1,2,4-oxadiazole and 1,2,4-thiadiazole β-lactamase inhibitors
View Patent ↗β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein
Z is selected from a 1,2,4-oxadiazole or a 1,2,4-thiadiazole;
R is selected from
and
R 1 is selected from:
hydrogen,
wherein R 2 is selected from
wherein each of R 3 , R 4 and R 5 is independently selected from hydrogen, (C 1 -C 3 )-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl, and n is selected from 1, 2 or 3, amino,
wherein R 6 is selected from H, (C 1 -C 3 )-unsubstituted alkyl, amino-(C 2 -C 3 )-alkyl, aminocycloalkyl, hydroxyalkyl,
and each of p and q is independently selected from 1 or 2; and
—CH 2 (R 7 )CH 2 NH 2
wherein R 7 is selected from amino or hydroxyl.
2. The compound of claim 1 wherein Z-R 1 is
wherein X is selected from O or S and wherein R and R 1 are as previously described.
3. The compound of claim 1 wherein Z-R 1 is
wherein X is selected from O or S and wherein R and R 1 are as previously described.
4. A pharmaceutical composition comprising a compound of claim 1 and at least 1 β-lactam antibiotic or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4 wherein the β-lactam antibiotic is selected from the group consisting of: a cephalosporin, a carbapenem and a monobactam.
6. The pharmaceutical composition of claim 5 wherein the cephalosporin is Ceftolozane.
7. The compound of claim 1 wherein the compound of Formula (I) exhibits a binding affinity for the KPC-2 β-lactamase enzyme of at least 250 mM −1 s −1 .
8. A compound selected from the group consisting of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII), and pharmaceutically acceptable salts thereof:
9. A pharmaceutical composition comprising a compound of claim 1 and a cephalosporin antibiotic.
10. The pharmaceutical composition of claim 9 , wherein the cephalosporin antibiotic is selected from the group consisting of: Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazaflur, Cefazedone, Cefazolin, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Cefuzonam, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Cefoperazone, Ceftazidime, Cefclidine, Cefepime, Cefluprenam, Cefoselis, Cefozopran, Cefpirome, Cefquinome, Cefaclomezine, Cefaloram, Cefaparole, Cefcanel, Cefedrolor, Cefempidone, Cefetrizole, Cefivitril, Cefmatilen, Cefmepidium, Cefovecin, Cefoxazole, Cefrotil, Cefsumide, Ceftaroline, Ceftioxide, Cefuracetime, cefbuperazone, cefminox, ceforanide, cefotiam, cefpiramide, cefsulodin, ceftobiprole latamoxef, loracarbef, and Ceftolozane.
11. A pharmaceutical composition comprising a compound of claim 1 and a carbapenem antibiotic.
12. The pharmaceutical composition of claim 11 , wherein the carbapenem antibiotic is selected from the group consisting of: Imipenem, Impenem/Cilastatin, Biapenem, Doripenem, Meropenem, Ertapenem, and Paripenem.
13. A pharmaceutical composition comprising a compound of claim 1 and a monobactam antibiotic.
14. The pharmaceutical composition of claim 13 , wherein the monobactam antibiotic is selected from the group consisting of: Aztreonam, Tigemonam, Carumonam, BAL30072, and Nocardicin A.
15. A pharmaceutical composition comprising a compound of claim 7 and a cephalosporin antibiotic.
16. The pharmaceutical composition of claim 15 , wherein the cephalosporin antibiotic is selected from the group consisting of: Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazaflur, Cefazedone, Cefazolin, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefmetazole, Cefonicid, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Cefuzonam, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefixime, Cefmenoxime, Cefodizime, Cefotaxime, Cefpimizole, Cefpodoxime, Cefteram, Ceftibuten, Ceftiofur, Ceftiolene, Ceftizoxime, Ceftriaxone, Cefoperazone, Ceftazidime, Cefclidine, Cefepime, Cefluprenam, Cefoselis, Cefozopran, Cefpirome, Cefquinome, Cefaclomezine, Cefaloram, Cefaparole, Cefcanel, Cefedrolor, Cefempidone, Cefetrizole, Cefivitril, Cefmatilen, Cefmepidium, Cefovecin, Cefoxazole, Cefrotil, Cefsumide, Ceftaroline, Ceftioxide, Cefuracetime, cefbuperazone, cefminox, ceforanide, cefotiam, cefpiramide, cefsulodin, ceftobiprole latamoxef, loracarbef, and Ceftolozane.
17. A pharmaceutical composition comprising a compound of claim 7 and a carbapenem antibiotic.
18. The pharmaceutical composition of claim 17 , wherein the carbapenem antibiotic is selected from the group consisting of: Imipenem, Impenem/Cilastatin, Biapenem, Doripenem, Meropenem, Ertapenem, and Paripenem.
19. A pharmaceutical composition comprising a compound of claim 7 and a monobactam antibiotic.
20. The pharmaceutical composition of claim 19 , wherein the monobactam antibiotic is selected from the group consisting of: Aztreonam, Tigemonam, Carumonam, BAL30072, and Nocardicin A.