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. Compounds of the invention include those of formula: and pharmacologically acceptable salts thereof where variables Z, Y, M, y, n, R, R 4 , R 5 , R 1 and R 2 are as defined in the specification. M most generally represents a chemical moiety which is in conjugation with the nitrogen of the core beta-lactam ring system of the compound, such that one or more reactive species, e.g., electrophilic or nucleophilic sites are generated on modification of M which is initiated by cleavage of the beta-lactam ring. Also provided are methods of making beta-lactamase inhibitors and beta-lactam antibiotics exhibiting such inhibition. Additionally provided are pharmaceutical compositions containing compounds of the invention for treatment or prevention of bacterial infections and methods of treatment of such infections employing such compounds.
1. A compound of formula:
and pharmacologically acceptable salts thereof wherein:
R is an acylamine group;
R 1 and R 2 , are independently selected from hydrogen, halogen, a (C1-C6) alkyl group, a (C1-C6) alkoxy group or a (C1-C6) —S-alkyl group; each of which groups is optionally substituted;
Y is O—C+ or OR 3 , where R 3 is hydrogen, an alkyl group or an aryl group, each of which groups is optionally substituted, and C+ is a pharmacologically acceptable cation; and M is selected from:
where W is O and R 6 and R 7 are hydrogen, halogen or optionally substituted (C1-C6) alkyl groups; or
where:
each R 8 is independently selected from hydrogen, halogen, or an optionally substituted (C1-C6) alkyl group;
each R 10 is independently selected from hydrogen, halogen, an optionally substituted (C1-C6) alkyl group, or a —CH 2 —X group;
R 12 is selected from hydrogen, an optionally substituted (C1-C6) alkyl group, or X;
R 13 and R 14 are independently selected from hydrogen, an optionally substituted (C1-C6) alkyl group, or X; and
X is a leaving group selected from halogen, a pyridinium, SC(O)R′, —OCOR′, —SH, —SR′, phenoxy, pentafluorophenoxy, tosyl, p-fluorotosyl, p-bromotosyl, p-nitrobenzyltosyl, or pentafluorotosyl group, where R′ is selected from optionally substituted alkyl and aryl groups; and
wherein the compound contains one R 2 and one M group, and formula B is substituted with at least one —CH 2 —X group and formulas E or F are substituted with at least one —CH 2 —X or X group.
2. The compound of claim 1 wherein X is selected from —SC(O)R′, —OCOR′, —SH, —SR′, phenoxy, pentafluorophenoxy, tosyl, p-fluorotosyl, p-bromotosyl, p-nitrobenzyltosyl, pentafluorotosyl, or a pyridinium group, where R′ is selected from optionally substituted alkyl and aryl groups.
3. The compound of claim 1 and pharmacologically acceptable salts thereof wherein:
R 1 and R 2 , are independently selected from hydrogen, halogen, a (C1-C6) alkyl group, or a (C1-C6) alkoxy group; each of which groups is optionally substituted;
and
X is a leaving group selected from the group consisting of halogen, —SC(O)R′, —OCOR′, —SH, —SR′, phenoxy, pentafluorophenoxy, tosyl, p-fluorotosyl, p-bromotosyl, p-nitrobenzyltosyl, and pentafluorotosyl groups, where R′ is selected from optionally substituted alkyl and aryl groups.
4. The compound of claim 1 and pharmacologically acceptable salts thereof
wherein:
R 1 and R 2 , are independently selected from hydrogen, halogen, a (C1-C6) alkyl group, or a (C1-C6) alkoxy group; each of which groups is optionally substituted;
and X is a pyridinium group.
5. The compound of claim 1 wherein the acylamine group has the formula A-CO—NH—, where A-CO is selected from:
where:
U is CH, CH 2 , NH or N;
R″ is selected from hydrogen, (C1-C6) alkyl group, or a 3-7-member-ring cyclic hydrocarbon group each of which groups are optionally substituted; and R′″ is selected from hydrogen, (C1-C6) alkyl group, (C2-C6) alkenyl group, (C2-C6) alkynyl group, (C7-C19) aralkyl group, a 3-7-member-ring cyclic hydrocarbon group, a 3-7 member heterocyclic group, or a (C6-C10) aromatic group, each of which groups are optionally substituted, and wherein syn/anti isomers are included.
6. The compound of claim 5 wherein A-CO is selected from optionally substituted groups:
where R″ is selected from hydrogen and optionally substituted (C1-C6) alkyl groups.
7. The compound of claim 6 wherein M is
8. The compound of claim 7 wherein each R 8 is independently selected from hydrogen or halogen and each R 10 is independently selected from hydrogen, halogen, or a —CH 2 —X, and at least one of R 10 is —CH 2 —X.
9. The compound of claim 8 wherein X is a halogen or a pyridinium group.
10. The compound of claim 9 where A-CO is selected from optionally substituted groups:
11. The compound of claim 1 wherein M is
12. The compound of claim 11 wherein each R 8 is independently selected from hydrogen or halogen and each R 10 is independently selected from hydrogen, halogen, or a —CH 2 —X, and at least one of R 10 is —CH 2 —X.
13. The compound of claim 12 wherein X is a halogen or a pyridinium group.
14. The compound of claim 1 wherein M is:
15. The compound of claim 14 wherein M is a pharmacologically acceptable salt of
16. The compound of claim 15 wherein A is selected from optionally substituted groups:
where R″ is selected from hydrogen and optionally substituted (C1-C6) alkyl groups.
17. Compounds of claim 15 which are pharmacologically acceptable salts of the species of formulas:
18. Compounds of claim 15 which have formula:
19. Compounds of formulas:
pharmacologically acceptable salts thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of claim 1 and a pharmaceutically acceptable carrier.
21. A method of treatment of bacterial infections, which comprises the step of administering a therapeutically effective amount of one or more compounds of claim 1 to an individual in need of treatment.
22. A method of inhibiting the growth of a bacterium which comprises the step of contacting the bacterium with an effective amount of one or more compounds of claim 1 .
23. A method for inhibiting a beta-lactamase which comprises the step of contacting the beta-lactamase with an effective amount of a compound of claim 1 .