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(12) Patent Application Publication (10) Pub. No.: US 2015/0150995 A1 Taft, III Et Al

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US 2015O150995A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0150995 A1 Taft, III et al. (43) Pub. Date: Jun. 4, 2015 (54) CONJUGATED ANTI-MICROBIAL Publication Classification COMPOUNDS AND CONUGATED ANT-CANCER COMPOUNDS AND USES (51) Int. Cl. THEREOF A647/48 (2006.01) A63/546 (2006.01) (71) Applicant: PONO CORPORATION, Honolulu, HI A633/38 (2006.01) (US) (52) U.S. Cl. CPC ........... A61K47/480.15 (2013.01); A61K33/38 (72) Inventors: Karl Milton Taft, III, Honolulu, HI (2013.01); A61 K3I/546 (2013.01) (US); Jarred Roy Engelking, Honolulu, HI (US) (57) ABSTRACT (73) Assignee: PONO CORPORATION, Honolulu, HI Disclosed herein are synthesis methods for generation of (US) conjugated anti-microbial compounds and conjugated anti cancer compounds. Several embodiments, related to the uses (21) Appl.ppl. NNo.: 14/418,9079 of Such compoundsp in the treatment of infections, in particu lar those caused by drug-resistant bacteria. Some embodi (22) PCT Filed: Aug. 9, 2013 ments relate to targeting cancer based on the metabolic sig (86). PCT No.: PCT/US2O13/O54391 nature of tumor cells. S371 (c)(1), (2) Date: Jan. 30, 2015 NH Related U.S. Application Data O Ag" (60) Provisional application No. 61/742,443, filed on Aug. B-Lactam Silver Ion 9, 2012, provisional application No. 61/742,444, filed on Aug. 9, 2012. O O O O O O HSONaNO -pE (CHO)2SO2 OEt Br2 OEt 2W4 OH NOMe 1 2 3 Q Q H.N.S NH, NHT chicci -VV653C(CH) NaOH Bra-oe 2 2 S1N (C6H5)3C- SNN a NOMe MeO -co. Et MeO -co. Et 4 6 H2S HNC(C6H5)3 H2N-TJO-OA OMe H sen CO2H - HN S OA 1) HCOOH -co." DCC J. a C 2) EtOH, A e MeO (C6H5)3C HO YO O 7 8 HO OMe Me N. O N. O A s M Es HN- HN N all OAC AgN N 2 Nel OAC NH HONO MeOH/H2O N-, OH 3. 9 10 Patent Application Publication Jun. 4, 2015 Sheet 1 of 9 US 2015/O150995 A1 NH Ag" O B-Lactam Silver Ion FIG. Patent Application Publication Jun. 4, 2015 Sheet 2 of 9 US 2015/O150995 A1 Nº?N-N S“? O |(í). OH Patent Application Publication Jun. 4, 2015 Sheet 3 of 9 US 2015/O150995 A1 ?WOOIN []\4() OLO OHO Patent Application Publication Jun. 4, 2015 Sheet 4 of 9 US 2015/O150995 A1 O O NaNO, (CH3O)2SO, l Br2 -N-oe HRHos-H2SO4 1, OEt NOMeOEt 1 2 3 O O i th HN-C(C6H5)3 Br OEt HN1YNH SSN (C6H5)3C-Cl sen NaOH NOMe COEt COEt MeO MeO 4 5 6 HN-T s OMe HN-C(C6H5)3 2 JO-OA A H sen CO2H -(N-- 1) HCOOH co2 H DCC N 2-0 2) EtOH, A MeO CH) C NH HO-so O 7 (C6H5)3 8 HO OMM, OMUM N H S M H S - HNL 2 OACC AgNO3 - HN 2 OA C 2 MeOH/H2O fr O 9 10 FG. L. Patent Application Publication Jun. 4, 2015 Sheet 5 of 9 US 2015/O150995 A1 O Patent Application Publication Jun. 4, 2015 Sheet 6 of 9 US 2015/O150995 A1 F.G. 6A F.G. 6B OH HO HO,--OH HO w 1. O HOY YO | HO O. OH -N . NH OH OHP O H O O O OH 2-OH O OH OH HO F.G. 6C F.G. 6D Patent Application Publication Jun. 4, 2015 Sheet 7 of 9 US 2015/O150995 A1 O O l 1. y 7-O 2 & O O i-K)CS T O O C 2is a Pt N y ss O Os Sr. 5 2 w O O S-g O it a s sae O Z N 5 O 5 R 2 Patent Application Publication Jun. 4, 2015 Sheet 8 of 9 US 2015/O150995 A1 5 p V3. O d o O C O & O C N O O O C - C /" O as O O on 25 o C n 8 OO O O 2 C2 5 O C Y-5 O O 8N S SA s 23A C2 O O C O C Wed C O w O O C Patent Application Publication Jun. 4, 2015 Sheet 9 of 9 US 2015/O150995 A1 O OBn O OH NH 1) CHI, K2CO Schmidt 2) Pd/C, H, Reaction BochN COH BochN COMe BochN COMe 21 22 23 1)NaHCO, Fmoc-ClWl ? NHF OC Oxyma,DIPEA9 EDC H',O 2 eaCOMe 2) TFA ) H, NCO.Me 92Y-N^comeNSN Moc' NHFmoc 24 25 26 S- O O O 1) Morphaline MeOCHC's AgNO3 - MeOCH', A/ 2) EtOH, A N MeOH/HO N-A9 27 28 29 US 2015/O150995 A1 Jun. 4, 2015 CONUGATED ANT-MICROBAL 0007. In several embodiments, the the anti-bacterial agent COMPOUNDS AND CONUGATED is a peroxide generator. Peroxide generators may include, but ANT-CANCER COMPOUNDS AND USES are not limited to vitamin C and E. In additional embodi THEREOF ments, Superoxide generating compounds can be used as the anti-bacterial agent. Further, the anti-bacterial agents may RELATED CASES comprises compounds that promote or otherwise generate a 0001. This application claims the benefit of U.S. Provi localized oxidizing environment, which is damaging to the sional Application Nos. 61/742,443 and 61/742,444, both infectious microorganisms. filed on Aug. 9, 2012 the entire disclosure of each of which is 0008. In several embodiments, the anti-bacterial conju incorporated by reference herein. gate comprises B-lactam antibiotic. In several embodiments, the use of a targeting antibiotic improves the specificity of the BACKGROUND anti-bacterial conjugate (e.g., to reduce the risk of adverse side effects of the anti-bacterial agent on normal, non-infec 0002 1. Field tious cells). In several embodiments, the B-lactam antibiotic 0003. Several embodiments of the invention relate gener comprises one or more of aminopenicillin, amoxicillin, ampi ally to processes for synthesizing antimicrobial agents that cillin, pivampicillin, hetacillin, bacampicillin, metampicillin, are effective against targets such as gram-negative and gram talampicillin, epicillin, carboxypenicillin, carbenicillin (i.e. positive bacteria, gram-variable, and gram-indeterminate carindacillin), ticarcillin, temocillin, ureidopenicillins, bacteria, including multidrug resistant strains, viruses, fungi, aZlocillin, piperacillin, mezlocillin, mecillinam (or pivmecil and other microorganisms. Additionally, several embodi linam), Sulbenicillin, methicillin, benzylpenicillin, clometo ments relate generally to processes for synthesizing and using cillin, benzathine benzylpenicillin, procaine benzylpenicil novel compounds as anti-cancer agents. Methods for using lin, azidocillin, penamecillin, phenoxymethylpenicillin, the resultant compounds to treat or prevent microbial infec penicillin G, penicillin V, epropicillin, benzathine phenoxym tions and/or cancer are also disclosed herein. ethylpenicillin, pheneticillin, cloxacillin, dicloxacillin, flu 0004 2. Description of Related Art cloxacillin, oxacillin, meticillin, nafcillin, faropenem, biap 0005 Pathogenic microbial agents include viruses, bacte enem, ertapenem, antipseudomonal, doripenem, imipenem, ria, fungi, parasites, and prions, among others and may be meropenem, panipenem, cefazolin, cefacetrile, cefadroxil, primary or opportunistic pathogens. Primary pathogens cause cephalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, infection as a direct result of their virulence, while opportu cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, nistic pathogens typically require a compromised host cefroxadine, ceftezole, cefaclor, cefamandole, cefiminox, defense system to produce an infection. While modern medi cefonicid, ceforanide, cefotiam, cefprozil, cefbuperaZone, cine has reduced the prevalence of many infections due to cefuroxime, cefuZonam, cephamycin, cefoxitin, cefotetan, pathogenic microorganisms, such microorganisms continue cefnetazole, carbacephem, loracarbef, cefixime, ceftriaxone, to account for a large degree of morbidity and mortality. antipseudomonal B-lactam, ceftazidime, cefoperaZone, cef capene, cefdaloxime, cefdinir, cefditoren, cefetamet, cef SUMMARY menoXime, cefodizime, cefotaxime, cefpimizole, cefpira 0006 Given the increasing prevalence of microorganisms mide, cefpodoxime, cefsulodin, cefteram, ceftibuten, that are resistant to one or more types of drugs, there is a ceftiolene, ceftizoxime, oxacephem, flomoxef, latamoxef. significant need to reduce the associated morbidity and mor cefepime, cefoZopran, cefpirome, cefiguinome, ceftobiprole, tality related to infections by Such microorganisms. To ceftaroline fosamil, ceftiofur, cefiguinome, cefoVecin, aztre address not only infections from drug-resistant microorgan onam, tigemonam, carumonam, nocardicin A, Sulbactam, isms, but also from non-resistant microorganisms, there is taZobactam, clavam, clavulanic acid, imipenem, cilastatin, provided herein, in several embodiments, an anti-bacterial and Sultamicillin. conjugate, comprising a targeting antibiotic and an anti-bac 0009. In several embodiments, the B-lactam antibiotic terial agent, wherein the anti-bacterial agent has generalized comprises one or more of cefazolin, a cefotaxime derivative, anti-bacterial activity, and wherein the anti-bacterial agent is a cephalothin derivative, a tetracycline derivative, a ceftriax an agent to which bacteria do not develop resistance. In sev one derivative, and an aztreonam derivative (e.g., the anti eral embodiments, the anti-bacterial agent is a microbicidal bacterial conjugate may, in some embodiments, comprise a metal or metallic ion. In several embodiments, the metal or mixture of various targeting antibodies). In additional metallic ion is selected from the group consisting of silver, embodiments, non-f-lactam antibiotics are used as the tar mercury, copper, iron, lead, zinc, bismuth, gold, aluminum, geting antibodies. and combinations thereof. In one embodiment, the anti-bac 0010 Furthermore, there is provided herein a method of terial agent is ionic silver. In additional embodiments, other treating or preventing a bacterial infection in a subject, com metals or metallic ions may be used, including but not limited prising identifying a subject Suffering from a bacterial infec to Sc,Ti,V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Rb, Sr, Y, Zr, Nb, tion or in need of bacterial infection prophylaxis; and deliv Mo, Tc, Ru, Rh, Pd, Cd, In, Sn, Cs, Ba, Ce, Pr, Nd, Pm, Sm, ering an anti-bacterial conjugate according to any of the Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Jr., Pt, embodiments disclosed herein, thereby treating the infection.
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    Andrew V DeLong, Jared C Harris, Brittany S Larcart, Chandler B Massey, Chelsie D Northcutt, Somuayiro N Nwokike, Oscar A Otieno, Harsh M Patel, Mehulkumar P Patel, Pratik Pravin Patel, Eugene I Rowell, Brandon M Rush, Marc-Edwin G Saint-Louis, Amy M Vardeman, Felicia N Woods, Giso Abadi, Thomas J. Manning Computational Antibiotics Valdosta State University is located in South Georgia. Computational Antibiotics Index • Computational Details and Website Access (p. 8) • Acknowledgements (p. 9) • Dedications (p. 11) • Antibiotic Historical Introduction (p. 13) Introduction to Antibiotic groups • Penicillin’s (p. 21) • Carbapenems (p. 22) • Oxazolidines (p. 23) • Rifamycin (p. 24) • Lincosamides (p. 25) • Quinolones (p. 26) • Polypeptides antibiotics (p. 27) • Glycopeptide Antibiotics (p. 28) • Sulfonamides (p. 29) • Lipoglycopeptides (p. 30) • First Generation Cephalosporins (p. 31) • Cephalosporin Third Generation (p. 32) • Fourth-Generation Cephalosporins (p. 33) • Fifth Generation Cephalosporin’s (p. 34) • Tetracycline antibiotics (p. 35) Computational Antibiotics Antibiotics Covered (in alphabetical order) Amikacin (p. 36) Cefempidone (p. 98) Ceftizoxime (p. 159) Amoxicillin (p. 38) Cefepime (p. 100) Ceftobiprole (p. 161) Ampicillin (p. 40) Cefetamet (p. 102) Ceftoxide (p. 163) Arsphenamine (p. 42) Cefetrizole (p. 104) Ceftriaxone (p. 165) Azithromycin (p.44) Cefivitril (p. 106) Cefuracetime (p. 167) Aziocillin (p. 46) Cefixime (p. 108) Cefuroxime (p. 169) Aztreonam (p.48) Cefmatilen ( p. 110) Cefuzonam (p. 171) Bacampicillin (p. 50) Cefmetazole (p. 112) Cefalexin (p. 173) Bacitracin (p. 52) Cefodizime (p. 114) Chloramphenicol (p.175) Balofloxacin (p. 54) Cefonicid (p. 116) Cilastatin (p. 177) Carbenicillin (p. 56) Cefoperazone (p. 118) Ciprofloxacin (p. 179) Cefacetrile (p. 58) Cefoselis (p. 120) Clarithromycin (p. 181) Cefaclor (p.
  • Antibiotic Use for Sepsis in Neonates and Children: 2016 Evidence Update

    Antibiotic Use for Sepsis in Neonates and Children: 2016 Evidence Update

    Antibiotic Use for Sepsis in Neonates and Children: 2016 Evidence Update Aline Fuchsa, Julia Bielickia,b, Shrey Mathurb, Mike Sharlandb, Johannes N. Van Den Ankera,c a Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland b Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, London, United Kingdom c Division of Clinical Pharmacology, Children’s National Health System, Washington, DC, USA WHO-Reviews 1 TABLE OF CONTENTS 1. INTRODUCTION ............................................................................................................................... 3 1.1. Aims ......................................................................................................................................... 3 1.2. Background ............................................................................................................................. 3 1.2.1. Definition and diagnosis ................................................................................................. 3 Neonatal Sepsis ............................................................................................................................... 3 Paediatric Sepsis ............................................................................................................................. 4 Community versus hospital acquired sepsis .................................................................................. 5 1.2.2. Microbiology ..................................................................................................................