5-(3-Phenyl-3-oxo-propyl)-1H-tetrazole derivatives

Details 5-(3-Phenyl-3-oxo-propyl)-1H-tetrazole derivatives 5-(3-Phenyl-3-oxo-propyl)-1H-tetrazole derivatives

1999-12-30

2000-10-17

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548253, A61K 3141, C07D25704

Patent

active

061333026

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to 5-(3-phenyl-3-oxo-propyl)-1H-tetrazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use in therapy.
The compounds of the invention are inhibitors of Kynurenine-3-hydroxylase (KYN-OH), an enzyme which is involved in the metabolic pathway of kynurenine.


BRIEF DESCRIPTION OF DRAWING

It is well known in the art that through the kynurenine pathway, tryptophan metabolism gives rise to the formation of both 3-hydroxykynurenine(3-OHKYN) and quinolinic acid (QUIN) on the one side, and kynurenic acid (KYNA) on the other side, as shown in FIG. 1. (The legend to FIG. 1 has to be found on the last page of the experimental part of the specification).
Both KYNA and QUIN are known to possess biological activities. KYNA, in particular, is endowed with neuroprotective properties (J. Neurosci. 1990,10,2965-2973), whereas QUIN is a potent neurotoxin which has been implicated in the pathogenesis of a variety of neurological disorders (Life Sci. 1984,35,19-32; Nature, 1986,321,168-171; Science, 1983,219,316-318).
Increasing concentrations of QUIN have also been indicated as responsible of neurological disorders accompanying many infections and inflammatory diseases including Acquired Immunodeficiency Syndrome (AIDS) (Ann. Neurol. 1991,29,202-209).
One of the main strategies aimed at altering the KYNA/QUIN balance, either blocking 3-OHKYN and QUIN's production or increasing KYNA production, entails the inhibition of the key enzymes of kynurenine (KYN) pathway among which, particularly relevant is Kynurenine-3-hydroxylase.
Consequently, there is a need in therapy of compounds enabling the inhibition of said enzyme.
We have surprisingly found that some derivatives of 5-(3-phenyl-3-oxo-propyl)-1H-tetrazole, being endowed with inhibitory activity towards Kynurenine-3-hydroxylase, fulfil such a need.
Accordingly, the present invention provides a compound which is a 5-(3-phenyl-3-oxo-propyl)-1H-tetrazole derivative of formula (I) ##STR2## wherein each of R and R.sub.1, being the same or different, is hydrogen, halogen, hydroxy, trifluoromethyl, cyano, nitro, phenyl, benzyl, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, SOR.sub.4 or SO.sub.2 R.sub.4 wherein R.sub.4 is C.sub.1 -C.sub.6 alkyl, --N(R.sub.5 R.sub.6) in which each of R.sub.5 and R.sub.6 is, independently, hydrogen, C.sub.1 -C.sub.6 alkyl, formyl or C.sub.2 -C.sub.6 acyl; benzyl, phenyl; alkoxy, benzyl, phenyl or a group --N(R.sub.7 R.sub.8) in which each of R.sub.7 and R.sub.8 is, independently, hydrogen, C.sub.1 -C.sub.4 alkyl, benzyl, phenyl, or one of R.sub.7 and R.sub.8 is hydrogen and the other is COR.sub.9 wherein R.sub.9 is hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, phenyl or a group --N(R.sub.10 R.sub.11) in which R.sub.10 and R.sub.11 are, each independently, hydrogen or C.sub.1 -C.sub.4 alkyl or, taken together, R.sub.2 and R.sub.3 form a carbocyclic C.sub.3 -C.sub.6 ring; or a pharmaceutically acceptable salt thereof;
In the present description, the alkyl and alkoxy groups of the compounds of formula (I) may be branched or straight groups.
Representative examples of C.sub.1 -C.sub.6 alkyl groups include C.sub.1 -C.sub.4 alkyl groups such as methyl, ethyl, n- and isopropyl, n-, iso-, sec- and tert-butyl groups.
Representative examples of C.sub.1 -C.sub.6 alkoxy groups include C.sub.1 -C.sub.4 alkoxy groups such as methoxy or ethoxy.
Representative examples of C.sub.1 -C.sub.6 alkylthio groups include C.sub.1 -C.sub.4 alkylthio groups such as methylthio or ethylthio groups.
Representative examples of C.sub.1 -C.sub.6 acyl groups include C.sub.1 -C.sub.4 acyl groups such as acetyl or propionyl.
Representative examples of C.sub.1 -C.sub.6 alkoxycarbonyl groups include C.sub.1 -C.sub.4 alkoxycarbonyl groups such as methoxycarbonyl or ethoxycarbonyl groups.
A halogen atom is fluorine, bromine, chlorine or iodine;
Pharmaceutically acceptable salts of the compounds of formula (I) are the acid addition salts with inorganic, e.g

REFERENCES:
patent: 4764521 (1988-08-01), Herron

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