Angiogenesis inhibitors

Abstract

An object of the present invention is to find new pharmacological actions of urea compounds having structure represented by the general formula [1]. The urea compounds having the structure represented by the general formula [1] have excellent angiogenesis inhibitory actions. [wherein “A” is —(NR 4 )—, —(CR 5 R 6 )— or —O—, “B” is alkylene or alkenylene, R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen, alkyl, alkenyl, adamantylalkyl or the like, R 3 is aryl or an unsaturated heterocycle, and X is oxygen or sulfur.]

1 . A method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of a compound represented by the following general formula [1] or a salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein “A” is —(NR 4 )—, —(CR 5 R 6 )— or —O—;
 “B” is alkylene or alkenylene which can contain —O—, —S—, —(NR 7 )—, —CO—, —N═ or the following group in its chain, 
 
       
         
           
           
               
               
           
         
       
       wherein the alkylene and alkenylene can be substituted by hydroxyl, alkoxy, cycloalkyl, aryl, siloxy or a saturated or unsaturated heterocycle and can be bonded to “A” to form a saturated heterocycle;
 R 1 , R 2 , R 4 , R 5  and R 6 , the same or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxyl, or amino, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl can be substituted by halogen, hydroxyl, amino, cycloalkyl adamantyl aryl, carboxyl alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, cyano or a saturated or unsaturated heterocycle; 
 R 1  and R 2 , R 2  and R 4 , R 2  and R 6 , and R 2  and R 6  each can form a saturated or unsaturated heterocycle; 
 R 3  is aryl or an unsaturated heterocycle; 
 R 7  is hydrogen or alkyl; 
 X is ═O or ═S; 
 n is an integer of 1 to 5; and 
 hydrogen in each amino, hydroxyl and aminocarbonyl can be substituted by alkyl, cycloalkyl, adamantyl, adamantylalkyl, aryl, arylalkyl, acyl, alkoxyalkyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkyloxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, halogenoalkyloxycarbonyl, imidazolylcarbonyl a saturated or unsaturated heterocycle, or alkyl substituted by a saturated or unsaturated heterocycle. 
 
     
     
         2 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein R 3  is a pyridine ring. 
     
     
         3 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein at least one of R 1 , R 2 , R 4 , R 5  and R 6  is adamantylalkyl, adamantyloxyalkyl, adamantylaminoalkyl or adamantylaminocarbonylalkyl. 
     
     
         4 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein at least one of R 1  and R 2  is adamantylalkyl, adamantyloxyalkyl adamantylaminoalkyl or adamantylaminocarbonylalkyl. 
     
     
         5 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein at least one of R 1  and R 2  is adamantylalkyl. 
     
     
         6 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein
 “A” is —(NR 4 )—, —(CR 5 R 6 )— or —O—;   “B” is alkylene or alkenylene which can contain in its chain —O—, —S—, —(NR 7 )—, —CO—, —N═ or the following group,   
       
         
           
           
               
               
           
         
       
       wherein the alkylene can be substituted by hydroxyl, alkoxy, aryl siloxy or a saturated or unsaturated heterocycle and can be bonded to “A” to form a saturated heterocycle;
 R 1  is hydrogen, alkyl, alkenyl, alkyl, cycloalkyl, cycloalkenyl, hydroxyl or amino, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl can be substituted by halogen, hydroxyl, amino, cycloalkyl, aryl, carboxyl, alkoxycarbonyl, alkylaminocarbonyl, adamantyl, aryloxycarbonyl, cyano or a saturated or unsaturated heterocycle, and hydrogen in each amino, hydroxyl and aminocarbonyl can be substituted by alkyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxycarbonyl, cycloalkoxycarbonyl, arylalkoxycarbonyl, halogenoalkyloxycarbonyl, imidazolylcarbonyl, an unsaturated heterocycle or alkyl substituted by an unsaturated heterocycle; 
 R 2  is adamantylalkyl, adamantyloxyalkyl, adamantylaminoalkyl or adamantylaminocarbonylalkyl; 
 R 3  is an unsaturated heterocycle; 
 R 4  is hydrogen, alkyl, adamantylalkyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, amino, alkylamino, acylamino or alkoxycarbonylamino; 
 R 5  and R 6 , the same or different, are hydrogen, alkyl, amino or alkoxycarbonylamino; 
 R 7  is hydrogen or alkyl; 
 X is ═O or ═S; and 
 n is an integer of 1 to 5. 
 
     
     
         7 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 6 , wherein R 2  is adamantylalkyl, and R 3  is a pyridine ring. 
     
     
         8 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 6 , wherein
 “A” is —(NR 4 )—, —(CR 5 R 6 )— or —O—;   “B” is alkylene or alkenylene which can contain in its chain —S— or the following group,   
       
         
           
           
               
               
           
         
         R 1  is alkyl or alkenyl wherein the alkyl can be substituted by halogen or amino, and further the amino can be substituted by alkyl, acyl, arylalkyloxycarbonyl, cycloalkyloxycarbonyl or alkoxycarbonyl; 
         R 2  is adamantylalkyl; 
         R 3  is a pyridine ring; 
         R 4  is hydrogen; 
         R 5  and R 6  are hydrogen; 
         X is ═O; and 
         n is an integer of 1 to 5. 
       
     
     
         9 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 1 , wherein
 “A” is —(NR 4 )—, (CR 5 R 6 )— or —O—;   “B” is alkylene or alkenylene which can contain in its chain —O—, —S—, —(NR 7 )—, —N═ or the following group,   
       
         
           
           
               
               
           
         
       
       wherein the alkylene can be substituted by hydroxyl, alkoxy, aryl or a saturated or unsaturated heterocycle and can be bonded to “A” to form a saturated heterocycle;
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, hydroxyl or amino, wherein the alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl can be substituted by halogen, hydroxyl, amino, cycloalkyl, aryl, carboxyl, alkoxycarbonyl aryloxycarbonyl, aminocarbonyl, cyano or a saturated or unsaturated heterocycle, and hydrogen in each amino, hydroxyl and aminocarbonyl can be substituted by alkyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxycarbonyl cycloalkyloxycarbonyl, arylalkoxycarbonyl an unsaturated heterocycle or alkyl substituted by an unsaturated heterocycle; 
 R 2  is alkyl, alkenyl cycloalkyl, cycloalkylalkyl or aryalkyl; 
 R 3  is a pyridine ring; 
 R 4  is hydrogen, alkyl, adamantylalkyl, carboxyalkyl, alkoxycarbonylalkyl, amino, alkylamino, acylamino or alkoxycarbonylamino; 
 R 5  and R 6 , the same or different, are hydrogen or alkyl; 
 R 7  is hydrogen or alkyl; 
 X is ═O or ═S; and 
 n is an integer of 1 to 5. 
 
     
     
         10 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 9 , wherein
 “A” is —(NR 4 )— or —(CR 5 R 6 )—;   “B” is alkylene or alkenylene;   R 1  is alkyl or alkenyl, wherein the alkyl can be substituted by halogen, amino, cycloalkyl aryl imidazole or a pyridine ring, and further the amino can be substituted by alkyl, acyl alkoxycarbonyl, cycloalkyloxycarbonyl or arylalkoxycarbonyl;   R 2  is alkyl, alkenyl or arylalkyl;   R 3  is a pyridine ring;   R 4  is hydrogen;   R 5  and R 6  are hydrogen; and   X is ═O.   
     
     
         11 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 10 , wherein R 1  is alkyl, and R 2  is alkyl or arylalkyl. 
     
     
         12 . The method of treating diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis or corneal neovasculature, comprising administering to a patient an effective amount of the compound or a salt thereof as claimed in  claim 9 , wherein
 “A” is —(NR 4 )— or —(CR 5 R 6 )—;   “B” is alkylene or alkenylene;   R 1  is alkyl alkenyl or cycloalkyl, wherein the alkyl can be substituted by halogen, hydroxyl, amino, cycloalkyl, aryl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, a pyridine ring or a thiophene ring, and further hydrogen in each amino, hydroxyl and aminocarbonyl can be substituted by alkyl, aryl, arylalkyl, acyl, alkoxycarbonyl, cycloalkyloxycarbonyl or arylalkoxycarbonyl;   R 2  is cycloalkyl or cycloalkylalkyl;   R 3  is a pyridine ring;   R 4  is hydrogen;   R 5  and R 6  are hydrogen; and   X is ═O.