Isatine derivatives, their preparation and use

A method of treatment with compounds having the formula ##STR1## R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, C.sub.3-7 -cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or C.sub.3-7 -cycloalkyl; R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, CN, CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl; or R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which may be aromatic or partial saturated and which may be substituted with halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR" R"' wherein R" and R"' independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, and R.sup.4 and R.sup.5 have the meanings set forth above, are disclosed, as well as pharmaceutical compositions thereof. Certain of the compounds are novel. The compounds and pharmaceutical compositions containing the compounds are useful in the treatment of central nervous system disorders and especially conditions sensitive to excitatory amino acids.

The present invention relates to a method of treatment with compounds 
having excitatory amino acid antagonizing properties, pharmaceutical 
compositions comprising such compounds, and to novel compounds having 
excitatory amino acid antagonizing properties and to the preparation of 
such compounds. 
It is an object of the present invention to provide a method of treating 
diseases in mammals, including a human, by antagonizing an excitatory 
amino acid in such mammal. 
A second object of the present invention is to provide novel pharmaceutical 
compositions useful for the treatment of diseases in mammals, including a 
human, acting by antagonizing an excitatory amino acid in such mammal. 
A third object of the present invention is to provide novel compounds 
useful for the treatment of diseases in mammals, including a human, acting 
by antagonizing an excitatory amino acid in such mammal. 
BACKGROUND OF THE INVENTION 
It is well known from Wiss, Z. Ernst-Moritz-Arndt-Univ. Greifswald, 
Math.-nat.wiss. Reihe 35, 39-44 (1986) 4, Pharmazie 39, H.10, 713 (1984), 
Pharmazie 87, H.12, 858-861 (1982), Neuroscience Letters 107, 327-330 
(1989), PCT patent application International Publication Number WO 
89/03818, and Khim.-Farm.zh. 23(11), 1349-1352 (1989), that certain of the 
chemical entities comprised within the scope of method of treatment 
according to the present invention are known to possess biological 
activity. 
SUMMARY OF THE INVENTION 
The invention then, inter alia, comprises the following, alone or in 
combination: 
A method of antagonizing the biological effects of an excitatory amino acid 
of a subject in need of such antagonization comprising the step of 
administering to said subject an effective excitatory amino acid 
antagonizing amount of an indole-2,3-dione-3-oxime compound having the 
formula 
##STR2## 
wherein 
R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, C.sub.3-7 
-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, 
C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; 
R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or 
C.sub.3-7 -cycloalkyl; 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 
-alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, 
NO.sub.2, CN, CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R"' 
independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl; or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, 
and R.sup.4 and R.sup.5 have the meanings set forth above, 
a method as above wherein at least one of R.sup.4, R.sup.5, R.sup.6 or 
R.sup.7 is an electron withdrawing substituent such as NO.sub.2, CF.sub.3, 
CN, OCF.sub.3, SO.sub.2 NR"R'", or halogen and R.sup.1, R.sup.2, R.sup.4, 
R.sup.5, R.sup.6, R.sup.7, R", and R'" otherwise have the meanings set 
forth, 
a method as first above wherein R.sup.5 is NO.sub.2, F, CF.sub.3, 
OCF.sub.3, or CN, 
moreover a method of antagonizing the biological effects of an excitatory 
amino acid as first above, wherein the compound is administered in the 
form of a pharmaceutical composition thereof, in which it is present 
together with a pharmaceutically acceptable carrier or diluent, 
and a method of antagonizing the biological effects of an excitatory amino 
acid as second above, wherein the compound is administered in the form of 
a pharmaceutical composition thereof, in which it is present together with 
a pharmaceutically acceptable carrier or diluent, 
further a pharmaceutical composition for use in antagonizing the biological 
effects of an excitatory amino acid of a subject in need of such 
antagonization comprising an effective excitatory amino acid antagonizing 
amount of a compound having the formula 
##STR3## 
R.sup.1 is hydrogen; R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which 
may be branched, or C.sub.3-7 -cycloalkyl; 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 
-alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, 
NO.sub.2, CF.sub.3, OCF.sub.3, CN, or SO.sub.2 NR"R'" wherein R' and R"' 
independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, 
and R.sup.4 and R.sup.5 have the meanings set forth above, at least one of 
R.sup.4, R.sup.6 and R.sup.7 are other than hydrogen when R.sup.5 is not 
other than H, Cl or Br; 
or R.sup.1 is C.sub.1-6 -alkyl which may be branched, C.sub.3-7 
-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, 
C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, CH.sub.2 C(.dbd.NOH)NH.sub.2 ; 
R.sub.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or 
C.sub.3-7 -cycloalkyl; 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 
-alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, 
NO.sub.2, CF.sub.3, OCF.sub.3, CN, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, 
and R.sup.4 and R.sup.5 have the meanings set forth above, at least one of 
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are other than hydrogen when R.sup.1 
is not other than methyl, at least one of R.sup.4 and R.sup.5 are other 
than hydrogen when R.sup.1 is not other than phenyl which may be 
substituted, and at least one of R.sup.4 and R.sup.5 are other than 
hydrogen when R.sup.6 and R.sup.7 together form an additional benzene 
ring, 
and method of antagonizing the biological effects of an excitatory amino 
acid of a subject in need thereof comprising the step of administering to 
said subject a pharmaceutical composition as above, 
further a compound having the formula 
##STR4## 
wherein R.sup.1 is C.sub.1-6 -alkyl which may be branched, C.sub.3-7 
-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, 
C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; R.sup.2 is hydrogen, 
benzyl, C.sub.1-6 -alkyl which may be branched, or C.sub.3-7 -cycloalkyl; 
R.sup.5 is NO.sub.2, F, CN, OCF.sub.3, CF.sub.3, or SO.sub.2 NR"R'" wherein 
R" and R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 
-alkyl; and 
R.sup.4, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl 
which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, 
C.sub.3, OCF.sub.3, CN, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen aralkoxy, aralkyl, or C.sub.1-6 -alkyl, or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, 
SO.sub.2 NR"R'" wherein R" and R'" independently are hydrogen, aralkoxy, 
aralkyl or C.sub.1-6 -alkyl, R.sup.4 has the meaning set forth above, 
and a compound having the formula 
##STR5## 
wherein R.sup.1 is C.sub.1-6 -alkyl which may be branched, C.sub.3-7 
-cycloalkyl, benzyl, acyl, hydroxy, C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 
R' wherein R' is hydrogen or C.sub.1-6 -alkyl which may be branched, 
CH.sub.2 CN, CO.sub.2 CONR.sup.IV R.sup.V wherein R.sup.IV and R.sup.V 
independently are hydrogen or C.sub.1-6 -alkyl, or CH.sub.2 
C(.dbd.NOH)NH.sub.2 ; 
R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or 
C.sub.3-7 -cycloalkyl; 
R.sup.5 is NO.sub.2, F, CN, OCF.sub.3, CF.sub.3, or SO.sub.2 NR"R'" wherein 
R" and R'" independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 
-alkyl; and 
R.sup.4, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl 
which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, 
OCF.sub.3, CF.sub.3, CN, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, 
and R.sup.4 has the meaning set forth above, 
and a compound having the formula 
##STR6## 
wherein 
R.sup.1 is hydrogen, R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which 
may be branched, or C.sub.3-7 -cycloalkyl; R.sup.5 is NO.sub.2, F, 
CF.sub.3, CN, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl; and 
R.sup.4, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl 
which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, 
CF.sub.3, OCF.sub.3, CN, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkyl, aralkoxy or C.sub.1-6 -alkyl, and 
R.sup.4 has the meaning set forth above; and that R.sup.5 is different 
from NO.sub.2 and F when R.sup.1, R.sup.4, R.sup.6 and R.sup.7 are not 
other than hydrogen and R.sup.2 is not other than hydrogen or benzyl; and 
that R.sup.5 is different from NO.sub.2 when R.sup.1, R.sup.2, R.sup.4 and 
R.sup.6 are not other than hydrogen and R.sup.7 is not other than 
NO.sub.2, 
further a compound as above wherein R.sup.4 and R.sup.5 independently are 
hydrogen, F, NO.sub.2, CN, CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein 
R" and R'" independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 
-alkyl, and wherein R.sup.6 and R.sup.7 together form an additional 4 to 7 
membered ring which may be aromatic or partial saturated and which may be 
substituted with halogen, NO.sub.2, CF.sub.3, OCF.sub.3, CN, SO.sub.2 
NR"R'" wherein R" and R'" independently are hydrogen, aralkoxy, aralkyl or 
C.sub.1-6 -alkyl, 
and a compound as above wherein the additional ring formed by R.sup.6 and 
R.sup.7 is substituted with halogen, NO.sub.2, CF.sub.3, CN or SO.sub.2 
NR"R'" wherein R" and R'" independently are hydrogen, aralkoxy, aralkyl or 
C.sub.1-6 -alkyl, 
and a compound as above, which is 
6-(N-methylsulphamoyl)-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime, 
and a compound as above, which is 
5,7-dinitro-1-methyl-1H-indole-2,3-dione-3-(O-methyloxime), 
and a compound as above, which is 
5-(N-benzyloxysulphamoyl)-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3- 
oxime, 
moreover a method of treating a central nervous system disorder in a 
subject in need of such treatment, comprising the step of administering to 
said subject an effective amount of a compound having the formula 
##STR7## 
wherein R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, 
C.sub.3-7 -cycloalkyl, benzyl, phenyl which may be substituted, acyl, 
hydroxy, C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.1-6 C(.dbd.NOH)NH.sub.2 ; R.sup.2 is hydrogen, 
benzyl, C.sub.1-6 -alkyl which may be branched, or C.sub.3-7 -cycloalkyl; 
R.sup.5 is NO.sub.2, F, CF.sub.3, OCF.sub.3, CN, or SO.sub.2 NR"R'" wherein 
R" and R'" independently are hydrogen, aralkyl, aralkoxy or C.sub.1-6 
-alkyl; and 
R.sup.4 R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl which 
may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, CN, 
CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R'" independently 
are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, or R.sup.6 and 
R.sup.7 together form an additional 4 to 7 membered ring which may be 
aromatic or partial saturated and which may be substituted with halogen, 
NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, and 
R.sup.4 has the meaning set forth above; and that R.sup.5 is different 
from NO.sub.2 and F when R.sup.1, R.sup.4, R.sup.6 and R.sup.7 are not 
other than hydrogen and R.sup.2 is not other than hydrogen or benzyl; and 
that R.sup.5 is different from NO.sub.2 when R.sup.1, R.sup.2, R.sup.4 and 
R.sup. 6 are not other than hydrogen and R.sup.7 is not other than 
NO.sub.2, 
further a method of preparing a compound having the formula 
##STR8## 
wherein R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, 
C.sub.3-7 -cycloalkyl, benzyl, phenyl which may be substituted, acyl, 
hydroxy, C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; R.sup.2 is hydrogen, 
benzyl, C.sub.1-6 -alkyl which may be branched, or C.sub.3-7 -cycloalkyl; 
R.sup.5 is NO.sub.2, F, CF.sub.3, CN, OCF.sub.3, or SO.sub.2 NR"R'" wherein 
R" and R'" independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 
-alkyl; and 
R.sup.4 , R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 -alkyl 
which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, NO.sub.2, CN, 
CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R'" independently 
are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, or R.sup.6 and 
R.sup.7 together form an additional 4 to 7 membered ring which may be 
aromatic or partial saturated and which may be substituted with halogen, 
NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, and 
R.sup.4 has the meaning set forth above; and that R.sup.5 is different 
from NO.sub.2 and F when R.sup.1, R.sup.4, R.sup.6 and R.sup.7 are not 
other than hydrogen and R.sup.2 is not other than hydrogen or benzyl; and 
that R.sup.5 is different from NO.sub.2 when R.sup.1, R.sup.2, R.sup.4 
and R.sup.6 are not other than hydrogen and R.sup.7 is not other than 
NO.sub.2, comprising the step of reacting a compound of the formula 
##STR9## 
wherein R.sup.1, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 have the meanings 
set forth above, with a compound having the formula NH.sub.2 OR.sup.2, 
wherein R.sup.2 has the meaning set forth above, 
and moreover the use of a compound having the formula 
##STR10## 
wherein 
R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, C.sub.1-6 
-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, 
C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; 
R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or 
C.sub.3-7 -cycloalkyl; 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 
-alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, 
NO.sub.2, CN.sub.2 CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl; or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl, 
and R.sup.4 and R.sup.5 have the meanings set forth above, for the 
preparation of a medicament useful in the treatment of conditions 
sensitive to an excitatory amino acid, 
and the use as above wherein at least one of R.sup.4, R.sup.5, R.sup.6 or 
R.sup.7 is an electron withdrawing substituent such as NO.sub.2, CF.sub.3, 
CN, OCF.sub.3, SO.sub.2 NR"R'", or halogen and R.sup.1, R.sup.2, R.sup.4, 
R.sup.5, R.sup.6, R.sup.7, R" and R'" otherwise have the meanings set 
forth above, 
and further a method of preparing a pharmaceutical preparation containing 
as active ingredient an effective amount of a compound having the formula 
##STR11## 
wherein 
R.sup.1 is hydrogen, C.sub.1-6 -alkyl which may be branched, C.sub.3-7 
-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, 
C.sub.1-6 -alkoxy, CH.sub.2 CO.sub.2 R' wherein R' is hydrogen or 
C.sub.1-6 -alkyl which may be branched, CH.sub.2 CN, CH.sub.2 CONR.sup.IV 
R.sup.V wherein R.sup.IV and R.sup.V independently are hydrogen or 
C.sub.1-6 -alkyl, or CH.sub.2 C(.dbd.NOH)NH.sub.2 ; 
R.sup.2 is hydrogen, benzyl, C.sub.1-6 -alkyl which may be branched, or 
C.sub.3-7 -cycloalkyl; 
R.sup.4, R.sup.5, R.sup.6, R.sup.7 independently are hydrogen, C.sub.1-6 
-alkyl which may be branched, phenyl, halogen, C.sub.1-6 -alkoxy, 
NO.sub.2, CN, CF.sub.3, OCF.sub.3, or SO.sub.2 NR"R'" wherein R" and R'" 
independently are hydrogen, aralkoxy, aralkyl, or C.sub.1-6 -alkyl; or 
R.sup.6 and R.sup.7 together form an additional 4 to 7 membered ring which 
may be aromatic or partial saturated and which may be substituted with 
halogen, NO.sub.2, CF.sub.3, CN, OCF.sub.3, SO.sub.2 NR"R'" wherein R" and 
R'" independently are hydrogen, aralkoxy, aralkyl or C.sub.1-6 -alkyl, and 
R.sup.4 and R.sup.5 have the meanings set forth above. 
Biological Activity 
The compounds of the invention exhibit valuable biological properties 
because of their strong excitatory amino acid (EAA) (glycine, glutamate, 
quisqualate, ATPA, AMPA, kainate, NMDA) antagonizing properties. 
For example compounds of the invention exhibit strong pharmacological in 
vivo ATPA and quisqualate antagonizing effects demonstrating their utility 
as novel orally-bioavailable excitatory amino acid antagonists, which 
makes them useful in the treatment of for example excitatory amino acid 
dependent psychosis, excitatory amino dependent anoxia, excitatory amino 
acid dependent ischemia, excitatory amino acid dependent convulsions, and 
excitatory amino acid dependent migraine. 
Compounds of the invention will inhibit ATPA-induced rigidity and 
quisqualate or NMDA-induced convulsions with an ED.sub.50 in the range of 
0.1-10.0 mg/kg. Examples of such compounds are 
5,7-dinitro-1-methyl-1H-indole-2,3-dione-3-(O-methyloxime) and 
5,7-dinitro-1-(ethoxy carbonyl 
methyl)-1H-indole-2,3-dione-3-(O-methyloxime). 
Compounds of the invention show potent in vitro affinity for the glutamate 
subreceptors kainate, quisqualate and glycine receptors. These properties 
make the compounds useful in the treatment of human malfunctions related 
to the excitatory amino acids (EAA). 
For example some compounds of the invention exhibit binding at the .sup.3 
H-kainate, .sup.3 H-AMPA and/or .sup.3 H-glycine binding sites with 
IC.sub.50 in the range of 10-100 .mu.M. Examples of such compounds are for 
example 
5-bromo-7-nitro-1H-indole-2,3-dione-3-oxime, 
5-nitro-1H-indole-2,3-dione-3-oxime, 
5,7-dinitro-1H-indole-2,3-dione-3-oxime, 
5,7-dinitro-1-methyl-1H-indole-2,3-dione-3-oxime, 
1H-benz[g]indole-2,3-dione-3-oxime, 
5-nitro-1H-benz[g]indole-2,3-dione-3-oxime, 
5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-oxime. 
5-(N-methylsulphamoyl)-6,7,8,9-tetrahydro-1H-benz[g]indole-2,3-dione-3-oxim 
e, and 
5-(benzyloxysulphamoyl)-6,7,8,9-tetrahydro-1H-benz[g]indole-2,3-dione-3-oxi 
me 
Also the compounds of the invention as a secondary result of their 
EAA-antagonizing properties have been found to antagonize cocaine-induced 
hypermotility. For example the most potent compounds of the invention have 
been found to have an ED.sub.50 in the range of 0.5-1.0 mg/kg in this test 
when administered orally. An example of such a compound is 
5,7-dinitro-1-methyl-1H-indole-2,3-dione-3-(O-methyloxime). 
Furthermore it has been found that some of the compounds of the invention 
are metabolites of other compounds of the invention and that the 
metabolites exhibit biological activity in the same range or are even more 
potent than the precursor compounds of the invention. Accordingly both 
such parent or precursor compounds and such metabolites fall within the 
scope of the invention. Some of the compounds named in the foregoing will 
be recognized as metabolites of precursor compounds named in the 
foregoing, and vise versa. 
Such metabolites are for example: 
N-dealkylated derivatives, 1-N-hydroxyalkyl derivatives, 1-N-hydroxy 
derivatives, 1-N-oxide derivatives, O-dealkylated derivatives, pyrrolo 
ring opened hydrolyzed derivatives, pyrrolo ring opened hydrolyzed and 
decarboxylated derivatives as well as combinations of such metabolisation 
reactions. 
Biological testing 
The above mentioned tests are performed as described in more detail below 
and are based upon the principles also described hereinafter. 
ATPA-induced rigidity 
The selective quisqualate receptor agonist ATPA induces rigidity in female 
NMRI mice at doses between 3 and 15 mg/kg and clonic-tonic seizures and 
death, probably due to respiratory arrest, at doses between 15 and 40 
mg/kg after intravenous (i.v.) administration. 
Method 
ATPA ((RS)-.alpha.-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid) 
was dissolved in distilled water and test compound was dissolved in a 
polyoxyl 40 hydrogenated castor oil (5% Cremophor RH.TM. 40 (BASF)). 
Test compound was administered either i.v. 5, 30 or 120 min before or p.o. 
30 min before an i.v. administration of 15 mg/kg of ATPA to 8 female NMRI 
mice per dose and the number of mice experiencing rigidity 5 min later was 
noted. An ED.sub.50 value was calculated from at least three doses of test 
compound as the dose inhibiting 50% of the mice from having rigidity. 
Quiscualate-induced clonic seizures 
Quisqualate given icv (intracerebroventricular) to DBA/2 mice induces 
clonic seizures which can be inhibited by both NMDA and non-NMDA receptor 
antagonists after i.v. administration. 
Method 
Test compound was given i.v. 5 min before a 20 pg icv administration of 
quisqualate to 10 male DBA/2 mice (weighing 10-12 g) per dose. The number 
of mice experiencing clonic seizures within the next 2 min was noted. An 
ED.sub.50 value was calculated as the dose inhibiting 50% of the mice from 
having clonic seizures. 
NMDA-induced clonic seizures 
NMDA give icv to NMRI mice induces clonic seizures which can be inhibited 
by NMDA receptor antagonists. 
Method 
Test compound was given i.v. 5 min before a 0.5 .mu.g icv administration of 
NMDA to 10 male NMRI mice per dose. The number of mice experiencing clonic 
seizures within the next 2 min was noted. An ED.sub.50 value was 
calculated as the dose inhibiting 50% of the mice from having clonic 
seizures. 
Cocaine-induced hypermotility 
Quisqualate and kainate administered locally induce an increase in dopamine 
release in nucleus accumbens and nucleus caudatus accompanied by 
stereotype behaviour such as hyperlocomotion, rearing, sniffing and 
grooming. These effects can be inhibited by selective quisqualate 
antagonists administered locally by the micro-dialyses method. 
Also the dopamine uptake inhibitor cocaine administered s.c. induce 
hypermotility which can be inhibited by an administration of the glutamate 
antagonist GDEE into nucleus accumbens. 
For these reasons (and others) it has been concluded that non-NMDA 
receptors regulate the release of dopamine in nucleus accumbens and that 
non-NMDA receptor antagonists can alleviate the symptoms of psychosis. 
Method 
Test compound was administered orally at doses of 0.1, 1, 10 and 30 mg/kg 
30 min before the administration of 25 mg/kg cocaine i.p. to female NMRI 
mice and the locomotor activity of 2 mice per box was measured for the 
next 2 hours by use of 8 infrared photobeams per box. The mice had been 
adapted to the box for at least 16 hours to avoid exploratory motility 
(neophobia). 
The quisqualate binding assay was performed as described by T. Honore et 
al., Neuroscience Letters 54, 27-32 (1985). 
The kainate binding assay was performed as described by T. Honore et al., 
Neuroscience Letters 65, 47-52 (1986). 
The glycine binding assay was performed as described by W. Frost White et 
al., Journal of Neurochemistry 53(2), 503-512 (1989). 
Pharmaceutical Compositions 
The compounds of the invention, together with a conventional adjuvant, 
carrier, or diluent, may be placed into the form of pharmaceutical 
compositions and unit dosages thereof, and in such form may be employed as 
solids, such as tablets or filled capsules, or liquids such as solutions, 
suspensions, emulsions, elixirs, or capsules filled with the same, all for 
oral use, in the form of suppositories for rectal administration; or in 
the form of sterile injectable solutions for parenteral (including 
subcutaneous) use. Such pharmaceutical compositions and unit dosage forms 
thereof may comprise conventional ingredients in conventional proportions, 
with or without additional active compounds or principles, and such unit 
dosage forms may contain any suitable effective amount of the active 
ingredient commensurate with the intended daily dosage range to be 
employed. Tablets containing ten (10) milligrams of active ingredients or, 
more broadly, 0.1 to one hundred (100) milligrams, per tablet, are 
accordingly suitable representative unit dosage forms. 
Solid forms of pharmaceutical compositions for p.o. administration and 
injectable solutions are preferred. 
Method of Treating 
The compounds of this invention are extremely useful in the treatment of 
central nervous system disorders related to their biological activity. The 
compounds of this invention may accordingly be administered to a subject, 
including a human, in need of treatment, alleviation, or elimination of an 
indication associated with the biological activity of the compounds. This 
includes especially excitatory amino acid dependent psychosis, excitatory 
amino acid dependent anoxia, excitatory amino acid dependent ischemia, 
excitatory amino acid dependent convulsions and excitatory amino acid 
dependent migraine. Suitable dosage ranges are 0.1 to 1000 milligrams 
daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, 
dependent as usual upon the exact mode of administration, form in which 
administered, the indication toward which the administration is directed, 
the subject involved and the body weight of the subject involved, and 
further the preference and experience of the physician or veterinarian in 
charge. 
Chemical Examples 
Some compounds of the invention are old, and others are novel chemical 
entities. In any-way the compounds of the invention may be prepared 
according to chemical methods which are well known.