Polycyclic azaindole compounds

Details Polycyclic azaindole compounds Polycyclic azaindole compounds

2002-10-09

2003-12-23

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S183000, C514S279000, C514S410000, C514S422000, C540S484000, C540S544000, C546S026000, C546S061000, C546S070000, C546S071000

Reexamination Certificate

active

06667304

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to new polycyclic azaindole compounds. The compounds of the present invention are new and have very valuable pharmacological characteristics in respect of melatoninergic receptors.
DESCRIPTION OF THE PRIOR ART
The prior art describes polycyclic azaindole compounds for use in synthesis (Heterocycles, 41 (9), 1995, pp. 1987-98; Tetrahedron Letters, 26 (10), 1985, pp. 1295-6) or as anti-tumour and antiviral agents (Tetrahedron, 50 (13), 1994, pp. 3987-92).
BACKGROUND OF THE INVENTION
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 possibility 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 to have available specific ligands. 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 binding sites.
DETAILED DESCRIPTION OF THE INVENTION
More especially, the present invention relates to compounds of formula (I):
wherein:
the symbol
 represents the grouping
R
1
represents a halogen atom or a group —R, —OR, —S(O)
n
R, —NRR′.
 or —SO
2
NRR′ (wherein n is 0, 1 or 2. Z represents a sulphur or oxygen atom, and R, R′ and R″, which may be identical or different, represent a hydrogen atom or 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 (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group 10 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, a heteroaryl group or a heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, it also being possible for (R and R′) and (R′ and R″) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G
1
represents an alkylene chain having from 1 to 4 carbon atoms, optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore). or G
1
represents an alkylene chain having from 1 to 4 carbon atoms in which one of CH
2
group can be replaced by a cycloalkylene (C
3
-C
8
) group,
A represents a group
 wherein R, R′, R″ and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen.
R
2
and R
3
, which may be identical or different, represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)alkoxy group or a hydroxy group,
 or R
2
and R
3
together form an oxo group,
—R
4
and R1 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol
means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term “substituted” applied to the terms “alkyl”, “alkenyl”, “alkynyl”, “cycloalkyl”, “morpholinyl”, “piperidinyl”, “piperazinyl” and “pyrrolidinyl” means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term “substituted” applied to the term “cycloalkylalkyl” means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
“aryl” is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
“heteroaryl” is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An advantageous variant of the present invention relates to compounds of formula (1):
wherein:
the symbol
 represents the grouping
R
1
represents a halogen atom or a group —R, —OR, —S(O)
n
R, —NRR′,
 or —SO
2
NRR′ (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, R′ and R″, which may be identical or different, represent a hydrogen atom or 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 (C
3
-C
8
)cycloalkyl-(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, a heteroaryl group or a heteroaryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, it also being possible for (R and R′) and (R′ and R″) to form together with the nitrogen atom carryi

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