Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1995-05-04
1997-08-26
Conrad, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
558411, 558412, 562453, A61K 31195, C07C22900
Patent
active
056611838
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to novel derivatives of 3-hydroxyanthranilic acid, 3-HANA, methods and intermediates for their preparation, novel pharmaceutical compositions and the use thereof for inhibiting the enzyme 3-hydroxy-anthranilate oxygenase, 3-HAO, responsible for the production of the endogenous neurotoxin quinolinic acid, QUIN.
BACKGROUND OF THE INVENTION
3-HAO is the enzyme in the catabolic pathway of tryptophan responsible for the conversion of 3-hydroxyanthranilic acid into quinolinic acid. Both QUIN and its biosynthetic enzyme 3-HAO have been identified in rodent as well as in human brain tissue. QUIN is an excitatory amino acid acting through the N-methyl-D-aspartate (NMDA) receptor and has recently gained attention for its putative role as an endogenuos excitotoxin involved in neurodegenerative disorders such as Huntington's disease, stroke/cerebral ischemia, hypoxia, Alzheimer's disease and the Aids dementia complex as well as epilepsi. Inhibitors of 3-HAO activity are of obvious therapeutic interest in diseases which can be traced to an overabundance of quinolinic acid.
PRIOR ART
4-Halogenated substrate analogs have been described as inhibitors of 3-HAO activity. In 1980 it was shown by Parli C J, Krieter P, Schmedt B, in "Metabolism of 6-chlorotryptophan to 4-chloroanthranilic acid: A potent inhibitor of 3-hydroxyanthranilic acid oxidase", Arch Biochem and Biophys 203, pp 161-166, 1980, that 4-chloro-3-hydroxyanthranilic acid, a metabolite of 6-chlorotryptophan, is a potent inhibitor of 3-HAO in rat and pig liver and kidney. Later it was verified by Heyes M P, Hutto B, Markey S P, in "4-Chloro-3-hydroxyanthranilate inhibits brain 3-hydroxy-anthranilate oxidase", Neurochem Int 13, pp 405-408, 1988, that 4-chloro-3-hydroxyanthranilic acid also is an inhibitor of rat brain 3-HAO. In 1989 Todd W P, Carpenter B K and Schwarcz R, in "Preparation of 4-halo-3-hydroxyanthranilates and demonstration of their inhibition of 3-hydroxyanthranilate oxygenase activity in rat and human brain tissue," Prep Biochem 19, pp 155-165, 1989, showed that 4-fluoro-, 4-chloro- and 4-bromo-3-hydroxyanthranilic acid had very similar blocking potencies of 3-HAO in rat as well as in human brain.
BRIEF DESCRIPTION OF INVENTION
The present invention relates to compounds able to inhibit the enzyme 3-HAO with IC.sub.5o values similar to and in addition a stability superior to compounds according to the prior art.
The present invention, thus is related to a compound of the general formula I ##STR2## wherein R.sup.1 and R.sup.2 are the same or different and selected from H and alkyl; X is selected from alkylthio, arylthio, aryloxy, halogen and cyano; R.sup.3, R.sup.4 are the same or different and selected from halogen, methyl, fluoroalkyl, cyano and Z-R.sup.5 wherein Z is selected from CH.sub.n, NH.sub.m, O, S, SO.sub.2 and CO wherein n=1 or 2; m=0 or 1 and R.sup.5 is selected from alkyl, aryl and fluoroalkyl; or R.sup.3 and R.sup.4 together form a saturated or unsaturated ring system Y-V-Z wherein Y and Z, independently of each other, are as defined for Z above and V is selected from C.sub.1 -C.sub.3 alkylene or alkenylene, --N.dbd., --N.dbd.N-- and ##STR3## wherein R.sub.7 =H or alkyl; or a pharmaceutically acceptable salt thereof.
Another object of the invention is a process for the preparation of the compound of formula I by arylthio, aryloxy, halogen and cyano; R.sup.3, R.sup.4 are the same or different and selected from halogen, methyl, fluoroalkyl, cyano and Z-R.sup.5 wherein Z is selected from CH.sub.n, NH.sub.m, O, S, SO.sub.2 and CO wherein n=1 or 2; m=0 or 1 and R.sup.5 is selected from alkyl, aryl and fluoroalkyl; or R.sup.3 and R.sup.4 together form a saturated or unsaturated ring system Y-V-Z wherein Y and Z, independently of each other, are as defined for Z above and V is selected from C.sub.1 -C.sub.3 alkylene or alkenylene, --N.dbd., --N.dbd.N-- and ##STR4## wherein R.sub.7 =H or alkyl
reducing a compound of formula II ##STR5##
wherein X, R.sup.3 and R.sup.4 are as defined in
REFERENCES:
Prinz et al., "A Novel Synthetic Route To Oximindace T-2-Anisidides And Their Conversion To 3-Hydroxyanthranilic Acids Via 7-Methoxyisatins," J. Chem. Research (M), pp. 1346-1354 (1978).
Heyes et al., "4-Chloro-3-Hydroxy Anthranilate Inhibits Brain 3-Hydroxy Anthranilate Oxidase," Neurochem. Int., vol. 13, No. 3, pp. 405-408 (1988).
Parli et al., "Metabolism of 6-Chlorotryptophan to 4-Chloro-3-hydroxyanthranilic Acid: A Potent Inhibitor of 3-Hydroxyanthranilic Acid Oxidase," Archives of Biochemistry and Bio-physics, vol. 203, No. 1, pp. 161-166 (1980).
Prinz et al., Chemical Abstracts No. 89:197117K, vol. 89, p. 590 (1978).
Todd et al., "Preparation of 4-Halo-3-Hydroxyanthranilates and Demonstration of Their Inhibition of 3-Hydroxyanthranilate Oxygenase Activity in Rat and Human Brain Tissue," Preparative Biochemistry, vol. 19, No. 2, pp. 155-165 (1989).
Bjork Susanna Karin Maria
Gotthammar Birgitta Kristina
Linderberg Mats Torbjorn
Luthman Johan Per
Persson Kerstin Margareta Irma
Astra Aktiebolag
Conrad Joseph
The University of Maryland
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