Biocidal polymers
Pharmaceutical compositions containing biocidal co-polymers of poly(styrenes), poly(acrylates), poly(acrylamides), and poly(C 1 -C 6 )alkylene glycols are disclosed, along with methods of using the compositions to treat microbial infections in mammals.
1. A pharmaceutical composition for treating microbial infection in a subject in need thereof, the composition comprising an antimicrobial-effective amount of a compound selected from the group consisting of a polymer of formula -(A) n -, wherein each A is a residue independently selected from the group consisting of:
wherein each R is independently selected from the group consisting of hydrogen; linear or branched C 1 -C 30 -alkyl, alkenyl, or alkynyl; unsubstituted amino-C 1 -C 6 -alkyl; mono-substituted amino-C 1 -C 6 -alkyl; disubstituted amino-C 1 -C 6 -alkyl; mono- or bicyclic aryl; mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl; mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; —(CH 2 ) n+1 —OR 1 ; —(CH 2 ) n+1 —SR 1 ; —(CH 2 ) n+1 —S(═O)—CH 2 —R 1 ; —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 1 ; —(CH 2 ) n+1 —NR 1 R 1 ; —(CH 2 ) n+1 —NHC(═O)R 1 ; —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 1 ; —(CH 2 ) n+1 —O—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —S—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —S(═O)—(CH 2 ) m -R 2 ; —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —NH—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —N—[(CH 2 ) m —R 2 ] 2 ; —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 2 ; and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 2 ;
wherein each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl; mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl; and mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and
wherein each R 2 is independently selected from the group consisting of hydroxy; C 1 -C 6 -alkyloxy; aryloxy; heteroaryloxy; thio; C 1 -C 6 -alkylthio; C 1 -C 6 -alkylsulfinyl; C 1 -C 6 -alkylsulfonyl; arylthio; arylsulfinyl; arylsulfonyl; heteroarylthio; heteroarylsulfinyl; heteroarylsulfonyl; amino; mono- or di-C 1 -C 6 -alkylamino; mono- or diarylamino; mono- or diheteroarylamino; N-alkyl-N-arylamino; N-alkyl-N-heteroarylamino; N-aryl-N-heteroarylamino; aryl-C 1 -C 6 -alkylamino; carboxylic acid; carboxamide; mono- or di-C 1 -C 6 -alkylcarboxamide; mono- or diarylcarboxamide; mono- or diheteroarylcarboxamide; N-alkyl-N-arylcarboxamide; N-alkyl-N-heteroarylcarboxamide; N-aryl-N-heteroarylcarboxamide; sulfonic acid; sulfonamide; mono- or di-C 1 -C 6 -alkylsulfonamide; mono- or diarylsulfonamide; mono- or diheteroarylsulfonamide; N-alkyl-N-arylsulfonamide; N-alkyl-N-heteroarylsulfonamide; N-aryl-N-heteroarylsulfonamide; urea; mono- di- or tri-substituted urea, wherein the substitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, and heteroaryl; O-alkylurethane; O-arylurethane; and O-heteroarylurethane;
wherein R′ is selected from same group recited above for R, provided that one R′ is hydrogen;
wherein n is an integer≧6; and
wherein at least one A is a residue containing a nitrogen atom, the nitrogen atom being capable of being quaternized, or a pharmaceutically suitable salt thereof;
in combination with a pharmaceutical carrier suitable for oral, rectal, topical, parenteral, nasal or bronchial administration.
2. The pharmaceutical composition of claim 1 , wherein the compound has a molecular weight of between about 4.5 kDa and 11.5 kDa as determined by gel permeation chromatography.
3. The pharmaceutical composition of claim 1 , wherein each R is independently selected from the group consisting of hydrogen; linear or branched C 1 -C 30 -alkyl, alkenyl, or alkynyl; unsubstituted amino-C 1 -C 6 -alkyl; mono-substituted amino-C 1 -C 6 -alkyl; disubstituted amino-C 1 -C 6 -alkyl; mono- or bicyclic aryl; and mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S.
4. The pharmaceutical composition of claim 1 , wherein each R is independently selected from the group consisting of mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 —OR 1 , —(CH 2 ) n+1 —SR 1 , —(CH 2 ) n+1 —S(═O)—CH 2 —R 1 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 1 , —(CH 2 ) n+1 —NR 1 R 1 , —(CH 2 ) n+1 —NHC(═O)R 1 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 1 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —S—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —S(═O)—(CH 2 ) m -R 2 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 2 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —N—[(CH 2 ) m —R 2 ] 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 2 , and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 2 .
5. The pharmaceutical composition of claim 1 , wherein each R 1 is independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, alkenyl, or alkynyl.
6. A pharmaceutical composition for treating microbial infection in a subject in need thereof, the composition comprising an antimicrobial-effective amount of a compound selected from the group consisting of a polymer of formula -(A) n -, wherein each A is a residue independently selected from the group consisting of:
wherein each R is independently selected from the group consisting of hydrogen; linear or branched C 1 -C 30 -alkyl, alkenyl, or alkynyl; unsubstituted amino-C 1 -C 6 -alkyl; mono-substituted amino-C 1 -C 6 -alkyl; disubstituted amino-C 1 -C 6 -alkyl; mono- or bicyclic aryl; mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl; mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; —(CH 2 ) n+1 —OR 1 ; —(CH 2 ) n+1 —SR 1 ; —(CH 2 ) n+1 —S(═O)—CH 2 —R 1 ; —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 1 ; —(CH 2 ) n+1 —NR 1 R 1 ; —(CH 2 ) n+1 —NHC(═O)R 1 ; —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 1 ; —(CH 2 ) n+1 —O—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —S—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —S(═O)—(CH 2 ) m -R 2 ; —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —NH—(CH 2 ) m —R 2 ; —(CH 2 ) n+1 —N—[(CH 2 ) m —R 2 ] 2 ; —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 2 ; and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 2 ;
wherein each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 -alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl; mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C 1 -C 6 -alkyl; and mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl; and
wherein each R 2 is independently selected from the group consisting of hydroxy; C 1 -C 6 -alkyloxy; aryloxy; heteroaryloxy; thio; C 1 -C 6 -alkylthio; C 1 -C 6 -alkylsulfinyl; C 1 -C 6 -alkylsulfonyl; arylthio; arylsulfinyl; arylsulfonyl; heteroarylthio; heteroarylsulfinyl; heteroarylsulfonyl; amino; mono- or di-C 1 -C 6 -alkylamino; mono- or diarylamino; mono- or diheteroarylamino; N-alkyl-N-arylamino; N-alkyl-N-heteroarylamino; N-aryl-N-heteroarylamino; aryl-C 1 -C 6 -alkylamino; carboxylic acid; carboxamide; mono- or di-C 1 -C 6 -alkylcarboxamide; mono- or diarylcarboxamide; mono- or diheteroarylcarboxamide; N-alkyl-N-arylcarboxamide; N-alkyl-N-heteroarylcarboxamide; N-aryl-N-heteroarylcarboxamide; sulfonic acid; sulfonamide; mono- or di-C 1 -C 6 -alkylsulfonamide; mono- or diarylsulfonamide; mono- or diheteroarylsulfonamide; N-alkyl-N-arylsulfonamide; N-alkyl-N-heteroarylsulfonamide; N-aryl-N-heteroarylsulfonamide; urea; mono- di- or tri-substituted urea, wherein the substitutent(s) is selected from the group consisting of C 1 -C 6 -alkyl, aryl, and heteroaryl; O-alkylurethane; O-arylurethane; and O-heteroarylurethane;
wherein R′ is selected from same group recited above for R, provided that one R′ is hydrogen;
wherein n is an integer≧6; and
wherein at least one A is a residue containing a nitrogen atom, the nitrogen atom being capable of being quaternized, or a pharmaceutically suitable salt thereof.
7. The pharmaceutical composition of claim 1 , wherein the at least one residue containing the nitrogen atom is present in the polymer in proportion with other residues at no less than about 70%.
8. A method of preventing and treating microbial infections in a subject in need thereof, the method comprising administering to the subject an effective anti-microbial amount of a pharmaceutical composition as recited in claim 6 .
9. The pharmaceutical composition of claim 6 , further comprising, in combination, a pharmaceutically suitable carrier.
10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical carrier is suitable for oral, rectal, topical, parenteral, nasal or bronchial administration.
11. The pharmaceutical composition of claim 6 , wherein the compound has a molecular weight of between about 4.5 kDa and 11.5 kDa as determined by gel permeation chromatography.
12. The pharmaceutical composition of claim 6 , wherein each R is independently selected from the group consisting of hydrogen; linear or branched C 1 -C 30 -alkyl, alkenyl, or alkynyl; unsubstituted amino-C 1 -C 6 -alkyl; mono-substituted amino-C 1 -C 6 -alkyl; disubstituted amino-C 1 -C 6 -alkyl; mono- or bicyclic aryl; and mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S.
13. The pharmaceutical composition of claim 6 , wherein each R is independently selected from the group consisting of mono- or bicyclic aryl-C 1 -C 6 -alkyl, mono- or bicyclic heteroaryl-C 1 -C 6 -alkyl, —(CH 2 ) n+1 —OR 1 , —(CH 2 ) n+1 —SR 1 , —(CH 2 ) n+1 —S(═O)—CH 2 —R 1 , —(CH 2 ) n+1 —S(═O) 2 —CH 2 —R 1 , —(CH 2 ) n+1 —NR 1 R 1 , —(CH 2 ) n+1 —NHC(═O)R 1 , —(CH 2 ) n+1 —NHS(═O) 2 —CH 2 —R 1 , —(CH 2 ) n+1 —O—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —S—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —S(═O)—(CH 2 ) m -R 2 , —(CH 2 ) n+1 —S(═O) 2 —(CH 2 ) m —R 2 , —(CH 2 ) n+1 —NH—(CH 2 ) m —R 2 , —(CH 2 ) n+1 —N—[(CH 2 ) m —R 2 ] 2 , —(CH 2 ) n+1 —NHC(═O)—(CH 2 ) n+1 —R 2 , and —(CH 2 ) n+1 —NHS(═O) 2 —(CH 2 ) m —R 2 .
14. The pharmaceutical composition of claim 6 , wherein each R 1 is independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, alkenyl, or alkynyl.
15. The pharmaceutical composition of claim 6 , wherein the at least one residue containing the nitrogen atom is present in the polymer in proportion with other residues at no less than about 70%.