Boronic acid derivatives and therapeutic uses thereof

• US 9,101,638 B2
• Filed: 03/14/2013
• Issued: 08/11/2015
• Est. Priority Date: 01/04/2013
• Status: Expired due to Fees

• Current Assignee: The Medicines Company (San Diego), LLC. (Novartis Ag)
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Reddy, Raja, Glinka, Tomasz, Totrov, Maxim, Hecker, Scott
• Primary Examiner(s): Carter, Kendra D
• Application Number:
  US13/829,687
• Publication Number:
  US 20140194382A1
• Time in Patent Office: 880 Days
• Field of Search: 514/64, 544/229, 546/13, 548/110, 562/432
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/02 Boron compounds
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

Claims

1. A compound having the structure of formula I:

2. The compound of claim 1, having the structure of (Ia):

3. The compound of claim 1, wherein R is H.

4. The compound of claim 1, wherein R⁴ is H.

5. The compound of claim 1, wherein G is H.

6. The compound of claim 1, wherein G is —

NH₂.

7. The compound of claim 1, wherein G is —

C(O)NR¹R² and R¹ and R² are each independently selected from —

H and C_1-4alkyl.

8. The compound of claim 7, wherein R¹ is —

CH₃ and R² is —

CH₃.

9. The compound of claim 1, wherein G is —

CH₂C(O)NR¹R² and R¹ and R² are each independently selected from —

H and C_1-4alkyl.

10. The compound of claim 9, wherein R¹ is —

CH₃ and R² is —

CH₃.

11. The compound of claim 1, wherein R³ is CH₃.

12. The compound of claim 1, wherein:

G is Cl_2-Y—

Z;

Y is —

S—

; and

Z is selected from the group consisting of imidazole, N-methylimidazole, aminoimidazole, triazole, N-methyl triazole, aminotriazole, tetrazole, N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole, aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidine and pyrazine.

13. The compound of claim 12, wherein Z is N-methyltetrazole.

14. The compound of claim 12, wherein Z is thiadiazole.

15. The compound of claim 12, wherein Z is aminothiadiazole.

16. The compound of claim 1, wherein:

G is —

CH_2-Y—

X; and

Y is —

S—

.

17. The compound of claim 16, wherein X is CH₃.

18. The compound of claim 16, wherein X is CH₂CN.

19. The compound of claim 16, wherein X is CH₂N₃.

20. The compound of claim 16, wherein X is —

CH₂F.

21. The compound of claim 16, wherein X is —

CHF₂.

22. The compound of claim 16, wherein X is —

CF₃.

23. The compound of claim 1, having the structure selected from the group consisting of:

24. The compound of claim 1, having the structure selected from the group consisting of

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

31. The pharmaceutical composition of claim 30, further comprising an additional medicament.

32. The composition of claim 31, wherein the additional medicament is selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

33. The composition of claim 32, wherein the additional medicament is a β

-lactam antibacterial agent.

34. The composition of claim 33, wherein the β

-lactam is selected from Amoxicillin, Ampicillin, Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin, Epicillin, Carbenicillin, Carindacillin, Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam, Pivmecillinam, Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RW1-333441, or RWJ-333442.

35. The composition of claim 33, wherein the β

-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.

36. The composition of claim 33, wherein the β

-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

37. A method of treating a bacterial infection, comprising administering to a subject in need thereof, a compound according to claim 1 and a B-lactam antibacterial agent.

38. The method of claim 37, wherein the β

-lactam is selected from Amoxicillin, Ampicillin, Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin, Epicillin, Carbenicillin, Carindacillin, Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam, Pivmecillinam, Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, or RWJ-333442.

39. The method of claim 37, wherein the β

-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.

40. The method of claim 37, wherein the β

-lactam is selected from Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

41. The method of claim 37, wherein the subject is a mammal.

42. The method of claim 41, wherein the mammal is a human.

43. The method of claim 37, wherein the infection comprises a bacteria selected from Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella, Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452A homology group, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.

44. The method of claim 37, wherein the infection comprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.

25. A compound having the structure of formula II:

26. The compound of claim 25, having the structure of:

27. The compound of claim 25, having the structure selected from the group consisting of:

28. The compound of claim 25, having the structure selected from the group consisting of:

29. The compound of claim 25, wherein G is selected from the group consisting of