Claims for Patent: 10,172,874

Summary for Patent: 10,172,874

Title:	Pharmaceutical compositions comprising cyclic boronic acid ester derivatives
Abstract:	Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to cyclic boronic acid ester derivatives and their use as therapeutic agents.
Inventor(s):	Hirst; Gavin (San Diego, CA), Reddy; Raja (San Diego, CA), Hecker; Scott (Del Mar, CA), Totrov; Maxim (San Diego, CA), Griffith; David C. (San Marcos, CA), Rodny; Olga (Mill Valley, CA), Dudley; Michael N. (San Diego, CA), Boyer; Serge (San Diego, CA)
Assignee:	REMPEX PHARMACEUTICALS, INC. (San Diego, CA)
Application Number:	15/935,862
Patent Claims:	1. A pharmaceutical composition comprising a compound of Formula (I) and an additional medicament selected from the group consisting of an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent, wherein Formula (I) has the structure: ##STR00210## or a pharmaceutically acceptable salt thereof, wherein: Y is a 1-4 atom alkylene or 2-4 atom alkenylene linker, optionally substituted by one or more substituents selected from the group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, wherein said alkylene or alkenylene linker is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R.sup.1 is selected from a group consisting of --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, -carbocyclyl-R.sup.11, --CH(OH)C.sub.1-9alkylR.sup.9, --CH(OH)C.sub.2-9alkenylR.sup.9, --CH(OH)C.sub.2-9alkynylR.sup.9, --CH(OH)carbocyclyl-R.sup.9, --C(.dbd.O)R.sup.9, --C(.dbd.O)C.sub.1-9alkylR.sup.9, --C(.dbd.O)C.sub.2-9alkenylR.sup.9, --C(.dbd.O)C.sub.2-9alkynylR.sup.9, --C(.dbd.O)C.sub.2-9carbocyclyl-R.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)OR.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.NR.sup.11)R.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.CR.sup.9R.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C.sub.1-4alkylN(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.NR.sup.10)R.sup.9, --C(.dbd.NR)NR.sup.9R.sup.10, --N.dbd.C(R.sup.9)NR.sup.9R.sup.10, --N(R.sup.9)SO.sub.2R.sup.9, --N(R.sup.9)SO.sub.2NR.sup.9R.sup.10, --N.dbd.CHR.sup.9, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; R.sup.6 is selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, carbocyclyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, carbocyclyl-R.sup.11, --C(.dbd.O)OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, and -carbocyclyl-CO.sub.2R.sup.9, or alternatively: (i) R.sup.6 and an R.sup.7 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, or (ii) R.sup.6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring; each R.sup.7 is independently selected from a group consisting of H, halo, --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, and -carbocyclyl-CO.sub.2R.sup.9, or independently: (i) R.sup.6 and an R.sup.7 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, or (ii) R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl; each R.sup.8 is independently selected from a group consisting of H, halo, --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, -carbocyclyl-CO.sub.2R.sup.9, or independently: (i) an R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form an optionally substituted carbocyclyl or optionally substituted heterocyclyl, (ii) a geminal R.sup.7 and R.sup.8 together form --C.sub.2-9 alkenylenylCO.sub.2R.sup.9, or (iii) each R.sup.8 attached to a ring atom forming part of an optionally substituted aryl is absent; each R.sup.9 is independently selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, carbocyclyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, -carbocyclyl-R.sup.11, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; each R.sup.10 is independently selected from a group consisting of H, --C.sub.1-9alkyl, --OR.sup.9, --CH(.dbd.NH), --C(.dbd.O)OR.sup.9, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; each R.sup.11 is independently selected from a group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; X is selected from a group consisting of --CO.sub.2R.sup.12, and a carboxylic acid isostere; R.sup.12 is selected from a group consisting of H, C.sub.1-9alkyl, --(CH.sub.2).sub.0-3--R.sub.11, --C(R.sup.13).sub.2OC(O)C.sub.1-9alkyl, --C(R.sup.13).sub.2OC(O)R.sup.11, --C(R.sup.13).sub.2OC(O)OC.sub.1-9alkyl and --C(R.sup.13).sub.2OC(O)OR.sup.11; each R.sup.13 is independently selected from a group consisting of H and C.sub.1-4alkyl; and m is independently zero or an integer from 1 to 2, wherein each C.sub.1-9alkyl, C.sub.2-9alkenyl, and C.sub.2-9alkynyl is independently optionally substituted. 2. The pharmaceutical composition of claim 1, having the structure of formula II: ##STR00211## or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond with the proviso that the dashed and solid line can only be a double bond when n is 1; R.sup.1 is selected from a group consisting of --NR.sup.9R.sup.10, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, -carbocyclyl-R.sup.11, --CH(OH)C.sub.1-9alkylR.sup.9, --CH(OH)C.sub.2-9alkenylR.sup.9, --CH(OH)C.sub.2-9alkynylR.sup.9, --CH(OH)carbocyclyl-R.sup.9, --C(.dbd.O)R.sup.9, --C(.dbd.O)C.sub.1-9alkylR.sup.9, --C(.dbd.O)C.sub.2-9alkenylR.sup.9, --C(.dbd.O)C.sub.2-9alkynylR.sup.9, --C(.dbd.O)C.sub.2-9carbocyclyl-R.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)OR.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.NR.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.CR.sup.9R.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C.sub.1-4 alkylN(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.NR.sup.10)R.sup.9, --C(NR.sup.10)NR.sup.9R.sup.10, --N.dbd.C(R.sup.9)NR.sup.9R.sup.10, --N(R.sup.9)SO.sub.2R.sup.9, --N(R.sup.9)SO.sub.2NR.sup.9R.sup.10, --N.dbd.CHR.sup.9, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; R.sup.2 and R.sup.4 are independently selected from a group consisting of H, Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9; R.sup.3 and R.sup.5 are independently selected from a group consisting of H, Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, with the proviso that if the bond represented by a dashed and solid line is a double bond then R.sup.3 and R.sup.5 are absent; R.sup.6 is selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, --C(.dbd.O)OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9; each R.sup.7 is independently selected from a group consisting of H, --NR.sup.9R.sup.10, --OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9; each R.sup.8 is independently selected from a group consisting of H, --NR.sup.9R.sup.10, --OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9; each R.sup.9 is independently selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted --(CH.sub.2).sub.0-3carbocyclyl, and optionally substituted heterocyclyl; each R.sup.10 is independently selected from a group consisting of H, --C.sub.1-9alkyl, --OR.sup.9, --CH(.dbd.NH), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl; X is --CO.sub.2H; and n is independently zero or an integer from 1 to 2. 3. The pharmaceutical composition of claim 2, wherein n is 1. 4. The pharmaceutical composition of claim 2, wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are hydrogen. 5. The pharmaceutical composition of claim 1, wherein the compound has the structure of formula Ma, IIIb, IVa, IVb, or IVc: ##STR00212## or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond; each R.sup.2 and R.sup.4 are independently selected from a group consisting of H, Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9; and each R.sup.3 and R.sup.5 are independently selected from a group consisting of H, Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, with the proviso that if the bond represented by a dashed and solid line is a double bond then R.sup.3 and R.sup.5 are absent. 6. The pharmaceutical composition of claim 1, wherein R.sup.1 is --NHC(.dbd.O)C.sub.1-9alkylR.sup.11. 7. The pharmaceutical composition of claim 6, wherein R.sup.11 is optionally substituted aryl or optionally substituted heteroaryl. 8. The pharmaceutical composition of claim 7, wherein R.sup.11 is thien-2-yl. 9. The pharmaceutical composition of claim 1, wherein m is 1. 10. The pharmaceutical composition of claim 1, wherein R.sup.6 and each R.sup.7 and R.sup.8 is hydrogen. 11. The pharmaceutical composition of claim 1, wherein X is --CO.sub.2H. 12. The pharmaceutical composition of claim 1, having a structure selected from the group consisting of: ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228## or a pharmaceutically acceptable salt thereof. 13. The pharmaceutical composition of claim 1, wherein the compound is: ##STR00229## or a pharmaceutically acceptable salt thereof. 14. The pharmaceutical composition of claim 1, wherein the additional medicament is a .beta.-lactam antibacterial agent. 15. The pharmaceutical composition of claim 14, wherein the .beta.-lactam antibacterial agent is a carbapenem selected from the group consisting of simipenem, biapenem, doripenem, meropenem, and ertapenem. 16. The pharmaceutical composition of claim 15, wherein the carbapenem is meropenem. 17. The pharmaceutical composition of claim 14, wherein the .beta.-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, 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, RWJ-333441, ME1036, BAL30072, BAL19764, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, and RWJ-333442. 18. The pharmaceutical composition of claim 1, in a solid form. 19. The pharmaceutical composition of claim 1, further comprising sodium carbonate. 20. The pharmaceutical composition of claim 1, further comprising saline. 21. A pharmaceutical composition in a solid form comprising a compound and meropenem, the compound having the structure: ##STR00230## or a pharmaceutically acceptable salt thereof. 22. The pharmaceutical composition of claim 21, further comprising sodium carbonate. 23. A pharmaceutical composition comprising a compound, meropenem, sodium carbonate and saline, the compound having the structure: ##STR00231## or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising a compound and meropenem, the compound having the structure: ##STR00232## or a pharmaceutically acceptable salt thereof.