Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-10
1998-01-13
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514291, 514312, 546 90, 546153, 546175, C07D21512, C07D21516, C07D21560, A61K 3147
Patent
active
057080054
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/01759, filed 26 Jun. 1996.
TECHNICAL FIELD
The present invention relates to a novel quinoline compound having an excellent binding affinity for melatonin receptor, a process for producing it, an intermediate for the production and a composition containing it.
BACKGROUND ART
Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone that is 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 be used for therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet lag syndrome and various aging disorders.
Recently it was reported in Ann. N.Y. Acad. Sci., Vol. 719, PP. 456-460 (1994) that the production of melatonin decline steadily into old age and the supplementing melatonin could reset the body's aging clock. However, in "Bioorganic & Medicinal Chemistry Letters, Vol. 4, p. 1485 (1994)", there is described that melatonin is shown to be inactive on central nervous system when administered peripherally because melatonin itself has poor intracerebral transferability. In addition, it is reported that melatonin is readily metabolized by metabolic enzymes in a living body (Rinsho Kensa, Vol. 38, No. 11 (1994)). For these reasons, melatonin agonist which has a different structure from melatonin, has stronger activities than melatonin, is metabolically stable, has excellent transferability into brain, and can be expected to show superior therapeutic effects to those of melatonin.
As a melatonin agonist, naphthalene derivatives having an acylaminoethyl have been reported (EP-A-447285, JP-A 7-48331). As a melatonin agonist, a melatonin derivative having an indole skeleton (EP-A-578620, JP-A 6-72874, etc.), a tetrahydronaphthalene derivative having an acylamino group at the 2-position (EP-A-420064, JP-A 3-169840, etc.), etc., have been reported. However, no melatonin agonistic or antagonistic compound having a quinoline skeleton has been known.
As compounds having a quinoline skeleton, a compound of the formula: ##STR2## having gramicidin channel activity is disclosed in International Journal of Peptide and Protein Research, Vol. 38, PP 218-228 (1991).
Also, a compound of the formula: ##STR3## wherein R.sup.0 is H, etc., R.sup.1 is H, etc., R.sup.2 is H, halogens, etc., R.sup.3 is hydroxyl, lower alkoxy, etc., R.sup.4 is H, --COR.sup.5, etc., R.sup.5 is lower alkyl, etc., A is lower alkylene, and n is 0 or 1, having anti-ulcer activity, is disclosed in U.S. Pat. No. 4,578,381.
Additionaly, a compound of the formula: ##STR4## having .beta.-blocker activity is disclosed in Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft Vol. 305 (4), PP 244-248 (1972).
However, not one of these references refers to melatonin receptor affinities.
A melatonin agonist, which is different from melatonin in the structure, has an excellent affinity for melatonin receptor, is metabolically stable and is excellent in the transferability into brain, can be expected to show superior therapeutic effects to those of melatonin. And, when the antagonistic activities of melatonin are desired, creation of a new melatonin antagonist is necessary.
At the present circumstances, no compound which are fully satisfactory in the activities of melatonin receptors, in metabolical stability and in transferability into brain have been found. So, development of compounds, which are different from the above-mentioned known compounds in chemical structure, have excellent melatonin receptor affinities and are fully satisfactory as medicines, is ardently desired.
DISCLOSURE OF INVENTION
The present inventors have firstly succeeded in creation of a novel quinoline compound characterized by an acylamino(halogeno)lower alkyl group
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Miyamoto Masaomi
Ohkawa Shigenori
Uchikawa Osamu
M. Mach D. Margaret
Rotman Alan L.
Takeda Chemical Industries Ltd.
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