Substituted dimeric compounds

Details Substituted dimeric compounds Substituted dimeric compounds

2000-03-24

2001-11-20

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S414000, C514S443000, C514S469000, C514S539000, C546S113000, C548S455000, C549S058000, C549S407000, C549S467000, C549S487000, C560S028000, C560S056000, C564S056000, C564S158000, C564S220000

Reexamination Certificate

active

06319930

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new substituted dimeric compounds having very valuable pharmacological properties in respect of melatoninergic receptors.
DESCRIPTION OF THE PRIOR ART
From the prior art dimeric naphthalenic structures are known (J. Chem. Soc., Dalton Trans., 1979, (10), pp. 1497-502) that have been studied for their coordination properties in metal complexes. Indole dimers have also been described for their “curare-like” activity (Khim.-Farm. Zh., 1984, 18(1), pp. 29-31).
BACKGROUND OF THE INVENTION
Owing to their novel structure, the compounds of the present invention are new and have pharmacological properties that are very valuable in respect of melatoninergic receptors.
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. Its half-like is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possiblity of providing the clinician with melatonin analogues that are metabolically more stable, have an agonist or antagonist character and that may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson's disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer's disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatonin—Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage that specific ligands are available. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they show very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic receptor sub-types.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more especially to compounds of formula (I):
A—G
1
—Cy—G
2
—Cy—G
3
—B  (I)
wherein:
A represents a grouping of formula
wherein
Q represents a sulphur or oxygen atom,
R
1
, R
2
and R
3
, which may be identical or different, represent a hydrogen atom or a group R
a
(wherein R
a
represents an unsubstituted or substituted linear or branched (C
1
-C
6
)alkyl group, an unsubstituted or substituted linear or branched (C
2
-C
6
)alkenyl group, an unsubstituted or substituted linear or branched (C
2
-C
6
)alkynyl group, an unsubstituted or substituted (C
3
-C
8
)-cycloalkyl group, an unsubstituted or substituted cycloalkyl-(C
3
-C
8
)alkyl (C
1
-C
6
)group in which the alkyl moiety is linear or branched, a polyhalo-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, an aryl(C
2
-C
6
)alkenyl group in which the alkenyl moiety is linear or branched, a heteroaryl group, a heteroaryl(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched or a heteroaryl(C
2
-C
6
)alkenyl group in which the alkenyl moiety is linear or branched),
or the groupings R
2
and R
3
form, with the nitrogen atom carrying them, a group selected from piperazinyl, piperidinyl and pyrrolidinyl,
represents a grouping of formula
or
—NR
2
R
3
wherein Q, R
1
, R
2
and R
3
are as defined hereinbefore,
G
1
and G
3
, which may be identical or different, represent a linear or branched alkylene chain having from 1 to 4 carbon atoms that is optionally substituted by one or more identical or different groups selected from hydroxy, carboxy, formyl, R
a
, OR
a
, COOR
a
and COR
a
(wherein R
a
is as defined hereinbefore),
Cy represents
a ring structure of formula (II):
wherein:
X and Y, which may be identical or different, represent a sulphur, oxygen or carbon atom, or a CH or CH
2
group,
R
4
represents a hydrogen or halogen atom, or a CF
3
, hydroxy, carboxy, formyl, amino, NHR
a
, NR
a
R
1
a
, NHCOR
a
, CONHR
a
, R
a
, OR
a
, COR
a
or COOR
a
group (wherein R
a
is as defined hereinbefore and R
1
a
can have any of the meanings of R
a
),
the symbol
- - - -
means that the bonds are single or double, with the proviso that the valency of the atoms is respected,
wherein G
2
substitutes the benzene ring, and G
1
(and G
3
respectively) substitutes the ring containing X and Y,
or a ring structure of formula (III):
wherein:
Z represents a sulphur or oxygen atom, or a CH, CH
2
, NH, NSO
2
Ph or NR
a
group (wherein R
a
is as defined hereinbefore),
D represents a benzene or pyridine ring,
R
4
is as defined hereinbefore,
the symbol
- - - -
means that the bond is single or double, with the proviso that the valency of the atoms is respected,
wherein G
2
substitutes the D ring, and G
1
(and G
3
respectively) substitutes the ring containing Z,
it being understood that the two rings (Cy) of the compounds of formula (I) represent the same basic ring structure (indole/indole, naphthalene
aphthalene, benzofuran/ benzofuran, etc.), but the substituent R
4
may be different,
G
2
represents a chain of formula (IV):
wherein:
W
1
, W
2
and W
3
, which may be identical or different, represent a bond, an oxygen or sulphur atom, or a CH
2
, CHR
a
, NH or NR
a
group (wherein R
a
is as defined hereinbefore),
n represents an integer wherein 0≦n≦6,
m represents an integer wherein 0≦m≦6,
with the proviso that it is not possible to have two consecutive hetero atoms and that the chain of formula (IV) so defined may have one or more unsaturated bonds,
wherein:
the compound of formula (I) cannot represent diethyl 2-(acetylamino)-2-{[5-({3-[2-(acetylamino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl]-1H-indol-5-yl}methyl)-1H-indol-3-yl]methyl}malonate,
or N-{2-[5-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}methyl)-1H-indol-3-yl]-ethyl}acetamide,
“aryl” is understood to mean the groups naphthyl, phenyl and biphenyl,
“heteroaryl” is understood to mean any saturated or unsaturated mono- or bi-cyclic group containing from 5 to 10 atoms and containing from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen,
it being possible for the “aryl” and “heteroaryl” groups to be substituted by one or more identical or different radicals selected from hydroxy, carboxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl, polyhalo-(C
1
-C
6
)-alkyl in which the alkyl moiety is linear or branched, formyl, cyano, nitro, amino, linear or branched (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino in which each alkyl moiety is linear or branched, and halogen atoms,
the term “substituted” a

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