Anthranilamides and their use as pharmaceutical agents

Abstract

Substituted anthranilamides and use thereof as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis as well as their intermediate products for the production of anthranilamides are described.

1 - 13 . (canceled)  
     
     
         14 . A method for treating treating a tumor; psoriasis; arthritis; an eye disease; a renal disease; a fibrotic disease; ascites; or a VEGF-induced edema; which comprises administering to a patient in need thereof an effective treating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       in which 
 A is —NR 7 —,  
 W is oxygen, sulfur, two hydrogen atoms or the group NR 8 ,  
 Z stands for a bond, —NR 10 —, ═N—, branched or unbranched C 1-12 -alkyl or the group  
                     
 wherein m, n and o stand for 0-3,  
 R a , R b , R c , R d , R e , R f , independently of one another, stand for hydrogen, fluorine, C 1-4  alkyl or the group ═NR 11 , and/or R a  and/or R b  can form a bond with R c  and/or R d , or R e  can form a bond with R e  and/or R f , or up to two of radicals R a -R f  can close a bridge with up to 3 C-atoms each to form R 1  or to form R 7 ,  
 R 1  stands for branched or unbranched C 1 -C 12 -alkyl or C 2-12 -alkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl; and/or NR 12 R 13 ; or C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, C 1-6 -alkyl and/or NR 12 R 13 ; or aryl or hetaryl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl and/or C 1-6 -alkyl that is substituted in one or more places with halogen,  
 X stands for C 1-6 -alkyl,  
 R 2  stands for C 3-10  alicyclene, alicyclic ketones or non-aromatic heterocyclic compounds that are unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -acyl, amino, C 1-6 -carboxyalkylamino and/or hydroxy, and  
 D means N or C—R 3 ,  
 E means N or C—R 4 ,  
 F means N or C—R 5 , and  
 G means N or C—R 6 , whereby  
 R 3 , R 4 , R 5  and R 6  stand for hydrogen, halogen or C 1-6 -alkoxy, C 1-6 -alkyl or C 1-6 -carboxyalkyl that is unsubstituted or optionally substituted in one or more places with halogen,  
 R 7  stands for hydrogen or C 1-6 -alkyl or forms a bridge with up to 3 ring members with R a -R f  from Z,  
 R 8 , R 9 , R 10  and R 11  stand for hydrogen or C 1-6 -alkyl,  
 R 12  and R 13  stand for hydrogen or C 1-6 -alkyl or form a ring that can contain another heteroatom,  
 or a pharmaceutically acceptable isomer or salt thereof,  
 but excluding compounds wherein, simultaneously:  
 A is —N(R 7 )—,  
 W is oxygen, or sulfur,  
 Z is a bond,  
 R 1  is C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, C 1-6 -alkyl and/or NR 12 R 13 ; or aryl or hetaryl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl and/or C 1-6 -alkyl that is substituted in one or more places with halogen,  
 X is C 1-6 -alkyl,  
 R 2  is a C 3-10  cycloalkyl, cycloalkene, alicyclic ketone or non-aromatic heterocyclic group that is unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -acyl, amino, C 1-6 -carboxyalkylamino and/or hydroxy,  
 D is C—R 3 ,  
 E is C—R 4 ,  
 F is C—R 5 , and  
 G is C—R 6 ,  
 wherein R 3 , R 4 , R 5  and R 6  are hydrogen, halogen or C 1-6 -alkoxy, C 1-6 -alkyl or C 1-6 -carboxyalkyl that is unsubstituted or optionally substituted in one or more places with halogen,  
 R 7  is hydrogen or C 1-6 -alkyl,  
 R 9  is hydrogen or C 1-6 -alkyl,  
 R 12  and R 13  are hydrogen or C 1-6 -alkyl or together form a ring that can contain another heteroatom.  
 
     
     
         15 . A method of  claim 14 , wherein the method is for treating rheumatoid arthritis, hemangioma, angiofibroma, diabetic retinopathy, a neovascular glaucoma, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, a transplant rejection, a glomerulopathy, cirrhosis of the liver, a mesangial cell proliferative disease, arteriosclerosis, or an injury to nerve tissue.  
     
     
         16 . A method of  claim 14 , wherein the method is for treating a tumor.  
     
     
         17 . A method for treating treating a psoriasis; arthritis; an eye disease; a renal disease; a fibrotic disease; ascites; or a VEGF-induced edema; which comprises administering to a patient in need thereof an effective treating amount of a compound of formula I:  
       
         
           
           
               
               
           
         
       
       in which 
 A is —N(R 7 )—,  
 W is oxygen, or sulfur,  
 Z is a bond,  
 R 1  is C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, C 1-6 -alkyl and/or NR 12 R 13 ; or aryl or hetaryl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl and/or C 1-6 -alkyl that is substituted in one or more places with halogen,  
 X is C 1-6 -alkyl,  
 R 2  is a C 3-10  cycloalkyl, cycloalkene, alicyclic ketone or non-aromatic heterocyclic group that is unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -acyl, amino, C 1-6 -carboxyalkylamino and/or hydroxy,  
 D is C—R 3 ,  
 E is C—R 4 ,  
 F is C—R 5 , and  
 G is C—R 6 ,  
 wherein R 3 , R 4 , R 5  and R 6  are hydrogen, halogen or C 1-6 -alkoxy, C 1-6 -alkyl or C 1 -carboxyalkyl that is unsubstituted or optionally substituted in one or more places with halogen,  
 R 7  is hydrogen or C 1-6 -alkyl,  
 R 9  is hydrogen or C 1-6 -alkyl,  
 R 12  and R 13  are hydrogen or C 1-6 -alkyl or together form a ring that can contain another heteroatoms,  
 or a pharmaceutically acceptable isomer or salt thereof.  
 
     
     
         18 . A method of  claim 17 , wherein the method is for treating rheumatoid arthritis, hemangioma, angiofibroma, diabetic retinopathy, a neovascular glaucoma, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, a transplant rejection, a glomerulopathy, cirrhosis of the liver, a mesangial cell proliferative disease, arteriosclerosis, or an injury to nerve tissue  
     
     
         19 . A method of  claim 14 , wherein, in formula I, Z is a bond and R 7  is hydrogen or C 1-6 -alkyl.  
     
     
         20 . A method of  claim 14 , wherein, in formula I, W is oxygen, Z is a bond, and R 7  is hydrogen or C 1-6 -alkyl.  
     
     
         21 . A method of  claim 14 , wherein, in formula I: 
 R 1  is phenyl or isoquinolinyl that is optionally substituted in one or more places with halogen and/or trifluoromethyl, and    R 2  is cyclohexyl, piperidinyl or oxocyclohexyl that is unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkylenedioxy or phenyl.    
     
     
         22 . A method of  claim 17 , wherein, in formula I: 
 R 1  is phenyl or isoquinolinyl that is optionally substituted in one or more places with halogen and/or trifluoromethyl, and    R 2  is cyclohexyl, piperidinyl or oxocyclohexyl that is unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxycarbonyl, C 1-6 -alkylenedioxy or phenyl.    
     
     
         23 . A method of  claim 14 , wherein, in formula I: 
 D is C—R 3 ,    E is C—R 4 ,    F is C—R 5 , and    G is C—R 6 .    
     
     
         24 . An intermediate compound selected from the group consisting of: 
 4,4-(ethylenedioxy)cyclohexanecarbaldehyde,    tetrahydropyranyl-4-carbaldehyde,    N-BOC-4-formylpiperidine,    N-benzylpiperidine-4-carbaldehyde,    2-(4,4-ethylenedioxy)cyclohexyl-methyl)-aminobenzoic acid methyl ester,    6-fluoro-2-(tetrahydropyran-4-yl)methyl-aminobenzoic acid methyl ester,    2-(tetrahydropyran-4-yl)methylaminobenzoic acid-methyl ester,    2-(1-benzylpiperidin-4-yl)methylaminobenzoic acid methyl ester,    N-benzylpiperidine-4-carboxylic acid ethyl ester,    2-cyclohexylmethylaminonicotinic acid ethyl ester and    N-cyclohexylmethylisatoic acid anhydride.    
     
     
         25 . A method for preparing a compound of the formula I:  
       
         
           
           
               
               
           
         
       
       in which 
 A is —NR 7 —,  
 W is oxygen, sulfur, two hydrogen atoms or the group —NR 8 ,  
 Z stands for a bond, —NR 10 —, ═N—, branched or unbranched C 1-12 -alkyl or the group  
                     
 wherein m, n and o stand for 0-3,  
 R a , R b , R c , R d , R e , R f , independently of one another, stand for hydrogen, fluorine, C 1-4  alkyl or the group ═NR 11 , and/or R a  and/or R b  can form a bond with R c  and/or R d , or R c  can form a bond with R e  and/or R f , or up to two of radicals R a -R f  can close a bridge with up to 3 C-atoms each to form R 1  or to form R 7 ,  
 R 1  stands for branched or unbranched C 1 -C 12 -alkyl or C 2-12 -alkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl; and/or NR 2 R 3 ; or C 3-10 -cycloalkyl or C 3-10 -cycloalkenyl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, C 1-6 -alkyl and/or NR 12 R 13 ; or aryl or hetaryl that is optionally substituted in one or more places with halogen, hydroxy, C 1-6 -alkyloxy, aralkyloxy, C 1-6 -alkyl and/or C 1-6 -alkyl that is substituted in one or more places with halogen,  
 X stands for C 1-6 -alkyl,  
 R 2  stands for C 3-10  alicyclene, alicyclic ketones or non-aromatic heterocyclic compounds that are unsubstituted or optionally substituted in one or more places with halogen, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -acyl, amino, C 1-6 -carboxyalkylamino and/or hydroxy, and  
 D means N or C—R 3 ,  
 E means N or C—R 4 ,  
 F means N or C—R 5 , and  
 G means N or C—R 6 , whereby  
 R 3 , R 4 , R 5  and R 6  stand for hydrogen, halogen or C 1-6 -alkoxy, C 1-4 -alkyl or C 1-6 -carboxyalkyl that is unsubstituted or optionally substituted in one or more places with halogen,  
 R 7  stands for hydrogen or C 1-6 -alkyl or forms a bridge with 1 to 3 ring members with R a -R f  from Z or with R 1 ,  
 R 8 , R 9 , R 10  and R 11  stand for hydrogen or C 1-6 -alkyl,  
 R 12  and R 13  stand for hydrogen or C 1-6 -alkyl or form a ring that can contain another heteroatom,  
 or a pharmaceutically acceptable isomer or salt thereof;  
 which method comprises reacting a compound of  claim 24  as in intermediate in the preparation of the compound of formula I.  
 
     
     
         26 . A method of  claim 14 , wherein the compound of formula I is administered in a daily dose of 0.5-1000 mg.  
     
     
         27 . A method of  claim 14 , wherein the compound of formula I is administered in a daily dose of 50-200 mg.  
     
     
         28 . A method of  claim 17 , wherein the compound of formula I is administered in a daily dose of 0.5-1000 mg.  
     
     
         29 . A method of  claim 17 , wherein the compound of formula I is administered in a daily dose of 50-200 mg.