Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1998-01-16
2001-04-10
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S600000, C514S601000, C514S604000, C564S085000, C564S086000, C564S088000
Reexamination Certificate
active
06214882
ABSTRACT:
The present invention relates to benzenesulphonamide derivatives, to their preparation and to their application in therapy.
The compounds of the invention correspond to the general formula (I)
in which:
R
1
represents a hydrogen atom, a halogen atom such as chlorine or fluorine or a linear or branched C
1-4
alkyl or C
1-4
alkoxy group,
R
2
, R
3
and R
4
represent, independently of one another, hydrogen atoms or linear, branched or cyclic C
1-4
alkyl groups, and
R
5
represents a hydrogen atom or a C
1-2
alkyl, C
1-2
fluoroalkyl or C
1-2
perfluoroalkyl group.
The term C
1-4
alkyl comprises linear, branched-chain or cyclized radicals having up to 4 carbon atoms, comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, preferably C
1-2
alkyl such as methyl and ethyl.
The term C
1-2
fluoroalkyl comprises linear radicals having 1 to 2 carbon atoms as defined above, in which at least one of the hydrogen atoms is substituted with a fluorine, on the understanding that not all the hydrogen atoms are substituted with fluorine atoms. The term C
1-2
perfluoroalkyl comprises linear radicals having 1 to 2 carbon atoms as defined above, in which all the hydrogen atoms are substituted with a fluorine.
The term C
1-4
alkoxy comprises linear radicals having up to 4 carbon atoms, attached via an oxygen atom, comprising methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy, preferably C
1-2
alkoxy, methoxy and ethoxy.
The compounds of general formula (I) contain one or more asymmetric carbon atoms. They may hence exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers as well as mixtures thereof, including the racemic mixtures, form part of the invention.
The compounds of general formula (I) can take the form of addition salts with pharmaceutically acceptable acids, which also form part of the invention. According to the present invention, the preferred salts are the oxalate and fumarate salts.
The compounds of general formula (I) in which R
5
represents a C
1-2
alkyl, C
1-2
fluoroalkyl or C
1-2
perfluoroalkyl group exist in the form of syn or anti isomers. These forms as well as mixtures thereof form part of the invention.
Preferred compounds are those for which R
5
represents a hydrogen atom, a methyl or an ethyl, preferably a hydrogen or a methyl, in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures, as well as their addition salts with pharmaceutically acceptable acids.
Other preferred compounds are those for which R
1
represents a hydrogen atom, a fluorine, a chlorine or a C
1-4
alkoxy group, preferably methoxy or ethoxy, in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures, as well as their addition salts with pharmaceutically acceptable acids.
Other compounds of choice are those for which R
2
and R
3
represent, independently of one another, a hydrogen atom, a methyl, an ethyl or an isopropyl, preferably a hydrogen, in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures, as well as their addition salts with pharmaceutically acceptable acids.
Among these, there may be mentioned the compounds for which:
R
1
represents a hydrogen atom, a fluorine, a chlorine or a C
1-4
alkoxy group, preferably methoxy or ethoxy,
R
2
and R
3
represent, independently of one another, a hydrogen atom, a methyl, an ethyl or an isopropyl, preferably a hydrogen,
R
4
represents a hydrogen or a linear, branched or cyclic C
14
alkyl group, and
R
5
represents a hydrogen atom, a methyl or an ethyl, preferably a hydrogen atom or a methyl, in the form of enantiomers or diastereoisomers or mixtures of these different forms, including racemic mixtures, as well as their addition salts with pharmaceutically acceptable acids,
and very special mention may be made of
&agr;-(aminomethyl)-2-methoxy-5-sulphamoylbenzenemethanol and its salts,
(+)-&agr;-(aminomethyl)-2-methoxy-5-sulphamoylbenzenemethanol and its salts,
(−)-&agr;-(aminomethyl)-2-methoxy-5-sulphamoylbenzenemethanol and its salts,
&agr;-(aminomethyl)-2-chloro-5-sulphamoylbenzenemethanol and its salts, and
&agr;-(aminomethyl)-2-fluoro-5-sulphamoylbenzenemethanol and its salts.
The compounds of general formula (I) in which R
1
represents an alkoxy group and R
2
and R
3
represent hydrogen atoms may be prepared according to the process shown in Appendix 1, which consists in treating a benzaldehyde derivative of formula (V), in which R
1
is defined as above, with ethyl orthoformate in the presence of ammonium chloride, and then with chlorosulphonic acid, in treating the 5-chlorosulphonylbenzaldehyde derivative of formula (IV) with an amine of formula R
4
NH
2
in which R
4
is defined as in the general formula (I), in thereafter reacting the 5-sulphamoylbenzaldehyde derivative of formula (III) with trimethylsilyl cyanide (TMSCN) in the presence of zinc iodide, and lastly reducing the compound of formula (II) thereby obtained with lithium borohydride in the presence of trimethylsilyl chloride (TMSCl).
The compounds of general formula (I) may also be prepared according to the process shown in Appendix 2, from a sulphamoylacetophenone derivative of formula (XII).
In the case where R
1
is defined as in the general formula (I) with the exception of the meaning alkyl, this process consists in treating the 5-sulphamoylphenyl ketone derivative of formula (XII) with bromine, in then reacting the compound of formula (XI), either with lithium chloride to obtain the compound of formula (X) which is thereafter reduced with borane to give the compound of formula (IX) and then treated with sodium azide to give the compound of formula (VIII), or with sodium azide and then sodium borohydride to obtain the compound of formula (VIII), or with sodium borohydride in the presence of potassium carbonate to obtain the compound of formula (VII), and lastly in treating the compound of formula (VIII) with hydrogen in the presence of a catalyst such as palladium on charcoal in the case where R
1
is not a chlorine atom, or with triphenylphosphine and then with aqueous ammonia in the case where R
1
is a chlorine atom, to obtain the compound of general formula (I) in which R
2
and R
3
are hydrogen atoms, or in treating the compound of formula (VII), either with an amine of formula R
2
(R
3
)NH in which R
2
represents a hydrogen atom or a C
1-4
alkyl group and R
3
a C
1-4
alkyl group, to obtain the compound of general formula (I) in which R
2
and R
3
are defined as above, or with an amine of formula R
2
(Bn)NH in which R
2
is a C
1-4
alkyl group and Bn a benzyl group, to obtain a compound of formula (VI), which is thereafter reduced with hydrogen in the presence of a catalyst such as palladium on charcoal, to give the compound of general formula (I) in which R
2
is an alkyl group.
In the case where R
1
is an alkyl group, this process consists in treating the compound of formula (XII) with benzyltrimethylammonium dichloroiodate to obtain the compound of formula (X) in which R
1
is an alkyl group, which is thereafter treated as described above to obtain the compound of general formula (I) in which R
2
and R
3
are hydrogen atoms and R
1
an alkyl group, via the corresponding intermediate compounds of formulae (IX) and (VIII).
The compounds of formula (XII)
in which R
1
, R
4
and R
5
are defined as in the general formula (I), may be prepared by reacting a phenyl ketone derivative of formula (XIV)
in which R
1
is defined as in the general formula (I), with chlorosulphonic acid, to give a chlorosulphonylphenyl ketone derivative of formula (XIII)
which is thereafter treated with an amine of formula R
4
NH
2
in which R
4
is defined as in the general formula (I).
The compounds of formula (XII) in which R
4
represents a hydrogen atom may also be prepared by reacting a compound of formula (XVII)
in which A is identical to R
1
as defined in the general formula (I) or alternatively represents a hydro
Philippo Christophe
Purcell Thomas
Jacobson Price Holman & Stern PLLC
Synthelabo
Wilson James O.
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