Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-05-04
1999-03-16
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514535, 562433, 562405, 562452, 560 19, 560 45, A61K 3119, A61K 3124, C07C22900, C07C22952
Patent
active
058831290
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE94/00153 Feb. 24, 1995.
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-hydroxyanthranilate 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, Alzheimers 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-hydroxyanthranilate 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.50 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, alkyl, aryl and arylalkyl; X and Y are the same or different and selected from alkoxy, aryloxy, alkyl, alkylthio, arylthio, fluoroalkyl, halogen, cyano, OSO.sub.2 CH.sub.3, OSO.sub.2 CF.sub.3, OCF.sub.3 and SCF.sub.3 with the proviso that the compound of formula I wherein R.sup.1 and R.sup.2 =H, X=Br and Y=Me is excluded; or a pharmaceutically acceptable salt thereof.
Another object of the invention is a process for the preparation of the compound of formula I by different and selected from alkoxy, aryloxy, alkyl, alkylthio, arylthio, fluoroalkyl, halogen, cyano, OSO.sub.2 CH.sub.3, OSO.sub.2 CF.sub.3, OCF.sub.3 and SCF.sub.3 ##STR3## wherein X and Y are as defined in A) above; B) in the case where R.sup.1 and R.sup.2 are the same or different and selected from H, alkyl, aryl and arylalkyl; X and Y are the same or different and selected from alkoxy, aryloxy, alkyl, alkylthio, arylthio, fluoroalkyl, halogen, cyano, OSO.sub.2 CH.sub.3, OSO.sub.2 CF.sub.3, OCF.sub.3 and SCF.sub.3 ##STR4## wherein R.sup.1, R.sup.2, X and Y are as defined in B) above and PG is a protecting group such as alkyl, benzyl (Bn), 2-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or 2-methoxyethoxymethyl (MEM); selected from H, alkyl, aryl and arylalkyl; X and Y are the same or different and selected from alkoxy, aryloxy, alkyl, alkylthio, arylthio, fluoroalkyl, halogen, cyano, OSO.sub.2
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Bjork Susanna Karin Maria
Carpenter Barry K.
Gotthammar Birgitta Kristina
Linderberg Mats Torbjorn
Luthman Johan Per
Astra Aktiebolag
Lambkin Deborah C.
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