Oxidation derivatives of indolylalkylamines and their use as dru

Details Oxidation derivatives of indolylalkylamines and their use as dru Oxidation derivatives of indolylalkylamines and their use as dru

1998-08-11

2000-05-23

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548473, 548472, A01N 4338, C07D20944, C07D20946

Patent

active

060666633

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel oxidation derivatives of indolylalkylamines, which are melatoninergic agonists, to a process for their preparation and to their use as drugs.
Melatonin, N-acetyl-5-methoxytryptamine, is a hormone from the pineal gland, isolated by Lerner et al. (J. Am. Chem. Soc., 80, 1958, 2587), and has been 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 use melatonin and its analogues in particular for the treatment of depression and psychiatric disorders, in particular stress, anxiety, depression, insomnia, schizophrenia, psychoses 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 proven to be very satisfactory, given that a first passage through the liver extracts more than 90% of the active principle.
Various melatonin analogues have been described, demonstrating two routes of research focused either on 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 on the aromatic ring by replacing the indolyl group by a naphthyl (FR-A-2 658 818, FR-A-2 689 124).
The present patent application thus relates to the preparation and use, as drugs, of novel oxidation derivatives of indolylalkylamines.
The present invention thus relates to novel derivatives of general formula I ##STR2## in which: ##STR3## represents one of the following three radicals: ##STR4## n is equal to 1, 2 or 3, preferably 2, R1, R2, R3 and R4 represent, independently of each other, a hydrogen atom, a hydroxyl radical, a lower alkyl, cycloalkyl, lower alkoxy, aryloxy, lower aralkoxy, lower perhaloalkyl, lower perhaloalkoxy, halo or nitro radical or an unsaturated aliphatic chain, radical, each optionally substituted with one or more halogens, an amino, (lower)alkyl-amino or (lower)dialkyl-amino, arylalkylamino, aralkylamino or diaralkylamino radical or a lower alkoxy, (lower)alkyloxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl radical, alkyl, aryl, lower aralkyl, lower alkoxy, aryloxy, lower aralkoxy, lower perhaloalkyl, (lower)perhaloalkyl-carbonyloxy, halo, alkylsulphonyl, arylsulphonyl, aralkylsulphonyl or (lower)perhaloalkylsulphonyl radical, sulphur atom, substituted with one or more halogens, an alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, (lower)perhaloalkyl-carbonyl or perhaloaralkyl-carbonyl radical, or a (lower)alkyl-sulphonyl, arylsulphonyl, aralkylsulphonyl, (lower)perhaloalkyl-sulphonyl or perhaloaralkylsulphonyl radical, linked to form a saturated or unsaturated ring containing at least 5 atoms and preferably 6, it being possible for this ring to contain several hetero atoms and to be substituted with one or more groups which may be, independently of each other, a hydroxyl radical, a lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, halo or nitro radical or an unsaturated aliphatic chain, it being possible for R1 and R2, R2 and R3, and R3 and R4 to form part of another aromatic or non-aromatic ring with or without a hetero atom, containing at least 5 and preferably 6 atoms, it being possible for this ring to contain several hetero atoms and to be substituted with one or more groups which may be, independently of each other, a hydroxyl radical, a lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, halo or nitro radical or an unsaturated aliphatic chain, proportions, and their therapeutically acceptable salts.
The expressions lower alkyl, lower alkoxy and lower perhaloalkyl are generally understood to refer to radicals whose alkyl residue comprises between 1 and 6 carbon atoms.
These are preferably linear or branched C1-C4 alkyl residues chosen more particularly from

REFERENCES:
Fourtillan, J.B. et al., Preparation of Spiro (indole-3,3'-pyrrolidine) Derivatives as Melatoninergic Agonists, Chemical Abstracts, vol. 124, No. 13, Abstract No. 175864 (1996).

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