HETEROCYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20140206648A1
• Filed: 08/30/2012
• Published: 07/24/2014
• Est. Priority Date: 08/31/2011
• Status: Active Grant

• Current Assignee: The Medicines Company (San Diego), LLC. (Novartis Ag)
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Reddy, Raja K., Boyer, Serge Henri, Totrov, Maxim, Hecker, Scott
• Granted Patent: US 9,012,491 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• 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 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• 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: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• 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 cyclic boronate compounds and their use as therapeutic agents.

Claims

1. A compound having the structure of formula I:

2. The compound of claim 1, having the defined stereochemistry at 3-position shown in formula Ia:

3. The compound of claim 1 wherein Y is CR⁶, having the defined 3,7-trans-stereochemistry shown in formula Ib:

4. The compound of claim 1 wherein Y is CR⁶, having the defined 3,7-cis-stereochemistry shown in formula Ic:

5. The compound of claim 1, wherein R¹ is —

NHC(═

O)R⁹.

6. The compound of claim 5, wherein R⁹ is —

C_1-9alkylR¹¹.

7. The compound of claim 6, wherein R¹¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

8. The compound of claim 7, wherein R¹¹ is thien-2-yl.

9. The compound of claim 1, wherein R¹ is —

N(R⁹)C(═

O)C(═

NR¹⁰)R⁹.

10. The compound of claim 1, wherein R¹ is —

N(R⁹)C(═

O)C(═

C)R⁹R¹⁰)R⁹.

11. The compound of claim 1, wherein R⁹ is —

C_1-9alkyl.

12. The compound of claim 1, wherein R⁹ is —

C_1-9alkylR¹¹.

13. The compound of claim 1, wherein R⁹ is —

C_1-9alkylCO₂R¹².

14. The compound of claim 1, wherein R⁹ is substituted or unsubstituted heteroaryl.

15. The compound of claim 1, wherein G¹ is a bond.

16. The compound of claim 1, wherein G² is —

C(R^eR^f)—

.

17. The compound of claim 1, wherein G² is —

C(═

O)—

.

18. The compound of claim 1, wherein G² is C(═

O)C(R^eR^f)—

.

19. The compound of claim 1, wherein G¹ is —

C(R^aR^b)— and

G² is —

C(R^eR^f)—

.

20. The compound of claim 1, wherein Z is —

O—

.

21. The compound of claim 1, wherein Z is —

S—

.

22. The compound of claim 1, wherein Z is —

N(R⁹)—

.

23. The compound of claim 1, wherein Z is —

N[C(═

O)R⁹]—

.

24. The compound of claim 1, wherein Z is —

N[C(═

O)OR⁹]—

.

25. The compound of claim 1, wherein Z is —

C(R⁹R¹⁰)—

.

26. The compound of claim 1, wherein Z is —

N(R^k)—

.

27. The compound of claim 1, wherein Y is CR⁶.

28. The compound of claim 1, wherein Y is N.

29. The compound of claim 1, wherein m is 1.

30. The compound of claim 1, wherein R⁷ and R⁸ are H.

31. The compound of claim 1, wherein R¹⁰ is —

OR⁹—

.

32. The compound of claim 1 any one of claims 1-30, wherein R¹⁰ is —

C(═

O)OR⁹—

.

33. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted aryl.

34. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted heteroaryl.

35. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted carbocyclyl.

36. The compound of claim 1, wherein R¹¹ is substituted or unsubstituted heterocyclyl.

37. The compound of claim 1, wherein X is CO₂R¹² or carboxylic acid isosteres.

38. The compound of claim 37, wherein X is CO₂H.

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

40. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

42. A method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound of claim 1 or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, further comprising administering an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory went, or an anti-allergic agent.

45. The method of claim 43, wherein the additional medicament is a β

-lactam antibacterial agent.

46. The method of claim 45, 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, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, 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, Cefinetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, or Carumonam.

47. The method of claim 45, wherein the O-lactam is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or Panipenem.

48. The method of claim 45, wherein the O-lactam is selected from Aztreonam, Tigemonam, or Carumonam.

51. The method of claim 42, wherein the infection comprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, 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, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, 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.

52. The method of claim 42, 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.

41. (canceled)

44. (canceled)

49. The method of 42, wherein the subject is a mammal.

50. (canceled)

53-61. -61. (canceled)