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(12) United States Patent (10) Patent No.: US 8,334,413 B2 Stock Et Al

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(12) United States Patent (10) Patent No.: US 8,334,413 B2 Stock Et Al USOO8334413B2 (12) United States Patent (10) Patent No.: US 8,334,413 B2 Stock et al. (45) Date of Patent: Dec. 18, 2012 (54) TOPICAL COMPOSITIONS AND METHODS 5,837,224 A 11/1998 Voorhees et al. FOR EPITHELLAL-RELATED CONDITIONS 6,015,877 A 1/2000 Rando 6,096,740 A 8, 2000 Mechoulam et al. 6,114,388 A 9, 2000 Geffard (75) Inventors: Jeffry B. Stock, Princeton, NJ (US); 6,159,485 A 12/2000 Yu et al. Joel Gordon, Princeton Junction, NJ 6,251,882 B1 6/2001 Uckun et al. (US); Maxwell Stock, Rocky Hill, NJ 6,372,793 B1 4/2002 Lamango et al. 6,403,619 B1 6/2002 Jacobson et al. (US) 6,414,037 B1 7/2002 Pezzuto et al. 6,440,966 B1 8, 2002 Barrett et al. (73) Assignee: Signum Biosciences, Inc., Monmouth 6,462,086 B1 10/2002 Kloog et al. Junction, NJ (US) 6,482,086 B1 1 1/2002 Rimoto et al. 6,492,128 B1 12/2002 Haklai et al. (*) Notice: Subject to any disclaimer, the term of this 6,946,485 B2 9/2005 Kloog et al. patent is extended or adjusted under 35 7,365,080 B2 4/2008 Gregor et al. 7,576,094 B2 8, 2009 Chu et al. U.S.C. 154(b) by 0 days. 7,846,915 B2 12/2010 Wong et al. 2002/0010128 A1 1/2002 Parks et al. (21) Appl. No.: 12/968,800 2002/0182237 A1 12/2002 Bissett et al. 2003/005.9450 A1* 3/2003 Maibach et al. .............. 424/401 (22) Filed: Dec. 15, 2010 2003.0143288 A1* 7/2003 Mayne et al. ................. 424,725 2003. O180719 A1 9/2003 Herget et al. (65) Prior Publication Data 2003/0203942 A1 10/2003 Kloog et al. 2003/0228688 A1 12/2003 Dobie US 2011 FO117187 A1 May 19, 2011 2004/0082015 A1 4/2004 Geffard 2004/O138446 A1 7/2004 Kharrat et al. 2004/O152O73 A1 8/2004 Herget et al. Related U.S. Application Data 2005/0277694 A1 12/2005 Stock et al. (62) Division of application No. 1 1/151,174, filed on Jun. 2007,0004803 A1 1/2007 Gibbs et al. 13, 2005. FOREIGN PATENT DOCUMENTS (60) Provisional application No. 60/652,921, filed on Feb. WO WO-91f17261 A1 11F1991 14, 2005, provisional application No. 60/579,093, WO WO-01/07086 A1 2, 2001 WO WOO230453 A1 * 4, 2002 filed on Jun. 12, 2004. WO WO-02/060426 A3 8, 2002 WO WO-03/018062 A1 3, 2003 (51) Int. Cl. WO WO-03078448 A1 9, 2003 C07C38L/00 (2006.01) WO WO-2004/042081 A1 5, 2004 WO WO-2004/087064 A2 10, 2004 A61O 19/00 (2006.01) WO WO-2006,102126 A2 9, 2006 (52) U.S. Cl. .............. 568/44; 568/39;568/45; 424/401; WO WO-2006 125930 A1 11 2006 514/562 (58) Field of Classification Search ........................ None OTHER PUBLICATIONS See application file for complete search history. Leonard; J Med Chem 40(19), p. 2971-2990, 1997.* Aharonson, et al., “Stringent structural requirements for anti-Ras (56) References Cited activity of S-prenyl analogues.” Biochim Biophy's Acta, 1406:40-50, (1998). U.S. PATENT DOCUMENTS Ahmad et al., “Role ofisoprenylcysteine carboxyl methyltransferase 4.294,852 A 10, 1981 Wildnauer et al. in tumor necrosis factor-alpha stimulation of expression of vascular 4,380,549 A 4, 1983 Van Scott et al. cell adhesion molecule-1 in endothelial cells.” Arterioscler: Thromb. 4,552,872 A 1 1/1985 Cooper et al. 4,612,331 A * 9/1986 Barratt et al. ................. 514,558 Vasc. Biol., 22:759-764, (2002). 5,019,569 A 5/1991 Kligman et al. 5,043,268 A 8, 1991 Stock (Continued) 5,188,826 A * 2/1993 Chandrasekaran et al. .......................... 424/78.04 Primary Examiner — Nissa Westerberg 5,202,456 A 4, 1993 Rando (74) Attorney, Agent, or Firm — SorinRand LLP 5,284,867 A 2/1994 Kloog et al. 5,308,840 A 5/1994 Sugiyama et al. (57) ABSTRACT 5,455,274 A 10, 1995 Suh 5,482,710 A 1/1996 Slavtcheffetal. The present invention relates to pharmaceutical, cosmetic and 5,521,215 A 5, 1996 Mechoulam et al. cosmeceutical topical compositions containing polyisopre 5,567,729 A * 10/1996 Bradfute et al. .............. 514,546 nyl-protein inhibitor compounds and methods useful in the 5,571.687 A 1 1/1996 Casey et al. 5,639,768 A 6/1997 Morrissey et al. promotion of healthy epithelium and the treatment of epithe 5,658,881 A 8, 1997 Gelland et al. lial-related conditions. 5,705,528 A 1/1998 Kloog 5,789,541 A 8, 1998 Rando 42 Claims, 13 Drawing Sheets US 8,334.413 B2 Page 2 OTHER PUBLICATIONS Halaschek-Wiener et al., (2003) “Farnesyl Thiosalicylic Acid Chemosensitizes Human Melanoma. In Vivo.” J. Invest. Dermatol. Anderson et al., “Purification, functional reconstitution, and charac 120(1): 109-15. terization of the Saccharomyces cerevisiae isoprenylcysteine Hasne et al., (1999) Characterization of prenylated protein carboxylmethyltransferase Ste14p.” J. Biol. 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(2000), Targeted inactivation of the isoprenylcysteine agonist-receptor-mediated signal transduction in human platelets. carboxyl methyltransferase gene causesmislocalizalion of K-Ras in Proc. Natl. Acad. Sci. U. S. A.,90:868-872. mammalian cells. J. Biol. Chem., 275:17605-17610. Huzoor-Akbar. (1992) Role of protein methylation in agonist-in Bergo et al., “Isoprenylcysteine carboxyl methyltransferase defi duced signal transduction in human platelets. SAAS Bull. Biochem. ciency in mice”. J. Biol. Chem., 276:5841-5845, (2001). Biotechnol. 5:7-12. Boivinet al. (1997) Essential arginine residues in isoprenylcysteine International Search Report for PCT/US06/23022 mailed Sep. 21, protein carboxyl methyltransferase. Biochem. Cell Biol. 75:63-69. 2006. Brown et al., “Dermal and Transdermal Drug Delivery Systems: Jonakait et al., (2000) Macrophage cell-conditioned medium pro Current and Future Prospects' Drug Delivery, 13:175-87. (2006). motes cholinergic differentiation of undifferentiated progenitors and Capdevila et al. (1997) Pancreatic exocrine secretion is blocked by Synergizes with nerve growth factor action in the developing basal inhibitors of methylation. Arch. Biochem. BiophyS., 345:1:47-55. forebrain. Exp. Neurol. 161:285-296. Carlson, R.P. et al., (1985) “Modulation of mouse ear edema by Katsuki et al., (1998) A potential role of Ras-mediated signal cyclooxygenase and lipoxygenase inhibitors and other transduction for the enhancement of depolarization-induced Ca2+ pharmacologic agents.” Agents Actions, vol. 17. No. 2, pp. 197-204. responses in hippocampal neurons by basic fibroblast growth factor. Brain Res. Dev. Brain Res., 111: 169-176. Chiu et al., (2004) Carboxyl methylation of Ras regulates membrane Kilic et al., (1997) In Vitro Assay and Characterization of the targeting and effector engagement. J. Biol. Chem., 279:7346-7352. Farnesylation-dependent Prelamin A Endoprotease, Joumal of Bio Choy et al. (1999) Endomembrane trafficking of Ras: the CAAX logical Chemistry, 272:8:5298–5304. motif targets proteins to the ER and Golgi. Cell, 98:69-80. Kloog, Y. and Cox, A.D. (2004) Prenyl-binding domains: potential Choy, E. and Philips, M. (2000). Expression and activity of human targets for Ras inhibitors and anti-cancer druos. Semin. Cancer Biol. prenylcysteine-directed carboxyl methyltransferase, Methods 14:253-261. Enzymol. 325: 101-114. Kowluru et al., (1996) Carboxylmethylation of the catalytic subunit Clarke et al., “Ras Antagonist Farnesylthiosalicylic Acid (FTS) of protein phosphatase 2A in insulin-secreting cells: evidence for Reduces Glomerular Cellular Proliferatio and Macrophase Number functional consequences on enzyme activity and insulin Secretion in Rat Thy-1 Nephritis.” JAm. Soc. Nephrol. 14:848-854, (2003). Endocrinology, 137:2315-2323. Crowell et al. (1998) Prenylcysteine alpha-carboxyl meth Kowluru, A. (2000) Evidence for the carboxyl methylation of nuclear Itransferase in Suss ension-cultured tobacco cells. Plant Ph siol. lamin-B in the pancreatic beta cell. Biochem. Biophys. Res. Com 118:115-123. mun., 268:249-254. Dai et al., (1998) Mammalian prenylcysteine carboxyl Kramer et al., (2003) Isoprenylcysteine carboxyl methyltransferase methyltransferase is in the endoplasmic reticulum. J. Biol. Chem. activity modulates endothelial cell apoptosis. Mol. Biol. Cell, 273:15030-15034. 14:848-857. Desrosiers et al., (2000) Modulation of Rho and cytoskeletal protein Kuehl, F.A., Jr., et al., (1977) “Role of prostaglandin endoperoxide attachment to membranes by a prenylcysteine analog. J. Biol. Chem. PGG2 in inflammatory processes.” Nature, vol. 265, pp. 170-173. 2.75:14949-14957. Lamango et al., (2003) Inhibition mechanism of Desrosiers, R.R. and Beliveau, R. 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