CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20120040932A1
• Filed: 08/08/2011
• Published: 02/16/2012
• Est. Priority Date: 08/10/2010
• Status: Active Grant

• Current Assignee: Melinta Therapeutics, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hirst, Gavin, Hecker, Scott, Totrov, Maxim, Griffith, David C., Dudley, Michael N., Boyer, Serge, Reddy, Raja, Rodny, Olga
• Granted Patent: US 8,680,136 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 31/407 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 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• 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 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 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 1 cyclic boronic acid ester 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 formula II:

3. The compound of claim 2 having the defined 3,6-cis-stereochemistry shown in formula IIa:

4. The compound of claim 2 having the defined 3,6-trans-stereochemistry shown in formula IIb:

5. The compound of claim 2, wherein:

R¹ is selected from a group consisting of —

C_1-9alkyl, —

C_2-9alkenyl, —

C_2-9alkynyl, —

NR⁹R¹⁰, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

CH(OH)C_1-9alkylR⁹, —

CH(OH)C_2-9alkenylR⁹, —

CH(OH)C_2-9alkynylR⁹, —

C(═

O)R⁹, —

C(═

O)C_1-9alkylR⁹, —

C(═

O)C_2-9alkenylR⁹, —

C(═

O)C_2-9alkynylR⁹, —

C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

O)NR⁹R¹⁰, —

N(R⁹)C(═

O)OR⁹, —

N(R⁹)C(═

O)C(═

NR¹⁰)R⁹, —

N(R⁹)C(═

O)C_1-4alkylN(R⁹)C(═

O)R⁹, —

N(R⁹)C(═

NR¹⁰)R⁹, —

C(═

NR¹⁰)NR⁹R¹⁰, —

N═

C(R⁹)NR⁹R¹⁰, —

N(R⁹)SO₂R⁹, —

N(R⁹)SO₂NR⁹R¹⁰, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

R⁶ is selected from a group consisting of H, —

C_1-9alkyl, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, —

C(═

O)OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or alternatively R⁶ and an R⁷ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁷ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, R⁶ and an R⁷ or independently an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁸ is independently selected from a group consisting of H, —

NR⁹R¹⁰, —

OR⁹, and —

C_1-9alkylCO₂R⁹, —

C_2-9alkenylCO₂R⁹, and —

C_2-9alkynylCO₂R⁹, or independently, an R⁷ and an R⁸ are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R⁹ is independently selected from a group consisting of H, —

C_1-9alkyl, C_2-9alkenyl, —

C_2-9alkynyl, —

C_1-9alkylR¹¹, —

C_2-9alkenylR¹¹, —

C_2-9alkynylR¹¹, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —

(CH₂)_0-3-carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R¹⁰ is independently selected from a group consisting of H, —

C_1-9alkyl, —

OR⁹, —

CH(═

NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and

X is selected from a group consisting of H, —

CO₂H and carboxylic acid isosteres.

6. The compound of claim 2, wherein n is 1.

7. The compound of claim 2, wherein R², R³, R⁴, and R⁵ are hydrogen.

8. The compound of claim 2, wherein the bond represented by a dashed and solid line is a single bond.

9. The compound of claim 2, wherein the bond represented by a dashed and solid line is a double bond.

10. The compound of claim 1, having the structure of formula IIIa or IIIb:

11. The compound of claim 10, having the 3,7-cis-stereochemistry shown in formula IIIc and IIId:

12. The compound of claim 10, having the 3,7-trans-stereochemistry shown in formula IIIe and IIIf:

13. The compound of claim 1, having the structure of formula IVa, IVb, or IVc:

14. The compound of claim 13, having the 3,8-cis-stereochemistry shown in formula IVd, IVe, and IVf:

15. The compound of claim 13, having the 3,8-trans-stereochemistry shown in formula IVg, IVh, and IVi:

16. The compound claim 1, wherein R⁶ and each R⁷ and R⁸ is hydrogen.

17. The compound of claim 16, wherein m is 1.

18. The compound of claim 17, wherein R¹ is —

NHC(═

O)C_1-9alkylR¹¹.

19. The compound of claim 18, wherein R¹¹ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

20. The compound of claim 19, wherein R¹¹ is thien-2-yl.

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

NHC(═

O)C(═

NOR⁹)R^9′

, wherein R^9′

is selected from the group consisting of C_1-9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl.

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

CO₂H.

23. The compound of claim 1, wherein X is a carboxylic acid isostere.

24. The compound of claim 23, wherein the carboxylic acid isostere is selected from the group consisting of —

P(O)(OR⁹)₂, —

P(O)(R⁹)(OR⁹), —

P(O)(OR¹¹)₂, —

P(O)(R⁹)(OR^12′

), —

CON(R⁹)OH, —

SO₃H, —

SO₂N(R⁹)OH, and

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

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

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

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

29. The pharmaceutical composition of claim 28, further comprising an additional medicament.

30. The composition of claim 29, wherein the additional medicament is selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

31. The composition of claim 30, wherein the additional medicament is a β

-lactam antibacterial agent.

32. The composition of claim 31, 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, 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, Ceftazidime, 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, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442.

33. The composition of claim 31, wherein the β

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

34. The composition of claim 31, wherein the β

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

35. The composition of claim 34, wherein:

the β

-lactam is Tigemonam;

the composition is suitable for oral administration;

X is —

CO₂R¹²; and

R¹² is selected from a group consisting of C_1-9alkyl, —

(CH₂)_0-3—

R₁₁, —

C(R¹³)₂OC(O)C_1-9alkyl, —

C(R¹³)₂OC(O)R¹¹, —

C(R¹³)₂OC(O)OC_1-9alkyl and —

C(R¹³)₂OC(O)OR¹¹.

36. A method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound according to claim 1.

37. The method of claim 36, further comprising administering an additional medicament.

38. The method of claim 37, wherein the additional medicament is selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.

39. The method of claim 38, wherein the additional medicament is a β

-lactam antibacterial agent.

40. The method of claim 39, 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, 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, Ceftazidime, 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, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442.

41. The method of claim 39, wherein the β

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

42. The method of claim 39, wherein the β

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

43. The method of claim 36, wherein the subject is a mammal.

44. The method of claim 43, wherein the mammal is a human.

45. The method of claim 36, 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.

46. The method of claim 36, 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.

47. A sterile container, comprising:

a compound of claim 1 in solid form; and

an antibacterial agent in solid form.

48. The container of claim 47, wherein the antibacterial agent is a β

-lactam.

49. The container of claim 48, 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, 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, Ceftazidime, 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, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, or RWJ-333442.

50. The container of claim 48, wherein the β

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

51. The container of claim 48, wherein the β

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

52. The container of claim 47, wherein the compound and the antibacterial agent are blended.

53. The container of claim 47, wherein the compound and the antibacterial agent are not blended.

54. The container of claim 47, wherein the compound is in crystalline form.

55. The container of claim 47, wherein the antibacterial agent is in crystalline form.

56. The container of claim 47, wherein the compound and the antimicrobial agent are lyophiles.

57. The container of claim 47, wherein the molar ratio of compound to antibacterial agent is from 1:

8 to 8;

1.

58. The container of claim 47, wherein the molar ratio of compound to antibacterial agent is from 1:

2 to 2;

1.

59. The container of claim 47, wherein the molar ratio of compound to antibacterial agent is 1:

1.

60. The container of claim 47, further comprising a pH adjuster.

61. The container of claim 60, wherein the pH adjuster comprises NaOH.

62. The container of claim 60, wherein the pH adjuster comprises citric acid.

63. A method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of the sterile container of claim 47 using a pharmaceutically acceptable diluent.

64. The method of claim 63, wherein the diluent comprises a saline solution.

65. The method of claim 63, wherein the diluent comprises a dextrose solution.

66. A method of administration, comprising administering the reconstituted solution of claim 63 intravenously to a patient.