Substituted heterocyclic compounds, method for preparing and...

Details Substituted heterocyclic compounds, method for preparing and... Substituted heterocyclic compounds, method for preparing and...

1999-11-12

2001-11-06

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...

C514S456000, C549S023000, C549S406000, C549S407000

Reexamination Certificate

active

06313160

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new substituted heterocyclic compounds.
DESCRIPTION OF THE PRIOR ART
The new compounds have proved to be very powerfull ligands for melatoninergic receptors.
From the prior art there are known benzoxazin compounds used as fungicides (Hahn H. G. et al., J. Korean Chem. Soc., 1994, 38(10), pp. 776-81) or as lipogenesis inhibitors in mammals (U.S. Pat. No. 4,308,276).
Also known are a large number of (dihydro)chromene compounds as 5HT ligands for use in the treatment of hypertension, depression or anxiety (WO 9426703, DE 4135474), or dopaminergic receptor agonists (WO 9608489) for use in the treatment of cardiovascular diseases.
(Dihydro)benzodioxin compounds are furthermore described as anti-oxidants and inhibitors of lipid peroxidation (EP 624582), or for use in the treatment of liver diseases (J07242655 and J07242543), or as &agr;-adrenergic receptor blockers (Dewar G. H. et al., Eur. J. Med. Chem.—Chim. Ther., 1983, 18(3), pp 286-90).
BACKGROUND OF THE INVENTION
In the last ten years, numerous studies have demonstrated the major role played by melatonin (5-methoxy-N-acetyltryptamine) in the control of the circadian rhythm and of endocrinal functions. In addition, melatonin receptors have been characterised and located.
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 for 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) and also 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 exhibited activity in respect of certain cancers (Melatonin—Clinical Perspectives, Oxford University Press, 1988, pp 164-165), ovulation (Science 1987, 227, pp 714-720) and 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).
Compounds providing a means of acting on the melatoninergic system are accordingly excellent medicaments for the clinician for the treatment of pathologies associated with the melatoninergic system, especially those mentioned above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more especially to compounds of formula (I):
wherein
R
1
represents a hydrogen atom, 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 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, or an OR
4
group (wherein R
4
represents a hydrogen atom, 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, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted (C
3
-C
8
)cycloalkyl group or a substituted or unsubstituted (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
R
2
represents a hydrogen atom,
or R
1
and R
2
, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
X represents an oxygen atom, a sulphur atom, a C(H)
q
group (wherein q is equal to 0, 1 or 2), SO, SO
2
,
or X represents a single bond when R
1
and R
2
, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing two oxygen atoms,
Y represents an oxygen atom, a sulphur atom, a C(H)
q
group (wherein q is equal to 0, 1 or 2), SO or SO
2
,
it being understood that X and Y cannot simultaneously represent a C(H)
q
group (wherein q is equal to 0, 1 or 2),
R
3
represents a hydrogen atom, an aryl group, an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, or a linear or branched (C
1
-C
6
)alkyl group,
n is equal to 0, 1, 2, 3, 4 or 5 when R
1
and R
2
, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
or n is equal to 1, 2, 3, 4 or 5 when R
1
is as defined hereinabove and R
2
represents a hydrogen atom,
it being possible for the —(CH
2
)
n
— chain to be substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, OH, linear or branched (C
1
-C
6
)alkylcarbonyl and linear or branched (C
1
-C
6
)alkoxycarbonyl,
A represents
a NR
5
R
6
group wherein
R
6
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group,
R
5
represents a
 group wherein Z represents an oxygen atom
or a sulphur atom, and R
7
represents:
a hydrogen atom,
an R
8
group which represents a substituted or unsubstituted linear or branched (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 linear or branched (C
2
-C
6
)alkenyl group, a substituted or unsubstituted linear or branched (C
2
-C
6
)alkynyl group, an aryl group or an aryl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched,
or a NR
8
R
9
group wherein R
9
represents a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group and R
8
is as defined hereinabove,
or a
 group wherein Z, R
8
and R
9
are as defined hereinabove,
the symbol
means that the bonds can be single or double, it being understood that two adjacent bonds cannot simultaneously be double and that the valency of the atoms is respected,
it being understood that:
the term “aryl” denotes a phenyl or naphthyl group optionally substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C
1
-C
6
)alkoxy, linear or branched (C
1
-C
6
)alkyl, cyano, nitro, amino, alkylamino, dialkylamino and trihaloalkyl,
the term “substituted” used in respect of the terms “alkyl”, “alkenyl” and “alkynyl” means that the group is substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C
1
-C
6
)alkoxy, amino, alkylamino and dialkylamino,
the term “substituted” used in respect of the terms “cycloalkyl” and “cycloalkylalkyl” means that the cyclic moiety is substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy, hydroxy, oxo, amino, alkylamino and dialkylamino,
provided that:
when the compound of formula (I) is a 2,3-dihydro-1,4-benzodioxin compound (X and Y simultaneously represent an oxygen atom, R
1
, R
2
and R
3
simultaneously represent a hydrogen atom and the bonds
are single), the group —(CH
2
)
n
—A is other than the following groups:
—CH
2
—NHCOR
a
(wherein R
a
represents an ethyl, 3,4,5-trimethoxyphenyl, 2,6-dimethoxyphenylethyl, phenylethyl, benzyl, phenyl, chloromethyl or trifluoromethyl group),
—(CH
2
)
2
—NHCOR
b
(wherein R
b
represents a 2,3,4-trimethoxyphenyl group),
—CH
2
—CONHR
c
(wherein R
c
represents a methyl, ethyl, n-butyl, 2-hydroxypropyl or 3-methoxypropyl group),
—(CH
2
)
2
—CONHR
d
(wherein R
d
represents a methyl, 2-hydroxypropyl or 3-hydroxypropyl group),
when the compound of formula (I) is a chroman

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