Indole derivatives as 5-HT1A and/or 5-HT2 ligands

Details Indole derivatives as 5-HT1A and/or 5-HT2 ligands Indole derivatives as 5-HT1A and/or 5-HT2 ligands

1995-12-01

1998-11-10

Fan, Jane

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

5462774, A16K 3144, C07D40106

Patent

active

058344934

DESCRIPTION:

BRIEF SUMMARY
This is a B71 of PCT/EP94/0106 filed Mar. 31, 1994 now WO 94/24125.
The present invention relates to novel pharmacologically active indole derivatives and acid addition salts thereof, to processes for their preparation and to pharmaceutical compositions containing them. The new compounds possess central serotonergic activity and are useful in the treatment of central nervous system (CNS) disorders.
It is known that 1A and 2 serotonergic receptors (5-HT.sub.1A and 5-HT.sub.2) seem to be important for many functions in the animal body. For instance, altered function of these receptors is involved in the genesis and/or treatment of anxiety, depression, psychoses, abnormality of sleep and feeding, organic mental diseases and alteration of blood pressure. In spite of the clear involvement of 5-HT.sub.1A receptors in such a huge amount of pathological events, it is not clear why, for example, some compounds acting upon 5-HT.sub.1A receptors exert in humans a preferential anxiolytic effects, while others exert a preferential hypotensive action. The same holds for 5-HT.sub.2 antagonists. This is probably due to heterogeneous characteristics, so far unknown, of 5-HT.sub.1A and 5-HT.sub.2 receptors. Therefore, there is the possibility that compounds acting on 5-HT.sub.1A and/or 5-HT.sub.2 receptors may exert a wide range of therapeutic effects in humans.
WO Patent 9206973 refers to 5-substituted 3(N-methyl-pyrrolidin-2-yl-methyl) indoles. The compounds are said to be useful for the treatment of depression, anxiety, migraine. WO Patent 9213856 refer to 5-heteroyl indoles. The compounds are said to be useful in treating migraine.
European Patent Application Number 429341 refer to 5-substituted to heterocyclic derivatives, including among the others, the compound named e. Such compounds are said to be 5-HT reuptake inhibitors, useful in the treatment of depression.
We have now synthetized, and this is the object of the present invention, a novel class of structurally distinct compounds showing affinity for the 5-HT.sub.1A and/or 5-HT.sub.2 receptors. These new compounds may be useful in the treatment of CNS diseases such as affective disorders, (for example depression and bipolar disorders), anxiety, sleep and sexual disorders, psychosis, schizophrenia, personality disorders, mental organic disorders and mental disorders in childhood, aggressiveness, age associated memory impairment, cerebral ictus, motion sickness. Moreover they may be used for cardiovascular disorders such as hypertension and thrombosis.
The present invention has for object compounds of general formula (I) ##STR2## wherein: R represents H, C.sub.1-6 alkyl, lower alkoxy, aralkoxy, halogen, hydroxy, cyano or C.sub.1-6 acyl; C.sub.3-6 cycloalkyl C.sub.1-2 alkyl or lower alkyl bearing an optionally substituted phenyl; phenoxy or anilino, each group being optionally substituted by one or more substituents selected from lower alkyl, lower alkoxy, amino, halogen or trifluoromethyl; or R.sub.2 is a group selected from ##STR3## where n is an integer from 1 to 3; R.sub.3 represents an aryl or heteroaryl group, each group being optionally substituted by one or more substituents selected from lower alkyl, halogen or trifluoromethyl; C.sub.1-6 alkyl or C.sub.4 -C.sub.10 cycloalkyl; represents NH; where R.sub.4 is hydrogen, lower alkyl, lower alkyl bearing a phenyl being optionally substituted by one or more substituents selected from lower alkyl, lower alkoxy, halogen, trifluoromethyl; lower alkyl; together with the carbonyl group to which they are bound constitute benzocondensed cycloalkanones of formula ##STR4## m is an integer from 0 to 2; P represents H, lower alkyl, halogen or trifluoromethyl;
For pharmaceutical use the compounds of general formula (I) may be used as such or in the form of tautomers or of physiologically acceptable acid addition salts thereof. The term "acid addition salts" includes salts either with inorganic or organic acids. Physiologically acceptable organic acids which may be used in salt formation include, for example, maleic, citric,

REFERENCES:
Malleron et al. J. Med> Chem. 36,, 1194-1202, 1993.
Smallheer et al. CA 119: 130901, 1993.
Salas et al. CA 113:78791, 1991.
Martinez et al. CA 102:78668, 1985.
J. Perregaard et al., "Selective, Centrally Acting Serotonin 5-HT.sub.2 Antagonists. 1.2-and 6-Substituted 1-Phenyl-3-(4-piperidinyl)-1H-indoles", J. Med. Chem., 35, 4813-4822 (1992).
A. Agarwal et al., "Three Dimensional Quantitative Structure-Activity Relationships of 5-HT Receptor Binding Data for Tetrahydropyridinylindole Derivatives: A Comparison of the Hansch and CoMFA Methods", J. Med. Chem., 36, 4006-4014 (1993).
E. Friderichs et al., "Darstellung der isomeren 3-(Pyridylmethyl) -und 3-(Piperidylmethyl)-5-hydroxyindole", Archiv der Pharmazie.308, 209-217 (1975).

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