(12) United States Patent (10) Patent No.: US 8,173,622 B2 Wu Et Al
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US008173622B2 (12) United States Patent (10) Patent No.: US 8,173,622 B2 Wu et al. (45) Date of Patent: May 8, 2012 (54) ANTMICROBAL COMPOUNDS HAVING FOREIGN PATENT DOCUMENTS PROTECTIVE OR THERAPEUTICLEAVING JP O6049.220 A * 2, 1994 GROUPS JP O926.3731. A * 10, 1997 JP 2007-217683 A 8, 2007 (75) Inventors: Paul Hsien-Fu Wu, Edina, MN (US); WO WO 2007/O19478 A2 2, 2007 Catherine E. Taylor, Fridley, MN (US); OTHER PUBLICATIONS Linnus Cheruiyot, Andover, MN (US); English Machine translation of above JP 06049220A Feb. 1994 (9 Jianwei Li, Woodbury, MN (US); Terese pages). A. Bartlett, Forest Lake, MN (US); English Machine translation of above JP 09263.731A Oct. 1997 (43 Matt Bergan, Forest Lake, MN (US) pages). (PCT/US2009/053340) PCT Notification of Transmittal of the Inter national Search Report and the Written Opinion of the International (73) Assignee: Medtronic, Inc., Minneapolis, MN (US) Searching Authority. Database Registry, "Benzoic Acid, 4-(phenylmethoxy)-ethyl ester'. (*) Notice: Subject to any disclaimer, the term of this Nov. 16, 1984, XPOO2552306. patent is extended or adjusted under 35 Database Registry, Benzene, 1-methyl-1-(2-propen-1-yloxy) ethyl, U.S.C. 154(b) by 379 days. Nov. 16, 1984, XPOO25523.07. Database WPI Week 200780, Thomson Scientific, London, GB, AN (21) Appl. No.: 12/192,268 2007-864.588 & JP 2007 217683A (Hitachi Chem Co Ltd) Aug. 30, 2007, XP002662308. (22) Filed: Aug. 15, 2008 Yun-mi Kimetal. Structure-Antimicrobial Activity Relationship for Silanols, a New Class of Disinfectants, Compared with Alcohols and Prior Publication Data Phenols, International Journal of Antimicrobial Agents 29 (2007) (65) 217-222. US 2009/OO47321 A1 Feb. 19, 2009 Yun-mi Kim et al., Silanol-A Novel Class of Antimicrobial Agent, Electronic Journal of Biotechnology ISSN: 0717-3458, vol.9, No. 2, Related U.S. Application Data Issue of Apr. 15, 2006. (60) Provisional application No. 60/956,068, filed on Aug. * cited by examiner 15, 2007. Primary Examiner — Bethany Barham (51) Int. C. (74) Attorney, Agent, or Firm — Mueting Raasch & AOIN 55/00 (2006.01) Gebhardt, PA. (52) U.S. Cl. ............................................ 514/63:528/10 (58) Field of Classification Search ........................ None (57) ABSTRACT See application file for complete search history. Antimicrobial compounds, such as silanol or alcohol, include a protecting or leaving group that can protect the compound (56) References Cited from degradation during the process of preparing a medical device containing the compound or reduce the Volatility of the U.S. PATENT DOCUMENTS compound relative to its counterpart without the leaving 4,208,312 A * 6/1980 Okada et al. .................. 524/773 group. Nearly any hydrolysable leaving group may be 4,292.219 A 9/1981 Lyons et al. employed. The leaving group may be an agent that may serve 4.565,883 A * 1/1986 Sieger et al. ..... 549,475 a therapeutic function in addition to protecting or retainin 5.449,734. A * 9/1995 Kotani et al. ... ... 528, 12 peutic I p 9. 9. 2003/0129397 A1* 7, 2003 Wilson et al. ................. 428,375 the antimicrobial agents. 2006, O194764 A1 8, 2006 Kim et al. 2008/O125728 A1 5, 2008 Bischoff et al. 18 Claims, 1 Drawing Sheet U.S. Patent May 8, 2012 US 8,173,622 B2 10 US 8,173,622 B2 1. 2 ANTMICROBAL COMPOUNDS HAVING In an embodiment, a compound having the structure of PROTECTIVE OR THERAPEUTICLEAVING Formula VI is described: GROUPS RELATED APPLICATION (VI) O R This application claims the benefit of provisional U.S. UO-C o-- (A), where Application Ser. No. 60/956,068, filed Aug. 15, 2007. R FIELD OF THE INVENTION 10 U is hydrogen or straight or branched chain C1-C4 alkyl This application relates to antimicrobial agents for medical unsubstituted or substituted with halo or hydroxyl: devices and methods for forming devices having antimicro R and R are each independently hydrogen or C1-C5 bial agents; and, more particularly, to compounds, composi 15 straight or branched chain alkyl; tions and methods employing antimicrobial alcohols or sil A is hydrogen or straight or branched chain C1-C18 alkyl anols or compounds hydrolysable into alcohols or silanols. unsubstituted or substituted with halo or hydroxyl: Z is benzene, furan, pyrrole, thiophene or a cyclic structure BACKGROUND OF THE INVENTION according to Huckel's rule (4H--2), unsubstituted or sub stituted with straight or branched chain C1-C6 alkyl Silanol compounds have been reported to possess antimi unsubstituted or substituted with halo or hydroxyl: crobial activity. The antimicrobial activity may be due to high p is 0 or 1; and acidity and hydrophobicity relative to their alcohol counter G is silicon or carbon. parts. However, use of silanols as antimicrobial agents in A compound according to Formula VI may hydrolyze in medical device applications has drawbacks. For example, 25 situ into an antimicrobial paraben and an antimicrobial sil silanols tend to be volatile. Some silanols may also undergo anol, which may provide enhanced antibiotic efficacy relative condensation reaction and form siloxanes. Both of these char to the paraben or silanol alone. acteristics of silanols tends to leave little initial silanol In an embodiment, a compound having the structure of remaining by the time an implantable medical device con Formula I is described: taining the silanol is implanted in a patient. 30 SUMMARY (I) R The present disclosure describes hydroxyl compounds (such as silanol oralcohol) that containa protecting or leaving Q-O-G-Z(A), where group that can protect the hydroxyl compound from degra 35 dation during the process of preparing a medical device or R reduce the volatility of the compound relative to its counter part without the leaving group. Nearly any hydrolysable leav Q is a precursor to a steroid such that when hydrolyzed to ing group may be employed. In various embodiments the Q-OH, Q-OH acts as a steroid: leaving group is an agent that may serve a therapeutic func 40 R and R are each independently hydrogen or C1-C5 tion in addition to protecting or retaining the silanol. straight or branched chain alkyl; In an embodiment, a polymeric composition includes a A is hydrogen or straight or branched chain C1-C18 alkyl polymeric material and a compound of according to Formula unsubstituted or substituted with halo or hydroxyl: I: Z is benzene, furan, pyrrole, thiophene or a cyclic structure 45 according to Huckel's rule (4H--2), unsubstituted or sub stituted with straight or branched chain C1-C6 alkyl (I) unsubstituted or substituted with halo or hydroxyl: R p is 0 or 1; and Q-O-G-Z,(A), where 50 with the proviso that when p is 0, A is not hydrogen. G is silicon or carbon. R2 Such a compound may result in a steroid and an antimicro bial silanol upon hydrolysis in situ. Q is any hydrolyzable group having a molecular weight In an embodiment, a compound having the structure of Formula V is described: greater than or equal to methyl or greater than about 15 55 Daltons, R and R are each independently hydrogen or C1-C5 (V) straight or branched chain alkyl, methyl or ethyl: R A is hydrogen or straight or branched chain C1-C18 alkyl unsubstituted or substituted with halo or hydroxyl: 60 where Zis benzene, furan, pyrrole, thiophene or a cyclic structure according to Huckel's rule (4H--2), unsubstituted or sub R stituted with straight or branched chain C1-C6 alkyl unsubstituted or substituted with halo or hydroxyl: Y is straight or branched chain C1-C18 alkyl unsubstituted p is 0 or 1; and 65 or substituted with halo or hydroxyl; with the proviso that when p is 0, A is not hydrogen. R and R are each independently hydrogen or C1-C5 G is silicon or carbon. straight or branched chain alkyl; US 8,173,622 B2 3 A is hydrogen or straight or branched chain C1-C18 alkyl unsubstituted or substituted with halo or hydroxyl: (I) Zis benzene, furan, pyrrole, thiophene or a cyclic structure R according to Huckel's rule (4H--2), unsubstituted or sub Q-O-G-Z(A), where: stituted with straight or branched chain C1-C6 alkyl unsubstituted or substituted with halo or hydroxyl: n, and pare each independently 0 or 1; and Q is any hydrolysable group having a molecular weight G is silicon or carbon. 10 greater than or equal to methyl or greater than about 15 Such a compound may be bound to the surface of a device Daltons, that has been activated by generation of a free radical. The R and R are each independently hydrogen, methyl or free radical can initiate a bond between the surface of the ethyl: device and the vinyl group of a compound according to For A is hydrogen or straight or branched chain C1-C18 alkyl mula V. 15 unsubstituted or substituted with halo or hydroxyl: Z is benzene, furan, pyrrole, thiophene or a cyclic structure Some of the advantages of the various embodiments according to Huckel's rule (4H--2), unsubstituted or sub described herein will readily understood from the following stituted with straight or branched chain C1-C6 alkyl detailed description when read in conjunction with the unsubstituted or substituted with halo or hydroxyl: accompanying drawings. p is 0 or 1; and 2O with the proviso that when p is 0, A is not hydrogen. BRIEF DESCRIPTION OF THE DRAWINGS G is silicon or carbon. Q may function to decrease Volatility of a compound of Formula I relative to its silanol counterpart (i.e., where Q is FIG. 1 is a schematic drawing of a cross-section of an H).