# US 10,500,195 B2 · Antibacterial compounds > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,500,195 B2 - Document ID: US10500195B2 - Status: Granted - Kind: B2 - Application number: 15/547,487 - Filed: 2017-04-24 - Published: 2018-09-06 - Granted: 2019-12-10 - Earliest claimed: 2017-03-02 - Assignees: Wockhardt Limited - Applicants: Wockhardt Limited - Inventors: Vijaykumar Jagdishwar Patil; Ravikumar Tadiparthi; Piyush Ambalal Patel; Rajib Bhuniya; Sachin Bhagwat; Swapna Shripad Takalkar; Rajesh Chavan; Anusuya Patel; Vipul Rane; Mahesh Vithalbhai Patel - Web page: https://patentgrep.com/patent/US10500195B2 ## CPC - A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) - C07D 471/06: Peri-condensed systems - A61P 31/04: Antibacterial agents - A61K 31/34: having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide - A61K 31/382: having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) - A61K 31/397: having four-membered rings, e.g. azetidine - A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, their preparation, pharmaceutical compositions comprising such compounds and their use in treating and/or preventing bacterial infections are disclosed. ## Claims ### Claim 1 A compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) The compound according to claim 1, selected from: (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; and stereoisomer and pharmaceutically acceptable salts thereof. ### Claim 3 (depends on 1) The compound according to claim 1, selected from: Sodium salt of (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potassium salt of (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potassium salt of (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potassium salt of (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potassium salt of (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; and stereoisomers thereof. ### Claim 4 (depends on 1) A pharmaceutical composition comprising a compound according to claim 1. ### Claim 5 (depends on 4) The pharmaceutical composition according to claim 4, further comprising at least one antibacterial agent or pharmaceutically acceptable salt thereof. ### Claim 6 (depends on 5) The pharmaceutical composition according to claim 5, wherein each of the at least one antibacterial agent is a beta-lactam antibacterial agent. ### Claim 7 (depends on 5) The pharmaceutical composition according to claim 5, wherein each of the at least one antibacterial agent is independently selected from ansamycin, carbacephem, carbapenam, carbapenem, cephalosporin, cephamycin, cephem, lincosamide, lipopeptide, macrolide, ketolide, monobactam, nitrofuran, oxacephem, oxapenam, oxazolidinone, penam, penem, penicillin, polypeptide, quinolone, sulfonamide, and tetracycline antibacterial agents. ### Claim 8 (depends on 5) The pharmaceutical composition according to claim 5, wherein each of the at least one antibacterial agent is independently selected from cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefclidin, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefluprenam, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftolozane, ceftriaxone, cefuroxime, cefuzonam, cephaloridine, cephradine, flomoxef, latamoxef, loracarbef, moxalactam, and pharmaceutically acceptable salts thereof. ### Claim 9 (depends on 5) The pharmaceutical composition according to claim 5, wherein each of the at least one antibacterial agent is independently selected from cefaclor, cefadroxil, cefalexin, cefdinir, cefixime, cefpirome, cefpodoxime, cefprozil, cefradine, ceftibuten, cefuroxime, loracarbef, and pharmaceutically acceptable salts thereof. ### Claim 10 (depends on 1, 2, 3) A method for treating bacterial infection in a subject, said method comprising administering to said subject a compound as in one of claims 1-3. ### Claim 11 (depends on 4, 5, 6, 7, 8, 9) A method for treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutical composition as in one of the claims 4-9. ### Claim 12 (depends on 1) A method for treating bacterial infection in a subject, said method comprising administering to said subject: (a) a compound of Formula (I) according to claim 1 or a stereoisomer or a pharmaceutically acceptable salt thereof, and (b) at least one antibacterial agent or pharmaceutically acceptable salt thereof. ### Claim 13 (depends on 12) The method according to claim 12, wherein the compound of Formula (I) is: (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; or a stereoisomer or a pharmaceutically acceptable salt thereof. ### Claim 14 (depends on 12) The method according to claim 12, wherein the compound of Formula (I) is: Sodium salt of (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Sodium salt of (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potassium salt of (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potasium salt of (2S, 5R)-N-{[(2S, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potasium salt of (2S, 5R)-N-{[(2R, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; Potasium salt of (2S, 5R)-N-{[(2R, 4R)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide; or a stereoisomer thereof. ### Claim 15 (depends on 12) The method according to claim 12, wherein each of the at least one antibacterial agent is a beta-lactam antibacterial agent. ### Claim 16 (depends on 12) The method according to claim 12, wherein each of the at least one antibacterial agent is independently selected from ansamycin, carbacephem, carbapenam, carbapenem, cephalosporin, cephamycin, cephem, lincosamide, lipopeptide, macrolide, ketolide, monobactam, nitrofuran, oxacephem, oxapenam, oxazolidinone, penam, penem, penicillin, polypeptide, quinolone, sulfonamide, and tetracycline antibacterial agents. ### Claim 17 (depends on 12) The method according to claim 12, wherein each of the at least one antibacterial agent is independently selected from cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefclidin, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefluprenam, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftolozane, ceftriaxone, cefuroxime, cefuzonam, cephaloridine, cephradine, flomoxef, latamoxef, loracarbef, moxalactam, and pharmaceutically acceptable salts thereof. ### Claim 18 (depends on 12) The method according to claim 12, wherein each of the at least one antibacterial agent is independently selected from cefaclor, cefadroxil, cefalexin, cefdinir, cefixime, cefpirome, cefpodoxime, cefprozil, cefradine, ceftibuten, cefuroxime, loracarbef, and pharmaceutically acceptable salts thereof. ### Claim 19 A compound which is (2S, 5R)-N-{[(2S, 4S)-4-fluoropyrrolidin-2-yl]methyloxy}-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, or a stereoisomer or a pharmaceutically acceptable salt thereof. ### Claim 20 (depends on 19) A pharmaceutical composition comprising a compound according to claim 19. ### Claim 21 (depends on 20) The pharmaceutical composition according to claim 20, further comprising at least one antibacterial agent or pharmaceutically acceptable derivative thereof. ### Claim 22 (depends on 21) The pharmaceutical composition according to claim 21, wherein each of the at least one antibacterial agent is a beta-lactam antibacterial agent. ### Claim 23 (depends on 21) The pharmaceutical composition according to claim 21, wherein each of the at least one antibacterial agent is independently cefixime, cefpodoxime, ceftibuten, cefuroxime, or a pharmaceutically acceptable salt thereof. ### Claim 24 (depends on 19) A method for treating bacterial infection in a subject, said method comprising administering to said subject a compound according to claim 19. ### Claim 25 (depends on 20, 21, 22, 23) A method for treating bacterial infection in a subject, said method comprising administering to said subject a pharmaceutical composition as in one of claims 20-23. ### Claim 26 A process for preparation of a compound of Formula (Ia): comprising: (a) converting a compound of Formula (IIa) into a compound of Formula (IIIa) in the presence of a fluorinating agent: (b) converting a compound of Formula (IIIa) into a compound of Formula (IVa): (c) converting a compound of Formula (IVa) into a compound of Formula (Va): (d) converting a compound of Formula (Va) into a compound of Formula (VIa): (e) reacting a compound of Formula (VIa) with a compound of Formula (VII) to obtain a compound of Formula (VIIIa): (f) converting a compound of Formula (VIIIa) into a compound of Formula (IXa): (g) converting a compound of Formula (IXa) into a compound of Formula (Xa): and (h) converting a compound of Formula (Xa) into the compound of Formula (Ia).