US 2004O147581A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0147581 A1 Taylor et al. (43) Pub. Date: Jul. 29, 2004

(54) METHOD OF USING A COX-2 INHIBITOR Related U.S. Application Data AND A 5-HT1A RECEPTOR MODULATOR AS A COMBINATION THERAPY (60) Provisional application No. 60/427,198, filed on Nov. 18, 2002. (75) Inventors: Duncan P. Taylor, Kalamazoo, MI (US); Diane T. Stephenson, Portage, Publication Classification MI (US) (51) Int. Cl." ...... A61K 31/60; A61K 31/415; Correspondence Address: A61K 31/192; A61K 31/21 Charles E. Dunlap (52) U.S. Cl...... 514,406; 514/570; 514/569; P.O. Box 11070 514/509; 514/165 Columbia, SC 29211-1070 (US) (57) ABSTRACT (73) Assignee: Pharmacia Corporation, St. Louis, MO Compositions and methods to treat or prevent pain, inflam mation, or inflammation-related disorder, as well as a neu (US) rologic disorder involving neurodegrneration in a Subject (21) Appl. No.: 10/702,403 that is in need of Such prevention or treatment involve a combination of a Cox-2 inhibitor and a 5-HT1A receptor (22) Filed: Nov. 5, 2003 modulator. US 2004/O147581 A1 Jul. 29, 2004

METHOD OF USINGA COX-2 INHIBITOR AND A induced pain and Swelling associated with the inflammation 5-HT1A RECEPTOR MODULATOR ASA process are also active in affecting other prostaglandin COMBINATION THERAPY regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs CROSS-RELEFERENCE TO RELATED can produce Severe side effects, including life threatening PATENTS AND PATENT APPLICATIONS ulcers, that limit their therapeutic potential. Previous 0001. This application is a non-provisional of U.S. Pro NSAIDs have been found to prevent the production of visional Patent Application No. 60/427,198, filed Nov. 18, prostaglandins by inhibiting enzymes in the human arachi 2002, which is incorporated herein by reference in its donic acid/prostaglandin pathway, including the enzyme entirety. cyclooxygenase (Cox). The recent discovery of an inducible enzyme associated with inflammation (named “cyclooxyge BACKGROUND OF THE INVENTION nase-2 (Cox-2)" or “prostaglandin G/H synthase II”) pro vides a viable target of inhibition which more effectively 0002 (1) Field of the Invention reduces inflammation and produces fewer and less drastic 0003. The present invention relates to compositions and side effects. methods for the treatment or prevention of pain, inflamma 0008 Compounds that selectively inhibit the cyclooxy tion, or inflammation-related disorder in a mammal using a genase-2 enzyme have been discovered. These compounds combination of a Cox-2 inhibitor and a 5-HT1A receptor selectively inhibit the activity of Cox-2 to a greater extent modulator. than the activity of Cox-1. The Cox-2-selective inhibitors 0004) (2) Description of Related Art are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side 0005 Serotonin (5-hydroxytryptamine, or 5-HT) is effects associated with the inhibition of Cox-1. Thus, involved in the origin of many disease States. Recently, at cyclooxygenase-2-selective inhibitors have shown great least fourteen different 5-HT receptor subtypes have been promise for use in therapies-especially in therapies that identified and characterized (“A Review of Central 5-HT require extended administration, Such as for pain and Receptors and Their Function, N. M. Barnes and T. Sharp, inflammation control for arthritis. Additional information on Neuropharmacology, 38:1083-1152 (1999)). The 5-HT, the identification of cyclooxygenase-2-Selective inhibitors receptor family consists of five receptor Subtypes: 5-HT1A, can be found in: (1) Buttgereit, F. et al., Am. J. Med., 110(3 5-HT1B, 5-HT, 5-HT, and 5-HT. The 5-HT1A receptor Suppl. 1): 13-9 (2001); (2) Osiri, M. et al, Arthritis Care is the best known among the different 5-HT receptors and is Res., 12(5):351-62 (1999); (3) Buttar, N. S. et al., Mayo widely distributed in the central nervous system (L. Lanfur Clin. Proc., 75(10):1027-38 (2000); (4) Wollheim, F. A., ney and M. Hamon, Nuclear Medicine & Biology, 27:429 Current Opin. Rheumatol., 13:193-201 (2001); (5) U.S. Pat. 435 (2000)). No. 5,434,178 (1,3,5-trisubstituted pyrazole compounds); 0006 Studies on the 5-HT, receptor have shown poten (6) U.S. Pat. No. 5,476,944 (derivatives of cyclic phenolic tial roles in a variety of physiological processes including, thioethers); (7) U.S. Pat. No. 5,643,933 (substituted sulfo neuroendocrine function, thermoregulation, vasoreactive nylphenylheterocycles); U.S. Pat. No. 5,859,257 (isoxazole headaches, Sexual behavior, food intake, tooth-germ mor compounds); (8) U.S. Pat. No. 5,932,598 (prodrugs of phogenesis, immune function, aggression, depression and benzenesulfonamide-containing Cox-2 inhibitors); (9) U.S. anxiety (J. R. Raymond, et al., Br. J. Pharmacol., 127:1751 Pat. No. 6,156,781 (substituted pyrazolyl benzenesulfona 1764 (1999)). Other studies have shown the potential use of mides); and (10) U.S. Pat. No. 6,110,960 (for dihydroben 5-HTA agonists in glaucoma to lower intraocular pressure Zopyran and related compounds). in the eye (N. N. Osborne, et al., Eye, 14:454-463 (2000)). 0009 Cox-2 inhibitors have also been described for the Recent studies have shown the involvement of 5-HT treatment of cancer (WO98/16227) and for the treatment of receptors in the transmission of nociceptive (pain) informa tumors (See, EP 927.555, and Rozic et al., Int. J. Cancer, tion in the Spinal cord resulting from nerve injury or inflam 93(4):497-506 (2001)). Celecoxib, a selective inhibitor of mation (Z.-Y. Liu, et al, Neuroscience, 112(2):399-407 Cox-2, exerted a potent inhibition of fibroblast growth (2002)). Growing evidence Suggests that the 5-HT1A recep factor-induced corneal angiogenesis in rats. (Masferrer et al., tor is important in learning and memory processes (A. Proc. Am. Assoc. Cancer Research 1999, 40: 396). WO Meneses, Neurosci. Biobehav Rey, 23:1111-1125 (1999)) 98/41511 describes 5-(4-Sulphonyl-phenyl)-pyridazinone and that 5-HT1A receptor antagonists may have utility in derivatives used for treating cancer. WO98/41516 describes treating cognitive dysfunction associated with Alzheimer's (methylsulphonyl)phenyl-2-(5H)-furanone derivatives that disease (L. E. Schechter, et al., Curr: Pharm. DeS., 8(2): 139 can be used in the treatment of cancer. Kalgutkar, A.S. et al., 145 (2002)). A 5-HT, receptor agonist has shown a neu Curr. Drug Targets, 201):79-106 (2001) suggest that Cox-2 roprotective effect associated with its ability to inhibit Selective inhibitors could be used to prevent or treat cancer ischemia-induced release of glutamate in the brain in a by affecting tumor viability, growth, and metastasis. Mas stroke model (I. Semkova, et al., Eur: J. Pharmacol., ferrer et al., in Ann. NY Acad. Sci., 889:84-86 (1999) 359:251-260 (1998)). describe Cox-2 Selective inhibitors as antiangiogenic agents 0007 Prostaglandins play a major role in the inflamma with potential therapeutic utility in Several types of cancers. tion proceSS and the inhibition of prostaglandin production, The utility of Cox-2 inhibition in clinical cancer prevention especially production of PGG, PGH and PGE, has been a was described by Lynch, P. M., in Oncology, 15(3):21-26 common target of antiinflammatory drug discovery. How (2001), and Watanabe et al., in Biofactors 2000, 12(1- ever, common non-Steroidal antiinflammatory drugs 4): 129-133 (2000) described the potential of Cox-2 selective (NSAIDs) that are active in reducing the prostaglandin inhibitors for chemopreventive agents against colon cancer. US 2004/O147581 A1 Jul. 29, 2004

0.010 Additionally, various combination therapies using 0013 EP 1064967 describes the combination of 5-HT Cox-2 inhibitors with other selected combination regimens receptor agonists, caffeine, and either a Cox-2 inhibitor or for the treatment of cancer have also been reported. See e.g., NSAID for the treatment of migraine. FR 2771 005 (compositions containing a cyclooxygenase-2 0014 EP 1064966 describes the combination of a 5-HT inhibitor and N-methyl-d-aspartate (NMDA) antagonist receptor agonist, caffeine, and a Cox-2 inhibitor for the used to treat cancer and other diseases); WO 99/18960 treatment of migraine. (combination comprising a cyclooxygenase-2 inhibitor and an inducible nitric-oxide synthase inhibitor (iNOS) that can 0.015 EP 1064948 describes the combination of a 5-HT be used to treat colorectal and breast cancer); WO99/13799 receptor antagonist, caffeine, and a Cox-2 inhibitor for the (combination of a cyclooxygenase-2 inhibitor and an opioid treatment of migraine. analgesic), WO 97/36497 (combination comprising a 0016 EP 1051995 describes the combination of 5-HT cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor receptor agonists and either a Cox-2 inhibitor or NSAID for useful in treating cancer); WO97/29776 (composition com the treatment of migraine. prising a cyclooxygenase-2 inhibitor in combination with a 0017 EP1051994 describes the combination of a 5-HT leukotriene B4 receptor antagonist and an immunosuppres agonist and a Cox-2 inhibitor for the treatment of migraine. sive drug); WO97/29775 (use of a cyclooxygenase-2 inhibi tor in combination with a leukotriene A4 hydrolase inhibitor 0018 EP 1051993 describes the combination of 5-HT and an immunosuppressive drug); WO97/29774 (combina receptor agonists and either a Cox-2 inhibitor or NSAID for tion of a cyclooxygenase-2 inhibitor and prostagladin or the treatment of migraine. antiulcer agent useful in treating cancer); WO 97/11701 0.019 US 20020077328 describes the combination of (combination comprising of a cyclooxygenase-2 inhibitor Selective Cox-2 inhibitors and vasomodulator compounds and a leukotriene B receptor antagonist useful in treating for generalized pain and headache pain. colorectal cancer); WO 96/41645 (combination comprising 0020 WO 0048583 describes the combination of 5-HT a cyclooxygenase-2 inhibitor and leukotriene A hydrolase agonists with Cox-2 inhibitors for the treatment of migraine. inhibitor); WO 96/03385 (3,4-Disubstituted pyrazole com pounds given alone or in combination with NSAIDs, ste 0021 U.S. Pat. Nos. 6,420,432, 6,413,961, 6,261,279, roids, 5-LO inhibitors, LTB4 antagonists, or LTA4 hydrolase 6.254,585, 6,242,447, 6,210,394, 6,056,715, 5,860,950, inhibitors for the treatment of cancer); WO 98/47890 (sub 5,858,017, 5,820,583, and 5,800,385 describe various types Stituted benzopyran derivatives that may be used alone or in of irrigation Solution and a method for inhibition of pain and combination with other active principles); WO 00/38730 inflammation, where the Solutions can contain a Cox-2 (method of using cyclooxygenase-2 inhibitor and one or inhibitor and Some type of Serotonin agonist or 5-HTA more antineoplastic agents as a combination therapy in the receptor agonist. treatment of neoplasia); Mann, M. et al., Gastroenterology, 0022. In U.S. Patent Publication No. 2002/0077328 A1, 120(7): 1713-1719 (2001) (combination treatment with Hassan et al. disclose, among other things, a method for Cox-2 and HER-2/neu inhibitors reduced colorectal carci treatment of headache Symptoms by administering a Selec noma growth). tive Cox-2 inhibitor and a vasomodulator, where the ICs of 0011. Other reports have indicated the Cox-2 selective the combination for binding of 5THAHT1A receptors is at inhibitors have cardiovascular applications. For example, least about 250 nM. Saito, T. et al., in Biochem. BiophyS. Res. Comm., 273:772 0023) A need remains, however, for an improved method 775 (2000), reported that the inhibition of Cox-2 improves of treating and preventing pain, inflammation or inflamma cardiac function in myocardial infarction. Ridker, P. M. et tion-related disorders, and also for treating and preventing al., in The New England.J. of Med., 336(14):973-979 (1997), neorologic disorders involving neurodegeneration. In par raised the possibility that anti-inflammatory agents may ticular, it would be useful to provide such a method by have clinical benefits in preventing cardiovascular disease. utilizing a combination of therapeutic agents that is more In addition, Cox-2 selective inhibitors have been proposed efficacious and Safer that presently available methods. for therapeutic use in cardiovascular disease when combined with modulation of inducible nitric oxide synthase (See, SUMMARY OF THE INVENTION Baker, C. S. R. et al., Arterioscler. Thromb. Vasc. Biol., 0024 Briefly, therefore, the present invention is directed 19:646-655 (1999)), and with HMG-CoA reductase inhibitor to a novel composition comprising a CoX-2 inhibitor and a (U.S. Pat. No. 6,245,797). 5-HT1A receptor modulator. 0012 Recent studies have shown that Cox-2 and its reaction products participate in ischemic injury in the human 0025 The present invention is also directed to a novel brain caused by Stroke or other injury (C. Iadecola, et al., method for the treatment or prevention of pain, inflamma Proc. Natl. Acad. Sci. U.S.A., 98(3):1294-1299 (2001)). A tion, or inflammation-related disorder in a mammal in need selective Cox-2 inhibitor has been shown to be neuropro thereof, comprising administering to the mammal a Cox-2 tective, resulting in improvements in behavorial deficits inhibitor and a 5-HT1A receptor modulator. caused by Spinal cord ischemia (P. A. Lapchak, et al., Stroke, 0026. The present invention is also directed to a novel 32:1220-1225 (2001)). Studies have shown that Cox-2 pharmaceutical composition for the treatment or prevention expression is elevated in Alzheimer's disease brains, is of pain, inflammation, or inflammation-related disorder, the correlated with dementia, and causes detrimental alterations pharmaceutical composition comprising a Cox-2 inhibitor, a of the neuronal cell cycle (Xiang et al., Neurobiol. Aging, 5-HT1A receptor modulator, and a pharmaceutically-accept 23:327-334 (2002)). able excipient. US 2004/O147581 A1 Jul. 29, 2004

0027. The present invention is also directed to a novel kit drug compounds, a pharmaceutically acceptable Salt thereof, that is Suitable for use in the treatment or prevention of pain, or a pure (-) or (+) optical isomeric form thereof. inflammation, or inflammation-related disorder wherein the kit comprises a first dosage form comprising a Cox-2 0034) Examples of NSAID compounds that are useful in inhibitor and a Second dosage form comprising a 5-HTA the present invention include acemetacin, acetyl Salicylic receptor modulator, in quantities which comprise a thera acid, alclofenac, alminoprofen, azapropaZone, benorylate, peutically effective amount of the compounds for the treat benoxaprofen, bucloxic acid, carprofen, choline magnesium ment or prevention of pain, inflammation, or inflammation trisalicylate, clidanac, clopinac, dapSone, diclofenac, related disorder. diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fen clofenec, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)- 0028. The present invention is also directed to a novel flurbiprofen, (S)-flurbiprofen, furofenac, feprazone, flufe method for the treatment or prevention of neurologic disease namic acid, fluprofen, ibufenac, ibuprofen, indometacin, involving neurodegeneration in a mammal in need thereof, indomethacin, indoprofen, isoxepac, isoxicam, ketoprofen, comprising administering to the mammal a CoX-2 inhibitor ketorolac, miroprofen, piroXicam, meloxicam, mefenamic, and a 5-HT1A receptor modulator. mefenamic acid, meclofenamic acid, meclofen, nabume tone, naproxen, niflumic acid, Oxaprozin, OXipinac, 0029. Among the several advantages found to be OxyphenbutaZone, phenylbutaZone, podophyllotoxin deriva achieved by the present invention, therefore, may be noted the provision of an improved method of treating or prevent tives, proglumetacin, piprofen, pirprofen, prapoprofen, Sali ing pain, inflammation or inflammation-related disorders, cylic acid, Salicylate, Sudoxicam, Suprofen, Sulindac, tenoxi and treatment or prevention of neurologic diseases involving cam, tiaprofenic acid, tiopinac, tioxaprofen, tolfenamic acid, neurodegeneration, the provision of Such a method by uti tolmetin, Zidometacin, Zomepirac, and 2-fluoro-a-methyl1, lizing a combination of therapeutic agents that is more 1'-biphenyl-4-acetic acid, 4-(nitrooxy)butyl ester. efficacious and Safer than methods and compositions that are 0035) In a preferred embodiment, the Cox-2 inhibitor is presently available, and the provision of therapeutic com a Cox-2 selective inhibitor. The term “CoX-2 selective binations and methods for the prevention and treatment of inhibitor' embraces compounds which selectively inhibit pain, inflammation and inflammation-related disorders. the Cox-2 enzyme over the Cox-1 enzyme, and also include pharmaceutically acceptable Salts and prodrugs of those DETAILED DESCRIPTION OF THE compounds. INVENTION 0036. In practice, the selectivity of a Cox-2 inhibitor 0.030. In accordance with the present invention, it has varies depending upon the condition under which the test is been discovered that pain, inflammation, or inflammation performed and on the inhibitors being tested. However, for related disorders in a Subject-in particular, a mammal-can the purposes of this Specification, the Selectivity of a Cox-2 be treated or prevented by a combination therapy method inhibitor can be measured as a ratio of the in vitro or in vivo that involves administering to the Subject an amount of a ICso value for inhibition of Cox-1, divided by the ICs value Cox-2 inhibitor and an amount of a 5-HT1A receptor modu for inhibition of Cox-2 (Cox-1 ICs/Cox-2 ICs). A Cox-2 lator. In preferred embodiments, the amount of the Cox-2 selective inhibitor is any inhibitor for which the ratio of inhibitor and the amount of the 5-HT1A receptor modulator Cox-1 ICso to Cox-2 ICso is greater than 1. In preferred together comprise a therapeutically effective amount for the embodiments, this ratio is greater than 2, more preferably treatment or prevention of pain, inflammation or inflamma greater than 5, yet more preferably greater than 10, Still more tion-related disorder in the Subject. preferably greater than 50, and more preferably still greater than 100. 0031. Also disclosed herein is a composition comprising an amount of a CoX-2 inhibitor and an amount of a 5-HTA 0037 As used herein, the term “ICs” refers to the receptor modulator wherein the amount of the Cox-2 inhibi concentration of a compound that is required to produce tor and the amount of the 5-HT1A receptor modulator 50% inhibition of cyclooxygenase activity. Preferred Cox-2 together comprise a therapeutically effective amount for the selective inhibitors of the present invention have a Cox-2 treatment or prevention of pain, inflammation or inflamma IC of less than about 1 uM, more preferred of less than tion-related disorder. about 0.5 uM, and even more preferred of less than about 0.2 0032. A component of the present invention is a Cox-2 luM. inhibitor. The terms “cyclooxygenase-2 inhibitor', or 0038 Preferred Cox-2 selective inhibitors have a Cox-1 “Cox-2 inhibitor', which can be used interchangeably ICso of greater than about 1 uM, and more preferably of herein, embrace compounds which inhibit the Cox-2 greater than 20 M. Such preferred Selectivity may indicate enzyme regardless of the degree of inhibition of the Cox-1 an ability to reduce the incidence of common NSAID enzyme, and include pharmaceutically acceptable Salts of induced Side effects. those compounds. Thus, for purposes of the present inven tion, a compound is considered a Cox-2 inhibitor irrespec 0039. Also included within the scope of the present tive of whether the compound inhibits the Cox-2 enzyme to invention are compounds that act as prodrugs of Cox-2- an equal, greater, or lesser degree than the Cox-1 enzyme. Selective inhibitors. As used herein in reference to Cox-2 selective inhibitors, the term “prodrug” refers to a chemical 0033. In one embodiment of the present invention, it is compound that can be converted into an active Cox-2 preferred that the Cox-2 inhibitor compound is a non Selective inhibitor by metabolic or simple chemical pro steroidal anti-inflammatory drug (NSAID). Therefore, pre cesses within the body of the subject. One example of a ferred materials that can serve as the Cox-2 inhibitor of the prodrug for a Cox-2 Selective inhibitor is parecoxib, which present invention include non-Steroidal anti-inflammatory is a therapeutically effective prodrug of the tricyclic Cox-2 US 2004/O147581 A1 Jul. 29, 2004 selective inhibitor Valdecoxib. An example of a preferred pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, Cox-2 Selective inhibitor prodrug is Sodium parecoxib. A hexyl-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl class of prodrugs of Cox-2 inhibitors is described in U.S. radicals, and the like. Pat. No. 5,932,598. 004.5 The term “oxo” means a single double-bonded 0040. The Cox-2 selective inhibitor of the present inven OXygen. tion can be, for example, the Cox-2 Selective inhibitor 0046) The terms “hydrido”, “-H”, or “hydrogen”, meloxicam, Formula B-1 (CAS registry number 71125-38 denote a single hydrogen atom (H). This hydrido radical 7), or a pharmaceutically acceptable Salt or prodrug thereof. may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH-) radical. B-1 0047 The term “halo' means halogens such as fluorine, chlorine, and bromine or iodine atoms. The term “haloalkyl embraces radicals wherein any one or more of the alkyl N --> carbon atoms is Substituted with halo as defined above. s1 N N Specifically embraced are monohaloalkyl, dihaloalkyl, and MV polyhaloalkyl radicals. A monohaloalkyl radical, for one O O example, may have a bromo, chloro, or a fluoro atom within the radical. Dihalo alkyl radicals may have two or more of the same halo atoms or a combination of different halo 0041. In another embodiment of the invention the Cox-2 radicals and polyhaloalkyl radicals may have more than two Selective inhibitor can be the Cox-2 selective inhibitor RS of the same halo atoms or a combination of different halo 57067, 6-5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2- radicals. yl)methyl-3(2H)-pyridazinone, Formula B-2 (CAS registry 0048. The term “hydroxyalkyl” embraces linear or number 179382-91-3), or a pharmaceutically acceptable salt branched alkyl radicals having one to about ten carbon or prodrug thereof. atoms any one of which may be Substituted with one or more hydroxyl radicals. B-2 0049. The terms “alkoxy” and “alkoxyalkyl” embrace t O linear or branched oxy-containing radicals each having alkyl N N portions of one to about ten carbon atoms, Such as methoxy IN1,N \ f radical. The term “alkoxyalkyl also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl O 2 C radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl CH radicals. The “alkoxy” or “alkoxyalkyl radicals may be further Substituted with one or more halo atoms, Such as fluoro, chloro, or bromo, to provide “haloalkoxy” or 0042. As used herein, the term “alkyl', either alone or “haloalkoxyalkyl radicals. Examples of “alkoxy' radicals within other terms such as “haloalkyl and “alkylsulfonyl'; include methoxy, butoxy, and trifluoromethoxy. embraces linear or branched radicals having one to about 0050. The term “aryl', whether used alone or with other twenty carbon atoms. Lower alkyl radicals have one to about terms, means a carbocyclic aromatic System containing one, ten carbon atoms. The number of carbon atoms can also be two, or three rings wherein Such rings may be attached expressed as "C-Cs”, for example. Examples of lower alkyl together in a pendent manner, or may be fused. The term radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, “aryl” embraces aromatic radicals. Such as phenyl, naphthyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl tetrahydronapthyl, indane, and biphenyl. The term "hetero and the, like. cyclyl means a Saturated or unsaturated mono- or multi 0043. The term “alkenyl' refers to an unsaturated, acyclic ring carbocycle wherein one or more carbon atoms are hydrocarbon radical, linear or branched, in So much as it replaced by N, S, P, or O. This includes, for example, contains at least one double bond. The alkenyl radicals may Structures Such as: be optionally Substituted with groupS. Such as those defined below. Examples of Suitable alkenyl radicals include prope nyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, Z. 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hy ( Nz, O n f ( ) 2 droxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like. Z27, ZN2 Z. 0044) The term “alkynyl refers to an unsaturated, acy clic hydrocarbon radical, linear or branched, in So much as it contains one or more triple bonds, Such radicals preferably 0051 where Z, Z, Z, or Z is C, S, P, O, or N, with containing 2 to about 6 carbon atoms, more preferably from the proviso that one of Z, Z', Z, or Z is other than 2 to about 3 carbon atoms. The alkynyl radicals may be carbon, but is not O or S when attached to another Z optionally Substituted with groups Such as described below. atom by a double bond or when attached to another Examples of Suitable alkynyl radicals include ethynyl, proy O or S atom. Furthermore, the optional substituents nyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, are understood to be attached to Z, Z, Z, or Z only US 2004/O147581 A1 Jul. 29, 2004

when each is C. The term “heterocycle” also includes 0.058. In one embodiment of the invention the Cox-2 fully Saturated ring structures, Such as piperazinyl, Selective inhibitor is of the chromene/chroman structural dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, class, which encompasses Substituted benzopyrans or Sub morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, Stituted benzopyran analogs, as well as Substituted benzothi and others. opyrans, dihydroquinolines, or dihydronaphthalenes having 0.052 The term "heteroaryl” embraces unsaturated het the structure of any one of the general Formulas I, II, III, IV, erocyclic radicals. Examples of unsaturated heterocyclic V, and VI, shown below, and including, by way of non radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, limiting example, the Structures disclosed in Table 1, and the pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thia diastereomers, enantiomers, racemates, tautomers, Salts, Zolyl, pyranyl, and tetrazolyl. The term also embraces radi esters, amides and prodrugs thereof. cals where heterocyclic radicals are fused with aryl radicals. 0059 Benzopyrians that can serve as a Cox-2 selective Examples of Such fused bicyclic radicals include benzofu inhibitor of the present invention include substituted ben ran, benzothiophene, and the like. Zopyran derivatives that are described in U.S. Pat. Nos. 0053) The term “sulfonyl', whether used alone or linked 6,271,253 and 6,492.390. One such class of compounds is to other terms Such as alkylsulfonyl, denotes respectively defined by the general formula shown below in formula I: divalent radicals -SO-. “Alkylsulfonyl', embraces alkyl radicals attached to a Sulfonyl radical, where alkyl is defined as above. The term “arylsulfonyl” embraces Sulfonyl radi cals substituted with an aryl radical. The term “aminosul R2 fonyl' denotes a sulfonyl radical substituted with an amine A. R1 radical, forming a sulfonamide (-SO-NH). A22 N R4-- A 0054) The terms “carboxy” or “carboxyl”, whether used A. alone or with other terms, Such as "carboxyalkyl, denotes S. X1 R3 -CO-H. The term “carboxyalkyl embraces radicals having a carboxyradical as defined above, attached to an alkyl radical. The term “carbonyl', whether used alone or 0060 wherein X is selected from O, S, CRR and with other terms, such as “alkylcarbonyl', denotes NR; -(C=O)-. The term “alkylcarbonyl” embraces radicals 0061 wherein R is selected from hydrido, C-C- having a carbonyl radical Substituted with an alkyl radical. alkyl, (optionally Substituted phenyl)-C-C-alkyl, acyl An example of an “alkylcarbonyl" radical is CH-(CO)-. and carboxy-C-C-alkyl, The term “alkoxycarbonyl' means a radical containing an alkoxy radical, as defined above, attached via an oxygen 0062) wherein each of R and R is independently atom to a carbonyl (C=O) radical. Examples of such Selected from hydrido, C-C-alkyl, phenyl-C-C- “alkoxycarbonyl" radicals include (CH)-C-O- alkyl, C-C-perfluoroalkyl, chloro, C-C-alkylthio, C=O)- and -(O=)C-OCH. The term “amino', C-C-alkoxy, nitro, cyano and cyano-C-C-alkyl, or whether used alone or with other terms, Such as "aminocar wherein CRR forms a 3-6 membered cycloalkyl ring; bonyl', denotes -NH. 0063 wherein R' is selected from carboxyl, aminocar 0055. The term “heterocycloalkyl” embraces heterocy bonyl, C-C-alkylsulfonylaminocarbonyl and C-C- clic-Substituted alkyl radicals. Such as pyridylmethyl and alkoxycarbonyl, thienylmethyl. The terms “aralkyl', or “arylalkyl” embrace aryl-Substituted alkyl radicals Such as benzyl, diphenylm 0064) wherein R is selected from hydrido, phenyl, ethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The thienyl, C-C-alkyl and C-C-alkenyl, terms benzyl and phenylmethyl are interchangeable. The 0065 wherein R is selected from C-C-perfluoro term "cycloalkyl embraces radicals having three to ten alkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, carbon atoms, Such as cyclopropyl cyclobutyl, cyclopentyl, cyano and cyano-C-C-alkyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl embraces unsaturated radicals having three to ten carbon 0066 wherein R" is one or more radicals indepen atoms, Such as cylopropenyl, cyclobutenyl, cyclopentenyl, dently Selected from hydrido, halo, C-C-alkyl, C-C- cyclohexenyl, and cycloheptenyl. alkenyl, C-C-alkynyl, halo-C-C-alkynyl, aryl-C- C-alkyl, aryl-C-C-alkynyl, aryl-C-C-alkenyl, 0056. The term “alkylthio’ embraces radicals containing C-C-alkoxy, methylenedioxy, C-C-alkylthio, a linear or branched alkyl radical, of one to ten carbon C-C-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, het atoms, attached to a divalent Sulfur atom. An example of eroaryloxy, C-C-alkoxy-C-C-alkyl, aryl-C-C- “alkylthio” is methylthio, (CH-S). The term “alkyl alkyloxy, heteroaryl-C-C-alkyloxy, aryl-C-C- Sulfinyl' embraces radicals containing a linear or branched alkoxy-C-C-alkyl, C-C-haloalkyl, C-C- alkyl radical, of one to ten carbon atoms, attached to a haloalkoxy, C-C-haloalkylthio, C-C- divalent -S(-O)-atom. The term “acyl”, whether used haloalkylsulfinyl, C-C-haloalkylsulfonyl, C-C- alone, or within a term Such as “acylamino', denotes a (haloalkyl-1-C -hydroxyalkyl, C-C-hydroxyalkyl, radical provided by the residue after removal of hydroxyl hydroxyimino-C-C-alkyl, C-C-alkylamino, ary from an organic acid. lamino, aryl-C-C-alkylamino, heteroarylamino, het 0057 The term “cyano”, used either alone or with other eroaryl-C-C-alkylamino, nitro, cyano, amino, amino terms, such as “cyanoalkyl', refers to C=N. The term “nitro” Sulfonyl, C-C-alkylaminosulfonyl, denotes -NO. arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C- US 2004/O147581 A1 Jul. 29, 2004

Co-alkylaminoSulfonyl, heteroaryl-C-C-alkylamino hydroxyalkyl), C-C-hydroxyalkyl, hydroxyimino Sulfonyl, heterocyclylsulfonyl, C-C-alkylsulfonyl, C-C-alkyl, C-C-alkylamino, arylamino, aryl-C- aryl-C-C-alkylsulfonyl, optionally Substituted aryl, Co-alkylamino, heteroarylamino, heteroaryl-C-C- optionally Substituted heteroaryl, aryl-C-C-alkylcar alkylamino, nitro, cyano, amino, aminoSulfonyl, bonyl, heteroaryl-C-C-alkylcarbonyl, heteroarylcar C-C-alkylaminosulfonyl, arylaminoSulfonyl, het bonyl, arylcarbonyl, aminocarbonyl, C-C-alkoxycar eroarylaminosulfonyl, aryl-C-C-alkylaminosulfonyl, bonyl, formyl, C-C-haloalkylcarbonyl and C-C- heteroaryl-C-C-alkylaminoSulfonyl, heterocyclylsul alkylcarbonyl, and fonyl, C-C-alkylsulfonyl, aryl-C-C-alkylsulfonyl, optionally Substituted aryl, optionally Substituted het 0067 wherein the A ring atoms A, A, A and A" are eroaryl, aryl-C-C-alkylcarbonyl, heteroaryl-C-C- independently Selected from carbon and nitrogen with alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, ami the proviso that at least two of A, A, A and A" are nocarbonyl, C-C-alkoxycarbonyl, formyl, C-C- carbon; haloalkylcarbonyl and C-C-alkylcarbonyl; and 0068 or wherein R together with ring A forms a radical 0077 wherein the D ring atoms D, D, D and D'are Selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, independently Selected from carbon and nitrogen with quinoxalinyl and dibenzofuryl, or an isomer or pharmaceu the proviso that at least two of D', D, D and D" are tically acceptable Salt thereof. carbon; or 0069. Another class of benzopyran derivatives that can 0078 wherein R together with ring D forms a radical serve as the Cox-2 selective inhibitor of the present inven Selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, tion includes compounds having the Structure of formula II: quinoxalinyl and dibenzofuryl, or an isomer or pharmaceu tically acceptable Salt thereof. II 0079) Other benzopyran Cox-2 selective inhibitors useful R6 in the practice of the present invention are described in U.S. D R5 Pat. Nos. 6,034,256 and 6,077.850. The general formula for p? 5 N these compounds is shown in formula III: R8-D 3 D&s 1 s X2 R7

III

0070 wherein X is selected from O, S, CRR and NR; 0071 wherein R is selected from hydrido, C-C- alkyl, (optionally Substituted phenyl)-C-C-alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C-C-alkyl, 0080 wherein X is selected from the group consisting 0.072 wherein each of R and R is independently of O or S or NR; Selected from hydrido, C-C-alkyl, phenyl-C-C- 0081 wherein R is alkyl; alkyl, C-C-perfluoroalkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, cyano and cyano-C-C-alkyl, or 0082 wherein R is selected from the group consisting wherein CRR form a cyclopropyl ring; of H and aryl; 0073) wherein R is selected from carboxyl, aminocar 0083) wherein R" is selected from the group consist bonyl, C-C-alkylsulfonylaminocarbonyl and C-C- ing of carboxyl, aminocarbonyl, alkylsulfonylami alkoxycarbonyl, nocarbonyl and alkoxycarbonyl, 0074 wherein R is selected from hydrido, phenyl, 0084) wherein R' is selected from the group consist thienyl, C-C-alkynyl and C-C-alkenyl, ing of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally Substituted with one or more radicals 0075) wherein R is selected from C-C-perfluoro Selected from alkylthio, nitro and alkylsulfonyl, and alkyl, chloro, C-C-alkylthio, C-C-alkoxy, nitro, cyano and cyano-C-C-alkyl, 0085 wherein R' is selected from the group consist ing of one or more radicals Selected from H, halo, alkyl, 0076 wherein R is one or more radicals indepen aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, het dently Selected from hydrido, halo, C-C-alkyl, C-C- eroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, ary alkenyl, C-C-alkynyl, halo-C-C-alkynyl, aryl-C- lamino, aralkylamino, heteroarylamino, heteroaryla C-alkyl, aryl-C-C-alkynyl, aryl-C-C-alkenyl, lkylamino, nitro, amino, aminosulfonyl, C-C-alkoxy, methylenedioxy, C-C-alkylthio, alkylaminoSulfonyl, arylaminoSulfonyl, heteroarylami C-C-alkylsulfinyl, -O(CF)-O-, aryloxy, arylthio, noSulfonyl, aralkylaminoSulfonyl, heteroaralkylamino arylsulfinyl, heteroaryloxy, C-C-alkoxy-C-C-alkyl, Sulfonyl, heterocycloSulfonyl, alkylsulfonyl, aryl-C-C-alkyloxy, heteroaryl-C-C-alkyloxy, aryl hydroxyarylcarbonyl, nitroaryl, optionally Substituted C-C-alkoxy-C-C-alkyl, C-C-haloalkyl, C-C- aryl, optionally Substituted heteroaryl, aralkylcarbonyl, haloalkoxy, C-C-haloalkylthio, C-C-haloalkylsulfi heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and nyl, C-C-haloalkylsulfonyl, C-C-(haloalkyl-C-C- alkylcarbonyl, or US 2004/O147581 A1 Jul. 29, 2004

0086) wherein R' together with ring E forms a naphthyl independently optionally Substituted with one or more radical; or an isomer or pharmaceutically acceptable Salt radicals Selected from the group consisting of alkylthio, thereof, and including the diastereomers, enantiomers, race nitro and alkylsulfonyl; and mates, tautomers, Salts, esters, amides and prodrugs thereof. 0100 R is one or more radicals selected from the 0087. A related class of compounds useful as Cox-2 group consisting of hydrido, halo, alkyl, aralkyl, selective inhibitors in the present invention is described by alkoxy, aryloxy, heteroaryloxy, aralkyloxy, het Formulas IV and V below: eroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, ary lamino, aralkylamino, heteroarylamino, heteroaryla lkylamino, nitro, amino, aminosulfonyl,

IV alkylaminoSulfonyl, arylaminoSulfonyl, heteroarylami noSulfonyl, aralkylaminoSulfonyl, heteroaralkylamino Sulfonyl, heterocycloSulfonyl, alkylsulfonyl, optionally Substituted aryl, optionally Substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R' together with ring A forms a naphthyl radical; 0088 wherein X" is selected from O or S or NR; 0101 or an isomer or pharmaceutically acceptable salt 0089 wherein R is alkyl; thereof. 0090 wherein R' is selected from carboxyl, ami 0102) The Cox-2 selective inhibitor may also be a com nocarbonyl, alkylsulfonylaminocarbonyl and alkoxy pound of Formula V, wherein: carbonyl, 0103) X is selected from the group consisting of 0.091 wherein R'' is selected from haloalkyl, alkyl, Oxygen and Sulfur, aralkyl, cycloalkyl and aryl optionally Substituted with 0104) R' is selected from the group consisting of one or more radicals Selected from alkylthio, nitro and carboxyl, lower alkyl, lower aralkyl and lower alkoxy alkylsulfonyl; and carbonyl, 0092 wherein R' is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, 0105) R' is selected from the group consisting of heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, lower haloalkyl, lower cycloalkyl and phenyl, and haloalkoxy, alkylamino, arylamino, aralkylamino, het 0106) R' is one or more radicals selected from the eroarylamino, heteroarylalkylamino, nitro, amino, ami group of consisting of hydrido, halo, lower alkyl, lower noSulfonyl, alkylaminoSulfonyl, arylaminoSulfonyl, alkoxy, lower haloalkyl, lower haloalkoxy, lower alky heteroarylaminoSulfonyl, aralkylaminoSulfonyl, het lamino, nitro, amino, aminoSulfonyl, lower alkylami eroaralkylaminoSulfonyl, heterocycloSulfonyl, alkyl nosulfonyl, 5-membered heteroarylalkylaminosulfo Sulfonyl, optionally Substituted aryl, optionally Substi nyl, 6-membered heteroarylalkylaminoSulfonyl, lower tuted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, aralkylaminoSulfonyl, 5-membered nitrogen-contain arylcarbonyl, aminocarbonyl, and alkylcarbonyl, ing heterocycloSulfonyl, 6-membered nitrogen-con 0093) or wherein R' together with ring G forms a naph taining heterocycloSulfonyl, lower alkylsulfonyl, thyl radical; or an isomer or pharmaceutically acceptable Salt optionally Substituted phenyl, lower aralkylcarbonyl, thereof. and lower alkylcarbonyl, or 0107 wherein R' together with ring A forms a naphthyl 0094) Formula V is: radical; or an isomer or pharmaceutically acceptable Salt thereof.

0108. The Cox-2 selective inhibitor may also be a com pound of Formula V, wherein: 0109) X is selected from the group consisting of Oxygen and Sulfur, 0110) R' is carboxyl; 0.095 wherein: 0111) R'7 is lower haloalkyl; and 0096 X is selected from the group consisting of O or 0112) R' is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower S or NR; haloalkyl, lower haloalkoxy, lower alkylamino, amino, 0097 R is alkyl; aminoSulfonyl, lower alkylaminoSulfonyl, 5-membered 0098) R' is selected from the group consisting of heteroarylalkylaminoSulfonyl, 6-membered heteroary carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl lalkylaminoSulfonyl, lower aralkylaminoSulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing and alkoxycarbonyl, heterocycloSulfonyl, optionally Substituted phenyl, 0099) R' is selected from the group consisting of lower aralkylcarbonyl, and lower alkylcarbonyl, or haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein wherein R together with ring A forms a naphthyl haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is radical; US 2004/0147581 A1 Jul. 29, 2004

0113) or an isomer or pharmaceutically acceptable salt thereof. 0114) The Cox-2 selective inhibitor may also be a com pound of Formula V, wherein: 0115 X is selected from the group consisting of Oxygen and Sulfur, 0116) R' is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxy carbonyl; 0117) R' is selected from the group consisting of 0126 wherein: fluoromethyl, chloromethyl, dichloromethyl, trichlo romethyl, pentafluoroethyl, heptafluoropropyl, difluo 0127 X is selected from the group consisting of O and roethyl, difluoropropyl, dichloroethyl, dichloropropyl, S; difluoromethyl, and trifluoromethyl; and 0128) R' is lower haloalkyl; 0118) R' is one or more radicals selected from the 0129) R' is selected from the group consisting of group consisting of hydrido, chloro, fluoro, bromo, hydrido, and halo; iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobu tyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, ter 0130) R' is selected from the group consisting of thutyloxy, trifluoromethyl, difluoromethyl, trifluo hydrido, halo, lower alkyl, lower haloalkoxy, lower romethoxy, amino, N,N-dimethylamino, N,N- alkoxy, lower aralkylcarbonyl, lower dialkylaminosul diethylamino, N-phenylmethylaminosulfonyl, fonyl, lower alkylaminosulfonyl, lower aralkylamino N-phenylethylaminosulfonyl, N-(2-furylmethyl)ami Sulfonyl, lower heteroaralkylaminosulfonyl, 5-mem nosulfonyl, nitro, N,N-dimethylaminosulfonyl, amino bered nitrogen-containing heterocyclosulfonyl, and Sulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl; 2,2-dimethylethylaminosulfonyl, N,N-dimethylamino Sulfonyl, N-(2-methylpropyl)aminosulfonyl, N-mor 0131) R' is selected from the group consisting of pholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2- hydrido, lower alkyl, halo, lower alkoxy, and aryl; and dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R together with ring A forms a naphthyl (0132) R' is selected from the group consisting of the radical; or an isomer or pharmaceutically acceptable group consisting of hydrido, halo, lower alkyl, lower Salt thereof. alkoxy, and aryl; 0119) The Cox-2 selective inhibitor may also be a com 0.133 or an isomer or prodrug thereof. pound of Formula V, wherein: 0134) The Cox-2 selective inhibitor can also be a com 0120) X is selected from the group consisting of pound of having the structure of Formula VI, wherein: Oxygen and Sulfur, I0135) X is selected from the group consisting of O and 0121) R' is selected from the group consisting of S; carboxyl, lower alkyl, lower aralkyl and lower alkoxy 0136) R' is selected from the group consisting of carbonyl; trifluoromethyl and pentafluoroethyl; 0122) R' is selected from the group consisting trif 0137) R' is selected from the group consisting of luoromethyl and pentafluoroethyl; and hydrido, chloro, and fluoro; (0123) R' is one or more radicals selected from the 0138) R' is selected from the group consisting of group consisting of hydrido, chloro, fluoro, bromo, hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, tri trifluoromethoxy, methoxy, benzylcarbonyl, dimethy fluoromethyl, trifluoromethoxy, N-phenylmethylami laminosulfonyl, isopropylaminosulfonyl, methylami nosulfonyl, N-phenylethylaminosulfonyl, N-(2-furyl noSulfonyl, benzylaminosulfonyl, phenylethylamino methyl)aminosulfonyl, N,N-dimethylaminosulfonyl, Sulfonyl, methylpropylaminosulfonyl, methylsulfonyl, N-methylaminosulfonyl, N-(2,2-dimethylethyl)amino and morpholinosulfonyl; Sulfonyl, dimethylaminosulfonyl, 2-methylpropylami nosulfonyl, N-morpholinosulfonyl, methylsulfonyl, 0139) R' is selected from the group consisting of benzylcarbonyl, and phenyl; or wherein R together hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, with ring A forms a naphthyl radical; methoxy, diethylamino, and phenyl; and 0.124 or an isomer or prodrug thereof. 0140) R' is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert 0125 The Cox-2 selective inhibitor of the present inven butyl, methoxy, and phenyl; tion can also be a compound having the structure of Formula VI: 0141 or an isomer or prodrug thereof.

US 2004/O147581 A1 Jul. 29, 2004

0142. In preferred embodiments the chromene Cox-2 TABLE 1-continued inhibitor is selected from (S)-6-chloro-7-(1,1-dimethyl ethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic Examples of Chromene Cox-2 Selective Inhibitors acid, (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene Compound 3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluorom Number Structural Formula ethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trif luoromethoxy)-2-(trifluoromethyl)-2H-chromene-3- B-15 carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7-dimethyl N OH 2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof. N CF 0143. In a preferred embodiment of the invention the Cox-2 inhibitor can be selected from the class of tricyclic CH 6-Chloro-1,2-dihydro-1-methyl-2-(trifluoromethyl)-3- Cox-2 Selective inhibitors represented by the general Struc quinolinecarboxylic aci, ture of formula VII: B-16 N OH VII

CF 6-Chloro-2-(trifluoromethyl)- 1,2-dihydro1,8naphthyridine 3-carboxylic acid 0144) wherein: B-17 O 0145 Z is selected from the group consisting of par C tially unsaturated or unsaturated heterocyclyl and par N OH tially unsaturated or unsaturated carbocyclic rings, 0146) R' is selected from the group consisting of N CF H 3 heterocyclyl, cycloalkyl, cycloalkenyl and aryl, (S)-6-Chloro-1,2-dihydro-2-(trifluoromethyl)-3- wherein R' is optionally substituted at a substitutable quinolinecarboxylic acid position with one or more radicals Selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, B-18 O hydroxyalkyl, haloalkoxy, amino, alkylamino, ary lamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy N OH and alkylthio;

F 0147 R’ is selected from the group consisting of O F methyl or amino; and F 0148 R is selected from the group consisting of a (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3- radical Selected from H, halo, alkyl, alkenyl, alkynyl, carboxylic acid OXO, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, B-19 O haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, hetero O cyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxy FC1 N OH carbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthio alkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycar O CF bonylalkyl, aminocarbonyl, aminocarbonylalkyl, alky laminocarbonyl, N-arylaminocarbonyl, N-alkyl-N- (2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H arylaminocarbonyl, alkylaminocarbonylalkyl, chromene-3-carboxylic acid carboxyalkyl, alkylamino, N-arylamino, N-aralky lamino, N-alkyl-N-aralkylamino, N-alkyl-N-ary O lamino, aminoalkyl, alkylaminoalkyl, N-arylami noalkyl, N-aralkylaminoalkyl, N-alkyl-N- C N o1 H aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsul F fonyl, aminoSulfonyl, alkylaminoSulfonyl, N-arylami O F nosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfo F (2S)-6-chloro-5,7-dimethyl-2- nyl, (trifluoromethyl)-2H-chromene-3- carboxylic acid 0149 or a prodrug thereof. 0150. In a preferred embodiment of the invention the Cox-2 selective inhibitor represented by the above Formula US 2004/O147581 A1 Jul. 29, 2004 11

VII is Selected from the group of compounds, illustrated in Table 2, which includes celecoxib (B-21), Valdecoxib TABLE 2-continued (B-22), deracoxib (B-23), rofecoxib (B-24), etoricoxib (MK-663; B-25), JTE-522 (B-26), or prodrugs thereof. Examples of Tricyclic COX-2 Selective Inhibitors 0151. Additional information about selected examples of Compound the Cox-2 selective inhibitors discussed above can be found Number Structural Formula as follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Pat. No. 5,466,823); deracoxib (CAS B-25 On 29 RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); com PS CH pound B-24 (U.S. Pat. No. 5,840,924); compound B-26 HN 21 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, S N MK-663, SC-86218, and in WO 98/03484). / \ TABLE 2

Examples of Tricyclic COX-2 Selective Inhibitors C Compound B-26 OSa O Number Structural Formula HN

B-21 OnPS 2O CH HN O

fN \ CH N N

CF 0152. In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group B-22 OS2O consisting of celecoxib, rofecoxib and etoricoxib. PS HN 0153. In a preferred embodiment, parecoxib (See, U.S. Pat. No. 5,932,598), having the structure shown in B-27, and which is a therapeutically effective prodrug of the tricyclic ( \, Cox-2 selective inhibitor valdecoxib, B-22, (See, U.S. Pat. HC o1 No. 5,633,272), may be advantageously employed as the Cox-2 inhibitor of the present invention.

B-23 F O O B-27 N-2s S 2 OCH HN fN \ N N

CHF

B-24 s 29 PS 0154) A preferred form of parecoxib is sodium parecoxib. 0.155) Another tricyclic Cox-2 selective inhibitor useful HN CC in the present invention is the compound ABT-963, having O O the formula B-28 shown below, that has been previously described in International Publication Number WO 00/24719. US 2004/O147581 A1 Jul. 29, 2004 12

0172 wherein:

B-28 0173 R-7 is propyl; 0.174 R and Rare chloro; 0.175 R and R are methyl; and 0176 R is ethyl. 0177. Another phenylacetic acid derivative Cox-2 selec tive inhibitor that is disclosed in WO 02/20090 is a com pound that is referred to as COX-189 (also termed lumira coxib; CAS Reg. No. 220991-20-8), having the structure shown in formula VIII, 0178 wherein: 0156. In a further embodiment of the invention, the 0179 R7 is methyl; Cox-2 inhibitor can be selected from the class of pheny lacetic acid derivative Cox-2 Selective inhibitors represented 0180 R is fluoro; by the general structure of formula VIII: 0181) R' is chloro; and 0182 R. R., and R are hydrogen. VIII R2 O 0183 Compounds having a structure similar to that shown in formula VIII, that can serve as the Cox-2 selective OH inhibitor of the present invention, are described in U.S. Pat. NH Nos. 6,451,858, 6,310,099, 6.291523, and 5,958,978. R28 R32 0.184 Other Cox-2 selective inhibitors that can be used in the present invention have the general Structure shown in formula IX, where the J group is a carbocycle or a hetero R29 R31 cycle. Preferred embodiments have the structure: R30 R33 X DX O157 wherein: Xs 0158 R7 is methyl, ethyl, or propyl; 0159 R is chloro or fluoro; CCDR34 R35 0160 R’ is hydrogen, fluoro, or methyl; 0161) R' is hydrogen, fluoro, chloro, methyl, ethyl, 0185 wherein: methoxy, ethoxy or hydroxyl, 0186 X7 is 0; J is 1-phenyl; R is 2-NHSOCH; R' 0162 R is hydrogen, fluoro, or methyl; and is 4-NO; and there is no R group, (nimeSulide), or 0163) R is chloro, fluoro, trifluoromethyl, methyl, or 0187 X7 is 0; J is 1-oxo-inden-5-yl; R is 2-F; R is ethyl, 4-F; and R is 6-NHSOCH, (flosulide); or 0164) provided that R, R, R and R are not all (0188) X7 is O; J is cyclohexyl; R is 2-NHSOCH; fluoro when R7 is ethyl and R is H. R is 5-NO.; and there is no R group, (NS-398); or 0.165 An exemplary phenylacetic acid derivative Cox-2 0189 X7 is S; J is 1-oxo-inden-5-yl; R is 2-F; R is Selective inhibitor that is described in WO 99/11605 is a 4-F; and R is 6-NSOCH.Na', (L-745337); or compound that has the structure shown in formula VIII, 0190 X7 is S; J is thiophen-2-yl; R is 4-F; there is no 0166 wherein: R" group; and R is 5-NHSOCH., (RWJ-63556); or 0167) R7 is ethyl; 0191 X7 is 0; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluo roethyl)furan-(5H)-3-yl; R is 3-F; R is 4-F, and R' 0168) R’ and R are chloro; is 4-(p-SOCH)C.H., (L-784512). 0169 R” and R are hydrogen; and 0192 The Cox-2 selective inhibitor NS-398, also known R’ is methyl. as N-(2-cyclohexyloxynitrophenyl)methane Sulfonamide 0170) (CAS RN 123653-11-2), having a structure as shown below 0171 Another phenylacetic acid derivative Cox-2 selec in formula B-29, has been described in, for example, tive inhibitor is a compound that has the Structure shown in Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406 formula VIII, 412 (1999). US 2004/O147581 A1 Jul. 29, 2004

0201 R, R-7 or R, R are an oxygen atom; or

B-29 0202) R, R-7 or R, R, together with the carbon H SOCH3 atom to which they are attached, form a Saturated n 1 hydrocarbon ring having from 3 to 7 carbon atoms, 0203 or an isomer or prodrug thereof. 0204 Particular diarylmethylidenefuran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2-cyclohexyloxynitro phenyl)methane Sulfonamide, and (E)-4-(4-methylphe NO nyl)(tetrahydro-2-oxo-3-furanylidene) methylbenzene Sulfonamide. 0193 An evaluation of the anti-inflammatory activity of 0205. Other Cox-2 selective inhibitors that are useful in the Cox-2 selective inhibitor, RWJ 63556, in a canine model the present invention include darbufelone (Pfizer), CS-502 of inflammation, was described by Kirchner et al., in J (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 Pharmacol Exp Ther 282, 1094-1101 (1997). (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Phar 0194 Materials that can serve as the Cox-2 selective macia, described in U.S. Pat. No. 6,034,256), BMS-347070 inhibitor of the present invention include diarylmethylidene (Bristol Myers Squibb, described in U.S. Pat. No. 6,180, furan derivatives that are described in U.S. Pat. No. 6,180, 651), MK-966 (Merck), L-783003 (Merck), T-614 651. Such diarylmethylidenefuran derivatives have the gen (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 eral formula shown below in formula X: (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo 9H-purin-8-yl-cinnamic acid (GlaxoWellcome), and S-2474 (Shionogi).

0206 Compounds that may act as Cox-2 selective inhibi tors of the present invention include multibinding com pounds containing from 2 to 10 ligands covanlently attached to one or more linkers, as described in U.S. Pat. No. 6,395,724. 0207 Conjugated linoleic, as described in U.S. Pat. No. 6,077.868, is useful as a Cox-2 selective inhibitor in the present invention. 0208 Compounds that can serve as a Cox-2 selective inhibitor of the present invention include heterocyclic aro matic oxazole compounds that are described in U.S. Pat. 0195 wherein: Nos. 5,994,381 and 6,362,209. Such heterocyclic aromatic 0196) the rings T and M independently are a phenyl Oxazole compounds have the formula shown below in radical, a naphthyl radical, a radical derived from a formula XI: heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a XI Saturated hydrocarbon ring having from 3 to 7 carbon R40 atoms, 0197) at least one of the substituents O, O, L' or L’ is an -S(O)-R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an -SO2NH group; 0209 wherein: 0198) and is located in the para position, 0210 Z is an oxygen atom; 0199 the others independently being a hydrogen atom, 0211 one of R' and R' is a group of the formula a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q" and R44 Q’ or L' and L are a methylenedioxy group; and 0200) R, R7, RandR independently are a hydro gen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical Selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl, or, US 2004/O147581 A1 Jul. 29, 2004 14

0212 wherein:

0213) R" is lower alkyl, amino or lower alkylamino; XIII and SORS 0214) R', R', R" and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, S-1s lower alkoxy, trifluoromethyl, hydroxyl or amino, pro vided that at least one of R", R", R" and R' is not hydrogen atom, and the other is an optionally Substi 4. Z4 tuted cycloalkyl, an optionally Substituted heterocyclic group or an optionally Substituted aryl; and 0225 wherein: 0215) R is a lower alkyl or a halogenated lower alkyl, 0226) R' is selected from the group consisting of CH, 0216) and a pharmaceutically acceptable Salt thereof. NH, NHC(O)CF, and NHCH.; 0217 Cox-2 selective inhibitors that are useful in the 0227 Z is a mono-, di-, or trisubstituted phenyl or method and compositions of the present invention include pyridinyl (or the N-oxide thereof), wherein the Sub compounds that are described in U.S. Pat. Nos. 6,080,876 Stituents are chosen from the group consisting of hydro and 6,133,292, and described by formula XII: gen, halo, C-C alkoxy, C-C alkylthio, CN, C-C, alkyl, C-C fluoroalkyl, N, -CO.R., hydroxyl, -C(R)(R)-OH,-C-C alkyl-CO-R, C-C, fluoroalkoxy,

XII 0228) R is chosen from the group consisting of halo, C-C alkoxy, C-C alkylthio, CN, C-C alkyl, C-C, fluoroalkyl, N, –COR7, hydroxyl, —C(R)(R)-OH,-C-C alkyl-CO-R', C-C, fluoroalkoxy, NO, NR'R'', and NHCOR; 0229) R53 R54 R55 R56 R57 R58 R59 RGO Ro1 Ro2 and R', are each independently chosen from the group ROS consisting of hydrogen and C-C alkyl, 0230 or R and R, R and R', or R and R' together with the atom to which they are attached form a Saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms. 0218 wherein: 0231 Materials that can serve as the Cox-2 selective 0219 Zi is selected from the group consisting of linear inhibitor of the present invention include diarylbenzopyran or branched C-C alkyl, linear or branched C-C, derivatives that are described in U.S. Pat. No. 6,340,694. alkoxy, unsubstituted, mono-, di- or tri-Substituted phe Such diarylbenzopyran derivatives have the general formula nyl or naphthyl wherein the Substituents are Selected shown below in formula XIV: from the group consisting of hydrogen, halo, C-C, alkoxy, CN, C-C fluoroalkyl C-C alkyl, and XIV -COH; X8 0220) R' is selected from the group consisting of NH X N R67 and CH, 0221) R' is selected from the group consisting of C C-C alkyl unsubstituted or substituted with Cs-C, cycloalkyl, and C-C cycloalkyl, R66 0222 R is selected from the group consisting of: C-C alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C-C cycloalkyl, 0232 wherein: 0223) with the proviso that R' and Rare not the same. 0233 X is an oxygen atom or a sulfur atom; 0224 Pyridines that are described in U.S. Pat. Nos. 0234) R' and R, identical to or different from each 6,596,736, 6,369,275, 6,127,545, 6,130,334, 6,204,387, other, are independently a hydrogen atom, a halogen 6,071,936, 6,001,843 and 6,040,450, and can seve as Cox-2 atom, a C-C lower alkyl group, a trifluoromethyl Selective inhibitors of the present invention, have the general group, an alkoxy group, a hydroxyl group, a nitro formula described by formula XIII: group, a nitrile group, or a carboxyl group; US 2004/O147581 A1 Jul. 29, 2004

0235 R is a group of a formula: S(O), R wherein n is an integer of 0-2, R is a hydrogen atom, a C-C, XV lower alkyl group, or a group of a formula: NR'R'' X9 wherein R'' and R", identical to or different from each other, are independently a hydrogen atom, or a C-C, lower alkyl group; and 75 N1 N 0236) R' is oxazolyl, benzobthienyl, furanyl, thie nyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl Substituted with a C-C lower alkyl group, indanyl, pyrazinyl, or a Substituted group represented by the following Structures: SONH2

R71 0242 wherein: R72 N 0243 X is selected from the group consisting of C-C trihalomethyl, preferably trifluoromethyl; C-C, alkyl, and an optionally Substituted or di-Substituted R75 R73 OlA. 2 phenyl group of formula XVI: 74 R76 R

N N XVI n n OA-4 Ce2 R76 N-x.

0244 wherein: 0237 wherein: 0245 R77 and Rare independently selected from the group consisting of hydrogen, halogen, preferably 0238) R' through R', identical to or different from chlorine, fluorine and bromine; hydroxyl, nitro, C-C, one another, are independently a hydrogen atom, a alkyl, preferably C-C alkyl, C-C alkoxy, preferably halogen atom, a C-C lower alkyl group, a trifluorom C-C alkoxy; carboxy; C-C trihaloalkyl, preferably ethyl group, an alkoxy group, a hydroxyl group, a trihalomethyl, most preferably trifluoromethyl; and hydroxyalkyl group, a nitro group, a group of a for cyano, mula: S(O),R, a group of a formula: NR'R'', a 0246 Z is selected from the group consisting of sub trifluoromethoxy group, a nitrile group a carboxyl Stituted and unsubstituted aryl. group, an acetyl group, or a formyl group, 0247 Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described 0239 wherein n, R, R and R79 have the same in U.S. Pat. No. 6,153,787. Such heterocycles have the meaning as defined by R above; and general formulas shown below in formulas XVII and XVIII: 0240) R' is a hydrogen atom, a halogen atom, a C-C, lower alkyl group, a trifluoromethyl group, an alkoxy XVII group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group. 0241 Materials that can serve as the Cox-2 selective inhibitor of the present invention include 1-(4-sulfamy laryl)-3-substituted-5-aryl-2-pyrazolines that are described in U.S. Pat. No. 6,376,519. Such 1-(4-sulfamylaryl)-3-sub stituted-5-aryl-2-pyrazolines have the formula shown below in formula XV: US 2004/O147581 A1 Jul. 29, 2004 16

0248 wherein: 0260 R is selected from the group consisting of CH, 0249) R' is a mono-, di-, or tri-substituted C-C, NH, and NHC(O)CF; alkyl, or a mono-, or an unsubstituted or mono-, di- or 0261) R' is chosen from the group consisting of halo, tri-Substituted linear or branched C-C alkenyl, or an C-C alkoxy, C-C alkylthio, CN, C-C alkyl, C-C, unsubstituted or mono-, di- or tri-Substituted linear or fluoroalkyl, Ns, -COR', hydroxyl, branched C-Co alkynyl, or an unsubstituted or mono-, -C(R)(R')-OH,-C-C alkyl-CO-R, C-C, di- or tri-Substituted C-C cycloalkenyl, or an unsub fluoroalkoxy, NO, NR'R'', and NHCOR; Stituted or mono-, di- or tri-Substituted Cs-C 0262 R to R are independently chosen from the cycloalkynyl, wherein the Substituents are chosen from group consisting of hydrogen and C-C alkyl, the group consisting of halo Selected from F, Cl, Br, and 1, OH, CF, C-C cycloalkyl, =O, dioxolane, CN; 0263 or R and R, or RandR together with the atoms to which they are attached form a carbocyclic 0250 R is selected from the group consisting of CH, ring of 3, 4, 5, 6 or 7 atoms, or R and R7 are joined NH, NHC(O)CF, and NHCH.; to form a bond. 0251) R' and Rare independently chosen from the 0264 Compounds that are useful as the Cox-2 selective group consisting of hydrogen and C-Co alkyl, inhibitor of the present invention include diaryl bicyclic heterocycles that are described in U.S. Pat. No. 6,329,421. 0252) or R and R together with the carbon to which Such diaryl bicyclic heterocycles have the general formula they are attached form a Saturated monocyclic carbon shown below in formula XX: ring of 3, 4, 5, 6 or 7 atoms.

0253) Formula XVIII is: XX R99

XVIII As R101N A927 7 x 8 f AR R102 A. X12

0265 and pharmaceutically acceptable salts thereof wherein: le:O HC 0266 -A=A-A’=A- is selected from the group con CH Sisting of: 0267 (a) -CH=CH-CH=CH-, 0254 wherein X" is fluoro or chloro. 0268 (b) CH-CH-CH-C(O), CH 0255 Materials that can serve as the Cox-2 selective CH-C(O)-CH-, CH-C(O)-CH-CH, inhibitor of the present invention include 2,3,5-trisubstituted -C(O)-CH-CH-CH, pyridines that are described in U.S. Pat. No. 6,046,217. Such 0269 (c) -CH-CH-C(O)-, -CH-C(O) pyridines have the general formula shown below in formula CH-, -C(O)-CH-CH XIX: 0270 (d) -CH-CH-O-C(O), CH-O C(O)-CH-, -O-C(O)-CH-CH-, XIX SOR8

2 0273) (g) -N=CH-CH=CH-, N x ---(-or" 0274 (h)-CH=N-CH=CH-, 0275 (i) -CH=CH-N=CH-, 0256 or a pharmaceutically acceptable salt thereof, 0276) ()-CH=CH-CH=N-, 0257 wherein: 0277 (k)-N=CH-CH=N-, 0258 X" is selected from the group consisting of O, S, 0278 (1)-N=CH-N=CH-, and a bond; 0279 (m)-CH=N-CH=N-, 0259 n is 0 or 1; 0280 (n) —S-CH=N-, US 2004/O147581 A1 Jul. 29, 2004 17

0281 (o) -S-N=CH-, 0315) R' and R'' are the substituents residing on any position of -A=A-A'=A- and are selected inde 0282) (p) -N=N-NH-, pendently from the group consisting of: 0283) (q) -CH=N-S-, and 0316 (a) hydrogen, 0284 (r)-N=CH-S-; 0285) R' is selected from the group consisting of 0317) (b) CF, S(O)CH, S(O)NH, S(O)NHCOCF, S(O)(N- 0318 (c) CN, H)CH, S(O)(NH)NH, S(O)(NH)NHCOCF, 0319 (d) C-C alkyl, P(O)(CH)OH, and P(O)(CH)NH; 0286) R' is selected from the group consisting of: wherein Q is Q', COH, 0287 (a) C-C alkyl, 0321) (f) -O-O", 0288 (b) C-C, cycloalkyl, 0322 (g) -S-Q", and 0289 (c) mono- or di-substituted phenyl or naphthyl wherein the Substituent is Selected from the group 0323 (h) optionally substituted: consisting of: 0324) (1) -C-Cs alkyl-Q, 0290 (1) hydrogen, 0325 (2)-O-C-C alkyl-Q, 0291 (2) halo, including F, Cl, Br, I, 0326 (3)-S-C1-C5 alkyl-Q, 0292 (3) C-C alkoxy, 0327 (4) -C-C alkyl-O-C alkyl-Q, 0293 (4) C-C alkylthio, 0328 (5)-C-C alkyl-S-C, alkyl-Q, 0294 (5) CN, 0329 (6) -C-C alkyl-O-Q", 0295 (6) CF, 0296 (7) C-C alkyl, 0330 (7) –C-C alkyl-S-Q", 0331 wherein the substituent resides on the alkyl chain 0297 (8) N., and the substituent is C-C alkyl, and Q is Q', COH, 0298 (9) -COH, C(R')(R')OH Q is CO-C-C alkyl, tetrazolyl 0299 (10) -CO-C-C alkyl, 5-yl, or C(R)(R')O-C-C alkyl; 0332 R', R'' and R'' are each independently 0300 (11) -C(R0)(R9")-OH, Selected from the group consisting of hydrogen and 0301 (12) –C(R')(R')-O-C-C alkyl, and C-C alkyl; or 0302) (13) -C-C alkyl-CO-R'; 0333) R' and R' together with the carbon to which 0303 (d) mono- or di-substituted heteroaryl wherein they are attached form a Saturated monocyclic carbon the heteroaryl is a monocyclic aromatic ring of 5 atoms, ring of 3,4, 5, 6 or 7 atoms, or two R' groups on the Said ring having one hetero atom which is S, O, or N, Same carbon form a Saturated monocyclic carbon ring and optionally 1, 2, or 3 additional N atoms; or the of 3, 4, 5, 6 or 7 atoms; heteroaryl is a monocyclic ring of 6 atoms, Said ring having one hetero atom which is N, and optionally 1, 2, 0334) R' is hydrogen or C-C alkyl; 3, or 4 additional N atoms, said Substituents are 0335) R' is hydrogen, C-C alkyl or aryl; Selected from the group consisting of: 0304 (1) hydrogen, 0305 (2) halo, including fluoro, chloro, bromo and iodo, 0337 Compounds that may act as Cox-2 selective inhibi 0306 (3) C-C alkyl, tors include Salts of 5-amino or a Substituted amino 1,2,3- triazole compound that are described in U.S. Pat. No. 0307) (4) C-C alkoxy, 6,239,137. The salts are of a class of compounds of formula 0308) (5) C-C alkylthio, XXI: 0309 (6) CN, 0310 (7) CF, XXI R110 N 0311) (8) N., V 0312 (9) –C(R)(R)-OH, and N R 109 NV 0313 (10) –C(R')(R')-O-C-C alkyl; R108 0314 (e) benzoheteroaryl which includes the benzo fused analogs of (d); US 2004/O147581 A1 Jul. 29, 2004

0338 wherein: 0353 Z is lower alkylthio, lower alkylsulfonyl or Sulfamoyl; 0339) Rios is: 0354 or a pharmaceutically acceptable salt thereof. 0355 Materials that can serve as a Cox-2 selective inhibi tor of the present invention include substituted derivatives of o (CH2) benzosulphonamides that are described in U.S. Pat. No. 6,297.282. Such benzosulphonamide derivatives have the formula shown below in formula XXIII:

0340 wherein: XXIII 0341 p is 0 to 2; m is 0 to 4; and n is 0 to 5; R118 XIS SO 119 0342 X is O, S, SO, SO, CO, CHCN, CH or O O 21 ( "N-R C=NR where R' is hydrogen, loweralkyl, V/ A hydroxyl, loweralkoxy, amino, loweralkylamino, -Sn N X R120 dilloweralkylamino or cyano; R NH R124 0343 R'' and R'' are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, low eralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, 0356) wherein: acetamido, loweralkylthio, loweralkylsulfinyl, lower 0357 X" denotes oxygen, sulphur or NH; alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trif luoromethylsulfinyl, or trifluoromethylsulfonyl; 0358) R' is an optionally unsaturated alkyl or alky loxyalkyl group, optionally mono- or polySubstituted or 0344) R' is amino, mono or diloweralkyl amino, mixed Substituted by halogen, alkoxy, OXO or cyano, a acetamido, acetimido, ureido, formamido, or guani cycloalkyl, aryl or heteroaryl group optionally mono dino, and or poly Substituted or mixed Substituted by halogen, 0345) R' is carbamoyl, cyano, carbazoyl, amidino or alkyl, CF, cyano or alkoxy; N-hydroxycarbamoyl; 0359 R'' and R', independently from one another, 0346 wherein the loweralkyl, loweralkyl containing, denote hydrogen, an optionally polyfluorised alkyl loweralkoxy and loweralkanoyl groups contain from 1 to 3 group, an aralkyl, aryl or heteroaryl group or a group carbon atoms. (CH), X', or 0347 Pyrazole derivatives such as those described in 0360 R'' and R', together with the N- atom, U.S. Pat. No. 6,136,831 can serve as a Cox-2 selective denote a 3 to 7-membered, Saturated, partially or com inhibitor of the present invention. Such pyrazole derivatives pletely unsaturated heterocycle with one or more het have the formula shown below in formula XXII: eroatoms N, O or S, which can optionally be substituted by OXO, an alkyl, alkylaryl or aryl group, or a group (CH), X'; XXII R114 0361 X' denotes halogen, NO,--OR',-COR'', e N -COR'', -OCOR'', -CN, -CONR'R'', R P. N I WR 117 -CONR'R'', SR'', -S(O)R'', -S(O).R'', -NR'R'', -NHC(O)R'', -NHS(O).R'; ya X14 I /k R116 0362 n denotes a whole number from 0 to 6; 0363) R' denotes a straight-chained or branched alkyl group with 1-10 C-atoms, a cycloalkyl group, an r alkylcarboxyl group, an aryl group, aralkyl group, a Sx76 heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy, 0348 wherein: 0364) R' denotes halogen, hydroxyl, a straight 0349) R" is hydrogen or halogen; chained or branched alkyl, alkoxy, acyloxy or alky loxycarbonyl group with 1-6 C-atoms, which can 0350) R' and R'' are each independently hydrogen, optionally be mono- or poly Substituted by halogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower NO,--OR',-COR'', -COR',-OCOR', alkanoyloxy, -CN, CONR 121R122, CONR 121R122, -SR'', -S(O)R'', -S(O).R'', -NR'R'', -NH 0351) R'7 is lower haloalkyl or lower alkyl; C(O)R'', -NHS(O).R'', or a polyfluoroalkyl O352 X" is sulfur, oxygen or NH; and grOup, US 2004/O147581 A1 Jul. 29, 2004

0365) R' and R', independently from one another, gol) X' Y-Z'-is selected from the group consisting denote hydrogen, alkyl, aralkyl or aryl; and O 0366) m denotes a whole number from 0 to 2, 0392 (a) =CH-O-CH=, and 0367) and the pharmaceutically-acceptable Salts thereof. 0393) (b) =CH-NR'27 -CH=, 0368 Compounds that are useful as Cox-2 selective 0394 (c) =N-S-CH=, inhibitors of the present invention include phenyl hetero cycles that are described in U.S. Pat. Nos. 5,474,995 and 0395) (d) =CH-S-N=, 6,239,173. Such phenyl heterocyclic compounds have the 0396 (e) =N-O-CH=, formula shown below in formula XXIV: 0397) (f) =CH-O-N=, 0398 (g) =N-S-N=, XXIV 0399) (h) =N-O-N=, 04.00 when sides a and c are double bonds and side b is a single bond; 0401) R' is selected from the group consisting of: 0402 (a) S(O), CH, 0403) (b) S(O), NH, 0404 (c) S(O)NHC(O)CF, 04.05) (d) S(O)(NH)CH, 0369 or pharmaceutically acceptable salts thereof 0406 (e) S(O)(NH)NH, wherein: 0407 (f) S(O)(NH)NHC(O)CF, 0370 X'7-Y-Z7-is selected from the group consist 0408 (g) P(O)(CH)OH, and ing of 0409 (h) P(O)(CH)NH; 0371 (a) -CH CHCH-, 0410) R' is selected from the group consisting of 0372 (b) –C(O)CHCH-, 0411 (a) C-C alkyl, 0373) (c) —CHCHC(O)—, 0412 (b) C, C, C, C, and C7, cycloalkyl, 0374) (d) –CR'(R')-O-C(O)-, 0413 (c) mono-, di- or tri-substituted phenyl or naph thyl, wherein the Substituent is Selected from the group 0375 (e) –C(O)-O-CR'(R')–, consisting of: 0376 (f) —CH-NR'7–CH-, 0414 (1) hydrogen, 0377 (g) -CR'(R')-NR'27-C(O)-, 0415 (2) halo, 0378 (h)-CR'Pi—CR'?' S-, 0416 (3) C-C alkoxy, 0379 (i) -S-CR'2=CR'? . 0417 (4) C-C alkylthio, 0380 () -S-N=CH-, 0418 (5) CN, 0381 (k) -CH=N-S-, 0419 (6) CF, 0382 (1)-N=CR'-O-, 0420 (7) C-C alkyl, 0383 (m) -O-CRP-N-, 0421 (8) N., 0384) (n)-N=CR-NH-, 0422 (9) -COH, 0385) (o)-N=CRP-S-, and 0423 (10) -CO-C-C alkyl, 0386 (p) –S-CR'*=N-, 0424 (11) –C(R')(R)-OH, 0387 (q)-C(O)-NR'27 CR(R)- 0425 (12) –C(R')(R)-O-C-C alkyl, and 0388 (r)-R''N-CH=CH- provided R' is not 0426 (13) -C-C alkyl-CO-R'; -S(O)CH, 0427 (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 0389) (s) -CH=CH-NR'' - provided R' is not 5 atoms, Said ring having one hetero atom which is S, -S(O)CH; O, or N, and optionally 1, 2, or 3 additionally Natoms; 0390 when side b is a double bond, and sides a and c are or the heteroaryl is a monocyclic ring of 6 atoms, Said Single bonds, and ring having one hetero atom which is N, and optionally US 2004/O147581 A1 Jul. 29, 2004 2O

1, 2, 3, or 4 additional N atoms, Said Substituents are 0467 (5)-C-C, alkyl-S-C1-C, alkyl-Q, Selected from the group consisting of: 0468 (6) -C-Cs alkyl-O-Q, 0428 (1) hydrogen, 0469 (7) –C-C alkyl-S-Q, 0429 (2) halo, including fluoro, chloro, bromo and iodo, 0470 wherein the substituent resides on the alkyl and the Substituent is C-C alkyl, and 0430) (3) C-C alkyl, 0471) R', R, R, R and R'' are each independently 0431 (4) C-C alkoxy, Selected from the group consisting of: 0432) (5) C-C alkylthio, 0472 (a) hydrogen, 0433) (6) CN, 0473) (b) C-C alkyl; 0434) (7) CF, 0474 or R'' and R' or R'' and R' together with the 0435) (8) N., carbon to which they are attached form a Saturated mono 0436 (9) –C(R')(R)-OH, and cyclic carbon ring of 3, 4, 5, 6 or 7 atoms, 0437 (10) –C(R')(R)-O-C-C alkyl; 0475 Q is COH, CO-C-C alkyl, tetrazolyl-5-yl, 0438 (e) benzoheteroaryl which includes the benzo C(R)(R')(OH), or C(R)(R')(O-C-C alkyl); fused analogs of (d); 0476 provided that when X-Y-Z is -S-CR =CR''' then R'' and R'' are other than 0439) R' is selected from the group consisting of: CF. 0440 (a) hydrogen, 0477. An exemplary phenyl heterocycle that is disclosed in U.S. Pat. No. 6,239,173 is 3-phenyl-4-(4-(methylsulfo 0441 (b) CF, nyl)phenyl)-2-(2H)-furanone. 0442 (c) CN, 0478 Bicycliccarbonyl indole compounds such as those 0443) (d) C-C alkyl, described in U.S. Pat. No. 6,303,628 are useful as Cox-2 0444 (e) hydroxyl C-C alkyl, Selective inhibitors of the present invention. Such bicyclic carbonyl indole compounds have the formula shown below 0445) (f) -C(O)-C-C alkyl, in formula XXV: 0446) (g) optionally Substituted: 0447) (1) -C-Cs alkyl-Q, XXV 0448 (2) -C-Cs alkyl-O-C-C alkyl-Q, 0449) (3)-C-C alkyl-S-C-C alkyl-Q, 0450 (4) -C1-C5 alkyl-O-Q, or 0451 (5) –C-C alkyl-S-Q, 0452 wherein the substituent resides on the alkyl and the Substituent is C-C alkyl, 0453 (h)-Q; 0454) R' and R'' are each independently selected from the group consisting of: 0479 or the pharmaceutically acceptable salts thereof 0455) (a) hydrogen, wherein: 0456) (b) CF, 0480 A is C-C alkylene or -NR' ; 0457) (c) CN, 0481) Z is C(=L)R'', or SOR; 0458) (d) C-C alkyl, 0482 Z is CH or N; 0459) (e) -Q, 0483 Z' and Y are independently selected from 0460) (f) -O-Q; -CH-, O, S and -N-R'; 0461) (g) -S-Q, and 0484 m is 1, 2 or 3; 0462) (h) optionally substituted: 0485 q and r are independently 0, 1 or 2; 0463) (1) -C-Cs alkyl-Q, 0486 X" is independently selected from halogen, 0464) (2) -O-C-Cs alkyl-Q, C-C alkyl, halo-substituted C-C alkyl, hydroxyl, C-C alkoxy, halo-substituted C-C, alkoxy, C-C, 0465 (3)-S-C-C alkyl-Q, alkylthio, nitro, amino, mono- or di-(C-C alky 0466 (4) -C-C, alkyl-O-C-C, alkyl-Q, l)amino and cyano; US 2004/0147581 A1 Jul. 29, 2004 21

0487 n is 0, 1, 2, 3 or 4; 0499 X is independently selected from halo, C-C, alkyl, hydroxyl, C-C alkoxy, halo-substituted C-C, 0488) L is oxygen or sulfur; alkyl, hydroxyl-substituted C-C alkyl, (C-C, 0489) R' is hydrogen or C-C alkyl; alkoxy)C-C alkyl, halo-substituted C-C alkoxy, amino, N-(C-C alkyl)amino, N,N-di(C-C alky 0490) R' is hydroxyl, C-C alkyl, halo-substituted l)amino, N-(C-C alkyl)aminoC-C alkyl, N,N- C-C alkyl, C-C alkoxy, halo-substituted C-C, di(C-C, alkyl)aminoC-C alkyl, N-(C-C alkanoy alkoxy, Ca-C, cycloalkoxy, C-C alkyl(C-C, l)amino, N-(C-C alkyl)-N-(C-C alkanoyl)amino, cycloalkoxy), -NR'R'', C-C alkylphenyl-O- or N-(C-C, alkyl)sulfonyl)amino, N-(halo-substituted phenyl-O-, said phenyl being optionally substituted C-C alkyl)sulfonyl)amino, C-C alkanoyl, carboxy, with one to five substituents independently selected (C-C alkoxy)hydroxyl, cabamoyl, N-(C-C alkyl) from halogen, C-C alkyl, hydroxyl, C-C alkoxy and aminocarbonyl, N,N-di(C-C alkyl)aminocarbonyl, nitro, N-carbomoylamino, cyano, nitro, mercapto, (C-C, alkyl)thio, (C-C alkyl)sulfinyl, (C-C alkyl)sulfonyl, 0491) R' is C-C alkyl or halo-substituted C-C, aminosulfonyl, N-(C-C alkyl)aminosulfonyl and alkyl, and N,N-di(C-C, alkyl)aminolsulfonyl; 0492) R' and R7 are independently selected from 0500) R' is selected from: hydrogen, Co alkyl and halo-Substituted C-C alkyl. 0501) hydrogen; 0493 Materials that can serve as a Cox-2 selective inhibi 0502) straight or branched C-C alkyl optionally sub tor of the present invention include benzimidazole com stituted with one to three substituent(s) wherein said pounds that are described in U.S. Pat. No. 6,310,079. Such Substituents are independently selected from halo, benzimidazole compounds have the formula shown below in hydroxyl, C-C alkoxy, amino, N-(C-C alkyl)amino formula XXVI: and N,N-di(C-C alkyl)amino; 0503 C-C cycloalkyl optionally substituted with one XXVI to three Substituent(s) wherein said substituents are N indepently Selected from halo, C-C alkyl, hydroxyl, 21 - N N 140- 139-D 138 (X") i 2 CRI'''CR R C-C alkoxy, amino, N-(C-C alkyl)amino and N,N- N di(C-C alkyl)amino; V A10- (X20) 0504 C-C cycloalkenyl optionally substituted with one to three Substituent(s) wherein said substituents are independently selected from halo, C-C alkyl, 0494 or a pharmaceutically acceptable salt thereof, hydroxyl, C-C alkoxy, amino, N-(C-C alkyl)amino wherein: and N,N-di(C-C alkyl)amino; 0505) phenyl optionally substituted with one to three 0495) A' is heteroaryl selected from Substituent(s) wherein said Substituents are indepen 0496) a 5-membered monocyclic aromatic ring having dently Selected from halo, C-C alkyl, hydroxyl, C-C, one hetero atom selected from O, S and N and option alkoxy, halo-Substituted C-C alkyl, Dydroxyl-substi ally containing one to three Natom(s) in addition to tuted C-C alkyl, (C-C alkoxy)C-C alkyl, halo Said hetero atom, or Substituted C-C alkoxy, amino, N-(C-C alky l)amino, N,N-di(C-C alkyl)amino, N-(C-C, 0497 a 6-membered monocyclic aromatic ring having alkyl)aminoC-C alkyl, N,N-di(C-C alkyl)amino one N atom and optionally containing one to four N C-C alkyl, N-(C-C alkanoyl)amino, N-C-C, atom(s) in addition to said Natom; and said heteroaryl alkyl)(C-C alkanoyl)amino, N-(C-C alkyl)sul being connected to the nitrogen atom on the benzimi fonylamino, N-(halo-substituted C-C alkyl)sulfonyl dazole through a carbon atom on the heteroaryl ring; amino, C-C alkanoyl, carboxy, (C-C alkoxy)carbo 0498) X” is independently selected from halo, C-C, nyl, carbomoyl, N-(C-C alky)aminocarbonyl, N,N- alkyl, hydroxyl, C-C alkoxy, halo-substituted C-C, di(C-C alkyl)aminolcarbonyl, cyano, nitro, mercapto, alkyl, hydroxyl-substituted C-C alkyl, (C-C, (C-C alkyl)thio, (C-C alkyl)sulfinyl, (C-C alkyl alkoxy)C-C alkyl, halo-Substituted C-C alkoxy, )Sulfonyl, aminosulfonyl, N-(C-C alkyl)aminosul amino, N-(C-C alkyl)amino, N,N-di(C-C alky fonyl and N,N-di(C-C alkyl)aminosulfonyl; and l)amino, N-(C-C alkyl)aminoC-C alkyl, N,N- 0506 heteroaryl selected from: di(C-C alkyl)aminolc-C alkyl, N-(C-C alkanoy l)amonio, N-(C-C alkyl)(C-C alkanoyl)amino, 0507) a 5-membered monocyclic aromatic ring having N-(C-C, alkyl)sulfonyl)amino, N-(halo-substituted one hetero atom selected from O, S and N and option C-C alkyl)sulfonyl)amino, C-C alkanoyl, carboxy, ally containing one to three Natom(s) in addition to (C-C alkoxy)carbonyl, carbamoyl, N-(C-C alky Said hetero atom; or a 6-membered monocyclic aro l)aminocarbonyl, N,N-di(C-C alkyl)aminocarbo matic ring having one N atom and optionally contain nyl, cyano, nitro, mercapto, (C-C alkyl)thio, (C-C, ing one to four N atom(s) in addition to said N atom; alkyl)sulfinyl, (C-C alkyl)sulfonyl, aminosulfonyl, and N-(C-C alkyl)aminosulfonyl and N,N-di(C-C, 0508) said heteroaryl being optionally substituted with alkyl)aminosulfonyl; one to three substituent(s) selected from X'; US 2004/O147581 A1 Jul. 29, 2004 22

0509) R' and R'' are independently selected from: hydroxyl, OR', S(O) R', amino, mono- or 0510) hydrogen; di-(C-C, alkyl)amino and CN; 0526 (d) a monocyclic aromatic group of 5 atoms, said 0511 halo; aromatic group having one heteroatom Selected from 0512 C-C alkyl; O, S and N and optionally containing up to three N 0513 phenyl optionally substituted with one to three atoms in addition to Said heteroatom, and Said aromatic Substituent(s) wherein said Substituents are indepen group being Substituted with up to three Substitutents dently selected from halo, C-C alkyl, hydroxyl, C-C, independently Selected from: alkoxy, amino, N-(C-C, alkyl)amino and N,N-di(C- 0527 (d-1) halo, C-C alkyl, halosubstituted C-C, Calkyl)amino; alkyl, hydroxyl, C-C alkoxy, haloSubstituted C-C, alkoxy, C-C alkyl-OH, S(O), R', SO. NH2, 0514) or R'' and R' can form, together with the SON(C-C, alkyl), amino, mono- or di-(C-C, carbon atom to which they are attached, a C-C, alkyl)amino, NHSOR'', NHC(O)R'', CN, cycloalkyl ring, COH, CO(C-C alkyl), C-C alkyl-OR'', 0515 m is 0, 1, 2, 3, 4 or 5; and CONH, CONH(C-C alkyl), CONCC-C alkyl), phenyl, and mono-, di- or tri-Substituted phenyl 0516 n is 0, 1, 2, 3 or 4. wherein the Substituent is independently Selected 0517 Compounds that may be employed as a Cox-2 from halo, CF, C-C alkyl, hydroxyl, C-C alkoxy, selective inhibitor of the present invention include indole OCF, SR', SO CH, SO. NH, amino, C. compounds that are described in U.S. Pat. No. 6,300,363. alkylamino and NHSOR'; Such indole compounds have the formula shown below in 0528 (e) a monocyclic aromatic group of 6 atoms, said formula XXVII: aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to XXVII Said heteroatom, and Said aromatic group being Substi R141 tuted with up to three Substituents independently Y R142 Selected from the above group (d-1); 0529) R' is hydrogen or C-C alkyl optionally sub N L4 stituted with a substituent selected independently from (x) + N hydroxyl, OR", nitro, amino, mono- or di-(C-C, 21 Y3-O6 alkyl)amino, COH, CO (C-C alkyl), CONH2, CONH(C-C, alkyl) and CONC-C, alkyl); 0530) R-2 is: 0518 and the pharmaceutically acceptable salts thereof, 0531 (a) hydrogen, wherein: 0519) L' is oxygen or sulfur; 0532 (b) C-C alkyl, 0520 Y is a direct bond or C-C alkylidene; 0533 (c) C(O)R'', 0534 wherein R' is selected from: 0521. Q is: 0535 (c-1) C-C alkyl or C-C alkenyl, said 0522) (a) C-C alkyl or halosubstituted C-C alkyl, alkyl or alkenyl being optionally Substituted with up Said alkyl being optionally Substituted with up to three to four Substituents independently Selected from: Substituents independently Selected from hydroxyl, C-C alkoxy, amino and mono- or di-(C-C alky 0536) (c-1-1) halo, hydroxyl, OR', S(O), R', l)amino, nitro, amino, mono- or di-(C-C alkyl)amino, NHSOR'', COH, CO(C-C alkyl), CONH, 0523) (b) C-C cycloalkyl optionally substituted with CONH(C-C alkyl), CONCC-C alkyl), up to three Substituents independently Selected from OC(O)R*, thienyl, naphthyl and groups of the hydroxyl, C-C alkyl and C-C alkoxy, following formulas: 0524) (c) phenyl or naphthyl, said phenyl or naphthyl being optionally Substituted with up to four Substituents independently Selected from: (x22), 0525 (c-1) halo, C-C alkyl, halosubstituted C-C, ox1 (X2), -- V , alkyl, hydroxyl, C-C alkoxy, haloSubstituted C-C, NHSO \ / NHSO \ / alkoxy, S(O), R', SONH, SON(C-C alkyl), amino, mono- or di-(C-C alkyl)amino, NHSOR'', NHC(O)R'', CN, COH, CO(C-C, alkyl), C-C alkyl-OH, C-C alkyl-OR'', CONH, CONH(C-C alkyl), CONCC-C alkyl). y- (X2), y- (X2), and -O-Y-phenyl, Said phenyl being optionally substituted with one or two substituents indepen dently Selected from halo, C-C alkyl, CF, US 2004/O147581 A1 Jul. 29, 2004 23

0544 (c-6) a group of the following formula: -continued (CH2)2 p. O (CH2)2 p. (CH2) o NC y- NC Yz11 / (CH2)

(C2), V -(y), 0545 X* is halo, C-C alkyl, hydroxyl, C-C alkoxy, -N Z11, and N Z11 halosubstitutued C-C alkoxy, S(O), R', amino, mono- or di-(C-C alkyl)amino, NHSOR'', nitro, halosubstitutued C-C alkyl, CN, COH, CO (C-C, alkyl), C-C alkyl-OH, C-C alkylOR'', CONH, 0537 (c-2) C-C alkyl or C-C alkenyl, said alkyl or alkenyl being optionally Substituted with CONH(C-C, alkyl) or CONC-C, alkyl); five to forty-five halogen atoms, 0546) R' is C-C alkyl or halosubstituted C-C, alkyl, 0538 (c-3) - Y-C-C, cycloalkyl or - Ys-C- C, cycloalkenyl, Said cycloalkyl or cycloalkenyl 0547 m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 or being optionally Substituted with up to three Sub 5; q is 2 or 3; Stituent independently Selected from: 0548) Z' is oxygen, sulfur or NR'; and 0539 (c-3-1) C-C alkyl, hydroxyl, OR' 0549 R is hydrogen, C-C alkyl, halosubstitutued S(O), R', amino, mono or di-(C-C alky C-C alkyl or -Y-phenyl, said phenyl being option l)amino, CONH, CONH(C-C alkyl) and ally substituted with up to two substituents indepen CONC-C, alkyl). dently selected from halo, C-C alkyl, hydroxyl, C-C, 0540 (c-4) phenyl or naphthyl, said phenyl or naph alkoxy, S(O), R', amino, mono- or di-(C-C alky thyl being optionally Substituted with up to seven l)amino, CF, OCF, CN and nitro; (preferably up to Seven) Substituents independently 0550 with the proviso that a group of formula-Y-Q Selected from: is not methyl or ethyl when X* is hydrogen; 0541 (c-4-1) halo, C-C alkyl, C-C alkyl-OH, 0551 L' is oxygen;yg hydroxyl, C-C alkoxy, haloSubstituted C-Cs alkyl, haloSubstituted C-C alkoxy, CN, nitro, 0552) R'' is hydrogen; and S(O), R', SO. NH, SO. NH(C-C alkyl), 0553) R'' is acetyl. SON(C-C alkyl), amino, C1-C, alkylamino, 0554 Aryl phenylhydrazides that are described in U.S. di-(C-C, alkyl)amino, CONH2, CONH(C-C, Pat. No. 6,077.869 can serve as Cox-2 selective inhibitors of alkyl), CONCC-C alkyl), OC(O)R', and phe the present invention. Such aryl phenylhydrazides have the nyl optionally substituted with up to three sub formula shown below in formula XXVIII: Stituents independently Selected from halo, C-C, alkyl, hydroxyl, OCH, CF, OCF, CN, nitro, amino, mono- or di-(C-C alkyl)amino, COH, XXVIII CO, (C-C, alkyl) and CONH2, O 0542 (c-5) a monocyclic aromatic group as defined N N1 N in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents - " - independently Selected from: X23 2. 0543 (c-5-1) halo, C-C alkyl, C-C alkyl-OH, hydroxyl, C-C alkoxy, CF, OCF, CN, nitro, 0555 wherein: S(O), R', amino, mono- or di-(C-C alky 0556 X and Y are selected from hydrogen, halogen, l)amino, CONH, CONH(C-C, alkyl), CONC alkyl, nitro, amino, hydroxy, methoxy and methylsul C alkyl), CO2H and CO (C-C alkyl), and fonyl; -Y-phenyl, Said phenyl being optionally Substi tuted with up to three Substituents independently 0557 or a pharmaceutically acceptable salt thereof. Selected halogen, C-C alkyl, hydroxyl, C-C, 0558 Materials that can serve as a Cox-2 selective inhibi alkoxy, CF, OCF, CN, nitro, S(O), R', amino, tor of the present invention include 2-aryloxy, 4-aryl furan mono- or di-(C-C alkyl)amino, COH, CO (C- 2-ones that are described in U.S. Pat. No. 6,140,515. Such C alkyl), CONH, CONH(C-C alkyl) and 2-aryloxy, 4-aryl furan-2-ones have the formula shown CONC-C, alkyl). below in formula XXIX: US 2004/O147581 A1 Jul. 29, 2004 24

transoid configuration and if a double bond is present, the bond is in the trans configuration, XXIX R 146 0571 (b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non R"R148 149 lipophilic, and 0572 (c) there exists an energetically stable configu ration planar with ring A to within about 15 degrees, 0573 or R'' and R'' are taken in combination and represent a 5- or 6-membered aromatic or non-aromatic ring D fused to ring A, Said ring D containing 0-3 heteroatoms selected from O, S and N, 0559 or a pharmaceutical salt thereof, wherein: 0574 said ring D being lipophilic except for the atoms 0560) R' is selected from the group consisting of attached directly to ring A, which are lipophilic or SCH, -S(O). CH and -SO). NH; non-lipophilic, and Said ring D having available an energetically stable configuration planar with ring A to 0561) R' is selected from the group consisting of OR', mono or di-substituted phenyl or pyridyl within about 15 degrees; wherein the Substituents are Selected from the group 0575 said ring D further being substituted with 1 R' consisting of methyl, chloro and F; group Selected from the group consisting of C-C, alkyl, -OC-C alkyl, -NHC, -C alkyl, -N(C-C, 0562) R' is unsubstituted or mono or di-substituted alkyl), -C(O)C-C alkyl, -S-C-C alkyl and phenyl or pyridyl wherein the Substituents are Selected -C(S)C-C, alkyl; from the group consisting of methyl, chloro and F; 0576 Y7 represents N, CH or C-OC-C alkyl, and 0563) R' is H, C-C alkyl optionally substituted when Z' is N, Y can also represent a carbonyl group; with 1 to 3 groups of F, Cl or Br; and 0577) R' represents H, Br, C1 or F; and 0564) R' is H, C-C alkyl optionally substituted with 1 to 3 groups of F, Clor Br, with the proviso that 0578 R'' represents H or CH. R'' and R'' are not the same. 0579 Compounds useful as Cox-2 selective inhibitors of the present invention include 1,5-diarylpyrazoles that are 0565) Materials that can serve as a Cox-2 selective inhibi described in U.S. Pat. No. 6,028,202. Such 1,5-diarylpyra tor of the present invention include bisaryl compounds that Zoles have the formula shown below in formula XXXI: are described in U.S. Pat. No. 5,994,379. Such bisaryl compounds have the formula shown below in formula XXX: XXXI R 158

N-N R160 S- (K R161 R1564 N Š. N-( R13 Nux R162 N O R155 R159

0580 wherein: R154 CO2H 0581) R', R', R'7, and R' are independently Selected from the groups consisting of hydrogen, C-Cs alkyl, C-C alkoxy, phenyl, halo, hydroxyl, C-C, 0566 or a pharmaceutically acceptable salt, ester or tau alkylsulfonyl, C-C alkylthio, trihaloC-C alkyl, tomer thereof, wherein: amino, nitro and 2-quinolinylmethoxy, 0567) Z' is C or N; 0582) R' is hydrogen, C1-C5 alkyl, trihaloC-Cs 0568 when Z' is N, R represents H or is absent, or alkyl, phenyl, Substituted phenyl where the phenyl Substitutents are halogen, C-C alkoxy, trihaloC-Cs is taken in conjunction with R" as described below: alkyl or nitro or R'' is heteroaryl of 5-7 ring members 0569 when Z' is C, R' represents H and R' is a where at least one of the ring members is nitrogen, moiety which has the following characteristics: Sulfur or oxygen; 0570 (a) it is a linear chain of 3-4 atoms containing 0-2 0583) R' is hydrogen, C1-C5 alkyl, phenyl C-C, double bonds, which can adopt an energetically Stable alkyl, Substituted phenyl C-C alkyl where the phenyl US 2004/O147581 A1 Jul. 29, 2004 25

Substitutents are halogen, C-C alkoxy, trihaloC-Cs 0596 wherein the substituents are independently alkyl or nitro, or R' is C-C alkoxycarbonyl, phe Selected from one or members of the group consisting noxycarbonyl, Substituted phenoxycarbonyl where the of C1-C5 alkyl, halogen, nitro, trifluoromethyl and phenyl Substitutents are halogen, C-C alkoxy, triha nitrile; loC-Cs alkyl or nitro; 0597) R' is hydrogen, 2-(trimethylsilyl)ethoxym 0584) R' is C-C alkyl, substituted C-C alkyl ethyl), C-C alkoxycarbonyl, aryloxycarbonyl, arylC where the Substituents are halogen, trihaloC-C alkyl, Cs alkyloxycarbonyl, arylC1-C5 alkyl, phthalimidoC C-C alkoxy, carboxy, C-C alkoxycarbonyl, amino, Cs alkyl, aminoC-C alkyl, diaminoC-C alkyl, C-Cs alkylamino, diC1-C5 alkylamino, diC1-C5 alky SuccinimidoC-Cs alkyl, C1-C5 alkylcarbonyl, arylcar laminoC-C alkylamino, C-C alkylaminoC-Cs bonyl, C-C alkylcarbonylC-C alkyl, aryloxycarbo alkylamino or a heterocycle containing 4-8 ring atoms nylc-Cs alkyl, heteroarylC1-C5 alkyl where the het where one more of the ring atoms is nitrogen, oxygen eroaryl contains 5 to 6 ring atoms, or Substituted or Sulfur, where Said heterocycle may be optionally arylC-C alkyl, wherein the aryl Substituents are inde substituted with C-C alkyl; or R' is phenyl, substi pendently Selected from one or more members of the tuted phenyl (where the phenyl Substitutents are one or group consisting of C-C alkyl, C-C alkoxy, halogen, more of C1-C5 alkyl, halogen, C-Cs alkoxy, trihaloC amino, C-C alkylamino, and diC-C alkylamino; Cs alkyl or nitro), or R' is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or (0598) R-7 is (A')-(CH)-X' wherein: Sulfur, fused heteroaryl where one or more 5-7 mem 0599 A' is sulfur or carbonyl; bered aromatic rings are fused to the heteroaryl; or 0600 n is 0 or 1; 0585) R' is NR'R'' where RandR'' are inde pendently selected from hydrogen and C-5 alkyl or 0601 q is 0-9; R and R' may be taken together with the depicted 0602 X" is selected from the group consisting of nitrogen to form a heteroaryl ring of 5-7 ring members hydrogen, hydroxyl, halogen, Vinyl, ethynyl, C-C, where one or more of the ring members is nitrogen, alkyl, C-C-7 cycloalkyl, C-C alkoxy, phenoxy, phe Sulfur or oxygen where Said heteroaryl ring may be nyl, arylC-C alkyl, amino, C-C alkylamino, nitrile, optionally substituted with C-C alkyl, R' is hydro phthalimido, amido, phenylcarbonyl, C-C alkylami gen, C1-C5 alkyl, nitro, amino, and halogen; nocarbonyl, phenylaminocarbonyl, arylC-C alky laminocarbonyl, C-C alkylthio, C-C alkylsulfonyl, 0586 and pharmaceutically acceptable salts thereof. phenylsulfonyl, 0587 Materials that can serve as a Cox-2 selective inhibi- 0603 Substituted sulfonamido, tor of the present invention include 2-Substituted imidazoles that are described in U.S. Pat. No. 6,040,320. Such 2-sub 0604 wherein the Sulfonyl Substituent is selected from stituted imidazoles have the formula shown below in for the group consisting of C1-C5 alkyl, phenyl, araC-Cs mula XXXII: alkyl, thienyl, furanyl, and naphthyl; Substituted vinyl, 0605 wherein the substituents are independently Selected from one or members of the group consisting R166 XXXII of fluorine, bromine, chlorine and iodine, Substituted R16S A ethynyl, N 167 0606 wherein the substituents are independently 2 R Selected from one or more members of the group R164 N consisting of fluorine, bromine chlorine and iodine, 0607 Substituted C-C alkyl, 0588) wherein: 0608 wherein the substituents are selected from the group consisting of one or more C-C alkoxy, triha 0589 R'' is phenyl, heteroaryl wherein the heteroaryl loalkyl, phthalimido and amino, contains 5 to 6 ring atoms, or 0609 substituted phenyl, 0590 substituted phenyl; 0610 wherein the phenyl substituents are indepen 0591 wherein the substituents are independently dently Selected from one or more members of the group Selected from one or members of the group consisting consisting of C-C alkyl, halogen and C-C alkoxy, of Cs alkyl, halogen, nitro, trifluoromethyl and nitrile; 0611 substituted phenoxy, 0592) R' is phenyl, heteroaryl wherein the heteroaryl 0612) wherein the phenyl Substituents are indepen contains 5 to 6 ring atoms, dently Selected from one or more members of the group 0593) substituted heteroaryl; consisting of C-C alkyl, halogen and C-C alkoxy, 0594 wherein the substituents are independently 0613) Substituted C-C alkoxy, Selected from one or more members of the group 0.614 wherein the alkyl substituent is selected from the consisting of C-C alkyl and halogen, or group consisting of phthalimido and amino, 0595) substituted phenyl, 0615. Substituted arylC-C alkyl, US 2004/O147581 A1 Jul. 29, 2004 26

0616 wherein the alkyl substituent is hydroxyl,

0617 substituted arylC-C alkyl, 169 XXXIII 0618 wherein the phenyl substituents are indepen / x dently Selected from one or more members of the group consisting of C-C alkyl, halogen and C-C alkoxy, N-N 0619 substituted amido, N \ 0620 wherein the carbonyl substituent is selected from the group consisting of C-C alkyl, phenyl, arylC-Cs alkyl, thienyl, furanyl, and naphthyl, Ž 2 0621 substituted phenylcarbonyl, 169 XXXIV 0622 wherein the phenyl substituents are indepen / XR dently Selected from one or members of the group consisting of C-C alkyl, halogen and C-C alkoxy, N-N 0623 substituted C-C alkylthio, N \ 0624 wherein the alkvly Substituent is selected from the group consisting of hydroxyl and phthalimido, 21 0625 substituted C-C alkylsulfonyl, Ž 0626 wherein the alkvly Substituent is selected from the group consisting of hydroxyl and phthalimido, 0637 wherein: 0638) R' and R'' are independently selected from 0627 substituted phenylsulfonyl, the group consisting of hydrogen, halogen, (C- 0628 wherein the phenyl substituents are indepen C.)alkyl, (C-C)alkoxy, nitro, amino, Dydroxyl, trif dently Selected from one or members of the group luoro, -S(C-C)alkyl, -SO(C-C)alkyl and -SO consisting of bromine, fluorine, chlorine, C-C alkoxy (C-C)alkyl, and and trifluoromethyl, 0639 the fused moiety M is a group selected from the group consisting of an optionally Substituted cyclo 0629 with the proviso: hexyl and cycloheptyl group having the formulae: 0630 if A' is sulfur and X* is other than hydrogen, C-Cs alkylaminocarbonyl, phenylaminocarbonyl, arylC-Cs alkylaminocarbonyl, C1-C5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than R173, or 1, 0631 if A' is sulfur and q is 1, then X cannot be C-C, alkyl; R170 R172 0632) if A' is carbonyl and q is 0, then X cannot be R171 vinyl, ethynyl, C-C alkylaminocarbonyl, phenylami R173 nocarbonyl, arylC-C alkylaminocarbonyl, C-Cs alkylsulfonyl or phenylsulfonyl; R172 0633) if A' is carbonyl, q is 0 and X* is H, then R' is not 2-(trimethylsilyl)ethoxymethyl; 171 0634) if n is 0 and q is 0, then X cannot be hydrogen; R170 R 0635 and pharmaceutically acceptable salts thereof. 0640 wherein: 0636. Materials that can serve as a Cox-2 selective inhibi tor of the present invention include 1,3- and 2,3-diarylcy 0641) R'' is selected from the group consisting of cloalkano and cycloalkeno pyrazoles that are described in hydrogen, halogen, hydroxyl and carbonyl, U.S. Pat. No. 6,083,969. Such 1,3- and 2,3-diarylpyrazole 0642 or R'' and R'7" taken together form a moiety compounds have the general formulas shown below in selected from the group consisting of -OCOCH-, formulas XXXIII and XXXIV: –ONH(CH)COCH-, -OCOCH= and -O-; US 2004/O147581 A1 Jul. 29, 2004 27

0643 R'7' and R'' are independently selected from 0652 wherein: the group consisting of hydrogen, halogen, hydroxyl, 0653 R'' is C-C alkyl, C-C branched alkyl, C-Cs carbonyl, amino, (C-C)alkyl, (C-C)alkoxy, cycloalkyl, C-C hydroxyalkyl, branched C-C, =NOH, -NR'R'7, –OCH –OCHCH, hydroxyalkyl, hydroxyl Substituted C-C aryl, pri –OSONHCOCH, =CHCOCHCH, mary, Secondary or tertiary C-C alkylamino, primary, -CHCO2H, -CHCO CH, -CHCOCH CH, Secondary or tertiary branched C-C alkylamino, pri -CHCON(CH), -CHCONHCH, mary, Secondary or tertiary C-C arylamino, C-C, -CHCHCOCHCH, –OCON(CH)OH, alkylcarboxylic acid, branched C-C alkylcarboxylic -C(COCH), di(C-C)alkyl and di(C-C)alkoxy; acid, C-C alkylester, branched C-C alkylester, C-Cs aryl, Ca-Cs arylcarboxylic acid, Ca-Cs arylester, 0644) R' is selected from the group consisting of C-C aryl Substituted C-C alkyl, C-C heterocyclic hydrogen, halogen, hydroxyl, carbonyl, amino, (C- alkyl or aryl with O, Nor S in the ring, alkyl-substituted C.)alkyl, (C-C)alkoxy and optionally Substituted car or aryl-substituted C-C heterocyclic alkyl or aryl with boxyphenyl, wherein Substituents on the carboxyphe nyl group are Selected from the group consisting of O, N or S in the ring, or halo-substituted versions halogen, hydroxyl, amino, (C-C)alkyl and (C- thereof, where halo is chloro, bromo, fluoro or iodo; C.)alkoxy; 0654) R'' is C-C alkyl, C-C branched alkyl, C-Cs cycloalkyl, C-C aryl, C-C aryl-Substituted C-C, 0645 or R'' and R7 taken together form a moiety alkyl, C-C alkoxy, C-C branched alkoxy, C-Cs Selected from the group consisting of -O- and aryloxy, or halo-substituted versions thereof or R'' is halo where halo is chloro, fluoro, bromo, or iodo; 0655 R7 is hydrogen, C-C alkyl or C-C branched alkyl, 0656) R'' is C-C alkyl, C-C aroyl, C-C aryl, C-C heterocyclic alkyl or aryl with O, N or S in the ring, C-C aryl-Substituted C-C alkyl, alkyl-SubSti tuted or aryl-Substituted C-C heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted C-C, aroyl, or alkyl-substituted C-C aryl, or halo-Substi tuted versions thereof where halo is chloro, bromo, or 0646) R' is selected from the group consisting of iodo; hydrogen, OH, -OCOCH, -COCH and (C- C.)alkyl, and 0657 n is 1, 2, 3, or 4; and 0658) X is O, NH, or N-R, where R is C-C, 0647) R'' is selected from the group consisting of or C-C branched alkyl. hydrogen, OH, -OCOCH, -COCH, (C-C)alkyl, 0659 Materials that can serve as a Cox-2 selective inhibi -CONH, and -SOCH; tor of the present invention include pyridaZinone compounds 0648 with the proviso that that are described in U.S. Pat. No. 6,307,047. Such pyridazi none compounds have the formula shown below in formula (0649) if M is a cyclohexyl group, then R7 through XXXVI: R may not all be hydrogen; and 0650 pharmaceutically acceptable salts, esters and pro XXXVI drug forms thereof. R184 N R181 21 nN.1 0651) Esters derived from indolealkanols and novel amides derived from indolealkylamides that are described in U.S. Pat. No. 6,306,890 can serve as Cox-2 selective inhibi R183 N X26 tors of the present invention. Such compounds have the general formula shown below in formula XXXV: R182 0660 or a pharmaceutically acceptable salt, ester, or XXXV O prodrug thereof, wherein: y-Rit 0661 X is selected from the group consisting9. of O, S, (CH)-X -NR', -NOR, and -NNRR, R17 0662) R' is selected from the group consisting of N alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalk R178 enylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, N and heterocyclic alkyl, V R179 0663) R, R, and R are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, US 2004/O147581 A1 Jul. 29, 2004 28

0664) R'' is selected from the group consisting of 0674) Z' is selected from the group consisting of: alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, X28 arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyha loalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, car / \ X27-X190 and boxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenyla lkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, hetero X28 cyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxy iminoalkoxy, -(CH),C(O)R', -(CH), CH(OH)R', -(CH),C(NOR")R', –KS > x-r -(CH), CH(NOR)R, -(CH), CH(NRR)R, R187R18s, -(CH),C=CR', -(CH), [CH(CX)),(CH.) R', —(CH),(CX'), (CH),R, and 0675 X 7 is selected from the group consisting of S(O), -(CH), (CHX)(CH), R: S(O)(NR'), S(O), Se(O), P(O)(OR'), and 0665) R' is selected from the group consisting of P(O)(NR 19R 19); hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, 0676 X is selected from the group consisting of cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, hydrogen, alkenyl, alkyl, alkynyl and halogen; haloalkynyl, heterocyclic, and heterocyclic alkyl, 0677) R' is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbony 0666) R' is selected from the group consisting of lamino, alkynyl, amino, cycloalkenyl, cycloalkyl, alkenylene, alkylene, halo-Substituted alkenylene, and dialkylamino, -NHNH, and -NCHN(R')R'; halo-Substituted alkylene, 0678) R', R', R', and R'' are independently 0667) R' is selected from the group consisting of Selected from the group consisting of hydrogen, alkyl, hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, and cycloalkyl, or R'' and R' can be taken together, with the nitrogen to which they are attached, to form a cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and 3-6 membered ring containing 1 or 2 heteroatoms heterocyclic alkyl, selected from the group consisting of O, S, and NR'; 0668) R' and R are independently selected from the 0679) Y is selected from the group consisting of group consisting of hydrogen, alkenyl, alkyl, alkynyl, - OR 195, - SR 195, C(R197)(R198)R 195, -C(O)R', aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, het -C(O)OR', -N(R7)C(O)R’, -NC(R97)R 19, erocyclic, and heterocyclic alkyl, and -N(R197)R 195; 0680) R' is selected from the group consisting of 0669 X is halogen; hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, 0670 m is an integer from 0-5; cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocy clic alkyl, hydroxyalkyl, and NR'R''; and 0671 n is an integer from 0-10; 0681 R7, R', R', and R'' are independently 0672 p is an integer from 0-10; Selected from the group consisting of hydrogen, alk enyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, ary 0673 R', R', and R'' are independently selected lalkyl, heterocyclic, and heterocyclic alkyl. from the group consisting of hydrogen, alkenyl, 0682 Benzosulphonamide derivatives that are described alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, in U.S. Pat. No. 6,004,948 are useful as Cox-2 selective alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbony inhibitors of the present invention. Such benzosulphonamide lamino, alkylcarbonylaminoalkyl, aminoalkoxy, ami derivatives have the formula shown below in formula XXX noalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, VII: arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbo nyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, XXXVII cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercap toalkoxy, nitro, phosphonatoalkoxy, Y, and Z"; pro vided that one of R'', R', or R' must be Z', and further provided that only one of R', R', or R'' is Z11; US 2004/O147581 A1 Jul. 29, 2004 29

0683 wherein: Such methanesulfonyl-biphenyl derivatives have the for 0684) A' denotes oxygen, sulphur or NH; mula shown below in formula XXXX: 0685) R' denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polySubstituted by halogen, XXXX alkyl, CF or alkoxy; s 2O 0686l D denotes a group of formula XXXVIII or XXXIX:

XXXVIII

XXXIX OR208 OR207

0699 wherein: 0687) R' and R' independently of each other denote hydrogen, an optionally polyfluorinated alkyl 0700 R7 and R' are respectively a hydrogen; radical, an aralkyl, aryl or heteroaryl radical or a radical 0701 C-C-alkyl substituted or not substituted by (CH), X', or halogens, 0688) R' and R' together with the N-atom denote a 0702 C-C-cycloalkyl; three- to Seven-membered, Saturated, partially or totally unsaturated heterocycle with one or more heteroatoms 0703 C-C-alkyl containing 1-3 ether bonds and/or N, O, or S, which may optionally be Substituted by Oxo, an aryl Substitute; an alkyl, alkylaryl or aryl group or a group (CH)- X', R' denotes hydrogen, an optionally polyfluori 0704 Substituted or not substituted phenyl; nated alkyl group, an aralkyl, aryl or heteroaryl group 0705 or substituted or not substituted five or six ring or a group (CH), X', cycled heteroaryl containing more than one hetero atoms Selected from a group consisting of nitrogen, Sulfur, and 0689) wherein: oxygen (wherein phenyl or heteroaryl can be one- or multi 0690 X denotes halogen, NO,--OR',-COR', Substituted by a Substituent Selected from a group consisting -CORO, -OCOR20, -CN, -CONRO'OR205, of hydrogen, methyl, ethyl, and isopropyl). - CONR'R'', SR', S(O)R', S(O).R.", 0706 Cox-2 selective inhibitors such as 1H-indole -NR'R''. -NHC(O)R’9, -NHS(O).R.'; derivatives described in U.S. Pat. No. 6,599,929 are useful 0691) Z' denotes -CH2-, -CH-CH2-, in the present invention. Such 1H-indole derivatives have CH-CH-CH-, CH-CH=CH-, the formula shown below in formula XXXXI: CH=CH-CH-, CH-CO-, CO CH-, -NHCO-, -CONH-, -NHCH-,

CH, NH-, -N=CH-, -NHCH-, -CH XXXXI CH, -NH-, -CH=CH-, >N-R, >C=O, >S(O); 0692) R' and R' independently of each other denote hydrogen, alkyl, aralkyl or aryl; 0693 n is an integer from 0 to 6; 0694) R' is a straight-chained or branched C-C, alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R' denotes CF, and 0695 m denotes an integer from 0 to 2; 0707 wherein: 0696) with the proviso that A' does not represent 0 if 0708 X is -NHSOR' wherein R' represents R° denotes CF; hydrogen or C-C-alkyl, 0697 and the pharmaceutically acceptable salts thereof. 0709) Y” is hydrogen, halogen, C-C-alkylsubstituted or not substituted by halogen, NO, NH, OH, OMe, 0698. Materials that can serve as Cox-2 selective inhibi tors of the present invention include methaneSulfonyl-biphe COH, or CN; and nyl derivatives that are described in U.S. Pat. No. 6,583,321. 0710 Q7 is C=O, C=S, or CH.

US 2004/O147581 A1 Jul. 29, 2004

0743 N-4-3-(difluoromethyl)-6-fluoro-1,5-dihy 0767 N-4-2-(3-chloro-4-fluorophenyl)cyclopenten dro-7-methoxy-2benzothiopyrano.4.3-cpyrazol-1- 1-yl)phenylsulfonyl)acetamide; yl)phenylsulfonyl)acetamide; 0744) N-(4-6-fluoro-1,5-dihydro-7-methoxy-3-(trif O768 4-2-4-f-L2-(4-fluorophenyl)-1H-pyrrol-1-yl)-N-meth henvl)-1H 1-1-vll-N-meth luoromethyl)-2benzothiopyrano.4.3-cpyrazol-1-yl) ylbenzeneSulfonamide, phenylsulfonyl)acetamide; 0769 N-4-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl) 0745) N-4-3-(difluoromethyl)-5-(3-fluoro-4-meth phenylsulfonylpropanamide; oxyphenyl)-1H-pyrazol-1-ylphenylsulfonyl)aceta 0770 N-4-2-(2-methylpyridin-3-yl)-4-trifluorom mide; ethylimidazol-1-yl)phenylsulfonylpropanamide; 0746 N-4-(2-methyl-4-phenyloxazol-5-yl)phenyl Sulfonyl)acetamide; 0771) 4-2-(4-fluorophenyl)cyclopenten-1-yl)-N-me 0747 methyl-4-(5-methyl-3-phenylisoxazol-4- thylbeneZeneSulfonamide, and yl)phenylsulfonyl)aminoloxoacetate; 0772 N-4-(3-phenyl-2,3-dihydro-2-oxofuran-4- 0748 2-methoxy-N-(4-(5-methyl-3-phenylisoxazol yl)phenylsulfonylpropanamide. 4-yl)phenylsulfonyl)acetamide; 0773) Those prodrugs disclosed in U.S. Pat. No. 6,613, 0749 N-4-5-(difluoromethyl)-3-phenylisoxazol-4- 790 have the general formula shown above in formula ylphenylsulfonylpropanamide; XXXXII wherein: 0750 N-4-5-(difluoromethyl)-3-phenylisoxazol-4- ylphenylsulfonylbutanamide; 0774 A' is a pyrazole group optionally substituted at a Substitutable position with one or more radicals 0751 N-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl independently Selected at each occurrence from the Sulfonyl)formamide; group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, OXO, cyano, intro, carboxyl, alkoxy, ami 0752 1,1-dimethylethyl-N-(4-(5-methyl-3-phenyl nocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, isoxazol-4-yl)phenylsulfonylcarbamate; hydroxyalkyl, haloalkylsulonyloxy, alkoxyalkyloxy 0753 N-sup.4-(5-methyl-3-phenylisoxazol-4- alkyl, carboxyalkoxyalkyl, alkenyl, alkynyl, alkylthio, yl)phenylsulfonylglycine; alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl, ami 0754) 2-amino-N-4-(5-methyl-3-phenylisoxazol-4- nocarbonylalkyl, alkylaminocarbonyl, alkylaminocar yl)phenylsulfonyl)acetamide; bonylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkylsulfinyl, alkylsulfonyl, aminoSulfonyl, and alky 0755 2-(acetylamino)-N-4-(5-methyl-3-phenylisox laminoSulfonyl, azol-4-yl)phenylsulfonyl)acetamide; 0756 methyl 4-4-(5-methyl-3-phenylisoxazol-4- 0775) R' is a phenyl group optionally substituted at yl)phenylsulfonyl)amino-4-oxobutanoate; a Substitutable position with one or more radicals independently Selected at each occurrence from the 0757 methyl N-4-(5-methyl-3-phenylisoxazol-4- group consisting of alkyl, haloalkyl, cyano, carboxyl, yl)phenylsulfonylcarbamate; alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, 0758) N-acetyl-N-(4-(5-methyl-3-phenylisoxazol-4- amino, alkylamino, nitro, alkoxyalkyl, alkylsulfinyl, yl)phenylsulfonylglycine, ethyl ester; halo, alkoxy, and alkylthio; 0759 N-4-(5-(4-methylphenyl)-3-(trifluoromethyl)- 0776 R'' and R'' are independently selected from 1H-pyrazol-1-yl)phenylsulfonyl)acetamide; the group consisting of hydroxyalkyl and hydrido but at 0760 methyl 3-4-(5-methyl-3-phenylisoxazol-4- least one of R'' and R' is other than hydrido; and yl)phenylsulfonyl)aminol-3-oxopropanoate; 0777 R’ is selected from the group consisting of 0761 4-5-(3-bromo-5-fluoro-4-methoxyphenyl)-2- hydrido and fluoro. (trifluoromethyl)oxazol-4-yl)-N-methylbenezene 0778 Examples of prodrug compounds disclosed in U.S. Sulfonamide; Pat. No. 6,613,790 that are useful as Cox-2 inhibitors of the 0762, N-(11,1-dimethylethyl)-4-(5-methyl-3-phenyl present invention include, but are not limited to, N-(2- isoxazol-4-yl)benzenesulfonamide; hydroxyethyl)-4-5-(4-methylphenyl)-3-(trifluoromethyl)- 0763 4-5-(4-fluorophenyl)-3-(trifluoromethyl)-1H 1H-pyrazol-1-yl)benzenesulfonamide, N,N-bis(2-hydroxy pyrazol-1-yl)-N-methylbenzenesulfonamide; ethyl)-4-5-(4-methylphenyl)-3-(trifluoromethyl)-1H pyrazol-1-ylbenzenesulfonamide, or pharmaceutically 0764 N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl acceptable Salts thereof. )benezenesulfonamide; 0779 Cox-2 selective inhibitors such as sulfamoylhel 0765 N-4-5-(hydroxymethyl)-3-phenylisoxazol-4- eroaryl pyrazole compounds that are described in U.S. Pat. ylphenylsulfonyl)acetamide: No. 6,583,321 may serve as Cox-2 inhibitors of the present 0766 N-4-5-(acetoxymethyl)-3-phenylisoxazol-4- invention. Such Sulfamoylheleroaryl pyrazole compounds ylphenylsulfonyl)acetamide; have the formula shown below in formula XXXXIII: US 2004/O147581 A1 Jul. 29, 2004 32

XXXXIII XXXXV O HN / O R220 Ns N R221 / M 21 Ng W A14-Y10 N-OH O M N -N O R222 N N CF X S.

R215 XXXXVI R214 R224 O R223 OH O H X32 M V 225 O) ()--si-'l- R

0780 wherein: 0791 Pyrazole Substituted hydroxamic acid derivatives 0781) R' is furyl, thiazolyl or oxazolyl; described in U.S. Pat. No. 6,432,999 have the formula 0782 R is hydrogen, fluoro or ethyl; and shown above in formula XXXXV, wherein: 0792 A' is pyrazolyl optionally substituted with a 0783 X and X’ are independently hydrogen or Substituent Selected from acyl, halo, hydroxyl, lower chloro. alkyl, lower haloalkyl, OXO, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, 0784 Heteroaryl Substituted amidinyl and imidazolyl lower carboxyalkyl, lower cyanoalkyl, and lower compounds such as those described in U.S. Pat. No. 6,555, hydroxyalkyl, 563 are useful as Cox-2 selective inhibitors of the present 0793 Y' is selected from lower alkenylene and lower invention. Such heteroaryl Substituted amidinyl and imida alkynylene; zolyl compounds have the formula shown below in formula 0794) R' is a substituent selected from 5- and XXXXIV: 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl Selected from phenyl, biphenyl and naphthyl, wherein R’ is optionally substituted at XXXXIV a Substitutable position with one or more Substituents R219 Selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower N R218 hydroxyalkyl, lower haloalkoxy, amino, lower alky N1 N lamino, phenylmino, nitro, lower alkoxyalkyl, lower ) -4. R217 alkylsulfinyl, halo, lower alkoxy and lower alkylthio; R216 0795) R’ is selected from lower alkyl and amino; and 0796 R’ is selected from hydrido, lower alkyl, phe nyl, 5- and 6-membered heterocyclo and lower 0785 wherein: cycloalkyl, or a pharmaceutically-acceptable Salt thereof. 0786) Z is O or S, 0797 Pyrazole Substituted hydroxamic acid derivatives 0787 R’ is optionally substituted aryl, described in U.S. Pat. No. 6,432,999 may also have the formula shown above in formula XXXXVI, wherein: 0788) R-7 is aryl optionally substituted with amino 0798 A' is pyrazolyl optionally substituted with a Sulfonyl, and Substituent Selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, OXO, cyano, nitro, carboxyl, 0789 R and R' cooperate to form an optionally lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, Substituted 5-membered ring. lower carboxyalkyl, lower cyanoalkyl, and lower 0790 Materials that can serve as Cox-2 selective inhibi hydroxyalkyl; tors of the present invention include Substituted hydroxamic 0799 Y''' is selected from lower alkylene, lower alk acid derivatives that are described in U.S. Pat. Nos. 6,432, enylene and lower alkynylene; 999, 6.512,121, and 6,515,014. These compounds also act as 0800 R’ is a substituent selected from 5- and inhibitors of the lipoxygenase-5 enzyme. Such Substituted 6-membered heterocyclo, lower cycloalkyl, lower hydroxamic acid derivatives have the general formulas cycloalkenyl and aryl Selected from phenyl, biphenyl shown below in formulas XXXXV and XXXXVI: and naphthyl, wherein R’ is optionally substituted at US 2004/O147581 A1 Jul. 29, 2004 33

a Substitutable position with one or more Substituents lamino, phenylamino, nitto, lower alkoxyalkyl, lower Selected from lower alkyl, lower haloalkyl, cyano, alkylsulfinyl, halo, lower alkoxy and lower alkylthio; carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alky 0814) R' is selected from lower alkyl and amino; and lamino, phenylmino, nitro, lower alkoxyalkyl, lower 0815 R’ is selected from hydrido and alkyl; or a alkylsulfinyl, halo, lower alkoxy and lower alkylthio; pharmaceutically-acceptable Salt thereof. 0801) R' is selected from lower alkyl and amino; and 0816. Thiophene Substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,515,014 have the formula 0802 R’ is selected from hydrido, lower alkyl; shown above in formula XXXXV, wherein: 0803 or a pharmaceutically-acceptable salt thereof. 0817 A' is thienyl optionally substituted with a sub 0804 Heterocyclo substituted hydroxamic acid deriva Stituent Selected from acyl, halo, hydroxy, lower alkyl, tives described in U.S. Pat. No. 6,512,121 have the formula lower haloalkyl, OXO, cyano, nitro, carboxyl, lower shown above in formula XXXXV, wherein: alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower 0805) A' is a ring substiuent selected from oxazolyl, carboxyalkyl, lower cyanoalkyl, and lower hydroxy furyl, pyrrolyl, thiazolyl, imidazolyl, isochiazolyl, alkyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl, 08.18 Y' is ethylene, isopropylene, propylene, buty wherein A' is optionally substituted with a substituent lene, lower alkenylene, and lower alkynylene; Selected from acyl, halo, hydroxy, lower alkyl, lower 0819 R’ is a substituent selected from 5- and haloalkyl, OXO, cyano, nitro, carboxyl, lower alkoxy, 6-membered heterocyclo, lower cycloalkyl, lower aminocarbonyl, lower alkoxycarbonyl, lower carboxy cycloalkenyl and aryl Selected from phenyl, biphenyl alkyl, lower cyanoalkyl, and lower hydroxyalkyl, and naphthyl, wherein R’ is optionally substituted at 0806) Y' is lower alkylene, lower alkenylene, and a Substitutable position with one or more Substituents lower alkynylene; Selected from lower alkyl, lower haloalkyl, cyano, 0807 R’ is a substituent selected from 5- and carboxyl, lower alkoxycarbonyl, hydroxyl, lower 6-membered heterocyclo, lower cycloalkyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alky cycloalkenyl and aryl Selected from phenyl, biphenyl lamino, phenylamino, nitro, lower alkoxyalkyl, lower and naphthyl, wherein R’ is otionallv Substituted at a alkylsulfinyl, halo, lower alkoxy and lower alkylthio; Substitutable position with one or more substituents 0820) R’ is selected from lower alkyl and amino; and Selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower 0821 R’ is selected from hydrido, lower alkyl, phe hydroxyalkyl, lower haloalkoxy, amino, lower alky nyl, 5- and 6-membered heterocyclo and lower lamino, phenylamino, nitro, lower alkoxyalkyl, lower cycloalkyl, or a pharmaceutically-acceptable Salt alkylsulfinyl, halo, lower alkoxy and lower alkylthio; thereof. 0822. Thiophene Substituted hydroxamic acid derivatives 0808 R’ is selected from lower alkyl and amino; and described in U.S. Pat. No. 6,515,014 may also have the 0809 R’ is selected from hydrido, lower alkyl, phe formula shown above in formula XXXXV, wherein: nyl, 5- and 6-membered heterocyclo and lower 0823) A' is thienyl optionally substituted with a sub cycloalkyl, or a pharmaceutically-acceptable Salt Stituent Selected from acyl, halo, hydroxy, lower alkyl, thereof. lower haloalkyl, OXO, cyano, nitro, carboxyl, lower 0810 Heterocyclo substituted hydroxamic acid deriva alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower tives described in U.S. Pat. No. 6,512,121 may also have the carboxyalkyl, lower cyanoalkyl, and lower hydroxy formula shown above in formula XXXXVI, wherein: alkyl, 0811) A' is a ring substituent selected from oxazolyl, 0824) Y''' is selected from lower alkyl, lower alkenyl furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isox and lower alkynyl, azolyl, cyclopentenyl, phenyl, and pyridyl, wherein A 0825 R’ is a substituent selected from 5- and is optionally substituted with a substituent selected 6-membered heterocyclo, lower cycloalkyl, lower from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, cycloalkenyl and aryl Selected from phenyl, biphenyl OXO, cyano, nitro, carboxyl, lower alkoxy, aminocar and naphthyl, wherein R’ is optionally substituted at bonyl, lower alkoxycarboryl, lower carboxyalkyl, a Substitutable position with one or more Substituents lower cyanoalkyl, and lower hydroxyalkyl, Selected from lower alkyl, lower haloalkyl, cyano, 08.12) Y''' is selected from lower alkyl, lower alkenyl carboxyl, lower alkoxycarbonyl, hydroxyl, lower and lower alkynyl, hydroxyalkyl, lower haloalkoxy, amino, lower alky lamino, phenylamino, nitro, lower alkoxyalkyl, lower 0813 R’ is a substituent selected from 5- and alkylsulfinyl, halo, lower alkoxy and lower alkylthio; 6-membered heterocyclo, lower cycloalkyl, lower cycloalkenyl and aryl Selected from phenyl, biphenyl 0826) R' is selected from lower alkyl and amino; and and naphthyl, wherein R’ is optionally substituted at a Substitutable position with one or more Substituents 0827 R’ is selected from hydrido and alkyl; or a Selected from lower alkyl, lower haloalkyl, cyano, pharmaceutically-acceptable Salt thereof. carboxyl, lower alkoxycarbonyl, hydroxyl, lower 0828 Compounds that are useful as Cox-2 selective hydroxyalkyl, lower haloalkoxy, amino, lower alky inhibitors of the present invention include pyrazolopyridine US 2004/O147581 A1 Jul. 29, 2004 34 compounds that are described in U.S. Pat. No. 6,498,166. cals; and R represents a substituted or non-substi Such pyrazolopyridine compounds have the formula shown tuted aromatic group of 5 to 10 atoms, below in formula XXXXVII: 0840 or a pharmaceutically-acceptable salt thereof. 0841 Cox-2 selective inhibitors that can be used in the XXXXVII present invention include 2-phenyl-1,2-benzisoSelenazol R229 3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl Ssa derivatives that are described in U.S. Pat. No. 6,492,416. Such 2-phenyl-1,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbomyl-phenylselenyl derivatives have the formulas shown below in formulas XXXXIX or XXXXIX:

XXXXIX O R238 W R237

S. R235 o 0829 wherein: SáSa Se C R239 0830) R' and R-7 are independently selected from R236 the group consisting of H, halogen, C-C alkyl, C-C, XXXXIX alkoxy, and C-C alkoxy Substituted by one or more O fluorine atoms, R238 W R237 0831) R' is halogen, CN, CONR'R'', COH, COC-C, alkyl or NHSO.R.", Sa R235-( o ) SáSa Se 0832 R’ is C-C alkyl or NH; and R239 0833 R’ and R’ are independently selected from 2 the group consisting of H, C-C alkyl, phenyl, phenyl Substituted by one or more atoms or groupS. Selected 0842 wherein: from the group consisting of halogen, C-C alkyl, 0843 R’ is a hydrogen atom or an alkyl group having C-C alkoxy, and C-C alkoxy substituted by one or 1-3 carbon atoms, more fluorine atoms, 0844 R is a hydrogen atom, a hydroxyl group, an 0834 or a pharmaceutically acceptable salt, Solvate, organothiol group that is bound to the Selenium atom by ester, or Salt or Solvate of Such ester thereof. its sulfur atom, or R' and R’ are joined to each other by a single bond; 0835 Materials that are useful as Cox-2 selective inhibi tors of the present invention include 4.5-diaryl-3(2H)-fura 0845 R7 is a hydrogen atom, a halogen atom, an none derivatives that are described in U.S. Pat. No. 6,492, alkyl group having 1-3 carbon atoms, an alkoxyl group 416. Such 4,5-diaryl-3(2H)-furanone derivatives have the having 1-3 carbon atoms, a trifluoromethyl group, or a formula shown below in formula XXXXVIII: nitro group; 0846 R and R'' are identical to or different from each other, and each is a hydrogen atom, a halogen

XXXXVIII atom, an alkoxyl group having 1-4 carbon atoms, a trifluoromethyl group, or R and R' are joined to each other to form a methylenedioxy group, 0847) a Salt thereof, or a hydrate thereof. 0848 Pyrones such as those disclosed in U.S. Pat. No. 6,465,509 are also useful as Cox-2 inhibitors of the present invention. These pyrone compounds have the general for mula shown below in formula XXXXX:

R233 R234 XXXXX SOR241 0836 wherein: 0837 X represents halo, hydrido, or alkyl; 0838 Y' represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)-sulfonyl, (N-alkylamino )sulfonyl, or alkylthio; (0839), Z7 represents oxygen or sulfur atom; R’ and R are selected independently from lower alkyl radi US 2004/O147581 A1 Jul. 29, 2004 35

0849 wherein: 0874) 6-Fluoromethyl-4-(4-methylsulfonyl)phenyl-3- 0850 X" is selected from the group consisting of: phenyl-pyran-2-one, 0851 (a) a bond, 0875 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phe nylthio-pyran-2-one, 0852 (b) -(CH), , wherein m 1 or 2, 0876 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phe 0853) (c) –C(O)—, noxy-pyran-2-one, 0854) (d) -O-, 0877 6-Methyl-4-(4-methylsulfonyl)phenyl-3-pyri 0855 (e) -S-, and din-3-yl-pyran-2-one, 0856) (f) -N(R')–: 0878 3-Isopropylthio-6-methyl-4-(4-methylsulfo 0857) R' is selected from the group consisting of: nyl)phenyl-pyran-2-one, 0858 (a) C-Co alkyl, optionally substituted with 1-3 Substituents independently Selected from the group 0879 4-(4-Methylsulfonyl)phenyl)-3-phenylthio-6- consisting of hydroxy, halo, C-Co alkoxy, C-Co trifluoromethyl-pyran-2-one, alkylthio, and CN, 0880 3-Isopropylthio-4-(4-methylsulfonyl)phenyl-6- 0859) (b) phenyl or naphthyl, and trifluoromethyl-pyran-2-one, 0860) (c) heteroaryl, which is comprised of a mono 0881 4-(4-Methylsulfonyl)phenyl-3-phenyl-6-(2,2,2- cyclic aromatic ring of 5 atoms having one hetero atom trifluoroethyl)-pyran-2-one, and which is S, O or N, and optionally 1, 2, or 3 additional N atoms; or 0882 3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4- 0861 a monocyclic ring of 6 atoms having one hetero methylsulfonyl)phenyl-pyran-2-one. atom which is N, and optionally 1, 2, or 3 additional N 0883 Organically synthesized or purified from plant atoms, wherein groups (b) and (c) above are each Sources, free-B-ring flavanoids Such as those described in optionally substituted with 1-3 substituents indepen U.S. Published Application No. 2003/0165588, are useful as dently Selected from the group consisting of halo, Cox-2 Selective inhibitors of the present invention. Such C-Clo alkoxy, C-Clo alkylthio, CN, C-Clo alkyl, free-B-ring flavanoids have the general Structure shown in optionally Substituted to its maximum with halo, and formula XXXXXI: N; 0862) R" is selected from the group consisting of

XXXXXI 0863 (a) C-C alkyl, optionally substituted to its maximum with halo, 0864 (b) NH, and 0865 (c) NHC(O)C-Co alkyl, optionally substituted to its maximum with halo, 08661 R'' and R' are eachh indindependently dentlv SelecteSelected from the group consisting of hydrogen, halo, and C-C alkyl, optionally substituted to its maximum with halo, and 0884 wherein: 0867) R' is selected from the group consisting of: hydrogen and C-C alkyl, optionally Substituted to its 0885) R', R'7, R", R', and R are indepen maximum with halo. dently Selected from the group consisting of: -H, OH, -SH, OR, -SR, -NH, -NHR', 0868 Examples of pyrone compounds that are useful as -N(R'), -N(R')"X, a carbon, oxygen, nitro Cox-2 selective inhibitors of the present invention include, gen or Sulfur, glycoside of a single or a combination of but are not limited to: multiple Sugars including, aldopentoses, methyl-aldo 0869) 4-(4-Methylsulfonyl)phenyl-3-phenyl-pyran-2- pentose, aldohexoses, ketohexose and their chemical One, derivatives thereof; wherein R' is an alkyl group 0870 3-(4-Fluorophenyl)-6-methyl-4-(4-methylsulfo having between 1-10 carbon atoms; and X is selected nyl)phenyl-pyran-2-one, from the group of pharmaceutically acceptable counter anions including, hydroxyl, chloride, iodide, Sulfate, 0871 3-(3-Fluorophenyl)-6-methyl-4-(4-methylsulfo phosphate, acetate, fluoride and carbonate. nyl)phenyl-pyran-2-one, 0886 Heterocyclo-alkylsulfonyl pyrazoles such as those 0872 6-Methyl-4-(4-methylsulfonyl)phenyl-3-phe described in European Patent Application No. EP 1312367 nyl-pyran-2-one, are useful as Cox-2 selective inhibitors of the present 0873 6-Difluoromethyl-4-(4-methylsulfonyl)phenyl invention. Such heterocyclo-alkylsulfonyl pyrazoles have 3-phenyl-pyran-2-one, the general formula shown below in formula XXXXXII:

US 2004/O147581 A1 Jul. 29, 2004 37

SO- and (C-C)alkyl optionally substituted with 0901) R' represents a methyl, hydroxymethyl, one to fourfluoro moieties, alkoxymethyl, C-C7 cycloalkoxymethyl, benzyloxym ethyl, hydroxycarbonyl, nitrile, trifluoromethyl or dif 0894 wherein said saturated (3- to 4-membered)- luoromethyl group or a CH-R' group wherein R' heterocyclyl ring radical; or said Saturated, partially represents an alkyl group; and Saturated or aromatic (7- to 9-membered)-heterocy clyl ring radical; may also optionally be Substituted 0902 X represents a single bond, an oxygen atom, a on any ring nitrogen atom by one to three Substitu Sulfur atom or a methylene group; ents per ring independently Selected from the group consisting of (C-C)cyoloalkyl, (C-C)aryl, (C- 0903 or a pharmaceutically acceptable salt thereof. Co)heterocyclyl, H-(C=O) , (C-C)alkyl 0904 Examples of 2-phenylpyran-4-one derivatives use (C=O) , (C-C)alkyl-O-(C=O)-, H.N- ful in the present invention include, but are not limited to: (C=O) , (C-C)alkyl-NH-(C=O) , (C- 0905 3-(4-fluorophenyl)-2-(4-methanesulfonylphe C.)alkyl-N-(C=O) , (C-C)aryl-NH nyl)-6-methylpyran-4-one, (C=O)-, (C-C)alkyl-((C-Co)aryl)-N- (C=O) , (C-C)alkyl-O-NH-(C=O) , and 0906 3-(2-fluorophenyl)-2-(4-methanesulfonylphe (C-C)alkyl optionally substituted with one to four nyl)-6-methylpyran-4-one, fluoro moieties, 0907 3-(4-chlorophenyl)-2-(4-methanesulfonylphe 0895) R' is an (C-C)alkyl radical optionally sub nyl)-6-methylpyran-4-one, stituted by one to four fluoro Substituents; and 0908 3-(4-bromophenyl)-2-(4-methylsulfonylphe nyl)-6-methylpyran-4-one, 0896) R255 is a radical Selected from the group con sisting of H, halo, -OH, (C-C)alkyl-O-, (C- 0909) 3-(2,4-difluorophenyl)-2-(4-methanesulfo C.)alkenyl, (C-C)alkynyl, (C-C7)cycloalkyl, -CN, nylphenyl)-6-methylpyran-4-one, H-(C=O) , (C-C)alkyl-(C=O) , (C-C)alkyl (C=O)-O-, HO-(C=O) , (C-C)alkyl-O- 0910 3-(3,4-dichlorophenyl)-2-(4-methanesulfo (C=O) , (C-C)alkyl-NH-. (C-C)alkyl)-N-, nylphenyl)-6-methylpyran-4-one, (C-C)cycloalkyl-NH-, (C-C)aryl-NH-, (C- 0911 3-(3-chloro-4-methylphenyl)-2-(4-methane C.)alkyl-((Co-Co)aryl)-NH., (C-C)heteroaryl Sulfonylphenyl)-6-methylpyran-4-one, NH-, HN-(C=O) , (C-C)alkyl-NH (C=O)-. (C-C)alkyl-N-(C=O) , (C- 0912 2-(4-methanesulfonylphenyl)-6-methyl-3-phe Co)aryl-(C=O)-, (C-C)alkyl-((C-C)aryl)- noxypyran-4-one, N-(C=O) , (C-C)alkyl-O-NH-(C=O) , (C- 0913 3-(4-fluorophenoxy)-2-(4-methanesulfonylphe C.)alkyl-S-, and (C-C)alkyl optionally Substituted nyl)-6-methylpyran-4-one, by one to four fluoro Substituents. 0914) 3-(2-fluorophenoxy)-2-(methanesulfonylphe 0897 2-phenylpyran-4-one derivatives such as those nyl)-6-methylpyran-4-one, described in U.S. Pat. No. 6,518,303 are also useful as Cox-2 0915. 3-(4-chlorophenoxy)-2-(methanesulfonylphe selective inhibitors of the present invention. Such 2-phe nyl)-6-methylpyran-4-one, nylpyran-4-one derivatives have the general formula shown 0916 3-(2-chlorophenoxy)-2-(methanesulfonylphe below in formula XXXXXIII: nyl)-6-methylpyran-4-one, 0917 3-(4-bromophenoxy)-2-(4-methanesulfonylphe XXXXXIII nyl)-6-methylpyran-4-one, 0918 2-(4-methanesulfonylphenyl)-6-methyl-3-(4- methylphenoxy)pyran-4-one, 0919 3-(2,4-difluorophenoxy)-2-(4-methanesulfo nylphenyl)-6-methylpyran-4-one, 0920 3-(2,5-difluorophenoxy)-2-(methanesulfo nylphenyl)-6-methylpyran-4-one, 0921] 3-(4-chlorophenyl)-2-(4-methanesulfonylphe 0898 wherein: nyl)-6-methoxymethylpyran-4-one, 0899) R' represents an alkyl or -NR'R' group, 0922 3-(4-chlorophenyl)-6-difluoromethyl-2-(4- wherein R and R' each independently represents a methaneSulfonylphenyl)pyran-4-one, hydrogen atom or an alkyl group; 0923) and pharmaceutically acceptable Salts thereof. 0900 R7 represents an alkyl, C-C, cycloalkyl, naph 0924 Cox-2 selective inhibitors that are useful in the thyl, tetrahydronaphthyl or indanyl group, or a phenyl Subject method and compositions can include the com group which may be unsubstituted or Substituted by one pounds that are described in U.S. Pat. No. 6,472,416 (sul or more halogen atoms or alkyl, trifluoromethyl, fonylphenylpyrazoles); U.S. Pat. No. 6,451,794 (2,3-diaryl hydroxy, alkoxy, methylthio, amino, mono- or dialky pyrazolo 1,5-b]pyridazines); U.S. Pat. Nos. 6,169,188, lamino, hydroxyalkyl or hydroxycarbonyl groups; 6,020,343, and 5,981,576 ((methylsulfonyl)phenyl fura

US 2004/O147581 A1 Jul. 29, 2004 41

1076 p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1- 1101 r7) 2-methyl-5-1-4-(methylsulfonyl)phenyl benzopyran-3-carboxylic acid; 4-trifluoromethyl-1H-imidazol-2-ylpyridine; 1077 p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H 1102 r8) 4-2-(5-methylpyridin-3-yl)-4-(trifluorom 1-benzopyran-3-carboxylic acid; ethyl)-1H-imidazol-1-yl)benzenesulfonamide; 1078) p4) 6-(phenylmethyl)aminosulfonyl-2-trif 1103 r9) 4-5-methyl-3-phenylisoxazol-4-ylbenzene luoromethyl-2H-1-benzopyran-3-carboxylic acid; Sulfonamide; 1079 p5) 6-(dimethylamino)sulfonyl-2-trifluorom 1104) r10) 4-5-hydroxymethyl-3-phenylisoxazol-4- ethyl-2H-1-benzopyran-3-carboxylic acid; ylbenzenesulfonamide; 1080 pé) 6-(methylamino)sulfonyl-2-trifluorom 1105 s1) 2-trifluoromethyl-5-(3,4-difluorophenyl)-4- ethyl-2H-1-benzopyran-3-carboxylic acid; Oxazolylbenzenesulfonamide; 1081 p7) 6-(4-morpholino)sulfonyl-2-trifluorom ethyl-2H-1-benzopyran-3-carboxylic acid; 1106 s2) 4-2-methyl-4-phenyl-5-oxazolylbenzene Sulfonamide; or 1082 p8) 6-(1,1-dimethylethyl)aminosulfonyl-2-trif luoromethyl-2H-1-benzopyran-3-carboxylic acid; 1107 s3) 4-5-(3-fluoro-4-methoxyphenyl-2-trifluo romethyl)-4-oxazolylbenzenesulfonamide; 1083 p9) 6-(2-methylpropyl)aminosulfonyl-2-trif luoromethyl-2H-1-benzopyran-3-carboxylic acid; 1108 or a pharmaceutically acceptable Salt or prodrug 1084) p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1- thereof. benzopyran-3-carboxylic acid; 1109] Cox-2 inhibitors that are useful in the methods and compositions of present invention can be Supplied by any 1085 q1) 8-chloro-6-(phenylmethyl)aminosulfo Source as long as the Cox-2 inhibitor is pharmaceutically nyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acceptable. Likewise, Cox-2 inhibitors that are useful in the acid; compositions and methods of present invention can by 1086 q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-ben Synthesized, for example, according to the description in Zopyran-3-carboxylic acid; Example 1. Several Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention 1087 q3) 6,8-dibromo-2-trifluoromethyl-2H-1-ben may be synthesized by the methods described in, for Zopyran-3-carboxylic acid; example, U.S. Pat. No. 5,466,823 to Talley, et al. Cox-2 1088 q4) 8-chloro-5,6-dimethyl-2-trifluoromethyl inhibitors can also be isolated and purified from natural 2H-1-benzopyran-3-carboxylic acid; Sources. Cox-2 inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical 1089) q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1- products. benzopyran-3-carboxylic acid; 1110 Preferred Cox-2 selective inhibitor compounds are 1090 q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1- those compounds Selected from the group consisting of benzopyran-3-carboxylic acid; celecoxib, parecoxib, deracoxib, Valdecoxib, etoricoxib, 1091 q7) 6-N-(2-furylmethyl)aminosulfonyl-2-tri meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, fluoromethyl-2H-1-benzopyran-3-carboxylic acid; BMS-347070 (Bristol Meyers Squibb, described in U.S. Pat. No. 6,180,651), JTE-522 (Japan Tabacco), S-2474 1092 q8) 6-N-(2-phenylethyl)aminosulfonyl-2-tri (Shionogi), SVT-2016, CT-3 (Atlantic Pharmaceutical), fluoromethyl-2H-1-benzopyran-3-carboxylic acid; ABT-963 (Abbott), SC-58125 (GD Searle), nimeSulide, flo 1093 q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran sulide, NS-398 (Taisho Pharmaceutical), L-745337 (Merck), 3-carboxylic acid; RWJ-63556, L-784512 (Merck), darbufelone (Pfizer), CS-502 (Sankyo), LAS-34475 (Almirall Prodesfarma), 1094) q10) 7-(1,1-dimethylethyl)-2-pentafluoroethyl LAS-34555 (Almirall Prodesfarma), S-33516 (Servier), 2H-1-benzopyran-3-carboxylic acid; SD-8381 (Pharmacia, described in U.S. Pat. No. 6,0340256), MK-966 (Merck), L-783003 (Merck), T-614 1095 r1) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-me (Toyama), D-1376 (Chiroscience), L-748731 (Merck), thyl-Sulphonyl-2(5H)-fluranone; CGP-28238 (Novartis), BF-389 (Biofor/Scherer), 1096 r2) 6-chloro-2-trifluoromethyl-2H-1-benzothi GR-253035 (GlaxoWellcome), prodrugs of any of them, opyran-3-carboxylic acid; and mixtures thereof. 1097 r3) 4-5-(4-chlorophenyl)-3-(trifluoromethyl)- 1111) More preferred is that the Cox-2 selective inhibitor 1H-pyrazol-1-ylbenzenesulfonamide; is Selected from the group consisting of celecoxib, pare coxib, deracoxib, Valdecoxib, lumiracoxib, etoricoxib, rofe 1098 r4) 4-5-(4-methylphenyl)-3-(trifluoromethyl)- coxib, prodrugs of any of them, and mixtures thereof. 1H-pyrazol-1-ylbenzenesulfonamide; 1112) Even more preferred still is that the Cox-2 selective 1099] ris) 4-5-(3-fluoro-4-methoxyphenyl)-3-(difluo inhibitor is celecoxib. romethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 1113 Various classes of Cox-2 inhibitors useful in the 1100 ré) 3-1-4-(methylsulfonyl)phenyl-4-trifluo present invention can be prepared as follows. Pyrazoles can romethyl-1H-imidazol-2-ylpyridine; be prepared by methods described in WO95/15316. Pyra US 2004/O147581 A1 Jul. 29, 2004 42

Zoles can further be prepared by methods described in WO 1129. The parecoxib used in the compositions and meth 95/15315. Pyrazoles can also be prepared by methods ods of the present invention can be prepared in the manner described in WO 96/03385. set forth in U.S. Pat. No. 5,932,598. 1114) Thiophene analogs useful in the present invention 1130 The rofecoxib used in the compositions and meth can be prepared by methods described in WO95/00501. ods of the present invention can be prepared in the manner Preparation of thiophene analogs is also described in WO set forth in U.S. Pat. No. 5,474,995. 94/15932. 1131 The deracoxib used in the compositions and meth 1115 Oxazoles useful in the present invention can be ods of the present invention can be prepared in the manner prepared by the methods described in WO95/00501. Prepa set forth in U.S. Pat. No. 5,521,207. ration of oxazoles is also described in WO 94/27980. 1132) The etoricoxib used in the compositions and meth 1116 Isoxazoles useful in the present invention can be ods of the present invention can be prepared in the manner prepared by the methods described in WO 96/25405. Set forth in WO 98/O3484. 1117 Imidazoles useful in the present invention can be 1133. The meloxicam used in the compositions and meth prepared by the methods described in WO 96/03388. Prepa ods of the present invention can be prepared in the manner ration of imidazoles is also described in WO 96/03387. set forth in U.S. Pat. No. 4,233,299. 1118 Cyclopentene Cox-2 inhibitors useful in the present 1134) The compound 4-(4-cyclohexyl-2-methyloxazol-5- invention can be prepared by the methods described in U.S. yl)-2-fluorobenzenesulfonamide used in the compositions Pat. No. 5,344,991. Preparation of cyclopentene Cox-2 and methods of the present invention can be prepared in the inhibitors is also described in WO95/00501. manner set forth in U.S. Pat. No. 5,994,381. 1119 Terphenyl compounds useful in the present inven 1135 The compound 2-(3,4-difluorophenyl)-4-(3-hy tion can be prepared by the methods described in WO droxy-3-methylbutoxy)-5-4-(methylsulfonyl)phenyl 96/16934. 3(2H)-pyridazinone used in the compositions and methods 1120) Thiazole compounds useful in the present inven of the present invention can be prepared in the manner Set tion can be prepared by the methods described in WO forth in WOOO/24719. 96/03,392. 1136 The compound 2-(3,5-difluorophenyl)-3-4-(meth 1121 Pyridine compounds useful in the present invention ylsulfonyl)phenyl-2-cyclopenten-1-one used in the compo can be prepared by the methods described in WO96/03392. Sitions and methods of the present invention can be prepared Preparation of pyridine compounds is also described in WO in the manner set forth in EP 863 134. 96/24,585. 1137) The compound 2-(2-chloro-6-fluoropheny 1122 Benzopyranopyrazolyl compounds useful in the l)amino-5-methyl-benzeneacetic acid used in the composi present invention can be prepared by the methods described tions and methods of the present invention can be prepared in WO 96/09304. in the manner set forth in WO 99/11605. 1123 Chromene compounds useful in the present inven 1138) The compound N-(2-(cyclohexyloxy)-4-nitrophe tion can be prepared by the methods described in WO nylmethaneSulfonamide used in the compositions and 98/47890. Preparation of chromene compounds is also methods of the present invention can be prepared in the described in WO 00/23433. Chromene compounds can manner set forth in U.S. Pat. No. 4,885,367. further be prepared by the methods described in U.S. Pat. No. 6,077,850. Preparation of chromene compounds is fur 1139 The compound (3Z)-3-(4-chlorophenyl)-4-(meth ther described in U.S. Pat. No. 6,034,256. ylsulfonyl)phenyl)methylenedihydro-2(3H)-furanone used in the compositions and methods of the present invention 1124) Arylpyridazinones useful in the present invention can be prepared in the manner set forth in U.S. Pat. No. can be prepared by the methods described in WO 00/24719. 6,180,651. Preparation of arylpyridazinones is also described in WO 99/10332. Arylpyridazinones can further be prepared by the 1140 Another element of the present invention is a methods described in WO 99/10331. 5-HT, receptor modulator. The expression "5-HT1A recep tor” refers to the 5-hydroxytryptamine receptor, which is 1125 5-Alkyl-2-arylaminophenylacetic acids and deriva pharmacologically characterized by its high affinity for tives useful in the present invention can be prepared by the 5-hydroxytryptamine (5-HT, serotonin). The expression methods described in WO 99/11605. “5-HT, receptor" refers to proteins having amino acid Sequences which are Substantially similar to native mam 1126 Diarylmethylidenefuran derivative Cox-2 selective malian 5-hydroxytryptamine A receptors O inhibitors useful in the present invention can be prepared by 5-hydroxytryptamine, amino acid sequences, and which are the methods described in U.S. Pat. No. 6,180,651. capable of binding 5-hydroxytryptamine molecules and 1127. The celecoxib used in the compositions and meth inhibiting 5-hydroxytyryptamine from binding to the ods of the present invention can be prepared in the manner 5-hydroxytryptamine, receptor. The human 5-HT1A recep set forth in U.S. Pat. No. 5,466,823. tor is located on chromosome 5q11.2-q13 and has 422 amino acids. 1128) The Valdecoxib used in the compositions and meth ods of the present invention can be prepared in the manner 1141. The expression “5-HT1A receptor modulator” set forth in U.S. Pat. No. 5,633,272. refers to a compound that binds to the 5-HT1A receptor and US 2004/O147581 A1 Jul. 29, 2004 43 modulates its activity, with, for example, agonist, reverse 1142 The structures of some examples of preferred agonist, antagonist or mixed effects. 5-HT, receptor modulators are listed in Table No. 3 below.

TABLE 3

Examples of 5-HT, Receptor Modulators

Compound Number Structure

H1 N O

H2 Nur N Cl

O

1. O

H3 C )

O

O O r N Sé N 1N1N1 Nu

O

H4

C N)

OHCI US 2004/O147581 A1 Jul. 29, 2004 44

TABLE 3-continued

Examples of 5-HT, Receptor Modulators

Compound Number Structure HS Cl

l NH

O

H6 No -> O wN-1S-1a

O O

H7 O

HS NN Cl O

H10 F US 2004/O147581 A1 Jul. 29, 2004 45

TABLE 3-continued

Examples of 5-HT, Receptor Modulators

Compound Number Structure H11 -- N21 O N Null O

H12

H13

H14 N21O

H15 N21O

Cl US 2004/O147581 A1 Jul. 29, 2004 46

TABLE 3-continued Examples of 5-HT, a Receptor Modulators Compound Number Structure H16 21

NN-1a 1. NN-- O

H18

H19 F

H2O O 'Ya N 21 NN H N

H22 21 NN US 2004/O147581 A1 Jul. 29, 2004 47

TABLE 3-continued Examples of 5-HT, a Receptor Modulators Compound Number Structure

H23 N21

ls N N

N 1N1\-1 Nu

H24 H N

r N CN

HN O OHCI

O

H26

H27 Cl N O

1143) The names, CAS registry numbers and references for examples of preferred 5-HT1A receptor modulators are listed in Table 4, below.

TABLE 4 Examples of preferred 5-HT, Receptor Modulator Names, CAS Registry Numbers and References Compound CAS Registry Number Name(s) Number Reference

H1 (R)-N-(1,3-benzodioxol-5- 151227-58-6 JPO7109281 ylmethyl)-1,2,3,4-tetrahydro

US 2004/O147581 A1 Jul. 29, 2004 50

TABLE 4-continued Examples of preferred 5-HT, Receptor Modulator Names, CAS Registry Numbers and References Compound CAS Registry Number Name(s) Number Reference butyl-8-azaspiro 4.5 decane-7,9-dione (S 23751) H77 SDZ 216-525 141533-35-9 HF8 SEP 109235 H79 SR 59026 HSO Sunepitron 131744-27-9 HS1 UH3O1 127126-21-0 1353O8-68-8 187593-75-5 HS2 WAY 1 OO135 133O25-23-7 HS3 WAY 100802 HS4 Zalospirone GBO2181731

1144. Also useful as a 5-HT, receptor modulator in the made from the ions of aluminum, calcium, lithium, magne present invention is (3-chloro-4-fluoro-phenyl)-4-fluoro sium, potassium, Sodium and Zinc. Preferred organic Salts 4-(5-methyl-pyridin-2-ylmethyl)amino-methyl)piperi can be made from tertiary amines and quaternary ammo din-1-yl)-methadone (F 13640), as described in Colpaert, F. nium Salts, including in part, trimethylamine, diethylamine, C. et al, Neuropharmacology, 43:945-958 (2002). N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl 1145 Especially preferred 5-HT1A receptor modulators glucamine) and procaine. All of the above Salts can be for the present invention include buspirone, gepirone, repi prepared by those skilled in the art by conventional means notan, tandoSpirone, Xaliproden and Ziprasidone. from the corresponding compound of the present invention. 1146 The compounds useful in the present invention 1150 Also included in the methods, combinations and optiontionally can have no asymmetric carbon atoms, or, compositions of the present invention are the prodrugs of the alternatively, the useful compounds can have one or more described compounds and the pharmaceutically-acceptable asymmetric carbon atoms. When the useful compounds have Salts thereof. The term “prodrug” refers to drug precursor one or more asymmetric carbon atoms, they therefore compounds which, following administration to a Subject and include racemates and Stereoisomers, Such as diastereomers Subsequent absorption, are converted to an active Species in and enantiomers, in both pure form and in admixture. Such Vivo Via Some process, Such as a metabolic process. Other Stereoisomers can be prepared using conventional tech products from the conversion proceSS are easily disposed of niques, either by reacting enantiomeric Starting materials, or by the body. More preferred prodrugs produce products from by Separating isomers of compounds of the present inven the conversion process that are generally accepted as Safe. A tion. nonlimiting example of a “prodrug” that will be useful in the 1147 ISomers may include geometric isomers, for methods, combinations and compositions of the present example cis-isomers or trans-isomers acroSS a double bond. invention is parecoxib (N-4-(5-methyl-3-phenyl-4-isox All Such isomers are contemplated among the compounds azolyl)phenylsulfonylpropanamide), which is a prodrug useful in the present invention. for Valdecoxib. 1148 Also included in the methods, combinations and 1151. The methods and combinations of the present compositions of the present invention are the isomeric forms invention are useful for the treatment or prevention of pain, and tautomers of the described compounds and the pharma inflammation, or inflammation-related disorder. In a pre ceutically-acceptable Salts thereof. Illustrative pharmaceuti ferred embodiment, the Subject is one that is in need of cally acceptable Salts are prepared from formic, acetic, treatment or prevention of pain, inflammation, or an inflam propionic, Succinic, glycolic, gluconic, lactic, malic, tartaric, mation-related disorder. citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspar 1152 The methods and combinations of the present tic, glutamic, benzoic, anthranilic, meSylic, Stearic, Salicylic, invention are also useful for the treatment or prevention of p-hydroxybenzoic, phenylacetic, mandelic, embonic neurologic disease involving neurodegeneration.

(pamoic), methaneSulfonic, ethaneSulfonic, benzene 66 Sulfonic, pantothenic, toluenesulfonic, 2-hydroxyethane 1153) The phrase “combination therapy” (or “co Sulfonic, Sulfanilic, cyclohexylaminosulfonic, algenic, b-hy therapy') embraces the administration of a Cox-2 inhibitor droxybutyric, galactaric and galacturonic acids. and a 5-HT1A receptor modulator as part of a specific treatment regimen intended to provide a beneficial effect 1149 Suitable pharmaceutically-acceptable base addition from the co-action of these therapeutic agents. The benefi Salts of compounds of the present invention include metallic cial effect of the combination includes, but is not limited to, ion Salts and organic ion Salts. More preferred metallic ion pharmacokinetic or pharmacodynamic co-action resulting Salts include, but are not limited to appropriate alkali metal from the combination of therapeutic agents. Administration (group Ia) Salts, alkaline earth metal (group IIa) Salts and of these therapeutic agents in combination typically is other physiological acceptable metal ions. Such Salts can be carried out over a defined time period (usually minutes, US 2004/O147581 A1 Jul. 29, 2004 hours, days or weeks depending upon the combination 1157. The term “comprising” means “including the fol Selected). “Combination therapy” generally is not intended lowing elements but not excluding others.” to encompass the administration of two or more of these therapeutic agents as part of Separate monotherapy regimens 1158 Combinations and Methods: that incidentally and arbitrarily result in the combinations of 1159 Among its several embodiments, the present inven the present invention. “Combination therapy” is intended to tion provides a composition comprising Cox-2 inhibitor and embrace administration of these therapeutic agents in a a 5-HT1A receptor modulator. It is preferred that the com Sequential manner, that is, wherein each therapeutic agent is position provides an amount of the Cox-2 inhibitor and an administered at a different time, as well as administration of amount of the 5-HT, receptor modulator wherein the these therapeutic agents, or at least two of the therapeutic amount of the Cox-2 inhibitor and the amount of the 5-HTA agents, in a Substantially simultaneous manner. Substantially receptor modulator together comprise a therapeutically Simultaneous administration can be accomplished, for effective amount for the treatment or prevention of pain, example, by administering to the Subject a single dosage inflammation, or an inflammation-related disorder, and for form, Such as a capsule, for example, having a fixed ratio of the treatment or prevention of a neurologic disorder involv each therapeutic agent or in multiple, Single dosage forms ing neurodegeneration. for each of the therapeutic agents. Sequential or Substan 1160. In one embodiment, the Cox-2 inhibitor compound tially simultaneous administration of each therapeutic agent is a non-Steroidal anti-inflammatory drug. can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular 1161 In another embodiment, the Cox-2 inhibitor is a routes, and direct absorption through mucous membrane Cox-2 selective inhibitor. tissues. The therapeutic agents can be administered by the 1162 Instill another embodiment, the the Cox-2 inhibitor Same route or by different routes. For example, a first compound is a prodrug of a Cox-2 inhibitor compound, therapeutic agent of the combination Selected may be admin illustrated herein with parecoxib. istered by intravenous injection while the other therapeutic agents of the combination may be administered orally. 1163. In yet another embodiment, the present invention Alternatively, for example, all therapeutic agents may be further provides a combination therapy method for the administered orally or all therapeutic agents may be admin treatment or prevention of pain, inflammation, or an inflam istered by intravenous injection. The Sequence in which the mation-related disorder in a mammal in need thereof, com therapeutic agents are administered is not narrowly critical. prising administering to the mammal an amount of a Cox-2 “Combination therapy' also can embrace the administration inhibitor and an amount of a 5-HT1A receptor modulator of the therapeutic agents as described above in further wherein the amount of the Cox-2 inhibitor and the amount combination with other biologically active ingredients and of the 5-HT1A receptor modulator together comprise a thera non-drug therapies. peutically effective amount for the treatment or prevention of pain, inflammation, or an inflammation-related disorder. 1154. The phrase “therapeutically effective' is intended to qualify the amount of compounds utilized in the therapy. 1164. In a further embodiment, the present invention This amount will achieve the goal of treating or preventing provides a pharmaceutical composition for the treatment or pain, inflammation or an inflammation-related disorder. prevention of pain, inflammation, or an inflammation-re lated disorder comprising an amount of a Cox-2 inhibitor 1155 “Therapeutic compound” means a compound use and an amount of a 5-HT1A receptor modulator and a ful in the treatment or prevention of pain, inflammation or an pharmaceutically-acceptable excipient. inflammation-related disorder, or of a neurologic disorder involving neurodegeneration. 1165. In still further embodiment, the present invention provides a kit that is Suitable for use in the treatment, 1156. The term “pharmaceutically acceptable” is used prevention or inhibition of pain, inflammation, or an inflam adjectivally herein to mean that the modified noun is appro mation-related disorder wherein the kit comprises a first priate for use in a pharmaceutical product. Pharmaceutically dosage form comprising a Cox-2 inhibitor and a Second acceptable cations include metallic ions and organic ions. dosage form comprising a 5-HT1A receptor modulator, in More preferred metallic ions include, but are not limited to quantities which comprise a therapeutically effective appropriate alkali metal Salts, alkaline earth metal Salts and amount of the compounds for the treatment, prevention or other physiological acceptable metal ions. Exemplary ions inhibition of pain, inflammation, or an inflammation-related include aluminum, calcium, lithium, magnesium, potassium, disorder. Sodium and Zinc in their usual Valences. Preferred organic 1166 The methods and compositions of the present ions include protonated tertiary amines and quaternary invention provide one or more benefits. Combinations of ammonium cations, including in part, trimethylamine, Cox-2 inhibitors and 5-HT1A receptor modulators are useful diethylamine, N,N'-dibenzylethylenediamine, chlorop in treating and preventing pain, inflammation, or an inflam rocaine, choline, diethanolamine, ethylenediamine, meglu mation-related disorder. Preferably, the Cox-2 inhibitors and mine (N-methylglucamine) and procaine. Exemplary phar the 5-HT1A receptor modulators of the present invention are maceutically acceptable acids include without limitation administered in combination at a low dose, that is, at a dose hydrochloric acid, hydrobromic acid, phosphoric acid, Sul lower than has been conventionally used in clinical Situa furic acid, methaneSulfonic acid, acetic acid, formic acid, tions. tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, Succinic acid, lactic acid, gluconic acid, glucuronic 1167. The combinations of the present invention will acid, pyruvic acid oxalacetic acid, fumaric acid, propionic have a number of uses. For example, through dosage adjust acid, aspartic acid, glutamic acid, benzoic acid, and the like. ment and medical monitoring, the individual dosages of the US 2004/O147581 A1 Jul. 29, 2004 52 therapeutic compounds used in the combinations of the inflammatory bowel disease, Crohn's disease, gastritis, irri present invention will be lower than are typical for dosages table bowel syndrome and ulcerative colitis. of the therapeutic compounds when used in monotherapy. The dosage lowering will provide advantages including 1176 Combinations and methods of the invention would be useful in treating inflammation in Such diseaseS as reduction of side effects of the individual therapeutic com migraine headaches, polyarteritis nodosa, thyroiditis, aplas pounds when compared to the monotherapy. In addition, tic anemia, Hodgkin's disease, Sclerodoma, rheumatic fever, fewer side effects of the combination therapy compared with type I diabetes, neuromuscular junction disease including the monotherapies will lead to greater Subject compliance myasthenia gravis, white matter disease including multiple with therapy regimens. Sclerosis, Sarcoidosis, nephrotic Syndrome, Behcet's Syn 1168 Alternatively, the methods and combination of the drome, polymyositis, gingivitis, nephritis, hyperSensitivity, present invention can also maximize the therapeutic effect at Swelling occurring after injury including brain edema, myo higher doses. cardial ischemia, and the like. 1169 When administered as a combination, the therapeu 1177. The combinations and methods of the invention tic agents can be formulated as Separate compositions that would also be useful in the treatment of ophthalmic diseases, are given at the same time or different times, or the thera Such as retinitis, conjunctivitis, retinopathies, uveitis, ocular peutic agents can be given as a single composition. photophobia, glaucoma and acute injury to the eye tissue. 1170. Inhibitors of the cyclooxygenase pathway in the 1178. The combinations and methods would also be metabolism of arachidonic acid that are used in the treat useful in the treatment of pulmonary inflammation, Such as ment, prevention or reduction of pain, inflammation, or an that associated with Viral infections and cystic fibrosis, and inflammation-related disorder may inhibit enzyme activity in bone resorption Such as associated with Osteoporosis. through a variety of mechanisms. By way of example, the cyclooxygenase-2 inhibitors used in the methods described 1179 The combinations and methods of the invention are herein may block the enzyme activity directly by binding at useful as anti-inflammatory agents, Such as for the treatment the Substrate site of the enzyme. The use of a Cox-2 selective of arthritis, with the additional benefit of having signifi inhibiting agent is highly advantageous in that it minimizes cantly leSS harmful Side effects. These combinations and the gastric Side effects that can occur with non-Selective methods would also be useful in the treatment of allergic non-steroidal antiinflammatory drugs (NSAIDs), especially rhinitis, respiratory distreSS Syndrome, endotoxin Shock Syn where prolonged treatment is expected. drome, and liver disease. 1171 Besides being useful for human treatment, these 1180 The combinations and methods would also be methods are also useful for veterinary treatment of compan useful in the treatment of pain, but not limited to postop ion animals, exotic animals and farm animals, including erative pain, dental pain, muscular pain, dysmennorrhea, mammals, rodents, avians, and the like. More preferred neuropathic pain and pain resulting from cancer. animals include horses, dogs, and cats. 1181. The combinations and methods above would be 1172. As used herein, the terms “therapeutically effective useful for, but not limited to, treating and preventing inflam amount” are intended to qualify the amount of a Cox-2 mation-related cardiovascular disorders in a Subject. The inhibiting agent and a 5-HT1A receptor modulator that are combinations and methods would be useful for treatment required to treat or prevent pain, inflammation, or an inflam and prevention of vascular diseases, coronary artery disease, mation-related disorder, or to treat or prevent neurologic aneurysm, Vascular rejection, arteriosclerosis, atherOSclero disease involving neurodegeneration. sis including cardiac transplant atherOSclerosis, myocardial infarction, embolism, stroke (hemorrhagic or ischemic), 1173) The combinations and methods of the present thrombosis, including venous thrombosis, angina including invention would be useful for, but not limited to, the unstable angina, coronary plaque inflammation, bacterial treatment of inflammation in a Subject, and for treatment of induced inflammation including Chlamydia-induced inflam other inflammation-related disorders, Such as, as an analge mation, Viral induced inflammation, and inflammation asso sic in the treatment of pain and headaches, or as an anti ciated with Surgical procedures Such as vascular grafting pyretic for the treatment of fever. For example, compounds including coronary artery bypass Surgery, revascularization of the invention would be useful to treat arthritis, including procedures including angioplasty, Stent placement, endart but not limited to rheumatoid arthritis, spondyloarthropa erectomy, or other invasive procedures involving arteries, thies, gouty arthritis, osteoarthritis, Systemic lupus erythe veins and capillaries. matosus and juvenile arthritis. 1182. The combinations and methods would be useful 1174. Such combinations and methods of the invention for, but not limited to, the treatment and prevention of would be useful in the treatment of asthma, bronchitis, angiogenesis-related disorders in a Subject. According to the menstrual cramps, overactive bladder (OAB), preterm labor, present invention, the compounds can be administered to a tendinitis, burSitis, allergic neuritis, cytomegalovirus infec Subject in need of angiogenesis inhibition. The method tivity, apoptosis including HIV induced apoptosis, lumbago, would be useful for treatment of neoplasia, including liver disease including hepatitis, skin-related conditions metastasis, ophthalmological conditions Such as corneal Such as psoriasis, eczema, acne, UV damage, burns and graft rejection, ocular neovascularization, retinal neovascu dermatitis, and postoperative inflammation including oph larization including neovascularization following injury or thalmic Surgery Such as cataract Surgery and refractive infection, diabetic retinopathy, macular degeneration, retro Surgery. lental fibroplasia and glaucoma; ulcerative diseaseS Such as 1175 Combinations and methods of the invention also gastric ulcer, pathological, but non-malignant, conditions would be useful to treat gastrointestinal conditions Such as Such as hemangiomas, including infantile hemaginomas, US 2004/O147581 A1 Jul. 29, 2004 53 angiofibroma of the nasopharynx and avascular necrosis of mental retardation; dementia, Such as associated with aging, bone; and disorders of the female reproductive System Such illness, neurodegeneration and dyskensia; dysthymia, dyS as endometriosis. tonia; eating disorders, Such as anorexia nervosa, bulimia 1183 Compounds of the invention would be useful for nervosa, obesity, epilepsy and fibromyalgia Syndrome the prevention or treatment of benign and malignant tumors/ (FMS); gastrointestinal disorders, such as irritable bowel neoplasia including cancer, Such as colorectal cancer, brain Syndrome, psychogenic effects and StreSS-related; growth cancer, bone cancer, epithelial cell derived neoplasia (epi retardation effects, Such as endocrine, psychoSocial and thelial carcinoma) Such as basal cell carcinoma, adenocar StreSS-related; heart rate modification; Huntington's Chorea; cinoma, gastrointestinal cancer Such as lip cancer, mouth hypertension, immune System disorders, Such as immune cancer, esophogeal cancer, Small bowel cancer and Stomach System depression; impulse control (related to conduct dis cancer, colon cancer, liver cancer, bladder cancer, pancreas order), incontinence, Such as mixed States, stress inconti cancer, OVarian cancer, cervical cancer, lung cancer, breast nence and urge incontinence; infectious neuropathy, Such as cancer and Skin cancer, Such as Squamous cell and basal cell AIDS; carpal tunnel syndrome; dementia; irritable bowel cancers, prostate cancer, renal cell carcinoma, and other Syndrome (IBS), Such as constipative and diarrhea-predomi known cancers that effect epithelial cells throughout the nant; inflammatory bowel disease (IBD), Such as constipa body. Preferably, neoplasia is Selected from gastrointestinal tion-predominant, diarrhea-predominant and mixed States, cancer, Barrett's esophagus, liver cancer, bladder cancer, inhalation disorder; lactation inhibition, metabolic & chro pancreas cancer, OVarian cancer, prostate cancer, cerVical mosomal disorders, Such as galactosemia phenylketonuria, cancer, lung cancer, breast cancer and Skin cancer, Such as fatty acid disorder, infantile nephropathic cystinosis, Squamus cell and basal cell cancers. The compounds can orthithrotranscarbamylase porphyria and migrane; mood also be used to treat the fibrosis which occurs with radiation disorders, Such as a typical depression, bipolar disorder therapy. The method can be used to treat Subjects having (including pychotic features), major depressive disorder, adenomatous polyps, including those with Sporadic mania, and Seasonal affective disorder; movement disorders, adenomatous polyposis (SAP) or familial adenomatous Such as athetosis, chorea, dyskinesia, dystonia, restleSS leg polyposis (FAP). Additionally, the method can be used to syndrome (RLS), tremor plus periodic limb movement prevent polyps from forming in subjects at risk of FAP. (PLM), periodic limb movements of sleep (PLMS), Hun 1184. The combinations and methods of the present tington's chorea, Parkinson's disease, PLM, PLMS, pro invention are useful for the prevention and treatment of pain, gressive Supranuclear palsy, Stereotypy (various), torticollis, inflammation and central nervous system (CNS) disorders, tic disorders and tremor; multisystemic atrophy (MSA), which include, for example, adjustment disorders, Such as Such as multiple Sclerosis; neuroendocrine System disorders, anxiety (mixed anxiety), mood (depressed), conduct distur neurologic diseases involving neurodegeneration, Such as bance, mixed anxiety and mood (conduct); addictive disor amyotrophy, amyotrophy diabetics, amyotrophic lateral ders, Such as alcohol abuse, intoxication disorders, nicotine Sclerosis (ALS), Alzheimer's disease, Huntington's chorea abuse, psychoactive Substances abuse and Substance disor and Parkinson's disease; neurological disorders; neuropathy, der; withdrawal Syndromes, acute trauma, age associated Such as diabetic and peripheral; neuroprotective effects, Such mental disorders, Such as learning and Alzheimer's disease; as for ischemic brain injury, myocardial infarction, Spinal agitation disorders, Such as agitation in Alzheimer's disease cord injury, traumatic brain injury and obesity, obsessive and agitation in the elderly; aggressive behavior, Such as in compulsive disorder (OCD); oncology related disorders, Alzheimers disease; amyloidosis, Such as aging/Senile, Such as with behavior abnormalities resulting from tumors hereditary, immunocyte derived, lichen, primary, reactive or treatments, Such as chemotherapy and induced Vomiting, Systemic, Secondary, Senile (Alzheimer's disease), amyotro oppositional defiant disorder; pain disorders, Such as acute, phy & amyotropic lateral Sclerosis (ALS), and anorexia chronic, cluster headache, dysmenorrhea, labor, migraine, nervosa, anxiety disorders, Such as generalized anxiety neuropathic, AIDS-related, cancer-related, chemotherapeu disorder (GAD), panic disorder, bipolar disorder, Social tic-induced, diabetic, post-herpetic neuralgia, radiation-in phobias and StreSS related diseases, apathy; attention deficit duced, osteoarthritis flare, phantom limb, Surgical, post disorder (ADD); attention deficit hyperactivity disorder Surgical and incisional, psychic, regional pain (Such as (ADHD), autism; auto immune disorders, Such as lupus abdominal region, chronic back pain, complex-regional pain erythematosis and multiple Sclerosis, behavioral distur disorder, dental, face and mouth, head, lower back and bances, Such as agitation plus diminished cognition, bipolar peripheral), rheumatoid arthritis, starting pain and System I disorder and bipolar II disorder; bulimia nervosa; cardio atic pain (Such as in connective tissue, Such as musculosk vascular, blood pressure modification, Such as for hyperten eletal, nervous System, urogenital, uterine contractions); Sion, hypotension and heart rate modification; chemo panic disorder, Such as with agoraphobia and without ago therapy-induced vomiting, chronic fatigue immune raphobia, Parkinson's disease; peripheral neuropathy; per disorders (CFIDS); chronic fatigue syndrome (CFS); cog Sonality disorders; phobias (simple), Such as phobias of nitive dysfunction, Such as cortical dementias including mild animals, closed spaces (claustrophobia), heights (acropho cognitive impairment (MCI), Lewy Body dementia, Vascu bia), public places (agoraphobia); phobias (Social), Such as, lar dementia, neurodegeneration, and cognitive dysfunction public eating, public embarrassment, public performance/ resulting from Stroke, ischemia, trauma, or Surgical proce Speaking and using public lavatories; SSRI poop out Syn dures, including coronary artery bypass Surgery; cognition drome; post-traumatic StreSS disorder; progressive Supra enhancement; conduct disorder; cyclothymia; delusional nuclear palsy (PSP); prolactin plasma level disorders; disorder, depression, Such as adolescent, in Alzheimer's psychotic disorders, Such as brief and long duration, due to disease, general, minor, in Parkinson's disease and diabetic medical condition, not otherwise specified (NOS) and rest neuropathy, dissociative disorders, developmental disor less leg Syndrome (RLS), Schizophrenias, Such as delusional ders, Such as learning disabilities, language disorders and (paranoid) disorder, Schizoaffective disorders, Schizophreni US 2004/O147581 A1 Jul. 29, 2004 54 form disorders and Seasonal affective disorder; Seizure dis and on the route of administration, the unit dosage for oral orders, Such as epilepsy (partial) and epilepsy (generalized); administration to a mammal of about 50 to 70 kg may Sexual dysfunction, Such as for female and for male, Sleep contain between about 5 and 500 mg of the active ingredient disorders, Such as apnea, parasomnias, insomnia, narco (for example, Cox-189). The amount of active ingredient lepsy, obstructive, and disorders of circadian rhythm, enure that may be combined with a 5-HT1A receptor modulator to sis, initiation and maintenance, Social phobias, Such as Social produce a single dosage form will vary depending upon the anxiety disorder; Somatoform disorders, Such as conversion, host treated and the particular mode of administration. body, dysmorphic, fibromyalgia syndrome (FMS), hypo 1191) A total daily dose of a 5-HT, receptor modulator chondriasis, NOS, Somatization and undifferentiated; Spe can generally be in the range of from about 0.001 to about cific developmental disorders, StreSS disorders, Such as 10,000 mg/day in single or divided doses, with preferred acute, chronic and incontinence, Spectrum disorders, Stroke; levels of about 1.0 mg to about 1,000 mg. It is understood, Suicidal behavior, and in particular, prevention of and ame however, that specific dose levels of the therapeutic agents lioration of; thyroid stimulating hormone disorders (TSH); or therapeutic approaches of the present invention for any Tourette's Syndrome, tooth-germ morphogenesis disorders, particular Subject depends upon a variety of factors includ thermoregulation disorders; TSH modulating agent disor ing the activity of the Specific compound employed, the age, ders, tic disorders, trauma, Such as acute head, and related body weight, general health, Sex, and diet of the Subject, the effects, Such as blood preSSure regulation, cerebral blood time of administration, the rate of excretion, the drug flow, CSF production, inflammation, and ischemia; vasos combination, and the Severity of the particular disease being pasms, vasoreactive headaches and violent behavior. treated and form of administration. 1185. As used herein, the term “treatment” includes par 1192 Treatment dosages generally may be titrated to tial or total inhibition of the dementia or cognitive dysfunc optimize Safety and efficacy. Typically, dosage-effect rela tion, including Alzheimer's disease, Vascular dementia, tionships from in Vitro initially can provide useful guidance multi-infarct dementia, pre-Senile dementia, alcoholic on the proper doses for Subject administration. Studies in dementia, and Senile dementia. animal models also generally may be used for guidance 1186 The combinations and methods of the present regarding effective dosages for treatment of pain, inflam invention are particularly useful for the treatment, preven mation, or an inflammation-related disorder in accordance tion or inhibition of a central nervous System disorder with the present invention. In terms of treatment protocols, asSociated with Stroke (ischemic or hemmorhagic) or other it should be appreciated that the dosage to be administered ischemic brain injury. will depend on Several factors, including the particular agent that is administered, the route administered, the condition of 1187. The phrases “low dose” or “low dose amount', in the particular Subject, etc. Generally Speaking, one will characterizing a therapeutically effective amount of the desire to administer an amount of the compound that is Cox-2 selective inhibitor and the 5-HT, receptor modulator effective to achieve a Serum level commensurate with the or therapy in the combination therapy, defines a quantity of concentrations found to be effective in vitro. Thus, where a Such agent, or a range of quantity of Such agent, that is compound is found to demonstrate in vitro activity at, e.g., capable of reducing the discomfort of pain, inflammation, or 10 uM, one will desire to administer an amount of the drug an inflammation-related disorder while optionally reducing that is effective to provide about a 10 uM concentration in or avoiding one or more Side effects of monotherapy with a vivo. Determination of these parameters is well within the 5-HT1A receptor modulator or other pain-relieving agent. skill of the art. Side effects of 5-HT, receptor modulators that the selected combinations of the present invention may reduce or avoid 1193 Effective formulations and administration proce are nausea, dizziness, insomnia, headache, fatigue, pares dures are well known in the art and are described in Standard thesias, uneasiness, nervousness, lightheadedness, excite textbooks. ment, tachycardia, malaise, dysphoria, dry mouth, headache, 1194 The Cox-2 inhibiting agents or the 5-HT1A receptor Somnolence, constipation, abnormal movements, respiratory modulators can be formulated as a single pharmaceutical disorders, dyspepsia, Skin rash, elevations in liver enzymes composition or as independent multiple pharmaceutical and gastrointestinal disturbances. compositions. Pharmaceutical compositions according to 1188 The phrase “adjunctive therapy” encompasses the present invention include those Suitable for oral, inha treatment of a Subject with agents that reduce or avoid side lation Spray, rectal, topical, buccal (e.g., Sublingual), or effects associated with the combination therapy of the parenteral (e.g., Subcutaneous, intramuscular, intravenous, present invention. intrathecal, intramedullary and intradermal injections, or infusion techniques) administration, although the most Suit 1189 Dosages, Formulations and Routes of Administra able route in any given case will depend on the nature and tion: Severity of the condition being treated and on the nature of 1190 Dosage levels of the Cox-2 inhibiting agent (e.g., a the particular compound which is being used. In most cases, Cox-2 Selective inhibiting agent or a prodrug of a Cox-2 the preferred route of administration is oral or parenteral. Selective inhibiting agent) on the order of about 0.1 mg to 1195 Compounds and composition of the present inven about 10,000 mg of the active ingredient compound are tion can then be administered orally, by inhalation spray, useful in the treatment of the above conditions, with pre rectally, topically, buccally or parenterally in dosage unit ferred levels of about 1.0 mg to about 1,000 mg. While the formulations containing conventional nontoxic pharmaceu dosage of active compound administered to a warm-blooded tically acceptable carriers, adjuvants, and vehicles as animal (a mammal), is dependent on the species of that desired. The compounds of the present invention can be mammal, the body weight, age, and individual condition, administered by any conventional means available for use in US 2004/O147581 A1 Jul. 29, 2004 55 conjunction with pharmaceuticals, either as individual thera intestine, Slow erosion of a tablet or capsule, retention in the peutic compounds or as a combination of therapeutic com Stomach based on the physical properties of the formulation, pounds. bioadhesion of the dosage form to the mucosal lining of the 1196 Pharmaceutically acceptable salts are particularly intestinal tract, or enzymatic release of the active drug from Suitable for medical applications because of their greater the dosage form. For Some of the therapeutic compounds aqueous Solubility relative to the parent compound. Such useful in the methods, combinations and compositions of the Salts must clearly have a pharmaceutically acceptable anion present invention the intended effect is to extend the time or cation. period over which the active drug molecule is delivered to 1197) The compounds useful in the methods, combina the site of action by manipulation of the dosage form. Thus, tions and compositions of the present invention can be enteric-coated and enteric-coated controlled release formu presented with an acceptable carrier in the form of a phar lations are within the Scope of the present invention. Suitable maceutical composition. The carrier must, of course, be enteric coatings include cellulose acetate phthalate, polyvi acceptable in the Sense of being compatible with the other nylacetate phthalate, hydroxypropylmethylcellulose phtha ingredients of the composition and must not be deleterious late and anionic polymers of methacrylic acid and meth to the recipient. The carrier can be a Solid or a liquid, or both, acrylic acid methyl ester. and is preferably formulated with the compound as a unit 1201 Pharmaceutical compositions suitable for oral dose composition, for example, a tablet, which can contain administration can be presented in discrete units, Such as from 0.05% to 95% by weight of the active compound. capsules, cachets, lozenges, or tablets, each containing a Other pharmacologically active Substances can also be predetermined amount of at least one therapeutic compound present, including other compounds of the present invention. useful in the present invention; as a powder or granules, as The pharmaceutical compositions of the invention can be a Solution or a Suspension in an aqueous or non-aqueous prepared by any of the well-known techniques of pharmacy, liquid, or as an oil-in-water or water-in-oil emulsion. AS consisting essentially of admixing the components. indicated, Such compositions can be prepared by any Suit 1198. The amount of compound in combination that is able method of pharmacy which includes the Step of bring required to achieve the desired biological effect will, of ing into association the active compound(s) and the carrier course, depend on a number of factorS Such as the Specific (which can constitute one or more accessory ingredients). In compound chosen, the use for which it is intended, the mode general, the compositions are prepared by uniformly and of administration, and the clinical condition of the recipient. intimately admixing the active compound with a liquid or finely divided Solid carrier, or both, and then, if necessary, 1199 The compounds of the present invention can be Shaping the product. For example, a tablet can be prepared delivered orally either in a Solid, in a Semi-Solid, or in a by compressing or molding a powder or granules of the liquid form. Dosing for oral administration may be with a regimen calling for Single daily dose, or for a single dose compound, optionally with one or more assessory ingredi every other day, or for multiple, Spaced doses throughout the ents. Compressed tablets can be prepared by compressing, in day. For oral administration, the pharmaceutical composi a Suitable machine, the compound in a free-flowing form, tion may be in the form of, for example, a tablet, capsule, Such as a powder or granules optionally mixed with a binder, Suspension, or liquid. Capsules, tablets, etc., can be prepared lubricant, inert diluent and/or Surface active/dispersing by conventional methods well known in the art. The phar agent(s). Molded tablets can be made by molding, in a maceutical composition is preferably made in the form of a Suitable machine, the powdered compound moistened with dosage unit containing a particular amount of the active an inert liquid diluent. ingredient or ingredients. Examples of dosage units are 1202 Liquid dosage forms for oral administration can tablets or capsules, and may contain one or more therapeutic include pharmaceutically acceptable emulsions, Solutions, compounds in an amount described herein. For example, in Suspensions, Syrups, and elixirs containing inert diluents the case of a 5-HT1A receptor modulator, the dose range may commonly used in the art, Such as water. Such compositions be from about 0.01 mg to about 5,000 mg or any other dose, may also comprise adjuvants, Such as wetting agents, emul dependent upon the Specific inhibitor, as is known in the art. Sifying and Suspending agents, and Sweetening, flavoring, When in a liquid or in a semi-solid form, the combinations and perfuming agents. of the present invention can, for example, be in the form of a liquid, Syrup, or contained in a gel capsule (e.g., a gel cap). 1203 Pharmaceutical compositions suitable for buccal In one embodiment, when a 5-HT1A receptor modulator is (Sub-lingual) administration include lozenges comprising a used in a combination of the present invention, the 5-HT1A compound of the present invention in a flavored base, receptor modulator can be provided in the form of a liquid, usually Sucrose, and acacia or tragacanth, and pastilles Syrup, or contained in a gel capsule. In another embodiment, comprising the compound in an inert base Such as gelatin when a Cox-2 inhibiting agent is used in a combination of and glycerin or Sucrose and acacia. the present invention, the Cox-2 inhibiting agent can be 1204 Pharmaceutical compositions suitable for provided in the form of a liquid, Syrup, or contained in a gel parenteral administration conveniently comprise Sterile capsule. aqueous preparations of a compound of the present inven 1200 Oral delivery of the combinations of the present tion. These preparations are preferably administered intra invention can include formulations, as are well known in the venously, although administration can also be effected by art, to provide prolonged or Sustained delivery of the drug to means of Subcutaneous, intramuscular, or intradermal injec the gastrointestinal tract by any number of mechanisms. tion or by infusion. Such preparations can conveniently be These include, but are not limited to, pH Sensitive release prepared by admixing the compound with water and ren from the dosage form based on the changing pH of the Small dering the resulting Solution Sterile and isotonic with the US 2004/O147581 A1 Jul. 29, 2004 56 blood. Injectable compositions according to the invention pounds is about 1% to 35%, preferably about 3% to 15%. As will generally contain from 0.1 to 10% w/w of a compound one particular possibility, the compound or compounds can disclosed herein. be delivered from the patch by electrotransport or ionto 1205 Injectable preparations, for example, Sterile inject phoresis, for example, as described in Pharmaceutical able aqueous or oleaginous Suspensions may be formulated Research, 3(6), 318 (1986). according to the known art using Suitable dispersing or 1211. In any case, the amount of active ingredients that Setting agents and Suspending agents. The Sterile injectable can be combined with carrier materials to produce a single preparation may also be a sterile injectable Solution or dosage form to be administered will vary depending upon Suspension in a nontoxic parenterally acceptable diluent or the host treated and the particular mode of administration. Solvent, for example, as a Solution in 1,3-butanediol. Among 1212. In combination therapy, administration of two or the acceptable vehicles and Solvents that may be employed more of the therapeutic agents useful in the methods, com are water, Ringer's Solution, and isotonic Sodium chloride binations and compositions of the present invention may Solution. In addition, Sterile, fixed oils are conventionally take place Sequentially in Separate formulations, or may be employed as a Solvent or Suspending medium. For this accomplished by Simultaneous administration in a single purpose any bland fixed oil may be employed including formulation or in a separate formulation. Independent Synthetic mono- or diglycerides. In addition, fatty acids Such administration of each therapeutic agent may be accom as oleic acid find use in the preparation of injectables. plished by, for example, oral, inhalation spray, rectal, topi 1206. The active ingredients may also be administered by cal, buccal (e.g., Sublingual), or parenteral (e.g., Subcutane injection as a composition wherein, for example, Saline, ous, intramuscular, intravenous, intrathecal, intramedullary dextrose, or water may be used as a Suitable carrier. A and intradermal injections, or infusion techniques) admin Suitable daily dose of each active therapeutic compound is istration. The formulation may be in the form of a bolus, or one that achieves the Same blood Serum level as produced by in the form of aqueous or non-aqueous isotonic Sterile oral administration as described above. injection Solutions or Suspensions. Solutions and Suspen Sions may be prepared from Sterile powders or granules 1207 The dose of any of these therapeutic compounds having one or more pharmaceutically-acceptable carriers or can be conveniently administered as an infusion of from diluents, or a binder Such as gelatin or hydroxypropylmethyl about 10 ng/kg body weight to about 10,000 ng/kg body cellulose, together with one or more of a lubricant, preser weight per minute. Infusion fluids Suitable for this purpose vative, Surface active or dispersing agent. The therapeutic can contain, for example, from about 0.1 ng to about 10 mg, compounds may further be administered by any combination preferably from about 1 ng to about 10 mg per milliliter. Unit of, for example, oral/oral, oral/parenteral, or parenteral/ doses can contain, for example, from about 1 mg to about 10 parenteral route. g of the compound of the present invention. Thus, ampules for injection can contain, for example, from about 1 mg to 1213. The therapeutic compounds which make up the about 100 mg. combination therapy may be a combined dosage form or in Separate dosage forms intended for Substantially Simulta 1208 Pharmaceutical compositions suitable for rectal neous oral administration. The therapeutic compounds administration are preferably presented as unit-dose Sup which make up the combination therapy may also be admin positories. These can be prepared by admixing a compound istered Sequentially, with either therapeutic compound being or compounds of the present invention with one or more administered by a regimen calling for two step ingestion. conventional Solid carriers, for example, cocoa butter, Syn Thus, a regimen may call for Sequential administration of the thetic mono- di- or triglycerides, fatty acids and polyethyl therapeutic compounds with Spaced-apart ingestion of the ene glycols that are Solid at ordinary temperatures but liquid Separate, active agents. The time period between the mul at the rectal temperature and will therefore melt in the tiple ingestion Steps may range from, for example, a few rectum and release the drug, and then Shaping the resulting minutes to Several hours to days, depending upon the mixture. properties of each therapeutic compound Such as potency, 1209 Pharmaceutical compositions suitable for topical solubility, bioavailability, plasma half-life and kinetic profile application to the Skin preferably take the form of an of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the ointment, cream, lotion, paste, gel, Spray, aeroSol, or oil. Subject. Circadian variation of the target molecule concen Carriers which can be used include petroleum jelly (e.g., tration may also determine the optimal dose interval. The Vaseline), lanolin, polyethylene glycols, alcohols, and com therapeutic compounds of the combined therapy whether binations of two or more thereof. The active compound or administered Simultaneously, Substantially simultaneously, compounds are generally present at a concentration of from or Sequentially, may involve a regimen calling for admin 0.1 to 50% w/w of the composition, for example, from 0.5 istration of one therapeutic compound by oral route and to 2%. another therapeutic compound by intravenous route. 1210 Transdermal administration is also possible. Phar Whether the therapeutic compounds of the combined maceutical compositions Suitable for transdermal adminis therapy are administered orally, by inhalation Spray, rectally, tration can be presented as discrete patches adapted to topically, buccally (e.g., Sublingual), or parenterally (e.g., remain in intimate contact with the epidermis of the recipi Subcutaneous, intramuscular, intravenous and intradermal ent for a prolonged period of time. Such patches Suitably injections, or infusion techniques), Separately or together, contain a compound or compounds of the present invention each Such therapeutic compound will be contained in a in an optionally buffered, aqueous Solution, dissolved and/or Suitable pharmaceutical formulation of pharmaceutically dispersed in an adhesive, or dispersed in a polymer. A acceptable excipients, diluents or other formulations com Suitable concentration of the active compound or com ponents. Examples of Suitable pharmaceutically-acceptable US 2004/O147581 A1 Jul. 29, 2004 57 formulations containing the therapeutic compounds are given above. Additionally, drug formulations are discussed TABLE 5-continued in, for example, Hoover, John E., Remington's Pharmaceu tical Sciences, Mack Publishing Co., Easton, Pa. 1975. Combinations of COX-2 selective inhibiting agents Another discussion of drug formulations can be found in and 5-HT1A receptor modulators. Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Example 5-HT, Receptor Dosage Forms, Marcel Decker, New York, N.Y., 1980. Number Cox-2 Inhibitor Modulator 1214. The following examples describe preferred 38 Celecoxib H38 embodiments of the invention. Other embodiments within . E. E. the Scope of the claims herein will be apparent to one skilled 41 Celecoxib H41 in the art from consideration of the Specification or practice 42 Celecoxib H42 of the invention as disclosed herein. It is intended that the 43 Celecoxib H43 Specification, taken together with the examples, be consid- 44 Celecoxib H44 ered to be exemplary only, with the Scope and Spirit of the 4645 Celecoxib H46H45 invention being indicated by the claims which follow the 47 Celecoxib H47 examples. In the examples, all percentages are given on a 48 Celecoxib H48 weight basis, unless otherwise indicated.- 5049 Celecoxib HSOH49 51 Celecoxib HS1 EXAMPLE 1. 52 Celecoxib HS2 1215. This example illustrates combinations of the 5. E. E. present invention. 55 Celecoxib H55 56 Celecoxib HS6 1216) Table 5 describes a number of combinations com- 57 Celecoxib H57 prising a Cox-2 Selective inhibitor and a 5-HT1A receptor 58 Celecoxib HS8 modulator. Designations of “H” corresponds to compounds ecoxip E. described above in the Specification. 61 CelecoxibeleCOX) H61 62 Celecoxib H62 TABLE 5 63 Celecoxib H63 64 Celecoxib H64 Combinations of COX-2 selective inhibiting agents 65 Celecoxib H65 and 5-HT1A receptor modulators. 66 Celecoxib H66 67 Celecoxib H67 Example 5-HT, Receptor 68 Celecoxib H68 Number Cox-2 Inhibitor Modulator 69 Celecoxib H69 70 Celecoxib H7O 1. Celecoxib H1 71 Celecoxib HF1 2 Celecoxib H2 72 Celecoxib H72 3 Celecoxib H3 73 Celecoxib HT3 4 Celecoxib H4 74 Celecoxib HF4 5 Celecoxib HS 75 Celecoxib H75 6 Celecoxib H6 76 Celecoxib HF6 7 Celecoxib H7 77 Celecoxib H77 8 Celecoxib HS 78 Celecoxib HF8 9 Celecoxib H9 79 Celecoxib H79 1O Celecoxib H10 8O Celecoxib HSO 11 Celecoxib H11 81 Celecoxib HS1 12 Celecoxib H12 82 Celecoxib HS2 13 Celecoxib H13 83 Celecoxib HS3 14 Celecoxib H14 84 Celecoxib HS4 15 Celecoxib H15 85 Valdecoxib H1 16 Celecoxib H16 86 Valdecoxib H2 17 Celecoxib H17 87 Valdecoxib H3 18 Celecoxib H18 88 Valdecoxib H4 19 Celecoxib H19 89 Valdecoxib HS 2O Celecoxib H2O 90 Valdecoxib H6 21 Celecoxib H21 91 Valdecoxib H7 22 Celecoxib H22 92 Valdecoxib HS 23 Celecoxib H23 93 Valdecoxib H9 24 Celecoxib H24 94 Valdecoxib H10 25 Celecoxib H25 95 Valdecoxib H11 26 Celecoxib H26 96 Valdecoxib H12 27 Celecoxib H27 97 Valdecoxib H13 28 Celecoxib H28 98 Valdecoxib H14 29 Celecoxib H29 99 Valdecoxib H15 3O Celecoxib H3O 1OO Valdecoxib H16 31 Celecoxib H31 101 Valdecoxib H17 32 Celecoxib H.32 102 Valdecoxib H18 33 Celecoxib H33 103 Valdecoxib H19 34 Celecoxib H34 104 Valdecoxib H2O 35 Celecoxib H35 105 Valdecoxib H21 36 Celecoxib H36 106 Valdecoxib H22 37 Celecoxib H37 107 Valdecoxib H23 US 2004/O147581 A1 Jul. 29, 2004 58

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number Cox-2 Inhibitor Modulator Number Cox-2 Inhibitor Modulator O8 Valdecoxib H24 78 Parecoxib H10 O9 Valdecoxib H25 79 Parecoxib H11 1O Valdecoxib H26 8O Parecoxib H12 11 Valdecoxib H27 81 Parecoxib H13 12 Valdecoxib H28 82 Parecoxib H14 13 Valdecoxib H29 83 Parecoxib H15 14 Valdecoxib H3O 84 Parecoxib H16 15 Valdecoxib H31 85 Parecoxib H17 16 Valdecoxib H.32 86 Parecoxib H18 17 Valdecoxib H33 87 Parecoxib H19 18 Valdecoxib H34 88 Parecoxib H2O 19 Valdecoxib H35 89 Parecoxib H21 2O Valdecoxib H36 90 Parecoxib H22 21 Valdecoxib H37 91 Parecoxib H23 22 Valdecoxib H38 92 Parecoxib H24 23 Valdecoxib H39 93 Parecoxib H25 24 Valdecoxib H4O 94 Parecoxib H26 25 Valdecoxib H41 95 Parecoxib H27 26 Valdecoxib H42 96 Parecoxib H28 27 Valdecoxib H43 97 Parecoxib H29 28 Valdecoxib H44 98 Parecoxib H3O 29 Valdecoxib H45 99 Parecoxib H31 3O Valdecoxib H46 2OO Parecoxib H.32 31 Valdecoxib H47 2O1 Parecoxib H33 32 Valdecoxib H48 2O2 Parecoxib H34 33 Valdecoxib H49 2O3 Parecoxib H35 34 Valdecoxib HSO 2O)4 Parecoxib H36 35 Valdecoxib HS1 205 Parecoxib H37 36 Valdecoxib HS2 2O6 Parecoxib H38 37 Valdecoxib HS3 2O7 Parecoxib H39 38 Valdecoxib HS4 208 Parecoxib H4O 39 Valdecoxib H55 209 Parecoxib H41 40 Valdecoxib HS6 210 Parecoxib H42 41 Valdecoxib H57 211 Parecoxib H43 42 Valdecoxib HS8 212 Parecoxib H44 43 Valdecoxib H59 213 Parecoxib H45 44 Valdecoxib H6O 214 Parecoxib H46 45 Valdecoxib H61 215 Parecoxib H47 46 Valdecoxib H62 216 Parecoxib H48 47 Valdecoxib H63 217 Parecoxib H49 48 Valdecoxib H64 218 Parecoxib HSO 49 Valdecoxib H65 219 Parecoxib HS1 50 Valdecoxib H66 22O Parecoxib HS2 51 Valdecoxib H67 221 Parecoxib HS3 52 Valdecoxib H68 222 Parecoxib HS4 53 Valdecoxib H69 223 Parecoxib H55 54 Valdecoxib H7O 224 Parecoxib HS6 55 Valdecoxib HF1 225 Parecoxib H57 56 Valdecoxib H72 226 Parecoxib HS8 57 Valdecoxib HT3 227 Parecoxib H59 58 Valdecoxib HF4 228 Parecoxib H6O 59 Valdecoxib H75 229 Parecoxib H61 60 Valdecoxib HF6 230 Parecoxib H62 61 Valdecoxib H77 231 Parecoxib H63 62 Valdecoxib HF8 232 Parecoxib H64 63 Valdecoxib H79 233 Parecoxib H65 64 Valdecoxib HSO 234 Parecoxib H66 65 Valdecoxib HS1 235 Parecoxib H67 66 Valdecoxib HS2 236 Parecoxib H68 67 Valdecoxib HS3 237 Parecoxib H69 68 Valdecoxib HS4 238 Parecoxib H7O 69 Parecoxib H1 239 Parecoxib HF1 70 Parecoxib H2 240 Parecoxib H72 71 Parecoxib H3 241 Parecoxib HT3 72 Parecoxib H4 242 Parecoxib HF4 73 Parecoxib HS 243 Parecoxib H75 74 Parecoxib H6 244 Parecoxib HF6 75 Parecoxib H7 245 Parecoxib H77 76 Parecoxib HS 246 Parecoxib HF8 77 Parecoxib H9 247 Parecoxib H79 US 2004/O147581 A1 Jul. 29, 2004 59

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number Cox-2 Inhibitor Modulator Number Cox-2 Inhibitor Modulator

248 Parecoxib 318 Deracoxi 249 Parecoxib 319 Deracoxi 250 Parecoxib 32O Deracoxi 251 Parecoxib 321 Deracoxi 252 Parecoxib 322 Deracoxi 253 Deracoxib 323 Deracoxi 254 Deracoxib 324 Deracoxi 255 Deracoxib 325 Deracoxi 256 Deracoxib 326 Deracoxi 257 Deracoxib 327 Deracoxi 258 Deracoxib 328 Deracoxi 259 Deracoxib 329 Deracoxi 260 Deracoxib 330 Deracoxi 261 Deracoxib 331 Deracoxi 262 Deracoxib 332 Deracoxi 263 Deracoxib 333 Deracoxi 264 Deracoxib 334 Deracoxi 265 Deracoxib 335 Deracoxi 266 Deracoxib 336 Deracoxi 267 Deracoxib 337 orixoci 268 Deracoxib 338 orixoci 269 Deracoxib 339 orixoci 270 Deracoxib 340 orixoci 271 Deracoxib 341 orixoci 272 Deracoxib 342 orixoci 273 Deracoxib 343 orixoci 274 Deracoxib 344 orixoci 275 Deracoxib 345 orixoci 276 Deracoxib 346 orixoci 277 Deracoxib 347 orixoci 278 Deracoxib 348 orixoci 279 Deracoxib 349 orixoci 28O Deracoxib 350 orixoci 281 Deracoxib 351 orixoci 282 Deracoxib 352 orixoci 283 Deracoxib 353 orixoci 284 Deracoxib 354 orixoci 285 Deracoxib 355 orixoci 286 Deracoxib 356 orixoci 287 Deracoxib 357 orixoci 288 Deracoxib 358 orixoci 289 Deracoxib 359 orixoci 290 Deracoxib 360 orixoci 291 Deracoxib 361 orixoci 292 Deracoxib 362 orixoci 293 Deracoxib 363 orixoci 294 Deracoxib 364 orixoci 295 Deracoxib 365 orixoci 296 Deracoxib 366 orixoci 297 Deracoxib 367 orixoci 298 Deracoxib 368 orixoci 299 Deracoxib 369 orixoci 3OO Deracoxib 370 orixoci 3O1 Deracoxib 371 orixoci 3O2 Deracoxib 372 orixoci 303 Deracoxib 373 orixoci 304 Deracoxib 374 orixoci 305 Deracoxib 375 orixoci 306 Deracoxib 376 orixoci 307 Deracoxib 377 orixoci 3O8 Deracoxib 378 orixoci 309 Deracoxib 379 orixoci 310 Deracoxib 38O orixoci 311 Deracoxib 381 orixoci 312 Deracoxib 382 orixoci 313 Deracoxib 383 orixoci 314 Deracoxib 384 orixoci 315 Deracoxib 385 orixoci 316 Deracoxib 386 orixoci 317 Deracoxib 387 orixoci US 2004/O147581 A1 Jul. 29, 2004 60

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number C O X 2 I hibitor Modulator Number Cox-2 Inhibitor Modulator

388 orixoci 58 Lumiracoxib 389 orixoci 59 Lumiracoxib 390 orixoci 60 Lumiracoxib 391 orixoci 61 Lumiracoxib 392 orixoci 62 Lumiracoxib 393 orixoci 63 Lumiracoxib 394 orixoci 64 Lumiracoxib 395 orixoci 65 Lumiracoxib 396 orixoci 66 Lumiracoxib 397 orixoci 67 Lumiracoxib 398 orixoci 68 Lumiracoxib 399 orixoci 69 Lumiracoxib 400 orixoci 70 Lumiracoxib O1 orixoci 71 Lumiracoxib O2 orixoci 72 Lumiracoxib O3 orixoci 73 Lumiracoxib O4 orixoci 74 Lumiracoxib 05 orixoci 75 Lumiracoxib O6 orixoci 76 Lumiracoxib O7 orixoci 77 Lumiracoxib O8 orixoci 78 Lumiracoxib O9 orixoci 79 Lumiracoxib 1O orixoci 8O Lumiracoxib 11 orixoci 81 Lumiracoxib 12 orixoci 82 Lumiracoxib 13 orixoci 83 Lumiracoxib 14 orixoci 84 Lumiracoxib 15 orixoci 85 Lumiracoxib 16 orixoci 86 Lumiracoxib 17 orixoci 87 Lumiracoxib 18 orixoci 88 Lumiracoxib 19 orixoci 89 Lumiracoxib 2O orixocib 90 Lumiracoxib 21 Lumiracoxi 91 Lumiracoxib 22 Lumiracoxi 92 Lumiracoxib 23 Lumiracoxi 93 Lumiracoxib 24 Lumiracoxi 94 Lumiracoxib 25 Lumiracoxi 95 Lumiracoxib 26 Lumiracoxi 96 Lumiracoxib 27 Lumiracoxi 97 Lumiracoxib 28 Lumiracoxi 98 Lumiracoxib 29 Lumiracoxi 499 Lumiracoxib 3O Lumiracoxi 500 Lumiracoxib 31 Lumiracoxi 5O1 Lumiracoxib 32 Lumiracoxi 5O2 Lumiracoxib 33 Lumiracoxi 503 Lumiracoxib 34 Lumiracoxi 504 Lumiracoxib 35 Lumiracoxi 505 Deracoxib 36 Lumiracoxi SO6 Deracoxi 37 Lumiracoxi 507 Deracoxi 38 Lumiracoxi 508 Deracoxi 39 Lumiracoxi 509 Deracoxi 40 Lumiracoxi 510 Deracoxi 41 Lumiracoxi 511 Deracoxi 42 Lumiracoxi 512 Deracoxi 43 Lumiracoxi 513 Deracoxi 44 Lumiracoxi 514 Deracoxi 45 Lumiracoxi 515 Deracoxi 46 Lumiracoxi 516 Deracoxi 47 Lumiracoxi 517 Deracoxi 48 Lumiracoxi 518 Deracoxi 49 Lumiracoxi 519 Deracoxi 50 Lumiracoxi 52O Deracoxi 51 Lumiracoxi 521 Deracoxi 52 Lumiracoxi 522 Deracoxi 53 Lumiracoxi 523 Deracoxi 54 Lumiracoxi 524 Deracoxi 55 Lumiracoxi 525 Deracoxi 56 Lumiracoxi 526 Deracoxi 57 Lumiracoxi 527 Deracoxi US 2004/O147581 A1 Jul. 29, 2004 61

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number Cox-2 In hibitor Modulator Number Cox-2 In hibitor Modulator

528 Deracoxi 598 Ro ecoxi 529 Deracoxi 599 Ro ecoxi 530 Deracoxi 6OO Ro ecoxi 531 Deracoxi 6O1 Ro ecoxi 532 Deracoxi 6O2 Ro ecoxi 533 Deracoxi 603 Ro ecoxi 534 Deracoxi 604 Ro ecoxi 535 Deracoxi 605 Ro ecoxi 536 Deracoxi 606 Ro ecoxi 537 Deracoxi 6O7 Ro ecoxi 538 Deracoxi 608 Ro ecoxi 539 Deracoxi 609 Ro ecoxi 540 Deracoxi 610 Ro ecoxi 541 Deracoxi 611 Ro ecoxi 542 Deracoxi 612 Ro ecoxi 543 Deracoxi 613 Ro ecoxi 544 Deracoxi 614 Ro ecoxi 545 Deracoxi 615 Ro ecoxi 546 Deracoxi 616 Ro ecoxi 547 Deracoxi 617 Ro ecoxi 548 Deracoxi 618 Ro ecoxi 549 Deracoxi 619 Ro ecoxi 550 Deracoxi 62O Ro ecoxi 551 Deracoxi 621 Ro ecoxi 552. Deracoxi 622 Ro ecoxi 553 Deracoxi 623 Ro ecoxi 554. Deracoxi 624 Ro ecoxi 555 Deracoxi 625 Ro ecoxi 556 Deracoxi 626 Ro ecoxi 557 Deracoxi 627 Ro ecoxi 558 Deracoxi 628 Ro ecoxi 559 Deracoxi 629 Ro ecoxi 560 Deracoxi 630 Ro ecoxi 561 Deracoxi 631 Ro ecoxi 562 Deracoxi 632 Ro ecoxi 563 Deracoxi 633 Ro ecoxi 564 Deracoxi 634 Ro ecoxi 565 Deracoxi 635 Ro ecoxi 566 Deracoxi 636 Ro ecoxi 567 Deracoxi 637 Ro ecoxi 568 Deracoxi 638 Ro ecoxi 569 Deracoxi 639 Ro ecoxi 570 Deracoxi 640 Ro ecoxi 571 Deracoxi 641 Ro ecoxi 572 Deracoxi 642 Ro ecoxi 573 Deracoxi 643 Ro ecoxi 574. Deracoxi 644 Ro ecoxi 575 Deracoxi 645 Ro ecoxi 576 Deracoxi 646 Ro ecoxi 577 Deracoxi 647 Ro ecoxi 578 Deracoxi 648 Ro ecoxi 579 Deracoxi 649 Ro ecoxi 58O Deracoxi 6SO Ro ecoxi 581 Deracoxi 651 Ro ecoxi 582 Deracoxi 652 Ro ecoxi 583 Deracoxi 653 Ro ecoxi 584 Deracoxi 654 Ro ecoxi 585 Deracoxi 655 Ro ecoxi 586 Deracoxi 656 Ro ecoxi 587 Deracoxi 657 Ro ecoxi 588 Deracoxi 658 Ro ecoxi 589 Rofecoxi 659 Ro ecoxi 590 Rofecoxi 660 Ro ecoxi 591 Rofecoxi 661 Ro ecoxi 592 Rofecoxi 662 Ro ecoxi 593 Rofecoxi 663 Ro ecoxi 594 Rofecoxi 664 Ro ecoxi 595 Rofecoxi 665 Ro ecoxi 596 Rofecoxi 666 Ro ecoxi 597 Rofecoxi 667 Ro ecoxi US 2004/O147581 A1 Jul. 29, 2004 62

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number Cox-2 Inhibitor Modulator Number Cox-2 Inhibitor Modulator

668 Rofecoxib 738 Meloxicam 669 Rofecoxib 739 Meloxicam 670 Rofecoxib 740 Meloxicam 671 Rofecoxib 741 Meloxicam 672 Rofecoxib 742 Meloxicam 673 Meloxicam 743 Meloxicam 674 Meloxicam 744 Meloxicam 675 Meloxicam 745 Meloxicam 676 Meloxicam 746 Meloxicam 677 Meloxicam 747 Meloxicam 678 Meloxicam 748 Meloxicam 679 Meloxicam 749 Meloxicam 68O Meloxicam 750 Meloxicam 681 Meloxicam 751. Meloxicam 682 Meloxicam 752 Meloxicam 683 Meloxicam 753 Meloxicam 684 Meloxicam 754. Meloxicam 685 Meloxicam 755 Meloxicam 686 Meloxicam 756 Meloxicam 687 Meloxicam 757 A chromene 688 Meloxicam Cox-2 inhibi O 689 Meloxicam 758 A chromene 690 Meloxicam Cox-2 inhibi 691 Meloxicam 759 A chromene 692 Meloxicam Cox-2 inhibi 693 Meloxicam 760 A chromene 694 Meloxicam Cox-2 inhibi 695 Meloxicam 761 A chromene 696 Meloxicam Cox-2 inhibi 697 Meloxicam 762 A chromene 698 Meloxicam Cox-2 inhibi 699 Meloxicam 763 A chromene 700 Meloxicam Cox-2 inhibi 701 Meloxicam 764 A chromene 702 Meloxicam Cox-2 inhibi 703 Meloxicam 765 A chromene 704 Meloxicam Cox-2 inhibi 705 Meloxicam 766 A chromene 7O6 Meloxicam Cox-2 inhibi 707 Meloxicam 767 A chromene 708 Meloxicam Cox-2 inhibi 709 Meloxicam 768 A chromene 710 Meloxicam Cox-2 inhibi 711 Meloxicam 769 A chromene 712 Meloxicam Cox-2 inhibi 713 Meloxicam 770 A chromene 71.4 Meloxicam Cox-2 inhibi 715 Meloxicam 771 A chromene 716 Meloxicam Cox-2 inhibi 717 Meloxicam 772 A chromene 718 Meloxicam Cox-2 inhibi 719 Meloxicam 773 A chromene 720 Meloxicam Cox-2 inhibi 721 Meloxicam 774 A chromene H 8 722 Meloxicam Cox-2 inhibi 723 Meloxicam 775 A chromene 724 Meloxicam Cox-2 inhibi 725 Meloxicam 776 A chromene H2O 726 Meloxicam Cox-2 inhibi 727 Meloxicam 777 A chromene H21 728 Meloxicam Cox-2 inhibi 729 Meloxicam 730 Meloxicam 778 A chromene H22 731 Meloxicam Cox-2 inhibi 732 Meloxicam 779 A chromene H23 733 Meloxicam Cox-2 inhibi 734 Meloxicam A chromene H24 735 Meloxicam Cox-2 inhibi 736 Meloxicam 781 A chromene 737 Meloxicam Cox-2 inhibi O US 2004/O147581 A1 Jul. 29, 2004

TABLE 5-continued TABLE 5-continued Combinations of COX-2 selective inhibiting agents Combinations of COX-2 selective inhibiting agents and 5-HT1A receptor modulators. and 5-HT1A receptor modulators. Example 5-HT, Receptor Example 5-HT, Receptor Number Cox-2 Inhibi O Modulator Number Cox-2 Inhibitor Modulator

782 A c 817 A chromene H61 Cox-2nomene inhibi Cox-2 inhibitor 783 A c 818 A chromene H62 Cox-2nomene inhibi Cox-2 inhibitor 784 A c Olee 819 A chromene H63 Cox-2 inhibi Cox-2 inhibitor 785 A c 82O A chromene H64 Cox-2nomene inhibi Cox-2 inhibitor 786 A c Olee 821 A chromene H65 Cox-2 inhibi Cox-2 inhibitor 787 A c 822 A chromene H66 Cox-2nomene inhibi Cox-2 inhibitor 788 A c Olee 823 A chromene H67 Cox-2 inhibi Cox-2 inhibitor 789 A c 824 A chromene H68 Cox-2nomene inhibi Cox-2 inhibitor 790 A c Olee 825 A chromene H69 Cox-2 inhibi Cox-2 inhibitor 791 A c 826 A chromene H7O Cox-2nomene inhibi Cox-2 inhibitor 792 A c Olee 827 A chromene HF1 Cox-2 inhibi Cox-2 inhibitor 793 A c 828 A chromene H72 Cox-2nomene inhibi Cox-2 inhibitor 794 A c Olee 829 A chromene HT3 Cox-2 inhibi Cox-2 inhibitor 795 A c Olee 830 A chromene HF4 Cox-2 inhibi Cox-2 inhibitor 796 A c Olee 831 A chromene H75 Cox-2 inhibi Cox-2 inhibitor 797 A c 832 A chromene HF6 Cox-2nomene inhibi Cox-2 inhibitor 798 A c 833 A chromene H77 Cox-2nomene inhibi Cox-2 inhibitor 799 A c 834 A chromene HF8 Cox-2nomene inhibi Cox-2 inhibitor 8OO A c 835 A chromene H79 Cox-2nomene inhibi Cox-2 inhibitor 8O1 A c 836 A chromene HSO Cox-2nomene inhibi Cox-2 inhibitor 8O2 A c 837 A chromene HS1 Cox-2nomene inhibi Cox-2 inhibitor 803 A c 838 A chromene HS2 Cox-2nomene inhibi Cox-2 inhibitor 804 A c 839 A chromene HS3 Cox-2nomene inhibi Cox-2 inhibitor 805 A c 840 A chromene HS4 Cox-2nomene inhibi Cox-2 inhibitor 806 A c HSO Cox-2nomene inhibi 807 A c HS1 Cox-2nomene inhibi 1217 Biological Assays 808 A c nomene Cox-2 inhibi 1218 Evaluation of Cox-1 and Cox-2 Activity In Vitro 809 A c nomene Cox-2 inhibi 1219. The Cox-2 inhibiting agents of this invention 810 A c nomene exhibit Cox-2 inhibition in vitro. The Cox-2 inhibition Cox-2 inhibi activity of the compounds illustrated in the example above 811 A c Olee H55 Cox-2 inhibi are determined by the following methods. The Cox-2 inhi 812 A c nomene bition activity of the other Cox-2 inhibitors of the present Cox-2 inhibi invention may also be determined by the following methods. 813 A c Olee H57 Cox-2 inhibi 1220 Preparation of Recombinant Cox Baculoviruses: 814 A c nomene Cox-2 inhibi 1221 Recombinant Cox-1 and Cox-2 are prepared as 815 A c Olee H59 Cox-2 inhibi described by Gierse et al., J. Biochem., 305, 479-84 816 A c Olee (1995). A 2.0 kb fragment containing the coding region of Cox-2 inhibi O either human or murine Cox-1 or human or murine Cox-2 is cloned into a BamH1 site of the baculovirus transfer vector US 2004/O147581 A1 Jul. 29, 2004 64 pVL1393 (Invitrogen) to generate the baculovirus transfer 1229 5-HTA Functional Activity Assay: vectors for Cox-1 and CoX-2 in a manner Similar to the 1230. A clonal cell line stably transfected with the human method of D. R. O'Reilly et al. (Baculovirus Expression 5-HT1A receptor is utilized to determine the intrinsic activity Vectors: A Laboratory Manual (1992)). Recombinant bacu of compounds (according to the general procedure described loviruses are isolated by transfecting 4 lug of baculovirus in J. Dunlop et al., J. Pharmacol. Tox. Methods, 40:47-55 transfer vector DNA into SF9 insect cells (2x10) along with (1998)). Compounds of the present invention are tested for 200 ng of linearized baculovirus plasmid DNA by the their efficacy in antagonizing the ability of 10 nM 8-OH calcium phosphate method. See M. D. Summers and G. E. DPAT to inhibit forskolin stimulated cAMP production in a Smith, A Manual of Methods for Baculovirus Vectors and concentration-related fashion. Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses are purified by three 1231 Biological Evaluation: rounds of plaque purification and high titer (107-108 pfu/ 1232 A combination therapy of a Cox-2 inhibiting agent mL) Stocks of virus are prepared. For large Scale production, and a 5-HT1A receptor modulator for the treatment or pre SF9 insect cells are infected in 10 liter fermentors (0.5x10/ vention of pain, inflammation, or an inflammation-related mL) with the recombinant baculovirus stock such that the disorder in a mammal can be evaluated as described in the multiplicity of infection is 0.1. After 72 hours the cells are following tests. centrifuged and the cell pellet is homogenized in Tris/ Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-(3- 1233) Rat Focal Stroke Model: cholamidopropyl)-dimethylammonio-1-propanesulfonate 1234. The efficacy of the compositions of the present (CHAPS). The homogenate is centrifuged at 10,000xG for invention for the prevention and treatment of focal Stroke in 30 minutes, and the resultant Supernatant is stored at -80 C. rats can be determined according to the method described in before being assayed for Cox activity. Nogawa, S. et al., J. of Neuroscience, 17(8):2748–2755 (1997). 1222 Assay for Cox-1 and Cox-2 Activity: 1235 Induction and Assessment of Collagen Induced 1223 Cox activity is assayed as PGE2 formed/ug protein/ Arthritis in Mice: time using an ELISA to detect the prostaglandin released. 1236 Arthritis is induced in 8-12 week old male DBA/1 CHAPS-solubilized insect cell membranes containing the mice by injection of 50 mg of chick type II collagen (CII) in appropriate Cox enzyme are incubated in a potassium phos complete Freunds adjuvant (Sigma) on day 0 at the base of phate buffer (50 mM, pH 8.0) containing epinephrine, phe the tail as previously described J. Stuart, Annual Rev. nol, and heme with the addition of arachidonic acid (10 uM). Immunol., 2:199 (1984)). Compounds are prepared as a Compounds are pre-incubated with the enzyme for 10-20 suspension in 0.5% methylcellulose (Sigma, St. Louis, Mo.), minutes prior to the addition of arachidonic acid. Any 0.025% Tween 20 (Sigma). The Cox-2 inhibitors and the reaction between the arachidonic acid and the enzyme is 5-HT, receptor modulator are administered alone or a COX-2 stopped after ten minutes at 37 C./room temperature by inhibitor and 5-HT1A receptor modulator in combination. transferring 40 ul of reaction mix into 160 ul ELISA buffer The compounds are administered in non-arthritic animals by and 25 Mindomethacin. The PGE2 formed is measured by gavage in a Volume of 0.1 ml beginning on day 20 post standard ELISA technology (Cayman Chemical). collagen injection and continuing daily until final evaluation on day 55. 1224) Fast Assay for Cox-1 and Cox-2 Activity: 1237 Animals are boosted on day 21 with 50 mg of 1225 Cox activity is assayed as PGE2 formed/ug protein/ collagen (CII) in incomplete Freunds adjuvant. The animals time using an ELISA to detect the prostaglandin released. are Subsequently evaluated Several times each week for CHAPS-solubilized insect cell membranes containing the incidence and Severity of arthritis until approximately day appropriate Cox enzyme are incubated in a potassium phos 56. Any animal with paw redness or Swelling is counted as phate buffer (0.05 M Potassium phosphate, pH 7.5, 2 uM arthritic. Scoring of Severity is carried out using a Score of phenol, 1 uM heme, 300 uM epinephrine) with the addition 0-3 for each paw (maximal score of 12/mouse) as previously of 20 ul of 100 uMarachidonic acid (10 uM). Compounds described P. Wooley, et al., Trans. Proc., 15:180 (1983)). are pre-incubated with the enzyme for 10 minutes at 25 C. The animals are measured for incidence of arthritis and prior to the addition of arachidonic acid. Any reaction severity in the animals where arthritis is observed. The between the arachidonic acid and the enzyme is stopped incidence of arthritis is determined at a groSS level by after two minutes at 37 C./room temperature by transferring observing the Swelling or redness in the paw or digits. 40 ul of reaction mix into 160 ul ELISA buffer and 25 uM Severity is measured with the following guidelines. Briefly, indomethacin. The PGE2 formed is measured by standard animals displaying four normal paws, i.e., no redness or ELISA technology (Cayman Chemical). Swelling are Scored 0. Any redness or Swelling of digits or the paw is Scored as 1. GroSS Swelling of the whole paw or 1226 Evaluation of 5-HTA Activity In Vitro deformity is Scored as 2. Ankylosis of joints is Scored as 3. 1227 5-HT Receptor Binding Profile: 1238 Histological Examination of Paws: 1228 Compounds are tested for binding to cloned human 1239. In order to verify the gross determination of a 5-HT1A receptors stably transfected into CHO cells using non-arthritic animal, a histological examination is per HI8-OH-DPAT as the 5-HT1A radioligand (according to formed. Paws from animals sacrificed at the end of the general procedure described in J. Dunlop et al., J. Pharma experiment are removed, fixed and decalcified as previously col. Tox. Methods, 40:47-55 (1998)). described R. Jonsson, J. Immunol. Methods, 88:109 US 2004/O147581 A1 Jul. 29, 2004

(1986)). Samples are paraffin embedded, sectioned, and meclofenamic acid, flufenamic acid, niflumic acid, Stained with hernatoxylin and eosin by Standard methods. flufenisal, Sudoxicam, etodolac, piprofen, Salicylic acid, Stained Sections are examined for cellular infiltrates, Syn choline magnesium trisalicylate, Salicylate, benorylate, fen ovial hyperplasia, and bone and cartilage erosion. tiazac, clopinac, feprazone, isoxicam, and 2-fluoro-a-methyl 1240 All references cited in this specification, including 1,1'-biphenyl-4-acetic acid, 4-(nitrooxy)butyl ester. without limitation all papers, publications, presentations, 5. The composition according to claim 4, wherein the texts, reports, manuscripts, brochures, books, internet post Cox-2 inhibitor comprises 2-fluoro-a-methyl1,1'-biphe ings, journal articles, periodicals, and the like, are hereby nyl-4-acetic acid, 4-(nitrooxy)butyl ester. incorporated by reference. The discussion of the references 6. The composition according to claim 1, wherein the herein is intended merely to Summarize the assertions made Cox-2 inhibitor comprises a Cox-2 selective inhibitor. by their authors and no admission is made that any reference 7. The composition according to claim 6, wherein the constitutes prior art. Applicants reserve the right to chal Cox-2 Selective inhibitor comprises at least one compound lenge the accuracy and pertinency of the cited references. Selected from the group consisting of celecoxib, deracoxib, parecoxib, Valdecoxib, rofecoxib, lumiracoxib, etoricoxib, 1241. In view of the above, it will be seen that the several meloxicam, and mixtures and prodrugs thereof. advantages of the invention are achieved and other advan 8. The composition according to claim 7, wherein the tageous results obtained. Cox-2 Selective inhibitor comprises at least one compound 1242. While the invention has been described and illus Selected from the group consisting of celecoxib, Valdecoxib, trated with reference to certain particular embodiments rofecoxib, and mixtures thereof. thereof, those skilled in the art will appreciate that various 9. The composition according to claim 1, wherein the changes, modifications and Substitutions can be made Cox-2 Selective inhibitor comprises a chromene Cox-2 therein without departing from the Spirit and Scope of the Selective inhibitor. invention. For example, effective dosages other than the 10. The composition according to claim 1, wherein the particular dosages as Set forth herein above may be appli 5-HT, receptor modulator comprises at least one compound cable as a consequence of variations in the responsiveness of Selected from the group consisting of (R)-N-(1,3-benzo the mammal being treated for any of the indications for the dioxol-5-ylmethyl)-1,2,3,4-tetrahydro-1 benzothieno 2,3- active agents used in the methods, combinations and com cpyridine-3-carboxamide (AP-521), 1-3-4-(3-chlorophe positions of the present invention as indicated above. Like nyl)-1-piperazinylpropyl-3,4-dihydro-5-methoxy-2(1H)- wise, the specific pharmacological responses observed may quinolinone (OPC-14523), 2-4-4-(7-chloro-2,3-dihydro-1, vary according to and depending upon the particular active 4-benzodioxin-5-yl)-1-piperazinylbutyl-1,2- compound Selected or whether there are present pharmaceu benzisothiazol-3(2H)-one-1,1-dioxide (DU-125530), 7-(4- tical carriers, as well as the type of formulation and mode of methyl-1-piperazinyl)-2(3H)benzoxazolone, administration employed, and Such expected variations or monohydrochloride (SLV-308), adatanserin, alnespirone, differences in the results are contemplated in accordance binospirone, buspirone, DU-127090, E-2101, eptapirone, with the objects and practices of the present invention. It is flibanserin, gepirone, ipsapirone, lesopitron, N-(2-4-(2- intended, therefore, that the invention be defined by the methoxyphenyl)-1-piperazinylethyl-N-2-pyridinyl-cyclo scope of the claims which follow and that such claims be hexanecarboxamidetrihydrochloride (WAY-100635), N-3- interpreted as broadly as is reasonable. (1,3-benzodioxol-5-yloxy)propyl-2,3-dihydro-(2S)-1,4- benzodioxin-2-methanaminehydrochloride (MKC-242), What is claimed is: repinotan, robalzotan, Sarizotan, SLV-319, SUN-N4057, tan 1. A composition comprising a Cox-2 inhibitor and a doSpirone, VilaZodone, VML-670, Xaliproden, Ziprasidone, 5-HT, receptor modulator. 6-hydroxy-buspirone, pyrazolidine derivative, heteroary 2. The composition according to claim 1, wherein the loxyethylamines, 5-hydoxytryptamine, 5-methox amount of the Cox-2 inhibitor and the amount of the 5-HTA ytryptamine, buspirone, 8-hydroxy-2-(di-n-propylamino)te receptor modulator together comprise a therapeutically tralin (8-OH-DPAT), ipsaspirone, gepirone, SM23997, effective amount for the treatment or prevention of pain, ly Sergic acid diethylamide, agonistic antibodies, piperazine inflammation or an inflammation-related disorder. derivatives, 8-(2-aminoalkoxy) fluorochroman derivatives, 3. The composition according to claim 1, wherein the abeo-ergoline derivatives, A-74283, AP-159, AZ 16596, Cox-2 inhibitor comprises a non-Steroidal anti-inflammatory 2-4-(2-methoxyphenyl)piperazin-1-yl)methyl octahy drug. droimidazo 1.5-alpyridine-1,3-dione (B 20991), BMS 4. The composition according to claim 3, wherein the 181100 (BMY42569), BMS 181970,1-methyl-4-7-(4-chlo Cox-2 inhibitor is Selected from the group consisting of rophenyl)methylaminocarbonyl napththyl-piperazine ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenopro (CP291952), (omega-piperazinylalkoxy) alkylenedioxyben fen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, Zene (BP 554), E 5165, E 6265, ebalzotan, eltoprazine, F Oxaprozin, prapoprofen, miroprofen, tioxaprofen, Suprofen, 11440, F. 13714, flesinoxan, 2-4-(3-phenylpyrrolidin-1-yl alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, )butyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (LB indomethacin, Sulindac, tolmetin, Zomepirac, diclofenac, 50016), LY41, (+/-)-4-substituted-amino-6-substituted-1,3, fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopi 4,5-tetrahydrobenzc,dinoles (LY 228729), LY228730, LY nac, Zidometacin, acetyl Salicylic acid, indometacin, piroxi 274600, LY 274601, LY 293284, 6-heterocyclyl-4-amino-1, cam, tenoxicam, nabumetone, ketorolac, azapropaZone, 3,4,5-tetrahydrobenz CD indoles (LY 297996), isoxazole mefenamic acid, tolfenamic acid, diflunisal, podophyllo derivatives (LY 315535), hetero-oxy alkanamines (LY toxin derivatives, acemetacin, droxicam, floctafenine, 333068), LY 426965, LY 433221, MDL 72832, MDL 73975, OxyphenbutaZone, phenylbutaZone, proglumetacin, acem NDL 249, nerisopam, Org 1301, 2-(2-oxo-hexahydropyri etacin, fentiazac, clidanac, OXipinac, mefenamic acid, midin-1-yl)propylaminomethyl-benzopyran (R137696), RU US 2004/O147581 A1 Jul. 29, 2004 66

24969, 1-5-4-substituted-1-pipe razinyl)methyl-pyrrol 4-benzodioxin-5-yl)-1-piperazinylbutyl-1,2- 2-yl or furan-2-yl)methyl-2-piperidinones (RWJ 25730), S benzisothiazol-3(2H)-one-1,1-dioxide (DU-125530), 7-(4- 14489, S 14506, S 14671, S 15535, S 15931, 8-4-N-(5- methyl-1-piperazinyl)-2(3H)benzoxazolone, Acetyl-3,4-dihydro-2H-1-benzopyran-3-yl)-Npropylamino monohydrochloride (SLV-308), adatanserin, alnespirone, butyl-8-azaspiro 4.5decane-7,9-dione (S 23751), SDZ binospirone, buspirone, DU-127090, E-2101, eptapirone, 216-525, SEP 109235, SR59026, Sunepitron, UH 301, WAY flibanserin, gepirone, ipsapirone, lesopitron, N-(2-4-(2- 100135, WAY 100802, (3-chloro-4-fluoro-phenyl)-4- methoxyphenyl)-1-piperazinylethyl-N-2-pyridinyl-cyclo fluoro-4-(5-methyl-pyridin-2-ylmethyl)amino-meth hexanecarboxamidetrihydrochloride (WAY-100635), N-3- yl)piperidin-1-yl)-methadone (F 13640), Zalospirone, a (1,3-benzodioxol-5-yloxy)propyl-2,3-dihydro-(2S)-1,4- pharmaceutically acceptable Salt of any one of the com benzodioxin-2-methanaminehydrochloride (MKC-242), pounds, and mixtures of two or more of the compounds. repinotan, robalzotan, Sarizotan, SLV-319, SUN-N4057, tan 11. The composition according to claim 1, wherein the doSpirone, VilaZodone, VML-670, Xaliproden, Ziprasidone, 5-HT, receptor modulator comprises at least one compound 6-hydroxy-buspirone, pyrazolidine derivative, heteroary that is Selected from the group consisting of buspirone, loxyethylamines, 5-hydoxytryptamine, 5-methox gepirone, repinotan, tandoSpirone, Xaliproden, Ziprasidone, ytryptamine, buspirone, 8-hydroxy-2-(di-n-propylamino)te and mixtures thereof. tralin (8-OH-DPAT), ipsaspirone, gepirone, SM23997, 12. A method for the treatment or prevention of pain, ly Sergic acid diethylamide, agonistic antibodies, piperazine inflammation, or inflammation-related disorder in a Subject derivatives, 8-(2-aminoalkoxy) fluorochroman derivatives, in need thereof, comprising administering to the Subject a abeo-ergoline derivatives, A-74283, AP-159, AZ 16596, Cox-2 inhibitor and a 5-HT1A receptor modulator. 2-4-(2-methoxyphenyl)piperazin-1-yl)methyl octahy 13. The method according to claim 12, wherein the droimidazo 1.5-alpyridine-1,3-dione (B 20991), BMS amount of the Cox-2 inhibitor and the amount of the 5-HTA 181100 (BMY42569), BMS 181970,1-methyl-4-7-(4-chlo receptor modulator together comprise a therapeutically rophenyl)methylaminocarbonyl napththyl-piperazine effective amount for the treatment or prevention of pain, (CP291952), (omega-piperazinylalkoxy) alkylenedioxyben inflammation or an inflammation-related disorder in the Zene (BP 554), E 5165, E 6265, ebalzotan, eltoprazine, F Subject. 11440, F. 13714, flesinoxan, 2-4-(3-phenylpyrrolidin-1-yl 14. The method according to claim 12, wherein the Cox-2 )butyl -1,2-benzisothiazol-3(2H)-one 1,1-dioxide (LB inhibitor comprises at least one non-Steroidal anti-inflam 50016), LY 41, (+/-)-4-Substituted-amino-6-substituted-1, matory drug that is selected from the group consisting of 3,4,5-tetrahydrobenzc,dinoles (LY 228729), LY 228730, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenopro LY 274600, LY 274601, LY 293284, 6-heterocyclyl-4- fen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, amino-1,3,4,5-tetrahydrobenz CD indoles (LY 297996), Oxaprozin, prapoprofen, miroprofen, tioxaprofen, Suprofen, isoxazole derivatives (LY315535), hetero-oxyalkanamines, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, (LY 333068), LY 426965, LY 433221, MDL 72832, MDL indomethacin, Sulindac, tolmetin, Zomepirac, diclofenac, 73975, NDL 249, nerisopam, Org 1301, 2-(2-oxo-hexahy fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopi dropyrim idin-1-yl)propylaminomethyl-benzopyran nac, Zidometacin, acetyl Salicylic acid, indometacin, piroxi (R137696), RU 24969,1-5-4-substituted-1-piperazinyl cam, tenoxicam, nabumetone, ketorolac, azapropaZone, methyl-pyrrol-2-yl or furan-2-yl)methyl-2-piperidinones mefenamic acid, tolfenamic acid, diflunisal, podophyllo (RWJ 25730), S 14489, S 14506, S 14671, S 15535, S toxin derivatives, acemetacin, droxicam, floctafenine, 15931, 8-4-N-(5-Acetyl-3,4-dihydro-2H-1-benzopyran-3- OxyphenbutaZone, phenylbutaZone, proglumetacin, acem yl)-Npropylaminobutyl-8-azaspiro etacin, fentiazac, clidanac, OXipinac, mefenamic acid, decane-7,9-dione (S 23751), SDZ 216-525, SEP 109235, meclofenamic acid, flufenamic acid, niflumic acid, SR59026, Sunepitron, UH 301, WAY 100135, WAY flufenisal, Sudoxicam, etodolac, piprofen, Salicylic acid, 100802, (3-chloro-4-fluoro-phenyl)-4-fluoro-4-(5- choline magnesium trisalicylate, Salicylate, benorylate, fen methyl-pyridin-2-ylmethyl)amino-methyl)piperidin tiazac, clopinac, feprazone, isoxicam, and 2-fluoro-a-methyl 1-yl)-methadone (F 13640), Zalospirone, and mixtures 1,1'-biphenyl-4-acetic acid, 4-(nitrooxy)butyl ester. thereof. 15. The method according to claim 12, wherein the Cox-2 inhibitor comprises a Cox-2 selective inhibitor. or a pharmaceutically acceptable Salt of the compound. 16. The method according to claim 12, wherein the Cox-2 19. The method according to claim 12, wherein the Selective inhibitor comprises at least one compound that is 5-HT, receptor modulator comprises at least one compound Selected from the group consisting of celecoxib, deracoxib, that is Selected from the group consisting of of buspirone, Valdecoxib, parecoxib, lumiracoxib, rofecoxib, etoricoxib, gepirone, repinotan, tandoSpirone, Xaliproden, Ziprasidone, meloxicam, and mixtures and prodrugs thereof. and mixtures thereof. 17. The method according to claim 12, wherein the Cox-2 20. The method according to claim 12, wherein the Selective inhibitor comprises at least one compound Selected inflammation-related disorder is Selected from the group from the group consisting of celecoxib, parecoxib, rofe consisting of central nervous System disorder, cognitive coxib, and mixtures thereof. dysfunction, and glaucoma. 18. The method according to claim 12, wherein the 21. The method according to claim 20, wherein the central 5-HT, receptor modulator comprises at least one compound nervous System disorder is a disorder associated with Stroke Selected from the group consisting of (R)-N-(1,3-benzo (ischemic or hemorrhagic) or ischemic brain injury. dioxol-5-ylmethyl)-1,2,3,4-tetrahydro-1 benzothieno 2,3- 22. The method according to claim 12, wherein the pain, cpyridine-3-carboxamide (AP-521), 1-3-4-(3-chlorophe inflammation or inflammation related disorder is Selected nyl)-1-piperazinylpropyl-3,4-dihydro-5-methoxy-2(1H)- from the group consisting of adjustment disorders, anxiety quinolinone (OPC-14523), 2-4-4-(7-chloro-2,3-dihydro-1, (mixed anxiety), mood (depressed), conduct disturbance, US 2004/O147581 A1 Jul. 29, 2004 67 mixed anxiety and mood (conduct), addictive disorders, protective effects for ischemic brain injury, neuroprotective alcohol abuse, intoxication disorders, nicotine abuse, psy effects for myocardial infarction, neuroprotective effects for choactive Substances abuse, Substance disorder, withdrawal Spinal cord injury, neuroprotective effects for traumatic Syndromes, acute trauma, age associated mental disorders, brain injury, neuroprotective effects for obesity, obsessive learning disorders, Alzheimer's disease, agitation disorders, compulsive disorder (OCD), oncology related disorders, agitation in Alzheimer's disease, agitation in the elderly, behavior abnormalities resulting from tumors or treatments, aggressive behavior, aggressive behavior in AlzheimerS dis oppositional defiant disorder, pain disorders, acute pain, ease, amyloidosis, aging/senile amyloidosis, hereditary chronic pain, cluster headache, dySmenorrhea, labor pain, amyloidosis, immunocyte derived amyloidosis, lichen amy migraine pain, neuropathic pain, AIDS-related pain, AIDS loidosis, primary amyloidosis, reactive Systemic amyloido sis, Secondary amyloidosis, Senile amyloidosis (Alzheimer's asSociated dementia, cancer-related pain, chemotherapeutic disease), amyotrophy & amyotripic lateral Scherosis (ALS), induced pain, diabetic pain, post-herpetic neuralgia, radia ALS, anorexia nervosa, anxiety disorders, generalized anxi tion-induced pain, osteoarthritis flare, phantom limb pain, ety disorder (GAD), Social phobias, stress related diseases, Surgical pain, post-Surgical pain, incisional pain, psychic apathy, attention deficit disorder (ADD), attention deficit pain, regional pain, abdominal pain, chronic back pain, hyperactivity disorder (ADHD), autism, auto immune dis complex-regional pain disorder, dental, face and mouth pain, orders, lupus erythematosis, multiple Sclerosis, behavioral head pain, lower back and peripheral pain, rheumatoid disturbances, agitation plus diminished cognition, bipolar I arthritis pain, Starting pain, Systematic pain, connective disorder, bipolar II disorder, bulimia nervosa, cardiovascular tissue pain, musculoskeletal pain, nervous System pain, disorders, blood pressure modification, hypertension, urogenital pain, uterine contraction pain, panic disorder, hypotension, heart rate modification, chemotherapy-induced agoraphobia, peripheral neuropathy, personality disorders, vomiting, chronic fatigue immune disorders (CFIDS), chronic fatigue Syndrome (CFS), cognitive dysfunction, phobias (simple), phobias of animals, phobias of closed cortical dementias, mild cognitive impairment (MCI), Lewy Spaces (claustrophobia), phobias of heights (acrophobia), Body dementia, Vascular dementia, neurodegeneration, cog phobias of public places (agoraphobia), Social phobias, nitive dysfunction resulting from Stroke, ischemia, trauma, phobia of public eating, phobia of public embarrassment, or Surgical procedures, including coronary artery bypass phobia of public performance/speaking and using public Surgery, cognition enhancement, conduct disorder, lavatories, poop out Syndrome, SSRI, post-traumatic StreSS cyclothymia, delusional disorder, depression, adolescent disorder, progressive Supranuclear palsy (PSP), prolactin depression, depression in Alzheimer's disease, general plasma level disorders, psychotic disorders, brief psychosis, depression, minor depression, depression in Parkinson's long duration pSychosis, psychosis due to medical condition, disease, depression in diabetic neuropathy, dissociative dis restless leg Syndrome (RLS), Schizophrenias, delusional orders, developmental disorders, learning disabilities, lan (paranoid) disorder, Schizoaffective disorders, Schizophreni guage disorders, mental retardation, dementia, dementias form disorders, Seasonal affective disorder, Seizure disor asSociated with aging, illness, neurodegeneration and dyS ders, epilepsy (partial), epilepsy (generalized), Sexual dys kensia, dysthymia, dystonia, eating disorders associated function, Sleep disorders, apnea, parasomnias, insomnia, with anorexia nervosa, bulimia nervosa, obesity, epilepsy, or narcolepsy, obstructive Sleep disorder, disorders of circadian fibromyalgia Syndrome (FMS), gastrointestinal disorders, rhythm, enuresis, initiation, or maintenance, Social phobias, irritable bowel Syndrome, psychogenic effects and StreSS Social anxiety disorder, Somatoform disorders, conversion, related; growth retardation effects, endocrine, psychoSocial body, dysmorphic Somatoform disorder, fibromyalgia Syn and StreSS-related retardation, heart rate modification, Hun tington's chorea, hypertension, immune System disorders, drome (FMS), hypochondriasis, NOS, somatization, undif immune System depression, impulse control disorders, ferentiated Somatoform disorder, developmental disorders, incontinence, infectious neuropathy, AIDS, carpal tunnel StreSS disorders, acute StreSS disorder, chronic StreSS disor syndrome, dementia, irritable bowel syndrome (IBS), con der, incontinence, spectrum disorders, Stroke, Suicidal stipative IBS, diarrhea-predominant IBS, inflammatory behavior, thyroid stimulating hormone disorders (TSH), bowel disease (IBD), constipation-predominant IBD, diar Tourette's Syndrome, tooth-germ morphogenesis disorders, rhea-predominant IBD, mixed states IBD, inhalation disor thermoregulation disorders, TSH modulating agent disor der, lactation inhibition, metabolic & chromosomal disor ders, tic disorders, trauma, acute trauma, head trauma, ders, galactosemia phenylketonuria, fatty acid disorder, vasospasms, vasoreactive headaches and violent behavior. infantile nephropathic cystinosis, orthithrotranscarbamylase 23. The method of claim 12, wherein the subject is a porphyria, migrane, mood disorders, a typical depression, mammal. bipolar disorder (including pychotic features), major depres 24. A pharmaceutical composition for the treatment or Sive disorder, mania, Seasonal affective disorder, movement prevention of pain, inflammation, or inflammation-related disorders, athetosis, chorea, dyskinesia, dystonia, restleSS disorder, the pharmaceutical composition comprising a leg Syndrome (RLS), tremor plus periodic limb movement (PLM), periodic limb movements of sleep (PLMS), Parkin Cox-2 inhibitor, a 5-HT1A receptor modulator, and a phar Son's disease, PLM, PLMS, progressive Supranuclear palsy, maceutically-acceptable excipient. Stereotypy (various), torticollis, tic disorders, tremor; mul 25. A kit that is Suitable for use in the treatment or tisystemic atrophy (MSA), multiple Sclerosis, neuroendo prevention of pain, inflammation, or inflammation-related crine System disorders, neurodegenerative disorders, amyo disorder wherein the kit comprises a first dosage form trophy, amyotrophy diabetics, amyotrophic lateral Sclerosis comprising a Cox-2 inhibitor and a Second dosage form (ALS), Parkinson's disease, neurological disorders, neur comprising a 5-HT1A receptor modulator, in quantities opathy, diabetic neuropathy, peripheral neuropathy, neuro which comprise a therapeutically effective amount of the US 2004/O147581 A1 Jul. 29, 2004 68 compounds for the treatment, prevention or inhibition of comprising administering to the Subject a Cox-2 inhibitor pain, inflammation, or an inflammation-related disorder. and a 5-HT1A receptor modulator. 26. A method for the prevention or treatment of a neuro logic disorder involving neurodegeneration in a Subject that is in need of Such prevention or treatment, the method k . . . .