Patent Publication Number: US-2004053900-A1

Title: Method of using a COX-2 inhibitor and an aromatase inhibitor as a combination therapy

Description:
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 09/470,951, filed Dec. 22, 1999, which claims priority to United States provisional patent application Serial No. 60/113,786, filed Dec. 23, 1998. The text of these applications is hereby incorporated by reference. 
    
    
     
       FIELD OF THE INVENTION  
       [0002] The present invention relates to compositions and methods for the treatment, prevention or inhibition of a neoplasia, a neoplasia-related disorder or osteoporosis in a mammal using a combination of a COX-2 selective inhibitor and an aromatase inhibitor.  
       BACKGROUND OF THE INVENTION  
       [0003] Cancer is now the second leading cause of death in the United States and over 8,000,000 persons in the United States have been diagnosed with cancer. In 1995, cancer accounted for 23.3% of all deaths in the United States. (See U.S. Dept. of Health and Human Services, National Center for Health Statistics, Health United States 1996-97 and Injury Chartbook 117 (1997)).  
       [0004] Cancer is not fully understood on the molecular level. It is known that exposure of a cell to a carcinogen such as certain viruses, certain chemicals, or radiation, leads to DNA alteration that inactivates a “suppressive” gene or activates an “oncogene”. Suppressive genes are growth regulatory genes, which upon mutation, can no longer control cell growth. Oncogenes are initially normal genes (called proto-oncogenes) that by mutation or altered context of expression become transforming genes. The products of transforming genes cause inappropriate cell growth. More than twenty different normal cellular genes can become oncogenes by genetic alteration. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and mortality (transformed cells can grow indefinitely).  
       [0005] A neoplasm, or tumor, is an abnormal, unregulated, and disorganized proliferation of cell growth, and is generally referred to as cancer. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body&#39;s circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.  
       [0006] Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery involves the bulk removal of diseased tissue. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, such as the backbone, nor in the treatment of disseminated neoplastic conditions such as leukemia. Radiation therapy involves the exposure of living tissue to ionizing radiation causing death or damage to the exposed cells. Side effects from radiation therapy may be acute and temporary, while others may be irreversible. Chemotherapy involves the disruption of cell replication or cell metabolism. It is used most often in the treatment of breast, lung, and testicular cancer.  
       [0007] The adverse effects of systemic chemotherapy used in the treatment of neoplastic disease are most feared by patients undergoing treatment for cancer. Of these adverse effects nausea and vomiting are the most common and severe side effects. Other adverse side effects include cytopenia, infection, cachexia, mucositis in patients receiving high doses of chemotherapy with bone marrow rescue or radiation therapy; alopecia (hair loss); cutaneous complications (see M. D. Abeloff, et al., Alopecia and Cutaneous Complications, p. 755-56 in Abeloff, M. D., Armitage, J. O., Lichter, A. S., and Niederhuber, J. E. (eds.), Clinical Oncology, Churchill Livingston, N.Y., 1992, for cutaneous reactions to chemotherapy agents), such as pruritis, urticaria, and angioedema; neurological complications; pulmonary and cardiac complications in patients receiving radiation or chemotherapy; and reproductive and endocrine complications. Chemotherapy-induced side effects significantly impact the quality of life of the patient and may dramatically influence patient compliance with treatment.  
       [0008] Additionally, adverse side effects associated with chemotherapeutic agents are generally the major dose-limiting toxicity (DLT) in the administration of these drugs. For example, mucositis, is one of the major dose limiting toxicities for several anticancer agents, including the antimetabolite cytotoxic agents 5-FU, methotrexate, and antitumor antibiotics, such as doxorubicin. Many of these chemotherapy-induced side effects if severe, may lead to hospitalization, or require treatment with analgesics for the treatment of pain.  
       [0009] Prostaglandins are arachidonate metabolites that are produced in virtually all mammalian tissues and possess diverse biologic capabilities, including vasoconstriction, vasodilation, stimulation or inhibition of platelet aggregation, and immunomodulation, primarily immunosuppression. They are implicated in the promotion of development and growth of malignant tumors (Honn et al., Prostaglandins, 21, 833-64 (1981); Furuta et al., Cancer Res., 48, 3002-7 (1988); Taketo, J. Natl. Cancer Inst., 90, 1609-20 (1998)). They are also involved in the response of tumor and normal tissues to cytotoxic agents such as ionizing radiation (Milas and Hanson, Eur. J. Cancer, 31A, 1580-5 (1995)). Prostaglandin production is mediated by two cyclooxygenase enzymes, COX-1 and COX-2. Cyclooxygenase-1 (COX-1) is constitutively expressed and is ubiquitous. Cyclooxygenase-2 (COX-2) is induced by diverse inflammatory stimuli (Isakson et al., Adv. Pros. Throm. Leuk Res., 23, 49-54 (1995)).  
       [0010] Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) non-selectively inhibit both cyclooxygenase enzymes and consequently can prevent, inhibit, or abolish the effects of prostaglandins. Increasing evidence shows that NSAIDs can inhibit the development of cancer in both experimental animals and in humans, can reduce the size of established tumors, and can increase the efficacy of cytotoxic cancer chemotherapeutic agents.  
       [0011] Investigations have demonstrated that indomethacin prolongs tumor growth delay and increases the tumor cure rate in mice after radiotherapy (Milas et al., Cancer Res., 50, 4473-7 (1990)). The influence of oxyphenylbutazone and radiation therapy on cervical cancer has been studied (Weppelmann and Monkemeier, Gyn. Onc., 17(2), 196-9 (1984)). However, treatment with NSAIDs is limited by toxicity to normal tissue, particularly by ulcerations and bleeding in the gastrointestinal tract, ascribed to the inhibition of COX-1. Recently developed selective COX-2 inhibitors exert potent anti-inflammatory activity but cause fewer side effects.  
       [0012] COX-2 has been linked to all stages of carcinogenesis (S. Gately, Cancer Metastasis Rev., 19(1/2), 19-27 (2000)). Recent studies have shown that compounds which preferentially inhibit COX-2 relative to COX-1 restore apoptosis and inhibit cancer cell proliferation (E. Fosslien, Crit. Rev. Clin. Lab. Sci., 37(5), 431-502 (2000)). COX-2 inhibitors, such as celecoxib, are showing promise for the treatment and prevention of colon cancer (R. A. Gupta et al., Ann. N.Y. Acad. Sci., 910, 196-206 (2000)) and in animal models for the treatment and prevention of breast cancer (L. R. Howe et al., Endocr.-Relat. Cancer, 8(2), 97-114 (2001)).  
       [0013] COX-2 inhibitors have been described for the treatment of cancer (WO 98/16227) and for the treatment of tumors (EP 927,555). Celecoxib, an anti-inflammatory drug showing a high degree of selectivity for COX-2, exerted potent inhibition of fibroblast growth factor-induced corneal angiogenesis in rats (Masferrer et al., Proc. Am. Assoc. Cancer Research, 40, 396 (1999)).  
       [0014] In 1896 Cecil Beatson demonstrated that ovariectomy resulted in tumor regression in premenopausal breast cancer patients. Subsequently, estrogens were identified as the mediator of ovarian dependency. The biological effect of estrogens was found to be mediated by the stimulation of a nuclear estrogen receptor (ER), which belongs to a family of hormone-activated transcription factors that can initiate or enhance the transcription of genes containing specific hormone response elements. Further, the sensitivity of breast cancer to estrogens has been found to increase in tumors positive for ER. Over the last two decades, several approaches have been attempted to develop pharmacological agents able to reduce estrogen effect.  
       [0015] Two pharmacological approaches are currently available: 1) the antiestrogens, which antagonize the effect of estrogens at the ER level; 2) the aromatase (estrogen synthetase) inhibitors, which inhibit the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The prototype antiestrogen, tamoxifen, is now largely used in the adjuvant systemic therapy of localized breast cancer (i.e., systemic therapy given at the time of primary local treatment in the absence of demonstrated metastasis) and in the treatment of advanced (metastatic) breast cancer. However, resistance to tamoxifen occurs, due to: 1) the intrinsic estrogenic effect of tamoxifen (i.e., partial estrogen agonism); 2) the formation of tamoxifen&#39;s estrogenic metabolites; 3) the stimulation by tamoxifen and its metabolites of a mutated ER; 4) the growth of estrogen independent tumor cells. In addition, some concerns are now being considered in the use of tamoxifen in the early disease, due to the increased risk of endometrial cancer. Therefore, new hormonal therapies without the negative effects of either tamoxifen or other similar compounds are under extensive evaluation.  
       [0016] The aromatase inhibitors represent one such new antihormonal treatment for breast cancer (V. C. O. Njar et al., Drugs, 58(2), 233-255 (1999)). In premenopausal women, the ovarian aromatase is the main source of circulating estrogens. In postmenopausal women, adipose tissue is considered to be the main site for estrogen synthesis. In addition, aromatase activity has been shown in the breast tissue, including the tumor itself. Therefore, the very high levels of intratumoral estrogens in comparison to the circulating estrogens are due to the local estrogen synthesis through the aromatase enzyme. Various steroidal and non-steroidal compounds have been described as aromatase inhibitors, including the steroidal derivatives exemestane and formestane, and the nonsteroidal derivatives aminoglutethimide, vorozole, fadrozole, letrozole, anastrozole and YM-511 (Kudoh, M. et al., J. Steroid. Biochem. Molec. Biol., 58,189-194 (1996)). The use of exemestane in postmenopausal women with advanced breast cancer has been reviewed (D. Clemett et al., Drugs, 59(6), 1279-1296 (2000)). Many clinical trials have shown that these compounds represent an effective second line treatment for metastatic breast cancer refractory to tamoxifen. In addition, these compounds are being clinically evaluated in the adjuvant setting, either alone or combined with tamoxifen, and as first-line treatment of the metastatic disease. The more complete estrogen blockade via aromatase inhibition is expected to result in greater tumor response than with tamoxifen, due to the weak or partial estrogen agonist effect of tamoxifen as above discussed.  
       [0017] Breast cancer was one of the first solid tumors to be treated with chemotherapy involving cytotoxic agents, and one of the first tumors to be treated with polychemotherapy. Menopausal status and ER status play an important role in therapy selection either in early or metastatic breast cancer. Chemotherapy is more commonly used in premenopausal women who are more likely to have ER-negative tumors. In the advanced disease, chemotherapy is recommended for ER-negative tumors and after hormonotherapy failures for ER-positive tumors. In several randomized trials, polychemotherapy has been established to be superior to monochemotherapy either in the adjuvant or metastatic setting. The cytotoxic compounds generally used in the polychemotherapy of breast cancer or that are under clinical evaluation belong to various classes including: 1) topoisomerase II inhibitors, such as the antracyclines doxorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide; 2) antimicrotubule agents, such as the taxanes paclitaxel and docetaxel, and the vinkaalkaloids vinblastine and vinorelbine; 3) alkylating agents, such as cyclophosphamide, ifosfamide and melphalan and the alkycycline derivative PNU-159548 (C. Geroni et al., Proc. Am. Assoc. Cancer Res. 39, 223 (1998)); 4) antineoplastic antimetabolites, such as 5-fluorouracil, capecitabine, gemcitabine, methotrexate and edatrexate; 5) topoisomerase I inhibitors, such as topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804).  
       [0018] Despite intensive efforts directed at prevention and early diagnosis, breast cancer remains one of the leading causes of morbidity and mortality in women. Although early-stage disease is now frequently cured by surgical intervention and adjuvant hormonal and/or chemotherapy, the prognosis for women with advanced or with metastatic disease remains poor. In fact, a median survival of only 2-3 years has been consistently reported over the last 20 years, in spite of the introduction of novel agents. Therefore, in advanced breast cancer patients, palliation of symptoms remains one of the primary objectives of treatment, and maintaining a reasonable quality of life is of paramount importance. Hormonal therapy is often the treatment of choice in such patients. However, current hormonal treatments of breast cancer in patients not selected on the basis of their receptor status, gives a maximal response rate of 30-35%. The median duration of response is 1 to 2 years and is influenced by the site of disease. If a patient&#39;s cancer responds to hormonal therapy but later progresses, the cancer may respond again to a second hormonal therapy, but the response rate decreases and the duration of response becomes shorter. Eventually, nearly all breast cancers become refractory to hormonal manipulation and the patients are candidates for cytotoxic chemotherapy. Chemotherapy is more toxic than hormonal therapy and is therefore generally reserved for patients refractory to hormonal treatment, patients with extensive visceral involvement, or patients with a rapidly growing tumor. Combination chemotherapy is generally more effective than single agent treatment. However, only 15% of patients have a complete remission, the duration of the response is limited, all the tumors become resistant to chemotherapy and the patients die. Therefore a major goal in breast cancer therapy is to develop new treatment modalities in order to increase tumor response and survival.  
       [0019] Accordingly, it would be desirable to have a drug combination modality having improved action over currently used treatment modalities. Ideally such a combination would have increased efficacy, e.g. by providing both better control of breast tumor growth and a longer duration of action. Such a strategy would also result in less toxic side effects, thus allowing for the administration of lower dosage levels of the chemotherapeutic agents. Adverse side effects induced by anticancer therapy have become of major importance to the clinical management of cancer patients undergoing treatment for cancer or neoplasia disease.  
       [0020] Recent studies have shown that there is a strong linear correlation between aromatase and cyclooxygenase gene expression in human breast cancer specimens (R. W. Brueggemeier, et al., Cancer Letters 140, 27-35 (1999)).  
       [0021] WO 98/16227 describes the use of COX-2 inhibitors in the treatment or prevention of neoplasia.  
       [0022] WO 98/41511 describes 5-(4-sulphonylphenyl)-pyridazinone COX-2 inhibitors used for treating cancer.  
       [0023] WO 98/41516 describes (methylsulphonyl)phenyl-2-(5H)-furanone COX-2 inhibitors that can be used in the treatment of cancer.  
       [0024] WO 98/47890 describes substituted benzopyran derivatives that may be used alone or in combination with other active principles for the treatment of neoplasia.  
       [0025] WO 96/41645 describes a combination comprising a COX-2 inhibitor and a leukotriene A hydrolase inhibitor.  
       [0026] WO 97/11701 describes a combination comprising a COX-2 inhibitor and a leukotriene B4 receptor antagonist useful in treating colorectal cancer.  
       [0027] WO 97/29774 describes the combination of a COX-2 inhibitor and prostaglandin or antiulcer agent useful in treating cancer.  
       [0028] WO 97/36497 describes a combination comprising a COX-2 inhibitor and a 5-lipoxygenase inhibitor useful in treating cancer.  
       [0029] WO 99/18960 describes a combination comprising a COX-2 inhibitor and an induced nitric-oxide synthase inhibitor (iNOS) that can be used to treat colorectal and breast cancer.  
       [0030] WO 99/25382 describes compositions containing a COX-2 inhibitor and a N-methyl-d-aspartate (NMDA) antagonist used to treat cancer and other diseases.  
       [0031] Osteoporosis is the most common type of metabolic bone disease and is characterized by the thinning of bone tissue and the progressive loss of bone density. Osteoporosis may occur when the body does not form enough new bone or when too much old bone is reabsorbed by the body. In the aging process, the body may reabsorb calcium and phosphate from the bones, making the bone tissue weaker. This situation results in fragile, brittle bones that are subject to fractures, even in the absence of trauma.  
       [0032] It is estimated that 23 percent of American women over the age of 50 have osteoporosis and an even larger percentage have osteopenia, which is abnormally low bone density. Researchers estimate that 50% of women over 50 will suffer an osteoporosis related fracture at some point in their life.  
       [0033] Therapies for the prevention and treatment of osteoporosis include estrogen replacement therapy and the use of drugs that slow the rate of bone loss, such as calcitonin, alendronate, and raloxifene (Lopez, F. J., Curr. Opin. Chem. Biol., 4(4), 383-393 (2000)).  
       [0034] U.S. Pat. No. 6,271,253 describes substituted benzopyran selective COX-2 inhibitors useful in treating or preventing bone resorption associated with osteoporosis.  
       [0035] WO 01/40216 describes heterocyclo-alkylsulfonyl pyrazole COX-2 inhibitors useful in treating osteoporosis.  
       [0036] U.S. Pat. No. 6,222,048 describes diaryl-2-(5H)-furanone COX-2 inhibitors useful in the prevention of bone loss.  
       [0037] WO 01/116138 describes sulfonylphenylpyrazole compounds useful as COX-2 inhibitors for the treatment of osteoporosis.  
       [0038] U.S. Pat. No. 6,071,936 describes substituted pyridine selective COX-2 inhibitors useful for the treatment of decreasing bone loss, particularly in postmenopausal women.  
       [0039] WO 99/11605 describes certain 5-alkyl-2-arylaminophenylacetic acids and derivatives as selective COX-2 inhibitors useful for the treatment of osteoporosis.  
       [0040] WO 01/03719 describes the use of a novel polypeptide, osteoprotegerin, in combination with a COX-2 inhibitor to treat bone diseases characterized by increased bone loss, such as osteoporosis.  
       [0041] U.S. Pat. No. 6,306,874 describes tyrosine kinase inhibitors, in combination with selective COX-2 inhibitors as being useful to treat and prevent conditions related to bone resorption, such as osteoporosis.  
       [0042] However, new therapies for the treatment and prevention of osteoporosis with minimized side effects are still needed. In particular, novel therapies for the treatment, prevention or inhibition of both neoplasia and osteoporosis, would be desirable.  
       SUMMARY OF THE INVENTION  
       [0043] Among its several embodiments, the present invention provides a composition comprising an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor wherein the amount of the COX-2 inhibitor compound source and the amount of the aromatase inhibitor together comprise a therapeutically effective amount for the treatment, prevention or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0044] In another embodiment, the present invention provides a combination therapy method for the treatment, prevention, or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis in a mammal in need thereof, comprising administering to the mammal an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor wherein the amount of the COX-2 inhibitor compound source and the amount of the aromatase inhibitor together comprise a therapeutically effective amount for the treatment, prevention, or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0045] In yet another embodiment, the present invention provides a pharmaceutical composition comprising an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor and a pharmaceutically-acceptable excipient.  
       [0046] In still another embodiment, the present invention provides a kit that is suitable for the treatment, prevention of inhibition of a neoplasia or a neoplasia-related disorder or osteoporosis, wherein the kit comprises a first dosage form comprising a COX-2 inhibitor compound source and a second dosage form comprising an aromatase inhibitor, in quantities which comprise a therapeutically effective amount of the compounds for the treatment, prevention or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0047] Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0048] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.  
       [0049] The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.  
       [0050] Definitions  
       [0051] The following definitions are provided in order to aid the reader in understanding the detailed description of the present invention.  
       [0052] The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical 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 2 —) radical. here used, either alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.  
       [0053] The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.  
       [0054] The term “alkynyl” denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.  
       [0055] The terms “alkenyl”, “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.  
       [0056] The term “cycloalkyl” embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkenyl” embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.  
       [0057] The term “halo” means halogens such as fluorine, chlorine, bromine or iodine. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.  
       [0058] The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.  
       [0059] The terms “alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six-carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.  
       [0060] The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.  
       [0061] The term “heterocyclo” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclo radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclo radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.  
       [0062] The term “heteroaryl” embraces unsaturated heterocyclo radicals. Examples of unsaturated heterocyclo radicals, also termed “heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclo group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic: group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term also embraces radicals where heterocyclo radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, benzopyran, and the like. Said “heterocyclo group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.  
       [0063] The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term “alkylthioalkyl” embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl.  
       [0064] The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)— radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.  
       [0065] The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO 2 —. “Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.  
       [0066] The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” denote NH 2 O 2 S—.  
       [0067] The term “acyl” denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and trifluoroacetyl.  
       [0068] The term “carbonyl”, whether used alone or with other terms, such as “alkoxycarbonyl”, denotes —(C═O)—. The term “aroyl” embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.  
       [0069] The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO 2 H. The term “carboxyalkyl” embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.  
       [0070] The terms “alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl” include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.  
       [0071] The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.  
       [0072] The term “heterocycloalkyl” embraces saturated and partially unsaturated heterocyclo-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroarylsubstituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.  
       [0073] The term “aralkoxy” embraces aralkyl radicals attached through an oxygen atom to other radicals. The term “aralkoxyalkyl” embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical. The term “aralkylthio” embraces aralkyl radicals attached to a sulfur atom. The term “aralkylthioalkyl” embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical.  
       [0074] The term “aminoalkyl” embraces alkyl radicals substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term “alkylamino” denotes amino groups that have been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl portions having 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino” denotes amino groups that have been substituted with one or two aryl radicals, such as N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical. The term “aralkylamino” embraces aralkyl radicals attached through an amino nitrogen atom to other radicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkylaminoalkyl” denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.  
       [0075] The term “aminocarbonyl” denotes an amide group of the formula —C(═O)NH 2 . The term “alkylaminocarbonyl” denotes an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above. The term “aminocarbonylalkyl” denotes a carbonylalkyl group that has been substituted with an amino radical on the carbonyl carbon atom.  
       [0076] The term “alkylaminoalkyl” embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term “aryloxyalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom. The term “arylthioalkyl” embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.  
       [0077] The phrase “combination therapy” (or “co-therapy”) embraces the administration of a COX-2 inhibitor and an aromatase inhibitor as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention. “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. “Combination therapy” also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). Where the combination therapy further comprises radiation treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.  
       [0078] The phrase “therapeutically effective” is intended to qualify the amount of inhibitors in the therapy. This amount will achieve the goal, e.g., of treating, preventing or inhibiting neoplasia or a neoplasia-related disorder, or of osteoporosis, where that is the therapeutic objective.  
       [0079] “Therapeutic compound” means a compound useful in the treatment, prevention or inhibition of neoplasia or a neoplasia-related disorder, or of osteoporosis, where that is the therapeutic objective.  
       [0080] The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.  
       [0081] The term “comprising” means “including the following elements but not excluding others.” 
       [0082] Combinations and Methods  
       [0083] Among its several embodiments, the present invention provides a composition comprising an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor wherein the amount of the COX-2 inhibitor compound source and the amount of the aromatase inhibitor together comprise a therapeutically effective amount for the treatment, prevention or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0084] In one embodiment, the source of the COX-2 inhibitor compound is a COX-2 inhibitor.  
       [0085] In another embodiment, the COX-2 inhibitor is a COX-2 selective inhibitor.  
       [0086] In yet another embodiment, the source of the COX-2 inhibitor compound is a prodrug of a COX-2 inhibitor compound, illustrated herein with parecoxib.  
       [0087] In still another embodiment, the present invention provides a combination therapy method for the treatment, prevention, or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis in a mammal in need thereof, comprising administering to the mammal an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor wherein the amount of the COX-2 inhibitor compound source and the amount of the aromatase inhibitor together comprise a therapeutically effective amount for the treatment, prevention, or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0088] In an additional embodiment, the present invention provides a pharmaceutical composition comprising an amount of a COX-2 inhibitor compound source and an amount of an aromatase inhibitor and a pharmaceutically-acceptable excipient.  
       [0089] In yet an additional embodiment, the present invention provides a kit that is suitable for the treatment, prevention of inhibition of a neoplasia or a neoplasia-related disorder or osteoporosis, wherein the kit comprises a first dosage form comprising a COX-2 inhibitor compound source and a second dosage form comprising an aromatase inhibitor, in quantities which comprise a therapeutically effective amount of the compounds for the treatment, prevention or inhibition of a neoplasia, a neoplasia-related disorder, or osteoporosis.  
       [0090] The methods and combinations of the present invention provide one or more benefits. Combinations of COX-2 inhibitors with the compounds, compositions, agents and therapies of the present invention are useful in treating, preventing or inhibiting neoplasia or a neoplasia-related disorder or osteoporosis. Preferably, the COX-2 inhibitors and the compounds, compositions, agents and therapies of the present invention are administered in combination at a low dose, that is, at a dose lower than has been conventionally used in clinical situations.  
       [0091] The combinations of the present invention will have a number of uses. For example, through dosage adjustment and medical monitoring, the individual dosages of the therapeutic compounds used in the combinations of the present invention will be lower than are typical for dosages of the therapeutic compounds when used in monotherapy. The dosage lowering will provide advantages including reduction of side effects of the individual therapeutic compounds when compared to the monotherapy. In addition, fewer side effects of the combination therapy compared with the monotherapies will lead to greater patient compliance with therapy regimens.  
       [0092] Alternatively, the methods and combinations of the present invention can also maximize the therapeutic effect at higher doses.  
       [0093] When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.  
       [0094] There are many uses for the present inventive combination. For example, aromatase inhibitors and COX-2 selective inhibiting agents (or prodrugs thereof) are each believed to be effective antineoplastic or antiangiogenic agents. However, patients treated with an aromatase inhibitor experience side effects, such as nausea, vomiting, pain and fatigue. The present inventive combination will allow the subject to be administered an aromatase inhibitor at a therapeutically effective dose yet experience reduced or fewer symptoms of nausea, vomiting, pain and fatigue. A further use and advantage is that the present inventive combination will allow therapeutically effective individual dose levels of the aromatase inhibitor and the COX-2 selective inhibitor that are lower than the dose levels of each inhibitor when administered to the patient as a monotherapy.  
       [0095] Inhibitors of the cyclooxygenase pathway in the metabolism of arachidonic acid used in the treatment, prevention or reduction of the risk of developing neoplasia disease may inhibit enzyme activity through a variety of mechanisms. By way of example, the cyclooxygenase inhibitors used in the methods described herein may block the enzyme activity directly by acting as a substrate for the enzyme. The use of a COX-2 selective inhibiting agent is highly advantageous in that they minimize the gastric side effects that can occur with non-selective non-steroidal antiinflammatory drugs (NSAIDs), especially where prolonged treatment is expected.  
       [0096] Besides being useful for human treatment, the present invention is also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.  
       Cyclooxygenase-2 Selective Inhibitors  
       [0097] A component of the combination of the present invention is a cycloxygenase-2 selective inhibitor. The terms “cyclooxygenase-2 selective inhibitor”, or “Cox-2 selective inhibitor”, which can be used interchangeably herein, embrace compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1, and also include pharmaceutically acceptable salts of those compounds.  
       [0098] In practice, the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC 50  value for inhibition of Cox-1, divided by the IC 50  value for inhibition of Cox-2 (Cox-1 IC 50 /Cox-2 IC 50 ). A Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC 50  to Cox-2 IC 50  is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still greater than 100.  
       [0099] As used herein, the term “IC 50 ” refers to the concentration of a compound that is required to produce 50% inhibition of cyclooxygenase activity. Preferred cyclooxygenase-2 selective inhibitors of the present invention have a cyclooxygenase-2 IC 50  of less than about 1 μM, more preferred of less than about 0.5 μM, and even more preferred of less than about 0.2 μM.  
       [0100] Preferred cycloxoygenase-2 selective inhibitors have a cyclooxygenase-1 IC 50  of greater than about 1 μM, and more preferably of greater than 20 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.  
       [0101] Also included within the scope of the present invention are compounds that act as prodrugs of cyclooxygenase-2-selective inhibitors. As used herein in reference to Cox-2 selective inhibitors, the term “prodrug” refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject. One example of a prodrug for a Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib. An example of a preferred Cox-2 selective inhibitor prodrug is parecoxib sodium. A class of prodrugs of Cox-2 inhibitors is described in U.S. Pat. No. 5,932,598.  
       [0102] The cyclooxygenase-2 selective inhibitor of the present invention can be, for example, the Cox-2 selective inhibitor meloxicam, Formula B-1 (CAS registry number 71125-38-7), or a pharmaceutically acceptable salt or prodrug thereof.  
                 
 
       [0103] In another embodiment of the invention the cyclooxygenase-2 selective inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone, Formula B-2 (CAS registry number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.  
                 
 
       [0104] In a another embodiment of the invention the cyclooxygenase-2 selective inhibitor is of the chromene/chroman structural class that is a substituted benzopyran or a substituted benzopyran analog, and even more preferably selected from the group consisting of substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the compounds having a structure shown by general Formulas I, II, III, IV, V, and VI, shown below, and possessing, by way of example and not limitation, the structures disclosed in Table 1, including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.  
       [0105] Benzopyrans that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Pat. No. 6,271,253. One such class of compounds is defined by the general formula shown below in formulas I:  
                 
 
       [0106] wherein X 1  is selected from O, S, CR c R b  and NR a ;  
       [0107] wherein R a  is selected from hydrido, C 1 -C 3 -alkyl, (optionally substituted phenyl)-C 1 -C 3 -alkyl, acyl and carboxy-C 1 -C 6 -alkyl;  
       [0108] wherein each of R b  and R c  is independently selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 3 -alkyl, C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl; or wherein CR b R c  forms a 3-6 membered cycloalkyl ring;  
       [0109] wherein R 1  is selected from carboxyl, aminocarbonyl, C 1 -C 6 -alkylsulfonylaminocarbonyl and C 1 -C 6 -alkoxycarbonyl;  
       [0110] wherein R 2  is selected from hydrido, phenyl, thienyl, C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl;  
       [0111] wherein R 3  is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl;  
       [0112] wherein R 4  is one or more radicals independently selected from hydrido, halo, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, aryl-C 2 -C 6 -alkynyl, aryl-C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, methylenedioxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyloxy, heteroaryl-C 1 -C 6 -alkyloxy, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, C 1 -C 6 -haloalkylthio, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 3 -(haloalkyl- 1 -C 3 -hydroxyalkyl, C 1 -C 6 -hydroxyalkyl, hydroxyimino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, arylamino, aryl-C 1 -C 6 -alkylamino, heteroarylamino, heteroaryl-C 1 -C 6 -alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C 1 -C 6 -alkylaminosulfonyl, heteroaryl-C 1 -C 6 -alkylaminosulfonyl, heterocyclylsulfonyl, C 1 -C 6 -alkylsulfonyl, aryl-C 1 -C 6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C 1 -C 6 -alkylcarbonyl, heteroaryl-C 1 -C 6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 C 6 -alkoxycarbonyl, formyl, C 1 -C 6 -haloalkylcarbonyl and C 1 -C 6 -alkylcarbonyl; and  
       [0113] wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least two of A 1 , A 2 , A 3  and A 4  are carbon;  
       [0114] or wherein R 4  together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl;  
       [0115] or an isomer or pharmaceutically acceptable salt thereof.  
       [0116] Another class of benzopyran derivatives that can serve as the Cox-2 selective inhibitor of the present invention includes a compound having the structure of formula II:  
                 
 
       [0117] wherein X 2  is selected from O, S, CR c R b  and NR a ;  
       [0118] wherein R a  is selected from hydrido, C 1 -C 3 -alkyl, (optionally substituted phenyl)-C 1 -C 3 -alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C 1 C 6 -alkyl;  
       [0119] wherein each of R b  and R c  is independently selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 3 -alkyl, C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl;  
       [0120] or wherein CR c R b  form a cyclopropyl ring;  
       [0121] wherein R 5  is selected from carboxyl, aminocarbonyl, C 1 -C 6 -alkylsulfonylaminocarbonyl and C 1 -C 6 -alkoxycarbonyl;  
       [0122] wherein R 6  is selected from hydrido, phenyl, thienyl, C 2 -C 6 -alkynyl and C 2 -C 6 -alkenyl;  
       [0123] wherein R 7  is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl;  
       [0124] wherein R 8  is one or more radicals independently selected from hydrido, halo, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, aryl-C 2 -C 6 -alkynyl, aryl-C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, methylenedioxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, —O(CF 2 ) 2  O—, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyloxy, heteroaryl-C 1 -C 6 -alkyloxy, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, C 1 -C 6 -haloalkylthio, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 3 -(haloalkyl-C 1 -C 3 -hydroxyalkyl), C 1 -C 6 -hydroxyalkyl, hydroxyimino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, arylamino, aryl-C 1 -C 6 -alkylamino, heteroarylamino, heteroaryl-C 1 -C 6 -alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C 1 -C 6 -alkylaminosulfonyl, heteroaryl-C 1 -C 6 -alkylaminosulfonyl, heterocyclylsulfonyl, C 1 C 6 -alkylsulfonyl, aryl-C 1 -C 6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C 1 -C 6 -alkylcarbonyl, heteroaryl-C 1 -C 6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, formyl, C 1 -C 6 -haloalkylcarbonyl and C 1 -C 6 -alkylcarbonyl; and  
       [0125] wherein the D ring atoms D 1 , D 2 , D 3  and D 4  are independently selected from carbon and nitrogen with the proviso that at least two of D 1 , D 2 , D 3  and D 4  are carbon; or  
       [0126] wherein R 8  together with ring D forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.  
       [0127] Other benzopyran Cox-2 selective inhibitors useful in the practice of the present invention are described in U.S. Pat. Nos. 6,034,256 and 6,077,850. The general formula for these compounds is shown in formula III:  
       [0128] Formula III is:  
                 
 
       [0129] wherein X 3  is selected from the group consisting of O or S or NR a ;  
       [0130] wherein R a  is alkyl;  
       [0131] wherein R 9  is selected from the group consisting of H and aryl;  
       [0132] wherein R 10  is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;  
       [0133] wherein R 11  is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and  
       [0134] wherein R 12  is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or  
       [0135] wherein R 12  together with ring E forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof; and including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.  
       [0136] A related class of compounds useful as cyclooxygenase-2 selective inhibitors in the present invention is described by Formulas IV and V:  
                 
 
       [0137] wherein X 4  is selected from O or S or NR a ;  
       [0138] wherein R a  is alkyl;  
       [0139] wherein R 13  is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;  
       [0140] wherein R 14  is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and  
       [0141] wherein R 15  is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R 15  together with ring G forms a naphthyl radical;  
       [0142] or an isomer or pharmaceutically acceptable salt thereof.  
       [0143] Formula V is:  
                 
 
       [0144] wherein:  
       [0145] X 5  is selected from the group consisting of O or S or NR b ;  
       [0146] R b  is alkyl;  
       [0147] R 16  is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;  
       [0148] R 17  is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and  
       [0149] R 18  is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R 18  together with ring A forms a naphthyl radical;  
       [0150] or an isomer or pharmaceutically acceptable salt thereof.  
       [0151] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula V, wherein:  
       [0152] X 5  is selected from the group consisting of oxygen and sulfur;  
       [0153] R 16  is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;  
       [0154] R 17  is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and  
       [0155] R 18  is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or  
       [0156] wherein R 18  together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
       [0157] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula V, wherein:  
       [0158] X 5  is selected from the group consisting of oxygen and sulfur;  
       [0159] R 16  is carboxyl;  
       [0160] R 17  is lower haloalkyl; and  
       [0161] R 18  is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R 18  together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
       [0162] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula V, wherein:  
       [0163] X 5  is selected from the group consisting of oxygen and sulfur;  
       [0164] R 16  is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;  
       [0165] R 17  is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and  
       [0166] R 18  is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R 2  together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
       [0167] The cyclooxygenase-2 selective inhibitor may also be a compound of Formula V, wherein:  
       [0168] X 5  is selected from the group consisting of oxygen and sulfur;  
       [0169] R 16  is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;  
       [0170] R 17  is selected from the group consisting trifluoromethyl and pentafluoroethyl; and  
       [0171] R 18  is one or more radicals selected from the group consisting of hydrido, chloro-, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R 18  together with ring A forms a naphthyl radical;  
       [0172] or an isomer or prodrug thereof.  
       [0173] The cyclooxygenase-2 selective inhibitor of the present invention can also be a compound having the structure of Formula VI:  
                 
 
       [0174] wherein:  
       [0175] X 6  is selected from the group consisting of O and S;  
       [0176] R 19  is lower haloalkyl;  
       [0177] R 20  is selected from the group consisting of hydrido and halo;  
       [0178] R 21  is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6-membered nitrogen-containing heterocyclosulfonyl;  
       [0179] R 22  is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl; and  
       [0180] R 23  is selected from the group consisting of the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl;  
       [0181] or an isomer or prodrug thereof.  
       [0182] The cyclooxygenase-2 selective inhibitor can also be a compound of having the structure of Formula VI, wherein:  
       [0183] X 6  is selected from the group consisting of O and S;  
       [0184] R 19  is selected from the group consisting of trifluoromethyl and pentafluoroethyl;  
       [0185] R 20  is selected from the group consisting of hydrido chloro, and fluoro;  
       [0186] R 21  is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl;  
       [0187] R 22  is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; and  
       [0188] R 23  is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or prodrug thereof.  
               TABLE 1                          Examples of Chromene Cox-2 Selective Inhibitors                     Compound           Number   Structural Formula                           B-3                                         6-Nitro-2-trifluoromethyl-2H-1-           benzopyran-3-carboxylic acid               B-4                                         6-Chloro-8-methyl-2-trifluoromethyl-           2H-1-benzopyran-3-carboxylic acid               B-5                                         ((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoro-           methyl-2H-1-benzopyran-3-carboxylic acid               B-6                                         2-Trifluoromethyl-2H-naphtho [2, 3-b]           pyran-3-carboxylic acid               B-7                                         6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1-           benzopyran-3-carboxylic acid               B-8                                         ((S)-6,8-Dichloro-2-(trifluoromethyl)-           2H-1-benzopyran-3-carboxylic acid               B-9                                         6-Chloro-2-(trifluoromethyl)-4-phenyl-2H-           1-benzopyran-3-carboxylic acid               B-10                                         6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)-           2H-1-benzopyran-3-carboxylic acid               B-11                                         2-(Trifluoromethyl)-6-[(trifluoromethyl) thio]-           2H-1-benzothiopyran-3-carboxylic acid               B-12                                         6,8-Dichloro-2-trifluoromethyl-2H-1-           benzothiopyran-3-carboxylic acid               B-13                                         6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-           2H-1-benzothiopyran-3-carboxylic acid               B-14                                         6,7-Difluoro-1,2-dihydro-2-(trifluoro-           methyl)-3-quinolinecarboxylic acid               B-15                                         6-Chloro-1,2-dihydro-1-methyl-2-(trifluoro-           methyl)-3-quinolinecarboxylic acid               B-16                                         6-Chloro-2-(trifluoromethyl)-1,2-dihydro           [1,8]naphthyridine-3-carboxylic acid               B-17                                         ((S)-6-Chloro-1,2-dihydro-2-(trifluoro-           methyl)-3-quinolinecarboxylic acid                  
 
       [0189] Examples of specific compounds that are useful for the cyclooxygenase-2 selective inhibitor include (without limitation):  
       [0190] a1) 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo[1,2-a)pyridine;  
       [0191] a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone;  
       [0192] a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole;  
       [0193] a4) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;  
       [0194] a5) 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide  
       [0195] a6) 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0196] a7) 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0197] a8) 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0198] a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0199] a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0200] b1) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide;  
       [0201] b2) 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide  
       [0202] b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0203] b4) 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0204] b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0205] b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0206] b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0207] b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0208] b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0209] b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0210] c1) 4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0211] c2) 4-[3-(d ifluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0212] c3) 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0213] c4) 4-[3-(d ifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0214] c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0215] c6) 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0216] c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0217] c8) 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0218] c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;  
       [0219] c10) 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;  
       [0220] d1) 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;  
       [0221] d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;  
       [0222] d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;  
       [0223] d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;  
       [0224] d5) 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;  
       [0225] d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;  
       [0226] d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;  
       [0227] d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;  
       [0228] d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;  
       [0229] d10) 4-(4-fluorophenyl)-5-(4-methylsulfonyl phenyl)-2-trifluoromethylthiazole;  
       [0230] e1) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;  
       [0231] e2) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;  
       [0232] e3) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;  
       [0233] e4) 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]thiazole;  
       [0234] e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;  
       [0235] e6) 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene;  
       [0236] e7) 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide;  
       [0237] e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene;  
       [0238] e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide;  
       [0239] e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;  
       [0240] f1) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile;  
       [0241] f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;  
       [0242] f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0243] f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0244] f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0245] f6) 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;  
       [0246] f7) 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;  
       [0247] f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;  
       [0248] f9) 2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;  
       [0249] f10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0250] g1) 2-(3,4-d ifluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;  
       [0251] g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0252] g3) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole;  
       [0253] g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole;  
       [0254] g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole;  
       [0255] g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazole;  
       [0256] g7) 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;  
       [0257] g8) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;  
       [0258] g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0259] g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;  
       [0260] h1) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0261] h2) 2-(3-methyl phenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole;  
       [0262] h3) 4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;  
       [0263] h4) 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole;  
       [0264] h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;  
       [0265] h6) 4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;  
       [0266] h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide;  
       [0267] h8) 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;  
       [0268] h10) 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide;  
       [0269] i1) N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;  
       [0270] i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate;  
       [0271] i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole;  
       [0272] i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;  
       [0273] i5) 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;  
       [0274] i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;  
       [0275] i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;  
       [0276] i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;  
       [0277] i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;  
       [0278] i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;  
       [0279] j1) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;  
       [0280] j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;  
       [0281] j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;  
       [0282] j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;  
       [0283] j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;  
       [0284] j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;  
       [0285] j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;  
       [0286] j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;  
       [0287] j9) 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0288] j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0289] k1) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0290] k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0291] k3) 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0292] k4) 1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0293] k5) 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0294] k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;  
       [0295] k7) 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0296] k8) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide;  
       [0297] k9) 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;  
       [0298] k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;  
       [0299] l1) 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0300] l2) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0301] l3) 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;  
       [0302] l4) 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;  
       [0303] l5) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;  
       [0304] l6) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;  
       [0305] l7) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2-benzyl-acetate;  
       [0306] l8) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;  
       [0307] l9) 2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;  
       [0308] l10) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;  
       [0309] m1) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and  
       [0310] m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide.  
       [0311] m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0312] m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0313] m5) 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0314] m6) 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0315] m7) 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0316] m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;  
       [0317] m9) 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0318] m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0319] n1) 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0320] n2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0321] n3) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0322] n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0323] n5) 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0324] n6) 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0325] n7) 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0326] n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0327] n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0328] n10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0329] o1) 6-chloro-7-phenyl-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid;  
       [0330] o2) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0331] o3) 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0332] o4) 2-trifluoromethyl-3H-naptho[2,1-b]pyran-3-carboxylic acid;  
       [0333] o5) 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0334] o6) 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0335] o7) 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0336] o8) 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0337] o9) 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0338] o10) 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0339] p1) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0340] p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0341] p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0342] p4) 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0343] p5) 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0344] p6) 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0345] p7) 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0346] p8) 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0347] p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0348] p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0349] q1) 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0350] q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0351] q3) 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0352] q4) 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0353] q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0354] q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0355] q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0356] q8) 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0357] q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0358] q10) 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid;  
       [0359] r1) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulphonyl-2(5H)-fluranone;  
       [0360] r2) 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;  
       [0361] r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0362] r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0363] r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;  
       [0364] r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
       [0365] r7) 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;  
       [0366] r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;  
       [0367] r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide;  
       [0368] r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;  
       [0369] s1) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide;  
       [0370] s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or  
       [0371] s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide;  
       [0372] or a pharmaceutically acceptable salt or prodrug thereof.  
       [0373] In a further preferred embodiment of the invention the cyclooxygenase inhibitor can be selected from the class of tricyclic cyclooxygenase-2 selective inhibitors represented by the general structure of formula VII:  
                 
 
       [0374] wherein:  
       [0375] Z 1  is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;  
       [0376] R 24  is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 24  is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;  
       [0377] R 25  is selected from the group consisting of methyl or amino; and  
       [0378] R 26  is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl;  
       [0379] or a prodrug thereof.  
       [0380] In a preferred embodiment of the invention the cyclooxygenase-2 selective inhibitor represented by the above Formula VII is selected from the group of compounds, illustrated in Table 2, which includes celecoxib (B-18), valdecoxib (B-19), deracoxib (B-20), rofecoxib (B-21), etoricoxib (MK-663; B-22), JTE-522 (B-23), or a prodrug thereof.  
       [0381] Additional information about selected examples of the Cox-2 selective inhibitors discussed above can be found as follows: celecoxib (CAS RN 169590-42-5, C-2779, SC-58653, and in U.S. Pat. No. 5,466,823); deracoxib (CAS RN 169590-41-4); rofecoxib (CAS RN 162011-90-7); compound B-24 (U.S. Pat. No. 5,840,924); compound B-26 (WO 00/25779); and etoricoxib (CAS RN 202409-33-4, MK-663, SC-86218, and in WO 98/03484).  
               TABLE 2                          Examples of Tricyclic COX-2 Selective Inhibitors                     Compound           Number   Structural Formula                           B-18                                     B-19                                     B-20                                     B-21                                     B-22                                     B-23                                        
 
       [0382] In a more preferred embodiment of the invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.  
       [0383] In a preferred embodiment of the invention, parecoxib (See, e.g. U.S. Pat. No. 5,932,598), having the structure shown in B-24, which is a therapeutically effective prodrug of the tricyclic cyclooxygenase-2 selective inhibitor valdecoxib, B-19, (See, e.g., U.S. Pat. No. 5,633,272), may be advantageously employed as a source of a cyclooxygenase inhibitor.  
                 
 
       [0384] A preferred form of parecoxib is sodium parecoxib.  
       [0385] In another embodiment of the invention, the compound ABT-963 having the formula B-25 that has been previously described in International Publication number WO 00/24719, is another tricyclic cyclooxygenase-2 selective inhibitor which may be advantageously employed.  
                 
 
       [0386] In a yet further embodiment of the invention, the cyclooxygenase inhibitor used in connection with the methods of the present invention can be selected from the class of phenylacetic acid derivative cyclooxygenase-2 selective inhibitors represented by the general structure of Formula VIII:  
                 
 
       [0387] or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof; wherein:  
       [0388] R 27  is methyl, ethyl, or propyl;  
       [0389] R 28  is chloro or fluoro;  
       [0390] R 29  is hydrogen, fluoro, or methyl;  
       [0391] R 30  is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;  
       [0392] R 31  is hydrogen, fluoro, or methyl; and  
       [0393] R 32  is chloro, fluoro, trifluoromethyl, methyl, or ethyl,  
       [0394] provided that R 28 , R 29 , R 30  and R 31  are not all fluoro when R 27  is ethyl and R 30  is H.  
       [0395] A phenylacetic acid derivative cyclooxygenase-2 selective inhibitor that is described in WO 99/11605 is a compound that has the structure shown in Formula VII,  
       [0396] wherein:  
       [0397] R 27  is ethyl;  
       [0398] R 28  and R 30  are chloro;  
       [0399] R 29  and R 31  are hydrogen; and  
       [0400] R 32  is methyl.  
       [0401] Another phenylacetic acid derivative cyclooxygenase-2 selective inhibitor is a compound that has the structure shown in Formula VIII,  
       [0402] wherein:  
       [0403] R 27  is propyl;  
       [0404] R 28  and R 30  are chloro;  
       [0405] R 29  and R 31  are methyl; and  
       [0406] R 32  is ethyl.  
       [0407] Another phenylacetic acid derivative cyclooxygenase-2 selective inhibitor that is described in WO 02/20090 is a compound that is referred to as COX-189 (also termed lumiracoxib), having CAS Reg. No. 220991-20-8, and having the structure shown in Formula VIII,  
       [0408] wherein:  
       [0409] R 27  is methyl;  
       [0410] R 28  is fluoro;  
       [0411] R 32  is chloro; and  
       [0412] R 29 , R 30 , and R 31  are hydrogen.  
       [0413] Compounds that have a structure similar to that shown in Formula VIII, which can serve as the Cox-2 selective inhibitor of the present invention, are described in U.S. Pat. Nos. 6,310,099, 6,291,523, and 5,958,978.  
       [0414] Other cyclooxygenase-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 heterocycle. Preferred embodiments have the structure:  
                 
 
       [0415] wherein:  
       [0416] X is O; J is 1-phenyl; R 33  is 2-NHSO 2 CH 3 ; R 34  is 4-NO 2 ; and there is no R 35  group, (nimesulide), and  
       [0417] X is O; J is 1-oxo-inden-5-yl; R 33  is 2-F; R 34  is 4-F; and R 35  is 6-NHSO 2 CH 3 , (flosulide); and  
       [0418] X is O; J is cyclohexyl; R 33  is 2-NHSO 2 CH 3 ; R 34  is 5-NO 2 ; and there is no R 35  group, (NS-398); and  
       [0419] X is S; J is 1-oxo-inden-5-yl; R 33  is 2-F; R 34  is 4-F; and R 35  is 6-N—SO 2 CH 3  Na + ,  
       [0420]  (L-745337); and  
       [0421] X is S; J is thiophen-2-yl; R 33  is 4-F; there is no R 34  group; and R 35  is 5-NHSO 2 CH 3 , (RWJ-63556); and  
       [0422] X is O; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl; R 33  is 3-F; R 34  is 4-F; and R 35  is 4-(p-SO 2 CH 3 )C 6 H 4 , (L-784512).  
       [0423] Further information on the applications of the Cox-2 selective inhibitor N-(2-cyclohexyloxynitrophenyl) methane sulfonamide (NS-398, CAS RN 123653-11-2), having a structure as shown in formula B-26, have been described by, for example, Yoshimi, N. et al., in  Japanese J. Cancer Res.,  90(4):406-412 (1999); Falgueyret, J.-P. et al., in  Science Spectra , available at: http://www.gbhap.com/Science_Spectra/20-1-article.htm (06/06/2001); and Iwata, K. et al., in  Jpn. J. Pharmacol.,  75(2):191-194 (1997).  
                 
 
       [0424] An evaluation of the anti-inflammatory activity of the cyclooxygenase-2 selective inhibitor, RWJ 63556, in a canine model of inflammation, was described by Kirchner et al., in  J Pharmacol Exp Ther  282, 1094-1101 (1997).  
       [0425] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Pat. No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula X:  
                 
 
       [0426] wherein:  
       [0427] rings T and M independently are:  
       [0428] a phenyl radical,  
       [0429] a naphthyl radical,  
       [0430] a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or  
       [0431] a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;  
       [0432] at least one of the substituents Q 1 , Q 2 , L 1  or L 2  is:  
       [0433] an —S(O) n —R group, in which n is an integer equal to 0, 1 or 2 and R is:  
       [0434] a lower alkyl radical having 1 to 6 carbon atoms or  
       [0435] a lower haloalkyl radical having 1 to 6 carbon atoms, or  
       [0436] an —SO 2 NH 2  group;  
       [0437] and is located in the para position,  
       [0438] the others independently being:  
       [0439] a hydrogen atom,  
       [0440] a halogen atom,  
       [0441] a lower alkyl radical having 1 to 6 carbon atoms,  
       [0442] a trifluoromethyl radical, or  
       [0443] a lower O-alkyl radical having 1 to 6 carbon atoms, or  
       [0444] Q 1  and Q 2  or L 1  and L 2  are a methylenedioxy group; and  
       [0445] R 36 , R 37 , R 38  and R 39  independently are:  
       [0446] a hydrogen atom,  
       [0447] a halogen atom,  
       [0448] a lower alkyl radical having 1 to 6 carbon atoms,  
       [0449] a lower haloalkyl radical having 1 to 6 carbon atoms, or  
       [0450] an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or,  
       [0451] R 36 , R 37  or R 38 , R 39  are an oxygen atom, or  
       [0452] R 36 , R 37  or R 38 , R 39 , together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms;  
       [0453] or an isomer or prodrug thereof.  
       [0454] Particular materials that are included in this family of compounds, and which can serve as the cyclooxygenase-2 selective inhibitor in the present invention, include N-(2-cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) methyl]benzenesulfonamide.  
       [0455] Cyclooxygenase-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No. 6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).  
       [0456] Information about S-33516, mentioned above, can be found in  Current Drugs Headline News , at http://www.current-drugs.com/NEWS/Inflam1.htm, 10/04/2001, where it was reported that S-33516 is a tetrahydroisoinde derivative which has IC 50  values of 0.1 and 0.001 mM against cyclooxygenase-1 and cyclooxygenase-2, respectively. In human whole blood, S-33516 was reported to have an ED 50 =0.39 mg/kg.  
       [0457] Compounds that may act as cyclooxygenase-2 selective inhibitors include multibinding compounds containing from 2 to 10 ligands covalently attached to one or more linkers, as described in U.S. Pat. No. 6,395,724.  
       [0458] Compounds that may act as cyclooxygenase-2 inhibitors include conjugated linoleic acid that is described in U.S. Pat. No. 6,077,868.  
       [0459] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include heterocyclic aromatic oxazole compounds that are described in U.S. Pat. Nos. 5,994,381 and 6,362,209. Such heterocyclic aromatic oxazole compounds have the formula shown below in formula XI:  
                 
 
       [0460] wherein:  
       [0461] Z 2  is an oxygen atom;  
       [0462] one of R 40  and R 41  is a group of the formula  
                 
 
       [0463] wherein:  
       [0464] R 43  is lower alkyl, amino or lower alkylamino; and  
       [0465] R 44 , R 45 , R 46  and R 47  are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino,  
       [0466] provided that at least one of R 44 , R 45 , R 46  and R 47  is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and  
       [0467] R 30  is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof.  
       [0468] Cox-2 selective inhibitors that are useful in the subject method and compositions can include compounds that are described in U.S. Pat. Nos. 6,080,876 and 6,133,292, and described by formula XII:  
                 
 
       [0469] wherein:  
       [0470] Z 3  is selected from the group consisting of:  
       [0471] (a) linear or branched C 1-6  alkyl,  
       [0472] (b) linear or branched C 1-6  alkoxy,  
       [0473] (c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of:  
       [0474] (1) hydrogen,  
       [0475] (2) halo,  
       [0476] (3) C 1-3  alkoxy,  
       [0477] (4) CN,  
       [0478] (5) C 1-3  fluoroalkyl  
       [0479] (6) C 1-3  alkyl,  
       [0480] (7)—CO 2 H;  
       [0481] R 48  is selected from the group consisting of NH 2  and CH 3 ,  
       [0482] R 49  is selected from the group consisting of:  
       [0483] C 1-6  alkyl unsubstituted or substituted with C 3-6  cycloalkyl, and  
       [0484] C 3-6  cycloalkyl;  
       [0485] R 50  is selected from the group consisting of:  
       [0486] C 1-6  alkyl unsubstituted or substituted with one, two or three fluoro atoms; and  
       [0487] C 3-6  cycloalkyl;  
       [0488] with the proviso that R 49  and R 50  are not the same.  
       [0489] Materials that can serve as cyclooxygenase-2 selective inhibitors include pyridines that are described in U.S. Pat. Nos. 6, 369,275, 6,127,545, 6,130,334, 6,204,387, 6,071,936, 6,001,843 and 6,040,450, and which have the general formula described by formula XIII:  
                 
 
       [0490] wherein:  
       [0491] R 51  is selected from the group consisting of:  
       [0492] (a) CH 3 ,  
       [0493] (b) NH 2 ,  
       [0494] (c) NHC(O)CF 3 ,  
       [0495] (d) NHCH 3 ;  
       [0496] Z 4  is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof),  
       [0497] wherein the substituents are chosen from the group consisting of:  
       [0498] (a) hydrogen,  
       [0499] (b) halo,  
       [0500] (c) C 1-6  alkoxy,  
       [0501] (d) C 1-6  alkylthio,  
       [0502] (e) CN,  
       [0503] (f) C 1-6  alkyl,  
       [0504] (g) C 1-6  fluoroalkyl,  
       [0505] (h) N 3 ,  
       [0506] (i) —CO 2 R 53 ,  
       [0507] (j) hydroxy,  
       [0508] (k) —C(R 54 )(R 55 )—OH,  
       [0509] (l) —C 1-6 alkyl-CO 2 —R 56 ,  
       [0510] (m) C 1-6 fluoroalkoxy;  
       [0511] R 52  is chosen from the group consisting of:  
       [0512] (a) halo,  
       [0513] (b) C 1-6 alkoxy,  
       [0514] (c) C 1-6  alkylthio,  
       [0515] (d) CN,  
       [0516] (e) C 1-6  alkyl,  
       [0517] (f) C 1-6  fluoroalkyl,  
       [0518] (g) N 3 ,  
       [0519] (h) —CO 2 R 57 ,  
       [0520] (i) hydroxy,  
       [0521] (j) —C(R 58 )(R 59 )—OH,  
       [0522] (k) —C 1-6 alkyl-CO 2 —R 60 ,  
       [0523] (l) C 1-6 fluoroalkoxy,  
       [0524] (m) NO 2 ,  
       [0525] (n) NR 61 R 62 , and  
       [0526] (o) NHCOR 63 ;  
       [0527] R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , are each independently chosen from the group consisting of:  
       [0528] (a) hydrogen, and  
       [0529] (b) C 1-6 alkyl;  
       [0530] or R 54  and R 55 , R 58  and R 59  or R 61  and R 62  together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.  
       [0531] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include diarylbenzopyran derivatives that are described in U.S. Pat. No. 6,340,694. Such diarylbenzopyran derivatives have the general formula shown below in formula XIV:  
                 
 
       [0532] wherein:  
       [0533] X 8  is an oxygen atom or a sulfur atom;  
       [0534] R 64  and R 65 , identical to or different from each other, are independently a hydrogen atom, a halogen atom, a C 1 -C 6  lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a nitro group, a nitrile group, or a carboxyl group;  
       [0535] R 66  is a group of a formula: S(O) n R 68  wherein n is an integer of 0˜2, R 68  is a hydrogen atom, a C 1 -C 6  lower alkyl group, or a group of a formula: NR 69  R 70  wherein R 69  and R 70 , identical to or different from each other, are independently a hydrogen atom, or a C 1 -C 6  lower alkyl group; and  
       [0536] R 67  is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C 1 -C 6  lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:  
                 
 
       [0537] wherein:  
       [0538] R 71  through R 75 , identical to or different from one another, are independently a hydrogen atom, a halogen atom, a C 1 -C 6  lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a hydroxyalkyl group, a nitro group, a group of a formula: S(O) n R 68 , a group of a formula: NR 69 R 70 , a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group,  
       [0539] wherein n, R 68 , R 69  and R 70  have the same meaning as defined by R 66  above; and  
       [0540] R 76  is a hydrogen atom, a halogen atom, a C 1 -C 6  lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxy group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.  
       [0541] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines that are described in U.S. Pat. No. 6,376,519. Such 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the formula shown below in formula XV:  
                 
 
       [0542] wherein:  
       [0543] X 9  is selected from the group consisting of C 1 -C 6  trihalomethyl, preferably trifluoromethyl; C 1 -C 6  alkyl; and an optionally substituted or di-substituted phenyl group of formula XVI:  
                 
 
       [0544] wherein:  
       [0545] R 77  and R 78  are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C 1 -C 6  alkyl, preferably C 1 -C 3  alkyl; C 1 -C 6  alkoxy, preferably C 1 -C 3  alkoxy; carboxy; C 1 -C 6  trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano;  
       [0546] Z 5  is selected from the group consisting of substituted and unsubstituted aryl.  
       [0547] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include heterocycles that are described in U.S. Pat. No. 6,153,787. Such heterocycles have the general formulas shown below in formulas XVII and XVIII:  
                 
 
       [0548] wherein:  
       [0549] R 79  is a mono-, di-, or tri-substituted C 1-12  alkyl, or a mono-, or an unsubstituted or mono-, di- or tri-substituted linear or branched C 2-10  alkenyl, or an unsubstituted or mono-, di- or tri-substituted linear or branched C 2-10  alkynyl, or an unsubstituted or mono-, di- or tri-substituted C 3-12  cycloalkenyl, or an unsubstituted or mono-, di- or tri-substituted C 5-12  cycloalkynyl, wherein the substituents are chosen from the group consisting of:  
       [0550] (a) halo, selected from F, Cl, Br, and I,  
       [0551] (b) OH,  
       [0552] (c) CF 3 ,  
       [0553] (d) C 3-6  cycloalkyl,  
       [0554] (e) ═O,  
       [0555] (f) dioxolane,  
       [0556] (g) CN; and  
       [0557] R 80  is selected from the group consisting of:  
       [0558] (a) CH 3 ,  
       [0559] (b) NH 2 ,  
       [0560] (c) NHC(O)CF 3 ,  
       [0561] (d) NHCH 3 ;  
       [0562] R 81  and R 82  are independently chosen from the group consisting of:  
       [0563] (a) hydrogen,  
       [0564] (b) C 1-10  alkyl;  
       [0565] or R 81  and R 82  together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.  
       [0566] Formula XVIII is:  
                 
 
       [0567] X 10  is fluoro or chloro.  
       [0568] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include 2,3,5-trisubstituted pyridines that are described in U.S. Pat. No. 6,046,217. Such pyridines have the general formula shown below in formula XIX:  
                 
 
       [0569] or a pharmaceutically acceptable salt thereof,  
       [0570] wherein:  
       [0571] X 11  is selected from the group consisting of:  
       [0572] (a) O,  
       [0573] (b) S,  
       [0574] (c) bond;  
       [0575] n is 0 or 1;  
       [0576] R 83  is selected from the group consisting of:  
       [0577] (a) CH 3 ,  
       [0578] (b) NH 2 ,  
       [0579] (c) NHC(O)CF 3 ;  
       [0580] R 84  is chosen from the group consisting of:  
       [0581] (a) halo,  
       [0582] (b) C 1-6  alkoxy,  
       [0583] (c) C 1-6  alkylthio,  
       [0584] (d) CN,  
       [0585] (e) C 1-6  alkyl,  
       [0586] (f) C 1-6  fluoroalkyl,  
       [0587] (g) N 3 ,  
       [0588] (h) —CO 2 R 92 ,  
       [0589] (i) hydroxy,  
       [0590] (j) —C(R 93 )(R 94 )—OH,  
       [0591] (k) —C 1-6  alkyl-CO 2 —R 95 ,  
       [0592] (l) C 1-16  fluoroalkoxy,  
       [0593] (m) NO 2 ,  
       [0594] (n) NR 96 R 97 ,  
       [0595] (o) NHCOR 98 ;  
       [0596] R 85  to R 98  are independently chosen from the group consisting of  
       [0597] (a) hydrogen,  
       [0598] (b) C 1-6  alkyl;  
       [0599] or R 85  and R 89 , or R 89  and R 90  together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R 85  and R 87  are joined to form a bond.  
       [0600] One preferred embodiment of the Cox-2 selective inhibitor of formula XIX is that wherein X is a bond.  
       [0601] Another preferred embodiment of the Cox-2 selective inhibitor of formula XIX is that wherein X is O.  
       [0602] Another preferred embodiment of the Cox-2 selective inhibitor of formula XIX is that wherein X is S.  
       [0603] Another preferred embodiment of the Cox-2 selective inhibitor of formula XIX is that wherein R 83  is CH 3 .  
       [0604] Another preferred embodiment of the Cox-2 selective inhibitor of formula XIX is that wherein R 84  is halo or C 1-6  fluoroalkyl.  
       [0605] Materials that can serve as the cyclooxygenase-2 selective inhibitor of the present invention include diaryl bicyclic heterocycles that are described in U.S. Pat. No. 6,329,421. Such diaryl bicyclic heterocycles have the general formula shown below in formula XX:  
                 
 
       [0606] and pharmaceutically acceptable salts thereof wherein:  
       [0607] -A 5 =A 6 -A 7 =A 8 - is selected from the group consisting of:  
       [0608] (a) —CH═CH—CH═CH—,  
       [0609] (b) —CH 2 —CH 2 —CH 2 —C(O)—, —CH 2 —CH 2 —C(O)—CH 2 —, —CH 2 —C(O)—CH 2 —CH 2 , —C(O)—CH 2 —CH 2 —CH 2 ,  
       [0610] (c) —CH 2 —CH 2 —C(O)—, —CH 2 —C(O)CH 2 —, —C(O)—CH 2 —CH 2    
       [0611] (d) —CH 2 —CH 2 —O—C(O)—, CH 2 —O—C(O)—CH 2 —, —O—C(O)—CH 2 —CH 2 —,  
       [0612] (e) —CH 2 —CH 2 —C(O)—O—, —CH 2 —C(O)—OCH 2 —, —C(O)—O-CH 2 —CH 2 —,  
       [0613] (f) —C(R 105 ) 2 —O—C(O)—, —C(OO—C(R 105 ) 2 —, —O—C(O)—C(R 105 ) 2 —, —C(R 105 ) 2 —C(O)—O—,  
       [0614] (g) —N═CH—CH═CH—,  
       [0615] (h) —CH═N—CH═CH—,  
       [0616] (i) —CH═CH—N═CH—,  
       [0617] (j) —CH═CH—CH═N—,  
       [0618] (k) —N═CH—CH═N—,  
       [0619] (l) —N═CH—N═CH—,  
       [0620] (m) —CH═N—CH═N—,  
       [0621] (n) —S—CH═N—,  
       [0622] (o) —S—N═CH—,  
       [0623] (p) —N═N—NH—,  
       [0624] (q) —CH═N—S—, and  
       [0625] (r) —N═CH—S—;  
       [0626] R 99  is selected from the group consisting of:  
       [0627] (a) S(O) 2  CH 3 ,  
       [0628] (b) S(O) 2  NH 2 ,  
       [0629] (c) S(O) 2  NHCOCF 3 ,  
       [0630] (d) S(O)(NH)CH 3 ,  
       [0631] (e) S(O)(NH)NH 2 ,  
       [0632] (f) S(O)(NH)NHCOCF 3 ,  
       [0633] (g) P(O)(CH 3 )OH, and  
       [0634] (h) P(O)(CH 3 )NH 2 ;  
       [0635] R 100  is selected from the group consisting of:  
       [0636] (a) C 1-6  alkyl,  
       [0637] (b) C 3-7 , cycloalkyl,  
       [0638] (c) mono- or di-substituted phenyl or naphthyl wherein the substituent is selected from the group consisting of:  
       [0639] (1) hydrogen,  
       [0640] (2) halo, including F, Cl, Br, I,  
       [0641] (3) C 1-6  alkoxy,  
       [0642] (4) C 1-6  alkylthio,  
       [0643] (5) CN,  
       [0644] (6) CF 3 ,  
       [0645] (7) C 1-6  alkyl,  
       [0646] (8) N 3 ,  
       [0647] (9) —CO 2 H,  
       [0648] (10) —CO 2 —C 1-4  alkyl,  
       [0649] (11) —C(R 103 )(R 140 )—OH,  
       [0650] (12) —C(R 103 )(R 104 )—O—C 1-4  alkyl, and  
       [0651] (13) —C 1-6  alkyl-CO 2 —R 106 ;  
       [0652] (d) mono- or di-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of:  
       [0653] (1) hydrogen,  
       [0654] (2) halo, including fluoro, chloro, bromo and iodo,  
       [0655] (3) C 1-6  alkyl,  
       [0656] (4) C 1-6  alkoxy,  
       [0657] (5) C 1-6  alkylthio,  
       [0658] (6) CN,  
       [0659] (7) CF 3 ,  
       [0660] (8) N 3 ,  
       [0661] (9) —C(R 103 )(R 104 )—OH, and  
       [0662] (10) —C(R 103 )(R 104 )—O—C 1-14  alkyl;  
       [0663] (e) benzoheteroaryl which includes the benzo fused analogs of (d);  
       [0664] R 101  and R 102  are the substituents residing on any position of -A 5 =A 6 -A 7 =A 8 - and are selected independently from the group consisting of:  
       [0665] (a) hydrogen,  
       [0666] (b) CF 3 ,  
       [0667] (c) CN,  
       [0668] (d) C 1-6  alkyl,  
       [0669] (e) Q 3  wherein Q 3  is Q 4 , CO 2 H, C(R 103 )(R 104 )OH,  
       [0670] (f) —O-Q 4 ,  
       [0671] (g) —S-Q 4 , and  
       [0672] (h) optionally substituted:  
       [0673] (1) —C 1-5  alkyl-Q 3 ,  
       [0674] (2) —O—C 1-5  alkyl-Q 3 ,  
       [0675] (3) —S—C 1-5  alkyl-Q 3 ,  
       [0676] (4) —C 1-3  alkyl-O—C 1-3  alkyl-Q 3 ,  
       [0677] (5) —C 1-3  alkyl-S—C 1-3  alkyl-Q 3 ,  
       [0678] (6) —C 1-5  alkyl-O-Q 4 ,  
       [0679] (7) —C 1-5  alkyl-S-Q 4 ,  
       [0680] wherein the substituent resides on the alkyl chain and the substituent is C 1-3  alkyl, and Q 3  is Q 4 , CO 2 H, C(R 103 )(R 104 )OH Q 4  is CO 2 —C 1-4  alkyl, tetrazolyl-5-yl, or C(R 103 )(R 104 )O—C 1-4  alkyl;  
       [0681] R 103 , R 104  and R 105  are each independently selected from the group consisting of  
       [0682] (a) hydrogen,  
       [0683] (b) C 1-6  alkyl; or  
       [0684] R 103  and R 104  together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two R 105  groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;  
       [0685] R 106  is hydrogen or C 1-6  alkyl;  
       [0686] R 107  is hydrogen, C 1-6  alkyl or aryl;  
       [0687] X 7  is O, S, NR 107 , CO, C(R 107 ) 2 , C(R 107 )(OH), —C(R 107 )═C(R 107 )—; —C(R 107 )═N—;  
       [0688] —N═C(R 107 )—.  
       [0689] Compounds that may act as cyclooxygenase-2 inhibitors include salts of 5-amino or a substituted amino 1,2,3-triazole compound that are described in U.S. Pat. No. 6,239,137. The salts are of a class of compounds of formula XXI:  
                 
 
       [0690] wherein:  
       [0691] p is 0 to 2; m is 0 to 4; and n is 0 to 5; X 13  is O, S, SO, SO 2 , CO, CHCN, CH 2  or C═NR 113  where R 113  is hydrogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, diloweralkylamino or cyano; and, R 111  and R 112  are independently halogen, cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, trifuloromethoxy, acetamido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl; R 109  is amino, mono or diloweralkylamino, acetamido, acetimido, ureido, formamido, formamido or guanidino; and R 110  is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the lower alkyl, lower alkyl containing, lower alkoxy and lower alkanoyl groups contain from 1 to 3 carbon atoms.  
       [0692] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include pyrazole derivatives that are described in U.S. Pat. No. 6,136,831. Such pyrazole derivatives have the formula shown below in formula XXII:  
                 
 
       [0693] wherein:  
       [0694] R 114  is hydrogen or halogen, R 115  and R 116  are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or lower alkanoyloxy;  
       [0695] R 117  is lower haloalkyl or lower alkyl;  
       [0696] X 14  is sulfur, oxygen or NH; and  
       [0697] Z 6  is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or a pharmaceutically acceptable salt thereof.  
       [0698] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include substituted derivatives of benzosulphonamides that are described in U.S. Pat. No. 6,297,282. Such benzosulphonamide derivatives have the formula shown below in formula XXIII:  
                 
 
       [0699] wherein:  
       [0700] X 15  denotes oxygen, sulphur or NH;  
       [0701] R 118  is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF 3 , cyano or alkoxy;  
       [0702] R 119  and R 120 , independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 ) n —X 16 ; or  
       [0703] R 119  and R 120 , together with the N— atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH 2 ) n —X 16 ;  
       [0704] X 16  denotes halogen, NO 2 , —OR 121 , —COR 121 , —CO 2  R 121 , —OCO 2  R 121 , —CN, —CONR 121 OR 122 , —CONR 121 R 122 , —SR 121 , —S(O)R 121 , —S(O) 2  R 121 , NR 121  R 122 , —NHC(O)R 121 , —NHS(O) 2  R 121 ;  
       [0705] n denotes a whole number from 0 to 6;  
       [0706] R 123  denotes a straight-chained or branched alkyl group with 1-10 C-atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy;  
       [0707] R 124  denotes halogen, hydroxy, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C— atoms, which can optionally be mono- or polysubstituted by halogen, NO 2 , —OR 121 , —COR 121 , —CO 2 R 121 ,—OCO 2 R 121 , —CN, —CONR 121 OR 122 , —CONR 121 R 122 , —SR 121 , —S(O)R 121 , —S(O) 2  R 121 , —NR 121 R 122 , —NHC(O)R 121 , —NHS(O) 2  R 121 , or a polyfluoroalkyl group;  
       [0708] R 121  and R 122 , independently from one another, denote hydrogen, alkyl, aralkyl or aryl; and  
       [0709] m denotes a whole number from 0 to 2;  
       [0710] and the pharmaceutically-acceptable salts thereof.  
       [0711] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanones that are described in U.S. Pat. No. 6,239,173. Such 3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanones have the formula shown below in formula XXIV:  
                 
 
       [0712] or pharmaceutically acceptable salts thereof wherein:  
       [0713] X 17 —Y 1 —Z 7 — is selected from the group consisting of:  
       [0714] (a) —CH 2  CH 2  CH 2 —,  
       [0715] (b) —C(O)CH 2  CH 2 —,  
       [0716] (c) —CH 2  CH 2  C(O)—,  
       [0717] (d) —CR 129  (R 129′ )—O—C(O)—,  
       [0718] (e) —C(O)—O—CR 129 (R 129′ )—,  
       [0719] (f) —CH 2 —NR 127 —CH 2 —,  
       [0720] (g) —CR 129 (R 129′ )—NR 127 —C(O)—,  
       [0721] (h) —CR 128 ═CR 128′ ′-S—,  
       [0722] (i) —S—CR 128 ═CR 128′ —,  
       [0723] (j) —S—N═CH—,  
       [0724] (k) —CH═N—S—,  
       [0725] (l) —N═CR 128 —O—,  
       [0726] (m) —O—CR 128 ═N—,  
       [0727] (n) —N═CR 128 —NH—,  
       [0728] (o) —N═CR 128 —S—, and  
       [0729] (p) —S—CR 128 ═N—,  
       [0730] (q) —C(O)—NR 127 —CR 129 (R 129′ )—,  
       [0731] (r) —R 127  N—CH═CH— provided R 122  is not —S(O) 2 CH 3 ,  
       [0732] (s) —CH═CH—NR 127 — provided R 125  is not —S(O) 2 CH 3 ,  
       [0733] when side b is a double bond, and sides a and c are single bonds; and  
       [0734] X 17 —Y 1 —Z 7 — is selected from the group consisting of:  
       [0735] (a) ═CH—O—CH═, and  
       [0736] (b) ═CH—NR 127 —CH═,  
       [0737] (c) ═N—S—CH═,  
       [0738] (d) ═CH—S—N═,  
       [0739] (e) ═N—O—CH═,  
       [0740] (f) ═CH—O—N═,  
       [0741] (g) ═N—S—N═,  
       [0742] (h) ═N—O—N═,  
       [0743] when sides a and c are double bonds and side b is a single bond;  
       [0744] R 125  is selected from the group consisting of:  
       [0745] (a) S(O) 2  CH 3 ,  
       [0746] (b) S(O) 2  NH 2 ,  
       [0747] (c) S(O) 2  NHC(O)CF 3 ,  
       [0748] (d) S(O)(NH)CH 3 ,  
       [0749] (e) S(O)(NH)NH 2 ,  
       [0750] (f) S(O)(NH)NHC(O)CF 3 ,  
       [0751] (g) P(O)(CH 3 )OH, and  
       [0752] (h) P(O)(CH 3 )NH 2 ;  
       [0753] R 126  is selected from the group consisting of  
       [0754] (a) C 1-6  alkyl,  
       [0755] (b) C 3 , C 4 , C 5 , C 6 , and C 7 , cycloalkyl,  
       [0756] (c) mono-, di- or tri-substituted phenyl or naphthyl,  
       [0757] wherein the substituent is selected from the group consisting of:  
       [0758] (1) hydrogen,  
       [0759] (2) halo,  
       [0760] (3) C 1-6  alkoxy,  
       [0761] (4) C 1-6  alkylthio,  
       [0762] (5) CN,  
       [0763] (6) CF 3 ,  
       [0764] (7) C 1-6  alkyl,  
       [0765] (8) N 3 ,  
       [0766] (9) —CO 2 H,  
       [0767] (10) —CO 2 —C 1-4  alkyl,  
       [0768] (11) —C(R 129 )(R 130 )—OH,  
       [0769] (12) —C(R 129 )(R 130 )—O—C 1-4  alkyl, and  
       [0770] (13) —C 1-6  alkyl-CO 2 —R 129 ;  
       [0771] (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of:  
       [0772] (1) hydrogen,  
       [0773] (2) halo, including fluoro, chloro, bromo and iodo,  
       [0774] (3) C 1-6  alkyl,  
       [0775] (4) C 1-6  alkoxy,  
       [0776] (5) C 1-6  alkylthio,  
       [0777] (6) CN,  
       [0778] (7) CF 3 ,  
       [0779] (8) N 3 ,  
       [0780] (9) —C(R 129 )(R 130 )—OH, and  
       [0781] (10) —C(R 129 )(R 130 )—O—C 1-4  alkyl;  
       [0782] (e) benzoheteroaryl which includes the benzo fused analogs of (d);  
       [0783] R 127  is selected from the group consisting of:  
       [0784] (a) hydrogen,  
       [0785] (b) CF 3 ,  
       [0786] (c) CN,  
       [0787] (d) C 1-6  alkyl,  
       [0788] (e) hydroxy C 1-6  alkyl,  
       [0789] (f) —C(O)—C 1-6  alkyl,  
       [0790] (g) optionally substituted:  
       [0791] (1) —C 1-5  alkyl-Q 5 ,  
       [0792] (2) —C 1-3  alkyl-O—C 1-3  alkyl-Q 5 ,  
       [0793] (3) —C 1-3  alkyl-S—C 1-3  alkyl-Q 5 ,  
       [0794] (4) —C 1-5  alkyl-O-Q 5 , or  
       [0795] (5) —C 1-5  alkyl-S-Q 5 ,  
       [0796] wherein the substituent resides on the alkyl and the substituent is C 1-3  alkyl;  
       [0797] (h) -Q 5 ;  
       [0798] R 128  and R 128′  are each independently selected from the group consisting of:  
       [0799] (a) hydrogen,  
       [0800] (b) CF 3 ,  
       [0801] (c) CN,  
       [0802] (d) C 1-6  alkyl,  
       [0803] (e) -Q 5 ,  
       [0804] (f) —O-Q 5 ;  
       [0805] (g) —S-Q 5 , and  
       [0806] (h) optionally substituted:  
       [0807] (1) —C 1-5  alkyl-Q 5 ,  
       [0808] (2) —O—C 1-5  alkyl-Q 5 ,  
       [0809] (3) —S—C 1-5  alkyl-Q 5 ,  
       [0810] (4) —C 1-3  alkyl-O—C 1-3  alkyl-Q 5 ,  
       [0811] (5) —C 1-3  alkyl-S—C 1-3  alkyl-Q 5 ,  
       [0812] (6) —C 1-5  alkyl-O-Q 5 ,  
       [0813] (7) —C 1-5  alkyl-S-Q 5 ,  
       [0814] wherein the substituent resides on the alkyl and the substituent is C 1-3  alkyl, and  
       [0815] R 129 , R 129 , R 130 , R 131  and R 132  are each independently selected from the group consisting of:  
       [0816] (a) hydrogen,  
       [0817] (b) C 1-6  alkyl;  
       [0818] or R 129  and R 130  or R 131  and R 132  together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;  
       [0819] Q 5  is CO 2 H, CO 2 —C 1-4  alkyl, tetrazolyl-5-yl, C(R 131 )(R 132 )(OH), or C(R 131 )(R 132 )(O—C 1-4  alkyl);  
       [0820] provided that when X—Y-Z is —S—CR 128 =CR 128′ , then R 128  and R 128′  are other than CF 3 .  
       [0821] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include bicycliccarbonyl indole compounds that are described in U.S. Pat. No. 6,303,628. Such bicycliccarbonyl indole compounds have the formula shown below in formula XXV:  
                 
 
       [0822] or the pharmaceutically acceptable salts thereof wherein  
       [0823] A 9  is C 1-6  alkylene or —NR 133 —;  
       [0824] Z 8  is C(=L 3 )R 134 , or SO 2 R 135 ;  
       [0825] Z 9  is CH or N;  
       [0826] Z 10  and Y 2  are independently selected from —CH 2 —, O, S and —N—R 133 ;  
       [0827] m is 1, 2 or 3;  
       [0828] q and r are independently 0, 1 or 2;  
       [0829] X 18  is independently selected from halogen, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino and cyano;  
       [0830] n is 0, 1, 2, 3 or 4;  
       [0831] L 3  is oxygen or sulfur;  
       [0832] R 133  is hydrogen or C 1-4  alkyl;  
       [0833] R 134  is hydroxy, C 1-6  alkyl, halo-substituted C 1-6  alkyl, C 1-6  alkoxy, halo-substituted C 1-6  alkoxy, C 3-7  cycloalkoxy, C 1-4  alkyl(C 3-7  cycloalkoxy), —NR 136 R 137 , C 1-4  alkylphenyl-O— or phenyl-O—, said phenyl being optionally substituted with one to five substituents independently selected from halogen, C 1-4  alkyl, hydroxy, C 1-4  alkoxy and nitro;  
       [0834] R 135  is C 1-6  alkyl or halo-substituted C 1-6  alkyl; and  
       [0835] R 136  and R 137  are independently selected from hydrogen, C 1-6  alkyl and halo-substituted C 1-6  alkyl.  
       [0836] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include benzimidazole compounds that are described in U.S. Pat. No. 6,310,079. Such benzimidazole compounds have the formula shown below in formula XXVI:  
                 
 
       [0837] or a pharmaceutically acceptable salt thereof, wherein:  
       [0838] A 10  is heteroaryl selected from  
       [0839] a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or  
       [0840] a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;  
       [0841] X 20  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N—(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N,N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N—(C 1 -C 4  alkanoyl)amonio, N—(C 1 -C 4  alkyl)(C 1 -C 4  alkanoyl)amino, N-[(C 1 -C 4  alkyl)sulfonyl]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)carbonyl, carbamoyl, [N—(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N—(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl;  
       [0842] X 21  is independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N—(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N,N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N—(C 0 -C 4  alkanoyl)amino, N—(C 1 -C 4  alkyl)-N—(C 1 -C 4  alkanoyl) amino, N-[(C 1 -C 4  alkyl)sulfonyl]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)cabonyl, cabamoyl, [N—(C 1 -C 4  alkyl) amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, N-carbomoylamino, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N—(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl;  
       [0843] R 138  is selected from  
       [0844] hydrogen, straight or branched C 1 -C 4  alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo hydroxy, C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino,  
       [0845] C 3 -C 8  cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino,  
       [0846] C 4 -C 8  cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino, phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, halo-substituted C 1 -C 4  alkyl, hydroxy-substituted C 1 -C 4  alkyl, (C 1 -C 4  alkoxy)C 1 -C 4  alkyl, halo-substituted C 1 -C 4  alkoxy, amino, N—(C 1 -C 4  alkyl)amino, N,N-di(C 1 -C 4  alkyl)amino, [N—(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, [N,N-di(C 1 -C 4  alkyl)amino]C 1 -C 4  alkyl, N—(C 1 -C 4  alkanoyl)amino, N-[C 1 -C 4  alkyl)(C 1 -C 4  alkanoyl)]amino, N-[(C 1 -C 4  alkyl)sulfony]amino, N-[(halo-substituted C 1 -C 4  alkyl)sulfonyl]amino, C 1 -C 4  alkanoyl, carboxy, (C 1 -C 4  alkoxy)carbonyl, carbomoyl, [N-(C 1 -C 4  alkyl)amino]carbonyl, [N,N-di(C 1 -C 4  alkyl)amino]carbonyl, cyano, nitro, mercapto, (C 1 -C 4  alkyl)thio, (C 1 -C 4  alkyl)sulfinyl, (C 1 -C 4  alkyl)sulfonyl, aminosulfonyl, [N-(C 1 -C 4  alkyl)amino]sulfonyl and [N,N-di(C 1 -C 4  alkyl)amino]sulfonyl; and  
       [0847]  heteroaryl selected from:  
       [0848] a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and  
       [0849] said heteroaryl being optionally substituted with one to three substituent(s) selected from X 20 ;  
       [0850] R 139  and R 140  are independently selected from:  
       [0851] hydrogen,  
       [0852] halo,  
       [0853] C 1 -C 4  alkyl,  
       [0854] phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C 1 -C 4  alkyl, hydroxy, C 1 -C 4  alkoxy, amino, N-(C 1 -C 4  alkyl)amino and N,N-di(C 1 -C 4  alkyl)amino,  
       [0855] or R 138  and R 139  can form, together with the carbon atom to which they are attached, a C 3 -C 7  cycloalkyl ring;  
       [0856] m is 0, 1, 2, 3, 4 or 5; and  
       [0857] n is 0, 1, 2, 3 or 4.  
       [0858] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include indole compounds that are described in U.S. Pat. No. 6,300,363. Such indole compounds have the formula shown below in formula XXVII:  
                 
 
       [0859] and the pharmaceutically acceptable salts thereof,  
       [0860] wherein:  
       [0861] L 4  is oxygen or sulfur;  
       [0862] Y 3  is a direct bond or C 1-4  alkylidene;  
       [0863] Q6 is:  
       [0864] (a) C 1-6  alkyl or halosubstituted C 1-6  alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxy, C 1-4  alkoxy, amino and mono- or di-(C 1-4  alkyl)amino,  
       [0865] (b) C 3-7  cycloalkyl optionally substituted with up to three substituents independently selected from hydroxy, C 1-4  alkyl and C 1-4  alkoxy,  
       [0866] (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from:  
       [0867] (c-1) halo, C 1-4  alkyl, halosubstituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halosubstituted C 1-4  alkoxy, S(O) m R 143 , SO 2  NH 2 , SO 2  N(C 1-4  alkyl) 2 , amino, mono- or di-(C 1-4  alkyl)amino, NHSO 2  R 143 , NHC(O)R 143 , CN, CO 2 H, CO 2  (C 1-4  alkyl), C 1-4  alkyl-OH, C 1-4  alkyl-OR 143 , CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2  and —O—Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo,  
       [0868]  C 1-4  alkyl, CF 3 , hydroxy, OR 143 , S(O) m R 143  amino, mono- or di-(C 1-4  alkyl)amino and CN;  
       [0869] (d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from:  
       [0870] (d-1) halo, C 1-4  alkyl, halosubstituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halosubstituted C 1-4  alkoxy, C 1-4  alkyl-OH, S(O) m  R 143 , SO 2  NH 2 , SO 2  N(C 1-4  alkyl) 2 , amino, mono- or di-(C 1-4  alkyl)amino, NHSO 2  R 143 , NHC(O)R 143 , CN, CO 2  H, CO 2  (C 1-4  alkyl), C 1-4  alkyl-OR 143 , CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF 3 , C 1-4  alkyl, hydroxy, C 1-4  alkoxy, OCF 3 , SR 143 , SO 2  CH 3 , SO 2  NH 2 , amino, C 1-4  alkylamino and NHSO 2 R 143 ;  
       [0871] (e) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from the above group (d-1);  
       [0872] R 141  is hydrogen or C 1-6  alkyl optionally substituted with a substituent selected independently from hydroxy, OR 143 , nitro, amino, mono- or di-(C 1-4  alkyl)amino, CO 2 H, CO 2  (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl) and CON(C 1-4  alkyl) 2 ;  
       [0873] R 142  is:  
       [0874] (a) hydrogen,  
       [0875] (b) C 1-4  alkyl,  
       [0876] (c) C(O)R 145 ,  
       [0877] wherein R 145  is selected from:  
       [0878] (c-1) C 1-22  alkyl or C 2-22  alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from:  
       [0879] (c-1-1) halo, hydroxy, OR 143 , S(O) m  R 143 , nitro, amino, mono- or di-(C 1-4  alkyl)amino, NHSO 2  R 143 , CO 2 H, CO 2  (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , OC(O)R 143 , thienyl, naphthyl and groups of the following formulae:  
                 
 
       [0880] (c-2) C 1-22  alkyl or C 2-22  alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms,  
       [0881] (c-3) —Y 5 —C 3-7  cycloalkyl or —Y 5 —C 3-7  cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from:  
       [0882] (c-3-1) C 1-4  alkyl, hydroxy, OR 143 , S(O) m  R 143 , amino, mono- or di-(C 1-4  alkyl)amino, CONH 2 , CONH(C 1-4  alkyl) and CON(C 1-4  alkyl) 2 ,  
       [0883] (c-4) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven (preferably up to seven) substituents independently selected from:  
       [0884] (c-4-1) halo, C 1-8  alkyl, C 1-4  alkyl-OH, hydroxy, C 1-8  alkoxy, halosubstituted C 1-8  alkyl, halosubstituted C 1-8  alkoxy, CN, nitro, S(O) m  R 143 , SO 2  NH 2 , SO 2  NH(C 1-4  alkyl), SO 2  N(C 1-4  alkyl) 2 , amino, C 1-4  alkylamino, di-(C 1-4  alkyl)amino, CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , OC(O)R 143 , and phenyl optionally substituted with up to three substituents independently selected from halo, C 1-4  alkyl, hydroxy, OCH 3 , CF 3 , OCF 3 , CN, nitro, amino, mono- or di-(C 1-4  alkyl)amino, CO 2 H, CO 2  (C 1-4  alkyl) and CONH 2 ,  
       [0885] (c-5) a monocyclic aromatic group as defined in (d) and (e) above, said aromatic group being optionally substituted with up to three substituents independently selected from:  
       [0886] (c-5-1) halo, C 1-8  alkyl, C 1-4  alkyl-OH, hydroxy, C 1-8  alkoxy, CF 3 , OCF 3 , CN, nitro, S(O) m  R 143 , amino, mono- or di-(C 1-4  alkyl)amino, CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , CO 2 H and CO 2  (C 1-4  alkyl), and —Y-phenyl, said phenyl being optionally substituted with up to three substituents independently selected halogen, C 1-4  alkyl, hydroxy, C 1-4  alkoxy, CF 3 , OCF 3 , CN, nitro, S(O) m  R 143 , amino, mono- or di-(C 1-4  alkyl)amino, CO 2 H, CO 2  (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl) and CON(C 1-4  alkyl) 2 ,  
       [0887] (c-6) a group of the following formula:  
                 
 
       [0888] X 22  is halo, C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halosubstitutued C 1-4  alkoxy, S(O) m  R 143 , amino, mono- or di-(C 1-4  alkyl)amino, NHSO 2  R 43 , nitro, halosubstitutued C 1-4  alkyl, CN, CO 2 H, CO 2  (C 1-4  alkyl), C 1-4  alkyl-OH, C 1-4  alkylOR 143 , CONH 2 , CONH(C 1-4  alkyl) or CON(C 1-4  alkyl) 2 ; R 143  is C 1-4  alkyl or halosubstituted C 1-4  alkyl;  
       [0889] m is 0, 1 or 2; n is 0, 1, 2 or 3; p is 1, 2, 3, 4 or 5; q is 2 or 3;  
       [0890] Z 11  is oxygen, sulfur or NR 144 ; and  
       [0891] R 144  is hydrogen, C 1-6  alkyl, halosubstitutued C 1-4  alkyl or —Y 5 -phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, C 1-4  alkyl, hydroxy, C 1-4  alkoxy, S(O) m  R 143 , amino, mono- or di-(C 1-4  alkyl)amino, CF 3 , OCF 3 , CN and nitro;  
       [0892]  with the proviso that a group of formula —Y 5 -Q is not methyl or ethyl when X 22  is hydrogen;  
       [0893] L 4  is oxygen;  
       [0894] R 141  is hydrogen; and  
       [0895] R 142  is acetyl.  
       [0896] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include aryl phenylhydrazides that are described in U.S. Pat. No. 6,077,869. Such aryl phenylhydrazides have the formula shown below in formula XXVIII:  
                 
 
       [0897] wherein:  
       [0898] X 23  and Y 6  are selected from hydrogen, halogen, alkyl, nitro, amino or other oxygen and sulfur containing functional groups such as hydroxy, methoxy and methylsulfonyl.  
       [0899] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 2-aryloxy, 4-aryl furan-2-ones that are described in U.S. Pat. No. 6,140,515. Such 2-aryloxy, 4-aryl furan-2-ones have the formula shown below in formula XXIX:  
                 
 
       [0900] or a pharmaceutical salt thereof,  
       [0901] wherein:  
       [0902] R 146  is selected from the group consisting of SCH 3 , —S(O) 2  CH 3  and —S(O) 2  NH 2 ;  
       [0903] R 3  is selected from the group consisting of OR 150 , mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;  
       [0904] R 150  is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;  
       [0905] R 148  is H, C 1-4  alkyl optionally substituted With 1 to 3 groups of F, Cl or Br; and  
       [0906] R 149  is H, C 1-4  alkyl optionally substituted with 1 to 3 groups of F, Cl or Br, with the proviso that R 148  and R 149  are not the same.  
       [0907] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S. Pat. No. 5,994,379. Such bisaryl compounds have the formula shown below in formula XXX:  
                 
 
       [0908] or a pharmaceutically acceptable salt, ester or tautomer thereof,  
       [0909] wherein:  
       [0910] Z 13  is C or N;  
       [0911] when Z 13  is N, R 151  represents H or is absent, or is taken in conjunction with R as described below:  
       [0912]  when Z 13  is C, R 151  represents H and R 152  is a moiety which has the following characteristics:  
       [0913] (a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration,  
       [0914] (b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and  
       [0915] (c) there exists an energetically stable configuration planar with ring A to within about 15 degrees;  
       [0916]  or R 151  and R 152  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;  
       [0917]  said ring D being lipophilic except for the atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said ring D having available an energetically stable configuration planar with ring A to within about 15 degrees;  
       [0918]  said ring D further being substituted with 1 R a  group selected from the group consisting of: C 1-2  alkyl, —OC 1-2  alkyl, —NHC 1-2  alkyl, —N(C 1-2  alkyl) 2 , —C(O)C 1-2  alkyl, —S—C 1-2  alkyl and —C(S)C 1-2  alkyl;  
       [0919]  Y 7  represents N, CH or C—OC 1-3  alkyl, and when Z 13  is N, Y 7  can also represent a carbonyl group;  
       [0920] R 153  represents H, Br, Cl or F; and  
       [0921] R 154  represents H or CH 3 .  
       [0922] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 1,5-diarylpyrazoles that are described in U.S. Pat. No. 6,028,202. Such 1,5-diarylpyrazoles have the formula shown below in formula XXXI:  
                 
 
       [0923] wherein:  
       [0924] R 155 , R 156 , R 157 , and R 158  are independently selected from the groups consisting of hydrogen, C 1-5  alkyl, C 1-5  alkoxy, phenyl, halo, hydroxy, C 1-5  alkylsulfonyl, C 1-5  alkylthio, trihaloC 1-5  alkyl, amino, nitro and 2-quinolinylmethoxy;  
       [0925] R 159  is hydrogen, C 1-5  alkyl, trihaloC 1-5  alkyl, phenyl, substituted phenyl where the phenyl substitutents are halogen, C 1-5  alkoxy, trihaloC 1-5  alkyl or nitro or R 159  is heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen;  
       [0926] R 160  is hydrogen, C 1-5  alkyl, phenyl C 1-5  alkyl, substituted phenyl C 1-5  alkyl where the phenyl substitutents are halogen, C 1-5  alkoxy, trihaloC 1-5  alkyl or nitro, or R 160  is C 1-5  alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl where the phenyl substitutents are halogen, C 1-5  alkoxy, trihaloC 1-5  alkyl or nitro;  
       [0927] R 161  is C 1-10  alkyl, substituted C 1-10  alkyl where the substituents are halogen, trihaloC 1-5  alkyl, C 1-5  alkoxy, carboxy, C 1-5  alkoxycarbonyl, amino, C 1-5  alkylamino, diC 1-5  alkylamino, diC 1-5  alkylaminoC 1-5  alkylamino, C 1-5  alkylaminoC 1-5  alkylamino or a heterocycle containing 4-8 ring atoms where one more of the ring atoms is nitrogen, oxygen or sulfur, where said heterocycle may be optionally substituted with C 1-5  alkyl; or  
       [0928] R 161  is phenyl, substituted phenyl (where the phenyl substitutents are one or more of C 1-5  alkyl, halogen, C 1-5  alkoxy, trihaloC 1-5  alkyl or nitro), or R 161  is heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur, fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or  
       [0929] R 161  is NR 163 R 164  where R 163  and R 164  are independently selected from hydrogen and C 1-5  alkyl or R 163  and R 164  may be taken together with the depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one or more of the ring members is nitrogen, sulfur or oxygen where said heteroaryl ring may be optionally substituted with C 1-5  alkyl;  
       [0930] R 162  is hydrogen, C 1-5  alkyl, nitro, amino, and halogen; and pharmaceutically acceptable salts thereof.  
       [0931] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 2-substituted imidazoles that are described in U.S. Pat. No. 6,040,320. Such 2-substituted imidazoles have the formula shown below in formula XXXII:  
                 
 
       [0932] wherein:  
       [0933] R 164  is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, or  
       [0934] substituted phenyl;  
       [0935] wherein the substituents are independently selected from one or members of the group consisting of C 1-5  alkyl, halogen, nitro, trifluoromethyl and nitrile;  
       [0936] R 165  is phenyl, heteroaryl wherein the heteroaryl contains 5 to 6 ring atoms, substituted heteroaryl;  
       [0937] wherein the substituents are independently selected from one or more members of the group consisting of C 1-5  alkyl and halogen, or substituted phenyl,  
       [0938] wherein the substituents are independently selected from one or members of the group consisting of C 1-5  alkyl, halogen, nitro, trifluoromethyl and nitrile;  
       [0939] R 166  is hydrogen, SEM, C 1-5  alkoxycarbonyl, aryloxycarbonyl, arylC 1-5  alkyloxycarbonyl, arylC 1-5 alkyl, phthalimidoC 1-5  alkyl, aminoC 1-5  alkyl, diaminoC 1-5  alkyl, succinimidoC 1-5  alkyl, C 1-5  alkylcarbonyl, arylcarbonyl, C 1-5  alkylcarbonylC 1-5  alkyl, aryloxycarbonylC 1-5  alkyl, heteroarylC 1-5  alkyl where the heteroaryl contains 5 to 6 ring atoms, or  
       [0940]  substituted arylC 1-5  alkyl,  
       [0941] wherein the aryl substituents are independently selected from one or more members of the group consisting of C 1-5  alkyl, C 1-5  alkoxy, halogen, amino, C 1-5  alkylamino, and diC 1-5  alkylamino;  
       [0942] R 167  is (A 11 ) n —(CH 165 ) q —X 24  wherein:  
       [0943] A 11  is sulfur or carbonyl;  
       [0944] n is 0 or 1;  
       [0945] q is 0-9;  
       [0946] X 24  is selected from the group consisting of hydrogen, hydroxy, halogen, vinyl, ethynyl, C 1-5  alkyl, C 3-7  cycloalkyl, C 1-5  alkoxy, phenoxy, phenyl, arylC 1-5  alkyl, amino, C 1-5  alkylamino, nitrile, phthalimido, amido, phenylcarbonyl, C 1-5  alkylaminocarbonyl, phenylaminocarbonyl, arylC 1-5  alkylaminocarbonyl, C 1-5  alkylthio, C 1-15  alkylsulfonyl, phenylsulfonyl,  
       [0947]  substituted sulfonamido,  
       [0948] wherein the sulfonyl substituent is selected from the group consisting of C 1-5  alkyl, phenyl, araC 1-5  alkyl, thienyl, furanyl, and naphthyl; substituted vinyl,  
       [0949] wherein the substituents are independently selected from one or members of the group consisting of fluorine, bromine, chlorine and iodine, substituted ethynyl,  
       [0950] wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine chlorine and iodine, substituted C 1-5  alkyl,  
       [0951] wherein the substituents are selected from the group consisting of one or more C 1-5  alkoxy, trihaloalkyl, phthalimido and amino, substituted phenyl,  
       [0952] wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5  alkyl, halogen and C 1-5  alkoxy, substituted phenoxy,  
       [0953] wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5  alkyl, halogen and C 1-5  alkoxy, substituted C 1-5  alkoxy,  
       [0954] wherein the alkyl substituent is selected from the group consisting of phthalimido and amino, substituted arylC 1-5  alkyl,  
       [0955] wherein the alkyl substituent is hydroxyl, substituted arylC 1-5  alkyl,  
       [0956] wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5  alkyl, halogen and C 1-5  alkoxy, substituted amido,  
       [0957] wherein the carbonyl substituent is selected from the group consisting of C 1-5  alkyl, phenyl, arylC 1-5  alkyl, thienyl, furanyl, and naphthyl, substituted phenylcarbonyl,  
       [0958] wherein the phenyl substituents are independently selected from one or members of the group consisting of C 1-5  alkyl, halogen and C 1-5  alkoxy, substituted C 1-5  alkylthio,  
       [0959] wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido,  
       [0960]  substituted C 1-5  alkylsulfonyl,  
       [0961] wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido, substituted phenylsulfonyl,  
       [0962] wherein the phenyl substituents are independently selected from one or members of the group consisting of bromine, fluorine, chlorine, C 1-5  alkoxy and trifluoromethyl, with the proviso:  
       [0963] if A 11  is sulfur and X 24  is other than hydrogen, C 1-5  alkylaminocarbonyl, phenylaminocarbonyl, arylC 1-5  alkylaminocarbonyl, C 1-5  alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1;  
       [0964] if A 11  is sulfur and q is 1, then X 24  cannot be C 1-2  alkyl;  
       [0965] if A 11  is carbonyl and q is 0, then X 24  cannot be vinyl, ethynyl, C 1-5  alkylaminocarbonyl, phenylaminocarbonyl, arylC 1-5  alkylaminocarbonyl, C 1-5  alkylsulfonyl or phenylsulfonyl;  
       [0966] if A 11  is carbonyl, q is 0 and X 24  is H, then R 166  is not SEM (2-(trimethylsilyl)ethoxymethyl);  
       [0967] if n is 0 and q is 0, then X 24  cannot be hydrogen; and pharmaceutically acceptable salts thereof.  
       [0968] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles that are described in U.S. Pat. No. 6,083,969. Such 1,3- and 2,3-diarylpyrazole compounds have the general formulas shown below in formulas XXXIII and XXXIV:  
                 
 
       [0969] wherein:  
       [0970] R 168  and R 169  are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, amino, hydroxy, trifluoro, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl and —SO 2  (C 1 -C 6 )alkyl; and  
       [0971]  the fused moiety M is a group selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:  
                 
 
       [0972] wherein:  
       [0973] R 170  is selected from the group consisting of hydrogen, halogen, hydroxy and carbonyl;  
       [0974] or R 170  and R 171  taken together form a moiety selected from the group consisting of —OCOCH 2 —, —ON H(CH 3 )COCH 2 —, —OCOCH.dbd. and —O—;  
       [0975] R 170  and R 171  are independently selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, ═NOH, —NR 174 R 175 , —OCH 3 , —OCH 2  CH 3 , —OSO 2  NHCO 2  CH 3 , ═CHCO 2  CH 2  CH 3 , —CH 2  CO 2 H, —CH 2  CO 2  CH 3 , —CH 2  CO 2  CH 2  CH 3 , —CH 2  CON(CH 3 ) 2 , —CH 2  CO 2  NHCH 3 , —CHCHCO 2  CH 2  CH 3 , —OCON(CH 3 )OH, —C(COCH 3 ) 2 , di(C 1 -C 6 )alkyl and di(C 1 -C 6 )alkoxy;  
       [0976] R 173  is selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxy, amino, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;  
       [0977] or R 172  and R 173  taken together form a moiety selected from the group consisting of —O— and  
                 
 
       [0978] R 174  is selected from the group consisting of hydrogen, OH, —OCOCH 3 , —COCH 3  and (C 1 -C 6 )alkyl; and  
       [0979] R 175  is selected from the group consisting of hydrogen, OH, —OCOCH 3 , —COCH 3 , (C 1 -C 6 )alkyl, —CONH 2  and —SO 2  CH 3 ;  
       [0980]  with the proviso that  
       [0981] if M is a cyclohexyl group, then R 170  through R 173  may not all be hydrogen; and  
       [0982] pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
       [0983] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include esters derived from indolealkanols and novel amides derived from indolealkylamides that are described in U.S. Pat. No. 6,306,890. Such compounds have the general formula shown below in formula XXXV:  
                 
 
       [0984] wherein:  
       [0985] R 176  is C 1  to C 6  alkyl, C 1  to C 6  branched alkyl, C 4  to C 8  cycloalkyl, C 1  to C 6  hydroxyalkyl, branched C 1  to C 6  hydroxyalkyl, hydroxy substituted C 4  to C 8  aryl, primary, secondary or tertiary C 1  to C 6  alkylamino, primary, secondary or tertiary branched C 1  to C 6  alkylamino, primary, secondary or tertiary C 4  to C 8  arylamino, C 1  to C 6  alkylcarboxylic acid, branched C 1  to C 6  alkylcarboxylic acid, C 1  to C 6  alkylester, branched C 1  to C 6  alkylester, C 4  to C 8  aryl, C 4  to C 8  arylcarboxylic acid, C 4  to C 8  arylester, C 4  to C 8  aryl substituted C 1  to C 6  alkyl, C 4  to C 8  heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted C 4  to C 8  heterocyclic alkyl or aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro or iodo;  
       [0986] R 177  is C 1  to C 6  alkyl, C 1  to C 6  branched alkyl, C 4  to C 8  cycloalkyl, C 4  to C 8  aryl, C 4  to C 8  aryl-substituted C 1  to C 6  alkyl, C 1  to C6 alkoxy, C 1  to C 6  branched alkoxy, C4 to C 8  aryloxy, or halo-substituted versions thereof or R 177  is halo where halo is chloro, fluoro, bromo, or iodo;  
       [0987] R 178  is hydrogen, C 1  to C 6  alkyl or C 1  to C 6  branched alkyl;  
       [0988] R 179  is C 1  to C 6  alkyl, C 4  to C 8  aroyl, C 4  to C 8  aryl, C 4  to C 8  heterocyclic alkyl or aryl with O, N or S in the ring, C 4  to C 8  aryl-substituted C 1  to C 6  alkyl, alkyl-substituted or aryl-substituted C 4  to C 8  heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted C 4  to C 8  aroyl, or alkyl-substituted C 4  to C 8  aryl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo;  
       [0989] n is 1, 2, 3, or 4; and  
       [0990] X 25  is O, NH, or N—R 180 , where R 180  is C 1  to C 6  alkyl or C 1  to C 6  branched alkyl.  
       [0991] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include pyridazinone compounds that are described in U.S. Pat. No. 6,307,047. Such pyridazinone compounds have the formula shown below in formula XXXVI:  
                 
 
       [0992] or a pharmaceutically acceptable salt, ester, or prodrug thereof,  
       [0993] wherein:  
       [0994] X 26  is selected from the group consisting of O, S, —NR 185 , —NOR a , and —NNR b R c ;  
       [0995] R 185  is selected from the group consisting of alkenyl; alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;  
       [0996] R a , R b , and R c  are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;  
       [0997] R 181  is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, —(CH 2 ) n  C(O)R 186 , —(CH 2 ) n  CH(OH)R 186 , —(CH 2 ) n  C(NOR d )R 186 , —(CH 2 ) n  CH(NOR d )R 186 , —(CH 2 ) n  CH(NR d R e )R 186 , —R 187  R 188 , —(CH 2 ) n  C≡CR 188 , —(CH 2 ) n  [CH(CX 26′   3 )] m  (CH 2 ) p  R 188 , —(CH 2 ) n  (CX 26,   2 ) m  (CH 2 ) p  R 188 , and —(CH 2 ) n  (CHX 26,   3 ) m  (CH 2 ) m  R 188 ;  
       [0998] R 186  is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;  
       [0999] R 187  is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene;  
       [1000] R 188  is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;  
       [1001] R d  and R e  are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; X 26′  is halogen;  
       [1002] m is an integer from 0-5;  
       [1003] n is an integer from 0-10; and  
       [1004] p is an integer from 0-10; and  
       [1005] R 182 , R 183 , and R 184  are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y 8 , and Z 14 ;  
       [1006]  provided that one of R 182 , R 183 , or R 184  must be Z 14 , and further provided that only one of R 182 , R 183 , or R 184  is Z 14 ;  
       [1007] Z 14  is selected from the group consisting of:  
                 
 
       [1008] X 27  is selected from the group consisting of S(O) 2 , S(O)(NR 191 ), S(O), Se(O) 2 , P(O)(OR 192 ), and P(O)(NR 193  R 194 );  
       [1009] X 28  is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;  
       [1010] R 190  is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, —NHNH 2 , and —NCHN(R 191 )R 192 ;  
       [1011] R 191 , R 192 , R 193 , and R 194  are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193  and R 194  can be taken together, with the nitrogen to which they are attached, to form a 3-6 membered ring containing 1 or 2 heteroatoms selected from the group consisting of O, S, and NR 188 ;  
       [1012] Y 8  is selected from the group consisting of —OR 195 , —SR 195 , —C(R 197 )(R 198 )R 195 , —C(O)R 195 , —C(O)OR 195 , —N(R 197 )C(O)R 195 , —NC(R 197 )R 195 , and —N(R 197 )R 195 ;  
       [1013] R 195  is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl, and NR 199 R 200 ; and  
       [1014] R 197 , R 198 , R 199 , and R 200  are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl.  
       [1015] Materials that can serve as a cyclooxygenase-2 selective inhibitor of the present invention include benzosulphonamide derivatives that are described in U.S. Pat. No. 6,004,948. Such benzosulphonamide derivatives have the formula shown below in formula XXXVII:  
                 
 
       [1016] wherein:  
       [1017] A denotes oxygen, sulphur or NH;  
       [1018] R 201  denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF 3  or alkoxy;  
       [1019] D 5  denotes a group of formula XXXVIII or XXXIX:  
                 
 
       [1020] R 202  and R 203  independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH 2 ) n —X 29 ; or  
       [1021] R 202  and R 203  together with the N-atom denote a three- to seven-membered,  
       [1022]  saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which may optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH 2 ) n —X 29 , R 202 , denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 ) n —X 29 ,  
       [1023] wherein:  
       [1024] X 29  denotes halogen, NO 2 , —OR 204 , —COR 204 , —CO 2  R 204 , —OCO 2  R 204 , —CN, —CONR 204 OR 205 , —CONR 204 R 205 , —SR 204 , —S(O)R 204 , —S(O) 2  R 204 , —NR 204 R 205 , —NHC(O)R 204 , —NHS(O) 2 R 204 ;  
       [1025] Z 15  denotes —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH═CH—, —CH═CH—CH 2 —, —CH 2 —CO—, —CO—CH 2 —, —NHCO—, —CONH—, —NHCH 2 —, —CH 2  NH—, —N═CH—, —NHCH—, —CH 2 —CH 2 —NH—, —CH═CH—, &gt;N—R 203 , &gt;C═O, &gt;S(O) m ;  
       [1026] R 204  and R 205  independently of each other denote hydrogen, alkyl, aralkyl or aryl;  
       [1027] n is an integer from 0 to 6;  
       [1028] R 206  is a straight-chained or branched C 1-4 -alkyl group which may optionally be mono- or polysubstituted by halogen or alkoxy, or R 206  denotes CF 3 ; and  
       [1029] m denotes an integer from 0 to 2;  
       [1030] with the proviso that A1 does not represent O if R 206  denotes CF 3 ;  
       [1031] and the pharmaceutically acceptable salts thereof.  
       [1032] Cox-2 selective inhibitors that are useful in the subject method and compositions can include the compounds that are described in U.S. Pat. Nos. 6,169,188, 6,020,343, 5,981,576 ((methylsulfonyl)phenyl furanones); U.S. Pat. No. 6,222,048 (diaryl-2-(5H)-furanones); U.S. Pat. No. 6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Pat. No. 6,046,236 (carbocyclic sulfonamides); U.S. Pat. Nos. 6,002,014 and 5,945,539 (oxazole derivatives); and U.S. Pat. No. 6,359,182 (C-nitroso compounds).  
       [1033] Cyclooxygenase-2 selective inhibitors that are useful in the present invention can be supplied by any source as long as the cyclooxygenase-2-selective inhibitor is pharmaceutically acceptable. Cyclooxygenase-2-selective inhibitors can be isolated and purified from natural sources or can be synthesized. Cyclooxygenase-2-selective inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products.  
       [1034] Further preferred COX-2 inhibitors that may be used in the present invention include, but are not limited to:  
                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 
 
       [1035] The CAS reference numbers for nonlimiting examples of COX-2 inhibitors are identified in Table No. 3 below.  
               TABLE No. 3                          COX-2 Inhibitor&#39;s CAS Reference Numbers                             Compound Number   CAS Reference Number                       C1   180200-68-4           C2   202409-33-4           C3   212126-32-4           C4   169590-42-5           C5   162011-90-7           C6   181695-72-7           C7   198470-84-7           C8   170569-86-5           C9   187845-71-2           C10   179382-91-3           C11   51803-78-2           C12   189954-13-0           C13   158205-05-1           C14   197239-99-9           C15   197240-09-8           C16   226703-01-1           C17   93014-16-5           C18   197239-97-7           C19   162054-19-5           C20   170569-87-6           C21   279221-13-5           C22   170572-13-1           C23   123653-11-2           C24   80937-31-1           C25   279221-14-6           C26   279221-15-7           C27   187846-16-8           C28   189954-16-3           C29   181485-41-6           C30   187845-80-3           C31   158959-32-1           C32   170570-29-3           C33   177660-77-4           C34   177660-95-6           C35   181695-81-8           C36   197240-14-5           C37   181696-33-3           C38   178816-94-9           C39   178816-61-0           C40   279221-17-9           C41   123663-49-0           C42   197905-01-4           C43   197904-84-0           C44   169590-41-4           C45   88149-94-4           C46   266320-83-6           C47   215122-43-3           C48   215122-44-4           C49   215122-74-0           C50   215123-80-1           C51   215122-70-6           C52   264878-87-7           C53   279221-12-4           C54   215123-48-1           C55   215123-03-8           C56   215123-60-7           C57   279221-18-0           C58   215123-61-8           C59   215123-52-7           C60   279221-19-1           C61   215123-64-1           C62   215123-70-9           C63   215123-79-8           C64   215123-91-4           C65   215123-77-6           C66   71125-38-7           C67   220991-33-3           C68   197438-41-8           C69   137945-48-3           C70   189954-66-3           C71   251442-94-1           C73   158089-95-3                      
 
       [1036] Nonlimiting examples of COX-2 inhibitors that may be used in the present invention are identified in Table No. 4 below. The individual references in Table No. 4 are each herein individually incorporated by reference.  
               TABLE No. 4                          COX-2 Inhibitors                             Trade/           Compound   Research Name   Reference               6-chloro-4-hydroxy-2-methyl-N-2-   lornoxicam;   CAS No.       pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-   Safem ®   70374-39-9       carboxamide, 1,1-dioxide       1,5-Diphenyl-3-substituted pyrazoles       WO               97/13755           radicicol   WO               96/25928.               Kwon et al               (Cancer               Res(1992)               52 6296)           GB-02283745           TP-72   Cancer Res               1998 58 4               717-723       1-(4-chlorobenzoyl)-3-[4-(4-fluoro-phenyl)   A-183827.0       thiazol-2-ylmethyl]-5-methoxy-2-       methylindole           GR-253035       4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-   JTE-522   JP 9052882       fluorobenzenesulfonamide       5-chloro-3-(4-(methylsulfonyl)phenyl)-2-       (methyl-5-pyridinyl)-pyridine       2-(3,5-difluoro-phenyl)-3-4-       (methylsulfonyl)-phenyl)-2-cyclopenten-       1-one           L-768277           L-783003           MK-966;   US           VIOXX ®,   5968974           Rofecoxib       indomethacin-derived indolalkanoic acid       WO               96/374679       1-Methylsulfonyl-4-[1,1-dimethyl-4-(4-       WO       fluorophenyl)cyclopenta-2,4-dien-3-       95/30656.       yl]benzene       WO               95/30652.               WO               96/38418.               WO               96/38442.       4,4-dimethyl-2-phenyl-3-[4-       (methylsulfonyl)phenyl]cyclo-butenone       2-(4-methoxyphenyl)-4-methyl-1-(4-       EP 799823       sulfamoylphenyl)-pyrrole       N-[5-(4-fluoro)phenoxy]thiophene-2-   RWJ-63556       methanesulfon-amide       5(E)-(3,5-di-tert-butyl-4-       hydroxy)benzylidene-2-ethyl-1,2-   S-2474   EP 595546       isothiazolidine-1,1-dioxide       3-formylamino-7-methylsulfonylamino-6-   T-614   DE       phenoxy-4H-1-benzopyran-4-one       3834204       Benzenesulfonamide, 4-(5-(4-   celecoxib   US       methylphenyl)-3-(trifluoromethyl)-1H-       5466823       pyrazol-1-yl)-       CS 502   (Sankyo)       MK 633   (Merck)           meloxicam   US               4233299           nimesulide   US               3840597                  
 
       [1037] The following references listed in Table No. 5 below, hereby individually incorporated by reference, describe various COX-2 inhibitors suitable for use in the present invention described herein, and processes for their manufacture.  
               TABLE No. 5                       COX-2 Inhibitor References                                                WO 99/30721   WO 99/30729   US 5760068   WO 98/15528       WO 99/25695   WO 99/24404   WO 99/23087   FR 27/71005       EP 921119   FR 27/70131   WO 99/18960   WO 99/15505       WO 99/15503   WO 99/14205   WO 99/14195   WO 99/14194       WO 99/13799   GB 23/30833   US 5859036   WO 99/12930       WO 99/11605   WO 99/10332   WO 99/10331   WO 99/09988       US 5869524   WO 99/05104   US 5859257   WO 98/47890       WO 98/47871   US 5830911   US 5824699   WO 98/45294       WO 98/43966   WO 98/41511   WO 98/41864   WO 98/41516       WO 98/37235   EP 86/3134   JP 10/175861   US 5776967       WO 98/29382   WO 98/25896   ZA 97/04806   EP 84/6,689       WO 98/21195   GB 23/19772   WO 98/11080   WO 98/06715       WO 98/06708   WO 98/07425   WO 98/04527   WO 98/03484       FR 27/51966   WO 97/38986   WO 97/46524   WO 97/44027       WO 97/34882   US 5681842   WO 97/37984   US 5686460       WO 97/36863   WO 97/40012   WO 97/36497   WO 97/29776       WO 97/29775   WO 97/29774   WO 97/28121   WO 97/28120       WO 97/27181   WO 95/11883   WO 97/14691   WO 97/13755       WO 97/13755   CA 21/80624   WO 97/11701   WO 96/41645       WO 96/41626   WO 96/41625   WO 96/38418   WO 96/37467       WO 96/37469   WO 96/36623   WO 96/36617   WO 96/31509       WO 96/25405   WO 96/24584   WO 96/23786   WO 96/19469       WO 96/16934   WO 96/13483   WO 96/03385   US 5510368       WO 96/09304   WO 96/06840   WO 96/06840   WO 96/03387       WO 95/21817   GB 22/83745   WO 94/27980   WO 94/26731       WO 94/20480   WO 94/13635   FR 27/70,131   US 5859036       WO 99/01131   WO 99/01455   WO 99/01452   WO 99/01130       WO 98/57966   WO 98/53814   WO 98/53818   WO 98/53817       WO 98/47890   US 5830911   US 5776967   WO 98/22101       DE 19/753463   WO 98/21195   WO 98/16227   US 5733909       WO 98/05639   WO 97/44028   WO 97/44027   WO 97/40012       WO 97/38986   US 5677318   WO 97/34882   WO 97/16435       WO 97/03678   WO 97/03667   WO 96/36623   WO 96/31509       WO 96/25928   WO 96/06840   WO 96/21667   WO 96/19469       US 5510368   WO 96/09304   GB 22/83745   WO 96/03392       WO 94/25431   WO 94/20480   WO 94/13635   JP 09052882       GB 22/94879   WO 95/15316   WO 95/15315   WO 96/03388       WO 96/24585   US 5344991   WO 95/00501   US 5968974       US 5945539   US 5994381   US 5521207                  
 
       [1038] Hormonal agents are useful as antineoplastic agents. Aromatase inhibitors, a class of hormonal agents, are useful in the prevention, treatment and inhibition of neoplasia or neoplasia-related orders. Aromatase inhibitors inhibit aromatase (estrogen synthase), a membrane-bound enzyme complex that catalyses the conversion of androgens to estrogens. Since estrogen receptor-positive breast cancers are stimulated to grow by endogenous estrogen, the use of aromatase inhibitors is useful in inhibiting estrogen production, resulting in tumor regression.  
       [1039] Aromatase inhibitor antineoplastic agents are broadly classified as steroidal and nonsteroidal. The majority of aromatase inhibitors known are steroidal compounds that are structurally related to the natural substrate of aromatase. Examples of steroidal aromatase inhibitors include formestane, exemestane, and atamestane. Nonsteroidal inhibitors have a heteroatom, usually in a nitrogen-containing heterocyclo, as a common feature that interferes with the steroidal hydroxylation of the aromatase enzyme. Examples of nonsteroidal aromatase inhibitors include rogletimide, letrozole and anastrozole.  
       [1040] Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to aminoglutethimide; anastrozole; exemestane; fadrozole; formestane; letrozole; liarozole; vorozole; and Yamanouchi YM-511.  
       [1041] Some aromatase inhibitors that may be used in the methods, combinations and compositions of the present invention include, but are not limited to, those identified in Table No. 6 below.  
               TABLE No. 6                          Aromatase Inhibitors                                     Common                       Name/Trade       Compound   Name   Company   Reference   Dosage                   letrozole       US 4749346           Androst-4-ene-3,6,17-   NKS01;   Snow Brand   EP 300062       trione, 14-hydroxy-   14alpha-           OHAT;           14OHAT       4-[N-(4-bromobenzyl)-N-   YM-511   Yamanou-chi       (4-cyanophenyl)amino]-       4H-1,2,4-triazole       2,6-Piperidinedione, 3-(4-   aminoglutethimide;   Novartis   US 3944671       aminophenyl)-3-ethyl-   Ciba-           16038;           Cytadren;           Elimina;           Orimeten;           Orimet-ene;           Orimetine       1,3-   anastro-zole;   Zeneca   EP 296749     1 mg/day       Benzenediacetonitrile, alpha,   Arimidex; ICI-       alpha, alpha′, alpha′-   D1033; ZD-       tetramethyl-5-(1H-1,2,4-   1033       triazol-1-ylmethyl)-       Androsta-1,4-diene-3,17-   exemes-tane;   Pharmacia &amp;   DE 3622841     5 mg/kg       dione, 6-methylene-   FCE-24304   Upjohn       Benzonitrile, 4-(5,6,7,8-   fadrozo-le;   Novartis   EP 165904     1 mg po bid       tetrahydroimidazo[1,5-   Afema;       a]pyridin-5-yl)-,   Aresin; CGS-       monohydrochloride   16949; CGS-           16949A;           CGS-20287;           fadrozole           monohydrochloride       Androst-4-ene-3,17-   formest-ane;   Novartis   EP 346953    250 or       dione, 4-hydroxy-   4-HAD; 4-            600 mg/wk po           OHA; CGP-           32349; CRC-           82/01; Depot;           Lentaron       Benzonitrile, 4,4′-(1H-   letroz-ole;   Novartis   EP 236940    2.5 mg/day       1,2,4-triazol-1-   CGS-20267;       ylmethylene)bis-   Femara       1H-Benzimidazole, 5-[(3-   liaro-zole;   Johnson &amp;   EP 260744    300 mg bid       chlorophenyl)-1H-   Liazal; Liazol;   Johnson       imidazol-1-ylmethyl]-   liaro-zole           fumarate; R-           75251; R-           85246; Ro-           85264       1H-Benzotriazole, 6-[(4-   vorozole; R-   Johnson &amp;   EP 293978    2.5 mg/day       chlorophenyl)-1H-1,2,4-   76713; R-   Johnson       triazol-1-ylmethyl]-1-   83842; Rivizor       methyl-                  
 
       [1042] The structures of preferred aromatase inhibitors are listed in Table No. 7 below.  
               TABLE No. 7                          Aromatase Inhibitor Structures                     Compound           Number   Structure                           A1                                     A2                                     A3                                     A4                                     A5                                     A6                                     A7                                     A8                                     A9                                     A10                                     A11                                     A12                                     A13                                     A14                                     A15                                     A16                                     A17                                     A18                                     A19                                     A20                                     A21                                     A22                                     A23                                     A24                                     A25                                     A26                                     A27                                     A28                                     A29                                     A30                                     A31                                     A32                                        
 
       [1043] The names, CAS registry numbers and references for preferred aromatase inhibitors are listed in Table No. 8 below. The individual references in Table No. 8 are each herein individually incorporated by reference.  
               TABLE No. 8                          Aromatase Inhibitor Antineoplastic Agent Names, CAS Registry       Numbers and References                             Compound                   Number   Name(s)   CAS Registry Number   Reference               A1   Aminoglutethimide   125-84-8   US 2848455       A2   Anastrozole   120511-73-1   US 4935437       A3   Atamestane   96301-34-7   US 4591585       A4   CGP-45688, 4,4′-(2H-   134520-88-0   EP 408509           tetrazol-2-ylmethylene)bis-           benzonitrile       A5   CGS-47645, 4,4′-(fluoro-1H-   143030-47-1   US 5227393           1,2,4-triazol-1-           ylmethylene)bis-benzonitrile       A6   Exemestane   107868-30-4   US 4808616       A7   Fadrozole   102676-47-1   US 4588732       A8   FCE-27993, 4-amino-6-   115837-67-7   US 5457097           methylene-androsta-1,4-           diene-3,17-dione       A9   Finrozole   204714-56-7   WO 9413645       A10   Formestane   566-48-3   US 4235893       A11   4-[1-(2-Hydroxyphenyl)-2-   194939-73-6   JP 09202776           (1H-imidazol-1-           yl)ethenyl]benzo-nitrile       A12   Letrozole   112809-51-5   US 4749713       A13   Liarozole   145858-52-2   US 4859684       A14   MEN-11066, 4-(2-   207288-29-7   WO 9818791           benzofuranyl-1H-1,2,4-           triazol-1-           ylmethyl)benzonitrile       A15   MFT-279, N-[(2-   124079-28-3   JP 01139578           chlorophenyl)methyl]-6-(1H-           imidazol-1-yl)-3-           pyridazinamine,           dihydrochloride       A16   Minamestane   105051-87-4   US 4757061       A17   MR-20492, (7Z)-6-(4-   209529-76-0   P. Auvray, et           chlorophenyl)-6,7-dihydro-7-       al., J. Steroid           (4-pyridinylmethylene)-       Biochem. Mol.           8(5H)-indolizinone       Biol. (1999),                   70(1-3), 59-71       A18   NKS-01, 14-hydroxy-   120051-39-0   US 5098535           androst-4-ene-3,6,17-trione       A19   Org-33201, 1-[[(2S,3aR)-3a-   148714-92-5   J. A. A.           ethyl-9-(ethylthio)-       Geelen, et al.,           2,3,3a,4,5,6-hexahydro-1H-       J. Steroid           phenalen-2-yl]methyl]-1H-       Biochem. Mol.           imidazole,       Biol. (1993),           monohydrochloride       44(4-6), 681-2.       A20   Pentrozole   212894-59-2   WO 9101975       A21   Rogletimide   92788-10-8   US 5071857       A22   RU-54115, 10-[2-   137437-16-2   EP 434570           (methylthio)ethyl]-estra-           4,9(11)-diene-3,17-dione       A23   RU-56152, 10-[2-   137437-60-6   US 5086047           (methylthio)ethyl]-estr-9(11)-           ene-3,17-dione       A24   SEF-19, 2-(1H-imidazol-1-   153429-67-5   WO 9317009           yl)-4,6-di-4-morpholinyl-           1,3,5-triazine       A25   SNA-60-367, N-(3-hydroxy-   193738-68-0   Ken-lchi           14-methyl-1-oxopentadecyl)-       Kimura, et al.,           □-glutamylornithyl-       J. Antibiot.           tyrosylthreonyl-□-       (1997), 50(6),           glutamylalanylprolyl-       529-531           glutaminyltyrosyl-, (10□3)-           lactone       A26   TAN-931, 4-(2,6-   127448-92-4   US 5013757           dihydroxybenzoyl)-3-formyl-           5-hydroxy-benzoic acid       A27   Testolactone   968-93-4   US 2744120       A28   TZA-2209, (4aS,4bR,5R,-   159821-93-9   US 5539127           10aR,10bS,12aS)-           1,3,4,4a,4b,5,6,10a,-           10b,11,12,12a-dodecahydro-           5-mercapto-10a,12a-           dimethyl-8H-phenanthro[2,1-           c]pyran-8-one       A29   TZA-2237, (4aS,4bR,5R,-   159822-03-4   US 5539127           10aR,10bS,12aS)-           3,4,4a,5,6,10a,-           10b,11,12,12a-decahydro-5-           mercapto-10a,12a-dimethyl-           1H-phenanthro[2,1-c]pyran-           1,8(4bH)-dione       A30   Vorozole   118949-22-7   US 4943574       A31   YM-511, 4-[[(4-   148869-05-0   US 5674886           bromophenyl)methyl]-4H-           1,2,4-triazol-4-ylamino]-           benzonitrile       A32   YM-553, 4-[[(3,5-   157911-98-3   US 5538976           difluorophenyl)methyl]-5-           pyrimidinylamino]-           benzonitrile                  
 
       [1044] The anastrozole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 4,935,437. The letrozole used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Pat. No. 4,749,713.  
       [1045] More preferred aromatase inhibitors are selected from the group consisting of aminoglutethimide, anastrozole, atamestane, exemestane, fadrozole, finrozole, formestane, letrozole, testolactone, and 4-[[(4-bromophenyl)methyl]-4H-1,2,4-triazol-4-ylamino]benzonitrile.  
       [1046] The compounds useful in the present invention can have no asymmetric carbon atoms, or, alternatively, the useful compounds can have one or more asymmetric carbon atoms. When the useful compounds have one or more asymmetric carbon atoms, they therefore include racemates and stereoisomers, such as diastereomers and enantiomers, in both pure form and in admixture. Such stereoisomers can be prepared using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.  
       [1047] Isomers may include geometric isomers, for example cis-isomers or trans-isomers across a double bond. All such isomers are contemplated among the compounds useful in the present invention.  
       [1048] Also included in the methods, combinations and compositions of the present invention are the isomeric forms and tautomers of the described compounds and the pharmaceutically-acceptable salts thereof. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.  
       [1049] Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.  
       [1050] Also included in the methods, combinations and compositions of the present invention are the prodrugs of the described compounds and the pharmaceutically-acceptable salts thereof. The term “prodrug” refers to drug precursor compounds which, following administration to a subject and subsequent absorption, are converted to an active species in vivo via some process, such as a metabolic process. Other products from the conversion process are easily disposed of by the body. More preferred prodrugs produce products from the conversion process that are generally accepted as safe. A nonlimiting example of a “prodrug” that can be used in the methods, combinations and compositions of the present invention is parecoxib, (N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide).  
       [1051] The methods and combinations of the present invention are useful for the treatment, prevention or inhibition of neoplasia or a neoplasia-related disorder including malignant tumor growth, benign tumor growth and metastasis.  
       [1052] Malignant tumor growth locations comprise the nervous system, cardiovascular system, circulatory system, respiratory tract, lymphatic system, hepatic system, musculoskeletal system, digestive tract, renal system, male reproductive system, female reproductive system, urinary tract, nasal system, gastrointestinal tract, dermis, and head and neck region.  
       [1053] Malignant tumor growth locations in the nervous system comprise the brain and spine.  
       [1054] Malignant tumor growth locations in the respiratory tract system comprise the lung and bronchus.  
       [1055] Malignant tumor growths in the lymphatic system comprise Hodgkin&#39;s lymphoma and non-Hodgkin&#39;s lymphoma.  
       [1056] Malignant tumor growth locations in the hepatic system comprise the liver and intrahepatic bile duct.  
       [1057] Malignant tumor growth locations in the musculoskeletal system comprise bone, bone marrow, joint, muscle and connective tissue.  
       [1058] Malignant tumor growth locations in the digestive tract comprise the colon, small intestine, large intestine, stomach, colorectal, pancreas, liver, and rectum.  
       [1059] Malignant tumor growth locations in the renal system comprise the kidney and renal pelvis.  
       [1060] Malignant tumor growth locations in the male reproductive system comprise the prostate, penis and testicle.  
       [1061] Malignant tumor growth locations in the female reproductive system comprise the ovary and cervix.  
       [1062] Malignant tumor growth locations in the urinary tract comprise the bladder, urethra, and ureter.  
       [1063] Malignant tumor growth locations in the nasal sytem comprise the nasal tract and sinuses.  
       [1064] Malignant tumor growth locations in the gastrointestinal tract comprise the esophagus, gastric fundus, gastric antrum, duodenum, hepatobiliary, ileum, jejunum, colon, and rectum.  
       [1065] Malignant tumor growth in the dermis comprises melanoma and basal cell carcinoma.  
       [1066] Malignant tumor growth locations in the head and neck region comprise the mouth, pharynx, larynx, thyroid, and pituitary.  
       [1067] Malignant tumor growth locations further comprise smooth muscle, striated muscle, and connective tissue.  
       [1068] Malignant tumor growth locations even further comprise endothelial cells and epithelial cells.  
       [1069] Malignant tumor growth may be breast cancer.  
       [1070] Malignant tumor growth may be in soft tissue.  
       [1071] Malignant tumor growth may be a viral-related cancer, including cervical, T cell leukemia, lymphoma, and Kaposi&#39;s sarcoma.  
       [1072] Benign tumor growth locations comprise the nervous system, cardiovascular system, circulatory system, respiratory tract, lymphatic system, hepatic system, musculoskeletal system, digestive tract, renal system, male reproductive system, female reproductive system, urinary tract, nasal system, gastrointestinal tract, dermis, and head and neck region.  
       [1073] Benign tumor growth locations in the nervous system comprise the brain and spine.  
       [1074] Benign tumor growth locations in the respiratory tract system comprise the lung and bronchus.  
       [1075] A benign tumor growth in the lymphatic system may comprise a cyst.  
       [1076] Benign tumor growth locations in the hepatic system comprise the liver and intrahepatic bile duct.  
       [1077] Benign tumor growth locations in the musculoskeletal system comprise bone, bone marrow, joint, muscle and connective tissue.  
       [1078] Benign tumor growth locations in the digestive tract comprise the colon, small intestine, large intestine, stomach, colorectal, pancreas, liver, and rectum.  
       [1079] A benign tumor growth in the digestive tract may comprise a polyp.  
       [1080] Benign tumor growth locations in the renal system comprise the kidney and renal pelvis.  
       [1081] Benign tumor growth locations in the male reproductive system comprise the prostate, penis and testicle.  
       [1082] Benign tumor growth in the female reproductive system may comprise the ovary and cervix.  
       [1083] Benign tumor growth in the female reproductive system may comprise a fibroid tumor, endometriosis or a cyst.  
       [1084] Benign tumor growth in the male reproductive system may comprise benign prostatic hypertrophy (BPH) or prostatic intraepithelial neoplasia (PIN).  
       [1085] Benign tumor growth locations in the urinary tract comprise the bladder, urethra, and ureter.  
       [1086] Benign tumor growth locations in the nasal sytem comprise the nasal tract and sinuses.  
       [1087] Benign tumor growth locations in the gastrointestinal tract comprise the esophagus, gastric fundus, gastric antrum, duodenum, hepatobiliary, ileum, jejunum, colon, and rectum.  
       [1088] Benign tumor growth locations in the head and neck region comprise the mouth, pharynx, larynx, thyroid, and pituitary.  
       [1089] Benign tumor growth locations further comprise smooth muscle, striated muscle, and connective tissue.  
       [1090] Benign tumor growth locations even further comprise endothelial cells and epithelial cells.  
       [1091] Benign tumor growth may be located in the breast and may be a cyst or fibrocystic disease.  
       [1092] Benign tumor growth may be in soft tissue.  
       [1093] Metastasis may be from a known primary tumor site or from an unknown primary tumor site.  
       [1094] Metastasis may be from locations comprising the nervous system, cardiovascular system, circulatory system, respiratory tract, lymphatic system, hepatic system, musculoskeletal system, digestive tract, renal system, male reproductive system, female reproductive system, urinary tract, nasal system, gastrointestinal tract, dermis, and head and neck region.  
       [1095] Metastasis from the nervous system may be from the brain, spine, or spinal cord.  
       [1096] Metastasis from the circulatory system may be from the blood or heart.  
       [1097] Metastasis from the respiratory system may be from the lung or broncus.  
       [1098] Metastasis from the lymphatic system may be from a lymph node, lymphoma, Hodgkin&#39;s lymphoma or non-Hodgkin&#39;s lymphoma.  
       [1099] Metastasis from the heptatic system may be from the liver or intrahepatic bile duct.  
       [1100] Metastasis from the musculoskeletal system may be from locations comprising the bone, bone marrow, joint, muscle, and connective tissue.  
       [1101] Metastasis from the digestive tract may be from locations comprising the colon, small intestine, large intestine, stomach, colorectal, pancreas, gallbladder, liver, and rectum.  
       [1102] Metastasis from the renal system may be from the kidney or renal pelvis.  
       [1103] Metastasis from the male reproductive system may be from the prostate, penis or testicle.  
       [1104] Metastasis from the female reproductive system may be from the ovary or cervix.  
       [1105] Metastasis from the urinary tract may be from the bladder, urethra, or ureter.  
       [1106] Metastasis from the gastrointestinal tract may be from locations comprising the esophagus, esophagus (Barrett&#39;s), gastric fundus, gastric antrum, duodenum, hepatobiliary, ileum, jejunum, colon, and rectum.  
       [1107] Metastasis from the dermis may be from a melanoma or a basal cell carcinoma.  
       [1108] Metastasis from the head and neck region may be from locations comprising the mouth, pharynx, larynx, thyroid, and pituitary.  
       [1109] Metastasis may be from locations comprising smooth muscle, striated muscle, and connective tissue.  
       [1110] Metastasis may be from endothelial cells or epithelial cells.  
       [1111] Metastasis may be from breast cancer.  
       [1112] Metastasis may be from soft tissue.  
       [1113] Metastasis may be from a viral-related cancer, including cervical, T cell leukemia, lymphoma, or Kaposi&#39;s sarcoma.  
       [1114] Metastasis may be from tumors comprising a carcinoid tumor, gastrinoma, sarcoma, adenoma, lipoma, myoma, blastoma, carcinoma, fibroma, or adenosarcoma.  
       [1115] Malignant or benign tumor growth may be in locations comprising the genital system, digestive system, breast, respiratory system, urinary system, lymphatic system, skin, circulatory system, oral cavity and pharynx, endocrine system, brain and nervous system, bones and joints, soft tissue, and eye and orbit.  
       [1116] Metastasis may be from locations comprising the genital system, digestive system, breast, respiratory system, urinary system, lymphatic system, skin, circulatory system, oral cavity and pharynx, endocrine system, brain and nervous system, bones and joints, soft tissue, and eye and orbit.  
       [1117] The methods and compositions of the present invention may be used for the treatment, prevention or inhibition of neoplasia or neoplasia-related disorders including acral lentiginous melanoma, actinic keratoses, acute lymphocytic leukemia, acute myeloid leukemia, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectum cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, benign cysts, biliary cancer, bone cancer, bone marrow cancer, brain cancer, breast cancer, bronchial cancer, bronchial gland carcinomas, carcinoids, carcinoma, carcinosarcoma, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, colon cancer, colorectal cancer, connective tissue cancer, cystadenoma, cysts of the female reproductive system, digestive system cancer, digestive tract polyps, duodenum cancer, endocrine system cancer, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, endometriosos, endothelial cell cancer, ependymal cancer, epithelial cell cancer, esophagus cancer, Ewing&#39;s sarcoma, eye and orbit cancer, female genital cancer, fibroid tumors, focal nodular hyperplasia, gallbladder cancer, gastric antrum cancer, gastric fundus cancer, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, heart cancer, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatobiliary cancer, hepatocellular carcinoma, Hodgkin&#39;s disease, ileum cancer, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, intrahepatic bile duct cancer, invasive squamous cell carcinoma, jejunum cancer, joint cancer, Kaposi&#39;s sarcoma, kidney and renal pelvic cancer, large cell carcinoma, large intestine cancer, larynx cancer, leiomyosarcoma, lentigo maligna melanomas, leukemia, liver cancer, lung cancer, lymphoma, male genital cancer, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal cancer, mesothelial cancer, metastatic carcinoma, mouth cancer, mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal tract cancer, nervous system cancer, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, non-epithelial skin cancer, non-Hodgkin&#39;s lymphoma, oat cell carcinoma, oligodendroglial cancer, oral cavity cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary serous adenocarcinoma, penile cancer, pharynx cancer, pituitary tumors, plasmacytoma, prostate cancer, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, sinus cancer, skin cancer, small cell carcinoma, small intestine cancer, smooth muscle cancer, soft tissue cancer, somatostatin-secreting tumor, spine cancer, squamous carcinoma, squamous cell carcinoma, stomach cancer, striated muscle cancer, submesothelial cancer, superficial spreading melanoma, T cell leukemia, testis cancer, thyroid cancer, tongue cancer, undifferentiated carcinoma, ureter cancer, urethra cancer, urinary bladder cancer, urinary system cancer, uterine cervix cancer, uterine corpus cancer, uveal melanoma, vaginal cancer, verrucous carcinoma, vipoma, vulva cancer, well differentiated carcinoma, and Wilm&#39;s tumor.  
       [1118] The methods, combinations and compositions of the present invention will be useful for the treatment or prevention of a neoplasia disorder where the neoplasia disorder is located in a tissue of the mammal. The tissues where the neoplasia disorder may be located comprise the lung, breast, skin, stomach, intestine, esophagus, bladder, head, neck, brain, cervical, prostate or ovary of the mammal.  
       [1119] The methods and combinations of the present invention are preferred for the treatment, prevention or inhibition of prostate cancer.  
       [1120] The methods and combinations of the present invention are useful for the treatment, prevention or inhibition of osteoporosis. Osteoporosis may be treated, prevented or inhibited by enhancing the formation of new bone or by reducing or preventing the reabsorption of old bone by the body. Osteoporosis may be evaluated by bone mineral density testing performed by dual-energy X-ray absorptiometry to give a quantitative measure for the demineralization of the bones. A spine CT can show demineralization and quantitative computerized tomography (QCT) can evaluate bond density. Measurement of urinary N-telopeptide (Osteomark) can evaluate bone turnover.  
       [1121] The benefits of treating, preventing or inhibiting osteoporosis include the prevention of brittle, fragile bones that are subject to fracture, particularly of the vertebrae, wrists or hips. Hip fractures are particularly debilitating, leaving about 50% of victims unable to independently walk and is one of the major reasons for admittance to nursing homes. Other symptoms of osteoporosis that may be prevented or alleviated by the compositions and methods of the present invention are low back pain, neck pain, bone pain or tenderness, loss of height over time and stooped posture.  
       [1122] The phrase “neoplasia disorder effective” is intended to qualify the amount of each agent that will achieve the goal of improvement in neoplastic disease severity and the frequency of a neoplastic disease event over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.  
       [1123] The phrase “therapeutically effective” is intended to qualify the amount of each agent that will achieve the goal of improvement in neoplastic or osteoporotic disease severity and the frequency of a neoplastic or osteoporotic disease event over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.  
       [1124] A “neoplasia disorder effect” or “neoplasia disorder effective amount” is intended to qualify the amount of a COX-2 inhibiting agent and an aromatase inhibitor required to treat, prevent or inhibit a neoplasia disorder or relieve to some extent or one or more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5) inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with the disorder; or 7) relieving or reducing the side effects associated with the administration of anticancer agents.  
       [1125] A “therapeutically effective amount” is intended to qualify the amount of a COX-2 inhibiting agent and an aromatase inhibitor required to treat, prevent or inhibit osteoporosis, a neoplasia or a neoplasia-related disorder.  
       [1126] The term “inhibition,” in the context of neoplasia, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention.  
       [1127] The term “prevention,” in relation to neoplasia, tumor growth or tumor cell growth, means no tumor or tumor cell growth if none had occurred, no further tumor or tumor cell growth if there had already been growth.  
       [1128] The term “chemoprevention” refers to the use of agents to arrest or reverse the chronic cancer disease process in its earliest stages before it reaches its terminal invasive and metastatic phase.  
       [1129] The term “clinical tumor” includes neoplasms that are identifiable through clinical screening or diagnostic procedures including, but not limited to, palpation, biopsy, cell proliferation index, endoscopy, mammagraphy, digital mammography, ultrasonography, computed tomagraphy (CT), magnetic resonance imaging (MRI), positron emmission tomography (PET), radiography, radionuclide evaluation, CT- or MRI-guided aspiration cytology, and imaging-guided needle biopsy, among others. Such diagnostic techniques are well known to those skilled in the art and are described in Cancer Medicine 4th Edition, Volume One. J. F. Holland, R. C. Bast, D. L. Morton, E. Frei III, D. W. Kufe, and R. R. Weichselbaum (Editors). Williams &amp; Wilkins, Baltimore (1997).  
       [1130] The phrases “low dose” or “low dose amount”, in characterizing a therapeutically effective amount of the COX-2 inhibitor and the aromatase inhibitor in the combination therapy, defines a quantity of such agent, or a range of quantity of such agent, that is capable of improving osteoporotic or neoplastic disease severity while reducing or avoiding one or more antineoplastic-agent-induced side effects, such as myelosupression, cardiac toxicity, alopecia, nausea or vomiting.  
       [1131] The phrase “adjunctive therapy” encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for example, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence of nausea and vomiting associated with chemotherapy, radiotherapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.  
       [1132] The phrase a “device” refers to any appliance, usually mechanical or electrical, designed to perform a particular function.  
       [1133] The term “angiogenesis” refers to the process by which tumor cells trigger abnormal blood vessel growth to create their own blood supply. Angiogenesis is believed to be the mechanism via which tumors get needed nutrients to grow and metastasize to other locations in the body. Antiangiogenic agents interfere with these processes and destroy or control tumors. Angiogenesis an attractive therapeutic target for treating neoplastic disease because it is a multi-step process that occurs in a specific sequence, thus providing several possible targets for drug action. Examples of agents that interfere with several of these steps include compounds such as matrix metalloproteinase inhibitors (MMPIs) that block the actions of enzymes that clear and create paths for newly forming blood vessels to follow; compounds, such as avb 3  inhibitors, that interfere with molecules that blood vessel cells use to bridge between a parent blood vessel and a tumor; agents, such as COX-2 selective inhibiting agents, that prevent the growth of cells that form new blood vessels; and protein-based compounds that simultaneously interfere with several of these targets.  
       [1134] The phrase an “immunotherapeutic agent” refers to agents used to transfer the immunity of an immune donor, e.g., another person or an animal, to a host by inoculation. The term embraces the use of serum or gamma globulin containing performed antibodies produced by another individual or an animal; nonspecific systemic stimulation; adjuvants; active specific immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy refers to the treatment of a disease by therapy or agents that include host inoculation of sensitized lymphocytes, transfer factor, immune RNA, or antibodies in serum or gamma globulin.  
       [1135] The phrase a “vaccine” includes agents that induce the patient&#39;s immune system to mount an immune response against the tumor by attacking cells that express tumor associated antigens (TAAs).  
       [1136] The phrase “antineoplastic agents” includes agents that exert antineoplastic effects, i.e., prevent the development, maturation, or spread of neoplastic cells, directly on the tumor cell, e.g., by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification.  
       [1137] The present invention also provides a method for lowering the risk of a first or subsequent occurrence of a neoplastic disease event comprising the administration of a prophylactically effective amount of a combination of an aromatase inhibitor and a COX-2 inhibiting agent to a patient at risk for such a neoplastic disease event. The patient may already have non-malignant neoplastic disease at the time of administration, or be at risk for developing it.  
       [1138] Patients to be treated with the present combination therapy includes those at risk of developing neoplastic disease or of having a neoplastic disease event. Standard neoplastic disease risk factors are known to the average physician practicing in the relevant field of medicine. Such known risk factors include but are not limited to genetic factors and exposure to carcinogens such as certain viruses, certain chemicals, tobacco smoke or radiation. Patients who are identified as having one or more risk factors known in the art to be at risk of developing neoplastic disease, as well as people who already have neoplastic disease, are intended to be included within the group of people considered to be at risk for having a neoplastic disease event.  
       [1139] Studies indicate that prostaglandins synthesized by cyclooxygenases play a critical role in the initiation and promotion of cancer. Moreover, COX-2 is overexpressed in neoplastic lesions of the colon, breast, lung, prostate, esophagus, pancreas, intestine, cervix, ovaries, urinary bladder, and head and neck. Products of COX-2 activity, i.e., prostaglandins, stimulate proliferation, increase invasiveness of malignant cells, and enhance the production of vascular endothelial growth factor, which promotes angiogenesis. In several in vitro and animal models, COX-2 selective inhibiting agents have inhibited tumor growth and metastasis. The utility of COX-2 selective inhibiting agents as chemopreventive, antiangiogenic and chemotherapeutic agents is described in the literature, see for example Koki et al., Potential utility of COX-2 selective inhibiting agents in chemoprevention and chemotherapy. Exp. Opin. Invest. Drugs (1999) 8(10) pp. 1623-1638.  
       [1140] In addition to cancers per se, COX-2 is also expressed in the angiogenic vasculature within and adjacent to hyperplastic and neoplastic lesions indicating that COX-2. plays a role in angiogenesis. In both the mouse and rat, COX-2 selective inhibiting agents markedly inhibited bFGF-induced neovascularization.  
       [1141] Also, COX-2 levels are elevated in tumors with amplification and/or overexpression of other oncogenes including but not limited to c-myc, N-myc, L-myc, K-ras, H-ras, N-ras. Consequently, the administration of a COX-2 selective inhibiting agent and an aromatase inhibitor antineoplastic agent, in combination with an agent, or agents, that inhibits or suppresses oncogenes is contemplated to prevent or treat cancers in which oncogenes are overexpressed.  
       [1142] Accordingly, there is a need for a method of treating or preventing a cancer in a patient that overexpresses COX-2 or an oncogene.  
       [1143] Dosages, Formulations and Routes of Administration  
       Dosages  
       [1144] Dosage levels of the source of a COX-2 inhibiting agent (e.g., a COX-2 selective inhibiting agent or a prodrug of a COX-2 selective inhibiting agent) on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1,000 mg. While the dosage of active compound administered to a warm-blooded animal (a mammal), is dependent on the species of that mammal, the body weight, age, and individual condition, and on the routhe of administration, the unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 5 and 500 mg of the active ingredient (for example, COX-189). The amount of active ingredient that may be combined with other anticancer agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.  
       [1145] A total daily dose of an aromatase inhibitor can generally be in the range of from about 0.001 to about 10,000 mg/day in single or divided doses.  
       [1146] Table No. 9 provides illustrative examples of median dosages for selected aromatase inhibitors that may be used in combination with a COX-2 inhibitor. It should be noted that specific dose regimen for the chemotherapeutic agents below depends upon dosing considerations based upon a variety of factors including the type of neoplasia; the stage of the neoplasm; the age, weight, sex, and medical condition of the patient; the route of administration; the renal and hepatic function of the patient; and the particular combination employed.  
               TABLE No. 9                          Median Dosages For Selected Aromatase Inhibitor       Antineoplastic Agents                             Aromatase Inhibitor   Median Dosage                       Aminoglutethimide    250 mg/day           Anastrozole     1 mg/day           Exemestane     25 mg/day           Fadrozole     1 mg bid           Formestane    250 mg/2 wk           Letrozole    2.5 mg/day           Testolactone    250 mg qid           Vorozole    2.5 mg/day                      
 
       [1147] It is understood, however, that specific dose levels of the therapeutic agents or therapeutic approaches of the present invention for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the patient, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disease being treated and form of administration.  
       [1148] Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro initially can provide useful guidance on the proper doses for patient administration. Studies in animal models also generally may be used for guidance regarding effective dosages for treatment of cancers in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Thus, where a compound is found to demonstrate in vitro activity at, e.g., 10 μM, one will desire to administer an amount of the drug that is effective to provide about a 10 μM concentration in vivo. Determination of these parameters is well within the skill of the art.  
       Formulations and Routes of Administration  
       [1149] Effective formulations and administration procedures are well known in the art and are described in standard textbooks.  
       [1150] The COX-2 inhibiting agent and the aromatase inhibitor antineoplastic agent can be formulated as a single pharmaceutical composition or as independent multiple pharmaceutical compositions. Pharmaceutical compositions according to the present invention include those suitable for oral, inhalation spray, rectal, topical, buccal (e.g., sublingual), or parenteral (e.g., subcutaneous, intramuscular, intravenous, intramedullary and intradermal injections, or infusion techniques) administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used. In most cases, the preferred route of administration is oral or parenteral.  
       [1151] Compounds and composition of the present invention can then be administered orally, by inhalation spray, rectally, topically, buccally or parenterally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The compounds of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic compounds or as a combination of therapeutic compounds.  
       [1152] The compositions of the present invention can be administered for the treatment, prevention or inhibition of neoplastic disease or disorders by any means that produce contact of these compounds with their site of action in the body, for example in the ileum, the plasma, or the liver of a mammal.  
       [1153] Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compound. Such salts must clearly have a pharmaceutically acceptable anion or cation.  
       [1154] The compounds useful in the methods, combinations and compositions of the present invention can be presented with an acceptable carrier in the form of a pharmaceutical composition. The carrier must, of course, be acceptable in the sense of being compatible with the other ingredients of the composition and must not be deleterious to the recipient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmacologically active substances can also be present, including other compounds of the present invention. The pharmaceutical compositions of the invention can be prepared by any of the well-known techniques of pharmacy, consisting essentially of admixing the components.  
       [1155] The amount of compound in combination that is required to achieve the desired biological effect will, of course, depend on a number of factors such as the specific compound chosen, the use for which it is intended, the mode of administration, and the clinical condition of the recipient.  
       [1156] The compounds of the present invention can be delivered orally either in a solid, in a semi-solid, or in a liquid form. Dosing for oral administration may be with a regimen calling for single daily dose, or for a single dose every other day, or for multiple, spaced doses throughout the day. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. Capsules, tablets, etc., can be prepared by conventional methods well known in the art. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient or ingredients. Examples of dosage units are tablets or capsules, and may contain one or more therapeutic compounds in an amount described herein. For example, in the case of an aromatase inhibitor antineoplastic agent, the dose range may be from about 0.01 mg to about 5,000 mg or any other dose, dependent upon the specific inhibitor, as is known in the art. When in a liquid or in a semi-solid form, the combinations 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). In one embodiment, when an aromatase inhibitor antineoplastic agent is used in a combination of the present invention, the aromatase inhibitor antineoplastic agent can be provided in the form of a liquid, syrup, or contained in a gel capsule. In another embodiment, when a COX-2 inhibiting agent is used in a combination of the present invention, the COX-2 inhibiting agent can be provided in the form of a liquid, syrup, or contained in a gel capsule.  
       [1157] Oral delivery of the combinations of the present invention can include formulations, as are well known in the art, to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. These include, but are not limited to, pH sensitive release from the dosage form based on the changing pH of the small intestine, slow erosion of a tablet or capsule, retention in the stomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form. For some of the therapeutic compounds useful in the methods, combinations and compositions of the present invention the intended effect is to extend the time period over which the active drug molecule is delivered to the site of action by manipulation of the dosage form. Thus, enteric-coated and enteric-coated controlled release formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.  
       [1158] Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of at least one therapeutic compound useful in the present invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound(s) and the carrier (which can constitute one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more assessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.  
       [1159] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.  
       [1160] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth, and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.  
       [1161] Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the present invention. These preparations are preferably administered intravenously, although administration can also be effected by means of subcutaneous, intramuscular, or intradermal injection or by infusion. Such preparations can conveniently be prepared by admixing the compound with water and rendering the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 10% w/w of a compound disclosed herein.  
       [1162] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or setting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.  
       [1163] The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. A suitable daily dose of each active therapeutic compound is one that achieves the same blood serum level as produced by oral administration as described above.  
       [1164] The dose of any of these therapeutic compounds can be conveniently administered as an infusion of from about 10 ng/kg body weight to about 10,000 ng/kg body weight per minute. Infusion fluids suitable for this purpose can contain, for example, from about 0.1 ng to about 10 mg, preferably from about 1 ng to about 10 mg per milliliter. Unit doses can contain, for example, from about 1 mg to about 10 g of the compound of the present invention. Thus, ampoules for injection can contain, for example, from about 1 mg to about 100 mg.  
       [1165] Pharmaceutical compositions suitable for rectal administration are preferably presented as unit-dose suppositories. These can be prepared by admixing a compound or compounds of the present invention with one or more conventional solid carriers, for example, cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug; and then shaping the resulting mixture.  
       [1166] Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly (e.g., Vaseline), lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound or compounds are generally present at a concentration of from 0.1 to 50% w/w of the composition, for example, from 0.5 to 2%.  
       [1167] Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain a compound or compounds of the present invention in an optionally buffered, aqueous solution, dissolved and/or dispersed in an adhesive, or dispersed in a polymer. A suitable concentration of the active compound or compounds is about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compound or compounds can be delivered from the patch by electrotransport or iontophoresis, for example, as described in  Pharmaceutical Research,  3(6), 318 (1986).  
       [1168] In any case, the amount of active ingredients that can be combined with carrier materials to produce a single dosage form to be administered will vary depending upon the host treated and the particular mode of administration.  
       [1169] In combination therapy, administration of two or more of the therapeutic agents useful in the methods, combinations and compositions of the present invention may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or in a separate formulation. Independent administration of each therapeutic agent may be accomplished by, for example, oral, inhalation spray, rectal, topical, buccal (e.g., sublingual), or parenteral (e.g., subcutaneous, intramuscular, intravenous, intramedullary and intradermal injections, or infusion techniques) administration. The formulation may be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. Solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface active or dispersing agent. The therapeutic compounds may further be administered by any combination of, for example, oral/oral, oral/parenteral, or parenteral/parenteral route.  
       [1170] The therapeutic compounds which make up the combination therapy may be a combined dosage form or in separate dosage forms intended for substantially simultaneous oral administration. The therapeutic compounds which make up the combination therapy may also be administered sequentially, with either therapeutic compound being administered by a regimen calling for two step ingestion. Thus, a regimen may call for sequential administration of the therapeutic compounds with spaced-apart ingestion of the separate, active agents. The time period between the multiple ingestion steps may range from, for example, a few minutes to several hours to days, depending upon the properties of each therapeutic compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound, as well as depending upon the effect of food ingestion and the age and condition of the patient. Circadian variation of the target molecule concentration may also determine the optimal dose interval. The therapeutic compounds of the combined therapy whether administered simultaneously, substantially simultaneously, or sequentially, may involve a regimen calling for administration of one therapeutic compound by oral route and another therapeutic compound by intravenous route. Whether the therapeutic compounds of the combined therapy are administered orally, by inhalation spray, rectally, topically, buccally (e.g., sublingual), or parenterally (e.g., subcutaneous, intramuscular, intravenous and intradermal injections, or infusion techniques), separately or together, each such therapeutic compound will be contained in a suitable pharmaceutical formulation of pharmaceutically-acceptable excipients, diluents or other formulations components. Examples of suitable pharmaceutically-acceptable formulations containing the therapeutic compounds are given above. Additionally, drug formulations are discussed in, for example, Hoover, John E.,  Remington&#39;s Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa. 1975. Another discussion of drug formulations can be found in Liberman, H. A. and Lachman, L., Eds.,  Pharmaceutical Dosage Forms , Marcel Decker, New York, N.Y., 1980.  
       Treatment Regimen  
       [1171] Any effective treatment regimen can be utilized and readily determined and repeated as necessary to effect treatment. In clinical practice, the compositions containing a COX-2 inhibitor in combination with an aromatase inhibitor are administered in specific cycles until a response is obtained.  
       [1172] For patients who initially present without advanced or metastatic cancer, a COX-2 inhibitor based drug in combination with an aromatase inhibitor can be used as an immediate initial therapy prior to surgery, chemotherapy, or radiation therapy, and/or as a continuous post-treatment therapy in patients at risk for recurrence or metastasis (for example, in adenocarcinoma of the prostate, risk for metastasis is based upon high PSA, high Gleason&#39;s score, locally extensive disease, and/or pathological evidence of tumor invasion in the surgical specimen). The goal in these patients is to inhibit the growth of potentially metastatic cells from the primary tumor during surgery or radiotherapy and inhibit the growth of tumor cells from undetectable residual primary tumor.  
       [1173] For patients who initially present with advanced or metastatic cancer, a COX-2 inhibitor based drug in combination with an aromatase inhibitor is used as a continuous supplement to, or possible replacement for hormonal ablation. The goal in these patients is to slow or prevent tumor cell growth from both the untreated primary tumor and from the existing metastatic lesions.  
       [1174] In addition, the invention may be particularly efficacious during post-surgical recovery, where the present compositions and methods may be particularly effective in lessening the chances of recurrence of a tumor engendered by shed cells that cannot be removed by surgical intervention.  
       Combinations with Other Treatments  
       [1175] The methods, combinations amd compositions of the present invention may be used in conjunction with other treatment modalities, including, but not limited to surgery and radiation, hormonal therapy, antiangiogenic therapy, chemotherapy, immunotherapy, and cryotherapy. The present invention may be used in conjunction with any current or future therapy.  
       [1176] The following discussion highlights some agents in this respect, which are illustrative, not limitative. A wide variety of other effective agents also may be used.  
       Surgery and Radiation  
       [1177] In general, surgery and radiation therapy are employed as potentially curative therapies for patients under 70 years of age who present with clinically localized disease and are expected to live at least 10 years.  
       [1178] For example, approximately 70% of newly diagnosed prostate cancer patients fall into this category. Approximately 90% of these patients (65% of total patients) undergo surgery, while approximately 10% of these patients (7% of total patients) undergo radiation therapy. Histopathological examination of surgical specimens reveals that approximately 63% of patients undergoing surgery (40% of total patients) have locally extensive tumors or regional (lymph node) metastasis that was undetected at initial diagnosis. These patients are at a significantly greater risk of recurrence. Approximately 40% of these patients will actually develop recurrence within five years after surgery. Results after radiation are even less encouraging. Approximately 80% of patients who have undergone radiation as their primary therapy have disease persistence or develop recurrence or metastasis within five years after treatment. Currently, most of these surgical and radiotherapy patients generally do not receive any immediate follow-up therapy. Rather, for example, they are monitored frequently for elevated Prostate Specific Antigen (“PSA”), which is the primary indicator of recurrence or metastasis prostate cancer.  
       [1179] Thus, there is considerable opportunity to use the present invention in conjunction with surgical intervention.  
       Hormonal Therapy  
       [1180] Hormonal ablation is the most effective palliative treatment for the 10% of patients presenting with metastatic prostate cancer at initial diagnosis. Hormonal ablation by medication and/or orchiectomy is used to block hormones that support the further growth and metastasis of prostate cancer. With time, both the primary and metastatic tumors of virtually all of these patients become hormone-independent and resistant to therapy. Approximately 50% of patients presenting with metastatic disease die within three years after initial diagnosis, and 75% of such patients die within five years after diagnosis. Continuous supplementation with NAALADase inhibitor based drugs are used to prevent or reverse this potentially metastasis-permissive state.  
       [1181] Among hormones which may be used in combination with the present inventive compounds, diethylstilbestrol (DES), leuprolide, flutamide, cyproterone acetate, ketoconazole and amino glutethimide are preferred.  
       Immunotherapy  
       [1182] The combinations and methods of the present invention may also be used in combination with monoclonal antibodies in treating cancer. For example monoclonal antibodies may be used in treating prostate cancer. A specific example of such an antibody includes cell membrane-specific anti-prostate antibody.  
       [1183] The present invention may also be used with immunotherapies based on polyclonal or monoclonal antibody-derived reagents, for instance. Monoclonal antibody-based reagents are most preferred in this regard. Such reagents are well known to persons of ordinary skill in the art. Radiolabelled monoclonal antibodies for cancer therapy, such as the recently approved use of monoclonal antibody conjugated with strontium-89, also are well known to persons of ordinary skill in the art.  
       Antiangiogenic Therapy  
       [1184] The combinations and methods of the present invention may also be used in combination with other antiangiogenic agents in treating cancer. Antiangiogenic agents include but are not limited to MMP inhibitors, integrin antagonists, COX-2 inhibitors, angiostatin, endostatin, thrombospondin-1, and interferon alpha. Examples of preferred antiangiogenic agents include, but are not limited to vitaxin, marimastat, Bay-12-9566, AG-3340, metastat, EMD-121974, and D-2163 (BMS-275291).  
       Cryotherapy  
       [1185] Cryotherapy recently has been applied to the treatment of some cancers. Methods and compositions of the present invention also could be used in conjunction with an effective therapy of this type.  
       Chemotherapy  
       [1186] There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be included in the present invention for treatment of neoplasia by combination drug chemotherapy. For convenience of  
       [1187] discussion, antineoplastic agents are classified into the following classes, subtypes and species:  
       [1188] ACE inhibitors,  
       [1189] alkylating agents,  
       [1190] angiogenesis inhibitors,  
       [1191] angiostatin,  
       [1192] anthracyclines/DNA intercalators,  
       [1193] anti-cancer antibiotics or antibiotic-type agents,  
       [1194] antimetabolites,  
       [1195] antimetastatic compounds,  
       [1196] asparaginases,  
       [1197] bisphosphonates,  
       [1198] cGMP phosphodiesterase inhibitors,  
       [1199] calcium carbonate,  
       [1200] cyclooxygenase-2 inhibitors  
       [1201] DHA derivatives,  
       [1202] DNA topoisomerase,  
       [1203] endostatin,  
       [1204] epipodophylotoxins,  
       [1205] genistein,  
       [1206] hormonal anticancer agents,  
       [1207] hydrophilic bile acids (URSO),  
       [1208] immunomodulators or immunological agents,  
       [1209] integrin antagonists  
       [1210] interferon antagonists or agents,  
       [1211] MMP inhibitors,  
       [1212] miscellaneous antineoplastic agents,  
       [1213] monoclonal antibodies,  
       [1214] nitrosoureas,  
       [1215] NSAIDs,  
       [1216] ornithine decarboxylase inhibitors,  
       [1217] pBATTs,  
       [1218] radio/chemo sensitizers/protectors,  
       [1219] retinoids  
       [1220] selective inhibitors of proliferation and migration of endothelial cells,  
       [1221] selenium,  
       [1222] stromelysin inhibitors,  
       [1223] taxanes,  
       [1224] vaccines, and  
       [1225] vinca alkaloids.  
       [1226] The major categories that some preferred antineoplastic agents fall into include antimetabolite agents, alkylating agents, antibiotic-type agents, hormonal anticancer agents, immunological agents, interferon-type agents, and a category of miscellaneous antineoplastic agents. Some antineoplastic agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.  
       [1227] Therapeutic Illustrations  
       [1228] All of the various cell types of the body can be transformed into benign or malignant neoplasia or tumor cells and are contemplated as objects of the invention. A “benign” tumor cell denotes the non-invasive and non-metastasized state of a neoplasm. In man the most frequent neoplasia site is lung, followed by colorectal, breast, prostate, bladder, pancreas, and then ovary. Other prevalent types of cancer include leukemia, central nervous system cancers, including brain cancer, melanoma, lymphoma, erythroleukemia, uterine cancer, and head and neck cancer.  
       [1229] The following non-limiting illustrative examples describe various cancer diseases and therapeutic approaches that may be used in the present invention, and are for illustrative purposes only. Preferred COX-2 inhibitors of the below non-limiting illustrations include but are not limited to celecoxib, deracoxib, valdecoxib, chromene COX-2 inhibitors, parecoxib, rofecoxib, etoricoxib, meloxicam, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one, 2-(3,4-d ifluorophenyl)-4-(3-hydroxy-3-methyl butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, N-[2-(cyclohexyloxy)-4-n itrophenyl]methanesulfonamide, 2-[(2,4-dichloro-6-methylphenyl)amino]-5-ethyl-benzeneacetic acid, diarylmethylidenefuran derivative COX-2 inhibitors, and BMS 347070 or other similar compounds.  
       [1230] Preferred aromatase inhibitors of the below non-limiting illustrations include but are not limited to aminoglutethimide, anastrozole, atamestane, exemestane, fadrozole, finrozole, formestane, letrozole, testolactone and 4-[[(4-bromophenyl)methyl]-4H-1,2,4-triazol-4-ylamino]benzonitrile.  
       Illustration 1: Lung Cancer  
       [1231] In many countries including Japan, Europe and America, the number of patients with lung cancer is fairly large and continues to increase year after year and is the most frequent cause of cancer death in both men and women. Although there are many potential causes for lung cancer, tobacco use, and particularly cigarette smoking, is the most important. Additionally, etiologic factors such as exposure to asbestos, especially in smokers, or radon are contributory factors. Also occupational hazards such as exposure to uranium have been identified as an important factor. Finally, genetic factors have also been identified as another factor that increase the risk of cancer.  
       [1232] Lung cancers can be histologically classified into non-small cell lung cancers (e.g. squamous cell carcinoma (epidermoid), adenocarcinoma, large cell carcinoma (large cell anaplastic), etc.) and small cell lung cancer (oat cell). Non-small cell lung cancer (NSCLC) has different biological properties and responses to chemotherapeutics from those of small cell lung cancer (SCLC). Thus, chemotherapeutic formulas and radiation therapy are different between these two types of lung cancer.  
       [1233] Non-Small Cell Lung Cancer  
       [1234] In the present invention, a preferred therapy for the treatment of NSCLC is a combination of neoplasia disorder effective amounts of a COX-2 inhibitor and an aromatase inhibitor in combination with one or more of the following combinations of antineoplastic agents: 1) ifosfamide, cisplatin, etoposide; 2) cyclophosphamide, doxorubicin, cisplatin; 3) ifosfamide, carboplatin, etoposide; 4) bleomycin, etoposide, cisplatin; 5) ifosfamide, mitomycin, cisplatin; 6) cisplatin, vinblastine; 7) cisplatin, vindesine; 8) mitomycin C, vinblastine, cisplatin; 9) mitomycin C, vindesine, cisplatin; 10) ifosfamide, etoposide; 11) etoposide, cisplatin; 12) ifosfamide, mitomycin C; 13) flurouracil, cisplatin, vinblastine; 14) carboplatin, etoposide; or radiation therapy.  
       [1235] In the present invention, a further preferred therapy for the treatment of NSCLC is a composition of a neoplasia disorder effective amounts of a COX-2 selective inhibitor in combination with an aromatase inhibitor.  
       [1236] Small Cell Lung Cancer  
       [1237] In another embodiment of the present invention, a preferred therapy for the treatment of small cell lung cancer is a combination of neoplasia disorder effective amounts of a COX-2 inhibitor in combination with an aromatase inhibitor.  
       [1238] Additionally, radiation therapy in conjunction with the preferred combinations of COX-2 inhibitors and aromatase inhibitors is contemplated to be effective at increasing the response rate for SCLC patients. The typical dosage regimen for radiation therapy ranges from 40 to 55 Gy, in 15 to 30 fractions, 3 to 7 times week. The tissue volume to be irradiated will be determined by several factors and generally the hilum and subcarnial nodes, and bialteral mdiastinal nodes up to the thoraic inlet are treated, as well as the primary tumor up to 1.5 to 2.0 cm of the margins.  
       [1239] A preferred therapeutic combination for the treatment of small cell lung cancer in the present invention is a combination of celecoxib and exemestane.  
       Illustration 2: Colorectal Cancer  
       [1240] Tumor metastasis prior to surgery is generally believed to be the cause of surgical intervention failure and up to one year of chemotherapy is required to kill the non-excised tumor cells. Because severe toxicity is associated with the chemotherapeutic agents, only patients at high risk of recurrence are placed on chemotherapy following surgery. Thus, the incorporation of a COX-2 inhibitor and an aromatase inhibitor into the management of colorectal cancer will play an important role in the treatment of colorectal cancer and lead to overall improved survival rates for patients diagnosed with colorectal cancer.  
       [1241] In one embodiment of the present invention, a combination therapy for the treatment of colorectal cancer is surgery, followed by a regimen of a COX-2 inhibiting agent and an aromatase inhibitor, cycled over a one year time period. In another embodiment, a combination therapy for the treatment of colorectal cancer is a regimen of a COX-2 inhibiting agent and an aromatase inhibitor, followed by surgical removal of the tumor from the colon or rectum and then followed be a regimen of a COX-2 inhibiting agent and an aromatase inhibitor, cycled over a one year time period. In still another embodiment, a therapy for the treatment of colon cancer is a combination of neoplasia disorder effective amounts of a COX-2 inhibiting agent and an aromatase inhibitor.  
       [1242] A preferred therapeutic combination in the present invention for the treatment of colorectal cancer is a combination of celecoxib and exemestane.  
       Illustration 3: Breast Cancer  
       [1243] In the treatment of locally advanced noninflammatory breast cancer, a COX-2 inhibitor and an aromatase inhibitor will be useful to treat the disease in combination with surgery, radiation therapy and/or chemotherapy. Preferred combinations of chemotherapeutic agents, radiation therapy and surgery that can be used in combination with the present invention include, but are not limited to the following combinations: 1) doxorubicin, vincristine, radical mastectomy; 2) doxorubicin, vincristine, radiation therapy; 3) cyclophosphamide, doxorubicin, 5-flourouracil, vincristine, prednisone, mastecomy; 4) cyclophosphamide, doxorubicin, 5-flourouracil, vincristine, prednisone, radiation therapy; 5) cyclophosphamide, doxorubicin, 5-flourouracil, premarin, tamoxifen, radiation therapy for pathologic complete response; 6) cyclophosphamide, doxorubicin, 5-flourouracil, premarin, tamoxifen, mastectomy, radiation therapy for pathologic partial response; 7) mastectomy, radiation therapy, levamisole; 8) mastectomy, radiation therapy; 9) mastectomy, vincristine, doxorubicin, cyclophosphamide, levamisole; 10) mastectomy, vincristine, doxorubicin, cyclophosphamide; 11) mastecomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin, radiation therapy; 12) mastecomy, cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen, halotestin.  
       [1244] In the treatment of locally advanced inflammatory breast cancer, a COX-2 inhibitor and an aromatase inhibitor can be used to treat the disease in combination with surgery, radiation therapy or with chemotherapeutic agents. In one embodiment, combinations of chemotherapeutic agents, radiation therapy and surgery that can be used in combination with the present invention include, but or not limited to the following combinations: 1) cyclophosphamide, doxorubicin, 5-fluorouracil, radiation therapy; 2) cyclophosphamide, doxorubicin, 5-fluorouracil, mastectomy, radiation therapy; 3) 5-flurouracil, doxorubicin, clyclophosphamide, vincristine, prednisone, mastectomy, radiation therapy; 4) 5-flurouracil, doxorubicin, clyclophosphamide, vincristine, mastectomy, radiation therapy; 5) cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, radiation therapy; 6) cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine, mastectomy, radiation therapy; 7) doxorubicin, vincristine, methotrexate, radiation therapy, followed by vincristine, cyclophosphamide, 5-florouracil; 8) doxorubicin, vincristine, cyclophosphamide, methotrexate, 5-florouracil, radiation therapy, followed by vincristine, cyclophosphamide, 5-florouracil; 9) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, prednisone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine, tamoxifen; 10) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine, tamoxifen; 11) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine, tamoxifen; 12) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine; 13) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine; 15) surgery, followed by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by radiation therapy, followed by cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, vincristine; 16) 5-florouracil, doxorubicin, cyclophosphamide followed by mastectomy, followed by 5-florouracil, doxorubicin, cyclophosphamide, followed by radtiation therapy.  
       [1245] In the treatment of metastatic breast cancer, a COX-2 inhibitor and an aromatase inhibitor can be used to treat the disease in combination with surgery, radiation therapy or with chemotherapeutic agents. In one embodiment, combinations of chemotherapeutic agents that can be used in combination with a COX-2 inhibitor and an aromatase inhibitor of the present invention include, but are not limited to the following combinations: 1) cyclophosphamide, methotrexate, 5-fluorouracil; 2) cyclophosphamide, adriamycin, 5-fluorouracil; 3) cyclophosphamide, methotrexate, 5-flurouracil, vincristine, prednisone; 4) adriamycin, vincristine; 5) thiotepa, adriamycin, vinblastine; 6) mitomycin, vinblastine; 7) cisplatin, etoposide.  
       [1246] A preferred therapeutic combination for the treatment of breast cancer in the present invention is a combination of celecoxib and exemestane.  
       [1247] A further preferred therapeutic combination of the present invention for the treatment of breast cancer is a combination of celecoxib, exemestane and tamoxifen.  
     
    
    
     EXAMPLE 4  
     Prostate Cancer  
     [1248] U.S. Pat. No. 4,596,797 discloses aromatase inhibitors as a method of prophylaxis and/or treatment of prostatic hyperplasia.  
     [1249] In one embodiment of the present invention, a therapy for the treatment of prostate cancer is a combination of amounts of a COX-2 selective inhibitor and an aromatase inhibitor which together comprise a therapeutically effective amount.  
     [1250] A preferred therapeutic combination for the treatment of prostate cancer is a combination of celecoxib and exemestane.  
     [1251] Illustration 5: Bladder Cancer  
     [1252] The classification of bladder cancer is divided into three main classes: 1) superficial disease, 2) muscle-invasive disease, and 3) metastatic disease.  
     [1253] Currently, transurethral resection (TUR), or segmental resection, account for first line therapy of superficial bladder cancer, i.e., disease confined to the mucosa or the lamina propria. However, intravesical therapies are necessary, for example, for the treatment of high-grade tumors, carcinoma in situ, incomplete resections, recurrences, and multifocal papillary. Recurrence rates range from up to 30 to 80 percent, depending on stage of cancer.  
     [1254] Therapies that are currently used as intravesical therapies include chemotherapy, immunotherapy, bacille Calmette-Guerin (BCG) and photodynamic therapy. The main objective of intravesical therapy is twofold: to prevent recurrence in high-risk patients and to treat disease that cannot by resected. The use of intravesical therapies must be balanced with its potentially toxic side effects. Additionally, BCG requires an unimpaired immune system to induce an antitumor effect. Chemotherapeutic agents that are known to be inactive against superficial bladder cancer include Cisplatin, actinomycin D, 5-fluorouracil, bleomycin, and cyclophosphamide methotrexate.  
     [1255] In the treatment of superficial bladder cancer, a COX-2 inhibitor can be used to treat the disease in combination with an aromatase inhibitor, or in combination with surgery (TUR), other chemotherapy and intravesical therapies.  
     [1256] In one embodiment, an intravesicle immunotherapeutic agent that may be used in the present invention is BCG. A preferred daily dose ranges from 60 to 120 mg, depending on the strain of the live attenuated tuberculosis organism used.  
     [1257] In another embodiment, a photodynamic therapeutic agent that may be used with the present invention is Photofrin I, a photosensitizing agent, administered intravenously. It is taken up by the low-density lipoprotein receptors of the tumor cells and is activated by exposure to visible light. Additionally, neomydium YAG laser activation generates large amounts of cytotoxic free radicals and singlet oxygen.  
     [1258] In the treatment of muscle-invasive bladder cancer, a COX-2 inhibitor and an aromatase inhibitor can be used to treat the disease in combination with surgery (TUR), intravesical chemotherapy, radiation therapy, and radical cystectomy with pelvic lymph node dissection.  
     [1259] In one embodiment, the radiation dose for the treatment of bladder cancer is between 5,000 to 7,000 cGY in fractions of 180 to 200 cGY to the tumor. Additionally, a 3,500 to 4,700 cGY total dose is administered to the normal bladder and pelvic contents in a four-field technique. Radiation therapy should be considered only if the patient is not a surgical candidate, but may be considered as preoperative therapy.  
     [1260] Currently no curative therapy exists for metastatic bladder cancer. The present invention contemplates an effective treatment of bladder cancer leading to improved tumor inhibition or regression, as compared to current therapies. In one embodiment for the treatment of metastatic bladder cancer, a COX-2 inhibitor and an aromatase inhibitor will be useful to treat the disease, optionally in combination with surgery, radiation therapy or with chemotherapeutic agents.  
     [1261] A preferred therapeutic combination of the present invention for the treatment of bladder cancer is a combination of celecoxib and exemestane.  
     Illustration 6: Pancreas Cancer  
     [1262] Approximately 2% of new cancer cases diagnosed in the United States are pancreatic cancer. Pancreatic cancer is generally classified into two clinical types: 1) adenocarcinoma (metastatic and non-metastatic), and 2) cystic neoplasms (serous cystadenomas, mucinous cystic neoplasms, papilary cystic neoplasms, acinar cell systadenocarcinoma, cystic choriocarcinoma, cystic teratomas, angiomatous neoplasms).  
     [1263] In one embodiment, a therapy for the treatment of non-metastatic adenocarcinoma that may be used in the present invention includes the use of a COX-2 inhibitor and an aromatase inhibitor along with preoperative bilary tract decompression (patients presenting with obstructive jaundice); surgical resection, including standard resection, extended or radial resection and distal pancreatectomy (tumors of body and tail); adjuvant radiation; antiangiogenic therapy; and chemotherapy.  
     [1264] In another embodiment for the treatment of metastatic adenocarcinoma, a therapy of the present invention comprises a COX-2 inhibitor and an aromatase inhibitor in combination with continuous treatment of 5-fluorouracil, followed by weekly cisplatin therapy.  
     [1265] In yet another embodiment, a combination therapy for the treatment of cystic neoplasms is the use of a COX-2 inhibitor and an aromatase inhibitor along with resection.  
     [1266] A preferred therapeutic combination of the present invention for the treatment of pancreatic cancer is a combination of celecoxib and exemestane.  
     Illustration 7: Ovary Cancer  
     [1267] Celomic epithelial carcinoma accounts for approximately 90% of ovarian cancer cases. In one embodiment, a therapy for the treatment of ovary cancer is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor.  
     [1268] In another embodiment, a method for the treatment of celomic epithelial—carcinoma is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamethylmelamine, cyclosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexamethylmelamine, 5-flurouracil, cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin; 10) hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide, hexamethlmelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.  
     [1269] Germ cell ovarian cancer accounts for approximately 5% of ovarian cancer cases. Germ cell ovarian carcinomas are classified into two main groups: 1) dysgerminoma, and nondysgerminoma. Nondysgerminoma is further classified into teratoma, endodermal sinus tumor, embryonal carcinoma, chloricarcinoma, polyembryoma, and mixed cell tumors.  
     [1270] In one embodiment of the present invention, a therapy for the treatment of germ cell carcinoma is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor.  
     [1271] In another embodiment of the present invention, a therapy for the treatment of germ cell carcinoma is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor in combination with the following combinations of antineoplastic agents: 1) vincristine, actinomycin D, cyclophosphamide; 2) bleomycin, etoposide, cisplatin; 3) vinblastine, bleomycin, cisplatin.  
     [1272] Cancer of the fallopian tube is the least common type of ovarian cancer, accounting for approximately 400 new cancer cases per year in the United States. Papillary serous adenocarcinoma accounts for approximately 90% of all malignancies of the ovarian tube.  
     [1273] In one embodiment of the present invention, a therapy for the treatment of fallopian tube cancer is a combination of neoplasia disorder effective amounts of a COX-2 inhibiting agent and an aromatase inhibitor.  
     [1274] Another embodiment of the present invention for the treatment of fallopian tube cancer is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor in combination with the following combinations of antineoplastic agents: 1) cisplatin, doxorubicin, cyclophosphamide; 2) hexamthylmelamine, cyclosphamide, doxorubicin, cisplatin; 3) cyclophosphamide, hexamehtylmelamine, 5-flurouracil, cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5) melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide, cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin, hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin, hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin; 10) hexamethylmelamine, doxorubicin, carboplatin; 11) cyclophosphamide, hexamethimelamine, doxorubicin, cisplatin; 12) carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.  
     [1275] A preferred therapeutic combination for the treatment of ovarian cancer is a combination of celecoxib and exemestane.  
     Illustration 8: Central Nervous System Cancers  
     [1276] Central nervous system cancer accounts for approximately 2% of new cancer cases in the United States. Common intracranial neoplasms include glioma, meninigioma, neurinoma, and adenoma.  
     [1277] In one embodiment of the present invention, a therapy for the treatment of central nervous system cancers is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor.  
     [1278] In another embodiment of the present invention, a therapy for the treatment of maligant glioma is a combination of therapeutically effective amounts of a COX-2 inhibitor and an aromatase inhibitor in combination with the following combinations of therapies and antineoplastic agents: 1) radiation therapy, BCNU (carmustine); 2) radiation therapy, methyl CCNU (lomustine); 3) radiation therapy, medol; 4) radiation therapy, procarbazine; 5) radiation therapy, BCNU, medrol; 6) hyperfraction radiation therapy, BCNU; 7) radiation therapy, misonidazole, BCNU; 8) radiation therapy, streptozotocin; 9) radiation therapy, BCNU, procarbazine; 10) radiation therapy, BCNU, hydroxyurea, procarbazine, VM-26; 11) radiation therapy, BNCU, 5-flourouacil; 12) radiation therapy, Methyl CCNU, dacarbazine; 13) radiation therapy, misonidazole, BCNU; 14) diaziquone; 15) radiation therapy, PCNU; 16) procarbazine (matulane), CCNU, vincristine. A preferred dose of radiation therapy is about 5,500 to about 6,000 cGY. Preferred radiosensitizers include misonidazole, intra-arterial Budr and intravenous iododeoxyuridine (IUdR). It is also contemplated that radiosurgery may be used in combinations with antiangiogenesis agents.  
     [1279] A preferred therapeutic combination of the present invention for the treatment of central nervous system cancers is a combination of celecoxib and exemestane.  
     Illustration 9  
     [1280] Additional examples of combinations are listed in Table No. 10.  
               TABLE No. 10                          Combination therapy examples                                 COX-2   Antineoplastic               Inhibitor   Agents   Indication                       Celecoxib   Anastrozole   Breast           Celecoxib   Letrozole   Breast           Celecoxib   Exemestane   Breast           Rofecoxib   Anastrozole   Breast           Rofecoxib   Letrozole   Breast           Rofecoxib   Exemestane   Breast           JTE-522   Anastrozole   Breast           JTE-522   Letrozole   Breast           JTE-522   Exemestane   Breast           Valdecoxib   Anastrozole   Breast           Valdecoxib   Letrozole   Breast           Valdecoxib   Exemestane   Breast           Parecoxib   Anastrozole   Breast           Parecoxib   Letrozole   Breast           Parecoxib   Exemestane   Breast           Etoricoxib   Anastrozole   Breast           Etoricoxib   Letrozole   Breast           Etoricoxib   Exemestane   Breast                      
 
     Illustration 10  
     [1281] Table 11 illustrates examples of some combinations of the present invention wherein the combination comprises an amount of a COX-2 selective inhibitor source and an amount of an aromatase inhibitor wherein the amounts together comprise a neoplasia disorder effective amount of the compounds.  
               TABLE No. 11                          Combinations of COX-2 selective inhibiting agents and       aromatase inhibitors                         Example       Aromatase       Number   COX-2 Inhibitor   Inhibitor                                 1   C1   A1       2   C1   A2       3   C1   A3       4   C1   A4       5   C1   A5       6   C1   A6       7   C1   A7       8   C1   A8       9   C1   A9       10   C1   A10       11   C1   A11       12   C1   A12       13   C1   A13       14   C1   A14       15   C1   A15       16   C1   A16       17   C1   A17       18   C1   A18       19   C1   A19       20   C1   A20       21   C1   A21       22   C1   A22       23   C1   A23       24   C1   A24       25   C1   A25       26   C1   A26       27   C1   A27       28   C1   A28       29   C1   A29       30   C1   A30       31   C1   A31       32   C1   A32       33   C2   A1       34   C2   A2       35   C2   A3       36   C2   A4       37   C2   A5       38   C2   A6       39   C2   A7       40   C2   A8       41   C2   A9       42   C2   A10       43   C2   A11       44   C2   A12       45   C2   A13       46   C2   A14       47   C2   A15       48   C2   A16       49   C2   A17       50   C2   A18       51   C2   A19       52   C2   A20       53   C2   A21       54   C2   A22       55   C2   A23       56   C2   A24       57   C2   A25       58   C2   A26       59   C2   A27       60   C2   A28       61   C2   A29       62   C2   A30       63   C2   A31       64   C2   A32       65   C3   A1       66   C3   A2       67   C3   A3       68   C3   A4       69   C3   A5       70   C3   A6       71   C3   A7       72   C3   A8       73   C3   A9       74   C3   A10       75   C3   A11       76   C3   A12       77   C3   A13       78   C3   A14       79   C3   A15       80   C3   A16       81   C3   A17       82   C3   A18       83   C3   A19       84   C3   A20       85   C3   A21       86   C3   A22       87   C3   A23       88   C3   A24       89   C3   A25       90   C3   A26       91   C3   A27       92   C3   A28       93   C3   A29       94   C3   A30       95   C3   A31       96   C3   A32       97   C4   A1       98   C4   A2       99   C4   A3       100   C4   A4       101   C4   A5       102   C4   A6       103   C4   A7       104   C4   A8       105   C4   A9       106   C4   A10       107   C4   A11       108   C4   A12       109   C4   A13       110   C4   A14       111   C4   A15       112   C4   A16       113   C4   A17       114   C4   A18       115   C4   A19       116   C4   A20       117   C4   A21       118   C4   A22       119   C4   A23       120   C4   A24       121   C4   A25       122   C4   A26       123   C4   A27       124   C4   A28       125   C4   A29       126   C4   A30       127   C4   A31       128   C4   A32       129   C5   A1       130   C5   A2       131   C5   A3       132   C5   A4       133   C5   A5       134   C5   A6       135   C5   A7       136   C5   A8       137   C5   A9       138   C5   A10       139   C5   A11       140   C5   A12       141   C5   A13       142   C5   A14       143   C5   A15       144   C5   A16       145   C5   A17       146   C5   A18       147   C5   A19       148   C5   A20       149   C5   A21       150   C5   A22       151   C5   A23       152   C5   A24       153   C5   A25       154   C5   A26       155   C5   A27       156   C5   A28       157   C5   A29       158   C5   A30       159   C5   A31       160   C5   A32       161   C6   A1       162   C6   A2       163   C6   A3       164   C6   A4       165   C6   A5       166   C6   A6       167   C6   A7       168   C6   A8       169   C6   A9       170   C6   A10       171   C6   A11       172   C6   A12       173   C6   A13       174   C6   A14       175   C6   A15       176   C6   A16       177   C6   A17       178   C6   A18       179   C6   A19       180   C6   A20       181   C6   A21       182   C6   A22       183   C6   A23       184   C6   A24       185   C6   A25       186   C6   A26       187   C6   A27       188   C6   A28       189   C6   A29       190   C6   A30       191   C6   A31       192   C6   A32       193   C7   A1       194   C7   A2       195   C7   A3       196   C7   A4       197   C7   A5       198   C7   A6       199   C7   A7       200   C7   A8       201   C7   A9       202   C7   A10       203   C7   A11       204   C7   A12       205   C7   A13       206   C7   A14       207   C7   A15       208   C7   A16       209   C7   A17       210   C7   A18       211   C7   A19       212   C7   A20       213   C7   A21       214   C7   A22       215   C7   A23       216   C7   A24       217   C7   A25       218   C7   A26       219   C7   A27       220   C7   A28       221   C7   A29       222   C7   A30       223   C7   A31       224   C7   A32       225   C23   A1       226   C23   A2       227   C23   A3       228   C23   A4       229   C23   A5       230   C23   A6       231   C23   A7       232   C23   A8       233   C23   A9       234   C23   A10       235   C23   A11       236   C23   A12       237   C23   A13       238   C23   A14       239   C23   A15       240   C23   A16       241   C23   A17       242   C23   A18       243   C23   A19       244   C23   A20       245   C23   A21       246   C23   A22       247   C23   A23       248   C23   A24       249   C23   A25       250   C23   A26       251   C23   A27       252   C23   A28       253   C23   A29       254   C23   A30       255   C23   A31       256   C23   A32       257   C44   A1       258   C44   A2       259   C44   A3       260   C44   A4       261   C44   A5       262   C44   A6       263   C44   A7       264   C44   A8       265   C44   A9       266   C44   A10       267   C44   A11       268   C44   A12       269   C44   A13       270   C44   A14       271   C44   A15       272   C44   A16       273   C44   A17       274   C44   A18       275   C44   A19       276   C44   A20       277   C44   A21       278   C44   A22       279   C44   A23       280   C44   A24       281   C44   A25       282   C44   A26       283   C44   A27       284   C44   A28       285   C44   A29       286   C44   A30       287   C44   A31       288   C44   A32       289   C46   A1       290   C46   A2       291   C46   A3       292   C46   A4       293   C46   A5       294   C46   A6       295   C46   A7       296   C46   A8       297   C46   A9       298   C46   A10       299   C46   A11       300   C46   A12       301   C46   A13       302   C46   A14       303   C46   A15       304   C46   A16       305   C46   A17       306   C46   A18       307   C46   A19       308   C46   A20       309   C46   A21       310   C46   A22       311   C46   A23       312   C46   A24       313   C46   A25       314   C46   A26       315   C46   A27       316   C46   A28       317   C46   A29       318   C46   A30       319   C46   A31       320   C46   A32       321   C66   A1       322   C66   A2       323   C66   A3       324   C66   A4       325   C66   A5       326   C66   A6       327   C66   A7       328   C66   A8       329   C66   A9       330   C66   A10       331   C66   A11       332   C66   A12       333   C66   A13       334   C66   A14       335   C66   A15       336   C66   A16       337   C66   A17       338   C66   A18       339   C66   A19       340   C66   A20       341   C66   A21       342   C66   A22       343   C66   A23       344   C66   A24       345   C66   A25       346   C66   A26       347   C66   A27       348   C66   A28       349   C66   A29       350   C66   A30       351   C66   A31       352   C66   A32       353   C67   A1       354   C67   A2       355   C67   A3       356   C67   A4       357   C67   A5       358   C67   A6       359   C67   A7       360   C67   A8       361   C67   A9       362   C67   A10       363   C67   A11       364   C67   A12       365   C67   A13       366   C67   A14       367   C67   A15       368   C67   A16       369   C67   A17       370   C67   A18       371   C67   A19       372   C67   A20       373   C67   A21       374   C67   A22       375   C67   A23       376   C67   A24       377   C67   A25       318   C67   A26       379   C67   A27       380   C67   A28       381   C67   A29       382   C67   A30       383   C67   A31       384   C67   A32       385   a chromene COX-2   A1           inhibitor       386   a chromene COX-2   A2           inhibitor       387   a chromene COX-2   A3           inhibitor       388   a chromene COX-2   A4           inhibitor       389   a chromene COX-2   A5           inhibitor       390   a chromene COX-2   A6           inhibitor       391   a chromene COX-2   A7           inhibitor       392   a chromene COX-2   A8           inhibitor       393   a chromene COX-2   A9           inhibitor       394   a chromene COX-2   A10           inhibitor       395   a chromene COX-2   A11           inhibitor       396   a chromene COX-2   A12           inhibitor       397   a chromene COX-2   A13           inhibitor       398   a chromene COX-2   A14           inhibitor       399   a chromene COX-2   A15           inhibitor       400   a chromene COX-2   A16           inhibitor       401   a chromene COX-2   A17           inhibitor       402   a chromene COX-2   A18           inhibitor       403   a chromene COX-2   A19           inhibitor       404   a chromene COX-2   A20           inhibitor       405   a chromene COX-2   A21           inhibitor       406   a chromene COX-2   A22           inhibitor       407   a chromene COX-2   A23           inhibitor       408   a chromene COX-2   A24           inhibitor       409   a chromene COX-2   A25           inhibitor       410   a chromene COX-2   A26           inhibitor       411   a chromene COX-2   A27           inhibitor       412   a chromene COX-2   A28           inhibitor       413   a chromene COX-2   A29           inhibitor       414   a chromene COX-2   A30           inhibitor       415   a chromene COX-2   A31           inhibitor       416   a chromene COX-2   A32           inhibitor       417   C68   A1       418   C68   A2       419   C68   A3       420   C68   A4       421   C68   A5       422   C68   A6       423   C68   A7       424   C68   A8       425   C68   A9       426   C68   A10       427   C68   A11       428   C68   A12       429   C68   A13       430   C68   A14       431   C68   A15       432   C68   A16       433   C68   A17       434   C68   A18       435   C68   A19       436   C68   A20       437   C68   A21       438   C68   A22       439   C68   A23       440   C68   A24       441   C68   A25       442   C68   A26       443   C68   A27       444   C68   A28       445   C68   A29       446   C68   A30       447   C68   A31       448   C68   A32                  
 
     [1282] Biological Assays  
     Evaluation of COX-1 and COX-2 Activity in Vitro  
     [1283] The COX-2 inhibiting agents of this invention exhibit inhibition in vitro of COX-2. The COX-2 inhibition activity of the compounds illustrated in the examples above are determined by the following methods. The COX-2 inhibition activity of the other COX-2 inhibitors of the present invention may also be determined by the following methods.  
     [1284] Preparation of Recombinant COX Baculoviruses  
     [1285] Recombinant COX-1 and COX-2 are prepared as described by Gierse et al, [J. Biochem., 305, 479-84 (1995)]. A 2.0 kb fragment containing the coding region of either human or murine COX-1 or human or murine COX-2 is cloned into a BamH1 site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-1 and COX-2 in a manner similar to the method of D. R. O&#39;Reilly et al ( Baculovirus Expression Vectors: A Laboratory Manual  (1992)). Recombinant baculoviruses are isolated by transfecting 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2×10 8 ) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. See M. D. Summers and G. E. Smith,  A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures , Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses are purified by three rounds of plaque purification and high titer (107-108 pfu/mL) stocks of virus are prepared. For large scale production, SF9 insect cells are infected in 10 liter fermentors (0.5×106/mL) with the recombinant baculovirus stock such that the multiplicity of infection is 0.1. After 72 hours the cells are centrifuged and the cell pellet is homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS). The homogenate is centrifuged at 10,000×G for 30 minutes, and the resultant supernatant is stored at −80° C. before being assayed for COX activity.  
     [1286] Assay for COX-1 and COX-2 Activity  
     [1287] COX activity is assayed as PGE2 formed/μg protein/time using an ELISA to detect the prostaglandin released. CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme are incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidbnic acid (10 μM). Compounds are pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme is stopped after ten minutes at 37° C./room temperature by transferring 40 μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. The PGE2 formed is measured by standard ELISA technology (Cayman Chemical).  
     [1288] Fast Assay for COX-1 and COX-2 Activity  
     [1289] COX activity is assayed as PGE2 formed/μg protein/time using an ELISA to detect the prostaglandin released. CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme are incubated in a potassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μM phenol, 1 μM heme, 300 μM epinephrine) with the addition of 20 μl of 100 μM arachidonic acid (10 μM). Compounds are pre-incubated with the enzyme for 10 minutes at 25° C. prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme is stopped after two minutes at 37° C./room temperature by transferring 40 μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. The PGE2 formed is measured by standard ELISA technology (Cayman Chemical).  
     Biological Evaluation  
     [1290] A combination therapy of a COX-2 inhibiting agent and an aromatase inhibitor for the treatment or prevention of a neoplasia disorder or osteoporosis in a mammal can be evaluated as described in the following tests.  
     [1291] Lewis Lung Model  
     [1292] Mice are injected subcutaneously in the left paw (1×10 6  tumor cells suspended in 30% Matrigel) and tumor volume is evaluated using a phlethysmometer twice a week for 30-60 days. Blood is drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data is expressed as the mean+/−SEM. Student&#39;s and Mann-Whitney tests are used to assess differences between means using the InStat software package. A COX-2 inhibitor and an aromatase inhibitor are administered to the animals in a range of doses. Analysis of lung metastasis is done in all the animals by counting metastasis in a stereomicroscope and by histochemical analysis of consecutive lung sections.  
     [1293] HT-29 Model  
     [1294] Mice are injected subcutaneously in the left paw (1×10 6  tumor cells suspended in 30% Matrigel) and tumor volume is evaluated using a phlethysmometer twice a week for 30-60 days. Implantation of human colon cancer cells (HT-29) into nude mice produces tumors that reach 0.6-2 ml between 30-50 days. Blood is drawn twice during the experiment in a 24 h protocol to assess plasma concentration and total exposure by AUC analysis. The data is expressed as the mean +/− SEM. Student&#39;s and Mann-Whitney tests are used to assess differences between means using the InStat software package.  
     [1295] A. Mice injected with HT-29 cancer cells are treated with an aromatase inhibitor i.p at doses of 50 mg/kg on days 5,7 and 9 in the presence or absence of celecoxib in the diet. The efficacy of both agents is determined by measuring tumor volume.  
     [1296] B. In a second assay, mice injected with HT-29 cancer cells are treated with an aromatase inhibitor on days 12 through 15. Mice injected with HT-29 cancer cells are treated with an aromatase inhibitor i.p at doses of 50 mg/kg on days 12, 13, 14, and 15 in the presence or absence of celecoxib in the diet. The efficacy of both agents is determined by measuring tumor volume.  
     [1297] C. In a third assay, mice injected with HT-29 colon cancer cells are treated with an aromatase inhibitor i.p 50 mg/kg on days 14 through 17 in the presence or absence of celecoxib (1600 ppm) and valdecoxib (160 ppm) in the diet. The efficacy of both agents is determined by measuring tumor volume.  
     NFSA Tumor Model  
     [1298] The NFSA sarcoma is a nonimmunogenic and prostaglandin producing tumor that spontaneously developed in C3Hf/Kam mice. It exhibits an increased radioresponse if indomethacin is given prior to tumor irradiation. The NFSA tumor is relatively radioresistant and is strongly infiltrated by inflammatory mononuclear cells, primarily macrophages which secrete factors that stimulate tumor cell proliferation. Furthermore, this tumor produces a number of prostaglandins, including prostaglandin E 2  and prostaglandin I 2 .  
     [1299] Solitary tumors are generated in the right hind legs of mice by the injection of 3×10 5  viable NFSA tumor cells. Treatment with a COX-2 inhibiting agent (6 mg/kg body weight) and an aromatase inhibitor or vehicle (0.05% Tween 20 and 0.95% polyethylene glycol) given in the drinking water is started when tumors are approximately 6 mm in diameter and the treatment ia continued for 10 consecutive days. Water bottles are changed every 3 days. In some experiments, tumor irradiation is performed 3-8 days after initiation of the treatment. The end points of the treatment are tumor growth delay (days) and TCD 50  (tumor control dose 50, defined as the radiation dose yielding local tumor cure in 50% of irradiated mice 120 days after irradiation). To obtain tumor growth curves, three mutually orthogonal diameters of tumors are measured daily with a vernier caliper, and the mean values are calculated.  
     [1300] Local tumor irradiation with single y-ray doses of 30, 40, or 50 Gy is given when these tumors reach 8 mm in diameter. Irradiation to the tumor is delivered from a dual-source  137 Cs irradiator at a dose rate of 6.31 Gy/minute. During irradiation, unanesthetized mice are immobilized on a jig and the tumor is centered in a circular radiation field 3 cm in diameter. Regression and regrowth of tumors is followed at 1-3 day intervals until the tumor diameter reaches approximately 14 mm.  
     [1301] The magnitude of tumor growth delay as a function of radiation dose with or without treatment with a COX-2 inhibiting agent and an aromatase inhibitor is plotted to determine the enhancement of tumor response to radiation. This requires that tumor growth delay after radiation be expressed only as the absolute tumor growth delay, i.e., the time in days for tumors treated with radiation to grow from 8 to 12 mm in diameter minus the time in days for untreated tumors to reach the same size. It also requires that the effect of the combined COX-2 inhibiting agent and aromatase inhibitor plus-radiation treatment be expressed as the normalized tumor growth delay. Normalized tumor growth delay is defined as the time for tumors treated with both a COX-2 inhibiting agent and radiation to grow from 8 to 12 mm in diameter minus the time in days for tumors treated with a COX-2 inhibiting agent and an aromatase inhibitor alone to reach the same size.  
     [1302] Ovariectomized Rat Model: A Model of Post-Menopausal Osteoporosis  
     [1303] In women, estrogen deficiency during the menopause results in increased bone turnover leading to bone loss. Ovariectomy in rats produces estrogen deficiency and increased bone turnover leading to trabecular bone loss similar to that observed in post-menopausal women (Kalu, D. N., Bone and Mineral 1991; 15:175; Frost, H. M., Jee W. S. S., Bone and Mineral 1992; 18:227; Wronski, T. J., Yen, C-F, Cells Materials 1991; (suppl. 1):69). The OVX rat is thus an appropriate model to evaluate compounds for the prevention and treatment of post-menopausal osteoporosis. The ability of bone resorption inhibiting COX-2 inhibitors and aromatase inhibitors in combination to inhibit estrogen deficiency bone loss is assessed in OVX rats, since ovariectomy causes significant bone loss in the lumbar vertebrae, proximal tibia, and distal femoral metaphyses (Ke, H. Z., et al., Endocrin 1995; 136:2435; Chen, H. K., et al., J Bone Miner Res 1995; 10:1256).  
     [1304] Seventy-five day old female Sprague Dawley rats (weight range of 225 to 275 g) are obtained from Charles River Laboratories (Portage, Mich.). They are housed in groups of 3 and have ad libitum access to food (calcium content approximately 1%) and water. Room temperature is maintained at 22.2° C. +/−1.7° C. with a minimum relative humidity of 40%. The photoperiod in the room is 12 hours light and 12 hours dark. One week after arrival, the rats undergo bilateral ovariectomy under anesthesia (44 mg/kg Ketamine TM and 5 mg/kg Xylazine TM (Butler, Indianapolis, Ind.) is administered intramuscularly). Treatment with vehicle or the test compositions is initiated either on the day of surgery following recovery from anesthesia or 35 days following the surgery. The rats are treated either with vehicle containing a bone resorption inhibiting combination of a COX-2 inhibitor and an aromatase inhibitor or with vehicle only. Oral dosage is by gavage in 0.5 mL of pH-adjusted 1% carboxymethylcellulose (CMC). Body weight is determined at the time of surgery and weekly during the study, and the dosage is adjusted with changes in body weight. Vehicle-treated ovariectomized (OVX) rats and non-ovariectomized (intact) rats are evaluated in parallel with each experimental group to serve as negative and positive controls. The rats are treated daily for 35 days (6 rats per treatment group) and are sacrificed by decapitation on the 36th day. The 35-day time period is sufficient to allow maximal reduction in bone density, measured as described below. At the time of sacrifice, the uteri are removed, are dissected free of extraneous tissue, and the fluid contents are expelled before determination of wet weight in order to confirm estrogen deficiency associated with complete ovariectomy. Uterine weight is routinely reduced about 75% in response to ovariectomy. The uteri are then placed in 10% neutral buffered formalin to allow for subsequent histological analysis.  
     [1305] Calcein at 10 mg/kg is injected s.c. into all rats 12 and 2 days before necropsy as a fluorochrome bone marker to measure bone dynamic histomorphometric parameters. The effects of a combination of COX-2 inhibitor and aromatase inhibitor on the following end points are determined: (a) serum osteocalcin, a biochemical marker of bone turnover, (b) bone mineral density of lumbar vertebrae and distal femoral metaphyses, (c) bone histomorphometry of fifth lumbar vertebral body and proximal tibial metaphyses.  
     [1306] For the measurement of the endpoints, serum osteocalcin concentration is determined by radioimmunoassay assays known in the art, and bone mineral content (BMC) and bone mineral density (BMD) are measured by standard procedures as described below:  
     [1307] The first to the sixth lumbar vertebrae from each rat are removed during necropsy. These are then scanned ex vivo using dual-energy X-ray absorptiometry. The scan images are analyzed, and bone area, BMC, and BMD of whole lumbar vertebrae (WLV), and LV1 through LV6 is determined.  
     [1308] Using dual-energy X-ray absorptiometry, the right femur of each rat is scanned ex vivo. Bone mineral density (BMD) of the distal femoral metaphyses (second 0.5 cm from the distal end of femur) and the proximal femur (the first 0.5 cm from the proximal end of femur, which contains the femoral head, neck, and greater trochanter) is determined. In order to determine the effects of a COX-2 inhibitor and an aromatase inhibitor on long bone metaphyses, histomorphometric analyses are performed on the proximal tibiae.  
     Example 5  
     Effect of Exemestane and Celecoxib Alone or in Combination on DMBA-Induced Mammary Carcinoma in Rats  
     [1309] The chemotherapeutic potential of exemestane (EXE) and celecoxib (CXB) alone and in combination was evaluated in DMBA-induced rat mammary tumors.  
     [1310] Tumor bearing rats were treated for four weeks, starting when tumor diameter was 1 cm. Doses of EXE and CXB yielding a limited response rate were used to highlight a potential synergistic activity. Experimental groups tested were: EXE 50 mg/kg/wk i.m. for four weeks, CXB in the diet (500 mg/kg of diet) for four weeks, the combination of these, vehicle alone, or ovariectomy. The test results are summarized in Table 12 below.  
               TABLE NO. 12                          Combination And Solo Administration of       Exemestane and Celecoxib                                     Treatment                           No. Rats/               Rats with   #       No. tumors   CR + PR, %   NC, %   P, %   NT, %   NT per rat                                             Vehicle   0   5   95   73   2.5       (15/21)       CXB (15/23)   0   30   70   67   1.6       Exe (15/23)   5   78   17   67   0.9       EXE + CXB   48   47   5   47   0.6       (15/23)       Ovariectomy   96   4   0   0   0       15/26                                                          
 
     [1311] As demonstrated the combination of EXE and CXB is significantly more effective than either alone in reducing tumor growth and in reducing new tumor incidence in a hormone-dependent breast cancer model.  
     [1312] The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety.  
     [1313] While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the active agents used in the methods, combinations and compositions of the present invention as indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.