Aralkyl esters and processes for their preparation

Details Aralkyl esters and processes for their preparation Aralkyl esters and processes for their preparation

1989-01-24

1991-02-05

Friedman, Stanley

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

A61U 3124

Patent

active

049905341

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The object of the present invention is to provide novel compounds and therapeutically acceptable salts thereof with a selectively potentiating effect on cholinergic responses.
This invention also relates to processes for the preparation of the new compounds as well as to the pharmacological use of the new compounds and to pharmaceutical preparations containing such compounds.


PRIOR ART

U.S. Pat. No. 4 237 311 describes some aralkyl esters of amino acids e.g. alaproclate, which have effect on the central nervous system in man, especially an antidepressive activity combined with a reduced frequency of side effects. These compounds exert their effect by blocking the neuronal 5-hydroxytryptamine (5-HT) uptake. Furthermore it is known from U.S. Pat. No. 4 469 707 that some of the compounds, including alaproclate, described in U.S. Pat. No. 4 237 311 apart from being inhibitors of 5-hydroxytryptamine uptake also have a potentiating effect on cholinergic responses. Thus they are not selective for cholinergic potentiation. Further aralkyl esters of amino acids are described by Lindberg U. H. et al in the Journal of Medicinal Chemistry 21, p. 448-456 (1978).


OUTLINE OF THE INVENTION

According to the present invention it has been found that compounds of the general formula I ##STR1## in racemic or preferably in optically active form or a pharmaceutically acceptable salt thereof, wherein and Y are hydrogen; having 2-5 carbon atoms, with the proviso that the racemate of the compound wherein X is 4-Cl, Y is H and R is --CH(CH.sub.3).sub.2 is excluded, exhibit a selectively potentiating effect on central cholinergic responses. This potentiation is probably mediated by effects on ion-channels, most likely of potassium type. The influence on ion-channels coupled to various receptors makes it possible to use the compounds defined above in the treatment of mental disturbances e.g. psychosis, schizophrenia, schizoaffective conditions, anxiety, unipolar and bipolar depression as well as in the treatment of minimal memory impairment (MMI) and of senile dementia of the Alzheimer type (SDAT). The latter two MMI and SDAT are regarded as associated with a cholinergic dysfunction.
Halogen is preferably chloro, bromo or fluoro, in the para and meta positions and in particular the para position when monosubstituted, that is when one of X and Y is hydrogen.
Especially preferred are compounds wherein
X is para-substituted fluoro or chloro or X and Y are both chloro, Y is H and R is a branched alkyl group or ethyl and propyl when not branched.
Most preferred are the following compounds ##STR2##
Illustrative examples of the substituents in the general formula I are given in the examples and in Table 1.


TABLE 1 ______________________________________ ##STR3## Compound according to Example No X Y R ______________________________________ 1,9 4-Cl H C.sub.2 H.sub.5 2,23,24 4-F H C.sub.2 H.sub.5 3 4-F H C.sub.3 H.sub.7 4,8 4-Cl H C.sub.3 H.sub.7 5 4-Cl H CH.sub.2CHCH.sub.2 6 4-Cl H (CH.sub.2).sub.4 CH.sub.3 7 4-Cl H CH.sub.2 CCH 11 4-Cl H CH.sub.2 CH(CH.sub.3).sub.2 12 4-Cl H CH(CH.sub.3)(C.sub.2 H.sub.5) 13 4-F H CH(CH.sub.3).sub.2 14,25 3-Cl 5-Cl CH(CH.sub.3).sub.2 15 4-F H CH(CH.sub.3)(C.sub.2 H.sub.5) (SS/RS) 16,22 3-Cl 4-Cl C.sub.2 H.sub.5 17 4-F H CH.sub.2 CH(CH.sub.3).sub.2 18 3-CF.sub.3 H C.sub.2 H.sub.5 19 3-CF.sub.3 H C.sub.3 H.sub.7 20 4-F H CH.sub.2 CH(CH.sub.3).sub.2 (S) 26,28 (+)4-Cl H CH(CH.sub.3).sub.2 27 (-)4-Cl H CH(CH.sub.3).sub.2 10 4-Cl H C.sub.3 H.sub.7 (R) 21 4-Cl H C.sub.3 H.sub.7 (S) ______________________________________


PREPARATION

The compounds with the general formula I in optically active form or in racemic form ##STR4## wherein X, Y and R are as defined above are prepared
(A) by converting the corresponding derivatives II having the identical R group, ##STR5## wherein X, Y and R are as defined above and Z represents a group which can be transformed to an NH.sub.2 -group, by a suitable hydrolytic, reductive, electroche

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