Patent EA-004682-B1 (EA)
Title: Benzothiadiazine compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: CORDI ALEX
IPC: A61K31/542
Filed: 2001-07-27
Abstract: 1. Compounds of formula (I): wherein: R1 represents a hydroxy, RCO-O- or RCO-NRa- group, R2 represents a hydrogen atom, a halogen atom, or a hydroxy, R'CO-O or R'CO-NR'a-group, R and R', which may be identical or different, represent a linear or branched (C1-C6)alkyl group optionally substituted by an aryl group, a linear or branched (C2-C6)alkenyl group optionally substituted by an aryl group, a linear or branched (C1-C6)perhaloalkyl group, a (C3-C7)cycloalkyl group, an adamantyl group, an aryl group or a heteroaryl group, Ra and R'a, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)perhaloalkyl group, a linear or branched (C1-C6)acyl group, an aryl group or a heteroaryl group, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: x "aryl group" is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups are optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, linear or branched (C1-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), aminosulphonyl (optionally substituted by one or more linear or branched (C1-C6)alkyl groups) and phenyl (optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)perhaloalkyl, hydroxy and linear or branched (C1-C6)alkoxy), x "heteroaryl group" is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups contain one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, and are optionally substituted by one or more, identical or different, groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)perhaloalkyl, linear or branched (C1-C6)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C1-C6)-alkyl groups) and aminosulphonyl (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). 2. Compounds of formula (I) according to claim 1, characterised in that R1 represents a hydroxy group and R2 represents a hydrogen or halogen atom. 3. Compounds of formula (I) according to claim 1, characterised in that R1 represents an RCO-O- group and R2 represents a hydrogen atom. 4. Compounds of formula (I) according to claim 3, characterised in that R represents a (C3-C7)cycloalkyl group, an aryl group or a heteroaryl group. 5. Compounds of formula (I) according to claim 1 which are: 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-benzoate. 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-cyclohexanecarboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-cyclobutanecarboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-4-methylbenzoate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-3-thiophenecarboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-2-thiophenecarboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-3-furan-carboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-2-furan-carboxylate, 5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl-nicotinate. 6. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material a compound of formula (II): wherein: R'1 represents a linear or branched (C1-C6)alkoxy group, R'2 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkoxy group, or a nitro group, which is reacted with the acid chloride of formula (III) in the presence of a base, in a tetrahydrofuran or acetonitrile medium: Cl-(CH2)3-COCl (III) to yield a compound of formula (IV): wherein R'1 and R'2 are as defined hereinbefore, which is then cyclised in a basic medium, to yield a compound of formula (V): wherein R'1 and R'2 are as defined hereinbefore, which is subjected to reduction, in an alcoholic medium or in a dimethylformamide medium, in the presence of sodium borohydride, to yield a compound of formula (VI): wherein R'1 and R'2 are as defined hereinbefore, which compound of formula (VI): is subjected to the action of boron tribromide, to yield: - either the compound of formula (I/a), a particular case of the compounds of formula (I): wherein R"2 represents a hydrogen atom, a halogen atom or a hydroxy group, - or the compound of formula (VII): which is then subjected to reduction, to yield the corresponding amine, which is optionally substituted, and then subjected to one or two successive acylations, to yield the compound of formula (I/b), a particular case of the compounds of formula (I): wherein R' and R'a are as defined for formula (I), wherein the hydroxy group(s) containing in compounds (I/a) and (I/b) can be acylated to yield the compounds (I/d), in which the hydroxy group(s) of the phenyl ring has/have been converted to R-CO-O or R'-CO-O- groups wherein R and R' are as defined for formula (I), and the resulted compounds (I/a), (I/b and (I/d) are purified, if necessary, according to a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 7. Process for the preparation of compounds of formula (I) according to claim 1, wherein R1 represents a RCO-NRa- group, characterised in that there is used as starting material a compound of formula (II): wherein: R'1 represents a nitro group, R'2 represents a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkoxy group, or a nitro group, which is reacted with the acid chloride of formula (III) in the presence of a base, in a tetrahydrofuran or acetonitrile medium: Cl-(CH2)3-COCl (III) to yield a compound of formula (IV): wherein R'1 and R'2 are as defined hereinbefore, which is then cyclised in a basic medium, to yield a compound of formula (V): wherein R'1 and R'2 are as defined hereinbefore, which is subjected to reduction, in an alcoholic medium or in a dimethylformamide medium, in the presence of sodium borohydride, to yield a compound of formula (VI): wherein R'1 and R'2 are as defined hereinbefore, which is then subjected to reduction, to yield the corresponding amine, which is optionally substituted, and then subjected to acylation to yield the compound of formula (I/c), a particular case of the compounds of formula (I): wherein R and Ra are as defined for formula (I), and R"2 represents a hydrogen atom, a halogen atom or a hydroxy group, or a R'CONR'a group, wherein R' and R'a are as defined for formula (I), wherein the hydroxy group containing in the compound (I/c) and (I/b) can be acylated to yield the compound (I/d), in which the hydroxy group of the phenyl ring has been converted to the R'-CO-O- group wherein R' is as defined for formula (I), and the resulted compounds (I/c) and (I/d) are purified, if necessary, according to a conventional purification technique, are separated, where appropriate, into their isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 8. Pharmaceutical compositions comprising as active ingredient a compound according to any one of claims 1 to 5 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 9. Pharmaceutical compositions according to claim 7 comprising as active ingredient a compound according to any one of claims 1 to 5 for use as medicaments, as AMPA modulators.