Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-31
2003-05-20
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S292000, C514S211150, C514S217070, C514S252040, C514S228200, C514S226800, C514S232800, C514S256000, C514S218000, C540S544000, C540S597000, C540S575000, C540S553000, C544S055000, C544S060000, C544S096000, C544S126000, C544S361000, C546S081000, C546S088000
Reexamination Certificate
active
06566362
ABSTRACT:
The present invention relates to benzo[f]naphthyridine derivatives of formula (I):
salts thereof, processes for preparing such compounds, and compositions comprising them.
European patent application no. EP 431 991 discloses benzo[b]naphthyridine derivatives of formula:
in which R
1
is H, hydroxyl or alkyl, R
2
is H, alkyl, fluoroalkyl, cycloalkyl, alkyloxy or alkylamino, R
3
is optionally substituted phenyl or phenylalkyl, and R
4
is H or a fluorine atom. These compounds are useful as antimicrobial agents.
French patent application no. FR 2 258 855 describes benzo[h]naphthyridine derivatives of formula:
in which R is an alkyl radical, and R
1
, R
2
and R
3
, which are identical or different, are chosen from H, alkyl, polyhaloalkyl, halogen, alkoxy, nitro, alkylsulphone, sulphamide, or R
1
and R
2
or R
2
and R
3
may be linked to each other to constitute a novel saturated or unsaturated carbon-containing ring comprising 5 or 6 carbon atoms, it being possible for the bonding between these radicals themselves and the base nucleus to take place via one or two heteroatoms of oxygen to form a novel heterocycle. These compounds are useful as antimicrobial agents.
U.S. Pat. No. 3,300,499 describes benzo[f]naphthyridine derivatives of formula:
in which X is a carboxyl or alkyloxycarbonyl group, R
1
is an alkyl or alkenyl group, and the 5, 7, 8, 9 and 10 positions may also carry substituents chosen from alkyl, alkyloxy, hydroxyl, halogen, alkylamino and alkylthio.
However, these compounds have not been found to be active in tests for bacteriological activity in vitro carried out by the instant inventors.
The inventors have now found that benzo[f]naphthyridine derivatives of formula (I), salts thereof, and, where appropriate, stereoisomers thereof or mixtures of stereoisomers thereof:
wherein:
R
1
, R
2
, and R
3
, which are identical or different, may each be chosen from a hydrogen atom, halogen atoms, and groups of formula (II):
wherein:
R
5
and R
6
form, together with the nitrogen atom to which they are attached, a 5-, 6-, or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises, in addition to the nitrogen atom, a heteroatom chosen from nitrogen, oxygen, and sulphur, and wherein the heterocycle may be optionally substituted with at least one group chosen from (i) an unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, (iii) a benzyl group, (iv) alkyl groups, (v) a hydroxyl group, (vi) aminoalkyl groups, (vii) alkylaminoalkyl groups, (viii) dialkylaminoalkyl groups, and (ix) benzylaminoalkyl groups,
provided that at least one of groups R
1
, R
2
, and R
3
is a group of formula (II), and
provided that at least one of groups R
1
, R
2
, and R
3
is chosen from halogen atoms,
R
4
is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C
3
to C
6
) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups, and
wherein the alkyl groups may be chosen from unbranched (C
1
to C
4
) alkyl groups and branched (C
1
to C
4
) alkyl groups,
manifest advantageous antibacterial activity, for example, for the topical route.
In formula (I), the halogen substituents may be chosen from a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom. Moreover, when R
5
and R
6
form, together with the nitrogen atom to which they are attached, a 5- to 7-membered heterocycle, the heterocycle may be chosen, with no limitation being implied, from pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, perhydroazepine, and perhydrodiazepine. In addition, the above-mentioned alkyl groups can be chosen from a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group.
According to one embodiment of the present invention, the benzo[f]naphthyridine derivatives can be chosen from derivatives of formula (I), salts thereof, and, where appropriate, stereoisomers thereof or mixtures of stereoisomers thereof:
wherein:
R
1
, R
2
, and R
3
, which are identical or different, may each be chosen from a hydrogen atom, halogen atoms, and groups of formula (II):
wherein:
R
5
and R
6
form, together with the nitrogen atom to which they are attached, a 6- or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises an additional nitrogen atom, and wherein the heterocycle may be optionally substituted with at least one group chosen from (i) an unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, and (iii) alkyl groups,
provided that at least one of groups R
1
, R
2
, and R
3
is a group of formula (II), and
provided that at least one of groups R
1
, R
2
, and R
3
is chosen from halogen atoms,
R
4
is chosen from alkyl groups and fluoroalkyl groups, and
wherein the alkyl groups may be chosen from unbranched (C
1
to C
4
) alkyl groups and branched (C
1
to C
4
) alkyl groups.
According to the invention, compounds of formula (I) may be prepared, for example, by reacting an amine of formula (III):
wherein:
R
5
and R
6
form, together with the nitrogen atom to which they are attached, a 5-, 6-, or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises, in addition to the nitrogen atom, a heteroatom chosen from nitrogen, oxygen, and sulphur, and wherein the heterocycle may be optionally substituted with at least one group chosen from an (i) unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, (iii) a benzyl group, (iv) alkyl groups, (v) a hydroxyl group, (vi) aminoalkyl groups, (vii) alkylaminoalkyl groups, (viii) dialkylaminoalkyl groups, and (ix) benzylaminoalkyl groups,
with a benzo[f]naphthyridine derivative of formula (IV):
wherein:
R
4
is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C
3
to C
6
) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group, and
R′
1
, R′
2
, and R′
3
, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of R′
1
, R′
2
, and R′
3
are chosen from halogen atoms,
wherein the halogen atoms may be chosen from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom,
separating the amine-containing compounds thus prepared, and
optionally converting the separated compound formed above to a salt.
The reaction of amines of formula (III) can be performed in the presence of an excess of a derivative of formula (III), as an acid acceptor in suitable organic solvents. It is possible to carry out the procedure with or without solvent, at a temperature ranging, for example, from 20 to 150° C. When the procedure is carried out in the presence of a solvent, the reaction can be carried out in aprotic polar solvents, such as, for example, pyridine, dimethylformamide, dimethyl sulphoxide, and acetonitrile. It is also possible to carry out the procedure in an aqueous medium.
Such reactions may also be carried out in the presence of an acid acceptor such as, for example, a nitrogenous organic base (for example, triethylamine), an alkali metal carbonate (for example, sodium carbonate), or an alkali metal or alkaline-earth metal hydroxide.
When an amine of formula (III) is
Desconclois Jean-François
Genevois-Borella Arielle
Girard Philippe
Kryvenko Michel
Lavergne Marc Pierre
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Huang Evelyn Mei
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