Tricyclic compounds, preparation method and pharmaceutical...

Details Tricyclic compounds, preparation method and pharmaceutical... Tricyclic compounds, preparation method and pharmaceutical...

2000-07-14

2002-07-23

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S337000, C514S339000, C514S411000, C514S443000, C514S463000, C514S585000, C514S613000, C514S623000, C514S627000, C514S628000, C514S629000, C514S630000, C548S436000, C548S437000, C548S438000, C549S043000, C549S044000, C549S045000, C549S047000, C549S458000, C564S026000, C564S047000, C564S048000, C564S056000, C564S074000, C564S123000, C564S173000, C564S172000, C564S180000, C564S182000, C564S183000, C564S207000, C564S211000, C564S221000

Reexamination Certificate

active

06423870

ABSTRACT:

The prsent application is a U.S. National Application filed under 35 USC 371 of PCT/FR98/02694 filed Dec. 11, 1998, based upon French application Serial No. 98.00424 filed Jan. 16, 1998.
FIELD OF THE INVENTION
The present invention relates to new tricyclic compounds.
DESCRIPTION OF THE PRIOR ART
There are known from the prior art 2,3-dihydrophenalene compounds (J. Chem. Soc. C, 1971, 9, pp1607-1609) which are described as synthesis intermediates, and 1,3,4,5-tetrahydrobenzo[cd]indole compounds (EP 353 557) for use in the preparation of platelet aggregation inhibitors.
Moreover, Application EP 737 670 describes tricyclic amide compounds as melatoninergic receptor ligands.
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-life 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 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 respect of 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.
The compounds of the present invention are new and have 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)
wherein:
A forms with the group to which it is bonded a tricyclic system selected from A
1
, A
2
, A
3
and A
4
:
R
1
represents a hydrogen atom, a halogen atom or a linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy or oxo group,
R
2
and R
3
, which may be the same or different, represent a halogen atom or an R
a
, OR
a
, COR
a
, OCOR
a
or COOR
a
group (wherein R
a
represents a hydrogen atom, an optionally substituted linear or branched (C
1
-C
6
)alkyl group, linear or branched (C
1
-C
6
)trihaloalkyl, an optionally substituted linear or branched (C
2
-C
6
)alkenyl group, an optionally substituted linear or branched (C
2
-C
6
)alkynyl group, an optionally substituted (C
3
-C
8
)cycloalkyl group, an optionally substituted (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, or an optionally substituted aryl group),
the symbols (R
2
)
m
and (R
3
)
m′
denote that the ring in question may be substituted by from 1 to 3 groups (which may be the same or different) belonging to the definitions for R
2
and R
3
,
X, when A represents a tricyclic system A
1
, A
2
, A
3
or A
4
, represents a sulphur atom, a (CH
2
)
q
group (wherein q is 1 or 2), a —CH═CH— group, or an NR
4
group (wherein R
4
represents a hydrogen atom or an optionally substituted linear or branched (C
1
-C
6
)alkyl group),
 or X represents an oxygen atom when A represents the tricyclic system A
1
,
n is an integer such that 0≦n≦3
p is an integer such that 1≦p≦3 when n is 1, 2 or 3 and the
 chain is in the b position and A represents either a group A
2
, A
3
or A
4
wherein X represents a —CH═CH— group, or a group A
1
,
 and such that 0≦p≦3 in all other cases,
 it being possible for the
 chain to be unsubstituted or substituted by one or more groups, which may be the same or different, selected from R
a
, OR
a
, COR
a
, COOR
a
or halogen atoms,
B represents:
an
 group wherein R
a
is as defined hereinbefore, Z represents an oxygen atom or a sulphur atom, and R
5
represents an R
a
group or an NR
6
R
7
group wherein R
6
and R
7
, which may be the same or different, represent an R
a
group,
or a
 group wherein Z, R
6
and R
7
are as defined hereinbefore,
the symbol
denotes that the bond may be single or double provided that the valency of the atoms is respected,
 it being understood that the symbol
 is used to denote the formula
 (in which case p is other than 0),
 with the proviso that:
when the tricyclic group of formula A
1
is a 6-methoxytetrahydrobenzo[cd]indole, B cannot represent an NHCOMe group,
the compound of formula (I) cannot represent N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-1-cyclopropanecarboxamide, N-(4-methyl-2,3-dihydro-1H-1-phenalenyl)-2-chloroacetamide, 2-methyl-1,3,4,5-tetrahydrobenzo[cd]indole-3-carboxamide, N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide, N-(5-hydroxy-1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)benzamide or N-(1,2,2a,3,4,5-hexahydro-4-acenaphthylenyl)acetamide,
 it being understood that:
“aryl” is used to denote a phenyl or naphthyl group each optionally substituted by one or more groups, which may be the same or different, selected from hydroxy, linear or branched (C
1
-C
6
)-alkoxy, linear or branched (C
1
-C
6
)alkyl, cyano, nitro, amino, trihaloalkyl, or halogen atoms,
the expression “optionally substituted” applied to the terms “alkyl”, “alkenyl” and “alkynyl” denotes that those groups may be substituted by one or more groups, which may be the same or different, selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, aryl, or halogen atoms,
the expression “optionally substituted” applied to the terms “cycloalkyl” and “cycloalkylalkyl” denotes that the cyclic moiety may be substituted by one or more groups selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, oxo, or halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Amongst the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
Amongst the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
An advantageous embodiment of the present invention relates to compounds of f

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