Broad spectrum beta-lactamase inhibitors
Broad spectrum beta-lactamase inhibitors. Certain inhibitors also exhibit potent antibiotic activity in addition to beta-lactamase inhibition. Compounds of the invention are designed such that on cleavage of the beta-lactam ring reactive moieties are generated which can inactivate beta-lactamase. Also provided are methods of making beta-lactamase inhibitors and beta-lactam antibiotics exhibiting such inhibition. Additionally provided are pharmaceutical compositions for treatment or prevention of bacterial infections and methods of treatment of such infections.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
R is an acylamino group or an optionally substituted benzyl-NH group;
R 1 , R 2 , R 4 and R 5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy and —S-alkyl, where the alkyl group is a C1-C6 alkyl;
n is 1 or 2;
Y is O—C + or OR 3 , where R 3 is hydrogen, or an optionally substituted alkyl or aryl group and C + is a pharmaceutically acceptable cation; and
M, which is in the cis or trans position with respect to R 1 , is selected from the group consisting of P, B, BZ, D, E, and F as follows:
where:
W is O or C(R″) 2 , where each R″ for W groups is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted; and
R 6 and R 7 are independently selected from hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, 6-10 member heterocyclic aromatic group, COR″, —COOR″, —CON(R″) 2 , wherein each R″ for R 6 and R 7 groups is independently selected from the group consisting of hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted;
where:
Z 2 is O, NR 11 or S, where R 11 is selected from the group consisting of hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, and C2-C6 alkynyl group, wherein each group is optionally substituted;
each R 8 is independently selected from hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, 6-10 member heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl, where the alkyl group is a C1-C6 alkyl, —CO—R′, —CO 2 R′, —CO—N(R′) 2 , —N(R′) 2 , —NR′—CO—R′, and —NR′CO 2 —R′, wherein each R′ for R 8 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, a C6-C10 aromatic group and a 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted; and
each R 9 is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted;
each R 10 is independently selected from the group consisting of —CH 2 —X, hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, 6-10 member heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl, where the alkyl group is a C1-C6 alkyl, —CO—R′, —CO 2 R′, —CO—N(R′) 2 ; —N(R′) 2 , —NR′—CO—R′, and —NR′—CO 2 —R′, wherein each R′ for R 10 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted;
R 12 is selected from the group consisting of X, hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl group, where the alkyl group is a C1-C6 alkyl group, —CO—R′, —CO 2 R′, —CO—N(R′) 2 ; —N(R′) 2, —NR′—CO—R′, and —NR′—CO 2 —R′, wherein each R′ for R 12 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, and a 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted;
R 13 and R 14 are independently selected from the group consisting of X, hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, 6-10 member heterocyclic aromatic group, C1-C6 alkoxy group, —S-alkyl group, where the alkyl group is a C1-C6 alkyl group, —CO—R′, —CO 2 R′, —CO—N(R′) 2 ; —N(R′) 2 , —NR′—CO—R′, and —NR′—CO 2 —R′, wherein each R′ for R 13 and R 14 groups is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted;
wherein optional substitution is substitution with one or more groups selected from C1-C3 alkyl, C6-C12 aryl, C1-C3 haloalkyl, I, Cl, Br, F, —CN, —OH, C1-C3 alkoxy, —O-aryl, —O-benzyl, -phenoxy, —SH, —S-alkyl, where the alkyl is a C1-C6 alkyl, —S-phenyl, —S-benzyl, —NH 2 , —N(R 16 ) 2 , where each R 16 is C1-C3 alkyl, benzyl or phenyl;
wherein X is a leaving group;
wherein in structures B and Bz at least one R 10 is —CH 2 —X, in structure E at least one R 10 is a —CH 2 —X group, or R 12 is X and in structure F one of R 13 or R 14 is X;
wherein the compound contains at least one M.
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 4 and R 5 are hydrogen.
3. The compound or pharmaceutically acceptable salt of claim 1 , wherein R is an acylamino group.
4. The compound or pharmaceutically acceptable salt of claim 1 , wherein n is 1.
5. The compound or pharmaceutically acceptable salt of claim 1 , wherein X is pyridinium.
6. The compound or pharmaceutically acceptable salt of claim 5 , wherein X is:
7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 and R 2 are both hydrogen.
8. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts of claim 1 .
9. A method of treatment of a bacterial infection which comprises the step of administering a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts of claim 1 to an individual in need of treatment.
10. A method of inhibiting the growth of a microorganism which comprises the step of contacting the microorganism with an effective amount of one or more compounds or pharmaceutically acceptable salts of claim 1 .
11. A method for inhibiting a beta-lactamase which comprises the step of contacting the beta-lactamase with an effective amount of one or more compounds or pharmaceutically acceptable salts of claim 1 .
12. The compound or pharmaceutically acceptable salt of claim 1 of formula:
13. The compound or pharmaceutically acceptable salt claim 12 , wherein the acyl group of the acylamino group of R is selected from:
where in A1-A14:
R′ is selected from hydrogen, C1-C6 alkyl, and C6-C12 aryl;
R″ is selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group; and
R′″ is selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, a 6-10 member heterocyclic aromatic group, —CO—R 15 , —CO 2- R 15 , —CO—N(R 15 ) 2 , —N(R 15 ) 2 , —NR 15 —CO—R 15 , and —NR 15 CO 2 —R 15 , wherein each R 15 is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted.
14. The compound of or pharmaceutically acceptable salt of claim 12 , wherein
M is selected from:
where:
each R 8 is independently selected from hydrogen, halogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, a C7-C19 aralkyl group, 3-7-member ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, or 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted, and X is a leaving group.
15. The compound or pharmaceutically acceptable salt of claim 14 , wherein X is halogen, pyridinium, phenoxy, pentafluorophenoxy, or tosyl.
16. The compound or pharmaceutically acceptable salt thereof of claim 14 , wherein X is halogen or pyridinium.
17. The compound or pharmaceutically acceptable salt of claim 14 , wherein X is halogen or pyridinium and each R 8 is independently hydrogen, an optionally substituted C1-C6 alkyl or an optionally substituted C6-C12 aryl.
18. The compound or pharmaceutically acceptable salt of claim 14 , wherein each R 8 is hydrogen.
19. The compound or pharmaceutically acceptable salt of claim 14 , wherein M is:
20. The compound or pharmaceutically acceptable salt of claim 19 , wherein X is halogen, pyridinium, phenoxy, pentafluorophenoxy, or tosyl.
21. The compound or pharmaceutically acceptable salt of claim 19 , wherein X is a halogen or pyridinium.
22. The compound or pharmaceutically acceptable salt of claim 21 , wherein X is Cl or Br.
23. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts of claim 14 .
24. The compound or pharmaceutically acceptable salt of claim 14 , wherein R 4 and R 5 are hydrogen.
25. The compound or pharmaceutically acceptable salt of claim 24 , wherein R 1 and R 2 are hydrogen.
26. The compound or pharmaceutically acceptable salt of claim 25 , wherein the acyl group of the acylamino group of R is selected from:
where in A1-A14:
R′ is selected from hydrogen, C1-C6 alkyl, and C6-C12 aryl;
R″ is selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group and 6-10 member heterocyclic aromatic group; and
R′″ is selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, a 6-10 member heterocyclic aromatic group, —CO—R 15 , —CO 2- R 15 , —CO—N(R 15 ) 2 , —N(R 15 ) 2 , —NR 15 —CO—R 15 , and —NR 15 CO 2 —R 15 , wherein each R 15 is independently selected from hydrogen, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C7-C19 aralkyl group, 3-7-member-ring cyclic hydrocarbon group, 3-7 member heterocyclic group, C6-C10 aromatic group, and 6-10 member heterocyclic aromatic group, wherein each of said groups is optionally substituted.
27. The compound or pharmaceutically acceptable salt of claim 26 , wherein the acyl group of the acylamino group of R is selected from:
28. The compound or pharmaceutically acceptable salt of claim 27 , wherein R″ is hydrogen or a C1-C6 alkyl group and R′″ is hydrogen or a C1-C6 alkyl group.
29. The compound or pharmaceutically acceptable salt of claim 27 , wherein X is halogen, pyridinium, phenoxy, pentafluorophenoxy, or tosyl.
30. The compound or pharmaceutically acceptable salt of claim 27 , wherein X is halogen or pyridinium.
31. The compound or pharmaceutically acceptable salt of claim 27 , wherein X is halogen or pyridinium and each R 8 is independently hydrogen, an optionally substituted C1-C6 alkyl or an optionally substituted C6-C12 aryl.
32. The compound or pharmaceutically acceptable salt of claim 31 , wherein each R 8 is hydrogen.
33. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts of claim 12 .
34. A method of treatment of a bacterial infection which comprises the step of administering a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts of claim 14 to an individual in need of treatment.
35. A method of inhibiting the growth of a microorganism which comprises the step of contacting the microorganism with an effective amount of one or more compounds or pharmaceutically acceptable salts of claim 14 .
36. A method for inhibiting a beta-lactamase which comprises the step of contacting the beta-lactamase with an effective amount of one or more compounds or pharmaceutically acceptable salts of claim 14 .
37. The compound or pharmaceutically acceptable salt of claim 14 , wherein M is:
38. The compound or pharmaceutically acceptable salt of claim 37 , wherein X is a halogen or pyridinium.
39. The compound or pharmaceutically acceptable salt of claim 37 , wherein X is Cl or Br.
40. The compound or pharmaceutically acceptable salt of claim 37 , wherein X is halogen, pyridinium, phenoxy, pentafluorophenoxy, or tosyl.
41. The compound or pharmaceutically acceptable salt of claim 37 , wherein the acyl group of the acylamino group of R is selected from:
42. The compound or pharmaceutically acceptable salt of claim 41 , wherein R″ is hydrogen or a C1-C6 alkyl group and R′″ is hydrogen or a C1-C6 alkyl group.
43. The compound or pharmaceutically acceptable salt thereof of claim 37 , wherein R 1 , R 2 , R 4 and R 5 are all hydrogens.
44. The compound or pharmaceutically acceptable salt thereof of claim 43 , wherein X is halogen or pyridinium.
45. The compound or pharmaceutically acceptable salt thereof of claim 43 , wherein X is pyridinium.
46. The compound or pharmaceutically acceptable salt of claim 43 , wherein X is: