Dimeric non-azo naphthalimides and uses for same

Abstract

A class of predominantly hydrophilic 1,8-naphthalimide dyes. The dye contains at least two 1,8-naphthalimide ring systems, joined by a spacer moiety. Each of the 1,8-naphthalimide ring system has a ring nitrogen atom and bears, at the 4 position, an amino nitrogen atom, carrying a hydrogen. The remaining unsatisfied valences, if present, of the ring nitrogen atoms or the amino nitrogen atoms, or all, are occupied by one or more alkyl substituents. Each of the 1,8-naphthalimide ring system is free of an azo substituent and is also free of a nucleofuge. Upon activation by an activating agent in an environment independent of the presence or absence of oxygen, these compounds generate activated species. The activated species can cause structural changes in lipid and any associated proteins and polypeptides, extra- or intra-cellular or transmembrane, leading to polymerization and crosslinking.

What is claimed is:  
     
         1 . A compound comprising: 
 a first 1,8-naphthalimide ring system having a first ring nitrogen atom and bearing, at a first 4-position, a first amino nitrogen atom carrying a first hydrogen, wherein the first 1,8-naphthalimide ring system is free of azo substituent and is free of nucleofuge;    a second 1,8-naphthalimide ring system having a second ring nitrogen atom and bearing, at a second 4-position, a second amino nitrogen carrying a second hydrogen, wherein the second 1,8-naphthalimide ring system is free of azo substituent and is free of nucleofuge; and    a spacer moiety joining the first and the second 1,8-naphthalimide ring systems, wherein the spacer moiety joins the first and the second ring nitrogen atoms, the first and the second amino nitrogen atoms, or the first ring nitrogen atom and the second amino nitrogen atom, and wherein remaining unsatisfied valences, when present, of the first and the second ring nitrogen atoms and of the first and the second amino nitrogen atoms are occupied by one or more alkyl substituents.    
     
     
         2 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers, wherein: 
 R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl. C n H k X m Y p  where X is a Group VIA element selected from the group O, S and Se. Y is a Group VA element selected from the group N. P and As (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦k≦2n+1+p) and wherein they are free of X—X, X—Y or Y—Y bonds: or  
 monocyclic, polycyclic, fused-ring. bridged ring or spirocyclic alicyclic alkyl C n H 2q+p+1 X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched, and wherein they are free of X—X, X—Y or Y-Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine, furan, pyrrole, thiophene, indole, imidazole, oxazole, isozazole, thiazole, benzofuran, benzothiophene. benzimidazole, quinoline. isoquinoline, naphthalene, anthracene, acridine, phenanthrene and their alkylated, halogenated, nitrated or sulfonated derivatives (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+1+p−r) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I, SiZ 3 , BZ 2  or AlZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t+1  (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1≦t≦s, 1≦k≦2n+1+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a poly(α-aminoacid) containing up to 300 residues, (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦b≦20, 1≦s≦20, 1≦t≦s, 1≦k≦2n+1+p−b) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 
 Q is: 
 a straight-chain or branched chain alkyl, C n H k X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, 1≦m≦n, 1≦p≦n 2n<m+p<4n, 1≦k≦2n+p) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 monocyclic, polycyclic, fused-ring, bridged ring or spirocyclic alicyclic alkyl C n H 2q+p X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se. Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched, and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine, furan, pyrrole. thiophene. indole, imidazole, oxazole, isozazole. thiazole, benzofuran, benzothiophene, benzimidazole, quinoline, isoquinoline, naphthalene, anthracene, acridine, phenanthrene and their alkylated, halogenated, nitrated or sulfonated derivatives (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+p−r) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I, SiZ 3 , BZ 2  or AlZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t=1 , (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1≦t≦s, 1≦k≦2n+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, B is a poly(α-aminoacid) containing up to 300 residues, (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦b≦20, 1≦s≦20, 1≦t≦s, 1≦k≦2n+p−b) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         3 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers, wherein: 
 R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl, C n H k X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se. Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦k≦2n+1+p) and wherein they are free of X—X, X—Y or Y—Y bonds: or  
 monocyclic, polycyclic, fused-ring, bridged ring or spirocyclic alicyclic alkyl C n H 2q+1+p X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se. Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched, and wherein they are free of X—X, X—Y or Y—Y bonds: or  
 a straight-chain or branched chain alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine. furan, pyrrole, thiophene, indole, imidazole, oxazole, isozazole. thiazole, benzofuran, benzothiophene, benzimidazole, quinoline. isoquinoline, naphthalene, anthracene, acridine, phenanthrene and their alkylated, halogenated, nitrated or sulfonated derivatives (n=2- 200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+1+p−r) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I. SiZ 3 , BZ 2 , or AlZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t+1  (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1 ≦t≦s, 1≦k≦2n+1+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds: or  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, B is a poly(α-aminoacid) containing up to 300 residues, (n=2- 200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦b≦20, 1≦k≦2n+1+p−b)and wherein they are free of X—X, X—Y or Y—Y bonds;  
 
 Q is: 
 a straight-chain or branched chain alkyl, C n H k X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦k≦2n+p) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 monocyclic, polycyclic, fused-ring, bridged ring or spirocyclic alicyclic alkyl C n H 2q+p X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched, and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine. furan, pyrrole, thiophene, indole, imidazole, oxazole, isozazole. thiazole, benzofuran, benzothiophene, benzimidazole, quinoline, isoquinoline, naphthalene, anthracene, acridine, phenanthrene and their alkylated. halogenated. nitrated or sulfonated derivatives (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+p−r) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I, SiZ 3 , BZ 2  or AlZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t+1  (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1≦t≦s, 1≦k≦2n+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, B is a poly(α-aminoacid) containing up to 300 residues, (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦d≦20, 1≦k≦2n+p−b) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         4 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers wherein: 
 R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl. C n H k X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦k≦2n+1+p) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 monocyclic, polycyclic. fused-ring. bridged ring or spirocyclic alicyclic alkyl C n H 2q−1+p X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched. and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain saturated alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine, furan. pyrrole, thiophene, indole, imidazole. oxazole. isozazole, thiazole, benzofuran, benzothiophene, benzimidazole. quinoline, isoquinoline, naphthalene, anthracene, acridine, phenanthrene and their alkylated. halogenated, nitrated or sulfonated derivatives (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+1+p−r) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 a straight-chain or branched chain saturated alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I, SiZ 3 , BZ 2 , or AIZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t+1  (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1≦t≦s, 1≦k≦2n+1+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, B is a poly(α-aminoacid) containing up to 300 residues. (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦b≦20, 1≦k≦2n+1+p−b)and wherein they are free of X—X, X—Y or Y—Y bonds;  
 
 Q is: 
 a straight-chain or branched chain alkyl, C n H k X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦k≦2n+p) and wherein they are free of X—X, X—Y or Y—Y bonds; or  
 monocyclic, polycyclic, fused-ring, bridged ring or spirocyclic alicyclic alkyl C n H 2q+p X m Y p  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As (n=2-200, q<n, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦m≦n) with saturated or unsaturated side-chains, branched or unbranched, and wherein they are free of X—X, X—Y or Y—Y bonds;  
 a straight-chain or branched chain alkyl, C n H k X m Y p Ar r  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, Ar is an aryl group derived from an aromatic compound selected from the group consisting of benzene, pyridine, furan, pyrrole, thiophene, indole, imidazole, oxazole, isozazole, thiazole. benzofuran, benzothiophene, benzimidazole, quinoline, isoquinoline. naphthalene, anthracene, acridine, phenanthrene and their alkylated, halogenated, nitrated or sulfonated derivatives (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦r≦20, 1≦k≦2n+p≦r) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 a straight-chain or branched chain alkyl, C n H k X m Y p A a  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, A is a substituent selected from the group consisting of F, Cl, Br, I, SiZ 3 , BZ 2  or AlZ 2 , Z is selected from the group consisting of F, Cl, Br, I, OH, OC s H 2t+1  (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦a≦2n, 1≦s≦20, 1≦t≦s, 1≦k≦2n+p−a) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 a straight-chain or branched chain alkyl, C n H k X m Y p B b  where X is a Group VIA element selected from the group consisting of O, S and Se, Y is a Group VA element selected from the group consisting of N, P and As, B is a poly(α-aminoacid) containing up to 300 residues, (n=2-200, 1≦m≦n, 1≦p≦n, 2n<m+p<4n, 1≦d≦20, 1≦k≦2n+p−d) and wherein they are free of X—X, X—Y or Y—Y bonds;  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         5 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers. wherein 1≦n≦20, and R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl. C m H k  (1≦m≦20 : 1≦k≦2m+1): or  
 a straight-chain or branched chain alkyl. C m H k+q O p N q  (1≦m≦20: 1≦k≦2m+1; 2≦2p≦m: 2m≦p+q≦4m), wherein they are free of O—O, N—N or N—O bonds:  
 R″ is: 
 H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 ; and  
 
 X is: 
 O, NH, NCH 3 , NC 2 H 5 ;  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         6 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers. wherein 1≦n≦20, and R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl, C m H k  (1≦m≦20: 1≦k≦2m+1): or  
 a straight-chain or branched chain alkyl. C m H k+q O p N q  (1≦m≦20: 1≦k≦2m+1; 2≦2p≦m; 2m≦p+q≦4m), wherein they are free of O—O, N—N or N—O bonds:  
 R″ is: 
 H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 : and  
 
 X is: 
 O, NH, NCH 3 , NC 2 H 5 :  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         7 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       which is a mixture of stereoisomers, wherein 1≦n≦20, and R and R′ are the same or different and are: 
 a straight-chain or branched chain alkyl, C m H k  (1≦m≦20 ; 1≦k≦2m+1): or  
 a straight-chain or branched chain alkyl. C m H k+q O p N q  (1≦m≦20; 1≦k≦2m+1; 2≦2p≦m; 2m≦p+q≦4m), wherein they are free of O—O , N—N or N—O bonds:  
 R″ is: 
 H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 ; and  
 
 X is: 
 O, NH, NCH 3 , NC 2 H 5 ;  
 or pharmaceutically acceptable salts thereof.  
 
 
     
     
         8 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof.  
     
     
         9 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof.  
     
     
         10 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof.  
     
     
         11 . A composition for cross-linking protein, which comprises an effective amount of a compound of  claim 1 , or its derivative, in combination with an acceptable carrier.  
     
     
         12 . A method for affixing a compound of  claim 1 , or its derivative, to a protein, comprising: 
 admixing an effective amount of the compound of  claim 1  with the protein to give a resultant mixture; and    activating the resultant mixture with a sufficient amount of an activating agent to affix the compound of  claim 1  to the protein.    
     
     
         13 . A method for cross-linking a first protein to a second protein, the method comprising: 
 admixing the first protein and the second protein with an effective amount of a compound of  claim 1 , or its derivative, to give a resultant mixture;    activating the resultant mixture with a sufficient amount of an activating agent to cross-link the first protein to the second protein.    
     
     
         14 . A method of bonding a first body tissue to a second body tissue, comprising: 
 coating a surface of each of the first and the second body tissues with a sufficient amount of a compound of  claim 1 , or its derivative, to give a first coated body tissue and a second coated body tissue;    placing the first coated body tissue and the second coated body tissue in close proximity to give a resultant mixture;    activating the resultant mixture with a sufficient amount of an activating agent to bond the first and the second body tissues.    
     
     
         15 . A method  claim 14 , wherein the first tissue is meniscal cartilage, articular cartilage or cornea.  
     
     
         16 . A method  claim 14 , wherein the second tissue is meniscal cartilage, articular cartilage or cornea.  
     
     
         17 . A bonded tissue, comprising at least two tissues, prepared in accordance with the method of claim  14 .