Dihydrofuro[3,4-b]quinolin-1-one compounds

Details Dihydrofuro[3,4-b]quinolin-1-one compounds Dihydrofuro[3,4-b]quinolin-1-one compounds

2000-11-22

2003-04-15

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S280000, C514S285000, C514S287000, C514S290000, C514S291000, C546S047000, C546S061000, C546S062000, C546S065000, C546S079000, C546S089000, C546S080000, C546S102000

Reexamination Certificate

active

06548515

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new dihydrofuro[3,4-b]quinolin-1-one compounds, and to the use thereof as anti-cancer agents.
BACKGROUND OF THE INVENTION
The requirements of anti-cancer therapeutics call for the constant development of new anti-tumour agents, with the aim of obtaining medicaments that are both more active and better tolerated.
The compounds of the invention are not only new but have very valuable anti-tumour properties.
DESCRIPTION OF THE PRIOR ART
Compounds of a similar structure have already been described in the literature, notably furo[3,4-b]quinolin-1-one compounds as anti-osteoporotics (patent EP 0 634 169).
On the other hand, a cytotoxic activity has never been described for those compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more especially to compounds of formula (I):
wherein:
represents a single or double bond,
R
0
represents a hydrogen atom, a hydroxy group or a linear or branched (C
1
-C
6
)alkoxy group,
R
1
and R
2
, which are identical or different, each represents:
a hydrogen atom,
a halogen atom,
a linear or branched (C
1
-C
6
)alkyl group,
a linear or branched (C
1
-C
6
)alkoxy group,
a hydroxy group,
a linear or branched (C
1
-C
6
)polyhaloalkyl group,
a nitro group,
an amino group optionally substituted by one or two linear or branched (C
1
-C
6
)-alkyl groups,
a group of formula
 wherein m represents an integer such that 1≦m≦4, or form together with the carbon atoms carrying them an aromatic or non-aromatic, mono- or bi-cyclic group having from 5 to 12 ring members, optionally containing 1 or 2 hetero atoms selected from O, S and N,
R
3
represents a hydrogen atom or a group of formula R
4
wherein R
4
represents:
an aryl group,
a heteroaryl group,
a (C
3
-C
8
)cycloalkyl group,
a linear or branched (C
1
-C
6
)alkyl group optionally substituted by an aryl group, by a heteroaryl group, by a hydroxy group, by a linear or branched (C
1
-C
6
)alkoxy group, or by a group of formula NR
5
R
6
wherein R
5
and R
6
, which are identical or different, each represents a linear or branched (C
1
-C
6
)alkyl group or a linear or branched (C
1
-C
6
)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
or a group of formula COR
7
, wherein R
7
represents one of the following groups:
aryl,
linear or branched (C
1
-C
6
)alkyl (optionally substituted by a group of formula NR
8
R
9
wherein R
8
and R
9
, which are identical or different, each represents a linear or branched (C
1
-C
6
)alkyl group or a linear or branched (C
1
-C
6
)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle),
amino optionally substituted by one or more groups aryl, heteroaryl, or linear or branched (C
1
-C
6
)alkyl optionally substituted by a group of formula NR
8
R
9
wherein R
8
and R
9
, which are identical or different, each represents a linear or branched (C
1
-C
6
)alkyl group or a linear or branched (C
1
-C
6
)-hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
or OR
10
wherein R
10
represents a hydrogen atom or a group aryl, or linear or branched (C
1
-C
6
)alkyl optionally substituted by a group of formula NR
8
R
9
wherein R
8
and R
9
, which are identical or different, each represents a linear or branched (C
1
-C
6
)alkyl group or a linear or branched (C
1
-C
6
)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
X represents an oxygen or sulphur atom or a —CH
2
— or —CH
2
—CH
2
— group,
Ar represents an aryl, heteroaryl or aryl-(C
1
-C
6
)alkyl group in which alkyl is linear or branched,
their optical isomers, addition salts thereof with a pharmaceutically acceptable acid, and hydrates and solvates thereof.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, benzenesulphonic and camphoric acid.
An aryl group is to be understood as phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and the groups linear or branched (C
1
-C
6
)-alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups), nitro, linear or branched (C
1
-C
6
)acyl and (C
1
-C
2
)alkylenedioxy.
A heteroaryl group is to be understood as an aromatic, mono- or bi-cyclic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl group may be optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and the groups linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)polyhaloalkyl, and amino (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, the groups thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl.
A nitrogen heterocycle is to be understood as a saturated monocyclic group having from 5 to 7 ring members and containing one, two or three hetero atoms, one of which is nitrogen while the additional hetero atom(s) optionally present is/are selected from oxygen, nitrogen and sulphur. Preferred nitrogen heterocycles are the groups pyrrolidinyl, piperidyl, morpholinyl and piperazinyl.
Among the aromatic or non-aromatic, mono- or bi-cyclic groups having from 5 to 12 ring members and optionally containing 1 or 2 hetero atoms selected from O, S and N there may be mentioned, without implying any limitation, the groups phenylene, naphthylene, cyclopentenylene and the groups of formulae G
1
to G
5
:
Preferred compounds of formula (I) are those wherein
represents a double bond.
Preferred compounds of formula (I) are those wherein R
0
represents a hydrogen atom.
An advantageous embodiment of the invention relates to compounds of formula (I) wherein R
1
and R
2
, which are identical or different, each represents
a hydrogen atom,
a halogen atom,
a linear or branched (C
1
-C
6
)alkyl group,
a linear or branched (C
1
-C
6
)alkoxy group,
a hydroxy group,
a linear or branched (C
1
-C
6
)polyhaloalkyl group,
a nitro group,
an amino group optionally substituted by one or two linear or branched (C
1
-C
6
)-alkyl groups, or
a group of formula
 wherein m represents an integer such that 1≦m≦4.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein R
1
and R
2
form together with the carbon atoms carrying them an aromatic or non-aromatic, mono- or bi-cyclic group having from 5 to 12 ring members and optionally containing 1 or 2 hetero atoms selected from O, S and N.
Among these are most preferred those wherein R
1
and R
2
together form, with the carbon atoms carrying them, a phenylene group or a group of formula G
3
or G
4
as defined hereinbefore.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents an oxygen or sulphur atom.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents a —CH
2
— or —CH
2
—CH
2
— group.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein Ar represents an aryl group, more preferably an optionally substituted phenyl group.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein Ar represents a heteroaryl group.
Among the preferred compounds of the invention, there may be mentioned:
(±)-4-methyl-6,7-methylenedi

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