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl or aryl; or R ⁵ represents -SO2-NR ^H R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl, aryl; or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SCh-alkyl, -SOaryl, or -SObenzyl; and optionally the heterocyclic ring is fused to aryl; and R ⁶ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy groups, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R ⁶ represents -NR ¹⁵ R ¹⁶ , -NHSOR ¹⁵ or -NHSOaryl, wherein aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF ₃ , OCF ₃ , -NO 2 and aryl; wherein the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure which is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2alkyl, -SCh-aryl or -SObenzyl and optionally the heterocyclic ring is fused to aryl; or » 0 0 • 0 • · ·· 123 • ·· ·· ·· • · · 0 · 00 · 0 0 0 0 0 0 · 00 000 00 0 0 0 0 0 0 0 0 000 00 00 00 R ⁶ represents aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R ⁶ represents HET which is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl and haloalkoxy; or R ⁶ represents -(alkyl)mSR ¹⁵ ; -(alkyl)m-SO-R ¹⁵ ; -(alkyl)m-SO2-R ¹⁵ ; -(alkyl)m-SO ₂ OR ¹⁵ ; (alkyl)m-SO2-NR ¹⁵ R ¹⁶ ; -(alkyl)m-NHCOR ¹⁵ ; -(alkyl)m-CONR ¹⁵ R ¹⁶ ; -(alkyl)mCR'=NOR; -(alkyl) _m -CO-R ¹⁵ ; -(alkyl) _m -CO ₂ -R ¹⁵ , where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; and R ⁷ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, nitroalkyl, alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO2-R ¹⁷ or -NHSO2-aryl, wherein aryl is optionally substituted with one or more substituents selected from halogen, alkyl, • _{· •} · ·· • _· R ⁷ represents -(alkyl)mSR ¹⁷ ; -(alkyl)m-SO-R ¹⁷ ; -(alkyl)m-SO2-R ¹⁷ ; -(alkyl)m-SO ₂ OR ¹⁷ ; (alkyl)m-SO2-NR ^I7 R ¹⁸ ; -(alkyl)m-NHCOR ¹⁷ ; -(alkyl)m-CONR ¹⁷ R ¹⁸ ; -(alkyl)m-CR =NOR”; (alkyl) _m -CO-R ¹⁷ or -(alkyl) _m -CO ₂ -R ¹⁷ , where the index m is 0 or 1; and the substituents R'and R” independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, benzyl; and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, SO ₂ alkyl, SO ₂ -aryl or SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R ⁷ represents HET, which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO-aryl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF ₃ or -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, 125 alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R together with the substituent R or together with the substituent R form a 5-membered to a 7-membered ring having one of the following structures -O-(CH2) _n -O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO ₂ -(CH ₂ ) _n -, where the index n is 2 or 3; -SO-(CH ₂ ) n -, where the index n is 2 or 3; -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ ) _n -NH-, where the index n is 1 or 2; -CO-NH-(CH ₂ ) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; or -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; and R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group or nitroalkyl; or R ⁸ represents aryl optionally substituted with one or more substituents selected from the group consisting of halogen, -CF 3 , -OCF 3 , -NO ₂ , alkyl, cycloalkyl and alkoxy; or R ⁸ represents HET optionally substituted with one or more substituents selected from the group consisting of halogen, -CF3, -OCF3, _-NO2 , alkyl, cycloalkyl and alkoxy; or φ 126 φφφφ Φ· • · φφ R ⁸ represents -(alkyl)mSR ¹⁹ ; -(alkyl)m-SO-R ¹⁹ ; -(alkyl)m-SO2-R ¹⁹ ; -(alkyl)m-SO ₂ OR ¹⁹ ; -(alkyl)m-SO2-NR ¹⁹ R ²⁰ ; -(alkyl)m-NHCOR ¹⁹ ; -(alkyl)m-CONR ¹⁹ R ²⁰ ; -(alkyl)mCR'=NOR; -(alkyl)m-CO-R ¹⁹ ; or -(alkyl) _m -CO ₂ -R ¹⁹ , where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or a compound represented by general formula I, where X represents _SO2 ; and Y represents CH(R ⁴ ), N(R ⁴ ), N(R ⁴ )-CH ₂ or O; and R ² represents a hydrogen atom; and R ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkyl, alkoxy group, haloalkoxy group, alkylNR ¹³ R ¹⁴ or alkyl-SR ¹³ , where the substituents R ¹³ and R ¹⁴ independently represent a hydrogen atom, alkyl or cycloalkyl; or the substituents R ¹³ and R ¹⁴ together with the nitrogen to which they are attached form a 3- to 8-membered heterocyclic ring structure; or R ³ represents a carbocyclic 7- to 12-membered ring which is optionally substituted with halogen, alkyl, hydroxy or alkoxy; or ΦΦ «« » · · • · ·· 127 ΦΦ ΦΦ ΦΦ R ³ represents a heterocyclic 3-membered to 8-membered ring which is optionally substituted with halogen, alkyl, hydroxy or alkoxy; and optionally the heterocyclic ring is fused to an aryl; or R ³ represents benzyl which is optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl, alkyl, hydroxy, alkoxy, amino, thio, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio and alkylamino; or R ³ together with the substituent R ⁴ and together with the atoms to which they are attached form a 4- to 7-membered ring which is optionally substituted with one or more 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 a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, -CO-R ¹⁰ or -CO2R ¹⁰ , where the substituent R ¹⁰ represents a hydrogen atom, cycloalkyl, alkyl, aryl or benzyl; or R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 4- to 7-membered ring which is optionally substituted with one or more 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 R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, aryl; or -SO ₂ -NR ⁿ R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or 128 tt ·» • · φ » • * · · ···· ·· • ♦ · · • Φ φφ 11 19 the substituents R and R together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SCh-alkyl, -SO2-aryl or -SO2-benzyl; and optionally the heterocyclic ring is fused to an aryl; R ⁶ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitro group, alkoxy group, haloalkoxy group, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R ⁶ represents -NR ^1S R ¹⁶ , -NHSO 2 -R ¹⁵ or -NHSO 2 -aryl, wherein aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF 3 , -OCF 3 , -NO 2 and aryl; wherein the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure which is optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2alkyl, -SCh-aryl or _-SO2- benzyl and optionally a heterocyclic ring fused to aryl; or R ⁶ is aryl, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl and amino; or R ⁶ HET, optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, halogen, haloalkyl and haloalkoxy; or 99 99 99 «9 9 9 9 9 9 99 9 9 9 9999 99 129 9 9 9 9 9*· • 9 9 99« 99 99 99 R ⁶ represents -(alkyl)mSR ¹⁵ ; -(alkyl)m-SO-R ¹⁵ ; -(alkyl)m-SO2-R ¹⁵ ; -(alkyl)m-SO ₂ OR ¹⁵ ; (alkyl)m-SO2-NR ¹⁵ R ¹⁶ ; -(alkyl)m-NHCOR ¹⁵ ; -(alkyl)m-CONR ¹⁵ R ¹⁶ ; -(alkyl)mCR'=NOR; -(alkyl) _m -CO-R ¹⁵ ; or-(alkyl) _m -CO ₂ -R ¹⁵ , where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; and R ⁷ represents a hydrogen atom, halogen, alkyl, cyano group, cyanoalkyl, nitroalkyl, alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohaloalkyl; or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO2-R ¹⁷ or -NHSO2-aryl, wherein aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF ₃ , OCF ₃ , -NO ₂ and aryl; or R ⁷ represents -(alkyl)mSR ¹⁷ ; -(alkyl)m-SO-R ¹⁷ ; -(alkyl)m-SO2-R ¹⁷ ; -(alkyl)m-SO ₂ OR ¹⁷ ; (alkyl)m-SO2-NR ¹⁷ R ¹⁸ ; -(alkyl)m-NHCOR ¹⁷ ; -(alkyl)m-CONR ¹⁷ R ¹⁸ ; -(alkyl)m-CR'=NOR”; (alkyl) _m -CO-R ¹⁷ or -(alkyl) _m -CO ₂ -R ¹⁷ , where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or 130 00 00 0 00 00 00 0 0 0 0 0 · · 00·· 0 00 000 0000 0000 00 00 00 00 00 17 1 β the substituents R and R together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO2alkyl, -SCh-aryl or -SCb-benzyl; and optionally the heterocyclic ring is fused to an aryl; or R ⁷ represents -(alkyl)m-SO ₂ -NR ¹⁷ R ¹⁸ , where the index m is 0 or 1; and the substituents R ¹⁷ and R ¹⁸ independently of each other represent alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET, which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO-aryl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ NR ^I7 R ¹⁸ ; or R ⁷ represents aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3 or -SO ₂ -NR ¹⁷ R ¹⁸ , where 131 φφ φφ * ·Φ ·· ·· ^φ · φ φ φ · φ φφφφ • φφφ ^φφφ φφφφ •Φ φ or R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH 2 ) _n -O-; where the index n is 1, 2 or 3; -SONR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO2-(CH2) _n- , where the index n is 2 or 3; -SO-(CH2) _n- , where the index n is 2 or 3; -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH2) _n -NH-, where the index n is 1 or 2; -CO-NH-(CH2) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; -O-(CH2) _n -O-; where the index n is 1,2 or 3; and R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro or nitroalkyl; or R ⁸ represents aryl optionally substituted with one or more substituents selected from the group consisting of halogen, -CF ₃ , -OCF ₃ , -NO ₂ , alkyl, cycloalkyl and alkoxy; or 132 ΦΦ φφ φ ·· ·· ·· • · φ φφφφ φφφφ φ φφφ φφφ φφφφ φφ φ · φφ φφφ φφ φ φ φφ φφφ φφφφ φφφφ φφ φφφ φφ φφ φφ R ⁸ represents HET optionally substituted with one or more substituents selected from the group consisting of halogen, -CF 3 , -OCF 3 , -NO 2 , alkyl, cycloalkyl and alkoxy; or R ⁸ represents -(alkyl)mSR ¹⁹ ; -(alkyl)m-SO-R ¹⁹ ;-(alkyl)m-SO2-R ¹⁹ ; -(alkyl)m-SO ₂ OR ¹⁹ ; -(alkyl)m-SO2-NR ¹⁹ R ²⁰ ; -(alkyl)m-NHCOR ¹⁹ ; -(alkyl)m-CONR ¹⁹ R ²⁰ ; -(alkyl)mCR'=NOR; -(alkyl) _m -CO-R ¹⁹ ; or -(alkyl) _m -CO ₂ -R ¹⁹ , where the index m is 0 or 1; and the substituents R' and R" independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl, or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; provided, however, that if X is _SO2 and Y is ^NR4 and if one of the substituents ^R5 , ^R6 , ^R7 or ^R8 is halogen or alkyl or alkoxy, then one or more of the remaining substituents R, R, R or R is not also halogen or alkyl and then one or more of the remaining substituents ^R5 , ^R6 , ^R7 or ^R8 is not hydrogen. 2. A compound according to claim 1, which is a 1,2,4-benzothiadiazine derivative having the general formula (II) 99 99 ·· ·· • · · • 999 9 9 9 9999 99 133 9 9 99 99 where R ³ represents a hydrogen atom, cycloalkyl, alkyl, cycloalkylalkyl, haloalkyl, alkoxy group, carbocyclic 7- to 10-membered ring, heterocyclic 5- to 6-membered ring or benzyl; or R ³ represents together with the substituent R ⁴ forms a 5- to 6-membered ring; and R ⁴ represents a hydrogen atom or alkyl or together with the substituent R ³ and together with the atoms to which they are attached, form a 5- to 6-membered ring which is optionally substituted with one or more 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 ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO ₂ -NR ^]1 R ¹² , where the substituents R ¹¹ and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 5- to 6-membered ring structure; R ⁶ represents a hydrogen atom, Br, F, I, cycloalkyl, alkyl, alkoxy group or alkoxyalkyl; or R ⁶ represents phenyl, 134 ·· • * • • • and · « · • ·· • • ·· • * • • * • • • • • and • • · • · • • • • • ···· • · ··· ·· which is optionally substituted with one or more substituents selected from the group consisting of alkyl and alkoxy groups; or R ⁶ HET; or R ⁶ represents -SR ¹⁵ , -SO-R ¹⁵ , -SO2-R ¹⁵ , -SO2OR ¹⁵ , -SO2-NR ¹⁵ R ¹⁶ , NHCOR ¹⁵ , -CONR ¹⁵ R ¹⁶ , -CR'=NOR, -CO-R ¹⁵ or -CO2-R ¹⁵ , where the index m is 0 or 1; and the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, phenyl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; and R ⁷ represents Br, F, I, alkyl, cyano group, cyanoalkyl, nitroalkyl; alkoxy group, haloalkoxy group, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl)mNR ¹⁷ R ¹⁸ , -NHSO2-R ¹⁷ , -SR ¹⁷ ; -SO-R ¹⁷ ; -SO2-R ¹⁷ ; -SO2OR ¹⁷ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; CR'=NOR; -CO-R ¹⁷ or -CO ₂ -R ¹⁷ ; where the index m is 0 or 1; and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, -SO ₂ -alkyl, -SO ₂ -aryl, -SO ₂ -benzyl and optionally the heterocyclic ring is fused to aryl; R ⁷ represents -(alkyl) _m -SO ₂ NR ¹⁷ R ¹⁸ , where the index m is 0 or 1 135 99 99 9 ·· ·· 99 • 99 99 99 9999 • 999 99 9 9 99 9 99 99 99 999 99 9 9 99 999 9999 9999 99 999 99 99 99 17 18 · the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R and R together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl and -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF ₃ or -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH ₂ ) _n -O-, where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO ₂ -(CH ₂ ) _n -, where the index is not 2 or 3; -SO-(CH ₂ ) _n -, where the index n is 2 or 3; • Φ φφ ΦΦ φφ • φ φ • · φφ φ φ φ φ 136 • · · φφ φφ -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH2) _n -NH-, where the index n is 1 or 2; -CO-NH-(CH2) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; -O-(CH2) _n -O-; where the index n is 1,2 or 3; and R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group or nitroalkyl; or R ⁸ represents phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl and alkoxy; or R ⁸ represents HET; or R ⁸ represents -SR ¹⁹ ; -SO-R ¹⁹ ; -SO2-R ¹⁹ ; -SO2O-R ¹⁹ ; -SO2-NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; -CONR ¹⁹ R ²⁰ ; -CR'=NOR; -CO-R ¹⁹ or -CO2-R ¹⁹ , where the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, SCh-alkyl, -SCh-aryl, -SCh-benzyl; and optionally the heterocyclic ring is fused to an aryl; 3. A compound of formula I according to claim 1, wherein R ² represents a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl. 137 « »9 99 ·· • · 9 · · • 9 • • 1 • ··· • and • 9 • • i • 4 • • · • · • • • • I • ·· * • » ·· »· 4. A compound according to any one of the preceding claims, wherein <3 R represents a hydrogen atom, a cycloalkyl, an alkyl, a haloalkyl, an alkoxy group, a carbocyclic 7- to 10-membered ring, a heterocyclic 5- to 6-membered ring, or benzyl; or R ³ together with the substituent R ⁴ forms a 5- to 6-membered ring optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups. 5. A compound according to any one of the preceding claims, wherein R ⁴ represents a hydrogen atom or alkyl; or together with the substituent R and together with the atoms to which they are attached, form a 5- to 6-membered ring which is optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino and thio and optionally containing one or more heteroatoms and optionally containing carbonyl groups. 6. A compound according to any one of the preceding claims, wherein R ⁵ represents a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, phenyl or -SO ₂ -NR ^H R ¹² , where the substituents R ^{6 * * * * 11} and R ¹² independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹¹ and R ¹² together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure. 0« 0» 0 0 0 0 000 0 0 0 0 0 0· 0000 ·0 0 0 0 0 0 0 0 0 0 0 0 0 138 R ⁶ «0 t 0 • · 0 0 0 0 0 0 000 0F 7. A compound according to any one of the preceding claims, wherein R represents a hydrogen atom, halogen, cycloalkyl, alkyl, alkoxy or alkoxyalkyl; or R ⁶ represents aryl optionally substituted with one or more substituents selected from the group consisting of alkyl and alkoxy; or R ⁶ represents HET; or R ⁶ represents -SR ¹⁵ , -SO-R ¹⁵ , -SO2-R ¹⁵ , -SO2O-R ¹⁵ , -SO2-NR ¹⁵ R ¹⁶ , -NHCO-R ¹⁵ , -CONR ¹⁵ R ¹⁶ , -CR'=NOR, -CO-R ¹⁵ or -CO2-R ¹⁵ , where the substituents R' and R” independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁵ and R ¹⁶ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁵ and R ¹⁶ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl. 8. A compound according to any one of the preceding claims, wherein R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, cyclohaloalkyl, -(alkyl) _m -NR ¹⁷ R ¹⁸ , -NHSO ₂ -R ¹⁷ , -SR 17 ; -SO-R ¹⁷ ; -SO2-R ¹⁷ ; -SO2O-R ¹⁷ ; -NHCOR ¹⁷ ; -CONR ¹⁷ R ¹⁸ ; -CR'=NOR; -CO-R ¹⁷ or -CO ₂ -R ¹⁷ , wherein the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl ^or benzyl; and 139 17 18 the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R and R together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with alkyl, -SO ₂ -alkyl, -SO ₂ -aryl, -SO 2 -benzyl and optionally the heterocyclic ring is fused to aryl; R ⁷ represents -(alkyl) _m -NR ¹⁷ R ¹⁸ , where the index m is 0 or 1; and the substituents R ¹⁷ and R ¹⁸ independently represent alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET optionally substituted with one or more substituents selected from halogen, alkyl, phenyl or -SO ₂ NR ^I7 R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R ⁷ represents phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF3 or -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally 140 substituted with halogen, alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl, and optionally the heterocyclic ring is fused to an aryl; or R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH 2 ) n O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO ₂ -(CH ₂ ) _n -, where the index n is 2 or 3; -SO-(CH ₂ )„-, where the index is not 2 or 3; -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH ₂ ) n -NH-, where the index n is 1 or 2; -CO-NH-(CH ₂ ) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; and 9. A compound according to any one of the preceding claims, wherein R ⁸ represents a hydrogen atom, alkyl, alkoxy group, hydroxyalkyl, halogen, haloalkyl, CN, cyanoalkyl, nitro group or nitroalkyl; or R ⁸ represents phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl or alkoxy; or R ⁸ represents HET; or R ⁸ represents -SR ¹⁹ ; -SO-R ¹⁹ ; -SO2-R ¹⁹ ; -SO2O-R ¹⁹ ; -SO ₂ -NR ¹⁹ R ²⁰ ; -NHCOR ¹⁹ ; » · «I • · · • · · 141 • · ·· • · 4 I · · · · · -CONR ¹⁹ R ²⁰ ; -CR'=NOR; -CO-R ¹⁹ ; or -CO ₂ -R ¹⁹ , where the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁹ and R ²⁰ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁹ and R ²⁰ together with the nitrogen to which they are attached form a heterocyclic 3-membered to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino or thio, phenyl, benzyl, -SC>2-alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally a heterocyclic ring fused to aryl; 10. A compound according to any one of the preceding claims, wherein X represents _SO2 ; Y represents N; and R ² represents H; and R ³ represents a cycloalkyl, carbocyclic 7-membered to 10-membered ring; heterocyclic 5- to 6-membered ring; and R ⁴ represents H; and R ⁵ represents H; and R ⁶ represents a hydrogen atom, alkyl or halogen; and R ⁷ represents cyanoalkyl, nitroalkyl, haloalkyl or -(alkyl) _m -SO-R ¹⁷ ; -(alkyl)m-SO2-R ¹⁷ ; (alkyl)m-CONR ¹⁷ R ¹⁸ ; -(alkyl)m-CR'=NOR; -(alkyl)m-CO-R ¹⁷ ; or -(alkyl)m-CO ₂ where the index m is 0 or 1 142 • · ·« • · »·· · ·< the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, -SCh-alkyl, -SCh-aryl or -SCh-benzyl; and optionally a heterocyclic ring fused to an aryl; or R ⁷ represents -(alkyl) _m -SO2-NR ¹⁷ R ¹⁸ , where the index m is 0 or 1; and the substituents R ¹⁷ and R ¹⁸ independently represent alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, -SOalkyl, -SOaryl or -SO ₂ -benzyl and optionally a heterocyclic ring fused to aryl; or R ⁷ represents HET; or R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH 2 ) _n -O-; where the index n is 1, 2 or 3; -SONR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH2) _n- , where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO2-( _CH2 ) _n- , where the index n is 2 or 3; -SO-(CH2) _n- , where the index n is 2 or 3; -CO-CH=CH-NH-; -CO-CH=CH-O-; -CO-(CH2) _n -NH-, where the index n is 1 or 2; 143 -CO-NH-(CH2) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; or -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; and R ⁸ represents alkyl, halogen, cyanoalkyl, nitroalkyl, haloalkyl, -(alkyl) _m -SO-R ¹⁷ ; -(alkyl) m -SO2R ¹⁷ ; -(alkyl) m -SO ₂ -NR ¹⁷ R ¹⁸ ; -(alkyl) m -CONR ¹⁷ R ¹⁸ ; -(alkyl) m -CR =NOR; -(alkyl) _m CO-R ¹⁷ ; or -(alkyl) _m -CO ₂ -R ¹⁷ , where the index m is 0 or 1, the substituents R' and R independently represent a hydrogen atom, alkyl, cycloalkyl, phenyl or benzyl; and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with alkyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R ⁸ represents HET. 11. A compound according to any one of the preceding claims, wherein R ³ represents a hydrogen atom, cyclopropyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, CF ₃ , ethoxy, norbomylene, norbomane, adamantane or benzyl; or R ³ together with the substituent R ⁴ and together with the atoms to which they are attached form a 5-membered ring; 12. A compound according to any one of the preceding claims, wherein R ⁴ represents 144 • 0 ·· • · • ·· · 0 0 • «· 00 0· • 0 · 0 0 0 0 · • 0 0 · 0 0 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0·· ·· 00 00 hydrogen, methyl or ethyl atom; or R ⁴ together with the substituent R ³ and together with the atoms to which they are attached form a 5-membered ring; A compound according to any one of the preceding claims, wherein R ⁵ represents a hydrogen atom, chlorine, bromine, methyl or phenyl. A compound of formula I according to any one of the preceding claims, wherein R ⁶ represents a hydrogen atom, 2-methoxyphenyl, 2-pyridyl, 3-pyridyl, methyl, methoxy group, chlorine or bromine; 15. A compound of formula I according to any one of the preceding claims, wherein R represents 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-triazolyl, 4-phenyl-triazol-5-yl, 5-methyll,2,4-oxadiazol-3-yl, CH ₃ CONH-, CH 3 SO 2 NH-, -SO ₂ OH, phenyl-SO ₂ -, N,N-dimethylsulfamoyl, Λζ/N-diethylsulfamoyl, N-phenyl-N-methyl-sulfamoyl or -SO ₂ 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; 16. A compound of formula I according to any one of the preceding claims, wherein R ⁸ represents a hydrogen atom, methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or a methoxy group. 0 0 · · 0 00 00 00 • •0 0000 000« • 000 00 0 0 00 * 145 0 00 000 0000 0000 00 000 90 0 0 00 17. A compound of formula II according to claim 2, wherein R ² represents a hydrogen atom or CH 3 ; and R ³ represents a cyclohexyl, cyclopentyl, norbomylene, norbomane, adamantane, or ethoxy group; and R ⁴ represents a hydrogen atom, or CH 3 ; and R ⁵ represents a hydrogen atom, CH 3 , phenyl, sulfamoyl, chlorine or bromine; and R ⁶ represents a hydrogen atom, CH3, 2-methoxyphenyl, methoxy group, chlorine, bromine, 2-pyridyl, 3-pyridyl; and R ⁷ represents chlorine, bromine, methyl, 1-hydroxyethyl, acetyl, -(CH3)C=N-OH, -CONH2, -CO2-ethyl, cyano group, phenyl, 2-N-acetylaminophenyl, 2-nitrophenyl, 2methoxyphenyl, 4-trifluoromethyl-2-methoxyphenyl, 2,4-dimethoxyphenyl, 2-N,Ndimethylsulfamoylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-hydroxyphenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-furyl, 3-furyl, 2-thienyl, 2-(Y-methyl)-imidazolyl, 5-triazolyl, 4-phenyl-triazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, CH3CONH-, CH3SO2NH-, SO2OH, phenyl-SO2-, N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-phenyl-N-methylsulfamoyl or -SCh-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 R ⁸ represents a methyl, hydroxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-pyridyl or methoxy group, 18. A compound of formula I according to claim 1, X is C=O; and Y is N, O or CH; and R ² represents a hydrogen atom; and R ³ represents a hydrogen atom, CH 3 , CF 3 , cyclohexyl, norbornylene, phenyl or ethyl; and 146 ·· ·· · ·· · · · · 9 9 9 99 · 9 9 9 9· 9999 999 9 · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9999 99 999 99 99 99 >ι R represents a hydrogen atom, N-dimethylsulfamoyl, N-cyclohexylsulfamoyl, tetrahydropyrid-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, sulfamoyl, bromine; and R ⁵ represents a hydrogen atom or bromine; and R ⁴ , R ⁶ and R ⁸ are hydrogen; 19. A compound of formula I according to claim 1, wherein X represents CH ₂ ; and YjeN;a R ³ represents cyclohexyl or norbornylene; and R ⁵ represents a hydrogen atom or bromine; and R ⁷ represents bromo or sulfamoyl; and R ² , R ⁴ , R ⁶ and R ⁸ are hydrogen; 20. A compound of formula I according to claim 1, wherein X is SO ₂ ; and N is -NHCH ₂ -; and R ³ represents 3-methylbut-2-yl, phenyl or cyclohexyl; and R ⁷ represents 1-piperidinyl sulfonyl. 21. A compound of formula I according to claim 1, which is: 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; 2-Ethyl-2-methyl-3,4-dihydro-1,3-benzoxazin-4-one; 2-Methyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide; 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonamide; 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline Ν,Ν-dimethylsulfonamide; 2-Trifluoromethyl-4-oxo-3,4-dihydro-8-quinazoline-1',2',3',6'-tetrahydropiperidinosulfonamide; 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline N-cyclohexylsulfonamide; 2-trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline morpholinosulfonamide; 2-Cyclohexyl-4-oxo-3,4-dihydro-6-quinazoline-N,N-dimethylsulfonamide; 9 9 ♦ 9 9 9 9 9 • · · 9 • 999 147 9 · · · 9999 ·· 999 9 9 9 9 99 99 2-Trifluoromethyl-4-oxo-3,4-dihydro-6-quinazoline sulfonic acid; 2- Cyclohexylmethylamino-5-N,N-dimethylsulfamoylbenzenesulfonamide; or 2-Ethylamino-7-(1',2',3',6'-tetrahydropiperidino)sulfonylbenzene sulfonamide or a pharmaceutically acceptable salt thereof. 22. A 1,2,4-benzothiadiazine derivative according to claim 2, which is: 3-Bicyclo[2,2,1]hept-5'-en-2'-yl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 1,2,3,5,10,1Oa-Hexahydrobenzo[e]pyrrolo[1,2-Ď]-1,2,4-thiadiazine-5,5-dioxide; 3-Cyclohexyl-6-(2-methoxy phenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-(2-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-(3-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3- Cyclohexyl-7-(1-hydroxyethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexy 1-7-(1-hydroxyiminoethyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-carbamoy 1-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-ethoxycarbonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-cyano-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-acetamidophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-nitrophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-methoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-methoxy-4'-trifluoromethylphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2',4'-dimethoxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-(N,N-dimethylsulfamoyl)phenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-chlorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-fluorophenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(3'-hydroxyphenyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; ·· ·· • φ φ φφφφ φφφ φφφ φφφφ φ φ 148 φ φφ φφ φφ φφφ φ φφφ · φφφ φφφφ φφ φφφ φφ · φφφ φφφφ φφφ φφ φφ φφ 3-Cyclohexyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; □ 3-Cyclohexy 1-7-(3'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-pyrimidinyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(3'-furyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(2'-thienyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(1-methyl-177-2-imidazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(5'-phenyl-1',2',3'-triazol-4'-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Cyclohexyl-7-(5'-methyl-1',2',4'-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-acetamido-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-methylsulfonylamino-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-phenylsulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 2- Cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline sulfonamide; 3- Methyl-7-dimethylsulfamoyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 2-cyclohexyl-1,2,3,4-tetrahydro-6-quinazoline Ν,Ν-dimethylsulfonamide; 3-Cyclohexyl-7-dimethylaminosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(N,N-diethylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Cyclohexyl-7-pyrrolidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopropyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-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-dioxide; 3-Benzyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopentyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Bicyclo[2,2,1]hept-5'-en-2'-yl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 149 ♦ Φ φφ φ φφ φφ ·· • φ φ φφφφ φφφφ •ΦΦΦ ΦΦΦ φφφφ φφ φφ φφ ΦΦΦ φφ φ ΦΦΦ ΦΦΦ φφφφ φφφφ φφ ΦΦΦ φφ φφ φφ 3-Cyclohexyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(N-methyl-N-phenylamino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(1'-(1',2',3',4'-tetrahydroquinolinyl))sulfonyl-1,2,3,4-tetrahydro-1,2,4benzothiadiazine-1,1-dioxide; 3-Cyclohexyl 1-7-(4'-methylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(4'-methylsulfonylpiperazino)sulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Methyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Methyl-7-(1',2',3',6'-tetrahydropiperidino)sulfonyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Trifluoromethyl-7-dimethylsulfamoyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-8-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 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-dioxide; 3-Cyclohexyl-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-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-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-2-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Cyclohexyl-4-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 7-Methylsulfonylamino-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide; 7-Sulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide; 7-Methylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide; 7-Dimethylsulfamoyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5dioxide; 7-Dimethylsulfamoyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide; φφ φφ φ φ φ φφφ φφ φ φ φ φ 150 φφφ φφφφ φφ φφφ φφ φφ φ φ φ φφφ φ φ φφφφ φφφ φ φφφ φφ φφ φφ 7-(r,2',3',6'-Tetrahydropiperidino)sulfonyl-1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4thiadiazine-5,5-dioxide; 3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-dimethyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-7-(N,N-diethylsulfamoyl)-5-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Bicyclo[2,2,1]hept-5'-en-2'-yl-5,7-diphenyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine 1,1dioxide; 3-Cyclohexyl-6-methyl-7-(2'-pyridyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclohexyl-6-methyl-7-(4'-triazolyl)-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-Cyclopentyl-6-methyl-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1dioxide; 3-Cyclohexyl-6-methyl-7-morpholinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Cyclohexyl-6-(2-methoxyphenyl)-7-methyl-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1dioxide; 3-Cyclohexyl-6-methoxy-7-piperidinosulfonyl-1,2,3,4-tetrahydro-1,2,4-benzothia-diazine-1,1dioxide; 3-Cyclohexyl-7,8-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; 3-cyclohexyl-6,7-ethylenedioxy-1,2,3,4-tetrahydro-1,2,4-benzothiadiazine-1,1-dioxide; or 3-Isobutyl-8-(piperidinosulfonyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-1,1-dioxide; or pharmaceutically acceptable salts thereof. 23. A compound having the general formula (III) where Y represents CH(R ⁴ ), N(R ⁴ ) or N(R ⁴ )-CH ₂ or O; and R ³ represents a carbocyclic 7-membered to 12-membered ring • 9 99 • 9 9 • ··· 9 9 9 9999 99 151 9 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 999 99 9 9 9 9 9 9 9 9 9 ··· 99 9· 99 optionally substituted with halogen, alkyl, hydroxy or alkoxy; and R ⁶ represents haloalkyl and R ⁷ represents halogen, alkyl, cyano, cyanoalkyl, nitroalkyl, alkoxy, haloalkoxy, haloalkyl, hydroxyalkyl, cycloalkyl or cyclohaloalkyl, or R ⁷ represents -NR ¹⁷ R ¹⁸ , -NHSO2-R ¹⁷ or -NH-SO2-aryl, wherein the aryl is optionally substituted with one or more substituents selected from halogen, alkyl, cycloalkyl, hydroxy, alkoxy, amino, thio, -CF3, -OCF3, -NO ₂ and aryl; or R ⁷ represents -(alkyl)mSR ¹⁷ ; -(alkyl)m-SO-R ¹⁷ ; -(alkyl)m-SO2-R ¹⁷ ; -(alkyl)m-SO ₂ OR ¹⁷ ; (alkyl) _m -NHCOR ¹⁷ ; -(alkyl)m-CONR ¹⁷ R ¹⁸ ; -(alkyl)m-CR'=NOR; -(alkyl) _m -CO-R ¹⁷ or (alkyl) _m -CO ₂ -R ¹⁷ ; where the index m is 0 or 1; and the substituents R'and R independently represent a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl or benzyl; and the substituents R and R independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ alkyl, SO ₂ -aryl or -SO ₂ -benzyl and optionally the heterocyclic ring is fused to an aryl; or R ⁷ represents -(alkyl) _m -SO ₂ NR ¹⁷ R ¹⁸ , where the index m is 0 or 1, and the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure, optionally 152 ΦΦ ♦· * φφ ·· ·· • φ φ φφφφ ΦΦΦ· φφφφ φ φφφφ φφφφ φφφφ φφφ φφφ ·« ·· substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to aryl; or R ⁷ represents HET optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, -S-alkyl, -S-aryl, -SO-alkyl, -SO-aryl, -SO ₂ -alkyl, -SO ₂ -aryl and -SO ₂ NR ¹⁷ R ¹⁸ ; or R ⁷ represents aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, hydroxyalkyl, halogen, haloalkyl, amino, -NHCO-alkyl, nitro, -OCF ₃ and -SO ₂ -NR ¹⁷ R ¹⁸ , where the substituents R ¹⁷ and R ¹⁸ independently represent a hydrogen atom, alkyl, cycloalkyl, benzyl or aryl; or the substituents R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocyclic 3- to 8-membered ring structure optionally substituted with halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, amino, thio, aryl, benzyl, -SO ₂ -alkyl, -SO ₂ -aryl or -SO ₂ -benzyl; and optionally the heterocyclic ring is fused to an aryl; or R ⁷ together with the substituent R ⁶ or together with the substituent R ⁸ form a 5- to 7-membered ring having one of the following structures -O-(CH ₂ ) _n -O-; where the index n is 1, 2 or 3; -SO ₂ -NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO-NR-(CH ₂ ) _n -, where the substituent R is hydrogen, alkyl, cycloalkyl, benzyl, or aryl, and the index n is 1 or 2; -SO ₂ -(CH ₂ ) _n -, where the index n is 2 or 3; -SO-(CH ₂ ) _n -, where the index n is 2 or 3; φφ »φ • φ φ φφφφ φ φ φ φ φφφ φφφφ φφ 153 * φφ φφ φφ • ΦΦ φ φ φφ φ φφφ φφφφ φφ φφφ φφ φ φφφ φφφφ φφφ φφ φφ φφ -CO-CH=CH-NH-; -CO-CH=CH-O-; -C0-(CH2) _n -NH-, where the index n is 1 or 2; -CO-NH-(CH2) _n , where the index n is 1 or 2; -CO-( _CH2 ) ₂ -O-; -O-(CH2) _n -O-; where the index n is 1,2 or 3. 24. A pharmaceutical composition comprising an effective amount of a chemical compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, optionally a pharmaceutically acceptable excipient, carrier or diluent. 25. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of disorders and diseases in living animal subjects, including humans, characterized in that the disorder or disease is responsive 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 the treatment of disorders and diseases in living animal subjects, including humans, wherein the disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system. 27. Use according to any one of claims 25 to 26, characterized in that the disorders or diseases are selected from memory or learning disorders, psychotic disorders, sexual dysfunctions, intellectual disorders, schizophrenia, depression, autism; Alzheimer's disease, learning deficits, attention deficits, memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia; 154 9· • 9 99 9 9 9 9 9 9 * 9 • 99 • 99 • • • 9 99 9 9 9 • 9 • • 4 * • ♦ 9 * • 9 9 • « • 9 * · ·· ♦ 99 9 9 9 9 99 28. A method of treating a disorder or disease in a living animal subject, including humans, wherein the disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system, the method comprising administering a therapeutically effective amount of a chemical compound according to any one of claims 1 to 23; 29. The method of claim 28, wherein the disorder or disease is responsive to modulation of the AMPA receptor complex of the central nervous system. 30. The method of any one of claims 28 to 29, wherein the disorders or diseases are selected from memory or learning disorders, psychotic disorders, sexual dysfunctions, intellectual disorders, schizophrenia, depression or autism; Alzheimer's disease, learning deficits, attention deficits, memory loss or senile dementia; or disorders or diseases resulting from trauma, stroke, epilepsy, Alzheimer's disease, neurotoxic agents, aging, neurodegenerative disorders, alcohol intoxication, substance abuse, cardiac bypass surgery or cerebral ischemia;