Cyclic compounds having a cycloalkylene chain

Details Cyclic compounds having a cycloalkylene chain Cyclic compounds having a cycloalkylene chain

1999-10-12

2003-06-24

Davis, Brian (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S215000, C564S219000, C514S622000, C514S630000

Reexamination Certificate

active

06583319

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new cyclic compounds having a cycloalkylene chain.
DESCRIPTION OF THE PRIOR ART
Hydroxy or alkoxy cyclopropane amides (WO 9209566, EP 436199, U.S. Pat. No. 5,459,150) and hydroxy or alkoxy cyclobutane amides (U.S. Pat. No. 5,187,192) are known from the prior art for use as 5-lipoxygenase inhibitors.
Other cyclopropane-amide or -thioamide compounds having an unsaturated chain are described as pesticides (EP 369762).
Cyclopropane-indole compounds for use in the treatment of neurodegenerative disorders (EP 568136) are also found.
Finally, some publications mention amide compounds having a cyclohexane chain as intermediates or synthesis products (Indian J. Chem., 1974, 12(7), pp. 664-7; Bull. Chem. Soc. Jap., 1968, 41(12), pp. 3008-11).
BACKGROUND OF THE INVENTION
The compounds of the present invention are new and exhibit pharmacological characteristics 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-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 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.
The compounds of the present invention, in addition to being new, exhibit a 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 represents:
a ring system of formula (II):
wherein X and Y, which may be identical or different, represent an oxygen atom, a sulphur atom or a CH
2
group,
D represents a benzene ring or a naphthalene,
and the symbol
means that the bonds may be single or double, with the proviso that the valency of the atoms is respected,
wherein R substitutes either the ring system D or the ring containing X and Y, and G
1
substitutes the ring containing X and Y,
or or a ring system of formula (III):
wherein Z represents an oxygen atom, a sulphur atom, a CH
2
group or an NR
1
group (wherein R
1
represents a hydrogen atom, a linear or branched (C
1
-C
6
)alkyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched),
D′ represents a benzene ring or a pyridine ring, and the symbol
is as defined hereinabove,
wherein R substitutes the D′ ring and G
1
substitutes the other ring, it being understood that the ring systems of formula (II) or (III) may be substituted, in addition to the R and G
1
groups, by from one to three identical or different groups selected from R
a
, OR
a
, hydroxyl, COR
a
, formyl, COOR
a
, carboxyl and OCOR
a
,
wherein R
a
represents a substituted or unsubstituted linear or branched (C
1
-C
6
)alkyl group, a substituted or unsubstituted linear or branched (C
2
-C
6
)alkenyl group, a substituted or unsubstituted linear or branched (C
2
-C
6
)alkynyl group, a linear or branched polyhalo-(C
1
-C
6
)alkyl group, a substituted or unsubstituted (C
3
-C
8
)cycloalkyl group, a substituted or unsubstituted (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted (C
3
-C
8
)cycloalkenyl group, a substituted or unsubstituted (C
3
-C
8
)cycloalkenyl-(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,
R represents a hydrogen or halogen atom, or a hydroxyl, SH, R
a
, OR
a
or S(O)
n
R
a
group wherein n is 0, 1 or 2 and R
a
is as defined hereinabove,
or forms, with the carbon atom carrying it and with an adjacent carbon atom, a ring of formula (IV):
wherein E represents an oxygen atom or an —S(O)
n
— group wherein n is as defined hereinabove,
wherein the resulting ring contains from 5 to 7 atoms, may contain one or more unsaturations and may be substituted by one or more groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, carboxy, linear or branched (C
1
-C
6
)alkoxy-carbonyl, hydroxy and oxo,
G
1
and G
2
, which may be identical or different, represent a single bond or an alkylene chain —(CH
2
)
t
—(wherein t is 1, 2, 3 or 4), unsubstituted or substituted by one or more identical or different radicals selected from hydroxy, carboxy, formyl, R
a
, OR
a
, COOR
a
, COR
a
, (wherein R
a
is as defined hereinabove) and halogen atoms,
p is 0,1, 2, 3 or 4,
q is 0,1, 2, 3 or 4,
with 1≧p+q≧4,
B represents an —NR
1
a
C(Q)R
2
a
, —NR
1
a
C(Q)NR
2
a
R
3
a
or —C(Q)NR
1
a
R
2
a
group wherein R
1
a
, R
2
a
and R
3
a
, which may be identical or different, can have any of the values of R
a
or may represent a hydrogen atom, and Q represents an oxygen or sulphur atom,
it being understood that:
the term “substituted” applied to the terms “alkyl”, “alkenyl” and “alkynyl” means that those groups are substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl, linear or branched polyhalo-(C
1
-C
6
)alkyl, amino and halogen atoms,
the term “substituted” applied to the terms “cycloalkyl”, “cycloalkylalkyl”, “cycloalkenyl” and “cycloalkenylalkyl” means that the cyclic moiety of those groups is substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl, linear or branched polyhalo-(C
1
-C
6
)alkyl, amino and halogen atoms,
“aryl” is understood to mean the groups phenyl, naphthyl or biphenyl, it being possible for those groups to be substituted by one or more identical or different radicals selected from hydroxy, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl, linear or branched p

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