Indole derivatives

Details Indole derivatives Indole derivatives

1990-10-02

1992-07-14

Lee, Mary C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548504, A61K 31405, C07D20916

Patent

active

051303272

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 2-aminomethyl-5-methoxyindole derivatives, processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them. The compounds of this invention are of use in treating depression and medical conditions which are characterised by depletion of biogenic amines in the brain.
The enzyme monoamine oxidase [MAO, EC 1.4.3.4.] catalyses the oxidative deamination of important neuronal monoamines, including catecholamines and 5-hydroxytryptamine (5-HT, serotonin). The enzyme is currently known in two forms MAO-A and MAO-B which are characterised by different selectivities with regard to inhibitors and substrates. 5-HT, adrenaline and noradrenaline are preferentially metabolised by MAO-A, whereas benzylamine and .beta.-phenethylamine are predominantly metabolised by MAO-B, and tyramine is a common substrate for both forms. Dostert P.L. et al., Med. Res. Rev. 9, 45-89 (1989).
The clinical usefulness of MAO inhibitors has been limited by the "cheese effect" (a hypertensive response to tyramine and other pressor amines present in some foodstuffs) and compounds which have good pharmacological activity and a weak "cheese effect" are of particular interest. Currently the inhibition of MAO-A is thought to give rise to anti-depressant effects, whereas the selective MAO-B inhibitor 1-deprenyl is used in combination with L-Dopa in the treatment of Parkinsonism.
Although many inhibitors of MAO are known, the 1989 review by Dostert et al. concluded that "no simple patterns have yet emerged which will allow the rational design of potent MAO inhibitors with predictable selectivity."
In Spanish Patent 407,703 and Spanish Patents 421,185 and 421,186 we described 3-aminomethylindole and 3-(2-aminoethyl)indole derivatives. In Spanish Patent 542,696 and Application 8602588 we described 2-aminomethylindoles which do not have methoxy substituents. All these compounds are characterised as having alkyne or allene groups.
G. Bertaccini and P. Zamboni, Arch. Int. Pharmacodyn. 1961] 133 138-158, tested aminoalkylindole derivatives for 5-hydroxytryptamine-like activity on the rat uterus and the authors noted that "none of the examined compounds had marked antagonistic activity". 5-Methoxy-2-(methylaminomethyl)-indole (Compound It herein) was described as compound 48 and was one of five compounds referred to as "a weak unspecific antagonistic activity was also noted in some compounds bearing the side chain at the 2 position." The authors' views on structure-activity relationships included: "substitution of the hydroxy group at the 5-position of the indole ring with a methoxy group ( . . . ) brought about a tenfold reduction in activity", "shifting of the side chain from 3 to 2 position produced a strong decrease in biological activity of the tryptamines", "the effect of alkyl substitution in the amino nitrogen was variable", and "indolealkylamines with a single carbon atom lateral chain (gramine derivative) showed a negligible activity."
According to the present invention there is described 2-aminomethyl-5-methoxyindole compounds of structure (1): ##STR2## and pharmaceutically acceptable salts thereof, wherein R is hydrogen or C.sub.1-4 alkyl, an alkyne or allene group, provided that R' is not methyl when R and R" are both hydrogen, and allene group.
Suitably R is hydrogen or methyl.
Suitably R' is propargyl, 2-butynyl, 2,3-butadienyl or hydrogen or methyl.
Suitably R" is hydrogen, propargyl, 2-butynyl or 2,3-butadienyl.
Preferably R is methyl.
Preferably R' is methyl or R' and R" are both hydrogen.
Preferably R" is propargyl or 2-butynyl.
Specific preferred compounds of this invention are:
Compounds of structure (1) can form pharmaceutically acceptable acid addition salts with suitable organic and inorganic acids, the nature of which will be apparent to persons skilled in the art. For example, pharmaceutically acceptable salts can be formed by reaction with hydrochloric, sulphuric, sulphonic or phosphonic acids, or aliphatic, alicyclic, aromatic or heterocyclic carboxy

REFERENCES:
Chem Abs., vol. 106, 1987, abstract 32831v, Alvarez et al., p. 529.
Chem Abs., vol. 111, 1989, abstract 133987j, Alvarez et al., p. 744.
J. Med. Chem., vol. 16, 1973, pp. 923-930, Fujita.

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