QUATERNARY AMMONIUM COMPOUNDS AS ANTIMICROBIALS

20240116857

18/348207

July 06, 2023

In one aspect, the present disclosure provides compounds such as those with one or more quaternary ammonium ions joined by one or more aromatic rings. These compounds may have a formula: [chemical expression included] These compounds may be used in the treatment of a microbial infection such as a bacterial infection including infections of drug resistant strains of bacteria.

Saint Louis University (St. Louis, MO, US), The Board of Regents of the University of Oklahoma (Norman, OK, US)

1. A compound of the formula: [chemical expression included] wherein: m is 1 or 2; X1 and X2 are each C, N, or +NRa; wherein: Ra is alkyl(C≤6) or substituted alkyl(C≤6); Y1 and Y2 are each C(O)O, C(O)NRb, S(O)a, or S(O)aNRb; wherein: Rb is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6); and a is 0, 1, or 2; Each R1 is amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), alkylsulfonyl(C≤8), substituted alkylsulfonyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), x is 0, 1, 2, 3, or 4; each Z1 and Z2 in each ring are each independently C, N, S, or O; R2 and R3 are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤12), substituted alkyl(C≤12), alkenyl(C≤12), substituted alkenyl(C≤12), alkynyl(C≤12), substituted alkynyl(C≤12), heterocycloalkyl(C≤8), substituted heterocycloalkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), alkenyloxy(C≤8), substituted alkenyloxy(C≤8), alkynyloxy(C≤8), substituted alkynyloxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), or a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein:  R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); or a group of the formula: +N(Rc)3 wherein: each Rc are each independently alkyl(C≤6) or substituted alkyl(C≤6); and y and z are each independently 1, 2, 3, 4, or 5 provided that if X1 or X2 is CH, then at least one or R2 or R3 is a group of the formula: —X3—Y3—R4; wherein if the compound contains one or more cationic groups; the compound further comprises one or more anionic groups to balance the charge of the cationic groups; or a pharmaceutically acceptable salt thereon.

2. The compound of claim 1 further defined as: [chemical expression included] wherein: m is 1 or 2; X1 and X2 are each CH, N, or NRa; wherein: Ra is alkyl(C≤6) or substituted alkyl(C≤6); Y1 and Y2 are each C(O)O, C(O)NRb, S(O)a, or S(O)aNRb; wherein: Rb is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6); and a is 0, 1, or 2; Each R1 is amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), x is 0, 1, 2, 3, or 4; R2 and R3 are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), or a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein:  R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); and y and z are each independently 1, 2, 3, 4, or 5 provided that if X1 or X2 is CH, then at least one or R2 or R3 is a group of the formula: —X3—Y3—R4; wherein if the compound contains one or more cationic groups; the compound further comprises one or more anionic groups to balance the charge of the cationic groups; or a pharmaceutically acceptable salt thereon.

3. The compound of claim 1 further defined as: [chemical expression included] wherein: X1 and X2 are each CH, N, or NRa; wherein: Ra is alkyl(C≤6) or substituted alkyl(C≤6); Y1 and Y2 are each C(O)O, C(O)NRb, S(O)a, or S(O)aNRb; wherein: Rb is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6); and a is 0, 1, or 2; Each R1 and R1′ are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), x and x′ are each independently 0, 1, 2, 3, or 4; R2 and R3 are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), or a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NR, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein:  R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); and y and z are each independently 1, 2, 3, 4, or 5 provided that if X1 or X2 is CH, then at least one or R2 or R3 is a group of the formula: —X3—Y3—R4; wherein if the compound contains one or more cationic groups; the compound further comprises one or more anionic groups to balance the charge of the cationic groups; or a pharmaceutically acceptable salt thereon.

4. The compound of claim 1 further defined as: [chemical expression included] wherein: X1 and X2 are each CH, N, or NRa; wherein: Ra is alkyl(C≤6) or substituted alkyl(C≤6); Each R1 and R1′ are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), x and x′ are each independently 0, 1, 2, 3, or 4; R2 and R3 are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), or a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein:  R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); and y and z are each independently 1, 2, 3, 4, or 5 provided that if X1 or X2 is CH, then at least one or R2 or R3 is a group of the formula: —X3—Y3—R4; wherein if the compound contains one or more cationic groups; the compound further comprises one or more anionic groups to balance the charge of the cationic groups; or a pharmaceutically acceptable salt thereon.

5. The compound of claim 1 further defined as: [chemical expression included] wherein: X1 and X2 are each CH, N, or NRa; wherein: Ra is alkyl(C≤6) or substituted alkyl(C≤6); Each R1 and R1′ are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), x and x′ are each independently 0, 1, 2, 3, or 4; R2 and R3 are each independently amino, cyano, halo, hydroxy, nitro, aminosulfonyl, hydroxysulfonyl, alkyl(C≤8), substituted alkyl(C≤8), alkoxy(C≤8), substituted alkoxy(C≤8), acyl(C≤8), substituted acyl(C≤8), amido(C≤8), substituted amido(C≤8), alkylamino(C≤8), substituted alkylamino(C≤8), dialkylamino(C≤8), or substituted dialkylamino(C≤8), or a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein:  R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); and y and z are each independently 1, 2, 3, 4, or 5 provided that if X1 or X2 is CH, then at least one or R2 or R3 is a group of the formula: —X3—Y3—R4; wherein if the compound contains one or more cationic groups; the compound further comprises one or more anionic groups to balance the charge of the cationic groups; or a pharmaceutically acceptable salt thereon.

6.-11. (canceled)

12. The compound of claim 1, wherein y is 0, 1, or 2.

13.-18. (canceled)

19. The compound wherein R2 is a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein: R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8).

20.-26. (canceled)

27. The compound of claim 19, wherein Y3 is arenediyl(C≤12) or substituted arenediyl(C≤12).

28.-29. (canceled)

30. The compound of claim 19, wherein Y3 is heteroarenediyl(C≤12) or substituted heteroarenediyl(C≤12).

31.-32. (canceled)

33. The compound of claim 19, wherein R4 is alkyl(C≤12) or substituted alkyl(C≤12).

34. The compound of claim 33, wherein R4 is on a nitrogen atom of a heteroarenediyl group at Y3.

35.-36. (canceled)

37. The compound of claim 19, wherein R4 is +N(R5)3.

38.-41. (canceled)

42. The compound of claim 1, wherein R3 is alkyl(C≤8) or substituted alkyl(C≤8).

43.-47. (canceled)

48. The compound of claim 1, wherein R3 is a group of the formula: —X3—Y3—R4 wherein: X3 is a covalent bond, O, NRc, S, alkanediyl(C≤6), or substituted alkanediyl(C≤6); Y3 is arenediyl(C≤12), heteroarenediyl(C≤12), or a substituted version of either of these groups; and R4 is alkyl(C≤12), substituted alkyl(C≤12), or +N(R5)3, wherein: R5 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8).

49.-55. (canceled)

56. The compound of claim 48, wherein Y3 is arenediyl(C≤12) or substituted arenediyl(C≤12).

57.-58. (canceled)

59. The compound of claim 48, wherein Y3 is heteroarenediyl(C≤12) or substituted heteroarenediyl(C≤12).

60.-61. (canceled)

62. The compound of claim 48, wherein R4 is alkyl(C≤12) or substituted alkyl(C≤12).

63.-69. (canceled)

70. The compound of claim 1, wherein the compound is further defined as: [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included] [chemical expression included]

71.-74. (canceled)

75. A pharmaceutical composition comprising: (A) a compound of claim 1; and (B) an excipient.

76.-77. (canceled)

78. A method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1.

79.-90. (canceled)

07; 61; 07; 07; 07; 07; 07

edspap.20240116857