(12) United States Patent (10) Patent No.: US 7.964,738 B2 Gately Et Al

US007964738B2

(12) United States Patent (10) Patent No.: US 7.964,738 B2 Gately et al. (45) Date of Patent: Jun. 21, 2011

(54) PHARMACEUTICAL COMPOSITIONS AND Chan, et al. "Pharmacology of a Selective Cyclooxygenase-2 Inhibi METHODS OF USE OF LIPOPHILIC, tor, L-745,337: A Novel Nonsteroidal Anti-inflammatory Agent with SILICON-SUBSTITUTED, an Ulcerogenic Sparing. Effect in Rat and Nonhuman Primate Stom CYCLOOXYGENASE-2 SELECTIVE ach” The Journal of Pharmacology and Experimental Therapeutics, vol. 274, No. 3, pp. 1531-1537 (1995). NON-STEROIDAL ANTI-NFLAMMATORY Flynn, et al. “Nonsteroidal Antiinflammatory Drug Hydroxamic DRUGS AND DERVATIVES Acids. Dual Inhibitors of Both Cyclooxygenase and 5-Lipoxygenase” J. Med. Chem, vol. 33, No. 8, pp. 2070-2072 (75) Inventors: Stephen Gately, Scottsdale, AZ (US); (1990). Stephen P. Wanaski, Chicago, IL (US) Futaki, et al. “NS-398, a New Anti-inflammatory Agent, Selectively Inhibits Prostaglandin G/H Synthase/Cyclooxygenase (COX-2) (73) Assignee: Silamed, Inc., Scottsdale, AZ (US) Activity in Vitro' Prostaglandins, vol. 47, pp. 55-59 (1994). Gans, et al. "Anti-Inflammatory and Safety Profile of DuP 697, a (*) Notice: Subject to any disclaimer, the term of this Novel Orally Effective Prostaglandin Synthesis Inhibitor J patent is extended or adjusted under 35 Pharmacol Exp. Ther. vol. 254, pp. 180-187 (1990). U.S.C. 154(b) by 1032 days. Kalgutkar, et al. "Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2” Science, vol. 280, pp. 1268-1270 (May 22, (21) Appl. No.: 11/551,579 1998). Khanna, et al. “1,2-Diarylimidazoles as Potent, Cyclooxygenase-2 (22) Filed: Oct. 20, 2006 Selective, and Orally Active Antiinflammatory Agents' J. Med. Chem., vol. 40, No. 11, pp. 1634-1647 (1997). (65) Prior Publication Data Khanna, et al. “1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2” J.Med. Chem... vol. 40, No. 11, pp. 1619-1633 US 2007/O129331 A1 Jun. 7, 2007 (1997). Kolasa, et al. “Nonsteroidal Anti-Inflammatory Drugs as Scaffolds Related U.S. Application Data for the Design of 5-Lipoxygenase Inhibitors' J. Med. Chem... vol. 40, (63) Continuation-in-part of application No. No. 5, pp. 819-824 (1997). Li, et al. “Cyclooxygenase-2 Inhibitors. Synthesis and Pharmaco PCT/US2005/013233, filed on Apr. 19, 2005. logical Activities of 5-Methanesulfonamido-1-indanone Deriva (60) Provisional application No. 60/563,673, filed on Apr. tives' J. Med. Chem., vol. 38, No. 25, pp. 4897-4905 (1995). 20, 2004. Li, et al. “1,2-Diarylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-inflammatory Agents' J. Med. (51) Int. Cl. Chem., vol. 38, No. 22, pp. 4570-4578 (1995). C07F 7/02 (2006.01) Li, et al. “Novel Terphenyls as Selective Cyclooxygenase-2 Inhibi A6 IK3I/695 (2006.01) tors and Orally Active Anti-inflammatory Agents' J. Med. Chem. vol.39, No. 9, pp. 1846-1856 (1996). CO7D 23/00 (2006.01) Luong, et al. "Flexibility of the NSAID Binding Site in the Structure (52) U.S. Cl...... 548/406; 514/63: 548/110 of Human Cyclooxygenase-2” Nature Structural Biology, vol. 3, No. (58) Field of Classification Search ...... 514/63; 11, pp. 927-933 (1996). 548/110, 406 Meade, et al. “Differential Inhibition of Prostaglandin Endoperoxide See application file for complete search history. Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non steroidal Anti-inflammatory Drugs' The Journal of Biological (56) References Cited Chemistry, vol. 268, No.9 pp. 6610-6614 (1993). U.S. PATENT DOCUMENTS (Continued) 3,285,908 A 11, 1966 Shen 3,336,194 A 8, 1967 Shen 5,436,265 A 7, 1995 Black et al. Primary Examiner — Shengjun Wang 5,510,368 A 4, 1996 Lau et al. (74) Attorney, Agent, or Firm — Robert M. Gould; Duane 5,607,966 A 3/1997 Hellberg et al. Morris LLP 5,681,964 A 10, 1997 Ashton et al. 5,811,438 A 9/1998 Hellberg et al. 6,399,647 B2 6/2002 Kalgutkar et al. (57) ABSTRACT 2002fO160988 A1 10, 2002 Amitai et al. FOREIGN PATENT DOCUMENTS Novel compositions of silicon-substituted carboxylic acid containing-nonsteroidal anti-inflammatory drugs, their WO WO96,01830 1, 1996 preparation and use in methods for treating, preventing and/or OTHER PUBLICATIONS reducing inflammation, pain, angiogenesis, and cortical International Search Report and written opinion from corresponding dementias including Alzheimer's disease, inflammation-re PCT Application No. PCT/US2005/013233 dated Dec. 15, 2006. lated cardiovascular disorders and cancer are described. The J. Schwartz, Remingtons's Pharmaceutical Sciences, Part 8 “Phar compositions and methods are effective at decreasing or maceutical Preparations and Their Manufacture', pp. 1435-1694, reversing the gastrointestinal, renal and other toxicities 1990. resulting from the use of non-selective carboxylate-contain W. Black, etal. "From Indomethacinto a Selective COX-2 Inhibitor: ing-nonsteroidal anti-inflammatory drugs. Development of Indolalkanoic Acids as Potent and Selective Cyclooxygenase-2 Inhibitors' Bioorganic & Medical Chemistry Let ters, vol. 6, No. 6, pp. 725-730 (1996). 6 Claims, No Drawings US 7.964,738 B2 Page 2

OTHER PUBLICATIONS Leblanc, et al. “A New Series of Selective COX-2 Inhibitors: 5, 6-Diarylthiazolo 3.2-b1,2,4-Triazoles' Bioorganic & Medicinal Nakamura, et al. “Studies of Antiinflammatory Agents. II. Synthesis Chemistry Letters, vol. 7, No. 1. pp. 57-62 (1997). and Pharmacological Properties of Showell, et al. "Chemistry Challenges in Lead Optimization: Silicon 2'-(Phenylthio)methanesulfonanilides and Related Derivatives' Isosteres in Drug Discovery” Drug Discovery Today, vol. 8, No. 12, pp. 551-556 (2003). Chem. Pharm. Bull, vol. 41, No. 5, pp. 894-906 (1993). Tacke, et al. “Sila-Substitution—AUsefult Strategy for Drug Design” Tsuji, et al. “Studies of Anti-inflammatory Agents. IV. Synthesis and Endeavour, vol. 10, No. 4, pp. 191-197 (1986). Pharmacological Properties of 1, 5-Diarylpyrazoles and Related Tanaka, et al. “Pharmacological Studies of the New Antiinflamma Derivatives” Chem. Pharm. Bull, vol. 45, No. 6, pp.987-995 (1997). tory Agent 3-Formylamino-7-methylsulfonylamino-6-phenoxy-4H Penning, et al. Synthesis and Biological Evaluation of the 1, 1-benzopyran-4-one” Arzneimittelforschung, vol. 42, No. 7, pp.935 5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identifica 944, 1992. tion of 4-5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- Therien, et al. “Synthesis and Biological Evaluation of 5. ylbenzenesulfonamide (SC-58635, Celecoxib) J. Med. Chem... vol. 6-Diarylimidazo 2.1-bl.Thiazole as Selective COX-2 Inhibitors' 40, No. 9, pp. 1347-1365 (1997). Bioorganic & Medicinal Chemistry Letters, vol. 7, No. 1, pp. 47-52 Prasit, et al. “L-745,337: A Selective Cyclooxygenase-2 Inhibitior” (1997). Medicinal Chemistry Research, vol. 5, pp. 364-374 (1995). Vane, etal. “Inducible Isoforms of Cyclooxygenase and Nitric-Oxide Reitz, et al. “Novel 1, 2-Diarylcyclopentenes are Selective, Potent, Synthase in Inflammation” Proc. Natl. Acad. Sci. USA. vol. 91, pp. and Orally Active Cyclooxygenase Inhibitors' Medicinal Chemistry 2046-2050 (1994). Research, vol. 5, pp. 351-363 (1995). Wiesenberg, et al. “The Pharmacological Profile of CGP 28238, A Remmel, et al. “Studies on the Metabolism of the Novel, Selective Novel Highly Potent Anti-Inflammatory Compound” Drugs Exptl. Cyclooxygenase-2 Inhibitor Indomethacin Phenethylamide in Rat, Clin. Res., vol. 15, pp. 501-509 (1989). Mouse, and Human Liver Microsomes: Identification of Active Futaki, et al. “NS-398, A Novel Non-Steroidal Anti-Inflammatory Metabolites' Drug Metabolism and Disposition, vol. 32, No. 1, pp. Drug with Potent Analgesic and Antipyretic Effects, Which Causes 113-122 (2004). Minimal Stomach Lesions' Gen. Pharmac., vol. 24. No. 1, pp. 105 Riendeau, et al. “Biochemical and Pharmacological Profile of a 110 (1993). Tetrasubstituted furanone as a Highly Selective COX-2 Inhibitor' Klein, et al. “Selective Inhibition of Cyclooxygenase 2' Biochemical British Journal of Pharmacology, vol. 121, pp. 105-117 (1997). Pharacology, vol. 48, No. 8, pp. 1605-1610 (1994). US 7,964,738 B2 1. 2 PHARMACEUTICAL COMPOSITIONS AND 1634-1647; Khanna, Weier, Yu, Collins, Miyashiro, Koboldt, METHODS OF USE OF LIPOPHILIC, Veenhuizen, Curie, Siebert, and Isakson, “1,2-Diarylpyrroles SILICON-SUBSTITUTED, as Potent and Selective Inhibitors of Cyclooxygenase-2, J. CYCLOOXYGENASE-2 SELECTIVE Med. Chem. (1997) Vol. 40, pp. 1619-1633:Tsuji, Nakamura, NON-STEROIDAL ANTI-NFLAMMATORY Konishi, Tojo, Ochi, Senoh, and Matsuo, “Synthesis and DRUGS AND DERVATIVES Pharmacological Properties of 1.5-Diarylyrazoles and Related Derivatives”, Chem. Pharm. Bull. (1997) Vol. 45, pp. The present application claims priority from and is a con 987-995; Riendeau, Percival, Boyce, Brideau, Charleson, tinuation-in-part of PCT/US2005/13233 filed Apr. 19, 2005, Cromlish, Ethier, Evans, Falgueyret, Ford-Hutchinson, Gor which is a continuation of U.S. application Ser. No. 60/563, 10 don, Greig, Gresser, Guay, Kargman, Leger, Mancini, 673 filed Apr. 20, 2004 which is now expired. O'Neill, Quellet, Rodger. Therien, Wang, Webb, Wong, Xu, Young, Zamboni, Prasit, and Chan, “Biochemical and Phar BACKGROUND OF THE INVENTION macological Profile of a Tetrasubstituted Furanone as a Highly Selective COX-2 Inhibitor, Br. J. Pharmacol. (1997) Non-steroidal anti-inflammatory drugs (NSAIDs) are 15 Vol. 121, pp. 105-117: Roy, Leblanc, Ball, Brideau, Chan, widely used because of their anti-inflammatory and analgesic Chauret, Cromlish, Ethier, Gauthier, Gordon, Greig, Guay, activity. It is commonly recognized that NSAIDs exert their Kargman, Lau, O'Neill, Silva, Therien, Van Staden, Wong, effect by blocking the activity of cyclooxygenase (COX), also Xu, and Prasit, “A New Series of Selective COX-2 Inhibitors: known as prostaglandin G/H synthase (PGHS), the enzyme 5,6-Diarylthiazolo 3.2-b1,2,4-triazoles'. Bioorg. Med. that converts arachidonic acid into prostanoids. Inhibition of Chem. Lett. (1997) Vol. 7, pp. 57-62: Therien, Brideau, Chan, the biosynthesis of prostanoids, the mediators of pain, fever, Cromlish, Gauthier, Gordon, Greig, Kargman, Lau, Leblanc, and inflammation, has long been a therapeutic target of anti Li, O’Neill, Riendeau, Roy, Wang, Xu, and Prasit, “Synthesis inflammatory drug discovery. The therapeutic use of conven and Biological Evaluation of 5,6-Diary limidazo[2.1-bithiaz tional NSAIDs is limited by drug-associated side effects, oles as Selective COX-2 Inhibitors’, Bioorg. Med. Chem. Such as severe gastric ulceration, bleeding and renal toxicity. 25 Lett. (1997) Vol. 7, pp. 47-52: Li, Norton, Reinhard, Ander Two forms of COX have been identified, a constitutive son, Gregory, Isakson, Koboldt, Masferrer, Perkins, Seibert, isoform (COX-1), and an inducible isoform (COX-2), of Zhang, Zweifel, and Reitz, “Novel Terphenyls as Selective which expression is upregulated at sites of inflammation (see Cyclooxygenase-2 Inhibitors and Orally Active Anti-Inflam Vane, J R; Mitchell, J A; Appleton, I: Tomlinson, A et al., matory Agents”. J. Med. Chem. (1996) Vol. 39, pp. 1846 Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 is 30 1856; Li, Anderson, Burton, Cogburn, Collins, Garland, Gre believed to play a physiological role in gastrointestinal and gory, Huang, Isakson, Koboldt, Logusch, Norton, Perkins, renal protection, while COX-2 appears to play a predominant Reinhard, Seibert, Veenhuizen, Zhang, and Reitz, "1,2-Dia pathological role in inflammatory conditions. The NSAIDs rylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors currently on the market inhibit both COX-1 and COX-2 iso and Orally Active Anti-Inflammatory Agents”. J. Med. Chem. forms with little variation in selectivity, explaining the ben 35 (1995) Vol. 38, pp. 4570-4578; Reitz, Li, Norton, Reinhard, eficial (inhibition of COX-2) and harmful (inhibition of COX Huang, Penick, Collins, and Garland, “Novel 1,2-Diarylcy 1) effects. The selective inhibition of COX-2 has been a goal clopentenes are Selective Potent and Orally Active Cyclooxy of drug developers. It is thought that this will reduce or genase Inhibitors’, Med. Chem Res. (1995) Vol. 5, pp. 351 eliminate the GI irritation caused by COX-1 inhibition. 363; Futaki, Yoshikawa, Hamasaka, Arai, Higuchi, lizuka, The differential tissue distribution of COX-1 and COX-2 40 and Otomo, “NS-398, A Novel Nonsteroidal Antiinflamma provides a basis for the development of drugs that are selec tory Drug with Potent Analgesic and Antipyretic Effects, tive COX-2 inhibitors, such that the specificity for the inhi which Causes Minimal Stomach Lesions', Gen. Phamacol. bition of COX-2 far exceeds inhibition of COX-1 (see Meade, (1993) Vol. 24, pp. 105-110; Wiesenberg-Boetcher, Sch Smith, and DeWift, J. Biol. Chem. (1993) 268:6610-6614)). weizer, Green, Muller, Maerki, and Pfeilschifter, “The Phar Detailed structure-activity relationship studies have been 45 macological Profile of CGP 28238, A Novel Highly Potent reported for two general structural classes of selective COX-2 Anti-Inflammatory Compound, Drugs Exptl Clin Res. inhibitors, including certain acidic sulfonamides and diaryl (1989) Vol. XV, pp. 501-509: Futaki, Takahashi, Yokoyama, heterocyclics. The in vivo activities of these selective COX-2 Arai, Higuchi, and Otomo, “NS-398, A New Anti-Inflamma inhibitors support the hypothesis that selective COX-2 inhi tory Agent, Selectively Inhibits Prostaglandin G/HSynthase/ bition is anti-inflammatory and non-ulcerogenic (see Gans, 50 Cyclooxygenase (COX-2) Activity in vitro. Prostaglandins Galbraith, Roman, Haber, Kerr, Schmidt, Smith, Hewes, and (1994) Vol. 47, pp. 55-59; Klein, Nusing, Pfeilschifter, and Ackerman, “Anti-Inflammatory and Safety Profile of DuP Ullrich, “Selective Inhibition of Cyclooxygenase-2, Bio 697, a Novel Orally Effective Prostaglandin Synthesis Inhibi chem. Pharmacol. (1994) Vol. 48, pp. 1605-1610; Li, Black, tor, J. Pharmcol Exp. Ther. (1990) Vol. 254, pp. 180-187: Chan, Ford-Hutchinson, Gauthier, Gordon, Guay, Kargman, Penning, Talley, Bertenshaw, Carter, Collins, Docter, 55 Lau, Mancini, Quimet, Roy, Vickers, Wong, Young, Zamboni, Graneto, Lee, Malecha, Miyashiro, Rogers, Rogier, Yu, and Prasit, “Cyclooxygenase-2 Inhibitors. Synthesis and Anderson, Burton, Cogburn, Gregory, Koboldt, Perkins, Pharmacological Activities of 5-Methanesulfonamido-1-in Seibert, Veenhuizen, Zhang, and Isakson, “Synthesis and danone Derivatives”,J.Med. Chem. (1995) Vol.38, pp. 4897 Biological Evaluation of the 1,5-Diarylpyrazole Class of 8905; Prasit, Black, Chan, Ford-Hutchinson, Gauthier, Gor Cyclooxygenase-2 Inhibitors: Identification of 4-5-(4-Me 60 don, Guay, Kargman, Lau, Li, Mancini, Quimet, Roy, Tagari, thylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-ylbenzene Vickers, Wong, Young, and Zamboni, “L-745,337: A Selec sulfonamide (SC-58635, Celecoxib), J. Med. Chem. (1997) tive Cyclooxygenase-2 Inhibitor, Med. Chem. Res. (1995) Vol. 40, pp. 1347-1365: Khanna, Weier, Yu. Xu, Koszyk, Vol. 5, pp. 364-374; Tanaka, Shimotori, Makino, Aikawa, Collins, Koboldt, Veenhuizen, Perkins, Casler, Masferrer, Inaba, Yoshida, and Takano, “Pharmacological Studies of the Zhang, Gregory, Seibert, and Isakson, "1,2-Diary limidazoles 65 New Antiinflammatory Agent 3-Formylamino-7-methylsul as Potent Cyclooxygenase-2 Selective, and Orally Active fonylamino-6-phenoxy-4H-1-benzopyran-4-one. 1st Com Antiinflammatory Agents”. J.Med. Chem. (1997) Vol. 40, pp. munication: Antiinflammatory, Analgesic and Other Related US 7,964,738 B2 3 4 Properties”, Arzniem.-Forsch./Drug Res. (1992) Vol. 42, pp. Cyclooxygenase and 5-Lipoxygenase'. J. Med. Chem. 935-944; Nakamura, Tsuji, Konishi, Okumura, and Matsuo, (1990) Vol. 33, pp. 2070-2072.) “Studies on Anti-Inflammatory Agents.I. Synthesis and Phar The generation of selective COX-2 analogues of macological Properties of 2'-(phenylthio)methanesulfona indomethacin and meclofenamic acid via amidation oresteri mides and Related Derivatives', Chem. Pharm. Bull. (1993) 5 fication has been described in U.S. Pat. No. 6,399,647. More Vol. 41, pp. 894-906; Chan, Boyce, Brideau, Ford-Hutchin recently the metabolism of one such indomethacin amide son, Gordon, Guay, Hill, Li, Mancini, Penneton, Prasit, analogue was published and was reported to be rapidly Rasori, Riendeau, Roy, Tagari, Vickers, Wong, and Rodger, metabolized by human liver microsomes (Remmel R Petal. "Pharmacology of a Selective Cyclooxygenase-2 Inhibitor, 10 Drug Metab Dispos 32:113-122, 2004). Thus, new composi L-745,337: A Novel Nonsteroidal Anti-Inflammatory Agent tions are needed that are selective COX-2 inhibitors and that with an Ulcerogenic Sparing Effect in Rat and Nonhuman have improved therapeutic properties, including pharmaco Primate Stomach”, J. Pharmacol. Exp. Ther. (1995) Vol. 274, kinetics. Simple methods for preparing and using Such com pp. 1531-1537. positions are also needed. There are only a few reports of attempts to convert NSAIDs 15 that are non-selective COX inhibitors into selective COX-2 SUMMARY OF THE INVENTION inhibitors. (See, Black, Bayly, Belley, Chan, Charleson, Denis, Gauthier, Gordon, Guay, Kargman, Lau, Leblanc, The present invention provides novel compounds that are Mancini, Quellet, Percival, Roy, Skorey, Tagari, Vickers, selective COX-2 inhibitors having improved therapeutic Wong, Xu, and Prasit, “From Indomethacinto a Selective properties, including pharmacokinetic properties. Methods COX-2 Inhibitor: Development of Indolalkanoic Acids as for preparing and using these compounds are also disclosed. Potent and Selective Cyclooxygenase-2 Inhibitors’, Bioorg. The invention covers drugs containing silicon Substitution Med. Chem. Lett. (1996) Vol. 6, pp. 725-730; Luong, Miller, that have beneficial properties. The approach involves replac Barnett, Chow, Ramesha, and Browner, "Flexibility of the ing specific atoms in the compounds with silicon, and select NSAID Binding Site in the Structure of Human Cyclooxyge- 25 ing those modified drugs having improved biological or nase-2, Nature Structural Biol. (1996) Vol. 3, pp. 927-933; therapeutic properties. A review of silicon chemistry is pro and Kalgutkar, Crews, Rowlinson, Garner, Seibert, and Mar vided in Tacke and Zilch, Endeavour, New Series, 10, 191 nett, “Aspirin-Like Molecules that Covalently Inactivate 197 (1986); and Showell, GA and Mills, J S. Chemistry Cyclooxygenase-2, Science (1998) Vol. 280, pp. 1268 challenges in lead optimization: silicon isosteres in drug dis 1270). 30 covery. Drug Discovery Today 8(12): 551-556, 2003. Efforts in drug development have focused on the biochemi The compositions of the invention include carboxylate cal conversion of various NSAIDs. Ashton et al., in U.S. Pat. containing drugs, including COOH-containing drugs, such as No. 5,681.964, discloses conversion of indomethacin (an COOH-containing NSAIDs, which are not selective COX-2 NSAID) into certain ester derivatives with concomitant 35 inhibitors (either display an inhibition for COX-1 far exceed reduction of GI irritation. U.S. Pat. Nos. 5,607,966 and 5,811, ing inhibition of COX-2 or display essentially the same inhi 438 disclose conversion of indomethacin into certain ester bition for COX-1 and COX-2) that when converted into derivatives and amide derivatives (which are useful as anti derivatives containing silicon atom(s) at feasible sites within oxidants and inhibitors of 5-lipoxygenase), but do not address the molecule, become selective COX-2 inhibitors (display an COX-2 selective inhibition. U.S. Pat. Nos. 3.285,908, 3.336, a inhibition for COX-2 exceeding inhibition for COX-1) and 194 describe secondary and tertiary amide derivatives of exhibit the improved biological properties and improved indomethacin, but fail to address COXinhibition. In addition, pharmacokinetics. These molecules retain the analgesic, anti COX-2 selective inhibitors 1-aroyl-3-indolyl alkanoic acids inflammatory, and/or antipyretic effect of their unmodified and N-benzyl-3-indoleacetic acids are described in U.S. Pat. counterpart parent drugs, and yet exhibits other effects not Nos. 5,436,265 and 5,510,368. 45 exhibited by the drug prior to derivatization. Various compounds have been used as starting points in the Silicon-containing compounds of the invention include design of selective COX-2 inhibitors, including NSAIDs, (1) NSAIDs that be selected from a variety of chemical classes that are selective COX-1 inhibitors or (2) that have essentially including, but not limited to fenamic acids, such as flufenamic the same inhibitory activity for both COX-1 and COX-2. The acid, niflumic acid, and mefenamic acid; indoles, such as conformational analysis of the human COX-2 crystal struc- 50 indomethacin, Sulindac, and tolmetin: phenylaikanoic acids, ture suggests that creating a wide range of analogs of COOH Such as Suprofen, ketorolac, flurbiprofen, and ibuprofen; and containing NSAIDs, each with a different functional group phenylacetic acids, such as diclofenac. replacing the OH of the COOH, could improve water-solu Further examples of NSAIDs are listed below: bility, bioavailability, or pharmacokinetics. Kolasa et al. and Flynn et al. attempted to replace the carboxylic acid group in 55 NSAIDs with a hydroxamic acid moiety or a hydroxyurea aceloferac moiety and achieved dual inhibition of COX and 5-lipoxyge alcofenac nase. However, none of the analogs displayed any significant amfenac selective COX-2 inhibition, with the hydroxamates undergo benoxaprofen 60 bromfenac ing facile hydrolysis (see Kolasa, Brooks, Rodriques, Sum carprofen mers, Dellaria, Hulkower, Bouska, Bell, and Carter, “Nonste clidanac roidal Anti-Inflammatory Drugs as Scaffolds for the Design diflunisal efenamic acid of 5-Lipoxygenase Inhibitors'.J.Med. Chem. (1997) Vol. 40. etodolic acid pp. 819-824; and Flynn, Capiris, Cetenko, Connor, Dyer, 6.5 fenbufen Kostlan, Niese, Schrier, and Sircar, “Nonsteroidal Antiin fenclofenac flammatory Drug Hydroxamic Acids. Dual Inhibitors of Both US 7,964,738 B2 5 6 -continued Another aspect of the invention is a pharmaceutical com position comprising a compound described herein and a phar fenclorac fenoprofen maceutically acceptable diluent or carrier. fleclozic acid Additional features and advantages of the present inven indoprofen isofezolac tion are described in, and will be apparent from, the following ketoprofen Detailed Description of the Invention and the figures. Oxoprofen meclofenamate DETAILED DESCRIPTION OF THE INVENTION naproxen orpanoxin 10 pirprofen In an embodiment, the invention is directed to a particular pranoprofen class of compounds having one or more siliconatoms. Silicon tolfenamic acid Zaltoprofen is highly lipophilic and thus enhances the penetration of the Zomopirac compounds across the gut wall, cell membranes and blood brain barrier. 15 The present invention provides compounds incorporating One object of the present invention is to provide methods silicon atom(s) that demonstrate enhanced pharmaceutical for generating silicon-Substituted analogues of certain properties. NSAIDs. Another object of the invention is to to generate In an embodiment, the invention is a silicon containing lipophilic sila-analogs of the carboxylic acid moiety of compound of the formula I: NSAIDs that are COX-2 selective. The resulting composi tions are also covered by the invention. Methods are also provided for administering to a mammal, (I) particularly a human, a treatment-effective amount of a sili con-containing carboxylic acid derivative of the invention 25 sufficient to inhibit cancer. Preferably, the derivative is selec tive for inhibition of COX-2. In an embodiment, compound (a) can be a cyclooxygenase inhibitor that is not selective for inhibition of COX-2 and (b) contains a carboxylic acid moi ety and includes pharmaceutically acceptable salts thereof. 30 Preferably, the compound is a non-steroidal anti-inflamma tory drug, or a pharmaceutically acceptable salt thereof. It is a further object of the present invention to provide a OH compounds that demonstrate enhanced pharmacokinetics, 35 and/or altered metabolism and/or improved drug bioavail wherein ability and half-life as compared to underivatized counter R is F, Cl, Br, or (Si)X wherein the groups X can be the same parts. or different and can include, by way of example, methyl, It is also an object of the present invention to provide ethyl, n-propyl, iso-propyl. n-butyl, iso-butyl, sec-butyl, compounds that demonstrate enhanced lipophilicity, tert-butyl, —CHCH(CHCH), 2-methyl-n-butyl, improved gastrointestinal absorption, and enhanced oral bio 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, availability. It is still a further object of the present invention cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2 that the novel compounds have an improved pharmacological cyclopropyl. —CH-cyclohexyl, -CHCH-cyclopropyl. profile compared to the underivatized counterpart com 45 —CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl) pounds, and as a result, are better tolerated by humans or phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, animals. m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, It is a further object of the present invention to provide a m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-tri treatment that minimizes or obviates GI irritation. It is a fluoromethylphenyl, p-(CH)NCHCHCH-O-benzyl, further object of the present invention to provide a treatment 50 p-(CH),COC(O)CHO-benzyl, p-(HOOCCHO)-ben that minimizes or obviates ulceration and bleeding time char Zyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH2O)- acterized by non-selective NSAIDs. benzyl, —CH2CHC(O)NH2, —CH-imidazol-4-yl, It is an additional object of the present invention to provide —CH-(3-tetrahydrofuranyl), —CH-thiophen-2-yl, a method for cancer treatment and prevention in a mammal, —CH2(1-methyl)cyclopropyl. —CH-thiophen-3-yl, particularly a human. Preferred compounds in addition to 55 thiophen-3-yl, thiophen-2-yl, —CH2—C(O)O-t-butyl, being effective in the treatment of cancer can also be analge —CH2—C(CH), —CH2CHCCHCH), -2-methylcy sic, anti-inflammatory, anti-angiogenic and/or antipyretic, clopentyl, -cyclohex-2-enyl, —CHICH (CH), ICOOCH, and thereby find use in the treatment of like angiogenesis —CH2CHN(CH), —CHC(CH)—CH, dependent or immunologic conditions, such as osteoarthritis 60 —CH-CH=CHCH (cis and trans), —CH2OH. —CH or rheumatoid arthritis. (OH)CH, —CH(O-t-butyl)CH, —CHOCH —(CH) It is a further object of the present invention to provide NH-Boc, -(CH2)NH2. —CH-pyridyl (e.g., 2-pyridyl, compounds for the treatment of Alzheimer's disease treat 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and ment and/or prevention in a mammal, particularly a human. 4-pyridyl), —CH2-naphthyl (e.g., 1-naphthyl and 2-maph Another aspect of the invention is the use of a compound 65 thyl), —CH2—(N-morpholino), p-(N-morpholino for the manufacture of a medicament for the treatment of CHCHO)-benzyl, benzobthiophen-2-yl, 5-chlo CaCC. robenzobthiophen-2-yl, 4,5,6,7-tetrahydrobenzob. US 7,964,738 B2 7 8 thiophen-2-yl, benzobthiophen-3-yl, 5-chlorobenzob. different and can include, by way of example, methyl, ethyl, thiophen-3-yl, benzobthiophen-5-yl, 6-methoxynaphth n-propyl, iso-propyl. n-butyl, iso-butyl, sec-butyl, tert-butyl, 2-yl, —CHCH-SCH, thien-2-yl, thien-3-yl, and the like: —CHCH(CHCH), 2-methyl-n-butyl, 6-fluoro-n-hexyl, R is alkoxy, YO-, wherein Y is an alkyl group. Exemplary phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, alkoxy groups include methoxy, ethoxy, t-butoxy, cyclo iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl. —CH2 pentyloxy and the like; or (Si)X wherein X is as described cyclohexyl, —CHCH-cyclopropyl. —CHCH-cyclo for R: hexyl, —CH-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, R is alkyl wherein alkyl refers to a lower alkyl group, a m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-meth haloalkyl group, an alkenyl group, an alkynyl group, a 10 oxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hy bridged cycloalkyl group, a cycloalkyl group or a hetero droxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, cyclic ring, as defined herein. The term “lower alkyl refers p-(CH)NCHCHCH-O-benzyl, p-(CH)COC(O)CHO to branched or straight chain acyclic alkyl group compris benzyl, p-(HOOCCHO)-benzyl, 2-aminopyrid-6-yl, p-(N- ing one to about ten carbon atoms (preferably one to about morpholino-CHCHO)-benzyl, - CHCHC(O)NH2, eight carbon atoms, more preferably one to about six car 15 —CH-imidazol-4-yl, —CH-(3-tetrahydrofuranyl), bonatoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, —CH2-thiophen-2-yl, —CH2(1-methyl)cyclopropyl. t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the —CH-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, like; or (Si)X wherein X is as described for R. —CH2—C(O)O-t-butyl, —CH2—C(CH), —CHCH The derivatives useful in the method of the present inven (CHCH), -2-methylcyclopentyl, -cyclohex-2-enyl, -CH tion are silicon modified indomethacin derivatives (sila-in CH(CH), ICOOCH, -CHCHN(CH), —CHC(CH) domethacin) where amines replace the carboxylic acid or a —CH2, —CH-CH=CHCH (cis and trans), —CH2OH. pharmaceutically acceptable salt thereof. —CH(OH)CH, -CH(O-t-butyl)CH, -CHOCH, Preferred are the secondary amide derivatives of sila-in —(CH)NH-Boc, —(CH)NH2, —CH-pyridyl (e.g., domethacin including, but not limited to, sila-indomethacin 25 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-py N-methylamide, sila-indomethacin-N-etan-2-ol-amide, sila ridyl and 4-pyridyl), —CH2-naphthyl (e.g., 1-naphthyl and indomethacin-N-Octyl amide, sila-indomethacin-N-nonyl 2-naphthyl), —CH2—(N-morpholino), p-(N-morpholino amide, sila-indomethacin-N-(2-methylbenzyl) amide, sila CHCHO)-benzyl, benzobthiophen-2-yl, 5-chlorobenzo indomethacin-N-(R)-4-dimethylbenzyl) amide, sila-in bithiophen-2-yl 4,5,6,7-tetrahydrobenzobthiophen-2-yl, domethacin-((S)-4-dimethylbenzyl)amide, sila-indometha 30 benzobthiophen-3-yl, 5-chlorobenzobthiophen-3-yl, cin-N-(2-phenethyl) amide, sila-indomethacin-N-(4- benzobthiophen-5-yl, 6-methoxynaphth-2-yl, fluorophenyl) amide, sila-indomethacin-N-(4-chlorophenyl) —CHCH-SCH, thien-2-yl, thien-3-yl, and the like. R, is an amide, sila-indomethacin-N-(4-acetamidophenyl) amide, NSAID moiety. sila-indomethacin-N-(4-methylmercapto)phenyl amide, sila 35 Preferred reagents for preparing silicon derivatives indomethacin-N-(3-methylmercaptophenyl) amide, sila-in include, aminomethyltrimethylsilane, aminopropyltrimeth domethacin-N-(4-methoxyphenyl) amide, sila-indometha ylsilane, (dimethyl(propyl)silyl)methanamine, aminobutylt cin-N-(3-ethoxyphenyl)amide, sila-indomethacin-N-(3,4,5- trimethoxyphenyl) amide, sila-indomethacin-N-(3-pyridy) rimethylsilane, (butyldimethylsilyl)methanamine, amino amide, sila-indomethacin-N-5-((2-chloro)pyridyl) amide, 40 pentyltrimethylsilane, (dimethyl(pentyl)silyl)methanamine, sila-indomethacin-N-5-((1-ethyl)pyrazolo) amide, sila-in aminohexyltrimethylsilane, (dimethyl(hexyl)silyl)metha domethacin-N-(3-chloropropyl) amide, sila-indomethacin namine, aminoheptyltrimethylsilane, (dimethyl(heptyl)silyl) N-methoxycarbonylmethyl amide, sila-indomethacin-N-2- methanamine, 1,1-dimethylsilinan -3-amine, 4-trimethylsi (2-L-methoxycarbonylethyl) amide, sila-indomethacin-N-2- lylaniline, (4-trimethylsilyl)phenyl)methanamine, (2-D-methoxycarbonethyl) amide, sila-indomethacin-N-(4- 45 4-((trimethylsilyl)methyl)benzamine, 2-trimethylsilyl-5- methoxycarbonylbenzyl) amide, sila-indomethacin-N-(4- aminopyridine, (dimethyl(pyridin-3-yl)silyl)methanamine, methoxycarbonylmethylphenyl) amide, sila-indomethacin 2-(dimethyl(pyridin-3-yl)silyl)ethanamine, (dimethyl(phe N-(2-pyrazinyl) amide, sila-indomethacin-N-2-(4- nyl)silyl)-methanamine, ((4-fluorophenyl)dimethylsilyl) methylthiazolyl) amide, sila-indomethacin-N-(4-biphenyl) 50 methanamine, ((4-chlorophenyl)dimethylsilyl)metha amide, and combinations thereof. In another embodiment, the invention is a silicon contain namine, ((4-methoxyphenyl)dimethylsilyl)methanamine, ing amide of (dimethyl(phenyl)silyl)-ethanamine, ((4-fluorophenyl)dim the formula II: ethylsilyl)ethanamine, ((4-chlorophenyl)dimethylsilyl)etha 55 namine, ((4-methoxyphenyl)dimethylsilyl)ethanamine. Specifically, preferred silicon-containing NSAID deriva (II) tives useful in the present invention include silicon-contain ing derivatives of the COOH-containing NSAIDs: fenamic acids, such as flufenamic acid, niflumic acid, and mefenamic 60 acid; indoles, such as indomethacin, Sulindac, and tolmetin: phenylalkanoic acids, such as Suprofen, ketorolac, flurbipro fen, and ibuprofen; and phenylacetic acids, such as diclofenac wherein with derivatives of indomethacin, and etodolac being pre n is an integer 1 or 2 65 ferred. Sila-derivatives of indomethacin, where the Cl at the R. Rs. R can be any group that does not substantially inter 4-position of the benzoyl moiety is replaced with Br or F are fere with amide formation, R. Rs. R can be the same or also contemplated. US 7,964,738 B2 9 10 Compound Preparation In effecting the foregoing reaction, the formation of the General Procedure to Prepare Silyl Amines azide can readily be accomplished by standard reaction con Many methods are known for preparing the substituted ditions for the displacement reaction, preferably by heating silylamines of the invention and can be used. Any mixtures of the reactants in an inert Solvent (e.g., dry dimethylforma final products or intermediates obtained can be separated on 5 mide) at 40°C. The conversion of the azide to the correspond the basis of the physical-chemical differences of the constitu ing amine can be effected through its N-Boc derivative by the ents, in known manner, into the pure final products or inter sequential treatment with (1) triphenylphosphine (PO) about mediates, for example by chromatography, distillation, frac room temperature in tetrahydrofuran (THF) (2) treatment tional crystallization, or by formation of a salt as appropriate 10 with water followed by (3) purification of the desired product in the circumstances. by the formation of its N-t-butoxycarbonyl derivative by reac The following routes of synthesis are merely exemplary tion with (BOC) O in THF at room temperature. The N-Boc methods for preparing formula II compounds. derivative is converted to its amine HCl salt by reaction with The procedures can utilize silyl derivatives obtained from gaseous HCl in diethylether (i.e., 3N HCl in diethylether) at tetrachlorosilane (SiC) or trichlorochlormethyl silane 15 room temperature. (ClSiCHCl) or a tailored modification thereof as starting To prepare compounds of formula II wherein n is 2, esters materials. In essence these silyl derivatives are of the formu derived from the appropriate silylchloride can be reduced to lae III and IV with R. Rs and R as defined for formula II or their corresponding alcohols, preferably with lithium alumi they are in a reaction-protected form of the R. Rs and R. num hydride and the alcohols can be converted to their cor Substituents. responding phthalimides using Mitsunobu reaction condi tions (i.e., treatment of the alcohol with diethylazodicarboxylate, triphenyl phosphine and phthalim (III) ide). The resulting phthalimides can be hydrolized to the 25 corresponding amine hydrochloride by sequential reaction with hydrazine hydrate and aqueous HC1. The esters can be R-i-c. and prepared by alkylation of the appropriate silylchloride with a R6 (IV) metallo derivative (preferably zinc or sodium) of ethylacetate R4 according to standard and well-known conditions. Alterna 30 tively, compounds may be reacted with magnesium in dieth R Y1\e\ ylether to form the appropriate Grignard reagent which, when R6 treated with formaldehyde (preferably using paraformalde hyde), will yield corresponding alcohols. The preparation of the R. Rs and R. Substituted silanes of 35 In certain methods, the final step utilized in the preparation of the compounds of formula II entails the removal of N-pro formulae III and IV is readily effected by successive alkyla tecting groups to form the free amine and/or pharmaceuti tions of tetrachloro-silane and trichlorochloromethylsilane cally acceptable salts thereof. Preferred N-protecting groups using organo-magnesium halide derivatives of the appropri are the phthalimide and the t-butoxycarbonyl (Boc) groups. ate R. Rs and R. Substituents. For example, SiCl is reacted 40 However, other equivalently functioning protecting groups with R Mghalides to produce R. SiCls compounds that are are known and may also be utilized and are contemplated. reacted with Rs Mg halides to produce R. R. SiCl, com Compounds of the invention may be prepared by any Suit pounds that are reacted with R Mghalides to produce R. Rs able method known in the art. Mixtures of final products or and R. SiCl compounds. Analogously, R Si(C1)CHCl, R. intermediates obtained can be separated on the basis of the Rs. Si(C1)CH2Cl and R. R. R. SiCHC1 compounds are pre 45 physical-chemical differences of the constituents, by known pared by these Successive alkylation procedures utilizing methods, into the pure final products or intermediates, for ClSiCH2Cl as a starting reactant. example by chromatography, distillation, fractional crystalli To prepare compounds of formula II wherein n is one, the Zation, or by formation of a salt if appropriate or possible appropriate RRs Resilyl methyl chloride can be subjected to under the circumstances. a displacement reaction by treatment with potassium phthal 50 One of skill can appreciate that chemical reactions and imide or Sodium azide to obtain the corresponding phthalim procedures analogous to those known in the art and the selec ide or azide. Conversion of the phthalimide to the desired tion of a particular route to obtain particular compounds is amine can be by reaction with hydrazine hydrate and conver governed by known principles and can be obtained using sion of the azide can be through chemical reduction to its methods that are analogous to the disclosed methods. amine, and Subsequent purification of the so-prepared amines 55 General Procedure to Prepare Disclosed Compounds may be accomplished via its N-Boc derivative that can then be The following routes of synthesis will serve to teach those converted to the amine by hydrolysis. ofordinary skill in the art how the compounds of the invention In effecting the foregoing reaction, the formation of the may be prepared. phthalimide can readily be accomplished by standard reac 60 In one embodiment carboxylic acid compounds are con tion conditions for the displacement reaction, preferably by verted to the acid chloride using thionyl chloride in dichlo heating the reactants in an inert solvent, e.g., dry dimethyl romethane. The excess of thionyl chloride can be removed by formamide at 70°C. The conversion of the phthalimide to its evaporation under reduced pressure. The acid chloride deriva corresponding amine can be effected by reaction with hydra tive can be immediately dissolved in dichloromethane with zine hydrate in a suitable solvent, preferably ethanol, fol 65 out purification, and allowed to cool to 0°C. in a salted lowed by treatment with aqueous acid, preferably HCl, under ice-bath. To the cooled solution, the mixture of appropriate reflux conditions. silyl amine derivative of formula II and triethylamine can be US 7,964,738 B2 11 12 added dropwise over 5 min, and the reaction allowed to pro 3-hydroxy-2-naphthoic acid, 2-hydroxyethanesulphonic ceed at 0° C. for 1 h and further, for overnight at room acid, lactobionic acid, n-dodecyl Sulphuric acid, maleic acid, temperature. The Volatiles can be removed on a rotary evapo malic acid, mandelic acid, methanesulphonic acid, methyl rator, and the residue suspended in acetone. The undissolved Sulpuric acid, mucic acid, 2-naphthalenesulphonic acid, pamoic acid, pantothenic acid, phosphanilic acid (4-ami salts can be filtered off and the acetone solution evaporated to 5 nophenyl) phosphonic acid), picric acid, salicylic acid, Stearic dryness. The residue can then be solidified with ice-cold acid, Succinic acid, tannic acid, tartaric acid, terephthalic water by stirring, filtered off and the product silyl amide acid, p-toluenesulphonic acid, 10-undecenoic acid and the derivative recrystallized from the appropriate solvent. like. In another embodiment carboxylic acid compounds are 10 It will be appreciated that such salts, provided that they are converted to the acid chloride using oxalyl chloride. For pharmaceutically acceptable, may be used in therapy. Such example oxalyl chloride (0.6 mL, 6.7 mmol) can be added salts may be prepared by reacting the compound with a Suit dropwise to a solution of indomethacin (2.0 g, 5.6 mmol) in able acid in a conventional manner. 20 mL of dry CH2Cl under nitrogen at room temperature. The reaction mixture is stirred for 8 h then solvent is evapo 15 COMPOUND EXAMPLES rated under vacuum. The crude product is washed three times with dry hexane (10 mL) and dried under vacuum to give Example 1 indomethacin acid chloride (2.0 g, 95% yield) as a pale gray Indomethacin (trimethylsilylpropyl)amide (2-(1-(4- solid. 'HNMR (CDC1,500MHz) & 2.43 (s.3H, Me), 3.86 (s, chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)- 3H, OMe), 4.19 (s. 2H, CH), 6.71 (dd, J=8.5, 2.5 Hz, 1H, N-(3-(trimethylsilyl)propyl)acetamide) aromatic), 6.88 (d. J–8.5 Hz, 1H, aromatic), 6.91 (d. J–2.5 HZ, 1H, aromatic), 7.50 (d. J=8.0 Hz, 2H, aromatic), 7.69 (d. Following the general procedure, indomethacin (trimeth J–8.0 Hz, 2H, aromatic). An aminosilane (1.0 mmol) is then ylsilylpropyl)amide was obtained from indomethacin acid added dropwise to a solution of indomethacin acid chloride 25 chloride and 3-aminopropyltrimethylsilane as a pale yellow (0.376 g, 1.0 mmol) in dry CHCl (20 mL) under nitrogen, solid: 0.285 g, yield 60%: mp 97-101° C. "H NMR (CDC1, followed by addition of triethylamine (140 uL. 1.0 mmol). 500MHz) 8-0.61 (s, 9H, TMS), 0.36 (m, 2H, CH), 1.40 (m, The reaction mixture is then stirred at room temperature for 2H, CH), 2.34 (s.3H, Me), 3.15 (m, 2H, CH), 3.59 (s. 2H, 15 hours. Next, 10 mL of CHCl is added and the reaction CH), 3.81 (s.3H, OMe), 5.94 (br. t. J=5.0Hz, 1H, NH), 6.68 mixture washed with saturated sodium bicarbonate (3x10 30 (dd, J-8.0, 2.0 Hz, 1H, aromatic), 6.92-6.96 (m. 2H, aro mL) and dried (MgSO). Solvent is evaporated under vacuum matic), 7.48 (d. J=8.5 Hz, 2H, aromatic), 7.61 (d. J=8.5 Hz, to give a residue which was purified by recrystallization from 2H, aromatic). C {H} NMR (CDC1, 125 MHz) 8-1.88 CHC1:hexane=1:4 (3C, TMS), 13.23 (CH), 13.63 (CH), 24.13 (Me), 32.28 Compounds of the invention may be chiral. They may be in (CH), 42.62 (CH), 55.69 (OMe), 100.84, 112.30, 112.95, the form of a single enantiomer or diastereomer, or a race 115.08, 129.21, 130.28, 130.88, 131.18, 133.56, 136.29, mate. The Stereochemistry of a chiral ring atom is preferably 139.59, 156.27 (aromatic), 168.33 (CO), 169.65 (CO). Si the same as that of the corresponding atom in the parent {H} NMR (CDC1, 99 MHz) & 2.36 (s, TMS). MS (Elec analog. More preferably, the stereochemistry of the com trospray Ionization, MeOH) m/z (M--Na) Calcd for pound as a whole corresponds to that of the parent molecule. 40 CHCINOSiNa, 493.1690; Found, 493.1696. Anal. Compounds of the invention can be prepared in racemic Calcd for CHCINOSi: C, 63.74; H, 6.63: N, 5.95. form, or prepared in individual enantiomeric form by specific Found: C, 63.41; H, 6.60; N, 5.88. The compound is illus synthesis or resolution. The compounds may, for example, be trated below: resolved into their enantiomers by standard techniques. Such as the formation of diastereomeric pairs by Salt formation 45 with an optically active acid followed by fractional crystalli C zation and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be chromato graphically separated, such as by HPLC, for example by using a chiral column. 50 Some compounds of the formula may exist in the form of various Solvates, such as hydrates and also fall within the Scope of the present invention. Compounds of the invention may be in the form of phar maceutically acceptable salts, for example, addition salts of 55 O N/ inorganic or organic acids. Such inorganic acid addition salts HN/N1 N include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and Sulphuric acid. Organic acid addition salts include, for example, salts of acetic acid, 60 Example 2 benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2-methylpropionic Indomethacin (trimethylsilylmethyl)amide (2-(1-(4- acid, 1.2-ethanedisulphonic acid, ethanesulphonic acid, eth chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)- ylenediaminetetraacetic acid (EDTA), fumaric acid, gluco N-((trimethylsilyl)methyl)acetamide) heptonic acid, gluconic acid, glutamic acid, N-glycolylarsa 65 nilic acid, 4-hexylresorcinol, hippuric acid, 2-(4- Following the general procedure, Indomethacin (trimeth hydroxybenzoyl) benzoicacid, 1-hydroxy-2-naphthoicacid, ylsilylmethyl)amide was obtained from indomethacin acid US 7,964,738 B2 13 14 chloride and aminomethyltrimethylsilane as an off-white (CO). 'Si {H} NMR (CDC1, 99 MHz) 8-3.27 (s, solid: 0.318g, yield 72%: mp 163-165° C. "H NMR (CDC1, SiMePh). MS (Electrospray Ionization, MeOH) m/z 500 MHz) 8-0.62 (s, 9H, TMS), 2.34 (s, 3H, Me), 2.69 (d. (M+Na)" Calcd for CHCINOSiNa, 527.1534: Found, J=6.0 Hz, 2H, CH), 3.60 (s. 2H, CH), 3.81 (s, 3H, OMe), 527.1515. Anal. Calcd for CHCINOSi: C, 66.58; H, 5.50 (br. t, J-=5.0 Hz, 1H, NH), 6.68 (dd, J=9.0, 2.5 Hz, 1H, 5.79; N, 5.55. Found: C, 66.24; H, 6.09: N, 5.44. The com aromatic), 6.92-6.95 (m, 2H, aromatic), 7.50 (d. J=9.0 Hz, pound is illustrated below: 2H, aromatic), 7.64 (d. J–8.5 Hz, 2H, aromatic). C {H} NMR (CDC1, 125 MHz) 8-2.71 (3C, TMS), 13.46 (Me), 30.04 (CH), 32.29 (CH), 55.96 (OMe), 101.17, 112.45, 10 113.69, 115.47, 129.47, 130.77, 131.29, 131.47, 134.28, 136.42, 139.52, 156.61 (aromatic), 168.53 (CO), 169.57 (CO). Si{H} NMR (CDC1, 99 MHz) & 2.04 (s, TMS). C MS (Electrospray Ionization, MeOH) m/z (M+Na)" Calcd for 15 C.H.CINOSiNa, 465. 1377: Found, 465.1371. Anal. Calcd for C.H.CINOSi: C, 62.36; H, 6.14; N, 6.32. Found: C, 61.86; H, 5.94: N, 6.20. The compound is illus trated below:

C 25 O

N 30 No Example 4 O

35 Indomethacin (triethoxysilylpropyl)amide (2-(1-(4- HN chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)- Y N-(3-(triethoxysilyl)propyl)acetamide) 1"V Following the general procedure, Indomethacin (triethoX 40 ysilylpropyl)amide was obtained from indomethacin acid chloride (1.0g, 2.7 mmol) and 3-aminopropyltriethoxysilane (0.62 mL, 2.7 mmol) and molecular sieves in dry CHCl (30 Example 3 mL) under nitrogen. The reaction mixture was stirred at room 45 temperature for 15 hours. Next, molecular sieves were filtered Indomethacin (dimethylphenylsilylmethyl)amide out and solvent was evaporated under vacuum to give a resi (2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H due which was purified by recrystallization from CHCl2: indol-3-yl)-N-((dimethyl(phenyl)silyl)methyl)aceta hexane=1:4 (1.09 g, yield 72%) as a yellow solid; mp 71-73° mide) 50 C. (dec.). H NMR (CDC1,500 MHz) & 0.51 (m, 2H, CH), 1.17 (t, J–7.0 Hz, 9H, OCHCH.), 1.54 (m. 2H, CH,), 2.38 Following the general procedure, Indomethacin (dimeth (s, 3H, Me), 3.22 (m, 2H, CH), 3.64 (s. 2H, CH), 3.74 (q. ylphenylsilylmethyl)amide was obtained from indomethacin J=70 Hz, 6H, OCHCH), 3.82 (s, 3H, OMe), 5.77 (br. t, acid chloride and aminomethyldimethylphenylsilane as a yel J=5.0 Hz, 1H, NH), 6.70 (dd, J=9.0, 2.0 Hz, 1H, aromatic), low solid: 0.320 g, yield 63%; mp 121-124° C. "H NMR 55 (CDC1, 500 MHz) & 0.25 (s, 6H, SiMePh), 2.22 (s, 3H, 6.87-6.90 (m, 2H, aromatic), 7.60 (d. J=8.5 Hz, 2H, aro Me), 2.91 (d. J=5.5 Hz, 2H, CH), 3.57 (s.2H, CH), 3.81 (s, matic), 7.67 (d. J=8.5 Hz, 2H, aromatic). C {H} NMR 3H, OMe), 5.44 (br. t, J=5.0 Hz, 1H, NH), 6.73 (dd, J=9.0, (CDC1, 125 MHz) & 7.43 (CH), 13.34 (CH), 18.21 (3C, 2.5 Hz, 1H, aromatic), 6.91 (d. J=2.5 Hz, 1H, aromatic), 7.00 OCHCH), 22.89 (Me), 32.26 (CH), 41.82 (CH), 55.68 (d. J–9.0 Hz, 1H, aromatic), 7.21-7.32 (m, 5H, aromatic), 60 (OMe), 58.35 (3C, OCHCH), 100.69, 112.94, 115.08, 7.50 (d. J=8.5 Hz, 2H, aromatic), 7.60 (d. J=8.5 Hz, 2H, 129.08, 129.20, 130.31, 130.87, 131.15, 133.63, 136.21, aromatic). C{H} NMR (CDC1, 125 MHz) 8–4.23 (2C, 139.52, 156.29 (aromatic), 168.27 (CO), 169.73 (CO). Si SiMePh), 13.37 (Me), 29.06 (CH), 32.27 (CH), 55.94 {H} NMR (CDC1, 99 MHz) 8-46.93 (s, Si(OEt)). MS (OMe), 101.11, 112.48, 113.52, 115.52, 128.24, 129.43, 65 (Electrospray Ionization, MeOH) m/z (M+H) Calcd for 129.70, 130.71, 131.26, 131.40, 133.74, 134.29, 136.28, C.H.CINOSi, 561.2187: Found, 561.2161. The com 136.66, 139.42, 156.63 (aromatic), 168.38 (CO), 169.63 pound is illustrated below:

US 7,964,738 B2 17 18 arachidonic acid at 37°C.). The reaction was incubated for 35 TABLE 2 s (maximum level of COX-2 accumulation as determined from time course studies), and terminated by addition of Compound 50-60 ul of SnCl (1 mg/ml) in 0.1 NHC1. PGE production Indo in the presence or absence of the drug was determined by 5 methacin Example 1 Example 2 Example 3 Example 4 Enzyme Immunoassay (EIA) analysis as described. ICso (IM) >100 6.6 14.3 4.8 2O EIA Determination of Prostaglandins EIA reagents for prostaglandin determination were pur Compounds of the present invention can be used in the chased from commercial sources. PGE levels in enzyme 10 treatment of inflammation in a subject, and for treatment of assays were measured against standards prepared in the same other cyclooxygenase-2 mediated disorders, including the milieu using standard methods. The EIA was conducted in treatment of pain and headaches, or as an antipyretic for the 96-well micotiter plates and optical density measured using a treatment of fever. For example, compounds of the invention microplate reader by standard methods. can be used to treat arthritis, including rheumatoid arthritis, In Vitro Cellular Proliferation Assay 15 spondyloarthropathies, gouty arthritis, osteoarthritis, sys In vitro cell proliferation assays were performed using a temic lupus erythematosus and juvenile arthritis. Compounds 96-well plate based SRB (Sulforhodamine-B) assay. Briefly, of the invention can be used in the treatment of asthma, human MiaPaca-2 pancreatic cancer cells were plated in 100 bronchitis, menstrual cramps, preterm labor, tendinitis, bur ul medium on day 0 in 96-well microtiter plates (Falcon sitis, allergic neuritis, cytomegalovirus infectivity, apoptosis #3072). On day 1, 10ul of serial dilutions of each compound including HIV induced apoptosis, lumbago, liver disease (Nine 1:2 dilutions with a starting concentration of 100 uM) including hepatitis, skin-related conditions such as psoriasis, were added in triplicates to the plates. As a vehicle control, eczema, acne, UV damage, burns and dermatitis, and from serial dilutions of DMSO with a starting concentration of post-operative inflammation including from ophthalmic Sur 25 gery such as cataract Surgery and refractive Surgery. Com 0.5% were also included. After incubation for 3 days at 37°C. pounds of the invention can also be useful to treat gastrointes in a humidified incubator, cells were fixed in situ with 50 uL tinal conditions such as inflammatory bowel disease, Crohn's of cold trichloroacetic acid (TCA, final concentration at 10% disease, gastritis, irritable bowel syndrome and ulcerative w/v) for 60 minutes. Cells were then washed 5 times with colitis. Compounds of the invention can be used to treat H2O and air-dried. Next, cells were stained with 20 uL of 30 inflammation in Such diseases as migraine headaches, periar 0.2% SRB in 1% acetic acid and incubated at room tempera teritis nodosa, thyroiditis, aplastic anemia, Hodgkin’s dis ture for 30 minutes and unbound SRB was removed by wash ease, sclerodoma, rheumatic fever, type I diabetes, neuromus ing 5 times with 1% acetic acid and air-dried. Finally, bound cular junction disease including myasthenia gravis, white SRB stain was solubilized in 50 uL of 50 uM Tris buffer matter disease including multiple Sclerosis, Sarcoidosis, before taking an optical density measurement at 570 nm using 35 nephrotic syndrome, Behcet’s syndrome, polymyositis, gin a BioTek SynergyTM HT Multiple Detection microplate givitis, nephritis, hypersensitivity, Swelling occurring after reader. The growth inhibition data were expressed as the injury including brain edema, myocardial ischemia, and the percentage of cell Survival calculated from the background like. The compounds can be used to treat ophthalmic diseases, corrected absorbance. The surviving fraction of cells was Such as retinitis, conjunctivitis, retinopathies, uveitis, ocular determined by dividing the mean absorbance values of the 40 photophobia, and of acute injury to the eye tissue. The com test agent-treated samples by the mean absorbance values of pounds can be used to treat pulmonary inflammation, Such as untreated control. that associated with viral infections and cystic fibrosis, and in bone resorption Such as associated with osteoporosis. In Vitro Results Certain compounds can be used in the treatment of certain When tested in the recombinant human COX-1 and -2 45 central nervous system disorders, such as cortical dementias enzyme assays described above, example compound of this including Alzheimer's disease, neurodegeneration, and cen invention were potent inhibitors of COX-2 (Table 1). The tral nervous system damage resulting from Stroke, ischemia example compounds were selective inhibitors of COX-2 rela and trauma. The term “treatment includes partial or total tive to COX-1 (Table 1). inhibition amelioration of the dementia, including Alzhe 50 imer's disease, vascular dementia, multi-infarct dementia, TABLE 1. pre-senile dementia, alcoholic dementia, and senile demen tia. Compound COX-1 ICso (M) COX-2 ICso (M) Certain compounds can be used as anti-inflammatory agents, such as for the treatment of arthritis, with the addi Indomethacin 4.7 x 108 5.9 x 107 55 tional benefit of having significantly less harmful side effects. Example 1 >1.0 x 108 2.1 x 107 Such compounds could also be used in the treatment of aller Example 2 2.7 x 106 3.9 x 107 gic rhinitis, respiratory distress syndrome, endotoxin shock Example 3 >1.0 x 108 3.1 x 107 syndrome, and liver disease. Example 4 5.0 x 10 5.7 x 107 Certain compounds can be used in the treatment of pain, 60 including postoperative pain, dental pain, muscular pain, and The IC50 value is above the highest tested concentration. The dose response curve has an pain resulting from cancer. inhibitory shape with less than 50% inhibition at the highest tested concentration. Certain compounds of the invention can be used to treat and prevent inflammation-related cardiovascular disorders in a Example compounds caused significant growth inhibition Subject. For example, such compounds could be used in the of human MiaPaca-2 pancreatic cell growth (s.50% of cell 65 treatment and prevention of vascular diseases, coronary proliferation) relative to the indomethacin and vehicle-treated artery disease, aneurysm, vascular rejection, arteriosclerosis, control group (Table 2). atherosclerosis including cardiac transplant atherosclerosis, US 7,964,738 B2 19 20 myocardial infarction, embolism, stroke, thrombosis, includ group consisting of 5-FU-fibrinogen, acanthifolic acid, ami ing venous thrombosis, angina including unstable angina, nothiadiazole, brequinar Sodium, carmofur, cyclopentyl coronary plaque inflammation, bacterial-induced inflamma cytosine, cytarabine phosphate Stearate, cytarabine conju tion including Chlamydia-induced inflammation, viral gates, deZaguanine, dideoxycytidine, dideoxyguanosine, induced inflammation, and inflammation associated with Sur didox, doxifluridine, fazarabine, floxuridine, fludarabine gical procedures Such as vascular grafting including coronary phosphate, 5-fluorouracil, N-(2-furanidyl)-5-fluorouracil, artery bypass Surgery, revascularization procedures including isopropyl pyrrolizine, methobenzaprim, methotrexate, nor angioplasty, stent placement, endarterectomy, or other inva spermidine, pentostatin, piritrexim, plicamycin, thioguanine, sive procedures involving arteries, veins and capillaries. tiazofurin, trimetrexate, tyrosine kinase inhibitors, tyrosine Certain compounds could be used for the treatment of 10 protein kinase inhibitors, UFT and uricytin. angiogenesis-related disorders in a Subject. In a method the A second family of antineoplastic agents that may be used compounds can be administered to a subject in need of angio in combination with compounds of the present invention con genesis inhibition. The compounds could be used in the treat sists of alkylating-type antineoplastic agents. Suitable alky ment of neoplasia, including metastasis; ophthalmological lating-type antineoplastic agents may be selected from the conditions such as corneal graft rejection, ocular neovascu 15 group consisting of aldo-phosphamide analogues, altre larization, retinal neovascularization including neovascular tamine, anaxirone, bestrabucil, budotitane, carboplatin, car ization following injury or infection, diabetic retinopathy, mustine, chlorambucil, cisplatin, cyclophosphamide, macular degeneration, retrolental fibroplasia and neovascular cyplatate, diphenylspiromustine, diplatinum cytostatic, Erba glaucoma; ulcerative diseases Such as gastric ulcer, patho distamycin derivatives, elmustine, estramustine phosphate logical, but non-malignant, conditions such as hemangiomas, Sodium, fotemustine, hepsul-fam, ifosfamide, iproplatin, including infantile hemaginomas, angiofibroma of the lomustine, mafosfamide, mitolactol, oxaliplatin, Upjohn nasopharynx and avascular necrosis of bone; and disorders of PCNU, prednimustine, ranimustine, Semustine, Spiromus the female reproductive system Such as endometriosis. tine, tauromustine, temozolomide, teroxirone, tetraplatin and Certain compounds of the invention can be used for the trimelamol. prevention and treatment of benign and malignant tumors/ 25 A third family of antineoplastic agents which may be used neoplasia including cancer, Such as colorectal cancer, brain in combination with compounds of the present invention con cancer, bone cancer, epithelial cell-derived neoplasia (epithe sists of antibiotic-type antineoplastic agents. Suitable antibi lial carcinoma) Such as basal cell carcinoma, adenocarci otic-type antineoplastic agents may be selected from the noma, gastrointestinal cancer Such as lip cancer, mouth can group consisting of aclarubicin, actinomycin D, actinopl cer, esophageal cancer, Small bowel cancer and stomach 30 anone, aeroplysinin derivative, anthracycline, azino-mycin cancer, colon cancer, liver cancer, bladder cancer, pancreas A, bisucaberin, bleomycin Sulfate, bryostatin-1, calichemy cancer, ovary cancer, cervical cancer, lung cancer, breast can cin, chromoximycin, dactinomycin, daunorubicin, cer and skin cancer, Such as Squamous cell and basal cell ditrisarubicin B, doxorubicin, doxorubicin-fibrinogen, cancers, prostate cancer, renal cell carcinoma, and other elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin known cancers that effect epithelial cells throughout the body. 35 A1, esperamicin-Alb, fostriecin, glidobactin, gregatin-A, Preferably, neoplasia is selected from gastrointestinal cancer, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, Barrett's esophagus, liver cancer, bladder cancer, pancreas kesarirhodins, menogaril, mitomycin, mitoxantrone, neoen cancer, ovary cancer, prostate cancer, cervical cancer, lung actin, oxalysine, oxaunomycin, peplomycin, pilatin, piraru cancer, breast cancer and skin cancer, such as Squamous cell bicin, porothramycin, pyrindamycin A, rapamycin, rhizoxin, and basal cell cancers. Certain compounds can also be used to 40 rodorubicin, Sibanomicin, Siwenmycin, Sorangicin-A, spar treat the fibrosis that occurs with radiation therapy. The Somycin, Steffimycin B, talisomycin, terpentecin, thrazine, method can be used to treat Subjects having adenomatous tricroZarin A, and Zorubicin. polyps, including those with familial adenomatous polyposis A fourth family of antineoplastic agents which may be used (FAP). Additionally, the method can be used to prevent polyps in combination with compounds of the present invention con from forming in patients at risk of FAP. Such conditions are 45 sists of a miscellaneous family of antineoplastic agents exemplary in nature, and are in no way meant to limit the selected from the group consisting of alpha-carotene, alpha Scope of the invention. difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin The compounds of the present invention may be adminis AHC-52, alstonine, amonafide, amphethinile, amsacrine, tered alone or in conjunction with additional therapies known Angiostat, ankinomycin, anti-neoplaston A10, antineoplas to those skilled in the art in the prevention or treatment of 50 ton A2, antineoplaston A3, antineoplaston A5, antineoplaston neoplasia. Alternatively, the compounds described herein AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, may be used in conjunctive therapy. By way of example, the Avarol, baccharin, batracylin, benfluron, benzotript, Ipsen compounds may be administered alone or in conjunction with Beaufour BIM-23015, bisantrene, Bristo-Myers BMY other antineoplastic agents or other growth inhibiting agents 40481, Vestar boron-10, bromofosfamide, Wellcome or other drugs or nutrients. 55 BW-502, Wellcome BW-773, caracemide, carmethizole There are large numbers of antineoplastic agents available hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, and in commercial use, in clinical evaluation and in pre Chemes CHX-2053, Chemex CHX-100, Warner-Lambert clinical development, which could be selected for treatment CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, of neoplasia by combination drug chemotherapy. Such anti Warner-Lambert CI-958, clanfenur, claviridenone, ICN com neoplastic agents fall into several major categories, namely, 60 pound 1259, ICN compound 4711, Contracan, Yakult Honsha antibiotic-type agents, alkylating agents, antimetabolite CPT-11, crisinatol, curaderm, cytochalasin B, cytarabine, agents, hormonal agents, immunological agents, interferon cytocytin, Merz D-609, DABIS maleate, dacarbazine, datel type agents and miscellaneous agents. liptinium, didemnin-B, dihaematoporphyrin ether, dihydro A first family of antineoplastic agents that may be used in lenperone, dinaline, distamycin, Toyo Pharmar DM-341, combination with compounds of the present invention con 65 Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, sists of antimetabolite-type antineoplastic agents. Suitable elliptinium acetate, Tsumura EPMTC, ergotamine, etopo antimetabolite antineoplastic agents may be selected from the side, etretinate, fenretinide, Fujisawa FR-57704, gallium US 7,964,738 B2 21 22 nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, noma, clear cell carcinoma, cystadenoma, endodermal sinus grifolan NMF-5N, hexadecylphosphocholine, Green Cross tumor, endometrial hyperplasia, endometrial stromal sar HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, coma, endometrioid adenocarcinoma, ependymal, epithe ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot loid, Ewing's sarcoma, fibrolamellar, focal nodular hyperpla K-477, Otsuak K-76COONa, Kureha Chemical K-AM, 5 sia, gastrinoma, germ cell tumors, glioblastoma, MECT Corp KI-81 10, American Cyanamid L-623, leuko glucagonoma, hemangiblastomas, hemangioendothelioma, regulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, hemangiomas, hepatic adenoma, hepatic adenomatosis, NCI (US) MAP. marycin, Merrel Dow MDL-27048, Medco hepatocellular carcinoma, insulinoma, intaepithelial neopla MEDR-340, merbarone, merocyanine derivatives, methyla sia, interepithelial squamous cell neoplasia, invasive squa nilinoacridine, Molecular Genetics MGI-136, minactivin, 10 mous cell carcinoma, large cell carcinoma, leiomyosarcoma, mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku lentigo maligna melanomas, malignant melanoma, malignant Kogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour mesothelial tumors, medulloblastoma, medulloepithelioma, Milling N-021, N-acylated-dehydroalanines, nafazatrom, melanoma, meningeal, mesothelial, metastatic carcinoma, Taisho NCU-190, nocodazole derivative, Normosang, NCI mucoepidermoid carcinoma, neuroblastoma, neuroepithelial NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI 15 adenocarcinoma nodular melanoma, oat cell carcinoma, oli NSC-95580, octreotide, Ono ONO-112, oduizanocine, Akzo godendroglial, osteosarcoma, pancreatic polypeptide, papil Org-10172, pancratistatin, pazelliptine, Warner-Lambert lary serous adenocarcinoma, pineal cell, pituitary tumors, PD-11 1707, Warner-Lambert PD-115934, Warner-Lambert plasmacytoma, pseudosarcoma, pulmonary blastoma, renal PD-131141, Pierre Fabre PE-1001, ICRT peptide D, pirox cell carcinoma, retinoblastoma, rhabdomyosarcoma, Sar antrone, polyhaematoporphyrin, polypreic acid, Efamol por- 20 coma, serous carcinoma, Small cell carcinoma, Soft tissue phyrin, probimane, procarbazine, proglumide, Invitron pro carcinomas, Somatostatin-secreting tumor, squamous carci tease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries noma, squamous cell carcinoma, Submesothelial, Superficial RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc spreading melanoma, undifferentiatied carcinoma, uveal RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F- melanoma, Verrucous carcinoma, Vipoma, well differentiated 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm 25 carcinoma, and Wilm's tumor. SP-10094, spatol, spirocyclopropane derivatives, spiroger The methods and compositions of the present invention manium, Unimed, SS Pharmaceutical SS-554, Strypoldinone, provide one or more benefits. Combinations of silicon-con Stypoldione, Suntory SUN 0237, Suntory SUN 2071, super taining NSAIDs that are COX-2 selective with radiation oxide dismutase, Toyama T-506, Toyama T-680, taxol. Teijin therapy of the present invention are useful in treating neopla TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, 30 sia disorders. Preferably, the COX-2 inhibitor agent or agents tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, and the radiation therapies of the present invention are admin Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, istered in combination at a low dose, that is, at a dose lower vinblastine Sulfate, Vincristine, Vindesine, vinestramide, than has been conventionally used in clinical situations for vinorelbine, vintriptol, Vinzolidine, with anolides and each of the individual components administered alone. Yamanouchi YM-534. 35 A benefit of lowering the dose of the radiation therapies of Examples of radioprotective agents which may be used in the present invention administered to a mammal includes a combination with compounds of the present invention are decrease in the incidence of adverse effects associated with AD-5, adohnon, amifostine analogues, detox, dimeSna, higher dosages. By lowering the incidence of adverse effects, 1-102, MM-159, N-acylated-dehydroalanines, TGF-Genen an improvement in the quality of life of a patient undergoing tech, tiprotimod, amifostine, WR-151327, FUT-187, keto- 40 treatment for cancer is contemplated. Further benefits of low profen transdermal, nabumetone, Superoxide dismutase. ering the incidence of adverse effects include an improve Treatment of a neoplasia disorder in a mammal in need of ment in patient compliance, and a reduction in the number of Such treatment is provided by methods and combinations hospitalizations needed for the treatment of adverse effects. using radiation and a COX-2 inhibitor. The method comprises Alternatively, the methods and combination of the present treating a mammal with a therapeutically effective amount of 45 invention can also maximize the therapeutic effect at higher a combination comprising a silicon-Substituted analogue of doses. certain NSAIDs that are COX-2 selective and a radiothera Besides being useful for human treatment, these com peutic agent. These inhibitors of COX-2 potentiate tumor pounds are also useful for veterinary treatment of companion response to radiation, thus, COX-2 inhibitors improve the animals, exotic animals and farm animals, including mam efficacy of radiotherapy. In one embodiment of the invention 50 mals, rodents, and the like. More preferred animals include a method for treating neoplasia in a Subject in need of Such horses, dogs, and cats. treatment comprises treating the Subject with radiation The present compounds may also be used in co-therapies, therapy and a therapeutically effective amount of a silicon partially or completely, in addition to other anti-inflammato substituted analogue of certain NSAIDs that are COX-2 ries, such as together with steroids, NSAIDs, iNOS inhibi selective or pharmaceutically acceptable salt or derivative 55 tors, p-38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibi thereof wherein the neoplasia is selected from lung cancer, tors, LTB receptor antagonists and LTA hydrolase breast cancer, gastrointestinal cancer, bladder cancer, head inhibitors. and neck cancer, and cervical cancer. The pharmaceutical composition may include, but is not The methods and combinations of the present invention limited to, at least one pharmaceutically acceptable carrier. may be used for the treatment of neoplasia disorders selected 60 The carrier is generally an inert bulk agent added to the from the group consisting of acral lentiginous melanoma, compound to make the active ingredients easier to handle, and actinic keratoses, adenocarcinoma, adenoid cycstic carci can be solid, semisolid, or liquid as well as any manner noma, adenomas, adenosarcoma, adenosquamous carci understood in the art. noma, astrocytic tumors, bartholin gland carcinoma, basal Pharmaceutical compositions of the invention may also cell carcinoma, bronchial gland carcinomas, capillary, carci- 65 include any delivery vehicle or device known in the art to noids, carcinoma, carcinosarcoma, cavernous, cholangiocar enhance transport in reaching the target site. Such delivery cinoma, chondrosarcoma, choriod plexus papilloma/carci vehicles or devices may be administered in admixtures with US 7,964,738 B2 23 24 any carrier aforementioned with regard to the route of admin is caused as a result of exposure to any number of pathogens; istration, and standard pharmaceutical practice. Dosages nutritional factors; environmental factors that act as stressors associated with Such vehicles or devices will vary according or pollutants; and/or physiological disorders such as those of to certain factors. Such as age, weight, and the condition of the the digestive tract, pulmonary/circulatory system, liver, kid human or animal, as well as the pharmacokinetics and release neys, colon, and/or pancreas. characteristics from said delivery vehicles or devices. In addition to the foregoing, the present invention also The present invention also involves a method for the treat contemplates a process for the production of a pharmaceuti ment of the conditions as noted above in mammals, particu cal composition. Such process comprises bringing at least one larly humans, Suffering therefrom. of the individual components described thereof into intimate The present invention also provides for the use of any such 10 admixture with a silicon-modified NSAID of the present compound of the above pharmaceutical compositions or salt invention, and when required, compounding the obtained thereof, in the manufacture of a therapeutic agent. composition(s) in unit dosage forms. Methods of preparation Treatment is contemplated in mammals, particularly of pharmaceutical compositions are well known in the art. For humans, as well as those mammals of economic or social 15 the discussion of such methods, pages 1435-1694 of Reming importance, or of an endangered status. Examples may be ton's Pharmaceutical Science (Part 8) are incorporated livestock or other animals expressly for human consumption, herein by reference. or domesticated animals such as dogs, cats, or horses. Also The present invention indicates that silicon-containing contemplated is the treatment of birds and poultry, such as COOH-containing drugs that are not COX-2 selective inhibi turkeys, chickens, and fowl of the like. tors, such as the NSAID known as indomethacin, when con The invention comprises administration of a treatment Verted into silicon-containing analogs, results in isozyme effective amount of at least one silicon-containing NSAID specificity for COX-2 and thus presents an efficient strategy derivative in a concentration calculated to provide the mam for the generation of potent and selective COX-2 inhibitors. mal being treated in the prevention, control, or cessation of Thus, this strategy has been used to develop nonulcerogenic disease. In a preferred embodiment, the silicon-containing 25 antiinflammatory agents that may have improved tolerability carboxylic acid NSAID derivatives possess an analgesic, and pharmacokinetics. anti-inflammatory, anti-angiogenic and/or antipyretic prop The foregoing descriptions have been directed to particular erty, providing an analgesic, anti-inflammatory, anti-angio embodiments of the invention in accordance with require genic and/or antipyretic effect. ments of the Patent Statutes for the purposes of illustration The derivatives useful in the method of the present inven 30 and explanation. It will be apparent however, to those skilled tion are silicon containing NSAID’s having a carboxylic acid in the art, that many modifications, changes and variations in moiety or a pharmaceutically acceptable salt thereof. For the claimed compositions, Solutions, methods of administra example, silicon-containing derivatives of indomethacin, tion of the compositions set forth will be possible without flufenamic acid or Sulindac sulfide or a pharmaceutically departing from the scope and spirit of the claimed invention. acceptable salt thereof. 35 It is intended that the following claims be interpreted to The mode of administration of the silicon-containing car embrace all Such modifications and changes. boxylic acid compound to the human or animal to be treated It should be understood that various changes and modifi is as such to deliver an inhibiting effective amount of the cations to the presently preferred embodiments described pharmaceutical composition. For example, therapeutic deliv 40 herein will be apparent to those skilled in the art. Such ery may be achieved, but is not limited to, enteral adminis changes and modifications can be made without departing tration, which includes oral, Sublingual, and rectal adminis from the spirit and scope of the present invention and without tration or via parenteral administration that includes diminishing its intended advantages. It is therefore intended intramuscular, intravenous, or Subcutaneous. Therapeutic that such changes and modifications be covered by the delivery may also be achieved via other routes including 45 appended claims. topical, transdermal, or inhalation. Formulations of the com The invention is claimed as follows: pounds may include, but are not limited to, transdermal patch, 1. A silicon containing compound of the formula II: Suppository, tablet, capsule, powder, or in an appropriate carrier fluid administered in a solution or Suspension. Also contemplated is administration of the solution or Suspension 50 (II) to the esophagus, stomach, and/or duodenum, Such as by O gavage, i.e., via a feeding tube. R4 It is also contemplated that additional ingredients, such as -----/7 various excipients, carriers, Surfactants, nutriments, and the H / SR like, as well as various medicaments other than a sila-NSAID 55 Rs derivative, or combinations thereof, may be present together with the sila-NSAID derivative. whereinnis an integer 1 or 2 and R. Rs. R can be the same A dosing amount of silicon-containing NSAID derivatives or different and are independently selected from the suitable to be therapeutically effective in a mammal, includ 60 group consisting of hydrogen, alkenyl, alkoxyalkyl, ing humans, can be calculated according to mg/kg of body alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkylcar weight, or body surface area (BSA). Administration may be bonylalkoxy, alkylcarbonylamino, alkylcarbonylami one or more times per day to achieve the total desired daily noalkyl, alkynyl, aminoalkoxy, aminoalkylcarbony dose, the amount varying as to the severity of the cancer or loxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, condition as previously discussed. 65 arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, The present invention may be useful in the treatment of cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, cancer in humans or animals, wherein the cancer or condition haloalkenyloxy, haloalkoxy, haloalkyl, halogen, het