Fluoro-substituted benzoylpropionic acid derivatives

Details Fluoro-substituted benzoylpropionic acid derivatives Fluoro-substituted benzoylpropionic acid derivatives

1998-04-20

1999-10-26

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514541, 514620, 560 38, 562449, 564164, A01N 3712, A01N 3718, C07C22928, C07C23305

Patent

active

059730064

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to fluoro-substituted benzoylpropionic acid derivatives, to their pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions comprising them.
2. Description of the Related Art
Our previous International patent application WO 95/03271 refers to 2-amino-4-phenyl-4-oxo-butyric acid derivatives of formula (IA) either as single isomers or as racemic mixture ##STR2## and pharmaceutically acceptable salts thereof, wherein
each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl, hydroxy, C.sub.1 -C.sub.5 alkyl, benzyl, C.sub.6 -C.sub.10 aryl, OR', --SR', SOR', SO.sub.2 R' in which R' is C.sub.1 -C.sub.5 alkyl or benzyl; and
R is hydroxy, OR', amino, NHR', --N(R').sub.2, hydroxylamine or --NHOR' in which R' is as defined above;
provided that R is not hydroxy when: simultaneously a hydroxy group or a --OR' group in which R' is methyl; or of the phenyl ring and is hydroxy, chlorine, fluorine, methyl, n-propyl or methoxy.
In WO 95/03271 the compounds of formula (IA) are described as effective in inhibiting the activity of the enzymes kynureninase and/or kynurenine-3-hydroxylase which are involved in the metabolic pathway of kynurenines leading to the formation of quinolinic acid, a tryptophan neurotoxic metabolite with excitatory activity in the mammalian central nervous system. The compounds of formula (IA) may therefore be employed in the prevention and/or treatment of a variety of nervous system diseases wherein the inhibition of the enzymes kynureninase or kynurenine-3-hydroxylase is needed; namely, they can be useful in the prevention and/or treatment of a nervous system disease related to a deranged production of quinolinic acid or excessive activation of neurotransmission mediated by N-methyl-D-aspartic acid.
For example, the compounds of formula (IA) may be useful in the prevention and/or treatment of neurodegenerative pathologies including, for example, Huntington's chorea, Alzheimer's disease, Parkinson's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), multi-infarctual dementia, cerebral ischemia, cerebral hypoxia and epilepsy.
The compounds of formula (IA) are, in general, soluble in aqueous vehicles suitable for parenteral administration.
In accordance with the present invention, it has now been surprisingly found that certain fluoro-substituted benzoylpropionic acid derivatives, which represent a selected class of compounds of formula (IA), not specifically disclosed in WO95/03271, possess excellent solubility. These novel fluoro derivatives, which are selective inhibitors of the enzyme Kynurenine-3-hydroxylase, are considerably more soluble than the corresponding di-chloro derivatives disclosed in WO 95/03271 and are therefore particularly useful for injectable administration purposes.


BRIEF SUMMARY OF THE INVENTION

Accordingly, the present invention provides an optically active or racemic substituted benzoylpropionic acid derivative of formula (I) ##STR3## wherein
R is hydroxy, amino, hydroxylamine, --OR', --NHR', --N(R').sub.2 or --NHOR' in which R' is C.sub.1 -C.sub.6 alkyl or benzyl;


DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) possess an asymmetric carbon atom in the asterisked position and can therefore exist either as individual optical isomers or as racemic mixture.
The scope of the present invention encompasses both the individual optical isomers and the racemic mixture of the formula (I) compounds.
With reference to formula (I), the preferred meanings of the substituent R are hydroxy, amino, hydroxylamino or OR' in which R' is C.sub.1 -C.sub.6 alkyl and benzyl.
The term C.sub.1 -C.sub.6 alkyl includes, for example C.sub.1 -C.sub.4 alkyl such as methyl, ethyl, n-propyl, isopropyl and n-butyl; preferably, it is methyl, ethyl or n-propyl.
The pharmaceutically acceptable salts of the compounds of formula (I) include both salts with pharmaceutically acceptable acids, either inorganic acids, such

REFERENCES:
patent: 5519055 (1996-05-01), Schwarcz et al.
patent: 5708030 (1998-01-01), Schwarcz et al.

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