Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonist

Details Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonist Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonist

1998-05-12

2000-09-26

Bernhardt, Emily

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514250, 544115, 544346, A61K 314985, C07D48704

Patent

active

06124287&

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

The present invention relates to the imidazo[1,2-a]quinoxalin-4-amines and their salts, that are active as antagonists of the adenosine receptors; a process for their preparation as well as the pharmaceutical compositions containing them as active ingredients that are useful in the theraphy for the treatment of various psychiatric and neurological disorders of the central nervous system.
It is known that theophylline (1,3-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) are capable of antagonizing the effect of adenosine through interaction with its receptors, and that it is mainly to such a property that their central nervous system stimulant effects are to be ascribed. However the presence of pharmacologically relevant effects also at the heart, kidney and smooth muscle level has determined a serious limitation to the therapeutical use of these substances as agents for effectively treating the central nervous system diseases characterized by abnormalities in the neuronal transmission processes, such as, for example, depression and senile dementia. Moreover, their low affinity to the adenosine receptors implies that the therapeutically effective dosages are too close to those causing serious side effects at the central level too. A series of compounds having various non-xanthine structures have exhibited in a various amount, affinity to the adenosine receptors (see for example documents EP 515,107 A2 and J. Med. Chem. 1991, 34, 1202), but none of them has the structure of imidazo[1,2-a]quinoxalin-4-amines.
Several derivative of imidazo[1,2-a]quinoxalin-4-amines have been described in the literature: for example in U.S. Pat. No. 5,182,386 imidazoquinoxalines are disclosed that interact with the central receptors of GABA, whilst in WO 94/22865 analogous compounds (especially derivatives of 4,5-dihydro-4-oxoimidazo [1,2-a]quinoxaline-2-carboxylic acid) are described as antagonists of excitatory amino acids. In no case, however, an affinity of such substances to the adenosine receptors has been pointed out. U.S. Pat. No. 4,229,452 discloses N-cyclohexyl-, N-butyl-, N-propylimidazo[1,2-a]quinoxalin-4-amine Chemical Abstracts 1972, 77:88433s describes imidazo[1,2-a]quinoxalin-4-amine. Such compounds, along with the whole subclass of unsubstituted N-alkyl- and N-cycloalkyl imidazo[1,2-a]quinoxalin-4-amines have been excluded from claim 1.
U.S. Pat. No. 4,780,464 and J. Med. Chem. 1990, 33, 2240-2254 disclose [1,2,4]triazolo[4,3-a]quinoxalin-4-amines having activity as adenosine antagonists and antidepressants. Such compounds are different from those claimed in the present invention. In addition, they are not particularly potent as antidepressants, having minimum effective doses in the Porsolt's forced swim test not lower than 1 mg/kg orally, with a consequent risk of developing significant side effects.
With the present invention, it has surprisingly been discovered that a group of imidazo[1,2-a]quinoxalin- 4-amines are potent antagonists of the adenosine receptors that are active in vivo onto the central nervous system at much lower dosage as compared with the compounds that are presently in general use in theraphy.
The compounds of the invention might therefore exhibit a lower incidence of side effects, especially at the peripheral level.
The present invention relates therefore to a compound of the formula (I): ##STR2## wherein R.sub.1 is hydrogen or methyl; that is possibly substituted with OH, (C.sub.3 -C.sub.8) cycloalkyl; ##STR3## wherein Z is a direct bond, or O, NR.sub.6, R.sub.6 being a straight- or branched- chain (C.sub.1 -C.sub.6) alkyl; halogen chosen from Cl, F, Br; with the proviso that when R.sub.1, R.sub.2, R.sub.4, R.sub.5 are hydrogen, R.sub.3 can not be hydrogen, straight- or branched-chain (C.sub.1 -C.sub.8) alkyl, (C.sub.3 -C.sub.8)cycloalkyl;
In the present invention, there are preferred the compounds of formula (I) in which R.sub.1 is hydrogen or methyl, R.sub.2 is hydrogen, R.sub.3 is hydrogen, straight- or branched- chain (C.sub.1 -C.sub.6)alkyl, that is possibly su

REFERENCES:
patent: 4229452 (1980-10-01), Warner et al.
patent: 4780464 (1988-10-01), Trivedi et al.
patent: 5182386 (1993-01-01), Albaugh et al.
Simonov et al, Chemical Abstracts, vol. 77,No. 88433, 1972.
van Galen et al., J.Med. Chem., vol. 34,p.1202-1206, 1991.

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