Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-27
1999-12-21
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548482, 548470, 514419, A01N 4328, G07D20944
Patent
active
06004991&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel melatoninergic agonist derivatives, to a process for their preparation and to their use as medicinal products.
Melatonin, N-acetyl-5-methoxytryptamine, is a hormone of the pineal gland, isolated by Lerner et al. (J. Am. Chem. Soc. 80, 1958, 2587), which has formed the subject of many studies for its circadian activity, in the rhythm of sleep, for its effects on the production of testosterone, for its activity on the hypothalamus and in psychiatric disorders.
It has thus been envisaged to employ melatonin and analogues thereof, especially for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychosis and epilepsy, and also for the treatment of sleeping disorders associated with travelling ("jet lag"), neurodegenerative diseases of the central nervous system such as Parkinson's disease or Alzheimer's disease, for the treatment of cancers, or alternatively as a contraceptive or as an analgesic.
However, the direct use of melatonin in vivo has not proved to be very satisfactory, given that a first passage through the liver extracts more than 90% of the active principle when it is administered orally.
Various melatonin analogues have been described, demonstrating two routes of research which relate either to the substituents of melatonin (WO-A-89/01472, U.S. Pat. No. 5,283,343, U.S. Pat. No. 5,093,352 or WO-A-93/11761) or to the aromatic ring by replacing the indolyl group by a naphthyl group (FR-A-2 658 818, FR-A 2 689 124).
The present patent application proposes a novel route of development of melatonin analogues having improved activity.
The present invention thus relates to novel derivatives of general formula I ##STR2## in which w represents an oxygen or sulphur atom or a radical .dbd.NR.sub.12, R.sub.12 being a hydrogen atom or a lower alkyl, aryl, lower aralkyl or cycloalkyl radical .dbd.CR.sub.14 -- or CR.sub.15 R.sub.16 --CR.sub.17 R.sub.18 -- having the same definition as above or CR.sub.20 R.sub.21 --CR.sub.19 --CR.sub.19 or --CR.sub.15 R.sub.16 --CW--CR.sub.24 R.sub.25 --CR.sub.19, or --CR.sub.15 R.sub.16 --CR.sub.17 R.sub.18 --CW--CR.sub.19 W having the same definition as above other, a hydrogen atom, a hydroxyl radical or a lower alkyl, cycloalkyl, lower alkoxy, aryloxy, lower aralkoxy, (lower)alkylthio, arylthio, (lower)aralkylthio, halo or nitro radical or an unsaturated aliphatic, lower alkenyl, lower alkinyl, lower alkyl, aryl or aralkyl chain, each optionally substituted with one or more hydroxyls, with one or more halogens, a lower perhaloalkyl radical, an amino, (lower)alkylamino, (lower)dialkylamino, arylamino, diarylamino, aralkylamino or arylalkylamino radical, a radical of the form CV--R.sub.11 or QCVR.sub.11, in which V represents an oxygen or sulphur atom or an imine radical .dbd.N--R.sub.12, R.sub.11 has one of the meanings of R.sub.1, and R18, R20 and R21, and R24 and R25 cannot simultaneously be a hydroxyl-radical, or an amine, or a hydroxyl and an amine, a hydroxyl and a halogen, or a hydroxyl and an alkoxy, can represent the radical SO.sub.2 R.sub.26, R.sub.26 being an alkyl or lower haloalkyl radical, in particular CF.sub.3, except that when YZ represents CR.sub.20 R.sub.21 --CR.sub.19, they cannot be an amino, (lower)alkylamino, hydroxyl, arylamino, aralkylamino or arylalkylamino radical, except that when X--YZ is of the form CR.sub.15 R.sub.16 --CR.sub.22 .dbd.CR.sub.23 --CR.sub.19, they cannot be a hydroxyl, amino, (lower)alkylamino, arylamino, aralkylamino or arylalkylamino radical, (chlorine, bromine, iodine or fluorine), or a group Q--CV--R.sub.11 in which Q, V and R11 are as defined above, or --CW--, m being an integer between 2 and 3, and W defined above, on condition that at least one of R1, R6, R7 or R8, R20, R21, R23, R24 and R25 represents a (lower)alkylcarbonyl or radical a (lower)alkylthiocarbonyl, their racemic mixtures, their pure enantiomers or their mixtures in all proportions, and their therapeutically acceptable salts.
The present invention also r
REFERENCES:
patent: 5093352 (1992-03-01), Dubocovich
patent: 5403851 (1995-04-01), D'Orlando et al.
Fourtillan Jean-Bernard
Fourtillan Marianne
Jacquesy Jean-Claude
Jouannetaud Marie-Paule
Karam Omar
CEMAF and Laboratoires Besins Iscovesco S.A.
Keating Dominic
McKane Joseph K.
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