Quaternary alkyl ammonium bacterial efflux pump inhibitors and therapeutic uses thereof
View Patent ↗Disclosed are compounds having at least one quaternary alkyl ammonium functionality. The compounds inhibit bacterial efflux pump inhibitors and are used in combination with an anti-bacterial agent to treat or prevent bacterial infections. These combinations can be effective against bacterial infections that have developed resistance to anti-bacterial agents through an efflux pump mechanism.
1. A compound having the structure of formula I:
or a pharmaceutically acceptable salt or pro-drug thereof wherein;
each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
each R 1 is independently selected from C 3 -C 6 carbocyclyl, aryl and heteroaryl, each optionally substituted with up to 3 substituents independently selected from the group consisting of halo, C 1 -C 6 alkyl, carbocyclyl, —(CH 2 ) n aryl, —OR 2 , —OR 14 , —S(R 2 ) 2 , —SO 2 NHR 14 , —(CH 2 ) n SH, —CF 3 , —OCF 3 , —N(R 2 ) 2 , —NO 2 , —CN, —CO 2 alkyl, and —CO 2 aryl;
each R 2 is independently selected from H and C 1 -C 6 alkyl;
R 3 is —(CH 2 ) n CHR 6 R 7 ;
each R 4 is independently selected from —(CH 2 ) m R 9 , allyl, —(CH 2 ) n CO 2 H—, —(CH 2 ) n CONH 2 and —(CH 2 ) n CHR 6 R 7 ;
each R 5 is independently selected from —(CH 2 ) m R 9 , —NHR 2 , and —(CH 2 ) n CHR 6 R 7 ;
each R 6 is independently selected from H and —(CH 2 ) m NH 2 ;
each R 7 is independently selected from —(CH 2 ) m NHR 8 , —(CH 2 ) m NHC(═NH)NH 2 , and —(CH 2 ) m NHC(R 2 )═NH;
each R 8 is independently selected from H, C 1 -C 6 alkyl, Alanine, Arginine, Aspartic acid, and Cysteine;
each R 9 is independently selected from H, C 1 -C 6 alkyl, SH and OH;
R 13 is H, with the proviso that R 13 is directly attached to the nitrogen;
R 14 is quinolin, optionally substituted with up to 3 substituents independently selected from the group consisting of a halide, alkyl, carbocyclyl, —(CH 2 ) n R 1 , —OR 2 , —OR 1 , ═O, —S(R 2 ) 2 , —SO 2 NHR 1 , —(CH 2 ) n SH, —CF 3 , —OCF 3 , —N(R 2 ) 2 , —NO 2 , —CN, —(C═X)R 1 , —(C═X)R 2 , —CO 2 alkyl, and —CO 2 aryl, with the proviso that R 14 is directly attached to the nitrogen;
A 1 is —(CH 2 ) m — or —[C(R 2 R 9 )] m —;
A 2 is —O(CH 2 ) n —;
A 3 is H or A 3 is —CH 2 — bonded to R 1 to form a ring;
a1, a2, and a3 are independently equal to 0 or 1;
D 1 is selected from —CH(NHR 8 )— and —CH(R 2 )—;
D 2 , D 3 , and D 4 are independently selected from the group consisting of —(CH 2 ) m —, —CH(R 2 )—, —CH(NHR 8 )—, —N(R 6 )—, —S—, —C(═O)—, and —SO 2 —,
D 5 is —(CH 2 ) m —,
d1, d2, d3, d4 and d5 are independently equal to 0 or 1;
Z 1 is an aryl or carbocyclyl;
z1 is 0 or 1;
if z1 is 0 then at least two of d1, d2, d3, d4 and d5 are equal to 1;
if z1 is 1 then at least one of d1, d2, d3, d4 and d5 is equal to 1;
X 1 and X 2 are each hydrogen or taken together are ═O,
or X 1 is absent and X 2 is —O— bonded to R 14 to form a 5- or 6-membered heteroaryl, wherein when X 1 is absent, the bond to nitrogen represented by a dashed and solid line is a double bond;
each X is independently O or S;
each n is independently an integer from 0 to 4; and
each m is independently an integer from 1 to 3.
2. The compound of claim 1 wherein R 1 is C 3-6 carbocyclyl.
3. The compound of claim 1 wherein R 1 is selected from cyclopentyl and cyclohexyl.
4. The compound of claim 1 wherein R 1 is selected from aryl and heteroaryl.
5. The compound of claim 1 wherein R 1 is aryl optionally substituted with up to 3 substituents independently selected from the group consisting of halo, C 1-6 alkyl, OR 2 , CF 3 , OCF 3 , and CN.
6. The compound of claim 1 wherein R 2 is selected from H and C 1 -C 2 alkyl.
7. The compound of claim 1 wherein R 2 is selected from H and Me.
8. The compound of claim 1 wherein R 2 is H.
9. The compound of claim 1 wherein R 3 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
10. The compound of claim 1 wherein R 3 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHC(═NH)NH 2 , n is 0 to 2, and m is 1 to 2.
11. The compound of claim 1 wherein R 3 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is (CH 2 ) m NHC(R 2 )═NH, R 2 is H, Me, or Et, n is 0 to 2, and m is 1 or 2.
12. The compound of claim 1 wherein R 3 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is —(CH 2 ) m NH 2 , R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
13. The compound of claim 1 wherein R 4 is selected from allyl and —(CH 2 ) m R 9 wherein R 9 is selected from H or Me and m is 1 or 2.
14. The compound of claim 1 wherein R 4 is —(CH 2 ) m R 9 wherein R 9 is selected from SH or OH and m is 1 or 2.
15. The compound of claim 1 wherein R 4 is selected from —(CH 2 ) n CO 2 H— and —(CH 2 )—CONH 2 wherein n is 1 or 2.
16. The compound of claim 1 wherein R 4 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
17. The compound of claim 1 wherein R 4 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHC(═NH)NH 2 , n is 0 to 2, and m is 1 or 2.
18. The compound of claim 1 wherein R 4 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is (CH 2 ) m NHC(R 2 )═NH, R 2 is selected from H, Me or Et, n is 0 to 2, and m is 1 or 2.
19. The compound of claim 1 wherein R 4 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is —(CH 2 ) m NH 2 , R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
20. The compound of claim 1 wherein R 5 is selected from allyl and —(CH 2 ) m R 9 wherein R 9 is selected from H and Me and m is 1 or 2.
21. The compound of claim 1 wherein R 5 is —(CH 2 ) m R 9 wherein R 9 is selected from SH and OH and m=1 or 2.
22. The compound of claim 1 wherein R 5 is —NHR 2 wherein R 2 is H.
23. The compound of claim 1 wherein R 5 is —NHR 2 wherein R 2 is selected from Me and Et.
24. The compound of claim 1 wherein R 5 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
25. The compound of claim 1 wherein R 5 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is —(CH 2 ) m NHC(═NH)NH 2 , n is 0 to 2, and m is 1 or 2.
26. The compound of claim 1 wherein R 5 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is H, R 7 is (CH 2 ) m NHC(R 2 )═NH, R 2 is selected from H, Me and Et, n is 0 to 2, and m is 1 or 2.
27. The compound of claim 1 wherein R 5 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is —(CH 2 ) m NH 2 , R 7 is —(CH 2 ) m NHR 8 , R 8 is H, n is 0 to 2, and m is 1 or 2.
28. The compound of claim 1 wherein R 5 is —(CH 2 ) n CHR 6 R 7 wherein R 6 is —(CH 2 ) m NH 2 , R 7 is —(CH 2 ) m NHR 8 , R 8 is selected from Alanine, Arginine, and Aspartic acid, n=0-2 and m=1 or 2.
29. The compound of claim 1 , wherein R 14 is quinolin, optionally substituted with up to 3 substituents independently selected from the group consisting of a halo, alkyl, carbocyclyl, —(CH 2 ) n R 1 , —OR 2 , —OR 1 , —S(R 2 ) 2 , —SO 2 NHR 1 , —CF 3 , —OCF 3 , and —CN.
30. The compound of claim 1 wherein A 1 is —(CH 2 ) m wherein m is 1 or 2; A 3 is H; a1 is 1; and a2 is 0.
31. The compound of claim 1 wherein A 1 is —(CH 2 ) m — wherein m is 1 or 2; A 2 is selected from —O(CH 2 ) n — wherein n is 0; A 3 is H; and a1 and a2 are equal to 1.
32. The compound of claim 1 wherein A 1 is selected from —[C(R 2 R 8 )] m — wherein m is 1 or 2, R 2 is H, and R 8 is selected from H, SH or OH with the proviso that at least one R 8 be SH or OH; A 3 is H; a1 is 1; and a2 is 0.
33. The compound of claim 1 wherein A 1 is —(CH 2 ) m — wherein m is 1 or 2; a1 is 1; a2 is 0; A 3 is —CH 2 — bonded to R 1 to form a ring; and R 1 is aryl optionally substituted with up to 2 substituents independently selected from the group consisting of halo, alkyl, OMe, CF 3 , OCF 3 , and CN.
34. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; d1 and d2 are equal to 1; and z1, d3, d4 and d5 are equal to 0.
35. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —CH(R 2 )— wherein R 2 is selected from Me and Et; D 3 is —(CH 2 ) m —; d1, d2 and d3 are equal to 1; and z1, d4 and d5 are equal to 0.
36. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m — wherein m is 1 or 2; D 3 is selected from —S—, —S(═O)— and —SO 2 —; D 4 is —(CH 2 ) m — wherein m is 1 or 2; d1, d2, d3, and d4 are equal to 1; and z1 and d5 are equal to 0.
37. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; D 3 is —C(═O)—; D 4 is —N(R 6 )— wherein R 6 is H; D 5 is —(CH 2 ) m —; d1, d2, d3, d4 and d5 are equal to 1; and z1 is equal to 0.
38. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; D 3 is —C(═O)—; D 4 is —N(R 6 )— wherein R 6 is —(CH 2 ) m NH 2 wherein m is 1 to 3; D 5 is —(CH 2 ) m —; d1, d2, d3, d4 and d5 are equal to 1; and z1 is equal to 0.
39. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; D 3 is —N(R 6 )— wherein R 6 is H; D 4 is —C(═O)—; D 5 is —(CH 2 ) m —; d1, d2, d3, d4 and d5 are equal to 1; and z1 is equal to 0.
40. The compound of claim 1 wherein D 1 is —CH(R 2 )— wherein R 2 is selected from H, Me and Et; D 2 is —N(R 6 )— wherein R 6 is H; D 3 is —C(═O)—; D 4 is —CH(NHR 8 )— wherein R 8 is H; D 5 is —(CH 2 ) m —; d1, d2, d3, d4 and d5 are equal to 1; and z1 is equal to 0.
41. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; D 3 is —N(R 6 )— wherein R 6 is H; d1, d2 and d3 are equal to 1; and z1, d4 and d5 are equal to 0.
42. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; D 3 is —C(═O)—; D 4 is —N(R 6 )— wherein R 6 is H; d1, d2, d3 and d4 are equal to 1; and z1, d5 are equal to 0.
43. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is selected from Alanine, Arginine, Aspartic acid, and Cysteine; D 2 is —(CH 2 ) m —; d1 and d2 are equal to 1; and z1, d3, d4 and d5 are equal to 0.
44. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; Z 1 is an aryl; z1, d1 and d2 are equal to 1; and d3, d4 and d5 are equal to 0.
45. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; Z 1 is an aryl; z1 and d1 are equal to 1; and d2, d3, d4 and d5 are equal to 0.
46. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; Z 1 is an aryl; D 3 is —(CH 2 ) m —; z1, d1 and d3 are equal to 1; and d2, d4 and d5 are equal to 0.
47. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; D 2 is —(CH 2 ) m —; Z 1 is a carbocyclyl; z1, d1 and d2 are equal to 1; and d3, d4 and d5 are equal to 0.
48. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; Z 1 is a carbocyclyl; z1 and d1 are equal to 1; and d2, d3, d4 and d5 are equal to 0.
49. The compound of claim 1 wherein D 1 is —CH(NHR 8 )— wherein R 8 is H; Z 1 is a carbocyclyl; D 3 is —(CH 2 ) m —; z1, d1 and d3 are equal to 1; and d2, d4 and d5 are equal to 0.
50. The compound of claim 1 wherein X 1 together with X 2 is O.
51. The compound of claim 1 wherein X 1 and X 2 are each H.
52. The compound of claim 1 , wherein A 3 is —CH 2 — bonded to R 1 to form a ring and a2 is 0.
53. The compound of claim 1 , wherein the combined length of D 2 , D 3 , D 4 and D 5 is not more than 10 atoms.
54. The compound of claim 1 , wherein Z 1 is attached to the rest of the compound by way of attachment points on two different atoms of Z 1 .
55. The compound of claim 1 , wherein the compound is selected from the group consisting of:
56. The compound of claim 1 , wherein the compound is selected from the group consisting of:
57. The compound of claim 1 , wherein the compound is selected from the group consisting of:
58. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.