Granted Patent B2

US 12,637,481 · App. 17/906,340 · Granted May 26, 2026

Inventors: Raja K. Reddy (San Diego, CA); David C. Griffith (San Marcos, CA); Emily Rigsbee (West Lafayette, IN); Serge Henri Boyer (San Diego, CA); Scott J. Hecker (Del Mar, CA); Matthew Jonathan Jones (Linz, AT)

Assignee: QPEX BIOPHARMA, INC.

C07F5/025A61K31/69A61K45/06A61P31/04C07B2200/13

Abstract

Claims (65)

1 . A crystalline form of Compound II′:

or a solvate thereof, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ.

2 . The crystalline form of claim 1 , wherein the crystalline form has an endotherm at about 141° C.

3 . A compound having the structure of

or a pharmaceutically acceptable salt of any of the foregoing.

4 . The compound of claim 3 , wherein the compound is anhydrous

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 3 , wherein the pharmaceutically acceptable salt is the sodium salt.

6 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 , and a pharmaceutically acceptable excipient.

7 . The pharmaceutical composition of claim 6 , further comprising an additional medicament.

8 . The pharmaceutical composition of claim 7 , wherein the additional medicament is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

9 . The pharmaceutical composition of claim 8 , wherein the additional medicament is a β-lactam antibacterial agent.

10 . The pharmaceutical composition of claim 9 , wherein the β-lactam antibacterial agent is selected from the group consisting of 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, Cefidericol, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefpodoxime protexil, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442.

11 . The pharmaceutical composition of claim 9 , wherein the β-lactam antibacterial agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, and Panipenem.

12 . The pharmaceutical composition of claim 9 , wherein the β-lactam antibacterial agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam.

13 . The pharmaceutical composition of claim 9 , wherein the β-lactam antibacterial agent is tebipenem pivoxil.

14 . The pharmaceutical composition of claim 9 , wherein the β-lactam antibacterial agent is ceftibuten.

15 . A method of treating a bacterial infection, comprising administering a compound according to claim 3 to a subject in need thereof.

16 . The method of claim 15 , further comprising administering to the subject an additional medicament.

17 . The method of claim 16 , wherein the additional medicament is an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent.

18 . The method of claim 17 , wherein the additional medicament is a β-lactam antibacterial agent.

19 . The method of claim 18 , wherein the β-lactam antibacterial agent is selected from the group consisting of 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, Cefidericol, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefpodoxime protexil, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831, RWJ-333441, and RWJ-333442.

20 . The method of claim 18 , wherein the β-lactam antibacterial agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil, Apapenem, and Panipenem.

21 . The method of claim 18 , wherein the β-lactam antibacterial agent is selected from the group consisting of Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam.

22 . The method of claim 18 , wherein the β-lactam antibacterial agent is tebipenem pivoxil.

23 . The method of claim 18 , wherein the β-lactam antibacterial agent is ceftibuten.

24 . The method of claim 15 , wherein the infection comprises a bacteria selected from the group consisting of 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 para pertussis, 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 , and Staphylococcus saccharolyticus ; or

wherein the infection comprises a bacteria selected from the group consisting of 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 , and Bacteroides splanchnicus.

25 . A method of preparing crystalline Form A or B of Compound II′

wherein crystalline Form A exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 4.3, 7.0, 7.2, 8.3, 11.0, 12.5, 15.0, 16.7, 17.5, 18.2, 19.1, 20.3, 22.3, 22.7, and 25.6 degrees 2θ;

wherein crystalline Form B exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ;

the method comprising the steps of:

(a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate;

(b) heating the crystallization solution;

(c) adding heptane to the crystallization solution; and

(d) adding seed crystals of crystalline Form A of Compound II′ to the crystallization solution; or

the method comprising the steps of:

(a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of isopropyl acetate and isopropanol;

(b) adding heptane to the crystallization solution; and

(c) adding seed crystals of crystalline Form B of Compound II′ to the crystallization solution; or

the method comprising the steps of:

(a) dissolving Compound II′ in a solvent system to form a crystallization solution, wherein the solvent system consists of hexanes and ethyl acetate;

(b) heating the crystallization solution;

(c) initially cooling the crystallization solution;

(d) stirring the crystallization solution;

(e) further cooling the crystallization solution to room temperature; and

(f) allowing the crystallization mixture to stand at room temperature; or

the method comprising the steps of

(a) dissolving Compound II′ in isopropanol to form a crystallization solution;

(b) heating the crystallization solution; and

cooling the crystallization solution to room temperature; or

the method comprising the steps of

(c) dissolving Compound II′ in isopropanol to form a crystallization solution;

(d) heating the crystallization solution; and

(e) cooling the crystallization solution to room temperature.

26 . A method of preparing Compound II′

comprising the steps of:

combining Compound I

or a salt thereof, a halomethyl isobutyrate, and a base in a polar organic solvent to form a reaction mixture 1; wherein the base is an inorganic base containing sodium; and

heating the reaction mixture to a temperature of from about 50° C. to about 80° C. for a period of 0.5 to 24 hours.

27 . A crystalline form of Compound II′:

or a solvate thereof, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising at least three characteristic peaks, wherein said characteristic peaks are selected from approximately 5.1, 7.0, 9.9, 11.0, 11.1, 14.1, 16.4, 17.1, 21.1, 22.3, 22.6, 26.9, and 28.3 degrees 2θ.

28 . The crystalline form of claim 27 , wherein the crystalline form has an endotherm at about 152° C.

29 . The crystalline form of claim 27 , wherein the crystalline form is unsolvated.

30 . The method of claim 26 , wherein the base is NaH 2 PO 4 or Na 2 B 4 O 7 .

Continuity (2)

References Cited (400)