MXPA06004657A - COMBINATIONS COMPRISING AN Hsp90 INHIBITOR AND A PHOPHODIESTERASE INHIBITOR FOR TREATING OR PREVENTING NEOPLASIA. - Google Patents

Abstract

A method for treating or preventing neoplasia or a neoplasia-related disorder in a subject is provided, the method comprising administering to the subject an effective amount of a combination comprising an Hsp90 inhibitor and a phosphodiesterase inhibitor, and optionally a Cox-2 inhibitor.

Description

COMBINATIONS COMPRISING AN Hsp90 INHIBITOR AND A PHOSPHODYSTERASE INHIBITOR TO TREAT OR PREVENT THE NEOPLASIA FIELD OF THE INVENTION The present invention relates generally to combinations of drugs and methods of their use for the prevention and / or treatment of neoplasia and disorders related to neoplasia, and more particularly to prevent or treat neoplasia and disorders. related to the neoplasm by administering a combination of enzyme inhibitors to a subject. BACKGROUND OF THE INVENTION More than 1.2 million Americans develop cancer each year, making cancer the second leading cause of death in the Un States. In 2000, cancer accounted for 23% of all deaths in the Un States. U.S. Dept. of Health and Human Services, National Center for Health Statistics, National Vital Statistics Report, Vol. 50, No. 16 (2002). Therefore, new treatment therapies are needed to cope with the growing threat of cancer. Cancer is a disorder that arises from one or more genetic mutations that eventually lead to the development of the neoplasm. It is known that the exposure of a cell to carcinogens, such as certain viruses, chemical agents and radiation, can lead to a DNA alteration that inactivates a "suppressor" gene or activates an "oncogene". The "suppressor" genes are growth regulating genes, which after the mutation can no longer control cell growth. The "oncogenes" are genes initially normal (protooncogenes) that through the mutation or altered context of the expression become transforming genes. Protein products of transforming genes cause inappropriate cell growth. This is produced by the activation of several intracellular signaling pathways, including the pathway of protein kinase C / mitogen-activated protein kinase (PKC / APK) and the Ras / Raf / MEK1 / 2 / ERK / 2 pathway. Transformed cells differ from normal cells in many aspects, including cell morphology, cell-to-cell interactions, membrane contents, cytoskeletal structure, protein secretion, gene expression and loss of apoptosis. Cells transformed by oncogenes and cells that have lost the regulation of the suppressor gene undergo uncontrolled proliferation, modified control of apoptosis and initiation of angiogenesis. These three effects are characteristic of the development of neoplasia and neoplasms. Neoplasia is an abnormal, unregulated, and disorganized proliferation of cell growth that is distinguished from normal cells by autonomic growth and somatic mutations. As the neoplastic cells grow and divide, they can transmit their genetic mutations and proliferative characteristics to offspring cells. A neoplasm, or tumor, is an accumulation of neoplastic cells. A neoplasm can be benign or malignant. Although several advances have been made in the detection and therapy of cancer, no universally satisfactory procedure for prevention or treatment is currently available. Currently, cancer therapy relies on a combination of early diagnosis and aggressive treatment, which may include surgical intervention, chemotherapy, radiation therapy and / or hormone therapy. Surgical intervention involves the removal of most neoplasms. Although surgical intervention is sometimes effective in removing tumors located in certain s, for example in the chest, colon or skin, it can not be used in the treatment of tumors located in other areas, such as the spine, or in the treatment of disseminated neoplastic conditions such as leukemia. In addition, surgical intervention treatments are generally satisfactory only if the cancer is detected at an early stage and before the cancer spreads by metastasis to the main organs., doing, therefore, that the surgical intervention is not feasible. Chemotherapy involves the alteration of cellular replication and / or cellular metabolism. It is used more frequently in the treatment of breast, lung and testicular cancer. The adverse effects of systemic chemotherapy used in the treatment of a neoplastic disease are problematic for patients receiving cancer treatment. Of these adverse effects, the most common and serious adverse side effects are nausea and vomiting. Many of these side effects induced by chemotherapy, if severe, can lead to hospitalization, or require treatment with analgesics to treat pain. Also, radiation therapy is not exempt from side effects such as nausea, fatigue and fever. A worrying aspect is that the side effects induced by chemotherapy and radiation therapy significantly affect the quality of life of the patient and can dramatically influence patient compliance with treatment. New cancer treatment strategies that eliminate the need for surgical intervention and reduce the side effects induced by chemotherapy would, therefore, benefit many patients suffering from cancer. Of particular interest is the discovery that, among the neoplastic cells, the molecular chaperone mRNA known as heat shock protein 90 (hereinafter "Hsp90") is differentially expressed at much higher levels than in non-neoplastic cells. Yano et al. (1999) Cancer Lett. 137 (1), 45-51. Hsp90 helps in protein refolding in cells exposed to environmental stress and is required for maturation conformation to several important signaling proteins. Parsell &; Lindquist (1993) Ann. Rev. Genet. 27. 437-496. Several of these signaling proteins are also required for the development of the neoplasm. For example, it has been reported that the "Client" proteins associated with Hsp90 that are associated with the growth and survival of the neoplasm include p53, HER-2, telomerase, V-Src, Bcr-Abl, Raf -1, Akt, ErbB2, and inducible factor by hypoxia 1 alpha (HIF-1 alpha). Blagosklonny et al. (2002) Leukemia 16 (4), 455-462. In this way, Hsp90 is a molecular chaperone whose association is required for the stability and function of several mutated and overexpressed signaling proteins that promote the growth and / or survival of neoplastic cells. Neckers (2002) Trends Mol. Med. 8 (4Suppl). S55-S61. Inhibition of Hsp90 function leads to the selective degradation of important neoplastic signaling oncoproteins that are involved in cell proliferation, cell cycle regulation and apoptosis.

Maloney and. col .. (2002) Expert Opin. Biol. Ther, 2 (1). 3-24. The current inhibitors of Hsp90 act by inhibiting the ATPase activity of Hsp90 and have shown a promising activity against cancer. Neckers (2002) op. cit. Many of these Hsp90 inhibitors are natural antibiotics, including benzoquinone ansamycins, such as geldanamycin and its 17-allylamino analogue (17AAG), and another natural product, radicicol. Unfortunately, several members of the benzoquinone ansamycin class of Hsp90 inhibitors have shown deleterious side effects including, for example, hepatotoxicity, due to their inhibition of the ATPase activity of Hsp90. Id. Recent investigations in alternative therapeutic approaches to the treatment of neoplasia have involved inhibitors of enzymes that hydrolyze cyclic GMP (cGMP) called phosphodiesterases ("PDE"). Sulindac sulfone and its exisulind analog are cGMP-specific PDE inhibitors, and have been shown to induce apoptosis, or programmed cell death, in cancer cells. Rice et al. (2001) Cancer Res., 61, 1541-1547. PDEs constitute a large family of enzymes that catalyze the hydrolysis of intracellular second messengers, cyclic nucleotides (cAMP and cGMP), to their biologically inactive forms, 5-AMP and 5-GMP. Together with adenylyl and guanylyl cyclase, PDEs can regulate cellular signaling mechanisms that are mediated by cAMP and cGMP by reducing available intracellular concentrations. These second messengers play a vital role in the transduction of extracellular signals to intracellular compartments. Eleven different PDE classes have been identified, each of which has unique catalytic properties, substrate specificities and tissue expression patterns. Uckert et al. (2001) World J. UroL 19,14-22 (2001). In the course of the discovery of these different families, selective inhibitors of the various classes of PDE have been designed and synthesized. PDEs 5, 6, and 9 have been identified to have cGMP-specific catalytic activity, therefore cGMP-specific PDE inhibitors that target these particular isozymes result in the accumulation of active cGMP in the cell. This results in an increase in the activity of cGMP-dependent protein kinase (PKG), an effector in many signal transduction pathways that can mediate apoptosis. Rice, et al, (200), supra. Due to the high incidence and high death rate associated with cancer, much research is being done in this field. Of particular interest is the recent discovery that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with the prevention and treatment of several types of cancer. Thun et al. (2002) J. National Cancer Inst. 94 (4), 252-266. Historically, physicians have treated inflammation-related disorders with an NSAID regimen such as, for example, aspirin and ibuprofen. However, it is undesirably known that some NSAIDs cause gastrointestinal (GI) hemorrhage or ulcers in patients undergoing long-term regimens of NSAID therapy. Henry et al. (1991) Release 337, 730. By the discovery that two cyclooxygenases are involved in the transformation. of arachidonic acid as the first stage in the prostaglandin synthesis route, it was possible to reduce the undesired side effects of common NSAIDs. These enzymes exist in two forms and have been designated cyclooxygenase-1 (Cox-1) and cyclo-oxygenase-2 (Cox-2). Needleman et al. (1997) J. Rheumatol. 24, Suppl. 49, Cox-1 _es. a constitutive enzyme responsible for the biosynthesis of prostaglandins in the gastric mucosa and in the kidney. Cox-2 is an enzyme that is produced by an inducible gene that is responsible for the biosynthesis of prostaglandins in inflammatory cells. Inflammation causes the induction of Cox-2, leading to a release of prostanoids (prostaglandin E2), which sensitize peripheral nociceptors terminals and produce hypersensitivity to localized pain, inflammation and edema. Samad et al. (2001) Nature 410 (6827), 471-475. It is now known that many common NSAIDs are inhibitors of both Cox-1 and Cox-2. Therefore, when administered at sufficiently high levels, these NSAIDs not only alleviate the inflammatory consequences of Cox-2 activity, but also inhibit the beneficial gastric maintenance activities of Cox-. The search in the area of arachidonic acid metabolism has led to the discovery of compounds that selectively inhibit the Cox-2 enzyme to a greater extent than they inhibit Cox-1. It is believed that these selective Cox-2 inhibitors offer advantages that include the ability to prevent or reduce inflammation while avoiding harmful side effects associated with inhibition of Cox-1. In this way, selective Cox-2 inhibitors have shown to be a great promise for use in therapies, especially in therapies that require maintenance of administration, such as for. the control of pain and inflammation. For the present invention it is of particular importance that the overexpression of Cox-2 is documented in several premalignant and malignant tissues. Subbaramaiah & Dannenberg (2003) Trends Pharmacol. Sci. 24, 96-102. It is believed that this increase in expression is a product of the stimulation of PKC signaling, which stimulates MAPK activity, enhancing transcription. of Cox-2 by nuclear factors. In addition, the increased stability of Cox-2 mRNA transcripts in cancer cells due to the increased binding of the HuR RNA binding protein, as well as the kinase activation related to extracellular signals 1/2 (ERK 1 / 2) and p38, contributes to increase the expression of Cox-2. Id. From the above, it can be seen that better procedures and therapeutic compositions are needed to treat neoplasia and disorders related to the neoplasia. It would also be useful to provide a better method and composition to reduce the symptoms associated with the neoplasm. Also, methods and compositions that improve patient outcomes after radiotherapy and chemotherapy treatment regimens for neoplasms would also be desirable. In addition, methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or for disorders related to the neoplasm are desired. Finally, methods and compositions that improve the efficacy of the treatment of the neoplasm or of a disorder related to the neoplasm that is considered resistant or intractable to known methods of therapy alone would also be desirable. SUMMARY OF THE INVENTION In summary, therefore, the present invention relates to a combination comprising an inhibitor of Hsp90 and a PDE inhibitor, in effective amounts when used in combination therapy for the treatment or prevention of neoplasia or a disorder related to the neoplasm.

In one embodiment the Hsp90 inhibitor comprises a compound having the structure shown in formula (I): where Qa is C or N; Xa is C or N; Za is C, N or O; Ma is C or N; Ga is selected from the group consisting of C, N, O and S; at least one of Qa, Xa, Za, Ma and Ga is C; R207, unless it is linked with R208 or R211 in a ring system, is selected from the group consisting of H, alkyl, aryl, amino, substituted or unsubstituted heteroaryl, haloalkyl, alkylaryl, haloaryl, haloarylsulfinylacetohydrazide, haloarylamino-carbonylamino, haloarylalcanonasulfanyl, arylalkylidene nitroaryl, alkoxyaryl, alkylthioaryl, alkylsulfonylaryl, haloalkoxy, alkoxypolyalkyl, carboxamidyl, carboxyalkyl, aminosulfonylaryl, alkoxycarbonyl, hydroxyaryl and halohydroxyaryl; R208, unless it is linked with R207 or R209 in a ring system, is selected from the group consisting of H, halo, alkyl, aryl, amino, substituted or unsubstituted heteroaryl, haloalkyl, nitroaryl, haloaryl, alkoxyaryl, aminosulfonylaryl, alkylsulfonylaryl, alkoxyhaloaryl, alkylnitriloaryl, alkylsulfonylalkyl, alkoxycarboximidyl, alkoxyhydroxyaryl and alkylthioaryl; R and R are optionally joined to form a ring system selected from the group consisting of: and aryl, wherein Ta and Tb are independently selected from C and S; R209, unless it is linked with R208 or R210 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted or unsubstituted heteroaryl, aikaryl, haloalkyl, haloaryl, alkoxyaryl, alkoxycarbonylaryl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonylaryl, alkoxyalkylaryl, "alkylaminoaryl, alkylalkanethiol, alkoxyhaloaryl and aminosulfonylaryl; R208 and R209 are optionally joined to form a ring system selected from the group consisting of: wherein X, Xc, and Xd are independently selected from the group consisting of C and N; - R210 unless it is linked with R209 or R211 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, aicylaryl, alkylthio, alkoxyaryl, alkylamino-aryl, alkylthioaryl, haloalkyl, haloaryl, carboxiaryl, aminocarbonyl, substituted or unsubstituted heteroaryl, carboxyalkyl, nitrile alcoxiarilaminoalqueno, nitroarilalquenoamida, acetamidoarilo, .. _ acetamidoarilcianoalquenil nitrile, carboxylalkoxy, alkylsulfonylaryl, haloalquilalcoxi, haloaryloxy, alcoxihaioarilo, alkoxycarbonyl, alquilsulfonilhaloarilo, aminosulfonylaryl, thioaryl, aminocycloalkyl, alkoxycarbonylaryl, alkane alcoxicarbonilaminociclo and alkylcarboxyl; R209 and R210 optionally join to form a ring system selected from the group consisting of: and aryl; - ··; || R21 unless it is linked with R210 or R207 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, hydroxyl, haloaryl, haioalkylaryl, substituted or unsubstituted heteroaryl, carboxiaryl , nitroaryl, aminosulfonylaryl, alkylsulfonylaryl, alquilsulfonilhaloarilo, alquilaminosulfonilarilo, alkylsulfonyl-aminoaryl, alkylaminocarbonyl, aminocarbonylaryl, halohidroxiaril-alquilidenacetohidrazida, hidroxialcoxiarilalquilidenacetohidrazida, carbonylaryl alkyl, alkoxyaryl, haloalcoxiarilo, alcoxialcoxoarilo, alkoxycarbonyl-aryl, haloalquilcarbonilarilo, alcohol and haloariloxiacetohidrazida; R210 and R2 optionally join to form a ring system selected from the group consisting of: oxoaryl and cycloalkyl; R207 and R211 are optionally joined to form a system selected from the group consisting of: R is selected from the group consisting of H, halo and alkoxy; R is selected from the group consisting of H and halo; R214 is selected from the group consisting of H and halo; R215 is selected from the group consisting of H, halo and alkoxy; and R216 is selected from the group consisting of H, and alkoxy; or a pharmaceutically acceptable salt or prodrug of said compound. In another embodiment the Hsp90 inhibitor comprises a compound having the structure shown in formula (II): where: A ', A ", Ea, Ja and La are independently selected from the group consisting of C and N, if either of Ea or Ja is N, then A', A" and La are C; at least three of A ', A ", Ea, Ja and La are C; R217 is selected from the group consisting of H, alkyl, halo, alkylsulfonyl, aminosulfonyl, alkoxy and alkylthio; R218 is selected from the group consisting of H, alkyl and alkoxy, R219, unless it is linked in a ring system with R2Z0, is selected from the group consisting of H, oxo, amino and alkoxy, R220, unless it is attached in a ring system with R129, selected from the group consisting of H, oxo, carboxyl, alkoxo, hydroxyalkyl, alkylnitrile, alkoxoaryl, haloalkoxo, and haloarylalkoxo; R219 and R220 are optionally attached to form a ring system consisting of a substituted or unsubstituted aryl ring; R223 are independently selected from the group consisting of H and alkoxy, and R222 is selected from the group consisting of H, halo, alkylsulfonyl, aminosulfonyl and alkylamino, or a pharmaceutically acceptable salt or prodrug of said compound. In addition, the Hsp90 inhibitor comprises a compound having the structure selected from the group consisting of: or a pharmaceutically acceptable salt or prodrug of said compound. Any Hsp90 inhibitor can be used in said combination, including, without limitation, the Hsp90 inhibitors of any of the embodiments described above. Any PDE inhibitor in such a combination can be used, including without limitation cGMP selective PDE inhibitors. - - - - - A method of treating or preventing neoplasia or a disorder related to a neoplasm in a subject is further provided, the method comprising administering said combination to the subject. According to this method, the Hsp90 inhibitor and the PDE inhibitor can be administered sequentially or substantially simultaneously to the subject. In certain embodiments, the Hsp90 inhibitor and the PDE inhibitor are co-formulated into a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier. Optionally, a combination of the invention may further comprise a Cox-2 inhibitor, for example a selective Cox-2 inhibitor. The present invention also relates to a kit for the purpose of preventing or treating neoplasia in a subject in need of such prevention or treatment, the kit comprising a first dosage form comprising an Hsp90 inhibitor in a first amount and a second dosage form comprising a PDE inhibitor in a second amount, and optionally a third dosage form comprising a Cox-2 inhibitor in a third amount; wherein said first, second and third optional amounts are effective when used in combination therapy to treat or prevent neoplasia or a disorder related to the neoplasm. Among the various advantages that are achieved by the present invention, therefore, provision can be observed, in certain embodiments, of methods and compositions that are directed to prevent or treat neoplasia in a subject in need of such prevention or treatment. treatment, comprising these methods administering to the subject an Hsp90 inhibitor alone or in combination with a PDE inhibitor and optionally a Cox-2 inhibitor. In certain embodiments, better methods and compositions are also provided to reduce the symptoms associated with. the. neoplasia In addition, according to certain embodiments, methods and compositions are provided that improve patient outcomes after radiation treatment regimens and chemotherapy for neoplasms. In addition, according to certain embodiments, methods and compositions are provided that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or disorders related to the neoplasm. further, according to certain embodiments, there are provided methods and compositions that improve the efficacy of the treatment of the neoplasm or of a disorder related to the neoplasm that is considered resistant or intractable to known methods of therapy alone. DETAILED DESCRIPTION OF THE INVENTION It has been discovered that Hsp90-is-a-target for inhibition by the compounds indicated and described in the tables and formulas of this document. It has been demonstrated that the presence of these compounds, both in vitro and in vivo, result in the alteration of the "client" protein complex associated with Hsp90. The "client" protein complexes associated with Hsp90 that are altered include, among others, those comprising mutant p53"client" proteins, proliferating cell nuclear antigen (PCNA), Raf-1, and many other regulatory proteins that are important in tumorigenesis or growth and proliferation of neoplasms. Such compounds that inhibit Hsp90 have a wide range of antitumor or anticancer activities. Several of these compounds inhibit both Hsp90 and the Cox-2 enzyme. Thus, it has been found that in one embodiment of the present invention, certain compounds can act as Hsp90 inhibitors and as Cox-2 inhibitors. The present invention encompasses such dual action compounds. These dual-acting compounds are referred to herein as "dual inhibitors of Hsp90 / Cox-2" or "dual compounds that inhibit Hsp90 / Cox-2". Thus, in one embodiment, the present invention provides compounds that act as a Cox-2 inhibitor and as an Hsp90 inhibitor. The present invention also encompasses a method for inhibiting the growth of the neoplasm, including a malignant tumor or cancer, the method comprising exposing the neoplasm to an inhibiting or therapeutically effective amount or concentration of at least one of the Hsp90-inhibiting compounds described herein. document, in combination with a PDE inhibitor. The administration of a combination of an Hsp90 inhibitor as described herein with a PDE inhibitor is an unexpectedly effective therapy for the prevention and treatment of neoplasia. Such administration is effective in preventing and treating the symptoms of neoplasia while reducing or avoiding the drawbacks and side effects associated with current treatment strategies. In certain embodiments, the present invention provides methods and compositions that improve patient outcomes after radiation treatment regimens and chemotherapy for the neoplasm. In certain embodiments, the present invention provides methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or disorders related to the neoplasm. In certain embodiments, the present invention provides methods and compositions that improve the efficacy of the treatment of neoplasia or of a disorder related to the neoplasm that is considered resistant or intractable to known methods of therapy alone. In certain embodiments, the administration of an Hsp90 inhibitor in combination with a PDE inhibitor for the prevention or treatment of neoplasia is unexpectedly superior to the use of any agent alone. Therefore, according to such embodiments, the treatment or prevention of neoplasia can be accomplished by administering to a subject suffering from or in need of the prevention of a neoplasia a combination therapy comprising an inhibitor of Hsp90 and a PDF inhibitor. In certain embodiments, such combination therapy is effective in decreasing the dosages of conventional chemotherapy and radiotherapy treatments that are usually prescribed as monotherapy. The administration of lower dosages of conventional treatment agents provides a reduction of side effects corresponding to such conventional agents. further, in certain embodiments, such combination therapy demonstrates a synergistic efficacy for treating or preventing neoplasia, when the efficacy is greater than would be expected by simply combining the two therapies. As used herein, the term "neoplasia" refers to new cell growth resulting from a loss of sensitivity to normal growth controls, eg, "neoplastic" cell growth. For the purposes of the present invention, cancer is a subtype of neoplasia. As used herein, the term "neoplasm-related disorder" encompasses neoplasia, but also encompasses other cellular abnormalities, such as hyperplasia, metaplasia, and dysplasia. The terms neoplasia, metaplasia, dysplasia, and hyperplasia generally refer to cells that undergo abnormal cell growth. Both the neoplasm and disorders related to the neoplasm may involve a neoplasm or tumor, which may be benign, premalignant, metastatic or malignant. In this way, the present invention encompasses methods and compositions useful for the treatment or prevention of benign, premalignant, metastatic and malignant neoplasms, and for benign, premalignant, metastatic and malignant tumors. In general, it is known in the art that tumors are formed from a mass of neoplastic cells. However, it will be understood that, for purposes of the present invention, even a neoplastic cell is considered a neoplasm or as an alternative neoplasm. The amount or dosage of a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor is one that provides a therapeutically effective amount of the combination therapy. In one embodiment, the present invention provides a method for preventing a pathological condition or physiological disorder characterized by or associated with the neoplasm in a patient in need of such prevention, the method comprising administering to the subject an Hsp90 inhibitor alone or in combination with a PDE inhibitor. In any of the embodiments of this document that specifies the presence of or administration of an Hsp90 inhibitor and a PDE inhibitor, it is understood that the combination may optionally further comprise a Cox-2 inhibitor. As used herein, the term "prevention" refers to any reduction, no matter how small, of a subject's predisposition or risk of developing a neoplasm or disorder related to the neoplasm. For purposes of prevention in this document, the subject is one who is to a certain degree at risk for, or who is to some degree predisposed to, developing a neoplasia, a disorder related to the neoplasm or a complication related to the neoplasm.

As used herein, a subject who is "predisposed to" or "at risk of" developing a neoplasm or disorder or condition related to the neoplasm includes any subject who has a greater likelihood or statistical likelihood of such development. Such greater possibility or probability may be due to various factors, including genetic predisposition, diet, age, exposure to agents that cause neoplasia, physiological factors such as anatomical and biochemical abnormalities and certain autoimmune diseases, and the like. In another embodiment, the present invention provides a method for treating an existing pathological condition or physiological disorder characterized by or associated with the neoplasm in a subject in need of such treatment, the method comprising administering to the subject an inhibitor of Hsp90 in combination with a PDE inhibitor. The term "treat" means alleviating the symptoms, eliminating the cause of the symptoms, on a temporary or permanent basis, or altering or delaying the onset of symptoms. The term "treatment" includes relief of, or elimination of, the cause of, symptoms associated with any of the diseases or disorders described herein. In yet another embodiment, the present invention provides a method for preventing or treating a pathological condition or physiological disorder characterized by or associated with neoplasia in a subject in need of such prevention. or ... treatment - the method comprising administering to the subject an inhibitor of Hsp90 and a PDE inhibitor, and optionally a Cox-2 inhibitor, in combination with radiation therapy, for example conventional radiation therapy. Thus, in one embodiment, a combination of three forms of an Hsp90 inhibitor, a PDE inhibitor and radiation therapy is administered to a subject in need thereof. In another embodiment, a combination of four forms is administered. of an Hsp90 inhibitor, a PDE inhibitor, a Cox-2 inhibitor and radiation therapy to a subject in need of! same. As used herein, the term "Hsp90 inhibitor" includes any compound that inhibits, alters or degrades the activity of Hsp90 by altering a "client" protein complex associated with Hsp90 or interfering with the synthesis of Hsp90. In one embodiment, the compound inhibits Hsp90 through direct contact. In specific embodiments, such contact is at a singular point. In other cases, this contact implies multiple and different contacts with residues in the Hsp90 protein. In additional specific embodiments, such multiple and distinct contacts are with residues in the nucleotide binding zone of the evolutionarily conserved highly unusual protein. In a specific embodiment, the nucleotide is ATP. The compounds that have been previously described by the formulas (I) and (II) include Hsp90 inhibitor compounds and certain analogs thereof, all of which are capable of altering a "client" protein complex associated with Hsp90. As a group, these compounds can be referred to herein as "Hsp90 inhibitors" or "compounds that inhibit Hsp90". When an object compound is said to inhibit Hsp90, this means that the activity of Hsp90 is lower, in the presence of the compound than in the same conditions in the absence of such a compound. When it is said that an Hsp90 inhibitor has activity against Hsp90, this means that the Hsp90 inhibitor can alter a "client" protein complex associated with Hsp90.

A method for expressing the potency of a compound as an Hsp90 inhibitor is to measure the "Cl50" value of the compound. The Cl50 value of a compound that inhibits Hsp90 is the concentration of the compound that is required to decrease the activity of Hsp90 by half. Accordingly, a compound having a lower CI5o value is considered to be a more potent inhibitor than a compound having a higher Cl50 value. It has been discovered that certain compounds containing heterocycle, such as, but not limited to, pyrazole, pyrrole, imidazoi, oxazole, pyrazole, thiazole, isoxazole, triazole and furan compounds and certain analogs of such compounds, can inhibit Hsp90. Many of these compounds show their effect-inhibitor in low concentrations, -with IC50 values of Hsp90 inhibition in vitro of less than approximately 100 μ ?, some with IC50 values of less than approximately 50 μ ?, some with values of Cl50 of less than about 20 μ ?, and even some with Cl 50 values of less than about 2.5 μ ?. In some embodiments, the Hsp90 inhibitor or dual inhibitor of Hsp90 / Cox-2 is one of the compounds of formula (I) indicated in Table 1.

In other embodiments, the Hsp90 inhibitor or dual inhibitor of Hsp90 / Cox-2 is one of the compounds of formula (II) in Table 2. In still other embodiments, the Hsp90 inhibitor or dual inhibitor of Hsp90 / Cox-2 it is one of the compounds indicated in Table 3.

Ni O Table 1: Hsp90 inhibitor compounds and double inhibitory compounds of Hsp90 / Cox-2 of formula (I) Inhib.

Structure 1 Cl60 of N ° Name Qa Xa z "a Ga R207 R20" R209 R21 ° R21 of tura Hsp90 1 Cox-2 C c N c 0 phenyl nitrophenyl methyl 2-methyl-4- (4-nitrophenyl) -5- 1 renil-1, 3- oxazole 4- [4- (4- C c N cs fluorophenyl carboxyphenyl, fluorophenyl) -1,3-t-azo-2-yl-2-benzoic acid 4- [4- cc N cs fluorophenyl methoxy carbonyl (4-fluorophenyl) - 1, 3- 3-Phenyl (iazol-2-yl) -N-benzoate 4-methyl 4- [4- (4- cc N cs methoxyphenyl acetamido tenyl methoxyphenyl) -1,3-thiazole-2-ii] - ! 4-methylbenzamide 4- [3- c C C N trifluoromethyl aminophenyl (trifluoromethyl) - N 1 H -pyrazol-1-yl] phenylamide 1- (4-nitrophenyl) -3- N c C C N trifluoromethyl nitrophenyl i (trifluororhyethyl ) - 6 1 H-pyrazole 4- (3,5-dimethyl-cC N methyl methyl ethoxy 1H-pyrazole-1-N carbonylphenium il) benzoate of 7 ethyl N c C C N methyl methyl. aminosulfonyl 0 phenyl 4- (3,5-dimethyl-1 H -pyrazol-: 1-yl) benzenesulfon 8 amide: CNC c S phenyl methylphenyl 4- (4-methylphenyl) -2- g phenyl-1,3-thiazole - (4-chlorophenyl) - CCC c N chlorophenyl thienyl methylthiophenyl methyl 1-methyl-2- [4- (methylthio) phenyl] -3- 10 thien-2-yl-1H-pyrrole OR or Inhib.

STRUCTURE Clso de No. Name Q Xa Xa Ga R208 R2"9 R2 0 R2" of tura Hsp90 Cox-2 NN imidazole ethoxyphenyl phenyl 2,5 (2E) -2-cyano-3- CC c [3- (4-ethoxyphenol ) - propylamino 1-phenyl-1H-pyrrazol-4-yl] -N- [3- carbonium (1 H -amidazol-1-propene I) propylflprop-2- 18 nitrile enamide c C c NN Chlorophenyl bromide 5.0 (with R211) (with R207)) 3-bromo-2- (4-chlorophenyl) pyrrazol or [1,5-a] pyrimidn-5,7 (4H, 6H) - 19 dione c N c CS chlorophenol chromenone 2,5 3- [4- (4-chlorophenyl) -1, 3-thiazol-5-yl] -4H-20 cramen-4-one hydrobromide c CNC s dichlorophenyl pyrimidyl 2,5 N- [4- (3,4-dichlorophenyl) -1,3-thiazol-2-yl] pyridin-2-aminocarbon (2E) -2- [4- (4- c CN cs methoxy methoxy phenyl 1,25-hydroxy-3-: hydroxyphenyl aminopropene methoxyphenyl) -1,3-thiazol-2-yl] '3 - [(3-nitrile methoxyphenyl) amin or] prop-2 ene 22 nitrile N c NNN phenyl bromo 20 '- [(1EH5I dihydroxyphenyl bromo-2,4'-methylidenehydroxifexyt) methide] -2- (5-phenyl-aceto-2H-tetraazole-2-hydrazide 23) acetohydrazlda or Inhib.

STRUCTURE C o N ° Name Xa z * G ° R207 R21 ° R211 of tura Hsp90 Cox-2 2- ( { 5- [2,6-CNN c N chlorophenyl dimethylamino methyl 5,0 bis (dimethylamino) ethanone sulfanyl pyrimidyl-4-pyrirnidinyl] -4-methyl-4H-1,2,4-triazole-3 - tl.}. sulfanyl) -1- (4-chlorophenyl) -1- 31 ethanone N-. { (E) - [4- (1-cN-phenylmethylidene-methyl-10-methyl-1-imidazol-2-yl) -3-nitrophenyl-nitrophenyl] -methyl-3-nichiline N- [4- ( { (E ) -2- [4- c CN c S benzodioxolyl acetamido 5,0 (1,3-phenylcyanobenzodioxol-5-yl) -1,3-thiazol-2-yl] -ethenyl nitrile 2-cyanoethenyl-jamin 33 o) phenyl] acetamide ((3Z) -2-oxo3- c CCNN ethyl acetate phenyl 2,5 | [(3-phenyl-1 H- 'oxoindol H pyrazol-5-yl) carbonyl] hydraz acetazoid idrazide onoV-2,3-dihydro- 1 H- indoM-34 il) ethyl acetate 5-t4- (4- c) NCCS triazolylpyridyl chlorophenyl 20 chlorophenylVI, 3-thiazol-2-yl] -2- (1H-1,2,4-triazol-1-yl-pyridine 4- [2- (2- c C c CN carboxyethyl pyridyl carboxyphenyl, non-carboxyethyl) -5- (4-methoxyphenyl) -1 H- pyrrole-1- 36 Jj] benzoic! c C c NN 7-chlorophenyl Q 7-chloro-1-phenyl-c XT 4,5-di idro-1H-37 benzo [g] indazol OR t or K5 O or O o OR l \ - > OR or or or or or or o o Inhib.

STRUCTURE Clso de No. Name X "z R208 R209 R21D R211 of Hura Hsp90 Cox-2 N C c c N ethylcarboxyl 2H-benzo [h] pyrazolo [4,3- flisoquinoline-3-carboxylate of ethyl ethyl N c c c N methyl methyl 1,3-dimethyl-6-y2-propoxyphenyl) -1,5-dhydro-4H-pyrazolo [3,4- or 5,202 d] pyrimidin-4-one or (-) Table 2: Hsp90 inhibitor compounds and double inhibitory compounds of Hsp90 / Cox-2 of formula (II) In ib.

Structure of No. Name A 'A "E" Ja L "217 R219 R221 R222 R223 ture Hsp90 Cox- 2 1-fluor- CCCCC methylsulfonyl fiuoro 4- { (Z) -2- [4- (methylsul- tonyl) feni I] etenl.} b 203 encene 4-fluoro-c CN c C methylsulfonyl 0X0 fluoro N) - [4- (methylsulphonyl) phen Ijbenza 204 mida N- { 4- c CCNC methylsulfonyl 0X0 tkjoro fluorofen il ) -4- H (methylsulphyl) ben 205 zamide N- (4- c CNNC methylsulfonyl amino fluoro fluorophenyl) -imino- H 4- (methylsulphonyl) ben cenomet 206 anamina 4-chloro-c GNNC chlorine amino methylsulfonyl imino-N- [4- H (methylsul fonyl) phenyl] benzene ometan 207 mine c CCC c amino phenol trifluor 4- [2- (4- fiuorofen sulfonyl I) phenyl] b encenos ulfonami 208 da or OR or or Table 3: Hsp90 inhibitor compounds and double inhibitory compounds of Hsp90 / Cox-2 In certain embodiments, the present invention provides a novel method for preventing or treating a pathological condition or a physiological disorder characterized by or associated with. neoplasia, including colorectal cancer, lung cancer, and breast cancer. It has been found that certain heterocyclic compounds, such as, but not limited to, pyrazole, pyrrole, imidazole, oxazole, pyrazole, thiazole, isoxazole, triazole, and furan compounds, and analogues of said compounds, can inhibit the activity of Hsp90. Many of these compounds show their inhibitory effect at low concentrations, presenting values of IC5o of inhibition in vitro of Hsp90 of less than approximately 00 μ ?, some have IC50 values of less than approximately 50 μ ?, some have values of Cl50 of less of approximately 20 μ ?, and some have Cl50 values of less than approximately 2.5 μ ?. . In certain embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: C is C or N; Xa is C or N; Za is C, N or O; a is C or N; Ga is selected from the group consisting of C, N, O and S; at least one of Qa, Xa, Za, Ma, and Ga is C; R207, unless it is linked with R208 or R211 in a ring system, is selected from the group consisting of H, CrC7 alkyl, phenyl, amino, purinyl substituted with aminohydroxythioacetamidyl-, indolyl substituted with C1-C4 alkyl acetate oxoaceto hydrazide, thienyl substituted with halo, thienyl, triazolopyridyl, pyridyl, haloalkyl (C C4), C 1 -C 4 alkyl phenyl, halophenyl, halophenyl-sulfinylacetohydrazide, haloalkyl (CrC 4) phenylaminocarbonylamino, halophenyl-alkanesulfanyl (C 1 -C 4 -phenylalkylidene (C C 4) nitrophenyl, C 1 -C 4 alkoxyphenyl, CrC 4 alkylthiophenyl, C 1 -C 4 alkylsulfonylphenyl, halo (C 1 -C 4) alkoxy, C 1 -C 4 alkoxy-dialkyl (CrC 4), carboxamidyl, carboxyl (C 1 -C 4) alkyl, aminosulfonylphenyl, C 1 -C 4 alkoxycarbonyl, hydroxyphenyl and halohydroxyphenyl; R208, unless it is linked with R207 or R209 in a ring system, is selected from the group consisting of H, halo, C1-C4 alkyl, phenyl, amino, imidazolium substituted with C4 alkyl aminocarbonyl-alkene (C2 -C4) nit rile, imidazolium substituted with C 1 -C 4 alkyl cyano-alkenne (C 2 -C 4) nitrile, benzene substituted with dioxolyl, pyridyl, haloalkyl (C 1 -C 4), nitrophenyl, halophenyl, C 4 alkoxyphenyl, aminosulfonylphenyl, alkylsulfonylphenyl CrC 4, alkoxy C 1 -C4 halophenyl, C4-C4-alkyl nitrilophenium, C4-alkyl-sulphonyl-alkyl (CrC4), C-1-C4-alkoxy-carboxymethyl, C1-C4-alkoxy-hydroxyphenyl, and C1-C4-alkylthiophenyl; R207 and R208 are optionally joined to form a ring system selected from the group consisting of: and aryl, wherein Ia and TB are independently selected from the group consisting of C and S; R209, unless it is linked with R208 or R2 0 in a ring system, is selected from the group consisting of H, C1-C4 alkyl, phenyl, pyridyl substituted with dialkyl CrC4 amino alkane (C1-C7), Midazolyl substituted with oxohydrotiene alkanenamide (C 1 -C 7) oxoxyaminoothio (C 1 -C 10) alkyl, midazolyl substituted with oxohydrotiene, alkanoylaminooxo (C C 7) alkylamino (CrC 7) alkanamidyl (CrC 7) alkyl (C 1 -C 4) amino, furyl, thienyl, pyridyl, pyrimidyl, C 1 -C 4 alkyl phenyl, haloalkyl (CrC 4), halophenyl, C 4 alkoxyphenyl, C 1 -C 4 alkoxycarbonyl, carboxyl, aminocarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonylphenyl, C 1 -C 4 alkoxy (C 1 -C 4) alkyl ) phenyl, C 1 -C 4 alkyl aminophenyl, C 1 -C 4 alkyl, C 1 -C 4 alkane thiol, C 1 -C 4 alkoxy halophenyl and aminosulfonyl phenyl; R208 and R209 are optionally joined to form a ring system selected from the group consisting of: wherein Xb, Xc, and Xd are independently selected from the group consisting of C and N; R210, unless it is linked with R209 or R21 in a ring system, is selected from the group consisting of H, C1-C4 alkyl, phenyl, oxo, C4 alkyl, phenyl, C4 alkyl, thio, C1-C4 alkoxyphenyl, C 1 -C 4 alkyl aminophenyl, C 4 alkyl thiophenyl, halo alkyl (CrC 4), halophenyl, carboxyphenyl, aminocarbonyl, pyrrolyl substituted with phenylcarbonylamino, pyridyl substituted with carbonylamino, pyridyl substituted with CrC 4 alkyl, pyrimidyl substituted with dialkyl CrC 4 amino, thiofuryl, chromenone, pyrimidyl, pyridyl, carboxyalkyl (C 1 -C 4), C 1 -C alkoxy phenylamino alkene (C 1 -C 7) nitrile, nitrophenyl alkene (C 1 -C 4) amide, acetamidophenyl, acetamidophenylcyanyl alkenyl (Ci-C 4) nitrile, carboxyl alkoxy (Cr C 4) , C 1 -C 4 alkyl sulfonylphenyl, halo (C 1 -C 4) alkyl (C 1 -C 4) alkoxy, halophenyloxy, C 1 -C 4 alkoxy halophenyl, C 4 carbon alkoxy, C 1 -C 4 alkyl sulfonylhalophenyl, aminosulfonylphenyl, thiophenyl, amino cycloalkyl (C 1) -C7), C1-C4 alkoxy carbonylphenyl, C44 alkoxy carbonylamino (C 1 -C 7) cycloalkane, and C 1 -C 4 alkylcarboxyl; R209 and R2 0 are optionally joined together to form a ring system selected from the group consisting of: and aryl; R2, unless it is linked with R210 or R207 in a ring system, is selected from the group consisting of H, C1-C4 alkyl, phenyl, oxo, hydroxyl, halophenyl, haloalkyl (CrC4) phenyl, pyrimidyl substituted with C1 alkyl -C4 thio, pyridyl, carboxyphenyl, nitrophenyl, aminosulfonylphenyl, C 4 alkyl sulphonylphenyl, C 1 -C 4 alkylsulfonylhalophenyl, alkyl CrC 4 aminosulfonylphenyl, C 1 -C 4 alkyl sulfonylaminophenyl, C 1 -C 4 alkyl aminocarbonyl, aminocarbonylphenyl, halohydroxyphenylalkylidene (C C4) acetohydrazide, hydroxy (C1-C4) alkyl phenyl alkylidene (CrC4) acetohydrazide, CrC4 alkylcarbonylphenyl, C1-C4 alkoxy phenyl, haloalkoxy (CrC4) phenyl, C4 alkoxy alkoxyphenyl (C4), C1-C4 alkoxycarbonylphenyl, haloalkyl (C-1-C4) carbonyl-phenyl, C1-C4 alcohol and halophenyloxyacetohydrazide; R2 0 and R211 are optionally joined to form a ring system selected from the group consisting of: oxoaryl and cycloalkyl; R207 and R211 optionally join to form a ring system selected from the group consisting of: R is selected from the group consisting of H, halo and C 1 -C 4 alkoxy; R213 is selected from the group consisting of H and halo; R2 4 is selected from the group consisting of H and halo; R2 is selected from the group consisting of H, halo and CrC4 alkoxy; Y R216 is selected from the group consisting of H and C4-alkoxy; or a pharmaceutically acceptable salt or prodrug of said compound.

In certain embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Qa is C or N; Xa is C or N; Za is C, N or O; Ma is C or N; Ga is selected from the group consisting of C, N, O and S; at least one of Qa, Xa, Za, Ma, and Ga is C; R207, unless it is linked with R2 1 or R208 in a ring system, is selected from the group consisting of H, methyl, ethyl, isopropyl, pentyl, phenyl, amino, purinyl substituted with aminohydroxythioacetamidyl, indoiyl substituted with ethylacetaoxoacetohydrazide, chlorothienyl , thienyl, triazolpiridilo, pyridyl, trlfluorometilo, methylphenyl, bromophenyl, chlorophenyl, fluorophenyl, clorofenilsulfinilacetohidrazida, clorodimetoxifenilaminocarbonil-amino, clorofeniletanonasulfanilo, fenilmetilidennitrofenilo, methoxyphenyl, methylthiophenyl, diíerc-butylthiophenyl, methylsulfonyl-phenyl, dichloromethoxy, metoximetilpropilo, carboxamidyl, carboxyethyl, aminosulfonylphenyl, ethoxycarbonyl , hydroxyphenyl and dibromohydroxyphenyl; R208, unless it is linked with R207 or R209 in a ring system, is selected from the group consisting of H, bromo, methyl, phenyl, amino, imidazolyl substituted with propylaminocarbonyl-propenonitrile, imidazolyl substituted with propylcyanopropenenitrile, benzene substituted with dioxolyl , pyridyl, difluoromethyl, trifluoromethyl, nitrophenyl, bromophenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, aminosulfonylphenyl, methylsulfonylphenyl, methoxyfluorophenyl, methylnitrilphenyl, methylsulfonylmethyl, methoxycarboximidyl, methoxyhydroxyphenyl and methylthiophenyl; R207 and R208 are optionally joined to form a ring system selected from the group consisting of: and phenyl, wherein Ta and Tb are independently selected from the group consisting of C and S; R209, unless it is linked with R208 or R210 in a ring system, is selected from the group consisting of H, methyl, propyl, phenyl, pyridyl substituted with diethyldiaminopentane, imidazolyl substituted with oxohydrothienopentanamide oxodioxidiaminothiononyl, imidazolyl substituted with oxohydrothienopentanoylaminooxohexylaminohexanamidyl-methylamino, furyl, thienyl, pyridyl, pyrimidyl, methylphenyl, difluoromethyl, trifluoromethyl, chlorophenyl, fluorophenyl, ethoxyphenyl, methoxycarbonylphenyl, carboxyl, aminocarbonyl, methyl-aminocarbonyl, dimethylaminocarboyl, methylsulfonylphenyl, methoxy-methylphenyl, methyldiaminophenyl, methylethanethiol, methoxyfluoro-phenyl and aminosulfonylphenyl; R208 and R209 are optionally joined to form a ring system selected from the group consisting of: wherein X, Xo, and Xd are independently selected from the group consisting of C and N; R210, unless it is linked with R209 or R21 in a ring system, is selected from the group consisting of H, methyl, ethyl, phenyl, oxo, methylphenyl, methylthio, methoxyphenyl, butoxyphenyl, dimethylaminophenyl, methyldiaminophenyl, methylthiophenyl, trifluoromethyl, chlorophenyl, fluorophenyl, dichloro-phenyl, chlorofluorophenyl, carboxyphenyl, aminocarbonyl, pyrrolyl substituted with phenylcarbonyl-amino, pyridyl substituted with carbonylamino, methylpyridyl, pyrimidyl substituted with dimethylamino, thiofuryl, chromenone, pyrimidyl, pyridyl, carboxymethyl, methoxyphenylampropenenitrile, nitrophenyl-propenamide, acetamidophenyl , acetamidophenylcyanatinyl nitrile, carboxylmethoxy, methylsulfonylphenyl, trifluoromethylmethoxy, chlorophenyloxy, methoxyfluorophenyl, methoxycarbonyl, methylsulfonylfluoro-phenyl, aminosulfonylphenyl, thiophenyl, aminocyclohexyl, methoxycarbonylphenyl, methoxycarbonylaminocyclohexane and methylcarboxyl; R209 and R2 0 optionally join to form a ring system selected from the group consisting of: and phenyl; R211, unless it is linked with R210 or R207 in a ring system, is selected from the group consisting of H, methyl, phenyl, oxo, hydroxyl, chlorophenyl, fluorophenyl, trifluoromethylphenyl, methylthiopyrimidyl, pyridyl, carboxyphenyl, nitrophenyl, aminosulfonylphenyl, methylsulfonylphenyl, metilsulfonilhalo-phenyl, dimetilaminosulfonilfenilo, methylsulfonylaminophenyl, methyl-aminocarbonyl, aminocarbonylphenyl, bromodihidroxifenilmetiliden-acetohydrazide, hidroximetoxifenilmetilidenacetohidrazida, methyl-carbonylphenyl, methoxyphenyl, trifluoromethoxyphenyl, metoxietoxo-phenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, trifluoromethyl-carbonylphenyl, ethanol and bromofeniloxiacetohidrazida; R210 and R211 optionally join to form a ring system selected from the group consisting of: oxophenyl and cyclopentyl; R and R are optionally joined to form a system selected from the group consisting of: R is selected from the group consisting of H, chloro, fluoro, and methoxy; R213 is selected from the group consisting of H and halo; R214 is selected from the group consisting of H and fluoro; R215 is selected from the group consisting of H, chloro, fluoro, and methoxy; and R216 is selected from the group consisting of H and methoxy; or a pharmaceutically acceptable salt or prodrug of said compound. In certain embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Qa, Xa, Za and Ma are independently selected from the group consisting of C and N, where at least one of Qa, Xa, Za and Ma is C; Ga is N or S; R207, unless it is linked with R2 1 in a ring system, is selected from the group consisting of H, alkylaryl, substituted or unsubstituted heteroaryl, haloaryl-sulfinylacetohydrazide, haloarylaminocarbonyl amino, haloarylalkanesulfanyl and arylalkylidene nitroaryl; R208 is selected from the group consisting of H, halo, aryl, haloaryl, alkoxyaryl, substituted or unsubstituted heteroaryl and alkoxyhydroxyaryl; R, unless it is linked with R in a ring system, is selected from the group consisting of H, aryl, haloaryl, heteroaryl and alkoxyaryl; R2 0, unless it is linked with R209 in a ring system, is selected from the group consisting of H, aryl, substituted heteroaryl, alkoxyarylaminoalkenenitrile, and nitroarylalkenoamide; R209 and R210 are optionally joined to form a ring system constituted by R211, unless it is linked with R207 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted heteroaryl, halohydroxyarylalkylidene-acetohydrazide, haloaryloxyacetohydrazide and hydroxyalkoxyaryl-alkylddenacetohydrazide; and R207 and R2 1 are optionally joined to form a ring system consisting of - or a pharmaceutically acceptable salt or prodrug of said compound.

In certain embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Qa, Xa, Za and Ma are independently selected from the group consisting of C and N ,. where at least one of Qa, Xa, Za and Ma is C; Ga is N or S; R207, unless it is linked with R2 1 in a ring system, is selected from the group consisting of H, phenylethyl, triazolopyridyl, ethylacetateoxoindolacetohydrazide, aminohydroxylpurinylthioacetamidyl, chlorophenylsulfinylactohydrazide, chlorodimethoxyphenylaminocarbonylamino, chlorophenylethanesulfanyl and phenylmethylidenethrophenyl; R208 is selected from the group consisting of H, bromine, phenyl, bromophenyl, dichlorophenyl, pyridyl, benzodioxolyl, midazolepropylaminocarbonyl-propenenitrile and methoxyhydroxyphenyl; R209, unless it is linked with R2O in a ring system, is selected from the group consisting of H, phenyl, chlorophenyl, furyl and ethoxyphenyl; R210, unless it is linked with R209 in a ring system, is selected from the group consisting of H, phenyl, chromenone, pyrimidyl, pyridylcarbonylamino, dimethylaminopyrimidyl, pyrrolylphenylcarbonylamino, acetamidophenyl-cyanoethylene nitrile, methoxyphenylaminopropenonitrile and nitrophenyl-propenamide; R209 and R210 are optionally joined to form a ring system constituted by R2, unless it is linked with R207, in a ring system, selects from the group consisting of H, methyl, phenyl, bromodihydroxyphenylmethylidene-acetohydrazide, bromophenoxyacetohydrazide and hydroxymethoxyphenyl-methylidenacetohydrazide; and R207 and R211 are optionally joined to form a ring system constituted by or a pharmaceutically acceptable salt or prodrug of said compound. In other embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula II, wherein: A ', A ", Ea, Ja and La are independently selected from the group consisting of C and N; of Ea or Ja is N, then A ', A "and La are C; at least three of A ', A ", Ea, Ja and La are C; R2 7 is selected from the group consisting of H, C 4 alkyl, halo, C 1 -C 4 alkylsulfonyl, aminosulfonyl, C 1 -C 4 alkoxy and alkyl CrC 4 thio; R is selected from the group consisting of H, C1-C4 alkyl and alkoxy C1-C4; R219, unless it is linked in a ring system with R220, is selected from the group consisting of H, oxo, amino and C44 aicoxo; R220, unless it is linked in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, C1-C4 alkoxy, hydroxyalkyl (C-C4), C4-C4-alkyl nitrile, C4-C4-alkoxy phenyl, haloalcoxo (C 1 -C 4) and halophenyl alkoxy (C C 4); R219 and R220 are linked optionally to form a ring system selected from the group consisting of phenyl and halophenyl; R221 and R223 are independently selected from the group consisting of H and C 1 -C 4 alkoxy; and R222 is selected from the group consisting of H, halo, C1-C4 alkylsulfonyl, amino-sulfonyl, and Ci-C-amino alkyl; or a pharmaceutically acceptable salt or prodrug of said compound. In certain embodiments, the Hsp90 inhibitor comprises a compound having the structure shown in formula II, wherein: A ', A ", Ea, Ja and La are independently selected from the group consisting of C and N; if either of Ea or Ja is N, then A ', A "and La are C, at least three of A", A ", Ea, Ja and Ia are C; R217 is selected from the group consisting of H, methyl, chloro, methylsulfonyl, aminosulfonyl, methoxy and methylthio; R218 is selected from the group consisting of H, methyl and methoxy; R, unless it is linked in a ring system with R, is selected from the group consisting of H, oxo, amino and ethoxo; R220, unless it is linked in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, ethoxo, propoxo, hydroxyethyl, methylnitrile, methoxyphenyl, trifluoroethoxo and fluorophenylmethoxo; R219 and R220 optionally join to form a ring system selected from the group consisting of phenyl and difluorophenyl; R221 and R223 are independently selected from the group consisting of H and methoxy; "and" 'R222 is selected from the group consisting of H, fluoro, methylsulfonyl, aminosulfonyl and dimethylamino; or a pharmaceutically acceptable salt or prodrug of said compound. In other embodiments, the Hsp90 inhibitor comprises a compound selected from the group consisting of: and mixtures thereof. As shown above, ring substituent groups that join to form additional ring structures adjacent to the substituted ring are described with reference to chemical formulas that show wavy lines that cut to the ring to which the substituents are attached, instead through the bond joining the substituent group to the ring. Accordingly, the partial ring shown is the ring to which the substituent groups are shown bound in the general formula. As used herein, the term "alkyl", alone or in combination, means an alkyl radical, linear, cyclic or branched, which, unless otherwise indicated, typically contains from 1 to about 10 carbon atoms, and more typically from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. The cyclic alkyl radicals ("cycloalkyl") contain from 3 to about 7 carbon atoms, typically from 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkyl". it further encompasses spiro systems in which the cycloalkyl ring has a ring carbon atom in common with the seven-membered benzothiepine heterocyclic ring. The alkyl radicals may be optionally substituted with substituent groups as defined below. Examples of said substituted alkyl radicals include chloroethyl, hydroxyethyl, trifluoromethyl, cyanobutyl, aminopentyl, and the like.

The term "alkenyl" refers to an unsaturated, linear, cyclic or branched hydrocarbon radical containing at least one double bond. Unless otherwise indicated, said radicals typically contain from 2 to about 6 atoms. carbon, more typically from 2 to 4 carbon atoms, for example from 2 to 3 carbon atoms. Cyclic alkenyl radicals ("cycloalkenyl") have from 3 to about 10 carbon atoms, and include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The alkenyl radicals may be optionally substituted with substituent groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3 -hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like. The term "hydrido" denotes a single hydrogen atom, (H). A hydrido radical can be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals can be attached to a carbon atom to form a methylene radical (-CH 2 -). The term "halo" means a halogen group such as fluoro, chloro, bromo or iodo radicals. The term "haloalkyl" describes alkyl radicals which are substituted with a halo group as defined above. The monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are specifically embraced. A monohaloalkyl radical, for example, may have a bromo, chloro or fluoro group attached to the alkyl radical. The dihalo radicals may have two or more of the same halo group or a combination of different halo groups, and the polyhaloalkyl radicals may have more than two of the same halo group or a combination of different halo groups.

The term "hydroxyalkyl" describes a linear or branched alkyl radical having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. The terms "alkoxy" and "alkoxyalkyl" - describe linear or branched oxy containing radicals, each having alkyl portions of 1 to about 10 carbon atoms, such as a methoxy radical. The term "alkoxyalkyl" describes alkyl radicals having one or more alkoxy radicals attached thereto, to form for example a monoalkoxyalkyl or dialkoxyalkyl radical. The alkoxy or alkoxyalkyl radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" or "haloalkoxyalkyl" radicals. Examples of alkoxy and haloalkoxy radicals include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, wherein said rings may be attached together in a pendant manner or may be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term "heterocyclyl" or "heterocyclic" means a saturated or unsaturated mono- or multi-ring carbocycle in which one or more carbon atoms are substituted by N, S, P, or O. This includes, for example, such structures like in which Z, Z Z2 and 2? are C, S, P, O or Ñ, with the proviso that at least one of Z, Z Z2 and Z3 is distinct from carbon, although it is not O or S when it is joined to another Z atom by a double bond or when It is further understood that optional substituents are attached to Z, Z, Z2 or Z3 only when the Z atom is C. The heterocyclic radicals may be ring-shaped radicals containing saturated hetero atoms , partially saturated or unsaturated, wherein the heteroatoms are selected from N, S and O. Examples of saturated heterocyclic radicals include piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. Examples of unsaturated heterocyclic radicals, also referred to as "heteroaryl" radicals, include thienyl, pyryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, quinolinyl, isoquinolinyl, benzothienyl, indolyl and tetrazolyl. Radicals are also included in which a heterocyclic ring is fused with an aryl ring. Examples of condensed bicyclic radicals include benzofuran, benzothiophene, and the like. The term "sulfonyl", when used alone or attached to other terms such as "alkylsulfonyl", denotes the divalent radical -S02-. "Alkylsulfonyl" denotes an alkyl radical attached to a sulfonyl radical, wherein alkyl is defined as in the previous case. The term "arylsulfonyl" denotes a sulfonyl radical substituted with an aryl radical. The terms "sulfamyl" or "sulfonamidyl", when alone or attached to other terms such as "N-alkylsulfamyl", "N-arylsulfamyl", "?,? - dialkylsulfamyl" and "N-alkyl-N-arylsulfamyl" , denote a sulphonyl radical substituted with an amine radical, forming a sulfonamide (-S02NH2). The terms "N-alkylsulfamyl" and "?,? - dialkylsulfamyl" denote substituted sulfamyl radicals- with 1 to 2 alkyl radicals or a cycloalkyl ring. The terms "N-arylsulfamyl" and "N-alkyl-N-arylsulfamyl" denote sulfamyl radicals substituted, respectively, with an aryl radical, or with an alkyl radical and an aryl radical. The terms "carboxy" or "carboxyl", when used alone or attached to other terms, such as in "carboxyalkyl", denote -C02H. The term "carboxyalkyl" denotes a carboxy radical as defined above, attached to an alkyl radical. The term "carbonyl", when used alone or attached to other terms, such as in "alkylcarbonyl", denotes - (C = 0) -. The term "alkylcarbonyl" denotes a carbonyl radical substituted with an alkyl radical, for example CH 3 - (C = 0) -. "Alkylcarbonylalkyl" denotes an alkyl radical substituted with an alkylcarbonyl radical. The term "alkoxycarbonyl" means a radical containing an alkoxy group, attached via an oxygen atom to a carbonyl radical, for example (CH3) 3CO-C (= 0) - or - (0 =) C-OCH3. The term "alkoxycarbonylalkyl" denotes a radical having alkoxycarbonyl, as defined above, attached to an alkyl radical. Examples of said alkoxycarbonylalkyl radicals include (CH 3) 3CO-C (= 0) (CH 2) 2 - V - (CH 2) 2 (= 0) C-OCH 3. The term "amido" when used alone or attached to other terms such as "amidoalkyl", "N-monoalkylamido", "N-monoanlamido", "N, N-dialkylamido", "N-alkyl-N-arylamido" , "N-alkyl-N-hydroxyamido" and "N-alkyl-N-hydroxyamido-alkyl", denotes a carbonyl radical substituted with an amino radical. The terms "N-alkylamido" and "α, β-dialkylamido" denote amido groups that have been substituted with one or two alkyl radicals, respectively. The terms "N-monoarylamido" and "N-alk II-N-arylamido" denote amido-substituted radicals, respectively, - with an aryl radical, or with an alkyl and an aryl radical. The term "N-alkyl-N-hydroxyamido" denotes an amido radical substituted with a hydroxyl radical and with an alkyl radical. The term "N-alkyl-N-hydroxyamidoalkyl" denotes an alkyl radical substituted with an N-alkyl-N-hydroxyamido radical. The term "amidoalkyl" denotes an alkyl radical substituted with one or more amido radicals. The term "aminoalkyl" denotes an alkyl radical substituted with one or more amino radicals. The term "alkylaminoalkyl" denotes an aminoalkyl radical having the nitrogen atom of the amino group substituted with an alkyl radical. The term "amidino" denotes a radical -C (= NH) -NH2. The term "cyanoamidino" denotes a radical -C (= N-CN) -NH2. The term "heterocycloalkyl" denotes an alkyl radical substituted with heterocyclyl such as pyridylmethyl or thienylmethyl. The term "aralkyl" denotes an alkyl radical substituted with aryl such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl or diphenethyl. The terms benzyl and phenylmethyl are interchangeable. The term "alkylthyl" denotes a radical containing a linear or branched alkyl radical of 1 to about 10 carbon atoms, attached to a divalent sulfur atom. An example is methylthio, (CH3-S-). The term "alkylsulfinyl" denotes a radical - which contains a linear or branched alkyl radical of 1 to about 10 carbon atoms, linked to a divalent group -S (= 0) -. The term "alkylthioalkyl" denotes an alkylthio radical attached to an alkyl group, an example being methylthiomethyl. The terms "N-alkylamino" and "?,? - dialkylamino" denote amino groups that have been substituted with an alkyl radical or with two alkyl radicals, respectively. The term "acyl", when used alone or within a term such as "acylamino", denotes a radical provided by the residue after removal of the hydroxyl from an organic acid. The term "acylamino" denotes an amino radical substituted with an acyl group, an example being acetylamine (CH3C (= 0) -NH-). In any heterocyclyl or heteroaryl ring, the point of attachment to the molecule of interest may be in the heteroatom or in any other site of the ring. The term "oxo" means oxygen bound by double bond. As used herein, "organic halide" means a compound having fluorine, chlorine, bromine, iodine or astatine covalently coupled with an alkyl, alkenyl, alkynyl, alkoxy, aralkyl, aryl, carbonyl, cycloalkyl, benzyl, phenyl group, alicyclic or heterocyclic. As used herein, the term "carbamoyl" refers to a carbonyl group covalently bonded by the oxo carbon to an amino group.

As used in this document, the term "hydroxamate" refers to a carbonyl group covalently linked by the oxo carbon to an amino group, wherein the amino group is in turn attached to a hydroxyl group. The term "oxime" means a radical comprising = NOH.

The present invention encompasses methods and compositions comprising compounds that inhibit Hsp90 including, but not limited to, the following examples: 2-methyl-4- (4-nitrophenyl) -5-phenyl-1-, 3-oxazole; 4- [4- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoic acid; Methyl 4- [4- (4-fluorophenyl) -1,3-thiazol-2-yl] benzoate; 4- [4- (4-methoxyphenyl) -1,3-thiazol-2-yl] -N-methylbenzamide; 4- [3- (trifluoromethyl) -1 H -pyrazol-1-yl] phenylamine; 1- (4-Nitrophenyl) -3- (trifluoromethyl) -1 H-pyrazole; Ethyl 4- (3,5-dimethyl-1 H-pyrazol-1-yl) benzoate; 4- (3,5-dimethyl-1H-pyrazol-1-yl) benzenesulfonamide; 4- (4-methylphenyl) -2-phenyl-1,3-tiazole; 5- (4-chlorophenyl) -1-methyl-2- [4- (methylthio) phenyl] -3-thien-2-yl -1 H-pyrrole; 3- (trifluoromethyl) -2H-benzo [h] pyrazolo [4,3-f] isoquinine hydrochloride; 2 H -benzo [h] pyrazolo [4,3-f] isoquinoline-3-carboxamide dehydrate; 2- [(2-chlorophenyl) sulfinyl] -N- [4- (4-chlorophenyl) -1,3-thiazol-2-yl] acetamide; N- [5- (1-phenylethyl) -1,3-thiazol-2-yl] -4- (1H-pyrrol-1-yl) benzamide; N- (5-chloro-2,4-dimethoxyphenyl) -N '- (5-phenyl-1,3-thiazol-2-yl) urea; N '- [(4-bromophenoxy) acetyl] -2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; (2E) -2-cyano-3- [3- (2-furyl) -1-phenyl-1 H -pyrazol-4-yl] -N- [3- (1 H-imidazol-1-yl) propyl] prop-2-enamide; (2E) -2-cyano-3- [3- (4-ethoxyphenyl) -1-phenyl-1 H -pyrazol-4-yl] -N- [3- (1 H-imidazol-1-yl) propyl] prop-2-enamide; 3- bromo-2- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidin-5,7 (4H, 6H) -dione; 3- [4- (4-chlorophenyl) -1,3-thiazol-5-yl] -4 H -chromen-4-one; N- [4- (3,4-dichlorophenyl) -1,3-thiazol-2-yl] pyrimidin-2-amine hydrobromide; (2E) -2- [4- (4-hydroxy-3-methoxyphenyl) -1,3-thiazol-2-yl] -3 - [(3-methoxyphenyl) amino] prop-2-enonitrile; N4 (1E) - (5-bromo-2,4-dihydraxyphenyl) methylidene} -2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; 2 - [(2-amino-6-hydroxy-7H-purin-8-yl) thio] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; (2E) -3- (4-nitrophenyl) -N- (4-pyridin-4-yl-1,3-thiazol-2-yl) prop-2-enamide; N '- [(i ^) - (2-hydroxy-4-methoxyphenyl) methyl] inden] -2- (5-pheny1-2H-tetra-yl) acetohydrazide; 2- (3,5-dimethyl-1 H-pyrazol-1-N) -6-methyl-4-pyrimidintiol; N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] nicotinamide; N- (1,3-benzothiazoI-2-yl) -7-oxo-1-phenyl-1,7-dihydropyrazolo [1, 5a] pyrimidine-6-carboxamide; 2- ( { 5- [2,6-bis (dimethylamino) -4-pyrimidinyl] -4-methyl-4H-1, 2,4-triazol-3-yl}. SuIfanyl) -1- (4 chlorophenyl) -1-ethanone; N-. { (E) - [4- (1-methyI-1 H-imidazol-2-yl) -3-nitrophenyl] methylidene} aniline; N - ^ - ÍÍÍE ^ - ^ - ÍI. S-benzodioxol-S-i-l ^ -thiazol ^ -ill ^ -cianoetenilJamino) phenyl] acetamide; ((3Z) -2-oxo-3- { [(3-pheny! -1 H -pyrazol-5-yl) carbonyl] hydrazone.} -2,3-dihydro-1 H-indol-1-yl) ethyl acetate; 5- [4- (4-chlorophenyl) -1,3-thiazol-2-yl] -2- (1 H-1, 2,4-triazol-1-yl) pyridine; 4- [2- (2-carboxyethyl) -5- (4-methoxyphenyl) -1 H -pyrrol-1-yl] benzoic acid; 7-chloro-1-phenyl-4,5-dihydro-1 H -benzo [g] indazole; 2- (4-fluorophenyl) -4,5-dihydro-2H-benzo [g] indazole; 4- (7-chloro-4,5-dihydro-1H-benzo [g] indazol-1-yl) benzoic acid; 4- (7-chloro-4,5-dihydro-2H-benzo [g] indazol-2-yl) benzoic acid; 7-chloro-1-phenyl-4,5-dihydro-1 H -benzo [g] indazole-3-carboxylic acid; 1, 3-diphenyl-1 ^. S ^ -tetra idro-TH-indazo! -T-Gna; - 2- (4-methoxyphenyl) -5-methyl-1- (4-nitrophenyl) -1 H-pyrrole; 1- [4- [2- (4-fluorophenyl) -5-methyl-1 H-pyrrol-1-yl] phenyl] ethanone; . { 4- [2- (4-fluorophenyl) -5-methyl-1 H-pyrroyl-1H] phenyl} methyl acetate; acid (. {(1S, 3R) -3 - [(3,5-di-er-butylphenyl) thio] cyclopentyl} oxy) acetic acid; 6-fluoro-10- (methylsulphoryl) dibenz [b, f] thieno [3,4-d] oxepin; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1,3-thiazole; 1- (Methylsulfonyl) -4- (2-phenylcyclopent-1-en-1-yl) benzene; 5- (4-fluorophenyl) -3-methyl-1 - [4- (methylsulfonyl) phenyl] -1 H-1, 2,4-triazole; 2- (2-chlorophenyl) -5- [4- (methylsulfonyl) phenyl] -4-phenyl-1,3-thiazole; 4- [3- (4-chlorophenyl) -5- (trifluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 4- (3-methyl-5-phenyl-1 H-pyrazol-1-yl) benzenesulfonamide; 2 - [(3,5-dichlorophenoxy) methyl] -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1,3-thiazole; 1- [4- (methylsulfonyl) phenyl] -3-phenyl-5- (trifluoromethyl) -1 H-pyrazole; 2- etl-1- (4-flurophenyl) -5- [4- (methylsulfonyl) phenyl] -1 H-pyrrole; 4- [4,5-dihydro-3- (trifluoromethyl) -1 H -benz [g] indazol-1-yl] benzenesulfonamide; ~ 1- (4-fluorophenyl) -2- [4- (methylsulfonyl) phenyl] -5-pentyl-1 H-pyrrole; 1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -4,5-dihydro-1 H -benzo [g] indazole; 5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1 H-pyrazole; 1 - [4- (Aminosulfonyl) phenyl] -5- (4-fluorophenyl) -1 H -pyrazole-3-carboxylic acid; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -N, N-dimethyl-benzenesulfonamide; 4- [5- (4-methyphenyl) -3- (trifluoromethyl) -1 H-pyrrazol-1-yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -1 H-pyrrazol-1-yl-benzenesulfonamide; 4- [5- (2,5-dichlorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-ylbenzenesulfonamide; 5- (4-fluorophenyl) -1 - (4-nitrophenyl) -1 H -pyrazole-3-carboxamide; N- [4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] phenyl] methane sulfonamide; 5- (4-chlorophenyl) -1 - (4-nitrophenyl) -3- (trifluoromethyl) -1 H-pyrazole; 1 - [4- (Aminosulfonyl) phenyl] -5- (4-methylphenyl) -1 H-pyrazole-3-carboxylic acid methyl ester; 4- [5- (4-butoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoro-methyl) -5- (2-methoxy-2-methylpropyl) -1H-pyrazol-1-yl] -benzenesulfonamide; 4- [5- (4-fluorophenyl) -4-propyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; (5Z) -5- (2,2,2-trifluoro-1-hydroxyethylidene) -6,7-dihydro-1-benzothiophen-4 (5H) -one; 4- [5- (3,5-dimethoxyphenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-ylbenzenesulfonamide; Methyl 4- [5- (5-chlorothien-2-yl) -3- (trifluoromethyl) -1 H-pyrazol-1-yl] benzoate; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] methyl benzoate; 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -H-pyrazol-1-yl] -N-methylbenzamide; 4- [7-Ratraetoxy-3- (trifluoromethyl) -4,5-chloro-1-methyl-1H-benzo [g] inda2ol-1-yl] benzoate; 1- [4- (aminosulfonyl) phenyl] -5- (4-chlorophenyl) -N, N-dimethyl'-1H-pyrazole-3-carboxamide; .. | - - - - 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1H-imidazole; 1- [4- (aminosulfonyl) phenyl] -5- (4-chlorophenol) -N-methyl-1 H-pyrrazol-3-carboxamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1 H-pyrrazol-1-yl] benzamide; 4- [7-methoxy-3- (trifluoromethyl) -4,5-dihydro-1 H -benzo [g] indazol-1-yl] benzamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzamide; 4- (3,5-diphenyl-1 H-pyrazol-1-l) benzenesulfonamide; 1 - [4- (Methylsulfonyl) phenyl] -3-phenylamide [5,1 -jisoquinoline; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-methyldazole; 3- (3-fluoro-4-methoxyphenyl) -2- [4- (methylsulfonyl) phenyl] -1-benzofuran; 1- [4- (aminosulfonyl) phenyl] -1,4-dihydrothiochromene [4,3-c] pyrazole-3-carboxamide; 3- (3-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] imidazo [5,1 -jisoquinoline; 5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2-t-ene-3-yl-1H-imidazole; 2- (4-bromophenyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyljphenyl] -1 H -imidazole; 5- (4-fluorophenyl) -2- (4-methoxyphenyl) -4- [4- (methylsulfonyl) phenyl] -1 H -imidazole; 3- {4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1H-imidazol-2-yl} pyridine; 1,4-bis [4- (methylsulfonyl) phenyl] -2- (4-chlorophenyl) -1 H -imidazole; 2,5-bis (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -1,3-oxazole; 4- [2- (4-chlorophen-N) -1- [4- (methylsulfonyl) phenyl] -1 H -imidazol-4-yl] benzonitrile; 5- (4-fluorophenyl) -2-isopropyl-4- [4- (methylsulfonyl) phenyl] -1H-imidazole; 4- [3- (4-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 2- (Trifluoromethyl) pyrazolo [1,5-f] phenanthridin-9-suphonamide; 4- [3,5-bis (4-chlorophenyl) -1 H-pyrazole-1-N-benzenesulfonamide; 4- [7-fluoro-3- (trifluoromethyl) isothiochromeno [4,3-c] pyrazol-1 (5H) -yl] benzenesulfonamide; 4- (4-methoxy-3-methylphenyl) -5- [4- (methylsulfonyl) phenyl] -2- (tnfluoromethyl) -1H-imidazole; 7-fludro-1, 5'-dihydrb-1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) [2] benthio thrano [4,3-c] pyrazole; 4- (4-fluorophenyl) -1-methyl-5- [4- (methylsulfonyl) pheny] -2- (trifluoromethyl) -1H-imidazole; 2- (4-chlorophenyl) -4 - [(methylsulfonyl) methy!] -1- [4- (methylsulfonyl) phenyl] -1 H-imidazole; N, N-dimethyl-4- [4- [4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazol-5-yl] benzenamine; 2- (4-chlorophenyl) -N-methoxy-N-methyl-1- [4- (methylsulfonyl) phenyl] -1H-imidazole-4-carboxamide; 3- [1 - [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; 4- (5-arnino-3-phenyl-1 H-pyrazol-1-yl) benzenesulfonamide; acid { 4- (4-fluorophenyl) -2- [4- (methylthio) phenyl] -1,3-thiazol-5-yl} acetic; 2,2,2-Trifluoro-1 - [4- [5- (4-fluorophenyl] -3- (trifluoromethyl) -1 H -pyrazol-1-l] phenyl] ethanone; 1- (4-chlorophenyl) -3-methyl-5-phenyl-1 H-pyrazole; 4- [5- (4-chlorophenyl) -3-methyl-1 H -pyrazol-1-yl-benzenesulfonamide; acid . { 3- [4- (Methylsulfonyl) phenyl] -4-phenylisoxazole-5-yl} acetic; 4- (5-methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; 3- (4-chlorophenyl) -1- (4-methoxyphenyl) -1 H-pyrazoyl-5-carboxylic acid methyl; 4- [2- (methylthio) -4-phenyl-1,3-oxazole = 5-yl] benzenesulfonamide; - 4- [4-phenyl] -2- (2,2,2-trifluoroethoxy) -1,3-oxazol-5-yl] benzenesulfonamide; 4- [2- (3-chlorophenoxy) -4-phenyl-1,3-oxazol-5-yl] benzenesulfonamide; acid { 3- (3-fluoro-4-methoxyphenyl) -4- [4- (methylsulfonyl) phenyl] isoxazole-5-acetic acid; 4- [1- [4- (Methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazol-2-yl] ^ 4- [5- (4-methylphenyl) -1 H-1, 2,4- triazol-1 -yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -2-methyl-1,3-thiazol-4-yl] benzenesulfonamide; 4- [4- (4-Coryophenyl) -2-methyl-1,3-thiazol-5-yl] benzenesulfonamide; 4- [4-phenyl-5- (trifluoromethyl) isoxazol-3-yl] benzenesulfonamide and 4- [3-phenyl-5 (trifluoromethyl) isoxazol-4-yl] benzenesulfonamide (1: 1); 4- [2- (2-chlorophenyl) -4- (3-fluoro-4-methoxyphenyl) -1,3-thiazol-5-yl] benzenesulfonamide; 5- (3-fluoro-4-methoxyphenyl) -2-methyl-4- [4- (methylsulfonyl) pheny] -1,3-thiazole; 2- [4- (methylthio) phenyl] -3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo [1,2-a] midazole; 4- [5- (3-chloro-4-fluorophenyl) -2- (trifluoromethyl) -1,3-oxazol-4-yl] benzenesulfonamide; 2- [4- (methylisulfinyl) pheny1] -3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo [1J2-a] midazo 3- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -1 H-pyrazole; 4- (2-methyl-5-phenyl-1,3-oxazol-4-yl) pyridine; 4- (2-methyl-5-phene-1,3-thiazole-4-ii) pyridine; 4- [2- (4-chlorophenyl) -5-phenyl-1,3-oxazol-4-yl] pyridine; 4- [2- (4-Raetoxyphenyl) -5-phenyl-1,3-thiazol-4-yl] pyridine; 5- phenyl-4-pyridin-4-yl-1,3-thiazol-2-amine; 4-methyl-3- [1- [4- (methylsulfonyl) pheny] -4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; . . . . . . . 4- (2-phenyl-1 H-imidazol-1-yl) benzenesulfonamide; 4- [2- (4-methylpyridin-3-yl) -4- (trifluoromethyl) -1 H -amidazol-1-yl] benzenesulfonamide; 4- (5-methyl-4-phenyl-1, 3-oxazol-2-yl) benzenesulfonamide; 4- (2-oxo-4-phenyl-2,5-dihydrofuran-3-yl) benzenesulfonamide; 4- (3-methyl-4-phenyl-1 H -pyraz-5-yl) pyridine; 4- [1-phenyl-4- (trifluoromethyl) -1 H -imidazol-2-yl] pyridine; 4- . { 5- [4- (Methylsulfonyl) phenyl] -1 H -imidazol-1-yl} pyridine; 6- (5-amino-2-propoxyphenyl) -1,3-dimethyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 5- (4-fluorophenyl) -3-methyl-4- [4- (methylsulfonyl) phenyl] isoxazole; (1 S, 2R, 3R) -1-phenyl-3-pyridin-4-yl-2,3-dihydro-1 H-inden-2-carboxylate ethyl; 4- [5-methyl-3- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -5-methyl-1 H -pyrazol-4-yl ] pyridine; 4- [1- (4-fluorophenyl) -5-methyl-1H-pyrazol-3-yl] pyridine; 2- (4-fluorophenyl) -3-pyridin-4-ylindan-1-ol; 4-. { 5 - (- 4-fluorophenyl) -2- [4- (methylsulfinyl) phenyl] -1 H -imidazol-4-yl} pyridine 3- [1-phenyl-3- (trifluoromethyl) -1 H -pyrazol-5-yl] benzenesulfonamide; 3-methyl-1H-benzo [h] pyrazolo [4,3-f] ¡hequinolyl-1-yl chloride; 2,6-dibromo-4- [5- (4-fluorophenyl) -4-pyridyl-4-yl-1H-imidazol-2-yl] phenol; 4- [5- (4-fluorophenyl) -4-pyridin-4-yl-1 H-imidazol-2-ll] phenol; 3- (4-fluorophenyl) -4-pyridin-4-ylfuran-2 (5H) -one; 4- [3- (4-fluorophenyl) -1-methyl-1 H -pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4-. { 4- (4-fluorophenyl) -2- [4- (methylthio) phenyl] -1 H-imidazol-5-yl} pyridine; 4- [5-ierc-butyl-2- (4-fluorophenyl) -1H-pyrrol-3-yl] pyridine; 4- [4- (4-fluorophenyl) -1-methyl-1H-pyrazol-3-yl] pyridine; 1-methyl-3-phenyl-4-pyridin-4-yl-1, 5-dihydro-2H-pyrrol-2-one; 4- (4-fluorophenyl) -5-pyridin-4-yl-1,3-thiazol-2-amine dibromhydrate; 4- (4-fluorophenyl) -5-pyridyl-4-yl-1"; 3-oxazbl-2-amine; 4- (2-oxo-4-phenyl-2,3-dihydro- 1,3-oxazole-5-N) benzenesulfonamide; 4- (2-phenyl-1H-imidazol-1-yl) pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] benzenecarboximidamide; N ~ 1 ~, N ~ 1 ~ -diethyl-N ~ 4 ~ - { 4- [3- (4-fluorophenyl) -1 H -pyrazol-4-yl] pyridin-2-yl}. Pentane- 1,4-diamine; 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] thiophene-2-carboxylic acid methyl ester; 4- [5- (4-chlorophenyl) isoxazol-4-yl] pyridine; 4- [5- (benzyloxy) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- (4-chlorophenyl) -5-pyridin-4-yl-1,3-thiazole-2-dibromohydrate -amine; 2- {4- [3- (4-chlorophenyl) -4-pyrimidin-4-yl-1 H -pyrazol-5-yl] piperidin-1-yl} -2-oxoethanol dihydrochloride hydrate; 5- [3-fluoro-4- (methylsulfonyl) phenyl] -3- ^ 1 H-pyrazole; 5- [3-fluoro-4- (methylsulfonyl) phenyl] -1- [4- (trifluoromethoxy) phenyl] -3- (trifluoromethyl) -l H-pyrazole; 3- (difluoromethyl) -5- [3-fluoro-4- (rnetylsulfonyl) phenyl] -1- (4-fluorophenyl) -1H-pyrazole; 4- [1- (4-chlorophenyl) -3-methyl-1 H -pyrazol-5-yl] benzenesulfonamide; 4-amino-2,3'-bithiophene-5-carboxamide; 4- [1- (4-chlorophenol) -5-methyl-1 H -pyrazol-3-yl] benzenesulfonamide; 4- [1- (4-chlorophenol) -3-phenyl] -1H-pyrazol-4-yl] benzenesulfonamide; 4- [1- (4-chlorophenyl) -5-phenyl] -1H-pyrazol-4-yl] benzenesulfonamide; 3- (4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl] imidazo [5,1-a] isoquinoline 2H-berlzo [h] pyrazolo [4,3-f] isoquinolln-2-yl chloride; 2-metll-2H-benzo [h] plrazolo [4,3-f] isoquinollna; 5- . { [1 - [4- (aminosulfonN) phenyl] -5- (4-chlorophenyl) -1 H -pyrazol-3-yl] methyl} ethanethioate; 5- [(3aR, 4R, 6aS) -2-oxohexa idro-1 H-thieno [3,4-d] imidazol-4-yl] -N-. { 13- [1 - [4- (aminosulfonyl) phenyl] -5- (4-chlorophenyl) -1 H -pyrazol-3-yl] -10-oxo-3,6-dioxa-12-thia-9 azatridec-1 -il} pentanamide; 6- ( {5 - [(3aR, 4R, 6aS) -2-oxohexahydro-1 H-tleno [3,4-d] imidazol-4-yl] pentanoyl.] Amino) -N- [ 6- ( { [1- [4- (aminosulfonyl) phenn] -5- (4-chlorophenyl) -1 H -pi il] methyl} amino) -6-oxohexyl] hexanamide; 7-fluoro-2H-benzo [h] pyrazolo [4,3-flisoquinoline hydrochloride; 2-phenyl-2H-benzo [h] pyrrazolo [4,3-f] isoquinolin-6-io chloride; 2 H -benzo [h] pyrazolo [4, -3-f] quinoline; 2H-benzo [f] pyrazolo [3,4-h] isoquinoline; 2- (2-hydroxyethyl) -2H-benzo [h] pyrrazolo [4,3-f] isoquinolyl-6-yl chloride; benzo [h] lsoxazolo [4,3-f] ¡hequinolin-6-io chloride; 9-fluoro-2H-benzo [h] pyrazolo [4,3-f] isoquinoline hydrochloride; 9-chloro-2H-benzo [h] pyrazolo [4,3-f] isoquinoline hydrochloride; 3-piperidin-4-yl-2H-benzo [h] pyrazolo [4,3-f] ¡-quinoline; 9,10-dimethoxy-2H-benzo [h] pyrazolo [4,3-f] isoquinoline hydrochloride; 3-ethyl-2H-benzo [h] pyrazolo [4,3-fJisoquinoline; - 2 H -benzo [h] pyrazolo [4,3-fyssoquinoline-3-carboxylic acid ethyl ester; 1 > 3-dimethyl-6- (2-propoxyphenyl) -1 I5-dihydro-4H-pyrazolo [3,4-d] pyrimidine- ' 1-fluoro-4-. { (Z) -2- [4- (Methylsulfonyl) phenyl] ethenyl} benzene; 4- fluoro-N- [4- (methylsulfohyl) feriyl] benzamide; N- (4-fluorophenyl) -4- (methylsulfonyl) benzamide; N- (4-fluorophenyl) -imino-4- (methylsulfonyl) benzenemethanamine; 4-chloro-irnino-N- [4- (methylsulfonyl) phenyl] benzenemethanamine; 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide; 4 \ 5, -difluoro-4"-methoxy-3 ', -methyl, 1': 2 ', 1" -terphenyl-4-sulfonamide; 4 5'-difluoro-2-5-methylpyridin-2-n) -1,1'-biphenyl-4-sulfonamide; (3E) -4- [4- (Methylsulfonyl) phenyl] -3-phenylbut-3-en-2-ol; 4 - [(1 E) -3-oxo-2-phenylbut-1-enyl] benzenesulfonamide; 4 - [(1 E) -3-oxo-2-phenylpent-1-enyl] benzenesulfonamide; (2E) -3- [4- (Aminosulfonyl) phenyl] -2- (4-fluorophenyl) prop-2-enoic acid; 4 - [(E) -2-cyano-2-phenylethenyl] benzenesulfonamide; 4 - [(1 E) -3-oxo-2,3-diphenylprop-1-enyl] benzenesulfonamide; (3E) -3-phenyl-4-pyridin-4-ylbut-3-en-2-one; (2E) -1, 2-diphenyl-3-pyridin-4-ylprop-2-en-1 -one; 4 - [(1 E) -4,4,4-trifluoro-3-oxo-2-phenylbut-1-enyl] benzenesulfonamide; (3E) -1,11-trifluoro-3-phenyl-4-pyridin-4-ylbut-3-en-2-one; (3E) -4-phenyl-3-pyridin-4-ylbut-3-en-2-one; (3E) -4- (4-chlorophenyl) -3-pyridin-4-ylbut-3-en-2-one; (3E) -4- [4- (Methylthio) phenyl] -3-pyridin-4-ylbut-3-en-2-one; (3E) -4- (3,4-dimethoxyphenyl) -3-pyridin-4-ylbut-3-en-2-one; (3E) -4- (3,5-dimethoxyphenyl) -3-pyridin-4-ylbut-3-en-2-one; (2E) -1- (4-fluorophenyl) -3-phenyl-2-pyridin-4-ylprop-2-en-1-one; (3E) -4- [4- (dimethylamino) phenyl] -3-pyridin-4-ylbut-3-en-2-one; 2- [4- (3,5-dimethylphenoxy) -3,5-diiodophenyl] acetic acid; acid (. {(S, 3R) -3 - [(3,5-di-Cér-butylphenyl) thio] cyclopentyl} oxy) acetic acid; 1- [Cyclobutylidene (4-fluorophenyl) methyl] -4- (methylsulfonyl) benzene; 4- ( { [(4-chlorophenyl) amino] carbonyl.} Amino) benzenesulfonamide; 4 - [(E) - (2-oxo-3,4-dihydronaphthalen-1 (2H) -lidene) methyl] benzenesulfonamide; 2- (5-amino-2-propoxyphenyl) -8-methoxyquinazolin-4 (3H) -one; (1S, 2R, 3R) -1-phenyl-3-pyridin-4-yl-2,3-dihydro-1 H-inden-2-carboxylic acid ethyl ester; 6,8-dichloro-2S- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; benzo [h] pyrido [4,3-t] quinazolin-2-amino chloride or; and mixtures thereof. The present invention encompasses process and compositions comprising compounds that inhibit Hsp90 selected from the group consisting of. 2 - [(2-chlorophenyl) sulfinyl] -N- [4- (4-chlorophenyl) -1,3-thiazol-2-yl] acetamide; N- [5- (1-phenylethyl]) -1,3-thiazol-2-yl] -4- (1 H -pyrrol-1-yl) benzamide; N- (5-chloro-2,4-dimethoxy-phenyl) -N '- (5-phenyl-1,3-thiazol-2-yl) urea; N '- [(4-bromophenoxy) acetyl] -2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; (2E) -2, cyano-3-y3- (2-furyl) -1-phenyl-1 H ^ p¡razol-4-yl] -N- [3- (1 H-imidazol-1-yl) propylJprop -2-enamide; (2E) -2-cyano-3- [3- (4-ethoxyphenyl) -1-phenyl-1 H -pyrazol-4-yl] -N- [3- (1 H-imidazol-1-yl) propyl] prop-2-enamide; .. - 3-bromo-2- (4-chlorophenyl) pyrazolo [1,5-a] pyrimidine-5,7 (4H, 6H) -dione; 3- [4- (4-chlorophenyl) -1,3-thiazol-5-yl] -4 H -chromen-4-one; N- [4- (3,4-dichlorophenyl) -1,3-thiazol-2-yl] pyrimidin-2-amine hydrobromide; (2E) -2- [4- (4-hydroxy-3-methoxyphenyl) -1,3-thiazol-2-yl] -3 - [(3-methoxyphenyl) aminolprop-2-iorium "nitrile; N '- [ (1EH5-bromo-2,4-dihydroxyphenyl) methylidene] 2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; 2 - [(2-amino-6-hydroxy-7H-purin-8-yl) thio] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; (2E) -3- (4-nitrophenyl) -N- (4-pyridin-4-yl-1,3-thiazole -2-1) prop-2-enamide; N '- [(1E) - (2-hydroxy-4-methoxyphenyl) methylidene] -2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] nicotinamide; N- (1,3-benzothiazol-2-yl) -7-oxo-1-phenyl-1, 7- dihydropyrazolo [1, 5a] pyrimidine-6-carboxamide; N- { (E) - [4- (1-methyl-1H-imidazol-2-yl) -3-nitrophenyl] methylidene} ani N - [4- ( { (E 2- [4- (1, 3-benzodioxol-5-yl) -1, 3-thiazol-2-yl] -2-cyanoethenyl}. Amino) phenyl] acetamide; ((3Z) -2-oxo-3 { [(3-phenyl-1 H -pyrazol-5-yl) carbonyl] hydrazone.} -2,3-dihydro-1 H-indole-1 -il) ethyl acetate: 5- [4- (4-chlorophenyl) -1,3-thiazol-1-yl) pyridine; and mixtures thereof. The present invention encompasses methods and compositions comprising compounds that inhibit Hsp90 selected from the group consisting of - - (2E) -2- [4- (4-hydroxy-3-methoxyphenyl) -1,3-thiazol-2-yl] -3 - [(3-methoxyphenyl) amino] prop-2-enonitrile; 2 - [(2-amino-6-hydroxy-7H-punn-8-yl) thio] -N- (4-phenyl-1,3-thiazol-2-yl) acetamide; N '- [(1E) - (2-hydroxy-4-methoxyphenyl) methylidene-3-2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; and mixtures thereof. Many of the Hsp90 inhibiting compounds described above can be synthesized by those skilled in the art in accordance with the procedures described in the patents cited individually below and incorporated herein by reference. U.S. Patent No. 5,466,823. U.S. Patent No. 5,504,215. U.S. Patent No. 5,508,426. U.S. Patent No. 5,510,496. U.S. Patent No. 5,719,163. U.S. Patent No. 5,756,529. U.S. Patent No. 5,760,068; - U.S. Patent No. 5,859,257. U.S. Patent No. 5,935,598. U.S. Patent No. 5,985,902. U.S. Patent No. 6,028,072.

U.S. Patent No. 6,090,834. U.S. Patent No. 6,156,781. U.S. Patent No. 6,413,960. U.S. Patent No. 6,492. 411. - U.S. Patent No. 6,586,603. In certain embodiments, the present invention provides novel methods and compositions useful therein for preventing or treating a pathological condition or physiological disorder characterized by or associated with the neoplasm in a subject that is in need of such prevention or treatment. Such methods comprise administering to the subject an Hsp90 inhibitor, a PDE inhibitor and a Cox-2 inhibitor. The present invention also encompasses therapeutic combinations comprising an Hsp90 inhibitor, a PDE inhibitor and a Cox-2 inhibitor. The present invention also encompasses pharmaceutical compositions comprising an Hsp90 inhibitor, a PDE inhibitor, a Cox-2 inhibitor and a pharmaceutically acceptable carrier. In one embodiment, the present invention provides a method for preventing or treating a pathological condition or physiological disorder characterized by or associated with neoplasia in a subject, the method comprising administering to the subject an inhibitor of Hsp90 in combination with a de-PDE inhibitor, where the Hsp90 inhibitor is a dual inhibitor of Hsp90 / Cox-2. The terms "cyclooxygenase-2 inhibitor" and "Cox-2 inhibitor", which may be used interchangeably herein, indicate compounds that inhibit the enzyme cyclooxygenase-2 (Cox-2) independently of the degree of inhibition of the enzyme cyclooxygenase-1 (Cox-1), and include pharmaceutically acceptable racemates, enantiomers, tautomers, salts, esters and prodrugs thereof compounds Thus, for the purposes of the present invention, a compound is considered a Cox-2 inhibitor although the compound inhibits Cox-2 to an extent equal to, greater or less than what Cox-1 inhibits. Therefore, in this document Cox-2 inhibitors encompass many traditional non-selective NSAIDs (non-steroidal anti-inflammatory drugs). Suitable NSAIDs include ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, thioxaprofen, suprofen, alminoprofen, thiaprofenic acid, fluprofen, bucilloxic acid, indomethacin, sulindac, tolmetin, zomepiraco, diclofenac, fenclofenac, alclofenac, ibufenac, soxepaco, furofenac, tiopinaco, zidometacin, acetylsalicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, derivatives. of podofillotoxin, acemetacin, droxicam, floctafenin, oxifenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazaco, clidanaco, oxipinaco, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, magnesium choline trisalicylate , salieílate, benorilate; -fentiazaco, clopirtaco, feprazone, isoxicam, 2-fluoro-a-methyl [1, 1'-biphenyl] -4-acetic acid, 4- (nitroxy) butyl ester (See Wenk et al (2002) Europ. J Pharmacol 453,319-324, incorporated herein by reference) and mixtures thereof.

Particular NSAIDs of interest include ibuprofen, naproxen, sulindac, ketoprofen, fenoprofen, thiaprofenic acid, suprofen, etodolac, carprofen, ketorolac, piprofen, indoprofen, salicylic acid, flurbiprofen, and mixtures thereof. -. - Other Cox-2 inhibitors useful in accordance with the embodiments of the present invention are agents and compounds that selectively or preferably inhibit Cox-2 to a greater degree than with that which inhibits Cox-1. Such agents and compounds are referred to herein as "selective Cox-2 inhibitors". "In practice, in an assay for the selectivity of a selective Cox-2 inhibitor, the observed selectivity varies depending on the conditions under which the assay is performed and the compound to be assayed, however, for the present purpose, the The selectivity of a Cox-2 inhibitor can be measured as the ratio of the Cl50 value in vitro or in vivo for the inhibition of Cox-1, divided by the corresponding Cl50 value for the inhibition of Cox-2 (IC50 of Cox-1). / Cox-2 Cl50.) Thus, in this document a selective Cox-2 inhibitor is any inhibitor for which the IC50 value of Cox-I / IC50 of Cox-2 is greater than 1. In various embodiments , this ratio is greater than about 2, greater than about 5, greater than about 10, greater than about 50, or greater than about-1-T? - The term "IC50" with respect to a Cox-2 inhibitor is referred to to the concentration of a compound that is required to produce 50% of the i inhibition of Cox-1 or Cox-2 activity. In various embodiments, the selective Cox-2 inhibitors useful in the present invention can have a Cl50-Cox-2 value of less than about 1 μ ?, less than about 0.5 μ? or less than about 0.2 μ ?. The selective Cox-2 inhibitors useful in the present invention can have a Cl50 value of Cox-1 of more than about 1-μ ?, for example of more than about 20 μ ?. Cox-2 inhibitors that show a high degree of selectivity for the inhibition of Cox-2 over Cox-1 may indicate the ability to reduce the incidence of side effects induced by common NSAIDs. A selective Cox-2 inhibitor can be used in the form of a prodrug thereof. In the present context, a "prodrug" is a compound that can be converted to a selective inhibitor of active Cox-2 by simple metabolic or chemical procedures in the subject's body. An example of a prodrug for a selective Cox-2 inhibitor is parecoxib, for example in the form of a salt such as parecoxib sodium, which is a therapeutically effective prodrug of the selective tricyclic Cox-2 inhibitor valdecoxib. A class of prodrugs of selective Cox-2 inhibitors is described in U.S. Patent No. 5,932,598 incorporated herein by reference. In one embodiment, the selective Cox-2 inhibitor is meloxicam or a pharmaceutically acceptasalt or prodrug thereof. In another embodiment, the selective Cox-2 inhibitor is RS 57067 (6 - [[5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrol-2-yl] methyl] -3 (2H) pyridazinone) or a pharmaceutically acceptasalt or prodrug thereof. In another embodiment, the selective Cox-2 inhibitor is of the chromene or chroman structural class which is a substituted benzopyran or a substituted benzopyran analog, for example selected from the group consisting of benzothiopyrans, dihydroquinolines and substituted dihydronaphthalenes. These compounds may have a structure as shown in any of the following formulas (III), (IV), (V), (VI), (Vll) and (VIII), -and as illustrated in Ta4, and they can be diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs of such compounds. The benzopyrans that can serve as the selective COX-2 inhibitor of the present invention include substituted benzopyran derivatives which are described in US Pat. No. 6,271,253, which is incorporated herein by reference. One such compound class is defined by the general formula shown below in formula (III): wherein: X1 is selected from O, S, CRcRb and NRa, where Ra is selected from hydrido, CrC3l alkyl (optionally substituted phenyl) -C1-C3 alkyl, acyl and carboxyC C6 alkyl; and wherein each of Rb and Rc is independently selected from hydrido, C1-C3 alkyl, phenyl-C1-C3 alkyl, C3 perfluoroalkyl, chloro, C- | -C6 alkyl, thio, C2C0 alkoxy, nitro, cyano and cyano -C C3 alkyl; or wherein CRbR ° forms a cycloalkyl ring of 3-6 members; R is selected from carboxy, aminocarbonyl, C6 alkyl sulphonylaminocarbonyl and C6 carbonyl alkoxy; R2 is selected from hydrido, phenyl, -thienyl, C6-alkyl, and C2-aikenyl.

R3 is selected from perfluoroalkyl CrC3, chloro, C1-C6 alkyl thio, Ci-C6 alkoxy, nitro, cyano and cyano-CrC3 alkyl; - - R4 is one or more radicals independently selected from hydrido, halo, C C6 alkyl, aiquenilo C2-C6 alkenyl, C2-C6, halo-C2-C6 alkynyl, CRC3 aryl-, aryl-C2-C6 alkynyl, aryl- C2-C6 alkenyl, C1-C6 alkoxy, methylenedioxy, alkyl C- | -C6 alkylthio, sulfinyl Cpce, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, alkoxy C ^ alkyl SCOR-Ce, aryl-C C6 alkyloxy, heteroaryl-alkyl- C C6 alkyloxy, aryl-alkoxy-Ci-C6 alkyl C C6, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, haloalkyl C C6 alkylthio, C C6 alkylsulfinyl, C C6 haloalkylsulfonyl, haloalkyl CRC3-C3 hydroxyalkyl, hydroxy Ci- C6 alkyl hydroxyimino-C C6L C6 alkyl C amino, arylamino, aryl-C C6 alkylamino, heteroarylamino, heteroaryl-Ci-C6 alkyl amino, nitro, cyano, amino, aminosulfonyl, C C6 alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl- Ci-C6 alkylsulfonyl, heteroaryl-Ci-C6 alkylsulfonyl, heterocyclylsulphonyl, CrC6 alkyl sulfonyl, aryl-C6 alkyl alkyls sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Ci-C6 alkylcarbonyl, heteroaryl-alkyl- CRC6 carbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, alkoxy C Ci alkoxycarbonyl, formyl, haloalkyl Ci-C6 alkoxycarbonyl and alkyl C- | -C6 carbonyl; and the atoms A1, A2, A3 and A4 of ring A are independently selected from carbon and nitrogen with the proviso that at least two of A1, A2, A3 and A4 are carbon; or R4 together with the ring A forms a radical selected from naphthyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxallyl and dibenzofuryl; or a pharmaceutically acceptable salt thereof or thereof. Another class of benzopyran derivatives that can serve as the selective COX-2 inhibitor of the present invention includes a compound having the structure of formula (IV) :. - wherein: X2 is selected from O, S, CR ° Rb and NRa; where Ra is selected from hydrido, C1-C3 alkyl, (optionally substituted phenyl) -alkyl or C1-C3, alkylsulfonyl, phenylisulfonyl, benzylisulfonyl, acyl and carboxy-C-i-Ce alkyl; and wherein each of Rb and R ° is independently selected from hydrido, C1-C3 alkyl, phenyl-C1-C3 alkyl, C1-C3 perfluoroalkyl, chloro, alkyl CrC6 thio, Ci-Ce alkoxy, nitro, cyano and cyano-alkyl C1-C3; or wherein CRcRb forms a cyclopropyl ring; R5 is selected from carboxyl, aminocarbonyl, CrC6 alkyl sulfonylaminocarbonyl and C-i-Ce carbonyl alkoxy; R6 is selected from hydrido, phenyl, thienyl, C2-C6 alkynyl and alkenyl C2-C6; R7 is selected from perfluoroalkyl C1-C3, chloro, C1-C6 alkylthio, C1-C6alkoxy, nitro, cyano, and cyano-C1-C3alkyl; R8 is one or more radicals independently selected from hydrido, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl-C1-C3 alkyl, aryl-C2-C6 alkynyl , C2-C6 aryl-alkenyl, C1-C6 alkoxy, methylenedioxy ,. alkyl C C6 alkylthio, C C6 haloalkylsulfinyl, -0 (CF2) 20-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 6 -alkyl alkoxy CRC6, aryl alkyl oxy CRC6, heteroaryl-alkyl- CRC6 oxy, aryl-Ci- alkoxy C6-C6alkyl, Ci-C6haloalkyl, haloCalkoxy CrC6 > haloalkyl Ci-C6 thio, haioalkyl C C6 sulfinyl, haloalkyl C-t-C6 sulfonyl, haloalkyl CrC3-hydroxyalkyl C1-C3, hydroxyalkylene CrC6, hydroxyimino-C6alkyl, Ci-C6alkylamino, arylamino, aryl-C1-C6alkylamino, heteroarylamino, heteroaryl-C6alkylamino, nitro, cyano, amino, aminosulfonyl C, C6 alkylsulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C6 alkylsulphonyl, heteroaryl-C6-alkylsulphonyl, heterocyclylsulfonyl, C6-alkylsulphonyl, aryl-CiC-6alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-alkyl CrC6 carbonyl, heteroaryl-C6-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, CrC6-alkoxycarbonyl, formyl, C1-C6-haloalkylcarbonyl and CrC6-alkylcarbonyl; and atoms D1, D2, D3 and D4 of the D ring are independently selected from carbon and nitrogen with the proviso that at least two of D1, D2, D3 and D4 are carbon; or R8 together with the ring D forms a radical selected from naphthyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or a pharmaceutically acceptable salt thereof. Other selective benzopyran COX-2 inhibitors useful in the practice of the present invention are described in U.S. Patent Nos. 6,034,256 and 6,077,850, which are incorporated herein by reference. The general formula for these compounds is shown in formula (V): wherein: X3 is selected from the group consisting of O or S or NRa where Ra is alkyl; R9 is selected from the group consisting of H and aryl; R10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R11 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 R 12 is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyl-oxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroaryl-amino, heteroarylalkyl , 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 R12 together with the ring E forms a naphthyl radical; or an isomer or a pharmaceutically acceptable salt thereof; and including diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof. A class of related compounds useful as selective inhibitors of COX-2 in the present invention is described by the formulas (VI) and (VII): wherein: X4 is selected from O or S or NRa where Ra is alkyl; R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarborylamine; 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 R15 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 R together with the ring G forms a naphthyl radical; or an isomer or a pharmaceutically acceptable salt thereof. The formula (VII) is: wherein: X5 is selected from the group consisting of O or S or NRb where R is alkyl; R 6 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R17 se. selects from, the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein each of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and R18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyoxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl , alkylaminosulfonyl, aryl-aminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkyl-amnesulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl; or in which R. together with the ring A forms a naphthyl radical; or an isomer or a pharmaceutically acceptable salt thereof. The selective COX-2 inhibitor can be a compound of formula (VII), in which: ... - X5 is selected from the group consisting of oxygen and sulfur; R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R17 is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and R18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitroL amino, aminosulfoniio, lower aicylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, araiquiiaminosuiphenyl, heterocyclosulfonyl containing 5 membered nitrogen, heterocyclosulfonyl containing 6 membered nitrogen, lower alkyl sulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or R 8 together with ring A forms a naphthyl radical; or an isomer or a pharmaceutically acceptable salt thereof. The selective COX-2 inhibitor can be a compound of formula (VII), wherein: X5 is selected from the group consisting of oxygen and sulfur; R16 is carboxyl; R 7 is lower haloalkyl; and R 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 heteroarylalkylamine sulfonyl, lower aralkylamino -sulfonyl, lower alkyl sulfonyl, 6-membered nitrogen-suifonyl-containing heterocycle, optionally substituted phenylene, lower aralkylcarbonyl, and lower alkylcarbonyl; or R18 together with ring A forms a naphthyl radical; or a pharmaceutically acceptable isomer or sai thereof. The selective COX-2 inhibitor can be a compound of formula (VII), wherein: X5 is selected from the group consisting of oxygen and sulfur; R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R17 is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl and trifluoromethyl; and R 8 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, fer-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tert-butyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N, N-dimethylamino,?,? -diethyl-amino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) aminosulfonyl, nitro,?,? -dimethylaminosulfonyl, aminosulfonyl, N -methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl,?,? -dimethylaminosulfonyl, N- (2-methylpropyl) aminosulfonyl, Nrmorpholinesulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or R18 together with ring A forms a naphthyl radical; or an isomer or a pharmaceutically acceptable salt thereof. - ----. The selective COX-2 inhibitor can be a compound of formula (VII), wherein: X5 is selected from the group consisting of oxygen and sulfur; R16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R 7 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; and R18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoro-methyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethyl-aminosulfonyl , N- (2-furylmethyl) aminosulfonyl,?,? - dimethylaminosulfonyl, N-methylaminosulfonyl, N- (2,2-dimethylethyl) aminosulfonyl, dimethyl-aminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinesulfonyl, methylsulfonyl, benzylcarbonyl and phenyl; or R 8 together with ring A forms a naphthyl radical; or an isomer or prodrug thereof. Another class of benzopyran derivatives that can serve as the selective COX-2 inhibitor of the present invention includes a compound having the structure of formula (VIII): wherein: X6 is selected from the group consisting of O and S; R19 is lower haloalkyl; R20 is selected from the group consisting of hydrido and halo; R 2 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxyl, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, heteroaralkull lower-aminosulfonyl, heterocyclosulfonyl containing 5-membered nitrogen, and heterocyclosulfonyl containing 6-membered nitrogen; R22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy and aryl; and R23 is selected from the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl; or an isomer or prodrug thereof. The selective COX-2 Inhibitor can be a compound of formula (VIII), wherein: X6 is selected from the group consisting of O and S; R19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R20 is selected from the group consisting of hydrido, chloro and fluoro; R is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, fer-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethyl-aminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl and morpholinosulfonyl; R22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, terebutyl, chloro, methoxy, diethylamino and phenyl; and R23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl; ethyl, fer-butyl, methoxy and phenyl; or an isomer or prodrug thereof. Table 4. Examples of selective chromene Cox-2 inhibitors In other embodiments, the selective COX-2 inhibitor can be selected from the class of selective COX-2 tricyclic inhibitors represented by the general structure of formula (IX): wherein: Z1 is selected from the group consisting of unsaturated or partially unsaturated heterocyclyl and unsaturated or partially unsaturated carbocyclic rings; R24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R24 is optionally substituted in 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; R25 is selected from the group consisting of methyl and amino; and R26 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, alkoxyalkyl aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl , aicylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N -aralkyl-aminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkyl uylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and pharmaceutically acceptable salts and prodrugs thereof. The selective COX-2 inhibitor of formula (IX) can be selected from the group of compounds illustrated in Table 5, which includes celecoxib (B ~ 18), valdecoxib (B-19), deracoxib (B-20), rofecoxib (B-21), etoricoxib or MK-663 (B-22) and JTE-522 (B-23), and pharmaceutically acceptable salts and prodrugs of the same. Additional information on these selective COX-2 inhibitors can be found in the patents cited individually below and incorporated herein by reference. U.S. Patent No. 5,466,823. U.S. Patent No. 5,840,924. International Patent Publication No. WO 00/25779. International Patent Publication No. WO 98/03484. Table 5. Examples of selective tricyclic Cox-2 inhibitors No. Structural formula B-18 CF3 is selected from the group consisting of celecoxib, rofecoxib and etoricoxib. In one embodiment of the invention, parecoxib (see, for example, U.S. Patent No. 5,932,598), which is a therapeutically effective prodrug of the selective tricyclic Cox-2 inhibitor valdecoxib, B-19 (see, e.g. , U.S. Patent No. 5,633,272), can be advantageously employed as a source of a Cox-2 inhibitor. Parecoxib can be used as a salt, for example parecoxib sodium.

In another embodiment of the invention, the compound ABT-963 having the formula: described above in International Patent Publication No. WO 00/24719, is another selective tricyclic COX-2 inhibitor that can be used advantageously. Examples of specific compounds that are useful as a selective COX-2 inhibitor include, but are not limited to: 8-acetyl-3- (4-fluorophenyl) -2- (4-methylsulfonyl) phen-imidazo (1,2-a) pyridine; 5,5-dimethyl-4- (4-methylsulfonyl) phenyl-3-phenyl-2- (5H) -furanone; 5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) pyrazole; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -1-phenyl-3- (trifluoromethyl) pyrazole; 4- (5- (4-chlorophenol) -3- (4-methoxyphenyl) -1H-pyrazol-1-yl) benzenesulfonamide; 4- (3,5-bis (4-methylphenyl) -1 H -pyrazol-1-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3-phenyl-1 H-pyrazol-1-yl) benzenesulfonamide; 4- (3,5-bis (4-methoxyphenyl) -1 H -pyrazol-1-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (4-methylphenyl) -1 H-pyrazolyl-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (4-nitrophenyl) -1 H -pyrazol-1-yl) benzenesulfonamide; 4- (5- (4-chlorophenyl) -3- (5-chloro-2-thienyl) -1 H -pyrazol-1-yl) benzenesulfonamide; 4- (4-chloro-3,5-diphenyl-1 H-pyrazol-1-yl) benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-N] benzenesulfonamide; 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1 H-pyrrazol-1-yl] benzenesulfonamide; 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [4-chloro-5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (4-methylphenyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5-phenyl-1 H -pyrazol-1-yl] benzenesulfonamide; 4- [3- (diTluoromethyl) -5- (4-methoxyphenyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3-cyano-5- (4-fluorophenyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [4-chloro-5-phenyl-1 H-p'irazol-1-yl] benzenesulfonamide; 4- [5- (4-chlorophenyl) -3- (hydroxymethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 4- [5- (4- (N, N-dimethylamino) phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-N] benzenesulfonamide; 5- (4-fluorophenyl) -6- [4- (m8tNsulfonyl) phenyl] spiro [2,4] hept-5-ene; 4- [6- (4-fluorophenyl) spiro [2,4] hept-5-en-5-yl] benzenesulfonamide; 6- (4-fluorophenyl) -7- [4- (methylsulfonyl) phenyl] spiro [3,4] oct-6-ene; 5- (3-chloro-4-methoxyphenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2,4] hept-5-ene; 4- [6- (3-chloro-4-methoxyphenyl) spiro [2,4] hept-5-en-5-yl] benzenesulfonamide; 5- (3,5-Dichloro-4-methoxy-phenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2,4] h8pt-5-ene 5- (3-chloro-4-fluorophenyl) -6- [4- (Methylsulfonyl) phenyl] spiro [2,4] hept-5-ene; 4- [6- (3,4-dichlorophenyl) spiro [2,4] hept-5-en-5-yl] benzenesulfonamide; 2- (3-Cioro-4-fluorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) thiazo !; 2- (2-chlorophenyl) -4- (4-fluorophenyl) -5- (4-methylsulfonylphenol) thiazole; 5- (4-fluorophenyl) -4- (4-methylsulfonylphenol) -2-methylthiazole; 4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -2-trifluoromethyltiazole; 4- (4-fluorophenyl) -5- (4-methylsulfonyl-lnl) -2- (2-thienyl) thiazole; 4- (4-fluorophenyl) -5- (4-methylsulfo-n-phenylene) -2-benzyl-thiazole; 4- (4-1-fluorophenyl) -5- (4-methylsulfonylphenyl) -2- (1-propylamino) thiazole; 2 - [(3,5-dichlorophenoxy) methyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] thiazole; 5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethylthiazoi; il] benzene; 4- [4- (4-fluorophenyl) -1,1-dimethylcyclopenta-2,4-dien-3-yl] benzenesulfonamide; 5- (4-fluorophenyl) -6- [4- (methylsulfonyl) phenyl] spiro [2,4] hepta-4,6-diene; 4- [6- (4-fluorophenyl) spiro [2,4] hepta-4,6-dien-5-yl] benzenesulfonamide; 6- (4-fluorophenyl) -2-methoxy-5- [4- (methylsuifonyl) phenyl] -pyridine-3-carbonyl ether; 2- bromo-6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -pyridine-3-carbonitrile; 6- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyl-pyridin-3-carbonitrile; 4- [2- (4-methy1pyridin-2-yl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 4- [2- (2-methy1pyridin-3-yl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 3- [1- [4- (methylsulfonyl) pheny] -4- (trifluoromethyl) -1 H -amidazo-2-yl] pyridine; 2- [1-4- (methylsuifoni1) pheny1-4- (tnTluorometi) -1H-imidazol-2-yl] pyridine; 2-methyl-4- [1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -1 H -amidazoi-2-yl] pyridine; 2-methyl-6- [1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine; 4- [2- (6-methylpyridyl-3-yl) -4- (trifluoromethyl] -1H-imidazol-1-yl] benzenesulfonamide; 2- (3,4-difluorophenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazole; 4- [2- (4-methylphenyl) -4- (trifluoromethyl) -1H-imidazoI-1-yl] benzenesulfonamide; 2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-methyl-1 H-imidazole; 2- (4-chlorophenyl) -1- [4- (methylsulfonyl) phenyl] -4-phenyl-1 H-imidazole; 2- (4-chlorophenyl) -4- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -1 H-imidazole; 2- (3-fluoro-4-methoxyphenyl) -1- [4- (methylsulfonyl) phenyl-4- (trifluoromethyl) -1 H-imidazole; 1- [4- (methylsulfonyl) pheny] -2-phenyl-4-trifluoromethyl-1 H-imidazole; 2- (4-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1 H-imidazole; 4- [2- (3-Chloro-4-methylphenyl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 2- (3-fluoro-5-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4- (trifluoromethyl) -1 H -imidazole; 4- [2- (3-fluoro-5-methylphenyl) -4- (trifluoromethyl) -1 H -imidazol-1-yl] benzenesulfonamide; 2- (3-methylphenyl) -1- [4- (methylsulfonyl) phenyl] -4-trifluoromethyl-1H-imidazole; 4- [2- (3-methylphenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; 1- [4- (methylsulfonyl) phenyl] -2- (3-chlorophenyl) -4-trifluoromethyl-1 H-imidazole; 4- [2- (3-chlorophenol) -4-triTluoromethyl-1H-ylamdazol-1-yl] benzenesulfonamide; 4- [2-phenyl] -4-trifluoromethyl-1 H-imidazol-1-yl] benzenesulfonamide; 4- [2- (4-methoxy-3-chlorophenyl) -4-trifluoromethyl-1H-imidazol-1-yl] benzenesulfonamide; 1-allyl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) f8nil] -5- (t-trifluoromethyl) -1 H-pyrazole; 4- [1-etl-4- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-3-yl] benzenesulfonamide; N-phenyl- [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1 H -pyrazol-1-yl] acetamide; [4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl] -1H-pyrazole-1-yl-ethyl acetate; 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl3-1- (2-phenylethyl) -1 H-pyrazole; 4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -1- (2-phenylethyl) -5- (trifluoromethyl) pyrazole; 1- etl-4- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] -5- (trifluoromethyl) -1 H-pyrazole; 5- (4-fluorophenyl) -4- (4-methylsulfonylphenyl) -2-trifluoromethyl-1 H-imidazo I; 4- [4- (methylsulfonyl) phenyl] -5- (2-thiophenyl) -2- (trifluoromethyl) -1H-imidazole; 5- (4-fluorophenyl) -2-methoxy-4- [4- (methylsulfonyl) phenyl] -6- (trifluoromethyl-2-ethoxy-5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] - 6- (trifluoromethyl) pyridin 5- (4-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2- (2-propynyloxy) -6- (trifluoromethyl) pyridine; 2-bromo-5- (4 -fluorophenyl) -4- [4 ^ (methylsulfonyl) phenyl] -6- (trifluoromethyl) pyrid - [2- (3-chloro-4-methoxyphenyl) -4,5-difluorophenyl] benzenesulfonamide; - (4-fluorophenyl) ) -2- [4- (Methylsulfonyl) phenyl] benzene; - difluoromethyl-4- (4-methylsulfonylphenol) -3-phenylisoxazole; - [3-ethyl-5-phenylisoxazol-4-yl] benzenesulfonamide; [5-difluoromethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; - [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; - [5-methyl-3-phenyl] -isoxazol-4-yl] benzenesulfonamide; - [2- (4-fluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-fluoro-2-methylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-chlorophenyl) cyclopenten-1-yl] -4- (rri-8-sulphsulfonyl) benzene; - [2- (2,4-dichlorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-trifluoromethylphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-methylthiophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-fluorophenyl) -4,4-dim-8-cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (4-fluorophenyl) -4,4-d-methyl-cyclopenten-1-yl] -benzenesulfonamide; - [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] -4- (methylsulfonic) benzene; - [2- (4-chlorophenyl) -4,4-dimethylcyclopenten-1-yl] benzenesulfonamide; - [2- (4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide; - [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide; - [2- (4-methoxyphenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (2,3-difluorophenyl) cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (3-fluoro-4-methoxy-phenyl) -cyclopenten-1-yl] -benzenesulfonamide; - [2- (3-chloro-4-methoxy-phenyl) -cyclopenten-1-yl] -4- (methylsulfonyl) benzene; - [2- (3-chloro-4-fluorophenol) cyclopenten-1-yl] benzenesulfonamide; - [2- (2-methyloxy-5-yl) cyclopenten-1-yl] benzenesulfonamide; Ethyl 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] -2-benzylacetate; 2- [4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazol-2-yl] acetic acid; - _. 2- (ε-butyl) -4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] oxazo !; 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-phenyloxazole; 4- (4-fluorophenyl) -2-methyl-5- [4- (methylsulfonyl) phenyl] oxazole; 4- [5- (3-fIuoro-4-methoxyphenyl) -2-trifluoromethyl-4-oxazolyl] benzenesulfonamide; 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 10 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-Chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid; 7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 20 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,8-bis (dimethylethyl) -2-trifiuoromethyl-2H-1-benzopyran-3-carboxylic acid; 7- (1-Methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7-f8nil-2-trifluoromethyl-2H-1-b6nzopyran-3-carboxylic acid; 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 2-trifluoromethyl-3H-naphtho [2,1-b] pyran-3-carboxylic acid; 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-cGoro-6-metha-2-t-trifluoromethyl-2H-1-b? nz (pyrazole-3-oxoxy) acid 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran 3-carboxylic acid: 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid: 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6-chloro acid -8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6 - [[(phenylmethyl)] amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6 - [(dimethylamino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6 - [( methylamino) sulfonyl] -2-trifluorornethyl-2H-1-benzopyran-3-carboxylic acid 6 - [(4-morpholino) sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6 - [(1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-2-carboxylic acid; 6 - [(2-methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6 - [[(phenylmethyl) amino] suphonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-Chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6 - [[N- (2-furylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran 3-carboxylic acid; 6 - [[N- (2-phenylethyl) amino] sulfonyl] -2-trifiuoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7- (1,1-dimethylethyl) -2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid; 5,5-dimethyl-3- (3-fluorophenyl) -4- (4-methylsulfonyl-2 (5H) -furanone; 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid; 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl) -3- (difluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide; 3- [1- [4- (Methylsulfonyl) phenyl] -4-trifluoromethyl-1 H-imidazol-2-yl] piYid 2-methyl-5- [1 - [4- (methylsulfonyl) fenU] -4-trifluoromethyl -1 H-imidazol-2-yl] pyridine; 4- [2- (5-methylpyridin-3-yl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; 4- [5-methyl-3-phenyl] -oxazol-4-yl] benzenesulfonamide; 4- [5-hydroxymethyl-3-phenylisoxazol-4-yl] benzenesulfonamide; [2-trifluoromethyl-5- (3,4-difluorophenol) -4-oxazoyl] benzenesulfonamide; 4- [2-methyl-4-phenyl-5-oxazolyl] benzenesulfonamide; 4- [5- (3-fluoro-4-methoxyphenyl-2-trifluoromethyl) -4-oxazolyl] benzenesulfonamide; and pharmaceutically acceptable salts and prodrugs thereof. In a further embodiment of the invention, the selective Cox-2 inhibitor used in the present invention can be selected from the class of phenylacetic acid derivatives represented by the general structure of formula (X): which: 27 is methyl, ethyl or propyl; R28 is chloro or fluoro; R29 is hydrogen, fluoro or methyl; R 30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R is hydrogen, fluoro or methyl; and R32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl; with the proviso that R28, R29, R30 and R3 are not all fluoro when R27 is ethyl and R30 is H; or a pharmaceutically acceptable isomer, salt, ester, or prodrug thereof. A selective inhibitor of Cox-2 derived from phenylacetic acid which is described in International Patent Publication No. WO 99/11605, incorporated herein by reference, is a compound having the structure shown in formula (X), in which: R27 is ethyl; R28 and R30 are chlorine; R29 and R31 are hydrogen; and R32 is methyl. Another selective inhibitor of Cox-2 derived from phenylacetic acid is a compound having the structure shown in formula (X), wherein: R27 is propyl; R28 and R30 are chlorine; R29 and R31 are methyl; and R32 is ethyl. Another selective Cox-2 inhibitor derived from phenylacetic acid, described in International Patent Publication No. WO 02/20090, which is incorporated herein by reference, is COX-189, also known as lumiracoxib, having the structure shown in the formula (X), wherein: R27 is methyl; R28 is fluoro; R is chlorine; and R29, R30, and R31 are hydrogen. Selective Cox-2 inhibitory compounds having a structure similar to that shown in formula (X) are described in the patents cited individually below and which are incorporated herein by reference. U.S. Patent No. 6,310,099. U.S. Patent No. 6,291,523. U.S. Patent No. 5,958,978. Other selective Cox-2 inhibitors that can be used in the present invention have the general structure shown in formula (XI), wherein group J is a carbocycle or a heterocycle. The illustrative embodiments have the structure: wherein: X is O; J is 1-phenyl; R "is 2-NHSO2CH3, R is 4-NO2, and there is no R35 group (nimesulide), X is O, J is 1-oxo-inden-5-yl, R33 is 2-F, R34 is 4-F; and R35 is 6-NHSO2CH3 (flosulide): X is O; J is cyclohexyl, R is 2-NHSO2CH3, R is 5-NO2, and there is no R group (NS-398 or N- (2-cyclohexyloxynitrophenyl) methanesulfonamide); X is S; J is 1-oxo-n-5-yl; R "is 2-F; R 4 is 4-F; and R35 is 6-N 'S02CH3-Na + (L-745337); X is S; J is thiophen-2-yl; R33 is 4-F; group R34, and R35 is 5-NHS02CH3 (RW.J.63556), or X is O; J is 2-oxo-5 (R) -methyl-5- (2,2,2-trifluoroethyl) furan- (5H ) -3-yl, R33 is 3-F, R34 is 4-F, and R35 is 4- (p-S02CH3) C6H4 (L-784512) Materials that can serve as a selective Cox-2 inhibitor of the present invention include diarylmethylidenefuran derivatives which are described in United States Patent No. 6,180,651, said diarylmethylidenefuran derivatives having the general formula shown below in formula (XII): wherein: the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising from 5 to 6 members and having 1 to 4 heteroatoms, or a radical derived from a hydrocarbon ring saturated having 3 to 7 carbon atoms; at least one of substituents Q, Q2, L1 and L2 is (a) a group -S (0) nR, wherein n is an integer equal to 0.1 or 2 and R is a lower alkyl radical having from 1 to 6 carbon atoms or a lower haloalkyl radical having from 1 to 6 carbon atoms, or (b) a -S02NH2 group, and is located in the para position; the others being independently a hydrogen atom, a halogen atom, a lower alkyl radical having from 1 to 6 carbon atoms ,. a radical. trifluoromethyl, or an O-lower alkyl radical having from 1 to 6 carbon atoms, or Q1 and Q2 or L1 and L2 form a methylenedioxy group; and R36, R37, R38 and R39 independently are a hydrogen atom, a halogen atom, a lower alkyl radical having from 1 to 6 carbon atoms, a lower haloalkyl radical having from 1 to 6 carbon atoms, or a aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or R36 and R37, or R38 and R39 are an oxygen atom, or R36 and R37, or R38 and R39, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms. carbon; or an isomer or prodrug thereof. Particular compounds of this family of compounds, which can serve as selective inhibitor of Cox-2 in the present invention, include N- (2-cyclohexyloxynitro-phenyl) methane sulfonamide and (E) -4 - [(4-methylphenyl) ( tetrahydro-2-0X0-3-furanylidene) methyl] benzenesulfonamide. Selective Cox-2 inhibitors that are useful in the present invention include darbufelone from Pfizer, CS-502 from Sankyo, LAS 34475 and LAS 34555 from Almirall Profesfarma, S-33516 from Servier, SD-8381 from Pharmacia, described in the patent. No. 6,034,256, BMS-347070 from Bristol Myers Squibb, described in U.S. Patent No. 6,180,651, Merck MK-966, L-783003 and L-748731 from Merck, T-614 Toyama, D-1367 from Chiroscience, CT3 from Atlantic Pharmaceutical, CGP-28238 from Novartis, BF-389 from Biofor / Scherer, GR-253035 from Glaxo Wellcome, 6-dioxo-9H-purin-8-yl cinnamic acid from Glaxo Wellcome, and S-2474 of Shionogi. The information on S-33516, mentioned above, can be found in the Current Druqs Headline News, on the website http://www.current-drugs.com/NEWS/lnflamlhtm (2001), where it was reported that S-33516 has Cl50 values of 0.1 and 0.001 mM against Cox-1 and Cox-2 respectively. Compounds that can act as selective Cox-2 inhibitors include multiple-binding compounds containing from 2 to 10 ligands or covalently linked to one or more linkers, as described in U.S. Patent No. 6,395,724. Compounds that can act as Cox-2 inhibitors include a conjugated linoleic acid as described in U.S. Patent No. 6,077,868. Compounds that can act as selective Cox-2 inhibitors include heterocyclic aromatic oxazole compounds as described in the patents cited individually below and which are incorporated herein by reference. U.S. Patent No. 5,994,381. 0 U.S. Patent No. 6,362,209. Said heterocyclic aromatic oxazole compounds have the formula shown below in formula (XIII): (???) where: Z2 is an oxygen atom; one of R40 and R4 is a group of the formula wherein R is lower alkyl, amino or lower alkylamino; and R44, R, R4 and R47 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or amino, with the proviso that at least one of R44, R45, R46 and R47 is not hydrogen; the other of R40 and R4 is an optionally substituted cycloalkyl, heterocyclyl or aryl; and R42 is a lower alkyl or a lower halogenated alkyl, or a pharmaceutically acceptable salt thereof. The selective Cox-2 inhibitors useful herein include the compounds described in the patents cited individually below and which are incorporated herein by reference. U.S. Patent No. 6,080, 876. U.S. Patent No. 6,133,292. Said compounds are described by the formula (XIV): wherein: Z3 is selected from the group consisting of (a) linear or branched C-? -β alkyl, (b) linear or branched Ci-6 alkoxy, (c) phenyl or unsubstituted naphthyl, mono-, di- or tri-substituted where the substituents are selected from the group consisting of hydrogen, halo, Ci-3 alkoxy, CN, fluoroalkyl Ci-3, Ci-3 alkyl and R48 is selected from the group consisting of NH2 and CH3, R49 is selected from the group consisting of Ci-6 alkyl unsubstituted or substituted by C3-6 cycloalkyl, and C3-6 cycloalkyl; R50 is selected from the group consisting of Ci_6 alkyl unsubstituted or substituted by one, two or three fluoro atoms; and C3-6 cycloalkyl with the proviso that R49 and R50 are not equal. Compounds that can act as selective inhibitors of Cox-2 include the pyridines described in the patents cited individually below and which are incorporated herein by reference. U.S. Patent No. 6,369,275. U.S. Patent No. 6,127,545. U.S. Patent No. 6,130,334. U.S. Patent No. 6,204,387. U.S. Patent No. 6,071,936.

U.S. Patent No. 6,001,843. U.S. Patent No. 6,040,450. Said compounds have the general formula described by the formula (XV): wherein: R51 is selected from the group consisting of: CH3) NH2, NHC (0) CF3 and NHCH3; Z4 is a phenyl or pyridinyl mono-, di-, or trisituited (or he N-oxide thereof), having substituents selected from the group consisting of hydrogen, halo, C1-6 alkoxy, Ci-6 alkyl thio, CN , alkyl Ci-6, fluoroalkyl CI-B, N3, -C02R53, hydroxy, -C (R54) (R55) -OH, -alkyl Ci-6-C02-R56 and fluoroalkoxy C1-6; R 52 is selected from the group consisting of halo, C 1-6 alkoxy, C 1-6 alkylthio, CN, C 1-6 alkyl, C 1-6 fluoroalkyl, N 3, -C02R57, hydroxy, -C (R58) (R59) -OH, -alkyl Ci-6-C02-R60, fluoroalkoxy C1-6, N02, NR61R62 and NHCOR63; and each of R53, R54 R55, R56, R57, R58, R59, R60, R61, R62 and R63 is independently selected from the group consisting of hydrogen, and C1-6alkyl; or R54 and R55, R58 and R59, or R61 and R62, together with the atom to which they are attached, form a saturated monocyclic ring of 3,4, 5, 6 or 7 atoms. Compounds that can act as selective inhibitors of Cox-2 include diarylbenzopyran derivatives as described in U.S. Patent No. 6,340,694, which is incorporated herein by reference. Said diarylbenzopyran derivatives have the general formula shown below in formula (XVI): wherein: X8 is an oxygen atom or a sulfur atom; R64 and R65, which are the same or different from each other, are independently hydrogen, halogen, C6 lower alkyl, trifluoro methyl, alkoxy, hydroxy, nitro, nitrile or carbokyl; R66 is a group of a formula S (0) nR68 where n is an integer from 0 to 2, R68 is hydrogen, lower alkyl C-1-C6, or a group of formula NR69R70 wherein R69 and R70, equal or different from each other, are independently hydrogen, or a lower C 1 -C 6 alkyl group; and R67 is oxazolyl, benzo [b] thienyl, furanyl, thienyl, naphthyl, thiazolium, indolyl, pyrrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a lower alkyl group CrC6, indanyl, pyrazinyl, or a substituted group represented by one of the following structures: wherein: from R71 to R75, equal or different from each other, are independently hydrogen, halogen, lower alkyl CrC6, trifluoromethyl, alkoxy, hydroxy, hydroxyalkyl, nitro, - a group -of formula S (0) nR68, a group of formula NR69R70, trifluoromethoxy, nitrile, carboxyl, acetyl or formyl, wherein n, R68, R69 and R70 have the same meaning defined for R66 above; and R76 is hydrogen, halogen, lower alkyl CrC6, trifluoromethyl, alkoxy, hydroxy, trifluoromethoxy, carboxyl or acetyl. Compounds that can act as selective inhibitors of Cox-2 include 1- (4-sulfamylaryl) -3-substituted-5-aryl-2-pyrazolines as described in U.S. Patent No. 6,376,519, which It is incorporated into this document as a reference. Said compounds have the formula shown below in formula (XVII): wherein: X is selected from the group consisting of trihalomethyl C C6! for example trifluoromethylalkyl CrC6; and an optionally substituted or di-substituted phenol group of formula wherein R and R are independently selected from the group consisting of hydrogen, halogen (eg, chlorine, fluorine or bromine), hydroxyl, nitro, C6 alkyl (eg, CrC3), coxy C6 (eg , C1-C3), carboxy, trihaloalkyl Ci-C6 (for example, trihalomethyl such as trifluoromethyl), and cyano; and Z5 is selected from the group consisting of substituted and unsubstituted aryl. Compounds that can act as selective Cox-2 inhibitors of the present invention include heterocycles as described in U.S. Patent No. 6,153,787, which is incorporated herein by reference. Said heterocycles have the general formulas shown below in formulas (XVIII) and (XIX): wherein: R79 is mono-, di- or trisubstituted Ci-12 alkyl, unsubstituted or linear or branched mono-, di- or tri- substituted alkenyl, unsubstituted C-2-io alkynyl or mono-, di- or tri- substituted linear or branched, C3.12 unsubstituted or mono-, di- or tri-substituted cycloalkenyl, or C5-12 cycloalkynyl unsubstituted or mono-, di- or tri-substituted, where substituents are selected from the group consisting of halo (selected from F, Cl, Br, and I), OH, CF3, C3-6 cycloalkyl, = 0, dioxolane and CN; R80 se. select from the group consisting of: CH3, NH2, NHC (O) CF3 and NHCH3; R81 and R82 are independently selected from the group consisting of hydrogen, and C1-10 alkyl; or R81 and R82 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. The formula (XIX) is: wherein X10 is fluoro or chloro. 2,3,5-trisubstituted pyridines as described in U.S. Patent No. 6,046,217, which is incorporated herein by reference, are compounds that can act as selective Cox-2 inhibitors. - Sayings - compounds - have the general formula shown below in formula (XX): or a pharmaceutically acceptable salt thereof, wherein: X11 is selected from the group consisting of O, S and a bond; n is 0 or 1; R83 is selected from the group consisting of CH3, NH2 and NHC (0) CF3; R is selected from the group consisting of halo, Ci-5 alkoxy, C1-6 alkyl thio, CN, C1-6 alkyl, C1-6 fluoroalkyl, N3, -CO2R92, hydroxy, -C (R93) (R94) -OH , alkyl C ^ -COa-R95 fluoroalkoxy C1-6, NO2, NR96R97 and NHCOR98; R85 to R98 are independently chosen from the group consisting of hydrogen, and C-i-6 alkyl; or R85 and R89, or R89 and R90, together with the atoms to which they are attached, form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms; or R85 and R87 join to form a bond. An exemplary embodiment of the selective Cox-2 inhibitor of formula (XX) is one in which X is a bond. Another exemplary embodiment of the selective Cox-2 inhibitor of formula (XX) is one in which X is O. Another exemplary embodiment of the selective Cox-2 inhibitor of formula (XX) is one in which X is S. Another exemplary embodiment of the selective Cox-2 inhibitor of formula (XX) is one in which R 83 is CH 3. Another exemplary embodiment of the selective Cox-2 inhibitor of formula (XX) is that in which R84 is halo or fluoroalkyl? 1-6. Compounds that can act as selective Cox-2 inhibitors include bicyclic diaryl heterocycles as described in U.S. Patent No. 6,329,421. Said compounds have the general formula shown below in formula (XXI): (XXI) and pharmaceutically acceptable salts thereof, wherein: -A5 = A6-A7 = A8- is selected from the group consisting of (a) -CH = CH-CH = CH-, (b) -CH2- CH2-CH2-C (0) -, -CH2-CH2-C (0) -CH2-, -CH2-C (0) -CH2-CH2, -C (0) -CH2-CH2-CH2, - (c ) -CH2-CH2-C (0) -, -CH2-C (0) -CH2-, -C (0) -CH2-CH2-, (d> CH2-CH2-0-C (0) -, -CH2-0-C (0) -CH2-, -0-C (0) -CH2-CH2-, (e) -CH2-CH2-C (0) -O-, -CH2-C (0) - OCH2-, -C (0) -0-CH2-CH2-, (f) -C (R05) 2-OC (O) -, -C (0) -0-C (R105) 2-, -OC (O) -C (R105) 2-, -C (R105) 2-C (O) -O-, (g) -N = CH-CH = CH-, (h) -CH = N-CH = CH -, (i) -CH = CH-N = CH-, (j) -CH = CH-CH = N-, (k) -N = CH-CH = N-, (I) -N = CH-N = CH-, (m) -CH = N-CH = N-, (n) -S-CH = N-, (o) -SN = CH- (p) -N = N-NH-, (q) -CH = NS- and (r) -N = CH-S-; R99 is selected from the group consisting of S (0) 2CH3, S (0) 2NH2, S (0) 2NHCOCF3, S (0) (NH) CH3, S (0) (NH) NH2, S (0) (NH) NHCOCF3, P (0) (CH3) OH and P (0) (CH3) NH2; R100 is selected from the group consisting of (a) alkyl Ci-6, (b) C3-7 cycloalkyl, (c) phenyl or mono- or di-substituted naphthyl where the substituent is selected between the group consisting of hydrogen, halo including F, Cl, Br and I, C 1-6 alkoxy, Ci-6 alkyl, CN, CF 3; C1-6alkyl, N3, -C02H, -C02-C1-4alkyl, -C (R103) (R104) -OH, -C (R103) (R104) -O-C1-4alkyl and -C1-6alkyl -C02-R106; (d) mono- or di-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having a heteroatom which is S, O, or N, and optionally 1, 2 or 3 additional N atoms; or a monocyclic ring of 6 atoms, said ring having a heteroatom which is N, and optionally 1, 2, 3 or 4 additional N atoms; and said substituents are selected from the group consisting of hydrogen, halo including F, Cl, Br and I, alkoxy Ci-6l alkyl Ci_6 thio, CN, CF3, C1-6 alkyl, N3, -C02H, -C02-C1- alkyl 4, - C (R1Ud) (R1U4) -OH and -C (RlO3) (R104) -O-C1-4alkyl; and (e) benzoheteroaryl including the benzo condensates of (d); Rioi and Rio2 are substitutents residing at any position of -A5 = A6-A7 = A8-y and are independently selected from the group consisting of hydrogen, CF3, CN, C1-6 alkyl, Q4, C02H, C (R3O) (R104 ) OH, -O-Q4, -S-Q4, and -alkyl C1-5-Q3 optionally substituted Ci-3 alkyl, -O-alkyl Ci-5-Q3, -S-alkyl Ci-5-Q3, -alkyl C -3-0-C 1-3 alkyl-Q 3, C 1-3 alkyl-S-C 1-3 alkyl-Q 3, C 1-5 alkyl-Q 4 and C 1 alkyl-5-S-Q 4, in the than the substituent residues in the alkyl chain; where Q3 is Q4, C02H or C (R3O) (R4O) OH and Q4 is C02-C1-4alkyl, tetrazolyl-5-yl, or C (R103) (R4O) O-C1-4alkyl; each of R103, R104 and R105 is independently selected from the group consisting of hydrogen, and Ci-6 alkyl; or R103 and R104 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 05 groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; R106 is hydrogen, or Ci-6 alkyl; R 07 is hydrogen, Ci-6 alkyl or aryl; and X7 is O, S, NR107, CO, C (R 07) 2, C (R107) (OH), -C (R107) = C (R107) -, -C (R107) = N- or -N = C (R107) -. Compounds that can act as selective Cox-2 inhibitors include salts of a 5-amino- or substituted amino-1, 2,3-triazole compound as described in U.S. Patent No. 6,239,137. These salts are of a class of compounds of formula (XXII): where: R108 is where p is from 0 to 2; m is from 0 to 4; n is from 0 to 5; X13 is O, S, SO, S02, CO, CHCN, CH2 or C = NR113 where R 13 is hydrogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di (lower alkyl) amino or cyano; and R111 and R112 are independently halogen, cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, trifluoromethoxy, acetamido, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethyl sulfonyl; R109 is amino, mono or di (alkyl) nifor) amino, acetamido, acetimido, ureido, formamido, formamido or guanidino; and R 0 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the lower alkyl groups, containing lower alkyl, lower alkoxy and lower alkanoyl contain from 1 to 3 carbon atoms. Compounds that can act as selective inhibitors of Cox-2 include pyrazole derivatives as described in U.S. Patent No. 6,136,831. Said compounds have the formula shown below in the formula (XXIII): wherein: R114 is hydrogen, or halogen; each of R 5 and R 6 is independently selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or lower alkanoyloxy; R1 is lower haloalkyl or lower alkyl; X14 is sulfur, oxygen or NH; and Z6 is lower alkyl uncle, lower alkyl sulfonyl or sulphamoyl; or a pharmaceutically acceptable salt thereof. Compounds that can act as selective Cox-2 inhibitors include substituted benzosulfonamide derivatives as described in U.S. Patent No. 6,297,282. Said compounds have the formula shown below in formula (XXIV): wherein: X15 denotes oxygen, sulfur or NH; R118 is an optionally unsaturated alkyl, or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted with halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or substituted mixed with halogen, alkyl, CF3, cyano or alkoxy; R 19 and R 120, independently selected from each other, denote hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2) n-X 16; or R119 and R120, together with the N atom, denote a saturated, or partially or completely unsaturated, heterocycle of 3 to 7 members with one or more N, O or S heteroatoms, which may be optionally substituted with oxo, an alkyl group , alkylaryl or aryl, or a group (CH2) n-X16; X16 denotes halogen, N02, -OR121, -COR121, -CO2R121, -OCO2R121, -CN, -CONR121OR122, -CONR121R122, -SR121, -S (O) R121, -S (O) 2R121, -NR121R122, -NHC ( O) R121 or -NHS (O) 2R121; n denotes an integer from 0 to 6; R123 denotes a straight or branched chain alkyl group with 1-10 C atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, an aralkyl group, a heteroaryl or heteroaralkyl group which may be optionally mono- or polysubstituted or substituted mixed with halogen or alkoxy; R 24 denotes halogen, hydroxy, a straight or branched chain alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 carbon atoms, which may be optionally mono- or polysubstituted with halogen, NO2, -OR121, -COR121, -CO2R121 , -OCO2R121, -CN, -CONR121OR122, -CONR 21R122, -SR121, -S (O) R121, -S (O) 2R121, -NR12 R122, -NHC (O) R121, -NHS (O) 2R121, or a polyfluoroalkyl group; R and R, independently selected from each other, denote hydrogen, alkyl, aralkyl or aryl; and m denotes an integer from 0 to 2; and pharmaceutically acceptable salts thereof. Compounds that can act as selective inhibitors of Cox-2 include 3-phenyl-4- (4- (methylsulfonyl) phenyl) -2- (5H) -furanones as described in U.S. Patent No. 6,239,173. Said compounds have the formula shown below in formula (XXV): or pharmaceutically acceptable salts thereof, wherein: -X 7-Y 1 -Z 7 -, when side b is a double bond, and sides a and c are single bonds, is selected from the group consisting of -CH 2 CH 2 CH 2 -, - C (0) CH2CH2-, -CH2CH2C (0) -, -CR129 (R129,) - 0-C (0) -, -C (0) -0-CR129 (R129, -CH2-NR127-CH2-, - CR129 (R1 9,) - NR127-C (0) -, -CR1 8 = CR128'-S-, -S-CR1 8 = CR128'-, -SN = CH-, -CH = NS-, -N = CR128-0-, -0-CR128 = N-, -N = CR128-NH-, -N = CR128-S-, -S-CR128 = N-, -C (0) -NR127-CR 29 (R129 ' ) -, -R127N-CH = CH- with the proviso that R is not -S (0) 2CH3, and -CHOH-NR1 1'2"7- with the proviso that R> 1125 either -S (0) 2CH3; -X 7-Y1-Z7-, when sides a and c are double bonds and side b is a single bond, it is selected from the group consisting of = CH-0-CH = = CH-NR127-CH = = NS-CH = = CH-SN =, = N-0-CH =, = CH-0-N = = NSN = y = N-0-N =; ... R 2L is selected from the group- consisting of S (0) 2CH3 | S (0) 2NH2, S (0) 2NHC (0) CF3, S (0) (NH) CH3, S (0) (NH) NH2I S (0) (NH) NHC (0) CF3, P (0) (CH3) OH and P (0) (CH3) NH2; R 26 is selected from the group consisting of (a) C 1-6 alkyl; (b) C3, C4, C5, C6 or C7 cycloalkyl; (c) phenyl or mono-, di- or tri-substituted naphthyl, wherein the substituent is selected from the group consisting of hydrogen, halo, Ci-6 alkoxy, Ci-6 alkyl thio, CN, CF3, C1-6 alkyl, N3, -C02H, -C02-C1-4alkyl, -C (R129) (R130) -OH, -C (R129) (R30) -O-C1-4alkyl, and -alkyl-COs-R 29; (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having a heteroatom which is S, O or N, and optionally 1, 2 or 3 N atoms further, or the heteroaryl is a monocyclic ring of 6 atoms, said ring having a heteroatom which is N, and optionally 1, 2, 3 or 4 additional N atoms, wherein the substituents are selected from the group consisting of hydrogen, halo ( including fluoro, chloro, bromo and iodo), Ci-6 alkyl. C1-6 alkoxy, C1-6 alkylthio, CN, CF3, N3, -C (R129) (R130) -OH, and -C (R129) (R130) -O-C1-4alkyl; and (e) benzoheteroaryl including the benzo-fused analogs of (d); R127 is selected from the group consisting of hydrogen, CF3, CN, Ci_6 alkyl, hydroxyCi-6 alkyl, -C (0) -alkyl d-6, alkyl-Ci-5-Q5 alkyl optionally substituted with Ci-3 alkyl , -alkyl C1-3-0-alkyl Ci-3-Q5, -alkyl Ci. 3-S-alkylCi-3-Q5, -alkyl C1-5-0-Q5 and -alkyl Ci-5-S-Q5 where the substituent resides on the alkyl; and -Q5; each of R and R is independently selected from the group consisting of hydrogen, CF3, CN, Ci-6 alkyl) -Q5, -O-Q5; -S-Q5, and -alkyl Ci-5-Q5 optionally substituted with C1-3 alkyl, -O-alkyl Ci-5-Q5, -S-alkylac1-5-Q5 > --alcjl.1.3- -alquiL.C1-3-Q5, -alkyl C1-3-S-alkyl C -3-Q5, -alkyl Ci-5-O-Q5, -alkyl Ci-5-S- Q5 wherein the substituent resides on the alkyl; each of R129, R129 ', R130, R 31 and R132 are independently selected from the group consisting of hydrogen, and C-i-e alkyl; or R129 and 0 R131 and R132 together 8n Q \ carbon a | which are unjd0Sj form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; and Q5 is C02H, C02-Ci-4 alkyl, tetrazolyl-5-yl, C (R 31) (R132) (OH) or C (R 31) (R132) (0-C 1-4 alkyl); with the proviso that when -X 7-Y1-Z7- is -S-CR128 = CR128 ', then R128 and R128' are different from CF3. Compounds that can act as selective inhibitors of Cox-2 include bicyclic carbonyl indole compounds as described in U.S. Patent No. 6,303,628. Said compounds have the formula shown below in formula (XXVI): pharmaceutically acceptable salts thereof, wherein: A9 is C1-6 alkylene or -NR133-; Z8 is C (= L3) R134 or S02R135; Z9 is CH or N; Z10 and Y2 are independently selected from -CH2-, O, S and -N-R133; .... m is 1, 2 or 3; - - - .. q and r are independently 0, 1 or 2; X18 is independently selected from halogen, C1-4 alkyl, Ci-4 alkyl substituted with halo, hydroxy, Ci-4 alkoxy, Ci-4 alkoxy substituted with halo, Ci-4 alkylthio, nitro, amino, mono- or di (alkyl) Ci-) amino and cyano; n is 0, 1, 2, 3 or 4; L3 is oxygen or sulfur; R133 is hydrogen, or C -4 alkyl; R 34 is hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted with halo, CIB alkoxy, C 1-6 alkoxy substituted with halo, C 3-7 cycloalkoxy alkyl C- (cycloalkoxy 03.7), -NR136R137, alkyl Cyphenyl-O - or phenyl-O-, said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci-4 alkyl, hydroxy, Ci-4 alkoxy and nitro; R 35 is C 1-6 alkyl or C 1-6 alkyl substituted with halo; and R136 and R137 are independently selected from hydrogen, C-i6 alkyl and C1-6 alkyl substituted with halo. Compounds that can act as selective Cox-2 inhibitors include benzimidazole compounds as described in U.S. Patent No. 6,310,079. Said compounds have the formula shown below in formula (XXVII): or a pharmaceutically acceptable salt thereof, wherein: A10 is heteroaryl selected from (a) a 5-membered monocyclic aromatic ring having a heteroatom selected from O, S and N and optionally containing from one to three N atoms in addition to said heteroatom, and (b) a 6-membered monocyclic aromatic ring having an N atom and optionally containing one to four N atoms in addition to said N atom; said heteroaryl being connected to the nitrogen atom of the benzimidazole by a carbon atom on the heteroaryl ring; X20 is independently selected from halo, C4 alkyl, hydroxy, Ci-C4 alkoxy, C4 alkyl substituted with halo, C4 alkyl substituted with hydroxy, (C1-C4 alkoxy) C4 alkyl, C1-C4 alkoxy substituted with halo, amino, N- (Ci-C4 alkyl) amino, N, N-di (Ci-C4 alkyl) amino, [N- (C4 alkyl) amino] C1-C4 alkyl, [N, N-di (alkyl CrC4) amino] C 1 -C 4 alkyl, N- (C 4 -C 4 alkanoyl) amino, N- (C 1 -C 4 alkyl) (N- [(C 1 -C 4 alkyl) sulfonyl] amino alkane, N- [substituted C 1 -C 4 alkyl] with halo) its fonyl] amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy) carbonyl, carbamoyl, [N- (Ci-C4 alkyl) amino] carbonyl, [N, N-di (C4 alkyl) amino] carbonyl, cyano, nitro, mercapto, (C 1 -C 4 alkyl) thio, (Cr C 4 alkyl) sulfinyl, (CrC 4 alkyl) sulfonyl, aminosulfonyl, [N- (C 4 alkyl) amino] sulfonyl and [N, N-di (C 1 -C 4 alkyl) amino] sulfonyl; X is independently selected from halo, C4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 4 alkyl substituted with halo, C 4 alkyl substituted with hydroxy, (C 4 alkoxy) C 1 -C 4 alkyl; C4 alkoxy substituted with halo, amino, N- (aikil CrC4) amino, N, N-, di (C4 alkyl) amino, [N- (alkyl CrC4) amino] alkyl CrC4, [N, N-di (alkyl Ci-C4) amino] C4 alkyl, N- (C4 alkanoyl) amino, N- (Ci-C4 alkyl) -N- (alkanoyl CrC4) amino, N - [(C4 alkyl) sulfonyl] amino, N- [Ci-C4 alkyl substituted with halo) sulfonyl] amino, C4 alkanoyl, carboxy, (C4) alkoxycarbonyl, carbamoyl, [N- (Ci-C alkyl) amino] carbonyl, [?,? -di (CC alkyl ) amino] carbonyl N-carbamoylamino, cyano, nitro, mercapto, (C1-C alkyl) thio, (Ci-C4 alkyl) sulfinyl, (C-1-C4 alkyl) sulfonyl, aminosulfonyl, [N- (C4 alkyl) amino] sulfonyl and [N, N-di (C 4 alkyl) amino] sulfonyl; R138 is selected from hydrogen; straight or branched C 4 alkyl optionally substituted with one to three substituents independently selected from halo, hydroxy, CrC 4 alkoxy, amino, N- (C 1 -C 4 alkyl) amino and N, N-di (C 4 alkyl) amino; C3-C8 cycloalkyl optionally substituted with one to three substituents independently selected from halo, C1-C4 alkyl, hydroxy, Ci-C4 alkoxy, amino, N- (CrC4 alkyl) amino and N, N-di (CrC4 alkyl) amino; C4-C8 cycloalkenyl optionally substituted with one to three substituents independently selected from halo, C1-C4 alkyl, hydroxy, Ci-C4 alkoxy, amino, N- (alky Ci-C4) amino and N, N-di (CrC4 alkyl) amino; phenyl optionally substituted with one to three substituents independently selected from halo, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl substituted with halo, C 1 -C 4 alkyl substituted with hydroxy, C 1 alkoxy C4) CrC4 alkyl, C1-C4 alkoxy substituted with halo, amino, N- (CrC4 alkyl) amino, N, N-di (C4 alkyl) amino, [N- (Ci-C4 alkyl) amino] CrC4 alkyl, [?,? - di (C 4 alkyl) amino] C 4 alkyl, N- (C 4 alkanoyl) amino, N - [(C 4 alkyl) (C 1 -C 4 alkanoyl)] amino, N - [(C 4 alkyl) sulfonyl] amino, N - [(CrC4 alkyl substituted with halo) sulfonyl] amino, CrC4 alkanoyl, carboxy, (C4) alkoxycarbonyl, carbamoyl, -j; Nalkyl- CrC4) amino] carbonyl, [N, N -di (C 4 alkyl) amino] carbonyl, cyano, nitro, mercapto, (CrC 4 alkyl) thi, (C 4 alkyl) sulfinyl, (C 4 alkyl) sulfonyl, aminosulfonyl, [N- (alkyl Gp C 4) amino ] sulfonyl and [N, N-di (C 4 alkyl) amino] sulfonyl; and heteroaryl selected from (a) a 5-membered monocyclic aromatic ring having a heteroatom selected from O, S and N and optionally containing from one to three N atoms in addition to said heteroatom; and (b) a 6-membered monocyclic aromatic ring having an N atom and optionally containing one to four N atoms in addition to said N atom; said heteroaryl being optionally substituted with one to three substituents selected from X20; R 39 and R 40 are independently selected from hydrogen; halo; C-i-C4 alkyl; phenyl optionally substituted with one to three substituents independently selected from halo, Ci-C4 alkyl, hydroxy, CrC4 alkoxy, amino, N- (C4 alkyl) amino and N, N-di (C4 alkyl) amino; or R38 and R139 can form, together with the carbon atom to which they are attached, a C3-C7 cycloalkyl ring; m is 0, 1, 2, 3, 4 or 5; and n is 0, 1, 2, 3 or 4. Compounds that can act as selective inhibitors of Cox-2 include indole compounds that are described in U.S. Patent No. 6,300,363. Said compounds have the formula shown below in formula (XXVIII): CXXVH3) and pharmaceutically acceptable salts thereof, wherein: L4 is oxygen or sulfur; Y3 is a direct bond or C1-4 alkylidene; Q6 is (a) C1-6 alkyl or C1-6 alkyl substituted with halo, said alkyl being optionally substituted with up to three substituents independently selected from hydroxy, C1-4 alkoxy, amino and mono- or di- (Ci-4 alkyl) Not me; (b) C3-7 cycloalkyl optionally substituted with up to three substituents independently selected from hydroxy, C4alkyl and Ci-4alkoxy; (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from halo, Ci-4 alkyl, C 1-4 alkyl substituted with halo, hydroxy, C 1-4 alkoxy, Ci-4 alkoxy substituted with halo , S (0) mR143, S02NH2, S02N (alkyl d ^, amino, mono- or di- (alkyl), NHS02R143, NHC (0) R143, CN, C02H, C02 (Ci.4 alkyl), alkyl CM-OH , C1-4 alkyl-OR143, CONH2, CONH (C1-4 alkyl), CON (C1-4 alkyl) 2 and -OY-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, C1-6 alkyl 4, CF3, hydroxy, OR 43, S (0) mR143, amino, mono- or di- (alkyl test and CN; (d) a monocyclic aromatic grof 5 atoms, said aromatic grhaving a heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic grbeing substituted with up to three substituents selected independently in halo, alkyl Ci-4, alkyl Ci-4 substituted with halo, hydroxy, alkoxy G-,. alkoxy -Ci-4 -substituted with halo, alkyl C1- OH, S (0) mR143, S02NH2l S02N (Ci-4 alkyl) 2, amino, mono- or di- (C1-4 alkyl) amino, NHS02R143 , NHC (0) R143, CN, C02H, C02 (C1-4 alkyl), C1-4 alkyl-OR143, CONH2, CONH (Ci-4 alkyl), CON (C -4 alkyl) 2, phenyl, and phenyl mono -, di- or tri-substituted where the substituent is independently selected from halo, CF3, Ci-4 alkyl, hydroxy, C1-4 alkoxy, OCF3, SR143, S02CH3, S02NH2, amino, Ci-4alkylamino and NHS02R143; or (e) a monocyclic aromatic grof 6 atoms, said aromatic grhaving a heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic grbeing substituted with up to three substituents independently selected from halo, Ci alkyl -4, C 1 - 4 alkyl substituted with halo, hydroxy, C 1 - alkoxy, C 1 - 4 alkoxy substituted with halo, C 1 --OH alkyl, S (0) mR 14 3, S 0 2 NH 2, S 0 2 N (C 1 - 4 alkyl) 2, amino, mono- or di- (alkyl Ci-4) amino, NHS02R143, NHC (0) R, CN, C02H, C02 (C1-4 alkyl), C1-4 alkyl-OR143, CONH2, CONH (Ci-4 alkyl), CON (C 1-4 alkyl) 2, phenyl, and mono-, di-ot-substituted-phenyl wherein the substituent is independently selected from halo, CF 3, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, OCF 3 ~ SR 14 3, SO2CH3, S02NH2, amino, C -4 amino alkyl and NHS02R143; R141 is hydrogen, or Ci-6 alkyl optionally substituted with a substituent independently selected from hydroxy, OR143, nitro, amino, mono- or di- (Ci-4 alkyl) amino, C02H, C02 (Ci-4 alkyl), CONH2, CONH (alkyl CM) and CON (C -4 alkyl) 2; R is -hydrogen; C1-4 alkyl; C (O) R145 where R is selected from (a) Ci.22 alkyl or C2-22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four independently selected substituents, -hydroxy-OR143, S (0) mR143, nitro, amino, mono- or di- (C1-4 alkyl) amino, NHS02R143, C02H, C02 (C1-4 alkyl), CONH2, CONH (C1-4 alkyl), CON (C -4 alkyl) 2, OC (O) R143, thienyl, naphthyl and gr of the following formulas: (b) C1-22 alkyl or C2-22 alkenyl, said alkyl or alkenyl being optionally substituted with from 5 to 45 halogen atoms; (c) -Y5-C-3-7 cycloalkyl or -Y5-C3-7 cycloalkenyl, said cycloaiquiio or cycloalkenyl being optionally substituted with up to three substituents independently selected from C- | 4 alkyl, hydroxy, OR143 S (0) mR143 , amino, mono- or di- (C1-4 alkyl) amino, CONH2 >; CONH (C 1-4 alkyl) and CON (C 1-4 alkyl) 2; (d) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven substituents independently selected from halo, C-i-s alkyl, C 4 -alkyl, hydroxy, C 1-8 alkoxy. halo-substituted alkyl, Cis alkoxy substituted with halo, CN, nitro, S (0) mR143, S02NH2, S02NH (C1-4 alkyl), S02N (C1-4 alkyl) 2, amino, C -4 amino alkyl, di - (alky Ci, 4) amino, CONH2, CONH (C1-4 alkyl), CON (C4 alkyl) 2, OC (0) R, and phenyl optionally substituted with - up to three substituents - independently selected from halo, alkyl Ci-4, hydroxy, OCH3, CF3, OCF3, CN, nitro, amino, mono- or di- (Ci-4 alkyl) amino, C02H, C02 (C1-4 alkyl) and CONH2; (e) a monocyclic aromatic group of 5 atoms, said aromatic group having a 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 independently selected substituents between halo, Ci-4 alkyl, Ci-4 alkyl substituted with halo, hydroxy, Ci-4 alkoxy, alkoxy CM substituted with halo, alkyl Ci-4-OH, S (0) mR143, S02NH2, S02N (C1-4 alkyl) ) 2, amino, mono- or di- (alkyl Ci-4) amino, NHS02R143, NHC (0) R143, CN, C02H, C02 (Ci-) alkyl, C1-4 alkyl-OR143, CONH2, CONH (C1 alkyl) -), CON (C1-) alkyl, phenyl, and mono-, di- or tri-substituted phenyl where the substituent is independently selected from halo, CF3, Ci-4 alkyl, hydroxy, Ci-4 alkoxy, OCF3, SR143 , S02CH3, S02NH2, amino, C -4 amino alkyl and NHS02R143; (f) a monocyclic aromatic group having 6 atoms, said aromatic group having a 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 halo, Ci- 4, Ci-4 alkyl substituted with halo, hydroxy, Ci-4 alkoxy, C- alkoxy substituted with halo, C 1-4 alkyl-OH, S (0) mR 143, S02NH 2, S02N (C 1-4 alkyl) 2, amino, mono- or di- (C1-4 alkyl) amino, NHS02R143, NHC (0) R143, CN, C02H, C02 (C1-4 alkyl), C1-4 alkyl-OR143, CONH2) CONH (C1-4 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, Ci-4 alkyl, hydroxy, Ci-4 alkoxy, OCF 3, SR 43, SO2CH3, S02NH2, amino, C1-4 aicylamino and NHS02R143; or (g) a group of the following formula: - - - - - X is halo, Ci-4 alkyl, hydroxy, Ci-4 alkoxy, Ci-4 alkoxy substituted with halo, S (0) mR143, amino, mono- or di- (Ci-4 alkyl) amino, NHSO2R143, nitro, alkyl C1-4 substituted with halo, CN, CO2H, C02 (Ci-4 alkyl), C ^ -OH alkyl, Ci-4 alkyl-OR143, CONH2, CONH (C1-4 alkyl) or CON (C1-4 alkyl) 2; R 43 is Ci-4 alkyl or Ci-4 alkyl substituted with halo; 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; Z 1 is oxygen, sulfur or NR144; and R144 is hydrogen, Ci-6 alkyl, Ci-4 alkyl substituted with halo or -Y5-phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, Ci-4 alkyl, hydroxy, Ci-4 alkoxy, S (0) mR143, amino, mono- or di- (alkyl Ci-4) amino, CF3, OCF3, CN and nitro; with the proviso that a group of formula -Y5-Q is not methyl or ethyl when X22 is hydrogen, L4 is oxygen, R141 is hydrogen, and R142 is acetyl. Compounds that can act as selective inhibitors of Cox-2 include arylphenylhydrazides as described in U.S. Patent No. 6,077,869. Said compounds have the formula shown below in formula (XXIX): wherein X23 and Y6 are selected from hydrogen, halogen, alkyl, nitro, amino and other functional groups containing oxygen and sulfur such as hydroxy, methoxy and methylsulfonyl. Compounds that can act as selective inhibitors of Cox-2 include 2-aryloxy-4-arylfuran-2-ones as described in the US Pat.

United States No. 6,140,515. Said compounds have the formula shown below in formula (XXX): or a pharmaceutically acceptable salt thereof, wherein: 46 is selected from the group consisting of SCH3, -S (0) 2CH3 and -S (0) 2NH2; R147 is selected from the group consisting of OR 50, phenyl or mono- or di-substituted pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro; R is unsubstituted or mono- or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro; R 48 is H or C-M alkyl optionally substituted with from 1 to 3 groups of F, Cl or Br; and R 49 is H and C 1-4 alkyl optionally substituted with from 1 to 3 groups of F, Cl or Br; with the proviso that R148 and R149 are not equal. Compounds that can act as selective inhibitors of Cox-2 include bisaryl compounds as described in U.S. Patent No. 5,994,379. Said compounds have the formula shown below in formula (XXXI): or a pharmaceutically acceptable salt, ester or tautomer thereof, wherein: Z13 is C or N; when Z13 is N, R151 represents H or is absent, or taken together with R152 as described below; when Z. is C, R15 represents H and R is a residue that has the following characteristics: (a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt a transoid configuration energetically-stable and if-is present a double bond, the linkage is in the trans configuration, (b) it is lipophilic except for the atom linked directly to ring A, which is lipophilic or non-lipophilic, and (c) there is an energetically stable planar configuration with ring A at about 15 degrees; or R151 and R 52 are taken in combination and represent a 5- or 6-membered aromatic or non-aromatic D-ring condensed with the A-ring, said ring D 0-3 containing heteroatoms selected from O, S and N; said lipophilic D-ring being the exception except for atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said D-ring having an energetically stable flat configuration with ring A at about 15 degrees; said ring D being additionally substituted with a group Ra selected from the group consisting of C -2 alkyl, -O-C1-2 alkyl, -NHalkyl C -2, -N (Ci-2 alkyl) 2. -C (0) C 1-2 alkyl, -S-C 2 alkyl and -C (S) C 2 alkyl; Y7 represents N, CH or C-O-Ci-3 alkyl, and when Z13 is N, Y7 may also represent a carbonyl group; R 53 represents H, Br, Cl or F; and R154 represents H or CH3. Compounds that can act as selective inhibitors of Cox-2 include 1,5-diarylpyrazoles as described in U.S. Patent No. 6,028,202. Said compounds have the formula shown below in formula (XXXII): (XXXII) wherein: R 55, R156, R157 and R158 are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1.5 alkoxy, phenyl, halo, hydroxy, Ci-5 alkylsulfonyl, C1-5 alkyl thio, trihalo-C 1-5 alkyl, amino, nitro and 2-quinolinylmethoxy; R 59 is hydrogen; Ci-5 alkyl; trihalo-C 1-5 alkyl; phenyl; substituted phenyl wherein the phenyl substituents are halogen, Ci-5 alkoxy, trihaloC1-5 alkyl or nitro; or 5-7 membered heteroaryl ring where at least one of the ring members is nitrogen, sulfur or oxygen; R160 is hydrogen; C1-5 alkyl; phenyl-C 1 -5 alkyl; substituted phenyl-C-i-alkyl wherein the substituents of the phenyl are halogen, d-5-alkoxy, trihalo-C-5-alkyl or nitro; C 1 -C 5 alkoxycarbonyl; phenoxycarbonyl; or substituted phenoxycarbonyl wherein the phenyl substituents are halogen, Ci-5 alkoxy, trihaloC1-5 alkyl or nitro; R 6 is C 1-10 alkyl; substituted C1-10 alkyl wherein the substituents are halogen, trihalo-C1.5alkyl, Ci-5alkoxy, carboxy, C1-5alkoxycarbonyl, amino, C1-5alkylamino, di (Ci_5alkylamino), di (Ci_alkyl) -5) amino-alkylated C1-5 amino, Ci-5alkylamino-C1-5alkylamino or a heterocycle containing 4-8 atoms in the ring where one or more of the ring atoms is nitrogen, oxygen or sulfur, said heterocycle being optionally substituted with Ci_5 alkyl; phenyl; substituted phenyl wherein the substituents of the phenyl are one or more of C1-5 alkyl, halogen, Cvs alkoxy, trihaloC1-5 alkyl or nitro; heteroaryl that has 5-7 atoms in e! ring where one or more atoms are nitrogen, oxygen or sulfur; condensed heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or NR163R164 where R163 and R164 are independently selected from hydrogen, and Ci-5 alkyl, or R163 and R164 can be taken together with the described nitrogen to form a 5-7 membered heteroaryl ring in the ring where one or more of the ring members is nitrogen, sulfur or oxygen, said heteroaryl ring being optionally substituted with C 1-5 alkyl; and R162 is hydrogen, Ci-5 alkyl, nitro, amino or halogen; or pharmaceutically acceptable salts thereof. Compounds that can act as selective inhibitors of Cox-2 include 2-substituted imidazoles as described in U.S. Patent No. 6,040,320. Said compounds have the formula shown below in formula (XXXIII): wherein: R164 is phenyl; heteroaryl containing from 5 to 6 ring atoms; or substituted phenyl wherein the substituents are independently selected from one or more members of the group consisting of Ci-5 alkyl, halogen, nitro, trifluoromethyl and nitrite; R165 is phenyl; heteroaryl containing from 5 to 6 ring atoms; substituted heteroaryl - - wherein the substituents are independently selected from one or more members of the group consisting of Ci-5 alkyl and halogen; or substituted phenyl wherein the substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen, nitro, trifluoromethyl and nitrite; R166 is hydrogen, 2- (trimethylsilyl) ethoxymethyl, "C-5 alkoxycarbonyl aryloxycarbonyl, aryl-alkyl Ci-5-oxycarbonyl, aryl-Ci-5-alkyl, phthalimido-C-5-alkyl, Ci-5-alkylamino, diamino-alkyl Ci-5, succinimido-C1-5 alkyl, C5 alkylcarbonyl, arylcarbonyl, C1-5 alkylcarbonylC1-5alkyl, aryloxycarbonylC1alkyl. 5, heteroaryl-C1.5 alkyl wherein the heteroaryl contains from 5 to 6 ring atoms, or substituted aryl-C5 alkyl in which the aryl substituents are independently selected from one or more members of the group consisting of Ci alkyl -5, Ci-5 alkoxy, halogen, amino, Ci-5-amino alkyl and di (Ci-5 alkyl) amino; and R167 is (A11) n- (CH165) q-X24 wherein A11 is sulfur or carbonyl; n is 0 or 1; q is 0-9; and X24 is selected from the group consisting of hydrogen; hldroxl; halogen; vinyl; ethynyl; Ci-5 alkyl; cycloalkyl 63-7; C1-5 alkoxy; phenoxy; phenyl; aryl-alkyl C-i-s; Not me; Ci-5-amino alkyl; nitrite; phthalimide; amido; phenylcarbonyl; Ci-5-aminocarbonyl alkyl; phenylaminocarbonyl; aryl-alqull C1-5 aminocarbonyl; alkyl Ci-5 thio; C1-5 alkylsulfonyl; phenylsulfonyl; substituted sulfonamido wherein the sulfonyl substituent is selected from the group consisting of C 1 -alkyl. 5, phenyl, C1-5 aralkyl, thienyl, furanyl and naphthyl; substituted vinyl wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine, chlorine and iodine; substituted ethynyl 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 wherein the substituents are selected from the group consisting of one or more C 1-5 alkoxy, trihaloalkyl, phthalimido and amino; substituted phenyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci-5 alkyl, halogen and C-5 alkoxy; substituted phenoxy wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci-5 alkyl, halogen and Ci-5 alkoxy; substituted C 1-5 alkoxy wherein the alkyl substituent is selected from the group consisting of phthalimido and amino; aryl-substituted C 1-5 alkyl wherein the alkyl substituent is hydroxyl; aryl-substituted C 1 -5 alkyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of Ci-5 alkyl, halogen and Ci-s alkoxy; substituted amide wherein the carbonyl substituent is selected from the group consisting of C 1-5 alkyl, phenyl, arylalkyl C i, thienyl, furanyl and naphthyl; substituted phenylcarbonyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of C 1-5 alkyl, halogen and Ci-5 alkoxy; C 1 -C 5 substituted alkyl wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido; C1-5 alkylsulfonyl substituted where the alkyl substituent is selected from the group consisting of hydroxy and phthalimido; and substituted phenylsulfonyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of bromine, fluorine, chlorine, d-5 alkoxy and trifluoromethyl; with the proviso that (a) if A11 is sulfur and X24 is other than hydrogen, C1-5alkylaminocarbonyl, phenylaminocarbonyl, arylC5-5alkylaminocarbonyl, C1-5alkylsulfonyl or phenylsulfonyl, then- it must be equal to or greater than 1; (b) if A11 is sulfur and q is 1, then X24 can not be C-i-2 alkyl; (c) if A is carbonyl and q is 0, then X24 can not be vinyl, ethynyl, Ci_5alkylaminocarbonyl, phenylaminocarbonyl, arylC1-5alkylaminocarbonyl, C5alkylsulfonyl or phenylsulfonyl; (d) if A11 is carbonyl, q is 0 and X24 is H, then R 66 is not 2- (trimethylsilyl) ethoxymethyl; (e) if n is 0 and q is 0, then X24 can not be hydrogen; and pharmaceutically acceptable salts thereof. Compounds that can act as selective inhibitors of Cox-2 include 1,3-and 2,3-diarylcycloalkane and cycloalkenepyrazoles as described in U.S. Patent No. 6,083,969. Said compounds have the general formulas (XXXIV) and (XXXV) shown below: (XXXIV) (XXXV) wherein: and R are independently selected from the group consisting of hydrogen, halogen, alkyl (Ci-C6), alkoxy (CrC6), nitro, amino, hydroxy, trifluoro, -S alkyl (C C6), -SO alkyl ( Ci-Ce) and -S02 alkyl (C C6); and the condensed residue is -selected- from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulas: wherein: R 70 is selected from the group consisting of hydrogen, halogen, hydroxy and carbonyl; R171 and R172 are independently selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, alkyl (C- | -C6), alkoxy (C6), = NOH, -NR17 R175, -OCH3l -OCH2CH3, -OS02NHC02CH3 , = CHC02CH2CH3, -CH2C02H, -CH2CO2CH3, -CHaCOZCHaCHa, -CH2CON (CH3) 2, -CH2C02NHCH3, -CHCHCO2CH2CH3, -OCON (CH3) OH, -C (COCH3) 2, dialkyl (? -? -? E) and dialkoxy (CrC6); and R173 is selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, (Ci-C6) alkyl, (C- | -C6) alkoxy and optionally substituted carboxyphenyl, wherein the substituents on the carboxyphenyl group are selected from the group consisting of a group consisting of halogen, hydroxy, amino, alkyl (Cr C6) and alkoxy (C6); or R and R taken together form a moiety selected from the group consisting of -OCOCH2-, -ONH (CH3) COCH2-, -OCOCH.dbd. I-; and / or R172 and R173 taken together form a moiety selected from the group consisting of. * 0 -.y. - " R174 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3 and alkyl (Ci-C6); and R175 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3, alkyl (C6), -CONH2 and -S02CH3; with the proviso that if M is a cyclohexyl group, then from R170 to R173 must not all be hydrogen; and forms of pharmaceutically acceptable salts, esters and prodrugs thereof. Compounds that can serve as selective inhibitors of Cox-2 include esters derived from indolalkanols and amides derived from indolalkylamides as described in U.S. Patent No. 6,306,890. Said compounds have the general formula shown below in formula (XXXVI): (XXXVI) where: > 176 is Ci-C6 alkyl, branched C6 alkyl, C4-C8 cycloalkyl, CrC6 hydroxyalkyl, branched CrC6 hydroxyalkyl, C4-C8 aryl substituted with hydroxy, primary, secondary or tertiary C6 alkyl amino, primary branched amino Ci-C6 alkyl, secondary or tertiary, aryl C4-C8 primary, secondary amino, or. tertiary ,, acid, alkyl Ci-Ce. carboxylic, branched alkyl d-C6 carboxylic acid, alkyl CI-C6 ester, C6 alkyl branched ester, C4-C8 aryl, aryl C4-CB carboxylic acid, C4-C8 aryl ester, C6 alkyl substituted with C4-C8 aryl , C -C8 heterocyclic alkyl or aryl with O, N or S in the ring, alkyl or C4-C8 heterocyclic aryl substituted with alkyl or substituted with aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chlorine, bromine, fluorine or iodine; R177 is halo, C-pCe alkyl, branched C1-C6 alkyl, C4-C8 cycloalkyl, C4-C8 aryl, C4-C8 aryl substituted alkyl, CrC6 alkoxy, branched CrC6 alkoxy, aryl C4: Cs oxy, or versions halo-substituted thereof, wherein halo is chloro, fluoro, bromo, or iodo; R178 is hydrogen, CrC6 alkyl or branched C-i-Ce alkyl; R179 is Ci-C6 alkyl > . aroyl C4-C8, C4-C8 aryl, heterocyclic C4-C8 heterocyclic alkyl or aryl with O, N or S on the ring, C6-C6-alkyl substituted with C4-C8-aryl, alkyl or C4-C8-heterocyclic aryl substituted or substituted with aryl with O, N or S in the ring, C4-C8 aroyl substituted with alkyl, or C4-Ca aryl substituted with alkyl, or halo-substituted versions thereof where halo is chloro, bromo, or iodo; n is 1, 2, 3, or 4; and X25 is O, NH, or N-R 80, where R180 is CrC6 alkyl or branched CrC6 alkyl. Compounds that can act as selective inhibitors of Cox-2 include pyridazinone compounds as described in U.S. Patent No. 6,307,047. Said compounds have the formula (XXXVII): or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein: X26 is selected from the group consisting of O, S, -NR185, -NORa and -NNRbRc; R185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclic alkyl; Ra, Rb and Rc are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R18 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylalkalkyl, arylalhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclyl, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, - (CH2) nC (0) R186, - (CH2) nCH ( OH) R186, - (CH2) nC (NORd) R186, - (CH2) nCH (NORd) R186, - (CH2) nCH (NRdRe) R186, -R187R188, - (CH2) nC = CR188, - (CH2) n [CH (CX26'3)] m (CH2) pR188, - (CH2) n (CX26.2) m (CH2) pR188i and (CH2) n (CHX26 ') m (CH2) mR184; R186 is selected from the group consisting of hydrogen, ayanyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclyl, and heterocyclic alkyl; R187 is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene; R188 is selected from the group consisting of hydrogen, anynyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclyl, and heterocyclic alkyl; Rd and R6 are independently selected from the group consisting of hydrogen, ayanyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclyl, and heterocyclic alkyl; X26 'is halogen; m is an integer from 0 to 5; n is an integer from 0 to 10; p is an integer from 0 to 10; R182, R183 and R184 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, heterocyclyl, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkyl, nitro, fbsforiatoalkoxy, Y8 ~ and Z14, with the proviso that one of R 82, R 83 or R 84 must be Z14, and furthermore with the proviso that only one of R 82, R 83 or R184 is Z14; Z14 is selected from the group consisting of: X27 is selected from the group consisting of S (0) 2, S (0) (NR191), S (O), Se (0) 2, P (0) (OR192) and P (0) (NR 93R194); X28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen; R 90 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH2 and -NCHN (R 91) R192; R191, R 92, R193 and R 94 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R193 and R194 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 NR188; Y8 is selected from the group -constituted by -OR 95, -SR195, -C (R197) (R198) R195, -C (0) R195, -C (0) OR195, -N (R197) C ( 0) R195, -NC (R197) R195 and -N (R197) R195.

R 95 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl; cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclic alkyl, hydroxyalkyl and NR 99R200; and R197, R198, R 99 and R200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, and heterocyclic alkyl. Compounds that can act as selective inhibitors of Cox-2 include benzosulfonamide derivatives as described in U.S. Patent No. 6,004,948. Said compounds have the formula (XXXVIII): (XXXVJH) wherein: A12 denotes oxygen, sulfur or NH; R201 denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted with halogen, alkyl, CF3 or alkoxy; D5 denotes a group: each of R202 and R203 independently of each other denotes hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, an aryl or heteroaryl radical or a radical (CH2) n-X29; or R202 and R203 together with the N atom denote a 3-7 membered heterocycle saturated, or partially or totally unsaturated with one or more N, O, or S heteroatoms, which may be optionally substituted with oxo, an alkyl, alkylaryl group or aryl or a group (CH2) n-X29; R202 'denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2) n-X29; X29 denotes halogen, N02) -OR204, -COR204, -C02R204, -OC02R204, -CN, -CONR204OR205, -CONR204R205, -SR204, -S (0) R204, -S (0) 2R204, -NR204R205, -NHC ( 0) R204 or -NHS (0) 2R204; Z15 denotes -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH = CH-, -CH = CH-CH2-, -CH2-CO-, -CO-CH2-, -NHCO -, -CONH-, -NHCH2-, -CH2NH-, -N = CH-, -NHCH-, -CH2-CH2-NH-, -CH = CH-, > N-R203, > C = 0 or > S (0) m; R204 and R205 independently selected from each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from 0 to 6; R206 is CF3 or a straight or branched chain Ci-4 alkyl group optionally mono- or polysubstituted by halogen or alkoxy; and m denotes an integer from 0 to 2; with the proviso that A12 does not represent O if R206 denotes CF3; and pharmaceutically acceptable salts thereof. The selective Cox-2 inhibitors useful in the present methods and compositions may include the compounds described in the patents cited individually below, and which are incorporated herein by reference. U.S. Patent No. 6,169,188. U.S. Patent No. 6,020,343. U.S. Patent No. 5,981,576. U.S. Patent No. 6,222,048. U.S. Patent No. 6,057,319. U.S. Patent No. 6,046,236. U.S. Patent No. 6,002,014. U.S. Patent No. 5,945,539. U.S. Patent No. 6,359,182. The selective Cox-2 inhibitors useful in the present invention can be delivered from any source as long as the selective Cox-2 inhibitor is pharmaceutically acceptable. Selective Cox-2 inhibitors can be isolated and purified from natural sources or can be synthesized. Selective Cox-2 inhibitors should have a quality and purity that is conventional in the market for use in pharmaceutical products. Likewise, the Cox-2 inhibitors useful in the compositions and methods of the present invention can be synthesized, for example, according to the description of the Example. Various Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention can be synthesized by the methods described, for example, in U.S. Patent No. 5,466,823 to Talley et al. Valdecoxib useful in therapeutic combinations of the present invention can be prepared in the manner indicated in the U.S. Pat. No. 5,633,272. Parecoxib useful in therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,932,598. The rofecoxib useful in therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,968,974. Japan Tobacco JTE-522 useful in therapeutic combinations of the present invention can be prepared in the manner indicated in Japanese Patent Publication Nc JP90 / 52882. The pyrazoles can be prepared by the methods described in International Patent Publication No. WO 95/15316. The pyrazoles can be further prepared by the methods described in International Patent Publication No. WO 95/15315. Pyrazoles can also be prepared by the methods described in International Patent Publication No. WO96 / 03385. The thiophene analogs can be prepared by the methods described in International Patent Publication No. WO95 / 0050. The preparation of thiophene analogs is also described in International Patent Publication No. WO 94/15932.

The oxazoles can be prepared by the methods described in International Patent Publication No. WO 95/00501. The preparation of oxazoles is also described in the Publication of International Patent-N0 WO 94/27980. - The soxazoles can be prepared by the methods described in International Patent Publication No. WO 96/25405. The imidazoles can be prepared by the methods described in International Patent Publication No. WO96 / 03388. The preparation of imidazoles is also described in International Patent Publication No. WO96 / 03387. Cyclopentane Cox-2 inhibitors can be prepared by the procedures described in U.S. Patent No. 5,344,991. The preparation of Cyclopentene Cox-2 inhibitors is also described in International Patent Publication No. WO 95/00501. The terphenyl compounds can be prepared by the methods described in International Patent Publication No. WO 96/16934. The thiazole compounds can be prepared by the methods described in International Patent Publication No. WO 96 / 03,392. The pyridine compounds can be prepared by the methods described in International Patent Publication No. WO 96/03392. The preparation of pyridine compounds is also described in International Patent Publication No. WO 96 / 24,585.

Exemplary Cox-2 selective inhibitor compounds are selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS 57067, T-614, BMS-347070, JTE-522, S-2474 , -SVT = 2016, - CT ^ 3-,. ABT-963, SC-58125, nimesulide, flosulide, NS-398, L-745337, RWJ-63556, L-784512, darbufelone, CS-502, LAS-34475, LAS-34555, S-33516, SD-8381, prodrugs of any of them, and mixtures thereof. More particularly, the selective Cox-2 inhibitor can be selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrugs of any of them, and mixtures thereof. In one embodiment, the selective Cox-2 inhibitor comprises celecoxib. In another embodiment, the selective Cox-2 inhibitor comprises valdecoxib. In another embodiment, the selective Cox-2 inhibitor comprises parecoxib sodium. In accordance with the method of the present invention, an Hsp inhibitor, with or without a Cox-2 inhibitor, is administered in combination with a PDE inhibitor. In another embodiment, the PDE inhibitor is a cGMP-specific PDE inhibitor. The cGMP specific PDEs include PDE 5, PDE6, and PDE9. Any agent that inhibits one or more of these PDE isoenzymes can be used in the present invention. Examples of the cGMP-specific PDE inhibitors that are useful in the present invention are shown in Table 6 and include, but are not limited to, exisulind, dipyridamole, MBCQ, MMPX, MY-5445, zaprinást, sildenafil, tadalafil, vardenafil, T-032, A02131-1, GF248, E-4021, sofoflavescenol, UK-122764, CP-131, CP-33, CP-165, CP-265, CP-132, CP-461, CP-248, SCH 51866 , imidazole [5,1-f] triazin-4 (3H) -ones, 4-benzylamino-1-chloro-6-substituted-phthalazines, ~ -zololyl-condensate compounds, flavanol glucosols, pharmaceutically acceptable salts and prodrugs of the same and combinations thereof. In some embodiments, the cGMP-specific PDE inhibitor is selected from the group consisting of exisulind, sildenafil citrate, tadalafil, vardenafil and zaprinást. In an illustrative embodiment, the cGMP-specific PDE inhibitor is exisulind. or Table 6: cGMP specific phosphodiesterase (PDE) inhibitors or Generic and chemical name Name Class of Manufacturer Reference trade drug and I MMPX Wells Inhibitor & Miller? 988) Methods Enzvmol. 159, 489 A4 8-m ethoxim ethyl-1-methyl ethyl-3- (2-PDE methylphenyl) -xanthine sensitive to! calmodulin i. (C½ = 5.2 μ?) MY-5445 Haaiwara Inhibitor v. Col. (1984 J. Pharmacol. Exp. Ther.

A5 1 - (3-chlorophenollamine) -4- PDE 5 228, 467 phenylftalazine zaprinast Christensen inhibitor v Torphv (1994) Ann. Rep. Med.

A6 2- (2-propylloxyphenyl) -8-azapurine-PDE 5, PDE 6 Chem. 29. 185! 6-one and PDE 9 Soderlina v col (1998) J. Biol. Chém. 273, 5553 Sildenafil Citrate Viagra Pfizer Inhibitor Boolell et al. (1996) Br. J. Urol. 78, 257-261 A7 1 - [[3- (6,7-dihydro-1-PDE 5 methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3-d] pyrimidin-5-y citrate] ) -4- ethoxyphenyl] sulfonyl] -4- tnethylpiperazine A8 tadalafil Cialis Inhibitor of Lilly Grosser (2002 Eur. J. Med. Res. 7, 435-446. or ? ° Generic and chemical name Name Class of Fabricant Reference trade drug and I PDE 5? 9 Vardenafil Levitra Inhibitor from Bayer Grosser (2002) Eur. J. Med. Res. 7, 435-446. 'PDE 5 T-1032 Inhibitor of Inoue, H. et al. (2001) Eur. J. Pharmacol. 422, 109-? 10 Sulfate 2- (4-aminophenyl) -1, 2-PDE 5 114 dihydro-1-oxo-7- (2-! Pyridinylmethoxy) -4- (3,4,5-trimetox Phenyl) -3-isoquinoline methyl carboxylate A02131-1 Inhibitor of Yu et al. (1996) Blood 87, 3758-3767? 11 3- (5'-hydroxymethyl-2'-furyl) -1- PDE specific benzylthiene (3,2-c) pyrazole of G Pc GF248 Inhibitor of Estrade et al. (1998) Eur. J. Pharmacol. 352, 157-? 12 5 (Pr ° poxy), 7 '(4-morpholino) -pecific PDE 163 phenacyl], [1-methyl-3-cGMP propyl] pyrazolo [4,3-d] pyrimidine- 7-ona E-4021 Kodama Inhibitor et al. (1994) Eur. J. Pharmacol. 263, 93- or Generic and chemical name Name Manufacturer's class Reference trademark drug 1 A13 1- (6-chloro-4- (3,4-specific PDE 99 methylbenzyl) amino-quinazolin-n-cGMP 2- l) piperidin-4- carboxylate. A14 sofoflavescenol | Shin inhibitor and col. (2002) Bioorg. Med. Chem. Lett. 12, PDE 5 2313-2316 UK-122764 Inhibitor of lllarion et al. (1999) Mol. Pharmacol. 56, 24-130 A15 derived from sildenafil PDE 5 CP-131 Cell Inhibitor www.cellpathways.com/3_RESEARCH/research.ht A16 Analog of Exisulind Specific PDE Pathways My of GMPc CP-33 Cell Inhibitor www.cellpathways.com/3_RESEARCH/research.ht A17 Analog of Exisulind Specific PDE Pathways My of GMPc CP-165 Cell Inhibitor www.cellpathways.com/3_RESEÁRCH/research.ht A18 Analog of Exisulind Specific PDE Pathways My of GMPc CP-265 Cell Inhibitor www.cellpathways.com/3_RESEARCH/research.ht A19 analog of exisulind specific PDE Pathways my t o Generic and chemical name Name Manufacturer's class Reference trademark drug 1 A25 phthalazines 4-benzylamino-1 inhibitors Watanabe et al. (1998) J. Med. Ghem. 27, 3367- chloro-6-substituted PDE 5 3372 Pirazolyl compounds US Pat. No. 6,518,294 PDE A26 1 -benzyl-3- (5-methoxycarbonyl- specific i-2-furyl) condensates - 5,6-GMPc methylenedioxoindazole; 1-benzyl-3- (5'-hydroxycarbonyl-2'-furyl) -5,6-methylenedioxoindazole; 1-Benzyl-3- (5'-methoxymethyl-2'-furyl) -5,6-methylenedoxoxindazole; 1-benzyl-3- (5'-hydroxylmethyl-2'-furyl) -5,6-methylenedioxoandazole A27 Flavanol glycosides US Patent Inhibitors No. 6,399,579 prenylated PDE 5 The Hsp90 inhibitors and PDE inhibitors useful in accordance with the present invention can be delivered from any source as long as they are pharmaceutically acceptable. Also, an Hsp90 inhibitor can be synthesized, for example, according to the description in Example 2, and a PDE inhibitor can be synthesized, for example, according to the description in Example 4. Hsp90 inhibitors and inhibitors of PDEs can also be isolated and purified from natural sources. The Hsp90 inhibitors and PDE inhibitors should be of a quality and purity that is conventional in the market for use in pharmaceutical products. In one embodiment of the present invention, a combination comprising an inhibitor of Hsp90 and a PDE inhibitor, and optionally a Cox-2 inhibitor, is administered to a subject in need of such treatment in accordance with conventional routes of drug administration. which are well known to a specialist skilled in the art. One, two or all three of the Hsp90 inhibitor, the Inhibitor of PDE and the optional Cox-2 inhibitor can optionally be supplied in the form of a pharmaceutically acceptable salt, a prodrug, an isomer, a racemic mixt or in any other form or chemical combination which, under physiological conditions, continues to provide inhibition of its respective enzymatic targets. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycoic, gluronic, 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, sulphanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactárico and galacturónico. Suitable pharmaceutically acceptable base-addition salts include metal ion salts and organic ion salts. The metal ion salts include, but are not limited to, appropriate alkali metal salts (la group), alkaline earth metal salts (lia group) and other physiologically acceptable metal ions. Such salts can be made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc ions. The organic salts can be made of tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, ty / V-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound. A combination of an Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, can be provided in a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition. The pharmaceutical compositions may also include stabilizers, antioxidants, colorants and diluents. The pharmaceutically acceptable carriers and additives are chosen so that the side effects of the pharmaceutical compound are minimized and that the yield of the compound is not canceled or inhibited in such a way that the treatment is ineffective. In one embodiment, an Hsp90 inhibitor and a PDE inhibitor are co-administered to a subject in a pharmaceutical carrier. In another embodiment, they are administered separately. When a Cox-2 inhibitor is present in the combination, it can be co-administered in a pharmaceutical carrier with either or both of the Hsp90 inhibitor and / or the inhibitor of Hsp90.

PDE, or separately from both ... The pharmaceutical compositions can be administered enterally and / or parenterally. The oral route (intragastric) is a typical route of administration. Pharmaceutically acceptable carriers can be in solid dosage forms, including tablets, capsules, pills and granules, which can be prepared with coatings and shells, such as enteric coatings and others well known in the art. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Parenteral administration includes the subcutaneous, intramuscular, intradermal, intramammary, intravenous and other routes known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules and syrups. When administered, the pharmaceutical composition may be at or near body temperat Compositions intended for oral use can be prepared according to any method known in the art for the manufactof pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives to provide pharmaceutically elegant and acceptable preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients, which are suitable for the manufacture of. tablets These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulation and disintegration agents, for example, corn starch or alginic acid, binding agents, for example starch, gelatin or gum arabic, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, for example to delay disintegration and absorption in the gastrointestinal tract and therefore to provide a sustained action for a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be present as hard gelatin capsules in which the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatine capsules in which the active ingredients are present as such, or mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions can be produced to contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic.; the dispersing agents or humectants can be natural phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products -of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters obtained from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters obtained from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, p-h idroxy ethyl benzoate or n-propyl, one or more coloring agents, one or more flavoring agents or one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those indicated above, and flavoring agents may be added to provide an acceptable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrated by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents. Syrups and elixirs containing Hsp90 inhibitors and / or PDE inhibitors and / or Cox-2 inhibitors can be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

An Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, can be administered parenterally, for example subcutaneously, intravenously, intramuscularly or intrasternally, or by infusion techniques, in the form of aqueous or oleaginous suspensions sterile injectables. Such suspensions may be formulated according to the known art using suitable dispersing agents or humectants and suspending agents such as those mentioned above or other acceptable agents. A sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, the sterile fixed oils are used conventionally as a solvent or suspension medium. -For this purpose, any insipid fixed oil, including synthetic mono- or diglycerides, can be used. In addition, omega-3 polyunsaturated fatty acids can be used in the preparation of injectable agents.

The administration can also be by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at the standard temperature, - ero liquid - the rectal temperature and therefore will melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols. The present invention also encompasses buccal and sublingual administration, including administration in the form of dragees, lozenges or a chewing gum comprising the compounds indicated herein. The compounds can be deposited in an aromatized base, usually sucrose and gum arabic or tragacanth. Other methods for administration of the Hsp90 inhibitor and the PDE inhibitor, and optionally the Cox-2 inhibitor, include dermal patches that release the drugs directly on and / or through the skin of a subject. The present invention also encompasses topical administration systems and includes ointments, powders, sprays, cream, jellies, eye drops, solutions or suspensions. Powders have the advantage of sticking to wet surfaces, and therefore, they can remain active for longer periods of time. Therefore, dusts are especially attractive for treating neoplasms in, for example, the ear canal. For the same reason, the creams are also pharmaceutically acceptable effective vehicles. The compositions of the present invention may optionally be supplemented with additional agents such as, for example, enhancers. of viscosity, preservatives-, surfactants and penetration enhancers. The viscosity forming agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from about 0.01% to about 2% by weight of a pharmaceutical composition. Preservatives are optionally used to prevent microbial growth before or during use. Suitable preservatives include polyquaternary-, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of from about 0.001% to about 1.0% by weight of a pharmaceutical composition. The solubility of the components of the present compositions can be improved by a suitable surfactant or other cosolvent in the composition. Such co-solvents include polysorbates 20, 60 and 80, polyoxyethylene polyoxypropylene surfactants (e.g., Pluronic ™ F-68, F-84, and P-103), cyclodextrin; or other agents known to those skilled in the art. Typically, such co-solvents are employed at a level of from about 0.01% to about 2% by weight of a pharmaceutical composition.

The pharmaceutically acceptable excipients and vehicles encompass all of the foregoing and the like. The above considerations concerning effective formulations and methods of administration are well known in the art and are described in conventional textbooks. See, for example, Reminaton: The Science and Practice of Pharmacv, 20th Edition, (Lippincott, Williams and Wilkins), 2000; Lieberman et al., Ed., Pharmaceutical Dosaqe Forms, Marcel Decker, New York, NY., 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipient (3rd Edition), American Pharmaceutical Association, Washington, 1999. When an inhibitor of Hsp90 and a PDE inhibitor, and optionally a Cox-2 inhibitor, are used in a combination therapy, the amount of the Hsp90 inhibitor and the amount of the PDE inhibitor, optionally together with the amount of the Cox-2 inhibitor, should comprise an effective amount of the combination of the two treatment agents. Thus, the present invention encompasses a method for treating or preventing neoplasia or a disorder related to neoplasia in a subject in need of such treatment or prevention, the method comprising administering a first amount of a Hsp90 inhibitor in combination with a second amount of a PDE inhibitor, wherein the amount of the combination, ie, the total of said first and second amounts, is therapeutically effective for such treatment or prevention. The present invention also encompasses a method for preventing and treating neoplasia or a neoplasm-related disorder in a subject in need of such prevention and treatment, the method comprising administering a first amount of an Hsp90 inhibitor in combination with a second amount. of a PDE inhibitor ~ and a third amount of a Cox-2 inhibitor, wherein the amount of the combination, i.e., the total of said first, second and third amounts, is therapeutically effective for such prevention or treatment. In determining an effective amount or dose, numerous factors are considered by the attending physician, including, but not limited to, the potency and duration of action of the compounds used, the nature and severity of the disease to be treated, as well as sex. , age, weight, the general state of health and the individual sensitivity of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that the dosages can also be determined with The Pharmacological Guide Basis of Therapeutics by Goodman & Goldman, Ninth Edition (1996), Appendix II, p. 1707-1711. It will be appreciated that the amount of the combination comprising an inhibitor of Hsp90 and a PDE inhibitor and optionally a Cox-2 inhibitor, required for use in the treatment or prevention of neoplasia and disorders related to the neoplasm will vary within broad limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, this document describes an appropriate daily dosage, although the limits that are identified as preferred may be exceeded if appropriate: The daily dosage may be administered in the form of a single dosage or in divided dosages.

The dosage level of an Hsp90 inhibitor will necessarily depend on the particular agent that is used. However, an appropriate dosage level of an Hsp90 inhibitor is generally between about -0.0000-1. mg / kg and approximately 200 mg / kg of body weight of the subject per day, administered in single or multiple doses. More typically, the dosage level is from about 0.1 mg / kg to about 25 mg / kg per day. - Also, the dosage level of a PDE inhibitor will depend on the particular agent that is used. However, an appropriate dosage level of a PDE inhibitor is generally between about 0, 01 mg / kg and approximately 10 mg / kg per day. In higher order mammals, for example, human beings, a typical dose indicated for the PDE inhibitor is from about 1 mg to about 500 mg per day. A combination therapy comprising an Hsp90 inhibitor, a PDE inhibitor and a Cox-2 inhibitor has an appropriate dosage level of the Cox-2 inhibitor which is generally from about 0.01 mg / kg to about 140 mg / kg of body weight of the subject per day, administered in single or multiple doses. More typically, the dosage level is from about 0.01 mg / kg to about 50 mg / kg per day, for example from about 0.1 mg / kg to about 25 mg / kg per day, of about 0.1. mg / kg to approximately 10 mg / kg per day, or from approximately 0.5 mg / kg to approximately 10 mg / kg per day. In higher order mammals, for example humans, a typical dose indicated for the Cox-2 inhibitor is from about 0.5 mg to about 7 grams orally per day. A compound can be administered in a regimen several times a day, for example from 1 to about 4 times a day, preferably once or twice a day.

The amount of the Cox-2 inhibitor that can be combined with carrier materials to produce a single dosage form varies depending on the subject to be treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 7 g of active agent optionally combined with an appropriate and convenient amount of carrier material which may vary from about 5% to about 95%. percent of the total composition. Dosage unit forms for the Cox-2 inhibitor generally contain from about 1 mg to about 500 mg of the active ingredient, for example 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. The exact dosage and regimen for administering an Hsp90 inhibitor in combination with a PDE inhibitor, and optionally with a Cox-2 inhibitor, will necessarily depend on the potency and duration of action of the compounds used, the nature and severity of the disease to treat, as well as sex, age, weight, general state of health and individual sensitivity of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that the dosages can also be determined with The Pharmacological Guide Basis of Therapeutics by Goodman & Goldman, Ninth Edition (1996), ~ Appendix II, pp. 1707-1711. The efficacy of a particular dosage of an Hsp90 inhibitor in combination with a PDE inhibitor and optionally with a Cox-2 inhibitor can be determined by monitoring the effect of a given dosage on the progression of the disorder or prevention of a neoplasia disorder.

In one embodiment, the efficacy of a particular dosage of a combination therapy comprising an inhibitor of Hsp90 and a PDE inhibitor, and optionally a Cox-2 inhibitor, can be established by determining the. stage of the disorder in multiple points during the treatment of a subject. For example, once the histological diagnosis has been made, the determination of the stage (ie, determination of the extent of the disease) helps to determine the decisions and prognosis of the treatment. The determination of the clinical stage uses data from the patient's history, physical examination and non-invasive studies. The determination of the pathological stage requires tissue samples. The pathological stage is determined by obtaining a biopsy of the neoplasm or tumor. A biopsy is performed by obtaining a sample of tumor tissue and examining the cells under a microscope. A bone marrow biopsy is especially useful in determining the metastasis of a malignant lymphoma and small cell lung cancer. Marrow biopsy will be positive in 50 to 70% of patients with malignant lymphoma (low and intermediate grade) and in 15-18% of patients with small cell lung cancer at diagnosis. See The Merck Manual of Diagnosis & Therapy, 17th Edition (1999), Sec. 11, Chapter 84, Hematology and Oncology, Overview of Cancer. The determination of the enzymatic and chemical levels in serum can also help in the determination of the stage. The increase in liver enzymes (alkaline phosphatase, LDH and ALT) suggests the presence of liver metastases. A high level of alkaline phosphatase and Ca in serum may be the first evidence of bone metastasis. A high level of acid phosphatase (inhibited by tartrate) suggests extracapsular extension of prostate cancer. Fasting hypoglycaemia may indicate an insulinoma, hepatocellular carcinoma, or retroperitoneal sarcoma. Elevated levels of BUN or creatinine may indicate an obstructive uropathy secondary to the pelvic mass, intrarenal obstruction of the tubular precipitation of the myeloma protein or nephropathy by uric acid of lymphoma or other cancers. Elevated levels of uric acid usually occur in myeloproliferative and lymphoproliferative disorders. The level of α-fetoprotein may be elevated in hepatocellular carcinoma and testicular carcinomas, carcinoembryonic S-antigen in colon cancer, human chorionic gonadotropin in choriocarcinoma and testicular carcinoma, serum immunoglobulins in multiple myeloma and DNA probes (bcr probe to identify the change of chromosome 22) in CML. Tumors can synthesize proteins that do not produce clinical symptoms, for example, human chorionic gonadotropin, α-fetoprotein, carcinoembryonic antigen, CA 125 and CA 153. These protein products can be used as tumor markers in the serial evaluation of patients to determine recurrence of the disease or response to therapy. In this way, the control of a subject with respect to these tumor markers indicates the progress of a neoplasia disorder. Such control also indicates how well the methods, combinations and compositions of the present invention are treating or preventing a neoplasia disorder. Also, control of tumor markers is effective to determine appropriate dosages of a combination or composition of the present invention to treat neoplasia.

Other techniques include mediastinoscopy, which is especially valuable in determining the stage of a non-small cell lung cancer. If mediastinoscopy shows the involvement of mediastinal lymph nodes, then the subject will not normally benefit from thoracotomy and lung resection. Imaging studies, especially CT and IMR, can detect metastases in the brain, lung, spinal cord or viscera of the abdomen, including the adrenal glands, retroperitoneal lymph nodes, liver and spleen. IMR (with gadolinium) is the procedure chosen to recognize and evaluate brain tumors. Ultrasonography can be used to study orbital, thyroid, cardiac, pericardial, hepatic, pancreatic, renal and retroperitoneal areas. It can guide percutaneous biopsies and differentiate renal cell carcinoma from a benign renal cyst. The lymphagiography reveals an increase in the lower lumbar and pelvic lymph nodes and is useful in determining the clinical stage of patients with Hodgkin's disease, although it is usually replaced by CT. Liver-spleen scans can identify liver metastases and splenomegaly. Bone scans are sensitive in the identification of metastases before they are evident in X-rays. As a positive scan requires new bone formation (ie, osteoblastic activity), this technique is useless in neoplasms that are purely lytic (e.g. , multiple myeloma); The usual bone X-rays are the study chosen in such diseases. Gallium scans can help in the determination of the stage of lymphoid neoplasms. Radiolabeled monoclonal antibodies (eg, against the carcnoembryonic antigen, small cell lung cancer cells) provide important data on the determination of the stage in various neoplasms (eg, colon cancer, lung cancer - small cell) . See The Merck Manual of Diagnosis & Therapy 17th Edition (1999), Sec. 11, Chapter 84, Hematology and Oncology, Overview of Cancer.

As used herein, the term "subject" for the purposes of treatment is that which is in need of the treatment of the neoplasm or a disorder related to the neoplasm. For the purposes of prevention, the subject is one who is at risk of, or is predisposed to, developing the neoplasm or a disorder related to neoplasia, including relapse of a neoplasm or disorder related to the neoplasm that has occurred previously. As used herein, the phrase "subject in need of" includes any subject who suffers from or is predisposed to neoplasia or any disorder related to the neoplasia described herein. The phrase "subject in need of" also includes any subject that requires a lower dose of conventional agents for treatment against the neoplasm. In addition, a "subject in need of" includes any subject that requires a reduction in the side effects of a conventional treatment agent. In addition, a "subject-in-need" includes any subject that requires a better tolerance to any conventional treatment agent for a therapy of the neoplasia disorder. The subject is an animal, typically a mammal, including humans, domestic and farm animals, zoo, animals for sport and companionship, such as dogs, horses, cats, cattle, etc. -The subject is more typically a human subject. The methods, combinations and compositions of the present invention can be used for the treatment or prevention of various disorders of neoplasia and disorders related to neoplasia including, but not limited to, acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma , adenosquamous carcinoma, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, astrocytic tumors, Bartolino gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brainstem glioma, brain tumor, breast cancer, bronchial gland carcinoma, capillary carcinoma, carcinoids, carcinoma, carcinosarcoma, cavernous cell carcinoma, central nervous system lymphoma, cerebral astrocytoma, childhood cancers, cholangiocarcinoma, chondrosarcoma, papilloma and choroidal plexus carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, eppendrum cancer, epithelioid carcinoma, esophageal cancer, Ewing sarcoma, extragonadal germ cell tumor, fibrolamellar carcinoma, focal nodular hyperplasia, gallbladder cancer, gastrinoma , germ cell tumors, trofob tumor gestational lesion, glioblastoma, glioma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and optic glioma, insulinoma, squamous cell carcinoma neoplasia, neoplasia Intraepithelial melanoma, intraocular melanoma, invasive squamous cell carcinoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, large cell carcinoma, cancer - larynx, leiomyosarcoma, melanoma - malignant lentigo, leukemia-related disorders, cancer lip and oral cavity, liver cancer, lung cancer, lymphoma, malignant mesothelial tumors, malignant tymoma, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, Merkel cell carcinoma, mesothelial carcinoma, metastatic carcinoma, mucoepidermoid carcinoma, multiple myeloma / plasma cell neoplasm, mycosis s fungoides, myelodysplastic syndrome, myeloproliferative disorders, cancer of the nasal cavity and paranasal sinus, nasopharyngeal cancer, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, non-Hodgkin's lymphoma, ovarian cell carcinoma, oligodendroglial carcinoma, oral cancer, oropharyngeal cancer, osteosarcoma , ovarian cancer, ovarian germ cell tumor, pancreatic cancer, papillary serous adenocarcinoma, parathyroid cancer, penile cancer, pheochromocytoma, pineal and supratentorial primitive neuroectodermal tumors, pineal cell carcinoma, pituitary tumors, plasma cell neoplasm, plasmacytoma, pleuropulmonary blastema, prostate cancer, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, small bowel cancer, soft tissue carcinomas, tumor that segregates somatostatin, carci squamous cell carcinoma, submesothelial carcinoma, superficial extensive melanoma, thyroid cancer, undifferentiated carcinoma, urethral cancer, uterine sarcoma, uveal melanoma, vagina cancer, verrucous carcinoma, vipoma, vulvar cancer, Waldenstrom macroglobulinemia, carcinoma well Differentiated and Wilm's tumor. - EXAMPLES -. - In the following examples, all percentages are given on a weight basis unless otherwise indicated. Example 1 This example shows the preparation of celecoxib. Step 1: Preparation of 1- (4-methylphenyl) -4,4,4-trifluorobutane-1,3-dione. Following the description provided in the United States Patent No. 5,760,068, 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 ml of methanol under an argon atmosphere and 12 ml (52.5 mmol) of sodium methoxide in methanol (25 ml) was d. %). The mixture was stirred for 5 minutes and 5.5 ml (46.2 mmol) of ethyl trifluoroacetate was d. After heating to reflux for 24 hours, the mixture was cooled to room temperature and concentrated. 100 ml of 10% HCl was d and the mixture was extracted with 4 x 75 ml of ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated giving 8.47 g (94%) of a brown oil which was continued using without further purification. Step 2: Preparation of 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -H-pyrazol-1-yl-benzenesulfonamide. - - - - To the dione of Step 1 (4.14 g, 18.0 mmol) in 75 ml of absolute ethanol, 4.26 g (19.0 mmol) of 4-sulfonamidophenylhydrazine hydrochloride was d. The reaction was heated to reflux under an argon atmosphere for 24 hours. After cooling to room temperature and filtering, the reaction mixture was concentrated giving 6.13 g of an orange solid. The solid was recrystallized from methylene chloride / hexane to give 3.11 g (8.2 mmol, 46%) of the product as a pale yellow solid, having a melting point of 157-159 ° C; and a calculated composition of Ci7Hi4 302SF3; C, 53.54; H, 3.70; N, 1, 02 The composition found by the analysis was: C, 53, 7; H, 3.81; N, 10.90. Example 2 This example demonstrates the production of 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide. Step 1: Preparation of 1-bromo-2- (4-fluorophenyl) benzene Following the general procedure described in U.S. No. 5,739,166, under a nitrogen atmosphere, 1.2 g (1.0 mmol) of Pd (PPh3) 4 were d to a stirred solution of 9.9 g (42 mmol) of 1,2-dibromobenzene (Aldrich) and 3.0 g (21 mmol) of 4-fluorophenylboronic acid in 42 ml of toluene, 42 ml of ethanol and 42 ml of 2 M Na 2 CO 3. After vigorous stirring at reflux for 3 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by chromatography on silica gel (Waters Prep-500A) with hexane gave 4.35 g (81%) of 1-bromo-2- (4-fluorophenyl) benzene as a colorless oil: NMR (CDCl 3)? 7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67 (d, J = 8 Hz, 1 H). Step 2: Preparation of 2- (4-fluorophenyl) phenylboronic acid. Following the general procedure described in Synthesis Scheme VIII in U.S. Patent No. 5,739,166, 4.35 g (17.3 mmol) of 1-bromo-2- (4-fluorophenyl) benzene from Step 1 were converted to 2- (4-fluorophenyl) phenylboronic acid mediant & (l) halogen-metal exchange in THP at -78 ° C to generate a corresponding organolithium reagent, (2) reaction of the organolithium species with borate trimethyl giving the corresponding methyl ester, and (3) hydrolysis with aqueous sodium hydroxide to give 2- (4-fluorophenyl) phenylboronic acid: NMR (CDCl 3)? 4.27 (s, 2H), 7.09-7.20 (m, 2H), 7.25-7.32 (m, 1H), 7.34-7.53 (m, 4H), 7, 90 (d, J = 8 Hz, 1 H). Step 3: Preparation of 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide. Following the general procedure described in Synthesis Scheme IX in U.S. Patent No. 5,739,166, 5 g (6.9 mmol) of 2- (4-fluorophenyl) fenoforic acid from Step 2 was reacted with 2, 5 g (10.4 mmol) of 4-bromobenzenesulfonamide (Lancaster) in toluene / refluxing ethanol in the presence of Pd ° catalyst, for example, tetrakis (terphenylphosphine) palladium (0), and 2 M sodium carbonate. Purification by chromatography on silica gel (Waters LC-2000) with ethyl acetate / hexane (3: 7) and the subsequent recrystallization from ethyl acetate / hexane gave 1. 04 g (46%) of 4- [2- (4- fluorophenyl) phenyl] benzenesulfonamide as a colorless solid: melting point 187.3-188.2 ° C; NMR (CDCI3)? 4.83 (s, 2H), 6.92 (t, J = 9 Hz, 2H), 7.02-7.11 (m, 2H), 7.27 (d, J = 9 Hz, 2H), 7.36-7.50 (m, 4H), 7.78 (d, J = 8 Hz, 2H). EM (IE)): m / e (intensity reí) 327 (75) 245 (00); HRMS calculated for C 8H14FN02S: 327.0729. Found: 327.0743, Analysis calculated for Ci8Hi4FN02S: C, 66.04; H, 4.31; N, 4.28. Found: C, 65.86; H, 4.51; N, 4.34. Example 3 This example illustrates the preparation of 4- [5- (2,5-dichlorophenyl) -3- (trifluoromethyl) -1 H -pyrazol-1-yl] benzenesulfonamide, following the description provided in U.S. Patent No. 5,516,907. 2,5-dichloroacetophenone (6.24 g, 33 mmol) is dissolved in 25 ml of methanol and 25% NaOMe in methanol (9 ml, 39.4 mmol) is added. The mixture is stirred at 25 ° C - ... for 5 minutes and ethyl trifluoroacetate (5 m! 42 mmol) is added. -The mixture is heated to 60 ° C for 24 hours, cooled and the volume is reduced by 50%. The mixture is poured into 100 ml of 10% HCl and extracted with four 75 ml portions of ethyl acetate. The combined extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude diketone as a brown gum "(8.54 g, 30 mmol) which is used without further purification.The crude diketone (1, 16 g, 11.1 mmol) and 4-sulfonamidophenylhydrazine HCI (3.31 g, 14.8 mmol) are dissolved in 75 ml of absolute ethanol and the mixture is stirred under reflux for 24 hours. and concentrated in vacuo to give the crude pyrazole, recrystallization from diethyl ether / hexane gives pure pyrazole Example 5 This example illustrates the preparation of 5-fluoro-2-methyl-1- (para-methyl-sulfinylbenzylidene) -indenyl- 3-acetic (sulindac sulfone, also known as exisulind), following the description provided in US Pat. No. 3,998,875.A solution of 0.01 mole of 5-fluoro-2-methyl-indanone-3 -acetic in 6 ml of isopropanol is basified by the addition of 2.5 M sodium hydroxide (up to about pH 9 to 10) To this solution is added 0.015 moles of sodium borohydride. The solution is stirred at room temperature for 80 minutes and at 60 ° C for 45 minutes. The solution is acidified by the addition of 6 M hydrochloric acid (to approximately a pH of 1 to 2), and heated to reflux for 30 minutes. The solution is allowed to cool and basify with sodium hydroxide to a pH of about 13.0. To the solution is added 0.01 mol of paramethylsulfinylbenza! Dehyde ~ and -0.0 equivalents of sodium hydroxide. The mixture is refluxed for 2 hours, cooled, neutralized with acetic acid and diluted with water. The reaction mixture is extracted into ethyl acetate which is washed with water and concentrated to give 5-fluoro-2-methyl-1- (para-methyl-1,4-benzylidene) -indenyl-3-acetic acid. Example 5 This example illustrates the production of a combination comprising celecoxib, exisulind and 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide, and of a pharmaceutical composition containing the combination. Celecoxib may be prepared as described in Example 1 or, alternatively, may be obtained under the name Celebrex® from Pharmacia Corporation, Peapack, NJ. Exisulind can be prepared as described in Example 4, or alternatively, it can be obtained under the tradename Aptosyn® from Cell Pathways, Inc., Horsham, PA. 4- [2- (4-Fluorophenol) phenyl] benzenesulfonamide can be prepared as described in Example 2. - A therapeutic composition of the present invention can be formed by mixing celecoxib (200 g), exisulind (250 g) and 4- [ 2- (4-fluorophenyl) phenyl] benzenesulfonamide (200 g) in a suspension or solution with a sterile pharmaceutically acceptable liquid.

After mixing, the combination of celecoxib, exisulind and 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide forms a therapeutic composition which is sufficient for the production of approximately 1000 single dose units. for_. Humans. Each single dose unit contains approximately 200 mg of celecoxib and approximately 200 mg of 4- [2- (4-fluorophenyl) phenyl] benzenesulfonamide. If desired, a solid carrier and other materials can be mixed with the therapeutic composition and the resulting pharmaceutical composition can be formed into capsules for human consumption, for example by conventional capsule-forming equipment, where each capsule can contain approximately the same amount of the active ingredients that each of the single dose units of the liquid preparation described above. All references cited in this specification are incorporated herein by reference in their entirety. The analysis of any reference in this document is intended merely to summarize the statements made by its authors and it is not admitted that any reference constitutes the antecedent technique. Applicants reserve the right to challenge the accuracy and pertinence of the references cited. In view of the foregoing, it will be noted that various advantages of the invention are achieved and other advantageous results are obtained. Since various changes can be made to the above methods and compositions without departing from the scope of the invention, it is intended that all of the material contained in the above description be construed as illustrative and not in a limiting sense.

Claims (1)

1. CLAIMS 1. A combination comprising an inhibitor of Hsp90 and a PDE inhibitor in effective amounts when used in combination therapy for the treatment or prevention of neoplasia or a disorder related to the neoplasm. 2. The combination of claim 1, wherein the Hsp90 inhibitor comprises (A) a compound having the formula (I): where Qa is C or N; Xa is C or N; Za is C, N or O; a is C or N; Ga is selected from the group consisting of C, N, O and S; at least one of Qa Xa, Za, Ma and Ga is C; R207, unless it is linked with R208 or R211 in a ring system, is selected from the group consisting of H, alkyl, aryl, amino, substituted or unsubstituted heteroaryl, haloalkyl, alkyaryl, haloaryl, haloarylsulfinylacetohydrazide, haloarylamino-carbonylamino, haloarylalcanonasulfanyl, arylalkylidene nitroaryl, alkoxyaryl, alkylthioaryl, alkylsulfonylaryl, haloalkoxy, alkoxypolyalkyl, carboxamidyl, carboxyalkyl, aminosulfonylaryl, alkoxycarbonyl, hydroxyaryl and halohydroxyaryl; 208, unless it is linked with R207 or R209 in a ring system, is selected from the group consisting of H, halo, alkyl, aryl, amino, substituted or unsubstituted heteroaryl, haloalkyl, nitroaryl, haloaryl, alkoxyaryl, aminosulfonylaryl, alkylsulfonylaryl, alkoxyhaloaryl, alkylnitriloaryl, alkylsulfonylalkyl, alkoxycarboximidyl, alkoxyhydroxyaryl and alkylthioaryl; R207 and R208 are optionally joined to form a ring system selected from the group consisting of: and aryl, wherein Ta and Tb are independently selected from C and S; R209, unless it is linked with R208 or R210 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted or unsubstituted heteroaryl, alkyaryl, haloalkyl, haloaryl, alkoxyaryl, alkoxycarbonylaryl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonylaryl, alkoxyalkylaryl, alkylaminoaryl, alkylalkanethiol, alkoxyhaloaryl and aminosulfonylaryl; R208 and R209 are optionally joined to form a ring system selected from the group consisting of: wherein Xb, Xo, and Xd are independently selected from the group consisting of C and N; 2 0 unless it is linked with R209 or R211 in a ring system, it is selected from the group consisting of H, alkyl, aryl, oxo, alkylaryl, alkylthio, alkoxyaryl, alkylamino-aryl, alkylthioaryl, haloalkyl, haloaryl, carboxiaryl, aminocarbonyl, substituted heteroaryl or unsubstituted carboxyalkyl, alcoxiarilaminoalqueno nitrile, nitroarilalquenoamida, acetamidoarilo, acetamidoarilcianoalquenil nitrile, carboxylalkoxy, alkylsulfonylaryl, haloalquiíalcoxi, haloaryloxy, alcoxihaloarilo, alkoxycarbonyl, alquilsulfonilhaloarilo, aminosulfonylaryl, thioaryl, aminocycloalkyl, alkoxycarbonylaryl, alcoxicarbonilaminociclo alkane and alquilcarboxiio; R209 and R210 optionally join to form a ring system selected from the group consisting of: and aryl; R211 unless it is linked with R210 or R207 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, hydroxyl, haloaryl, haloalkylaryl, substituted or unsubstituted heteroaryl, carboxiaryl, nitroaryl, aminosulfonylaryl, - alkylsulfonylaryl, alkylsulfonylhaloari! alkylaminosulfonylaryl, alkylsulfonyl-aminoaryl, alkylaminocarbonyl, aminocarbonylaryl, halohydroxyaryl-alkylidenacetohydrazide, hydroxyalkoxyarylalkylidenacetohydrazide, alkylcarbonylaryl, alkoxyaryl, haloalkoxyaryl, alkoxyalkoxoaryl, alkoxycarbonyl-aryl, haloalkylcarbonylaryl, alcohol and haloaryloxyacetohydrazide; R2 0 and R211 are optionally joined to form a ring system selected from the group consisting of: oxoaryl and cycloalkyl; R207 and R211 are optionally joined to form a ring system selected from the group consisting of: R2 2 is selected from the group consisting of H, halo and alkoxy; R2 3 is selected from the group consisting of H and halo; R214 is selected from the group consisting of H and halo; R215 is selected from the group consisting of H, halo and alkoxy; and _ R216..is selected from the group consisting of H, and alkoxy; (B) a compound having the formula (II): where: A ', A ", Ea, Ja and La are independently selected from the group consisting of C and N, if either of Ea or Ja is N, then A', A" and La are C; at least three of A ', A ", Ea, Ja and La are C; R217 is selected from the group consisting of H, alkyl, halo, alkylsulfonyl, aminosulfonyl, alkoxy and alkylthio; R2 8 is selected from the group consisting of H , alkyl and alkoxy, R219, unless it is linked in a ring system with R220, is selected from the group consisting of H, oxo, amino and alkoxo, R220, unless it is linked in a ring system with R219, it is selected from the group consisting of H, oxo, carboxyl, alkoxo, hydroxyalkyl, alkylnitrile, alkoxoaryl, haloalkoxp, and haloarylalkoxo; R219 and R220 are optionally linked to form a ring system consisting of a substituted or unsubstituted aryl ring; FC and R¿ are independently selected from the group consisting of H and alkoxy; and R222 is selected from the group consisting of H, halo, alkylsulfonyl, aminosulfonyl and alkylamino; (C) a compound selected from the group consisting of: or a pharmaceutically acceptable salt or prodrug of any of said compounds. 3. The combination of claim 1 wherein the Hsp90 inhibitor comprises a compound selected from the group consisting of 2 - [(2-chlorophenyl) sulfinyl] -N- [4- (4-chlorophenyl) -1,3-thiazole- 2-yl] acetamide; N- [5- (1-phenylethyl) -1,3-thiazol-2-yl] -4- (1 H-pyrrol-1-yl) benzamide; N-S-chloro-dimethoxy-phen-N-^ -phenyl-1,3-thiazol-2-yl) urea; N '- [(4-bromophenoxy) acetyl] -2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; . _. (2E) -2-cyano-3- [3- (2-furl) -1-phenyl-1H-pyrazol-4-yl] -N- [3- (1H-imidazol-1-yl) propyl] prop-2-enamide; (2E) -2-cyano-3- [3- (4-8 -toxyphenyl) -1-phenyl-1H-pyrazol-4-ii] -N- [3- (1 H-imidazol--yl) propyl] prop -2-enamida; 3-bromo-2- (4-chlorophenyl) prazolo [1,5-a] pyrimidine-5,7 (4H, 6H) -dione; 3- [4- (4-chlorophenyl) -1,3-thiazol-5-yl] -4 H -chromen-4-one; N- [4- (3,4-dichlorophenyl) -1,3-thiazol-2-yl] pyrimidin-2-amine hydrobromide; (2E) -2- [4- (4-hydroxy-3-methoxyphenyl) -1,3-thiazol-2-yl] -3 - [(3-methoxyphenyl) amino] prop-2-enonitrile; N '- [(1 E) - (5-bromo-2,4-dihydroxy-phenyl) methylidene] 2- (5-phenyl-2H-tetraazol-2-yl) acetohydrazide; 2 - [(2-amino-6-hydroxy-7H-purin-8-yl) t] o] -N 4 -phenyl-1,3-thiazole-2H1) acetamide; (2E) -3- (4-nitrophenol) -N- (4-pyridin-4-yl-1,3-thiazo-2-yl) prop-2-enamide; N '- [(1 E) - (2-hydroxy-4-methoxyphenyl) methylidene] -2- (5-phenyl] -2H-tetraazole-2-yl) acetohydrazide; N- [4- (4-bromophenyl) -1,3-thiazol-2-yl] n-cycamid; N- (1,3-benzothiazol-2-yl) -7-oxo-1-phenyl-1,7-dihydropyrazolo [1, 5a] pyrimidin-6-carboxamide; N-. { (E) - [4- (1-methyl-1 H -medazol-2-yl) -3-nitrophenyl] methylidene} aniline; N- [4- ( { (E) -2- [4- (1, 3-benzodioxol-5-yl) -1, 3-thiazol-2-yl] -2-cyanoethenyl}. Amino) phenyl ] acetamide; ((3Z) -2-oxo-3-. {[[(3-phenyl-1 H -pyrazol-5-yl) carbonyl] hydrazone] -2,3-dihydro-1H-indol-1-yl) ethyl acetate; 5- [4- (4-chlorophenyl) -1,3-thiazol-1-yl) pyridine; and mixtures thereof. 4. The combination of claim 1 wherein the Hsp90 inhibitor is 4- [2- (4-fluorophenyl) pheny1] benzenesulfonamide. 5. The combination of claim 1 wherein the Hsp90 inhibitor provides an IC5o for Hsp90 of less than about 100 μ ?. 6. The combination of claim 1 wherein the Hsp90 inhibitor provides an Cl50 for Hsp90 of less than about 2.5 μ ?. 7. The combination of claim 1 wherein the Hsp90 inhibitor is a dual inhibitor of Hsp90 / Cox-2. 8. The combination of claim 1 wherein the PDE inhibitor is an inhibitor of cGMP-specific PDE. 9. The combination of claim 8 wherein the cGMP-specific PDE inhibitor is selected from the group consisting of exisulind, dipyridamole, MBCQ, MMPX, MY-5445, zaprinast, sildenafil, tadalafil, vardenafil, T-1032, A02131-1, GF248, E-4021, sofoflavescenol, UK-122764, CP-131, CP-33, CP-165 , CP-265, CP-132, CP-461, CP-248, SCH 51866, imidazole [5,1-f] triazin-4 (3H) -ones, 4-benzylamino-1-chloro-6-substituted phthalazines, condensed pyrazolyl compounds, prenylated flavanol glycosides, and pharmaceutically acceptable salts and prodrugs thereof. 10. The combination of claim 8 wherein the cGMP-specific PDE inhibitor is selected from the group consisting of exisulind, sildenafil citrate, tadalafil, vardenafil and zaprinast. 11. The combination of claim 1, further comprising a Cox-2 inhibitor. .12 The. combination of claim 11 wherein the Cox-2 inhibitor is a selective inhibitor of Cox-2. 13. The combination of claim 12 wherein the selective Cox-2 inhibitor provides a Cl50 ratio of Cox-1 / IC50 of Cox-2 of at least about 10. 14. The combination of claim 12 wherein the selective Cox-2 inhibitor provides a Cl50 ratio of Cox-1 / IC50 of Cox-2 of at least about 100. 5. The combination of claim 12 wherein the selective Cox-2 inhibitor is a tricyclic compound, a substituted benzopyran derivative or a phenylacetic acid derivative. 16. The combination of claim 12 wherein the selective Cox-2 inhibitor is selected from the group consisting of celecoxib, vaidecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib and pharmaceutically acceptable salts thereof. 7. The combination of claim 12 wherein the selective Cox-2 inhibitor is parecoxib sodium. 18. A method for treating or preventing neoplasia or a disorder related to neoplasia in a subject, the method comprising administering to the subject the combination of claim 1. 19. The method of claim 18 wherein the Hsp90 inhibitor and the PDE inhibitor are sequentially administered. 20. The method of claim 8 wherein the Hsp90 inhibitor and the PDE inhibitor are substantially simultaneously administered. 21. The method of claim 18 wherein the neoplasm is selected from the group consisting of acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, lymphoma related to AIDS, anal cancer, astrocytic tumors, Bartolino gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brainstem glioma, brain tumor, breast cancer, bronchial gland carcinoma, capillary carcinoma, carcinoids, carcinoma, carcinosarcoma, carcinoma of cavernous cells, lymphoma of the central nervous system, cerebral astrocytoma, childhood cancers, cholangiocarcinoma, chondrosarcoma, papilloma and carcinoma of the choroid plexus, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, cystadenoma, tumor of the endodermal sinus, endometrial hyperplasia, stromal sarcoma to the endometrial, endometriolde adenocarcinoma, ependymal cancer, epithelioid carcinoma, esophageal cancer, Ewing's sarcoma, extragonadal germ cell tumor, fibrolamellar carcinoma, focal nodular hyperplasia, gallbladder cancer, gastrinoma, tumors of the _ .. cells, germinal, - gestational trophoblastic tumor, glioblastoma, glioma, 5 glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and optic glioma, insulinoma , squamous cell internepitelial neoplasia, intraepithelial neoplasia, intraocular melanoma, squamous cell carcinoma or invasive, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, large cell carcinoma, laryngeal cancer, leiomyosarcoma, malignant lentigo melanoma , disorders related to leukemia, cancer of the lip and the oral cavity, liver cancer, lung cancer, lymphoma, malignant mesothelial tumors, malignant thymoma, medulloblastoma, 5 medulloepithelioma, melanoma, meningeal carcinoma, Merkel cell carcinoma, mesothelial carcinoma , metastatic carcinoma, mucoepidermoid carcinoma, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, cancer of the nasal cavity and paranasal sinus, nasopharyngeal cancer, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, non-Hodgkin's lymphoma, cell carcinoma in oats, oligodendrogliai carcinoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian germ cell tumor, pancreatic cancer, papillary serous adenocarcinoma, parathyroid cancer, penile cancer, pheochromocytoma, pinee and supratentorial primitive neuroectodermal tumors, pineal cell carcinoma , pituitary tumors, plasma cell neoplasm, plasmacytoma, pleuropulmonary blastema, prostate cancer, pseudosarcoma, pulmonary blastema, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, carcinoma-serous, small cell carcinoma, small bowel cancer , soft tissue carcinomas, tumor that secretes somatostatin, squamous cell carcinoma, submesoteiial carcinoma, superficial extensive melanoma, thyroid cancer, undifferentiated carcinoma, urethral cancer, uterine sarcoma, uveal melanoma, vaginal cancer, verrucous carcinoma, vipoma , vulvar cancer, Waldenstrom's macroglobulinemia, well-differentiated carcinoma and Wilm's tumor. 22. A pharmaceutical composition comprising the combination of claim 1 and a pharmaceutically acceptable carrier. 23. A pharmaceutical composition comprising the combination of claim 11 and a pharmaceutically acceptable carrier. 24. A kit comprising a first dosage form comprising an inhibitor of Hsp90 in a first amount and a second dosage form comprising a PDE inhibitor in a second amount, wherein said first and second amounts are effective when used in combination therapy to treat or prevent neoplasia or a disorder related to the neoplasm. 25. A kit comprising a first dosage form comprising an Hsp90 inhibitor in a first quantity, a second dosage form comprising a PDE inhibitor in a second amount, and a third dosage form comprising a Cox inhibitor. 2 in a third amount; in which said first, second and third amounts are effective when used in combination therapy to treat or prevent neoplasia or a disorder related to the neoplasm.