Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-05
2003-09-16
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S105000, C544S051000
Reexamination Certificate
active
06620809
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new substituted (dihydro)benzoxazine and (dihydro) benzothiazine compounds that exhibit very valuable pharmacological properties in relation to melatoninergic receptors.
1. Description of the Prior Art
There may be found in the literature numerous substituted benzoxazine and benzothiazine structures for use both in synthesis (Tetrahedron, 53 (26), 1997, pp. 8853-8870; Heterocycl. Commun., 2 (3), 1996, pp. 273-274; J. Chem. Soc., Perkin Trans. 1, (10), 1991, pp. 2525-2529; Chem. Pharm. Bull., 34 (1), 1986, pp. 130-139; Indian J. Pharm., 35 (2), 1973, pp. 58-59) and as modulators of potassium channels (Eur J. Med. Chem., 33 (12), 1998, pp. 957-967; Chem. Pharm. Bull., 44 (1), 1996, pp. 103-114), or also as anti-cancer agents (Heterocycl. Commun., 3 (3), 1997, pp. 279-284; Heterocycl. Commun., 2 (6), 1996, pp. 587-592; Anti-Cancer Drugs, 6 (5), 1995, pp. 693-696).
2. 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 possiblity of providing the clinician with melatonin analogues that are metabolically more stable and 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 specific ligands 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 binding sites.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates more especially to the compounds of formula (I):
wherein:
R
1
represents a halogen atom or a group R, OR, SR, SO
2
NRR′, —NRR′,
(wherein Z represent a sulpur atom or an oxygen atom and R, R′ and R″, which are 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 alkyl is linear or branched, an aryl group, an aryl(C
1
-C
6
)alkyl group in which alkyl is linear or branched, a heteroaryl group or a heteroaryl-(C
1
-C
6
)alkyl group in which alkyl is linear or branched,
and wherein (R and R′) or (R′ and R″) may together form, with the nitrogen atom carrying them, a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group),
G represents an alkylene chain containing from 2 to 4 carbon atoms when A represents a group
and from 1 to 4 carbon atoms in all other cases, G being optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore),
A represents a group
(wherein R, R′ R″ and Z are as defined hereinbefore),
R
2
represents a halogen atom or a group R, OR, COR, COOR or OCOR (wherein R is as defined hereinbefore),
X represents an oxygen atom or a sulphur atom,
the symbol
denotes that the bond is single or double, the valency of the atoms being respected,
wherein:
the term “substituted” applied to “alkyl”, “alkenyl”, “alkynyl” or “cycloalkyl” denotes that those groups may be substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, polyhaloalkyl, amino (unsubstituted or substituted by one or two linear or branched (C
1
-C
6
)alkyl groups) and halogen atoms,
the term “substituted” applied to “cycloalkylalkyl” denotes that the cyclic moiety of the group is substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, polyhaloalkyl, amino (unsubstituted or substituted by one or two linear or branched (C
1
-C
6
)alkyl groups) and halogen atoms,
“aryl” denotes 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” denotes any mono- or bi-cyclic aromatic group containing from one to three hetero atoms selected from oxygen, sulphur and nitrogen, 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,
to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric, oxalic acid, etc.
Amongs the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are the compounds of formula (I) wherein X represents an oxygen atom.
The invention relates more especially to the benzoxazine compounds, and more preferably to the dihydrobenzoxazine compounds.
Preferred substituents R
1
are the groups alkyl, alkoxy and hydroxy.
Preferred substituents R
2
are the hydrogen atom and the groups aryl, heteroaryl, arylalkyl and heteroarylalkyl, and more especially the unsubstituted or substituted phenyl group.
Advantageously, the invention relates to the compounds of formula (I) wherein G represents a (CH
2
)
n
chain in which n is 2 or 3.
Preferred substituents A are the groups NHCOR and CONHR.
The invention relates even more especially to the following compounds of formula (I):
N-[2-(6-hydroxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]acetamide,
N-[2-(6-methoxy-2,3-dihydro-4H-1,4-benzoxazin-4-yl)
Bennejean Caroline
Daubos Philippe
Delagrange Philippe
Guillaumet Gerald
Renard Pierre
Berch Mark L.
Habte Kahsay
Les Laboratoires Servier
The Firm of Hueschen and Sage
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