US010385082B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 385, 082 B2 Cui et al. (45 ) Date of Patent: Aug. 20 , 2019 ( 54 ) ANTIOXIDANT COMPOUNDS AND THEIR ( 2013. 01 ) ; A6IN 1 / 3605 ( 2013 .01 ) ; CO7D USE 487/ 22 ( 2013. 01 ) ; C07F 3 / 02 ( 2013 .01 ) ; COFF 15 / 025 (2013 .01 ) ; C08K 5 / 3432 (2013 .01 ) ; ( 71 ) Applicant: University of Pittsburgh — Of the C09D 5 / 1625 ( 2013 .01 ) ; A61B 2017 /00889 Commonwealth System of Higher ( 2013. 01 ) ; A61B 2017 /00893 (2013 . 01 ) ; A61F Education , Pittsburgh , PA (US ) 2250 / 0067 ( 2013 .01 ) ; A61L 2300 / 404 (72 ) Inventors : Xinyan T. Cui, Wexford , PA (US ) ; ( 2013 .01 ) ; A61M 2205 / 0205 ( 2013 .01 ) Noah Snyder , Glenshaw , PA (US ) ; ( 58 ) Field of Classification Search Kasey Catt, Pittsburgh , PA (US ) ; CPC .. .. A61L 27 / 28 ; A61C 8 /0013 ; A61M James Eles , Pittsburgh , PA (US ) 2205 /0205 ; A61M 25 /0017 ; CO7D 487 / 22 ; C07F 3 /02 (73 ) Assignee : University of Pittsburgh — of the See application file for complete search history . Commonwealth System of Higher Education , Pittsburgh , PA (US ) ( 56 ) References Cited ( * ) Notice : Subject to any disclaimer , the term of this U . S . PATENT DOCUMENTS patent is extended or adjusted under 35 5 , 826 , 369 A 10 / 1998 Jordan U . S . C . 154 (b ) by 0 days . 8 , 183 , 364 B2 5 /2012 Batinic - Haberle et al . 8 , 355 , 802 B2 1 / 2013 Keitel et al . 8 , 946 , 202 B2 2 /2015 Crapo et al . ( 21 ) Appl. No. : 15 /239 ,473 9 ,416 , 282 B2 8 / 2016 Wilker et al. 2008 / 0199506 A1 8 /2008 Horres et al. ( 22 ) Filed : Aug. 17, 2016 2013 / 0034671 A1 2 / 2013 George et al . (65 ) Prior Publication Data 2014 / 0080797 Al 3 / 2014 Batinic -Haberle et al . US 2017 / 0050996 A1 Feb . 23 , 2017 FOREIGN PATENT DOCUMENTS wo WO 2005 / 114720 12 / 2005 Related U . S . Application Data WO WO 2015 /034777 3 / 2015 (60 ) Provisional application No . 62/ 206 , 748 , filed on Aug . WO WO 2015034777 A1 * 3 / 2015 . .. .. A61K 31 / 555 18 , 2015 . WO - 2015034777 A1 * 3 / 2015 . .. .. A61K 31 /555 ( 51 ) Int. Cl. OTHER PUBLICATIONS CO7F 13 / 00 ( 2006 .01 ) A61L 27 / 28 ( 2006 .01 ) Asayama, S . et al. “ Chemical modification of manganese porphyrins CO7F 15 / 02 ( 2006 .01 ) with biomolecules for new functional antioxidants ” J . Biomater . C07D 487 / 22 ( 2006 .01 ) Sci. Polymer Edn , vol. 14 , No . 11, pp . 1169 - 1179 (2003 ) . * CO7F 3 / 02 ( 2006 .01 ) Abutment (http :/ /www .knoxterracedental . com . au /dental - services / A61B 5 /04 ( 2006 .01 ) dental- implants / single - tooth - implant/ ) available Dec . 8 , 2014 , pp . 1 - 3 ( Year: 2014 ) . * A61B 17 /68 ( 2006 .01 ) Asayama, S . et al . “ Chemical modification of manganese porphyrins A61C 8 / 00 ( 2006 .01 ) with biomolecules for new functional antioxidants” J . Biomater. A61F 2 / 24 ( 2006 .01 ) Sci. Polymer Edn , vol. 14 , No. 11 , pp . 1169 - 1179 ( 2003 ) ( Year : A61F 2 / 82 ( 2013 .01 ) 2003 ) . * A61L 26 /00 ( 2006 . 01 ) Dental Post (http : // drstonedds. com / what - is - a -dental - post ) Aug . 19 , A61L 27 /52 ( 2006 .01 ) 2013, pp . 1 - 3 . ( Year : 2013 ) . * A61M 25 / 00 ( 2006 . 01 ) Asayama et al. , " Chemical modification of manganese porphyrins A6IN 1 / 36 ( 2006 .01 ) with biomolecules for new functional antioxidants , ” J . Biomater. A6IN 1 / 362 ( 2006 .01 ) Sci. Polymer Edn. , 2003, 14( 11) , pp . 1169 -1179 . C08K 5 / 3432 ( 2006 .01 ) (Continued ) C09D 5 / 16 ( 2006 .01 ) A61L 2734 ( 2006 .01 ) Primary Examiner - Andrew S Rosenthal A61L 27/ 54 ( 2006 . 01 ) ( 74 ) Attorney , Agent, or Firm — Klarquist Sparkman , A61L 31/ 10 ( 2006 .01 ) LLP A61L 31 / 16 ( 2006 .01 ) A61B 17 / 00 ( 2006 .01 ) (57 ) ABSTRACT (52 ) U . S . CI. Disclosed herein are novel amine - functionalized porphyrin CPC .. .. CO7F 13 /005 ( 2013 .01 ) ; A61B 5 / 04001 compounds , as wells as pharmaceutically acceptable salts or ( 2013 .01 ) ; A61B 17 /68 ( 2013 .01 ) ; A61C esters thereof. The disclosed compounds can be used to 8 / 0013 (2013 . 01 ) ; A61F 2 / 24 ( 2013 .01 ) ; A61F impart antioxidant, anti - inflammatory , anti -microbial , and / 2 /82 (2013 .01 ) ; A61L 26 /008 (2013 .01 ) ; AGIL or cell - adhesion specificity to a surface or material in need 27 /28 ( 2013 . 01 ) ; A61L 27 / 34 ( 2013 . 01 ) ; A61L thereof, such as a surface of an indwelling medical implant, 27/ 52 ( 2013 .01 ) ; A61L 27/ 54 (2013 .01 ) ; A61L or a marine surface . 31 / 10 (2013 . 01 ) ; A61L 31 / 16 ( 2013 .01 ) ; A61M 25 /0017 ( 2013 .01 ) ; AOIN 1362 6 Claims, 15 Drawing Sheets US 10 ,385 ,082 B2 Page 2 References Cited Miriyala et al. , “ Manganese superoxide dismutase , MnSOD and its ( 56 ) mimics , " Biochim . Biophys. Acta , May 2012 , 1822 ( 5 ) , pp . 794 -814 . Potter -Baker et al. , “ Development of superoxide dismutase mimetic surfaces to reduce accumulation of reactive oxygen species for OTHER PUBLICATIONS neural interfacing applications, " J . Mater. Chem . B . Mater. Biol. Azemi et al. , “ Surface immobilization of neural adhesion molecule Med ., Apr. 28 , 2014 , 2 ( 16 ) : pp . 2248 - 2258 . L1 for improving the biocompatibility of chronic neural probes : In Rogers et al. , “ Tandem dispersion and killing of bacteria from a biofilm , ” Org . Biomol. Chem . , 2009 , 7 , pp . 603 -606 . vitro characterization, ” Acta Biomater, Sep . 2008 , 4 (4 ), pp. 1208 Sia et al . , “ Microfluidic devices fabricated in poly - dimethylsiloxane ) 1217 . for biological studies ,” Electrophoresis , Nov . 2003, 24 (21 ) , pp . Chang et al ., “ Cell and protein compatibility of parylene - C sur 3563 - 3576 . faces , ” Langmuir , Nov. 6 , 2007 , 23 ( 23 ) , pp . 11718 - 11725 . Snyder et al ., “ Antioxidant Effects of a SOD mimic Functionalized International Search Report, dated Nov . 9 , 2016 , mailed by the ISA on Neural Implants Surfaces, ” Abstract and Poster Presentation in International Application No . PCT/ US2016 /047290 , 6 pp . 893. 10 /0017 , Oct . 17 , 2012 , Society for Neuroscience Annual Kiselev, BA and Kozlov, YN , “ Photoelectrochemistry of chloro Meeting , New Orleans , LA . phyll monolayers, ” Journal of Electroanalytical Chemistry and Written Opinion of the International Searching Authority , dated Interfacial Electrochemistry , 1980 , 116 , p . 247 -254 . Nov. 9 , 2016 , mailed by the ISA in International Application No. Lewicki. “ A review of methods for spike sorting : the detection and PCT/ US2016 / 047290 , 10 pp . classification of neural action potentials ,” Network : Comput. Neural Zhang et al. , " Chemical surface modification of parylene C for Syst. , 9 , 1998 , R53 - R78 , 26 pp . enhanced protein immobilization and cell proliferation , " Acta Biomater , Luo et al ., “ Pure graphene oxide doped conducting polymer 2011, 7 (10 ), pp . 3746 - 3756 . nanocomposite for bio - interfacing ," J . Mater. Chem . B , 2013 , 1 ( 1 ) , pp . 1340 - 1348 . * cited by examiner atent Aug . 20 , 2019 Sheet 1 of 15 US 10 , 385 ,082 B2 600 550 500 450 . 400 . 350 . , inducente. : . 300 Absortance ISODm FIG.1A Effect'Ortho""Ortho'Effect U .S . Patentatent Aug . 20 , 2019 Sheet 2 of 15 US 10 , 385 , 082 B2 . 250 . 300 . 350 BindingEnergyleV 400 . N1S 450 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : FIG.1B WOOSI499 THANSA 1.MTS 2.GMBS * H atent Aug . 20 , 2019 Sheet 3 of 15 US 10 , 385 , 082 B2 90 H 235 % eeeeeeeeeeeeeeeeeeeeeeeeeeee 230 . 100 285 105 SOMO 280 SY 110 29 FIG.2 130 15 OOOOOO 25 140 02 35 150 28Si Ma3p 45 100 55 2p$ 170 U . S . Patent Aug . 20, 2019 Sheet 4 of 15 US 10 , 385 ,082 B2 075370012x0.+Resvertrol=,Y 068+0.0006xY=MnTBAP,* 061705x+0.7E-SODm,Y= 0770014x+0.PBS,Y=.- 058905x+0.4E-ISODm,Y=* 30 409*** 20 * Time(min) FIG.3 ** *** ** * * * * ) 550nm ~ Absorbance( Oxidation FCC in Change U . S . Patent Aug. 20, 2019 Sheet 5 of 15 US 10 ,385 ,082 B2 FIG . 4 PercentChange(ComparedtoControl) VYYYYYYYOYO. 00299990. Glass iSODM SODIMn???? Resveratrol PMA Cell Stimulation atent Aug . 20 , 2019 Sheet 6 of 15 US 10 , 385 , 082 B2 LPS/IFN PMA . FIG.5 Control ISODm U . S . Patent Aug . 20, 2019 Sheet 7 of 15 US 10 , 385, 082 B2 w 41: . *. * uit n ** . 6.FIGFIG.6 20X 1011 . : ** to . ... #1 :. GFAPtubulinIIIBDAPI Control w U . S . Patent Aug . 20, 2019 Sheet 8 of 15 US 10 ,385 , 082 B2 FIG . 7 CellCount ana ARNA w Control SODm W FIG . 8 AverageCellCount/Bin winning ??????????????????? wi w ningLuncoated uncoated SODm Luncoated SODm Luncoated SODm Luncoated. SODm Luncoated! SODM Luncoated SODm Luncoated SODm uncoated iSoDmLuncoated! * afiSODm home ore 5-100t p 50-75 200ry-125 125 -150lu na 175-Sie200 Lune 200 -225 LUM225 -250 Radius of ring ( Bin ) from implant site ( um> ) atent Aug . 20 , 2019 Sheet 9 of 15 US 10 ,385 , 082 B2 iSODm - coated glass $ FIG . 9A . iSODm - coated glass Mold Hyphae FIG . 9B Uncoated Glass Uncoated Glass * * * Mold Hyphae FIG . 9C ** U . S . Patent Aug . 20, 2019 Sheet 10 of 15 US 10 , 385 ,082 B2 FIG . 10 M * U . S . Patent Aug . 20, 2019 Sheet 11 of 15 US 10 , 385 ,082 B2 FIG . 11 FIG . 12 U . S . Patent Aug . 20, 2019 Sheet 12 of 15 US 10 , 385 , 082 B2 13 Sameatl?ylammeacidition asforSODI Uudiod wwwwwwwwwwwws. FIG.13 ** U . S . Patent Aug . 20, 2019 Sheet 13 of 15 US 10 , 385 , 082 B2 FIG . 14A : 0 hrs 24 hrs 24 hrs VO U . S . Patent Aug. 20 , 2019 Sheet 14 of 15 US 10 , 385 ,082 B2 FIG . 14B Algae accumulation after 1 month incubation in freshwater tank Marine Epoxy : DOS coating Hum1.. * .*icient ciutat 0000000000090400 ** . XXX000 Marine Exopy + 1 % w / v iSODm coating OOC U. S . Patentatent Aug . 20 , 2019 Sheet 15 of 15 US 10 ,385 , 082 B2 250hrs 750hrs 0hrs Accelerated Corrosion Accelerated Corrosion Accelerated Corrosion . HU * * EpoxyCoating(1%w/viSODm) www. MX439 www *** DO Wowowewwwwwwwwwwwwww XXX Ww FIG.15 XXXXXX DRESSESSES EpoxyCoating(noiSODm) CORMOSION UncoatedLEDER WORROSO US 10 , 385 ,082 B2 ANTIOXIDANT COMPOUNDS AND THEIR -continued USE Formula II CROSS REFERENCE TO RELATED APPLICATION This application claims priority to U . S .