Cationic pillararene compounds and compositions

Abstract

Cationic pillar[n]arenes, e.g., positively charged poly-ammonium, poly-phosphonium and poly-imidazolium pillar[ 5 - 6 ]arene derivatives are capable of inhibiting or preventing biofilm formation, and facilitating existing biofilm decomposition. A composition for inhibiting or disrupting biofilm, e.g., bacterial or fungal biofilm, formation, or reducing biofilm, can include a pharmaceutically acceptable carrier, and a cationic pillar[n]ene.

What is claimed is: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —CR 6 R 7 —, wherein R 6  and R 7  each independently is H, halogen, —COR 8 , —COOR 8 , —OCOOR 8 , —OCON(R 8 ) 2 , —CN, —NO 2 , —SR 8 , —OR 8 , —N(R 8 ) 2 , —CON(R 8 ) 2 , —SO 2 R 8 , —SO 3 H, —S(═O)R 8 , or (C 1 -C 8 )alkyl optionally substituted by one or more groups each independently selected from the group consisting of —COR 8 , —COOR 8 , —OCOOR 8 , —OCON(R 8 ) 2 , —CN, —NO 2 , —SR 8 , —OR 8 , —N(R 8 ) 2 , —CON(R 8 ) 2 , —SO 2 R 8 , —SO 3 H, —S(═O)R 8 , —N + (R′) 3  and —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 6 )alkyl, phenyl, benzyl, or heterocyclyl, or two R's together with the N atom to which they are attached form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from the group consisting of O, S and N and optionally further substituted at the additional N atom; 
         R 2  and R 3  each independently is H, halogen, or (C 1 -C 8 )alkyl optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 8 , —COOR 8 , —OCOOR 8 , —OCON(R 8 ) 2 , —CN, —NO 2 , —SR 8 , —OR 8 , —N(R 8 ) 2 , —CON(R 8 ) 2 , —SO 2 R 8 , —SO 3 H, —S(═O)R 8 , —N + (R′) 3  and —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 6 )alkyl, phenyl, benzyl, or heterocyclyl, or two R's together with the N atom to which they are attached form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from the group consisting of O, S and N and optionally further substituted at the additional N atom; 
         R 4  and R 5  each independently is selected from the group consisting of (C 1 -C 10 )alkylene, (C 2 -C 10 )alkenylene, and (C 2 -C 10 )alkynylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 8 , —COOR 8 , —OCOOR 8 , —OCON(R 8 ) 2 , —CN, —NO 2 , —SR 8 , —OR 8 , —N(R 8 ) 2 , —CON(R 8 ) 2 , —SO 2 R 8 , —SO 3 H, —S(═O)R 8 , (C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, heteroaryl, and (C 1 —C 4 )alkylene-heteroaryl, and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, or by one or more groups each independently selected from the group consisting of —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, —N(C 6 -C 10 aryl)-, (C 6 -C 10 )arylenediyl, and heteroarylenediyl; 
         R 8  each independently is H or (C 1 -C 8 )alkyl; 
         Y each independently is (i) a cation derived from a nitrogen-containing group and selected from the group consisting of an ammonium [—N + (R′) 3 ], hydrazinium [—N + (R′) 2 —N(R′) 2 ], ammoniumoxy [—N + (R′) 2 →O], iminium [—N + (R′) 2 ═C<], amidinium [—N + (R′) 2 —C(R′)═NR′], and guanidinium [—N + (R′) 2 —C(═NR′)—N(R′) 2 ]; (ii) a cation derived from a nitrogen-containing mono- or polycyclic heteroaromatic group and selected from the group consisting of pyrazolium, oxazolium, thiazolium, pyridinium, pyrimidinium, quinolinium, isoquinolinium, 1,2,4-triazinium, 1,3,5-triazinium, and purinium, optionally substituted by one or more groups each independently selected from the group consisting of halogen, (C 1 -C 6 )alkyl, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, and —S(═O)H; or (iii) a cation derived from an onium group not containing nitrogen and selected from the group consisting of phosphonium [—P + (R′) 3 ], arsonium [—As + (R′) 3 ], oxonium [—O + (R′) 2 ], sulfonium [—S + (R′) 2 ], selenonium [—Se + (R′) 2 ], telluronium [—Te + (R′) 2 ], stibonium [—Sb + (R′) 3 ], and bismuthonium [—Bi + (R′) 3 ], wherein R′ each independently is H, (C 1 -C 6 )alkyl, phenyl, benzyl, or heterocyclyl, or two R's in the ammonium, hydrazinium, ammoniumoxy, iminium, amidinium or guanidinium groups, together with the N atom to which they are attached, form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from the group consisting of 0, S and N and optionally further substituted at the additional N atom; 
         X is a counter anion; and 
         n is an integer of 5-11, 
         but excluding the compounds wherein R 1  is —CH 2 —; R 2  and R 3  are H; and: (i) n is 5; R 4  and R 5  are —(CH 2 ) 2 —; and Y is —N + (CH 3 ) 3 ; (ii) n is 5; R 4  and R 5  are —(CH 2 ) 3 —; and Y is —P + (C 4 H 9 ) 3 ; (iii) n is 5; R 4  and R 5  are —(CH 2 ) 4 —; and Y is —N + (CH 3 ) 3 ; (iv) n is 6; R 4  and R 5  are —(CH 2 ) 2 —; and Y is —N + (CH 3 ) 3 ; (v) n is 6; R 4  and R 5  are —(CH 2 ) 4 —; and Y is —N + (CH 3 ) 3 ; or (vi) n is 6; R 4  and R 5  are —(CH 2 ) 4 —; and Y is 1-pyridinium. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 (i) R 1  is —CR 6 R 7 —, wherein R 6  and R 7  each independently is H, halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, or (C 1 -C 8 )alkyl optionally substituted by one or more groups each independently selected from the group consisting of —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, —N + (R′) 3  or —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 4 )alkyl, phenyl, or benzyl; or   (ii) R 2  and R 3  each independently is H, or (C 1 -C 4 )alkyl, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, —N + (R′) 3  and —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 4 )alkyl, phenyl, or benzyl; or   (iii) R 4  and R 5  each independently is (C 2 -C 10 )alkylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, (C 6 )aryl, (C 1 -C 4 )alkylene-(C 6 )aryl, heteroaryl, and (C 1 -C 4 )alkylene-heteroaryl, and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, or by one or more groups each independently selected from the group consisting of —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, —N(C 6 aryl)-, (C 6 )arylenediyl, and heteroarylenediyl; or   (iv) R 4  and R 5  are identical; or   (v) Y each independently is ammonium [—N + (R′) 3 ] or phosphonium [—P + (R′) 3 ], wherein R′ each independently is H, (C 1 -C 6 )alkyl, phenyl, benzyl, or heterocyclyl; or   (vi) n is 5, 6, 7 or 8.   
     
     
         3 . The compound of  claim 2 , wherein:
 (i) R 1  is —CH 2 —; or   (ii) R 2  and R 3  are H; or   (iii) R 4  and R 5  each independently is (C 2 -C 10 )alkylene, optionally interrupted by one or more O atoms; or   (iv) Y each independently is ammonium [—N + (R′) 3 ] or phosphonium [—P + (R′) 3 ], wherein R′ each independently is H, methyl, ethyl, or propyl.   
     
     
         4 . The compound of  claim 1 , wherein:
 R 1  is —CR 6 R 7 —, wherein R 6  and R 7  each independently is H, halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, or (C 1 -C 5 )alkyl optionally substituted by one or more groups each independently selected from the group consisting of —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, —N + (R′) 3  and —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 4 )alkyl, phenyl, or benzyl;   R 2  and R 3  each independently is H, or (C 1 -C 4 )alkyl, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, —N + (R′) 3  and —P + (R′) 3 , wherein R′ each independently is H, (C 1 -C 4 )alkyl, phenyl, or benzyl;   R 4  and R 5  each independently is (C 2 -C 10 )alkylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 3 H, —SO 2 H, —S(═O)H, (C 6 )aryl, (C 1 -C 4 )alkylene-(C 6 )aryl, heteroaryl, and (C 1 -C 4 )alkylene-heteroaryl, and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, or by one or more groups each independently selected from the group consisting of —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, —N(C 6 aryl)-, (C 6 )arylenediyl, and heteroarylenediyl; and   n is 5, 6, 7 or 8.   
     
     
         5 . The compound of  claim 4 , wherein R 1  is —CH 2 —; R 2  and R 3  are H; and R 4  and R 5  each independently is (C 2 -C 10 )alkylene, optionally interrupted by one or more O atoms. 
     
     
         6 . The compound of  claim 5 , wherein Y is ammonium [—N + (R′) 3 ] or phosphonium [—P + (R′) 3 ], wherein R′ each independently is H, (C 1 -C 6 )alkyl, phenyl, benzyl, or heterocyclyl. 
     
     
         7 . The compound of  claim 6 , wherein Y each independently is ammonium [—N + (R′) 3 ] or phosphonium [—P + (R′) 3 ], wherein R′ each independently is H, methyl, ethyl, or propyl. 
     
     
         8 . The compound of  claim 7 , wherein n is 5 or 6. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is —CH 2 —; R 2  and R 3  are H; X is a counter anion such as Br −  or Cl − ; and: (i) R 4  and R 5  are —(CH 2 ) 3 —, or —(CH 2 ) 6 —; Y is —N + (CH 3 ) 3 , —N + (C 2 H 5 ) 3 , —P + (CH 3 ) 3 , or —P + (C 2 H 5 ) 3 ; and n is 5; or (ii) R 4  and R 5  are —(CH 2 ) 3 —;
 Y is —N + (CH 3 ) 3 , or —P + (CH 3 ) 3 ; and n is 6. 
 
     
     
         10 . The compound of  claim 1 , wherein said counter anion is Br − , Cl − , F − , I − , PF 6   − , BF 4   − , OH − , ClO 4   − , HSO 4   − , CF 3 COO − , CN − , alkylCOO − , arylCOO − , a pharmaceutically acceptable anion, or a combination thereof. 
     
     
         11 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein R 1  is —CH 2 —; 
         R 2  and R 3  are each H; 
         R 4  and R 5  are each —(CH 2 ) 3 —; 
         Y is 1-methyl-imidazolium-3-yl; 
         n is 6; and 
         X is a counter anion. 
       
     
     
         12 . The compound of  claim 11 , wherein said counter anion is Br −  or Cl − . 
     
     
         13 . A composition comprising a compound of the formula I as claimed in  claim 1 . 
     
     
         14 . The composition of  claim 13 , comprising a compound of the formula I, wherein R 1  is —CH 2 —; R 2  and R 3  are H; X is a counter anion such as Br −  or Cl − ; and: (i) R 4  and R 5  are —(CH 2 ) 3 —, or —(CH 2 ) 6 —; Y is —N + (CH 3 ) 3 , —N + (C 2 H 5 ) 3 , —P + (CH 3 ) 3 , or —P + (C 2 H 5 ) 3 ; and n is 5; or (ii) R 4  and R 5  are —(CH 2 ) 3 —; Y is —N + (CH 3 ) 3 , or —P + (CH 3 ) 3 ; and n is 6. 
     
     
         15 . A composition comprising the compound of  claim 11 .