The present invention relates to novel derivatives of 3-hydroxyanthranilic acid, 3-HANA of general formula (I), 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 (a), wherein R.sub.7 .dbd.H or alkyl; or a pharmaceutically acceptable salt thereof, 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.

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 
A) in the case where R.sup.1 and R.sup.2 =H; 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 
##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 A) above, 
B) in the case where 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 
##STR6## 
wherein R.sub.7 =H or alkyl 
deprotecting a compound of formula III 
##STR7## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 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), 
C) in the case where 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 
##STR8## 
wherein R.sub.7 =H or alkyl 
deesterifying a compound of formula IV 
##STR9## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 are as defined in C) above 
and R.sup.6 is selected from alkyl, Bn, SEM, MEM, MOM and 
2,2,2-trichloroethyl, 
D) in the case where 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 
##STR10## 
wherein R.sub.7 =H or alkyl 
deesterifying and deprotecting a compound of formula V 
##STR11## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 are as defined in D) above 
and R.sup.6 and PG are selected from alkyl, Bn, SEM, MEM and MOM, 
E) in the case where R.sup.1 =alkyl, R.sup.2 =H or 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 
##STR12## 
wherein R.sub.7 =H or alkyl 
alkylating a compound of formula VI 
##STR13## 
wherein X, R.sup.3 and R.sup.4 are as defined in E) above. 
F) in the case where R.sup.1 and R.sup.2 are the same or different and 
selected from H and alkyl; X is selected from alkylthio, halogen and 
cyano; R.sup.3 =chloro, bromo or iodo; R.sup.4 =alkoxy, alkyl, alkylthio, 
cyano, fluoroalkyl, halogen, RSO.sub.2 or RCO wherein R=C.sub.1 -C.sub.5 
alkyl 
halogenating a compound of formula VII 
##STR14## 
wherein R.sup.1, R.sup.2, X and R.sup.4 are as defined in F) above. 
G) in the case where R.sup.1 and R.sup.2 are the same or different and 
selected from H and alkyl; X is selected from alkylthio, halogen and 
cyano; R.sup.3 =alkoxy, alkyl, alkythio, cyano, fluoroalkyl, halogen, 
RSO.sub.2 or RCO wherein R=C.sub.1 -C.sub.5 alkyl and R.sup.4 =chloro, 
bromo or iodo 
halogenation a compound of formula VIII 
##STR15## 
wherein R.sup.1, R.sup.2, X and R.sup.3 are as defined in G) above, 
or 
H) in the case where R.sup.1 and R.sup.2 are the same or different and 
selected from H and alkyl; X is selected from chloro, bromo and iodo; 
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 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 
##STR16## 
wherein R.sub.7 =H or alkyl 
halogenating a compound of formula IX 
##STR17## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in H) above. 
The present invention is also related to a pharmaceutical formulation 
containing a compound of formula I as active ingredient and a 
pharmaceutically acceptable carrier, the use of said compound for the 
manufacture of a medicament for the prevention or treatment of 
neurodegeneration. 
Further objects of the invention are synthesis intermediates for the 
preparation of the compound of formula I, namely a compound of the general 
formula II 
##STR18## 
wherein 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 
##STR19## 
wherein R.sub.7 =H or alkyl; a compound of the general formula III 
##STR20## 
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 
##STR21## 
wherein R.sub.7 =H or alkyl and PG is a protecting group, such as alkyl, 
benzyl (Bn), 2-(trimethylsilyl)ethoxymethyl (SEM), methoxymethyl (MOM) or 
2-methoxyethoxymethyl (MEM); 
a compound of the general formula IV 
##STR22## 
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 
##STR23## 
wherein R.sub.7 =H or alkyl and R.sup.6 is selected from alkyl, Bn, SEM, 
MEM, MOM and 2,2,2-trichloroethyl; 
a compound of the general formula V 
##STR24## 
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 
##STR25## 
wherein R.sub.7 =H or alkyl and N.dbd.N; R.sup.6 and PG are selected from 
alkyl, Bn, SEM, MEM and MOM; 
a compound of the general formula VI 
##STR26## 
wherein 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 
##STR27## 
wherein R.sub.7 =H or alkyl; a compound of the general formula VII 
##STR28## 
wherein R.sup.1 and R.sup.2 are the same or different and selected from H 
and alkyl; X is selected from alkylthio, halogen and cyano; R.sup.4 is 
selected from RSO.sub.2 and RCO wherein R=C.sub.1 -C.sub.5 alkyl; 
a compound of the general formula VIII 
##STR29## 
wherein R.sup.1 and R.sup.2 are the same or different and selected from H 
and alkyl; X is selected from alkylthio, halogen and cyano; R.sup.3 is 
selected from RSO.sub.2 and RCO wherein R=C.sub.1 -C.sub.5 alkyl; 
and 
a compound of the general formula IX 
##STR30## 
wherein R.sup.1 and R.sup.2 are the same or different and selected from H 
and alkyl; 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 and fluoroalkyl; or R.sup.3 and R.sup.4 
together form a saturated 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 
##STR31## 
wherein R.sub.7 =H or alkyl. 
DETAILED DESCRIPTION OF THE INVENTION 
The following definitions shall apply throughout the specification and the 
appended claims. 
Unless otherwise stated or indicated, the term "alkyl" denotes a straight 
or branched lower alkyl group, preferably a C.sub.1 -C.sub.6 alkyl. 
Examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, 
n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain 
pentyl and hexyl. 
Unless otherwise stated or indicated, the term "aryl" denotes a phenyl, 
furyl or thienyl group in which the ring is optionally further substituted 
by lower alkyl, lower alkoxy or halogen. 
Unless otherwise stated or indicated, the term "alkylthio" denotes a 
straight or branched lower alkylthio preferably a C.sub.1 -C.sub.6 
alkylthio. Examples of said lower alkylthio include methylthio, ethylthio, 
n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, 
t-butylthio and straight- and branched-chain pentylthio and hexylthio. 
Unless otherwise stated or indicated, the term "arylthio" denotes a 
phenylthio group in which the phenyl ring is optionally further 
substituted by lower alkyl, lower alkoxy or halogen. 
Unless otherwise stated or indicated, the term "aryloxy" denotes a phenoxy 
group in which the phenyl ring is optionally further substituted by lower 
alkyl, lower alkoxy or halogen. 
Unless otherwise stated or indicated, the term "halogen" shall mean 
fluorine, chlorine, bromine or iodine. 
The best mode of carrying out the invention known at present is to use 
4,6-dichloro-5-methylanthranilic acid. 
The compounds according to the present invention may be used in connection 
with prevention or treatment of neurodegeneration, especially in 
connection with conditions such as stroke, cerebral ischaemia, hypoxia, 
epilepsy and in neurodegenerative diseases such as Alzheimer's disease, 
multi-infarct dementia, Huntington's disease and the AIDS dementia 
complex. 
Below the methods for the preparation of the compound of formula I will be 
described in detail. 
METHODS OF PREATION 
Compounds of formula I 
##STR32## 
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; 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 
##STR33## 
wherein R.sub.7 =H or alkyl; may be prepared by one of the following 
methods. 
Method A Compounds of formula I wherein R.sup.1 and R.sup.2 =H; 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 
##STR34## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula II 
##STR35## 
wherein X, R.sup.3 and R.sup.4 are as defined in formula I in method A, 
for example by reduction with H.sub.2 and a catalyst such as Pd/C, Raney 
nickel or PtS.sub.2 at atmospheric or elevated pressure in a suitable 
solvent such as EtOH or EtOAc. The reduction can also be accomplished by 
reaction with SnCl.sub.2, NH.sub.2 NH.sub.2.H.sub.2 O or Na.sub.2 S.sub.2 
O.sub.5 in a suitable solvent such as EtOH. 
Method B Compounds of the general formula I 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 
##STR36## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula III 
##STR37## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 are as defined in formula 
I in method B and PG is selected from alkyl, Bn, SEM, MEM and MOM, by 
deprotection with for example a Lewis acid such as BBr.sub.3 or 
trimethylsilyl iodide or with alkyl- or arylSNa or alkyl- or arylSLi 
followed by adjustment of the pH to obtain the 3-hydroxyanthranilic acid 
derivative. In the case where PG=SEM, deprotection may be performed using 
tetrabutylammonium fluoride (TBAF) or CsF in a suitable solvent such as 
N,N-dimethylpropylenurea (DMPU) or N,N-dimethylformamide (DMF) at elevated 
temperature. A benzyl group may be removed by hydrogenolysis using for 
example H.sub.2 and Pd/C or PtS.sub.2 as a catalyst. A 
2,2,2-trichloroethyl group may be removed using Zn in acetic acid. 
Method C Compounds of formula I 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 
##STR38## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula IV 
##STR39## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 are as defined in formula 
I in method C and R.sup.6 is selected from alkyl, Bn, SEM, MEM, MOM and 
2,2,2-trichloroethyl, by deesterifying with for example a base such as KOH 
in a suitable solvent such as MeOH at room temperature or at elevated 
temperature, or by alkyl- or arylSLi or alkyl- or arylSNa or with Me.sub.3 
SiI followed by adjustment of the pH to obtain the 3-hydroxyanthranilic 
acid deivative. In the case where R.sup.6 =Bn, the carboxylic acid may be 
obtained by hydrogenolysis with for example H.sub.2 and Pd/C or PtS.sub.2. 
A 2,2,2-trichloroethylester may be cleaved with for example Zn in HOAc and 
a SEM-ester for example with TBAF in DMPU. 
Method D Compounds of formula I 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 
##STR40## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula V 
##STR41## 
wherein R.sup.1, R.sup.2, X, R.sup.3 and R.sup.4 are as defined in formula 
I in method D; PG and R.sup.6 are selected from alkyl, Bn, SEM, MEM and 
MOM, by deesterification and deprotection with for example alkyl- or 
arylSLi, alkyl- or arylSNa or with Me.sub.3 SiI followed by adjustment of 
the pH to obtain the 3-hydroxyanthranilic acid derivative. In the case 
where PG and R.sup.6 =Bn, the 3-hydroxyanthranilic acid derivative may be 
obtained by hydrogenolysis with for example H.sub.2 and Pd/C or PtS.sub.2 
and if PG and R.sup.6 =SEM, TBAF may be used. 
Method E Compounds of formula I wherein R.sup.1 =alkyl; R.sup.2 =H or 
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 
##STR42## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula VI 
##STR43## 
wherein X, R.sup.3 and R.sup.4 are as defined in formula I in method E, by 
reductive alkylation with for example an aldehyde corresponding to R.sup.1 
and a reducing agent such as NaCNBH.sub.3 and HCl in a suitable solvent 
such as CH.sub.3 CN, H.sub.2 O or MeOH. Mono- and di-N-alkylated 
derivatives can be separated for example by chromatography. 
Method F Compounds of formula I wherein R.sup.1 and R.sup.2 are the same or 
different and selected from H and alkyl; X is selected from alkylthio, 
halogen and cyano; R.sup.3 is selected from chloro, bromo and iodo; 
R.sup.4 is selected from alkoxy, alkyl, alkylthio, cyano, fluoroalkyl, 
halogen, RSO.sub.2 and RCO wherein R=C.sub.1 -C.sub.5 alkyl, may be 
prepared from compounds of formula VII 
##STR44## 
wherein R.sup.1, R.sup.2, X and R.sup.4 are as defined in formula I in 
method F, by halogenation with for example Br.sub.2, Cl.sub.2 or ICl in 
acetic acid at room- or elevated temperature. Alternatively, VII could be 
halogenated with Br.sub.2 or I.sub.2 and mercuric trifluoroacetate in 
trifluoroacetic acid at room- or elevated temperature. 
Method G Compounds of formula I wherein R.sup.1 and R.sup.2 are the same or 
different and selected from H and alkyl; X is selected from alkylthio, 
halogen and cyano; R.sup.3 is selected from alkoxy, alkyl, alkylthio, 
cyano, fluoroalkyl, halogen, RSO.sub.2 and RCO wherein R=C.sub.1 -C.sub.5 
alkyl; R.sup.4 is selected from chloro, bromo and iodo, may be prepared 
from compounds of formula VIII 
##STR45## 
wherein R.sup.1, R.sup.2, X and R.sup.3 are as defined in formula I in 
method G, by halogenation for example according to method F. 
Method H Compounds of formula I wherein R.sup.1 and R.sup.2 are the same or 
different and selected from H and alkyl; X is selected from bromo, chloro 
and iodo; 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 and fluoroalkyl; or R.sup.3 and R.sup.4 
together form a saturated 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 --N.dbd., --N.dbd.N-- and 
##STR46## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula IX 
##STR47## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in formula I 
in method H, by halogenation for example according to method F. 
INTERMEDIATES 
Method II:a Compounds of formula II wherein X is selected from akylthio, 
arylthio, aryloxy, halogen and cyano; R.sup.3 and 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, 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 
##STR48## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula X 
##STR49## 
wherein X, R.sup.3 and R.sup.4 are as defined in formula II in method 
II:a, by nitration using for example HNO.sub.3 in a solvent such as 
CH.sub.3 NO.sub.2, CH.sub.2 Cl.sub.2 or H.sub.2 O or a mixture of 
HNO.sub.3 and H.sub.2 SO.sub.4. 
Method II:b Compounds of formula II wherein X is selected from chloro, 
bromo and iodo; R.sup.3 and 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 and fluoroalkyl; or 
R.sup.3,R.sup.4 together form a saturated 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 --N--R.sub.7 wherein R.sub.7 =H or alkyl may be prepared 
from compounds of formula XI 
##STR50## 
wherein R.sup.3 and R.sup.4 are as defined in formula II in method II:b, 
by halogenation for example according to method F. 
Method III:a Compounds of formula III wherein R.sup.1 and R.sup.2 =H; X is 
selected from halogen and aryloxy; R.sup.3 and R.sup.4 are the same or 
different and selected from halogen, methyl, fluoroalkyl and Z-R.sup.5 
wherein Z is selected from CH.sub.n, NH.sub.m, O and SO.sub.2 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 
##STR51## 
wherein R.sub.7 =H or alkyl; and PG is selected from alkyl, Bn, MEM and 
MOM; may be prepared from compounds of formula XII 
##STR52## 
wherein X, R.sup.3, R.sup.4 and PG are as defined in formula III in method 
III:a by reacting a compound of formula XII with for example H.sub.2 
O.sub.2 and NaOH in a suitable solvent such as water or dioxan. The pH is 
then adjusted to obtain the 3-hydroxyanthranilic acid derivative. 
Method III:b Compounds of formula III wherein R.sup.1 and R.sup.2 =H; X is 
selected from alkylthio, chloro and fluoro; R.sup.3 and R.sup.4 are the 
same or different and selected from chloro, fluoro, methyl, fluoroalkyl 
and Z-R.sup.5 wherein Z is selected from CH.sub.n, N, O and S wherein n=1 
or 2; and R.sup.5 =alkyl; or R.sup.3 and R.sup.4 together form a saturated 
or unsaturated ring system Y-V-Z wherein Y and Z; 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 
##STR53## 
wherein R.sub.7 =H or alkyl; and PG is selected from alkyl, SEM, MEM and 
MOM; may be prepared from compounds of formula XIII 
##STR54## 
wherein X, R.sup.3, R.sup.4 and PG are as defined in formula III in method 
III:b; DMG=COtBu, CO.sub.2 tBu or COCF.sub.3 ; W=H or Br for example by 
reaction with alkyllithium in a suitable solvent such as tetrahydrofuran 
(THF) at low temperature. The aryllithium derivative is then reacted with 
CO.sub.2 (s), acidified and the DMG group is removed by aqueous HCl at 
elevated temperature. 
Method IV:a Compounds of formula IV wherein R.sup.1 and R.sup.2 are the 
same or different and selected from H and alkyl; X is selected from 
alkylthio, halogen and cyano; R.sup.3 is selected from chloro, bromo and 
iodo; R.sup.4 is selected from alkoxy, alkyl, alkylthio, cyano, 
fluoroalkyl, halogen, RSO.sub.2 and RCO wherein R=C.sub.1 -C.sub.5 alkyl; 
R.sup.6 is for example selected from SEM, MEM, MOM and 
2,2,2-trichloroethyl; may be prepared from compounds of formula XIV 
##STR55## 
wherein R.sup.1, R.sup.2, X, R.sup.4 and R.sup.6 are as defined in formula 
IV in method IV:a; by halogenation for example according to method F. 
Method IV:b Compounds of formula IV wherein R.sup.1 =H or alkyl; R.sup.2 
=alkyl; X is selected from alkylthio, arylthio, aryloxy, halogen and 
cyano; R.sup.3 and 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, 
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 
##STR56## 
wherein R.sub.7 =H or alkyl; R.sup.6 is selected from SEM, MEM, MOM and 
2,2,2-trichloroethyl; may be prepared from compounds of formula XV 
##STR57## 
wherein X, R.sup.3, R.sup.4 and R.sup.6 are as defined in formula IV in 
method IV:b; by alkylation for example according to method E. 
Method V Compounds of formula V 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, chloro, fluoro and cyano; R.sup.3, R.sup.4 are the same 
or different and selected from chloro, fluoro, 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, 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 
##STR58## 
wherein R.sub.7 =H or alkyl; R.sup.6 and PG are selected from alkyl and 
Bn; may be prepared from compounds of formula XVI 
##STR59## 
wherein R.sup.1, R.sup.2, X, R.sup.3, R.sup.4 and PG are as defined in 
formula V in method V and W=Br, I or OSO.sub.2 CF.sub.3 by reacting a 
compound of formula XVI with for example a mixture of Pd(OAc).sub.2, CO, 
1,3-bis(diphenylphosphino)-propane and an alcohol corresponding to R.sup.6 
in a suitable solvent such as DMF or dioxan containing a base such as 
Et.sub.3 N. 
Method VI Compounds of formula VI wherein X is selected from alkylthio, 
arylthio, aryloxy, halogen and cyano; R.sup.3 and 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, 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 
##STR60## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula 
XVII 
##STR61## 
wherein X, R.sup.3 and R.sup.4 are as defined in formula VI in method VI 
and R.sup.6 and PG are selected from alkyl, Bn, SEM, MEM and MOM; by 
deesterifying and deprotecting for example according to method D. 
Method VII:a Compounds of formula VII wherein R.sup.1 and R.sup.2 =H; X is 
selected from alkylthio, arylthio, aryloxy, halogen and cyano; R.sup.4 
=RSO.sub.2 or RCO wherein R=C.sub.1 -C.sub.5 alkyl; may be prepared from 
compounds of formula XVIII 
##STR62## 
wherein X and R.sup.4 are as defined in formula VII in method VII:a; by 
reduction for example according to method A. 
Method VII:b Compounds of formula VII 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.4 =RSO.sub.2 or RCO 
wherein R=C.sub.1 -C.sub.5 alkyl may be prepared from compounds of formula 
XIX 
##STR63## 
wherein R.sup.1, R.sup.2, X and R.sup.4 are as defined in formula VII in 
method VII:b and R.sup.6 and PG are selected from alkyl, Bn, SEM, MEM and 
MOM; by deesterifying and deprotecting for example according to method D. 
Method VIII Compounds of formula VIII wherein R.sup.1 and R.sup.2 are the 
same or different and selected from H and alkyl; X is selected from 
chloro, bromo and iodo; R.sup.3 is selected from RSO.sub.2 and RCO wherein 
R=C.sub.1 -C.sub.5 alkyl, may be prepared from compounds of formula XX 
##STR64## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined in formula VIII in 
method VIII, by halogenation for example according to method F. 
Method IX:a Compounds of formula IX wherein R.sup.1 and R.sup.2 are the 
same or different and selected from H and alkyl; R.sup.3 is selected from 
chloro, bromo and iodo; R.sup.4 is selected from alkoxy, alkyl, alkylthio, 
cyano, fluoroalkyl, halogen, RSO.sub.2 and RCO, may be prepared from 
compounds of formula XXI 
##STR65## 
wherein R.sup.1 , R.sup.2 and R.sup.4 are as defined in formula IX in 
method IX:a, by halogenation for example according to method F. 
Method IX:b Compounds of the formula IX wherein R.sup.1 and R.sup.2 are the 
same or different and selected from H and alkyl; R.sup.3 and 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, 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 
##STR66## 
wherein R.sub.7 =H or alkyl; may be prepared from compounds of formula 
XXII 
##STR67## 
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in formula IX 
in method IX:b and R.sup.6 is selected from alkyl, Bn, SEM, MEM, MOM and 
2,2,2-trichloroethyl, by deesterifying for example according to method C.