Indole-2,3-dione-3-oxime derivatives

Abstract

The present invention relates to novel indole-2,3-dione-3-oxime derivatives capable of antagonising the effect of excitatory amino acids, such as glutamate. More specifically the novel indole-2,3-dione-3-oxime derivatives of the invention may be described by general formula (I), wherein R3 represents "Het", or a group of formula (II), wherein "Het" represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, at least one of R31, R32, and R33 independendy represents hydrogen, alkyl, or hydroxyalkyl, and at least one of R31, R32, and R33 independently represents (CH2)nR34; wherein R34 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, CONR35R36, or "Het"; wherein n is 0, 1, 2, or 3; and R5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted. "A" represents a ring of five to seven atoms fused with the benzo ring at the positions marked "a" and "b", and formed by the following bivalent radicals: a-NR6-CH2-CH2-b; a-CH2-NR6-CH2-b; a-CH2-CH2-NR6-b; a-NR6-CH2-CH2-H2-b; a-CH2-NR6-CH2-CH2-b; a-CH2-CH2-NR6-CH2-b; a-CH2-CH2-CH2-NR6-b; a-NR6-CH2-CH2-CH2-CH2-b; a-CH2-NR6-CH2-CH2-CH2-b; a-CH2-CH2-NR6-CH2-CH2-b; a-CH2&mdas

What is claimed is:  
     
       1. A compound represented by the formula (I):                    
       wherein 
       R 1  represents hydrogen or lower alkyl;  
       R 3  represents a lactone ring of the formula ( VI ):                    
         wherein m is  2 , or    
         R   3    represents  a group of the formula                    
       wherein 
       R 31  and R 33  independently of each other represent hydrogenor , lower alkyl, or hydroxyalkyl; and  
       R 34  represents carboxy, alkoxycarbonyl, cycloalkylalkoxycarbonyl, a group of the formula —CONR 35 R 36 , or Het; wherein  
       R 35  and R 36  represent hydrogen, lower alkyl, hydroxyalkyl, phenyl, or a group of the formula —CH 2 —R 37 , wherein R 37  represents carboxy or alkoxycarbonyl; or  
       R 35  and R 36  together with the N-atom to which they are attached form a saturated 6-membered heterocyclic ring, optionally containing one additional O atom; and  
       Het represents a saturated or unsaturated 5-membered monocyclic, heterocyclic ring, containing N and/or O as the heteroatom, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, and oxo;  
       R 5  represents a phenyl group, which may be substituted once with a group of the formula —SO 2 NR 51 R 52 ; wherein R 51  and R 52  each independently represents hydrogen or lower alkyl; or  
       R 51  and R 52  together with the N-atom to which they are attached form a saturated 6-membered monocyclic, heterocyclic ring; and  
       R 6  represents hydrogen or lower alkyl;  
       or a pharmaceutically acceptable salt thereof.  
     
     
       2. The compound according to  claim 1 , wherein R 3  represents a lacton ring of the formula (VI):                    
       wherein m is 2. 
     
     
       3. The compound according to  claim 1 , wherein 
       R 3  represents a lactone of the formula (VII):                    
       wherein p is 2. 
     
     
       4. A compound according to  claim 1 , which is 
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(3-(2-oxo)tetrahydrofuryl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3,dione-3-O-(5-(5-(4-bromo-3-methoxy)isoxazolylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(5-(4-bromo-3-ethoxy)isoxazolylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-(N,5-dimethyl-3-oxo)isoxazolylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-(N-methyl-5-tertbutyl-3-oxo)isoxazolylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-(5-methyl-3-methoxy)isoxazolylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6-7-8-9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-(5-methyl-3-ethoxy)isoxazolylmethyl)oxime;  
       1-methyl-8-methyl-5-phenyl-6,7,8,9-tetrahydro-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(carboxymethyl) oxime;  
       1-methyl-8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;  
       1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl) phenyl)-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;  
       1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl) phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-ethoxycarbonyl-1-methylethyl)oxime;  
       1-methyl-8-methyl-5-(4-(N,N-dimethylsulfamoyl) phenyl-6,7,8,9-tetrahydro-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-carboxy-1-methylethyl) oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl) oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(isopropoxycarbonylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(1-ethoxycarbonyl-1-methyl)ethyloxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(t,butoxycarbonylmethyl) oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(N,N-dimethylcarbamoylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(N-methylcarbamoylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(N-phenylcarbamoylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(N,N-di(2-hydroxyethyl) carbamoylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(morpholinocarbonylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethylcarbamoylmethyl)oxime;  
       8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]isoquinoline-2,3-dione-3-O-(N,N-di(2-(N,N-diethylamino)ethyl)carbamoyl)oxime; 
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(carboxymethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9 -tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(2-hydroxyethyl)oxime; 
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(1-carboxy-1-methylethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(ethoxycarbonylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(cyclopropylmethoxycarbonylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(isopropoxycarbonylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(N,N-dimethylcarbamoylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(piperidinocarbonylmethyl)oxime;  
       8-methyl-5-(4-(piperdinosulfonyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(piperidinocarbonylmethyl)oxime;  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(morpholinocarbonylmethyl)oxime; or  
       8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime;  
       or a pharmaceutically acceptable salt hereof  thereof.  
     
     
       5. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims  1 - 4  together with a pharmaceutically acceptable excipient, carrier or diluent. 
     
     
       6. A method of preparing a compound according to any of claims  1 - 4  which method comprises the step of reacting a compound having the formula:                    
       wherein R 1 , R 5 , and R 6  have the meanings set forth in  claim 1  with a compound having the formula                    
       wherein R 3  and m have the meanings set forth in  claim 1 , optionally followed by converting the thus obtained compound to another compound of any of claims  1 - 4  or to a pharmaceutically acceptable salt thereof.