Benzocycloalkene compounds, their production and use

Details Benzocycloalkene compounds, their production and use Benzocycloalkene compounds, their production and use

1996-08-19

1999-07-13

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

549349, 549359, 549433, 560 28, 564 56, 564163, 564166, 564167, 564168, 564169, 564170, 564171, 564172, 564174, 564176, 564179, 564180, 564181, 564185, 564188, 564189, 564190, 564191, 564192, 564196, 564200, 564202, 564207, 564212, 564213, 564219, 564220, 514450, 514452, 514463, 514480, 514481, 514595, 514617, 514619, 514620, 514621, 514622, 514624, 514625, 514626, 514627, 514628, 514629, C07D31770, C07C23364, C07C23500, C07C23700, A61K 31335, A61K 3127, A61K 31165, A61K 3116

Patent

active

059227710

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to novel benzocycloalkene compounds having an excellent binding affinity for melatonin receptor, process for producing them and use.


BACKGROUND ART

Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Further, melatonin exerts suppressively on pigment cells or female gonad and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to have use for therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet lag syndrome and various disorders related to aging. Recently it has also been clarified that production of melatonin decreases as aging proceeds, and there is a report in Ann. N.Y. Acad. Sci., Vol.719, pp.456-460 (1994) that maintaining the production of melatonin can intervene in the aging process. However, "Bioorganic & Medicinal Chemistry Letters, Vol.4, p.1485(1994)" describes that when the action on central nervous system is expected, melatonin is shown to be inactive by peripheral administration because melatonin itself has poor intracerebral transferability. There is also reported in "Rinsho Kensa Vol.38, No.11, 1994" that melatonin is readily metabolized by metabolic enzyme in a living body. As a melatonin-agonistic substance, there are reported naphthalene derivatives, the formula: ##STR2## wherein R.sub.1 represents e.g. H and lower alkyl, and R.sub.2 represents e.g. H and an optionally halogenated lower alkyl (JP-A-7-48331, EP-A-447285), and tetrahydronaphthalene derivatives having acylamino group substituted at the 2-position of tetrahydrofuran (JP-A-3-169840, EP-A-420064).
On the other hand, as examples of a benzocycloalkene compound having endo double bond, the following compounds have been known. formula: ##STR3## are described in Tetrahedron Lett., p.2085(1969). 2) Compounds represented by the formula: ##STR4## wherein R represents CH.sub.3, Cl and NO.sub.2 are described in J. Chemi. Soc. (C), p.3506, (1971). No description on the use of these compounds are given. receptor antagonistic activity, compounds represented by the formula: ##STR5## wherein R.sup.1 represents e.g. H and an alkyl group, R.sup.3 and R.sup.4 represent e.g. H and a lower alkoxy group, P represents a protective group and m denotes 0 to 2 are described in U.S. Pat. No. 5,158,948. represented by the formula: ##STR6## wherein R.sub.1 represents e.g. aryl, R.sub.2 represents e.g. H and aryl, R.sub.3 represents e.g. H, R.sub.4 represents e.g. acyl, R.sub.5 represents lower alkyl, R.sub.6 represents e.g. H, and R.sub.7 represents e.g. H and lower alkoxy are described in U.S. Pat. No. 3,642,785. represented by the formula: ##STR7## wherein R.sup.1 represents H and lower alkyl, R.sup.2 represents e.g.--CH.sub.2 --CONRR.sup.4, R.sup.4 represents H and lower alkyl, R.sup.3 represents e.g. lower alkoxy, m denotes 1 to 4, and n denotes 1, 2 or 3 are described in U.S. Pat. No. 4,656,190.
However, no reports have been made on the relation of these compounds with a melatonin receptor.
A melatonin agonist, which is different from melatonin in the structure, has an excellent affinity for melatonin receptor, and has excellent transferability into brain and metabolic stability, is expected to show therapeutic effects superior to those of melatonin. At the present circumstances, no compounds which are fully satisfactory in the activities of melatonin receptors, in metabolic stability and in transferability into brain have been found. So development of suitable compounds, which are different from the above-mentioned known compounds in chemical structure, have excellent melatonin receptor agonistic activities and are fully satisfactory as medicines, is ardently desired.


DISCLOSURE OF INVENTION

The present inventors succeeded, for the first time, in creation of the novel compound represented by the followi

REFERENCES:
patent: 3642785 (1972-02-01), Shen et al.
patent: 4656190 (1987-04-01), Shen et al.
patent: 5158948 (1992-10-01), Schoenleber et al.
patent: 5194614 (1993-03-01), Andrieux et al.
patent: 5308866 (1994-05-01), Lesieur et al.
patent: 5668180 (1997-09-01), Lesieur et al.
patent: 5731352 (1998-03-01), Lesieur et al.
J. Chem. Soc., C.(1971) 3506-3510.
Tetrahedron Letters, No. 25 (1969) 2085-2088.
Mathe-Allainmat et al., Recent Developments in Melatonin Receptor Ligands, Expert Opinion on Therapeutic Patents, vol. 7, No. 12, pp. 1447-1458, Dec. 1997.

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