Pharmacologically active enantiomers

Details Pharmacologically active enantiomers Pharmacologically active enantiomers

1996-04-29

1998-04-21

Ford, John M.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544408, C07D24108, C07D40106

Patent

active

057419078

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/EP94/02061 filed Jun. 21, 1994.


DESCRIPTION

This invention relates to pharmacologically active enantiomers, their salts with physiologically acceptable acids, a method for their preparation and the pharmaceutical compositions containing them.
PCT/EP93/00080 describes a class of novel compounds of the general formula: ##STR2## where only one of R, R', R" and R'" is an alkyl having from 1 to 3 carbon atoms while the others are hydrogen.
The pharmacological data reported in the above mentioned application show that the compounds of formula (I) are endowed with a pharmacological profile similar to that of trazodone (I, R=R'=R.increment.=R'"=H) but also have some advantages such as, for example, a reduced affinity for adrenergic receptors.
It has now surprisingly been found that both (S) and (R) enantiomers of the compounds of formula (I), where R, R', R'" are hydrogen and R" is an aLkyL having from 1 to 3 carbon atoms, have an improved analgesic activity compared to their racemates.
This finding is even more surprising since both the enantiomers have a lower alphalytic activity, and consequently less undesirable effects, compared to the corresponding racemates.
It is therefore a first object of this invention to provide (S) and (R) enantiomers of the compounds of formula: ##STR3## where Alk is an alkyl having from 1 to 3 carbon atoms, and their addition salts with physiologically acceptable acids.
Examples of suitable acids are hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, lactic acid, succinic acid, acetic acid, tartaric acid, malic acid, citric acid, benzoic acid, 2-naphthalenesulfonic acid, adipic acid and pimelic acid.
Although both (R) and (S) enantiomers are more active than the corresponding racemates, (S) enantiomers are more active than (R) enantiomers. Hence, (S) enantiomers are preferred.
As far as the meanings of Alk are concerned, methyl is preferred.
Thus, the preferred compound of this invention is the (S) enantiomer of formula (IA) wherein Alk is methyl.
The analgesic activity of the compounds of this invention has been proved in mice by means of the phenylquinone test via subcutaneous route (Pharmacol. Exp. Ther., 125, pp 237-240, 1959). Thirty animals were treated with each product. The experimental results are reported in Table 1.


TABLE 1 ______________________________________ Compound IA ANALGESIC ACTIVITY Form Alk Phenylguinone, ED.sub.50 (mg/kg) ______________________________________ Racemate CH.sub.3 >12.50 (R) CH.sub.3 9.02 (S) CH.sub.3 7.80 ______________________________________
Table 1 shows that a higher dose of racemic compound is needed to achieve the same analgesic action. This means that the racemic compound has Less analgesic activity compared to the single enantiomers. TabLe 1 also shows that (S) enantiomer is more active than (R) enantiomer.
Since an interference with the adrenergic system is an index of undesirable effects, both the capability of binding to alpha 1 adrenergic receptors, as IC.sub.50 (TabLe 2), and the alphalytic activity (TabLe 3) of the same compounds have been evaluated.
As far as the receptor binding test is concerned, reference is made to "Moecular Pharmacology", 20, 295-301, (1981).
In turn, the alphalytic activity was evaluated on an isolated organ (deferent of rat) according to the technique described in "Clinical and Experimental Pharmacology & Physiology", 6, 275-279, (1979).
The experimental results are reported in Tables 2 and 3.


TABLE 2 ______________________________________ Compound IA Affinity for alpha 1 Form Alk adrenergic receptors (IC.sub.50) ______________________________________ Racemate CH.sub.3 471 (R) CH.sub.3 533 (S) CH.sub.3 981 ______________________________________


TABLE 3 ______________________________________ Compound IA Alphalytic activity Form Alk pA.sub.2 ______________________________________ Racemate CH.sub.3 7.70 .+-. 0.7 (R) CH.sub.3 6.75 .+-. 0.2 (S) CH.sub.3 5.40 .+-. 0.7 ________________________________

REFERENCES:
patent: 3381009 (1968-04-01), Palazzo et al.
patent: 5399765 (1995-03-01), Gao et al.

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