Method for inhibiting or disrupting biofilm formation, or reducing biofilm

Patent metadata

Field	Value
Publication number	US-12398092-B2
Application number	US-202318352955-A
Country	US
Kind code	B2
Filing date	Jul 14, 2023
Priority date	Aug 10, 2015
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

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.

First claim

What is claimed is:

1. A method for inhibiting or disrupting biofilm formation, or reducing biofilm, in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of 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, imidazolium, 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.

2. The method 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 and —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 (i) 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 (ii) imidazolium, 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
(vi) n is 5, 6, 7, or 8.

3. The method 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 0 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; or 1-methyl-imidazolium-3-yl.

4. The method 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 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 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;

Assignees

• Univ Ramot

Inventors

• Cohen Yoram
• Fridman Micha
• Joseph Roymon
• Naugolny Alissa
• Feldman Mark
• Herzog Ido M
• Kaizerman Dana

Classifications

• C09D5/1687

  Use of special additives · CPC title

• C07F9/5407

  Acyclic saturated phosphonium compounds · CPC title

• C07D233/60

  with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms · CPC title

• C02F2303/20

  Prevention of biofouling · CPC title

• C02F1/50

  by addition or application of a germicide or by oligodynamic treatment {(C02F1/4606, C02F1/467, C02F1/76 take precedence)} · CPC title