EP1682143A2 - Combinations comprising an hsp90 inhibitor and a phophodiesterase inhibitor for treating or preventing neoplasia - Google Patents

Combinations comprising an hsp90 inhibitor and a phophodiesterase inhibitor for treating or preventing neoplasia

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Publication number
EP1682143A2
EP1682143A2 EP04817484A EP04817484A EP1682143A2 EP 1682143 A2 EP1682143 A2 EP 1682143A2 EP 04817484 A EP04817484 A EP 04817484A EP 04817484 A EP04817484 A EP 04817484A EP 1682143 A2 EP1682143 A2 EP 1682143A2
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EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
cox
inhibitor
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP04817484A
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German (de)
French (fr)
Inventor
Jaime L. Masferrer
Thomas D. Penning
Xing Wang
Deborah M. Heuvelman
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Pharmacia LLC
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Pharmacia LLC
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Publication of EP1682143A2 publication Critical patent/EP1682143A2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to drug combinations and methods of use thereof for prevention and/or treatment of neoplasia and neoplasia-related disorders, and more particularly to treating or preventing neoplasia and neoplasia-related disorders by administration of a combination of enzyme inhibitors to a subject.
  • Cancer is a disorder arising from one or more genetic mutations that ultimately give rise to development of neoplasia. It is known that exposure of a cell to carcinogens, such as certain viruses, chemicals and radiation, can lead to DNA alteration that either inactivates a "suppressive" gene or activates an "oncogene”.
  • “Suppressive” genes are growth regulatory genes, which upon mutation can no longer control cell growth. "Oncogenes” are initially normal genes (protooncogenes) that by mutation or altered context of expression become transforming genes. The protein products of transforming genes cause inappropriate cell growth. This occurs through activation of several intracellular signaling pathways, including the protein kinase C/mitogen-activated protein kinase (PKC/MAPK) pathway and the Ras/Raf/MEK 1/2/ERK Vz pathway. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and loss of apoptosis.
  • Oncogene transformed cells and cells that have lost suppressive gene regulation undergo uncontrolled proliferation, modified control of apoptosis, and initiation of angiogenesis. All three of these effects are characteristic for development of neoplasia and neoplasms.
  • Neoplasia is an abnormal, unregulated and disorganized proliferation of cell growth that is distinguished from normal cells by autonomous growth and somatic mutations. As neoplastic cells grow and divide they pass on their genetic mutations and proliferative characteristics to progeny cells. A neoplasm, or tumor, is an accumulation of neoplastic cells. A neoplasm can be benign or malignant.
  • Cancer therapy currently relies on a combination of early diagnosis and aggressive treatment, which can include surgery, chemotherapy, radiation therapy and/or hormone therapy.
  • Surgery involves bulk removal of neoplasms. While surgery is sometimes effective in removing tumors located at certain sites, for example in the breast, colon or skin, it cannot be used in treatment of tumors located in other areas, such as the backbone, nor in treatment of disseminated neoplastic conditions such as leukemia. Moreover, surgical treatments are generally successful only if the cancer is detected at an early stage and before the cancer has metastasized to major organs, thus making surgery non- feasible.
  • Chemotherapy involves disruption of cell replication and/or cell metabolism. It is used most often in treatment of breast, lung and testicular cancer.
  • the adverse effects of systemic chemotherapy used in treatment of neoplastic disease is problematic for patients undergoing cancer treatment. Of these adverse effects nausea and vomiting are the most common and severe side effects. Many of these chemotherapy-induced side effects, if severe, can lead to hospitalization, or require treatment with analgesics for management of pain.
  • radiation therapy is also not without such side effects as nausea, fatigue and fever. Of concern is that chemotherapy and radiation therapy-induced side effects significantly impact quality of life of the patient and may dramatically influence patient compliance with treatment.
  • Novel cancer treatment strategies that eliminate the need for surgical intervention and reduce chemotherapy-induced side effects would, therefore, benefit many cancer sufferers.
  • Hsp90 heat shock protein 90
  • Hsp90-associated "client" proteins that are associated with the growth and survival of neoplasia have been reported to include p53, HER-2, telomerase, V-Src, Bcr-Abl, Raf-1, Akt, ErbB2, and hypoxia-inducible factor 1 alpha (HTF-1 alpha).
  • Hsp90 is a molecular chaperone whose association is required for the stability and function of several mutated and over-expressed signaling proteins that promote the growth and/or survival of neoplastic cells. Neckers (2002) Trends Mol. Med. 8(4 Suppl), S55 ⁇ S61.
  • Hsp90 Inhibition of Hsp90 function results in selective degradation of important neoplastic signaling oncoproteins that are involved in cell proliferation, cell cycle regulation and apoptosis.
  • Current Hsp90 inhibitors act by inhibiting Hsp90 ATPase activity and have shown promising activity against cancer. Neckers (2002) op. cit.
  • Many of these Hsp90 inhibitors are naturally occurring antibiotics, including benzoquinone ansamycins, such as geldanamycin and its 17-allylamino analogue (17AAG), and another natural product, radicicol.
  • benzoquinone ansamycin class of Hsp90 inhibitors have shown harmful side effects including, for example, hepatotoxicity, because of their inhibition of Hsp90 ATPase activity. Id.
  • PDEs constitute a large family of enzymes that catalyze hydrolysis of the intracellular second messengers, cyclic nucleotides (cAMP and cGMP), to their biologically inactive forms, 5'-AMP and 5'-GMP.
  • cyclic nucleotides cAMP and cGMP
  • PDEs are able to regulate cell signaling mechanisms that are mediated by cAMP and cGMP by reducing available intracellular pools.
  • These second messengers play a critical role in transduction of extracellular signals to intracellular compartments.
  • Eleven distinct classes of PDEs have been identified, each with unique catalytic properties, substrate specificities and tissue expression patterns. Uckert et al. (2001) World J. Urol.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • researchers have treated inflammation-related disorders with a regimen of NSAIDs such as, for example, aspirin and ibuprofen.
  • NSAIDs are known to cause gastrointestinal (Gl) bleeding or ulcers in patients undergoing consistent long term regimens of NS AID therapy.
  • Gl gastrointestinal
  • Cox-1 is a constitutive enzyme responsible for 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 biosynthesis of prostaglandins in inflammatory cells. Inflammation causes induction of Cox-2, leading to release of prostanoids (prostaglandin E2), which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation and edema.
  • prostanoids prostaglandin E2
  • Cox-2 selective inhibitors are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side effects associated with the inhibition of Cox-1.
  • Cox-2 selective inhibitors have shown great promise for use in therapies, especially in therapies that require maintenance administration, such as for pain and inflammation control.
  • Cox-2 has been documented in several premalignant and malignant tissues. Subbaramaiah & Dannenberg (2003) Trends Pharmacol. Sci. 24, 96-102. This increase in expression is thought to be a product of stimulation of PKC signaling, which stimulates activity of MAPK, enhancing transcription of Cox-2 by nuclear factors. Additionally, enhanced stability of Cox-2 mRNA transcripts in cancer cells due to augmented binding of the RNA-binding protein HuR, as well as activation of extracellular signal related kinase 1/2 (ERK 1/2) and p38, contributes to increased expression of Cox-2. Id.
  • the present invention is directed to a combination comprising an Hsp90 inhibitor and a PDE inhibitor, in amounts effective when used in combination therapy for treatment or prevention of neoplasia or a neoplasia-related disorder.
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula (I):
  • R 209 unless joined with R 208 or R 210 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted or unsubstituted heteroaryl, alkylaryl, haloalkyl, haloaryl, alkoxyaryl, alkoxycarbonylaryl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonylaryl, alkoxyalkylaryl, alkylaminoaryl, alkylalkanethiol, alkoxyhaloaryl and aminosulfonylaryl; R 208 and R 209 optionally join to form a ring system selected from the group consisting of:
  • R 210 unless joined with R 209 or R 211 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, alkylaryl, alkylthio, alkoxyaryl, alkylaminoaryl, alkylthioaryl, haloalkyl, haloaryl, carboxyaryl, aminocarbonyl, substituted or unsubstituted heteroaryl, carboxyalkyl, alkoxyarylaminoalkene- nitrile, nitroarylalkeneamide, acetamidoaryl, acetamidoarylcyanoalkenyl- nitrile, carboxylalkoxy, alkylsulfonylaryl, haloalkylalkoxy, haloaryloxy, alkoxyhaloaryl, alkoxycarbony
  • R unless joined with R or R in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, hydroxyl, haloaryl, haloalkylaryl, substituted or unsubstituted heteroaryl, carboxyaryl, nitroaryl, aminosulfonylaryl, alkylsulfonylaryl, alkylsulfonylhaloaryl alkylaminosulfonylaryl, alkylsulfonyl- aminoaryl, alkylaminocarbonyl, aminocarbonylaryl, halohydroxyaryl- alkylideneacetohydrazide, hydroxyalkoxyarylalkylideneacetohydrazide, alkyl- carbonylaryl, alkoxyaryl, haloalkoxyaryl, alkoxyalkoxoaryl, alkoxycarbonylaryl, haloalkylcarbonylaryl, alcohol and haloaryloxy
  • R 210 and R 211 optionally join to form a ring system selected from the group consisting of:
  • R and R optionally join to form a ring system selected from the group consisting of:
  • R 212 is selected from the group consisting of H, halo and alkoxy;
  • R 213 is selected from the group consisting of H and halo;
  • R 214 is selected from the group consisting of H and halo;
  • R 215 is selected from the group consisting of H, halo and alkoxy;
  • R 216 is selected from the group consisting of H, and alkoxy; or a pharmaceutically acceptable salt or prodrag of such a compound.
  • the Hsp90 inhibitor comprises a compound having the stracture shown in formula (II):
  • A', A", E a , J a and L a are independently selected from the group consisting of C and N; if either of E a or J a is N, then A', A" and L a are C; at least three of A', A", E a , J a and L a are C;
  • R 217 is selected from the group consisting of H, alkyl, halo, alkylsulfonyl, aminosulfonyl, alkoxy and alkylthio;
  • R 218 is selected from the group consisting of H, alkyl and alkoxy;
  • R unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and alkoxo;
  • R 220 unless joined in a ring system with R 219 , is selected from the group consisting of H, oxo, carboxyl, alkoxo, hydroxyalkyl, alkylnitrile, alk
  • Any Hsp90 inhibitor can be used in such a combination, including without limitation the Hsp90 inhibitors of any of the above-described embodiments.
  • Any PDE inhibitor can be used in such a combination, including without limitation cGMP-selective PDE inhibitors.
  • the Hsp90 inhibitor and the PDE inhibitor can be administered sequentially or substantially simultaneously to the subject.
  • the Hsp90 inhibitor and the PDE inhibitor are coformulated in a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.
  • a combination of the invention can further comprise a Cox-2 inhibitor, for example a Cox-2 selective inhibitor.
  • the present invention is also directed to a kit for the purpose of preventing or treating neoplasia in a subject that is in need of such prevention or treatment, the kit comprising a first dosage form that comprises an Hsp90 inhibitor in a first amount, 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 optional third amounts are effective when used in combination therapy for treating or preventing neoplasia or a neoplasia-related disorder.
  • methods and compositions are provided that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or neoplasia-related disorders. Still further, according to certain embodiments methods and compositions are provided that improve the efficacy of treating neoplasia or a neoplasia-related disorder that is considered resistant or intractable to l ⁇ iown methods of therapy alone.
  • DETAILED DESCRIPTION OF THE INVENTION [0034] It has been discovered that Hsp90 is a target for inhibition by the compounds listed and described by the tables and formulas herein. It has been demonstrated that the presence of these compounds, both in vitro and in vivo, result in disruption of the Hsp90- client protein complex.
  • Hsp90 client protein complexes that are disrupted include, among others, those comprising as client proteins mutant p53, proliferating cell nuclear antigen (PCNA), Raf-1, and many other regulatory proteins that are important in tumorigenesis or neoplasm growth and proliferation.
  • Such Hsp90 inhibiting compounds have a wide range of antitumor and anticancer activities.
  • the present invention provides compounds that act both as a Cox-2 inhibitor and as an Hsp90 inhibitor.
  • the present invention encompasses a method for inhibiting the growth of neoplasia, including a malignant tumor or cancer, the method comprising exposing the neoplasia to an inhibitory or therapeutically effective amount or concentration of at least one of the Hsp90 inhibiting compounds disclosed herein, 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 prevention and treatment of neoplasia.
  • Such administration is effective for preventing and treating the symptoms of neoplasia while reducing or avoiding the disadvantages and side effects associated with current treatment strategies.
  • the present invention provides methods and compositions that improve subject outcomes following radiation and chemotherapy treatment regimens for neoplasia. In certain embodiments, the present invention provides methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or neoplasia-related disorders. In certain embodiments, the present invention provides methods and compositions that improve the efficacy of treating neoplasia or a neoplasia-related disorder that is considered resistant or intractable to known methods of therapy alone.
  • administering to a subject suffering from or needing prevention of a neoplasia a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor.
  • such a combination therapy is effective for lowering the dosages of conventional chemotherapy and radiotherapy treatments that are normally prescribed as a monotherapy.
  • the administration of lower dosages of conventional treatment agents provides a reduction in side effects corresponding to such conventional agents.
  • such a combination therapy demonstrates a synergistic efficacy for treating and preventing neoplasia, when the efficacy is greater than would be expected from simply combining the two therapies.
  • neoplasia refers to new cell growth that results from a loss of responsiveness to normal growth controls, e.g., "neoplastic” cell growth.
  • cancer is one subtype of neoplasia.
  • neoplasia-related disorder encompasses neoplasia, but also encompasses other cellular abnormalities, such as hyperplasia, metaplasia and dysplasia.
  • the terms neoplasia, metaplasia, dysplasia and hyperplasia collectively refer generally to cells experiencing abnormal cell growth.
  • Both neoplasia and neoplasia-related disorders can involve a neoplasm or tumor, which can be benign, premalignant, metastatic or malignant.
  • the present invention thus encompasses methods and compositions useful for treating or preventing benign, premalignant, metastatic and malignant neoplasias, and benign, premalignant, metastatic and malignant tumors.
  • Tumors are generally known in the art to be formed from a mass of neoplastic cells. It is to be understood, however, that even one neoplastic cell is considered, for purposes of the present invention, to be a neoplasm or alternatively, neoplasia.
  • the amount or dosage of a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor is one that provide a therapeutically effective amount of the combination therapy.
  • the present invention provides a method for preventing a pathological condition or physiological disorder characterized by or associated with neoplasia in a subject that is in need of such prevention, the method comprising administering to the subject an Hsp90 inhibitor alone or in combination with a PDE inhibitor.
  • any of the embodiments herein specifying presence of or administration of an Hsp90 inhibitor and a PDE inhibitor, it is understood that the combination can optionally further comprise a Cox-2 inhibitor.
  • prevention refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing a neoplasia or neoplasia-related disorder.
  • the subject is one that is at some degree of risk for, or is to some degree predisposed to, developing a neoplasia, a neoplasia-related disorder or a neoplasia-related complication.
  • a subject that is "predisposed to” or “at risk for” developing neoplasia or a neoplasia-related disorder or condition includes any subject having an increased chance or statistical probability for such development.
  • Such increased chance or probability can be due to various factors, including genetic predisposition, diet, age, exposure to neoplasia causing agents, physiological factors such as anatomical and biochemical abnormalities and certain autoimmune diseases, and the like.
  • the present invention provides a method for treating an existing pathological condition or physiological disorder characterized by or associated with neoplasia in a subject that is in need of such treatment, the method comprising administering to the subject an Hsp90 inhibitor in combination with a PDE inhibitor.
  • treating or “to treat” mean to alleviate symptoms, eliminate the causation of symptoms, either on a temporary or permanent basis, or to alter or slow the appearance of symptoms.
  • treatment includes alleviation of, or elimination of causation of, symptoms associated with any of the diseases or disorders described herein.
  • 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 that is in need of such prevention or treatment, the method comprising administering to the subject an Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, in combination with radiation therapy, for example conventional radiation therapy.
  • a three-way combination of an Hsp90 inhibitor, a PDE inhibitor and radiation therapy is administered to a subject in need thereof.
  • a four-way combination of an Hsp90 inhibitor, a PDE inhibitor, a Cox-2 inhibitor and radiation therapy is administered to a subject in need thereof.
  • Hsp90 inhibitor includes any compound that inhibits, disrupts or degrades activity of Hsp90 by disrupting an Hsp90-client protein complex or by interfering with synthesis of Hsp90.
  • the compound inhibits Hsp90 through direct contact.
  • such contact is at a singular point.
  • such contact involves multiple and distinct contacts with residues in the Hsp90 protein.
  • such multiple and distinct contacts are with residues in the highly unusual, evolutionarily conserved nucleotide-binding pocket of the protein.
  • the nucleotide is ATP.
  • Hsp90 inhibitor compounds and certain analogs thereof, all of which are capable of disrupting an Hsp90-client protein complex.
  • these compounds may be referred to herein as "Hsp90 inhibitors" or "Hsp90 inhibiting compounds”.
  • Hsp90 inhibitors When it is said that a subject compound inhibits Hsp90, it is meant that Hsp90 activity is lower in the presence of the compound than it is under the same conditions in the absence of such compound.
  • an Hsp90 inhibitor has activity against Hsp90, it is meant that the Hsp90 inhibitor is capable of disrupting an Hsp90- client protein complex.
  • One method of expressing potency of a compound as an Hsp90 inhibitor is to measure the "IC 50 " value of the compound.
  • the IC 50 value of an Hsp90 inhibiting compound is the concentration of the compound that is required to decrease Hsp90 activity by one-half. Accordingly, a compound having a lower IC 50 value is considered to be a more potent inhibitor than a compound having a higher IC 5 o value.
  • certain heterocycle-containing compounds such as, but not limited to, pyrazole, pyrrole, imidazole, oxazole, pyrazole, thiazole, isoxazole, triazole, and furan compounds, and certain analogs of such compounds, can inhibit
  • Hsp90 Hsp90. Many of these compounds exhibit their inhibitory effect at low concentrations, having in vitro Hsp90 inhibition IC 50 values of less than about 100 ⁇ M, some having IC 50 values of less than about 50 ⁇ M, some having IC 50 values of less than about 20 ⁇ M, and some even having IC 50 values of less than about 2.5 ⁇ M.
  • the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds of formula (I) listed in Table 1.
  • the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds of formula (II) in Table 2.
  • the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds listed in Table 3.
  • the present invention provides a novel method for preventing or treating a pathological condition or physiological disorder characterized by or associated with neoplasia, including colorectal cancer, lung cancer, and breast cancer.
  • a pathological condition or physiological disorder including colorectal cancer, lung cancer, and breast cancer.
  • certain heterocycle compounds such as, but not limited to, pyrazole, pyrrole, imidazole, oxazole, pyrazole, thiazole, isoxazole, triazole, and furan compounds, and analogs of such compounds, can inhibit the activity of Hsp90.
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Q a is C or N; X a is C or N; Z a is C, N or O; M a is C or N; G a is selected from the group consisting of C, N, O and S; at least one of Q a , X a , Z a , M a , and G a is C; R 207 , unless joined with R 208 or R 211 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, amino, aminohydroxythioacetamidyl- substituted purinyl, Q-Q alkylacetateoxoaceto-hydrazide-substituted indolyl, halo-substituted thienyl, thienyl, triazolpyridyl, pyridyl, halo (Q-Q)
  • T a and T are independently selected from the group consisting of C and S;
  • R 209 unless joined with R 208 or R 210 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, Q-Q dialkylamino (Q-Q) alkane- substituted pyridyl, oxohydrothieno (Q-Q) alkanamide oxooxyaminothio (Q-Q 0 ) alkyl-substituted imidazolyl, oxohydrothieno (Q-Q) alkanoylaminooxo (Q-Q) alkylamino (Q-Q) alkanamidyl (Q-Q) alkylamino-substituted imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, Q-Q alkylphenyl, halo (Q-Q) al
  • X b , X c , and X d are independently selected from the group consisting of C and N;
  • R ,210 unless joined with R , 209 or R ,211 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, oxo, Q-Q alkylphenyl, Q-Q alkylthio, Q-Q alkoxyphenyl, Q-Q alkylaminophenyl, Q-Q alkylthiophenyl, halo (Q-Q) alkyl, halophenyl, carboxyphenyl, aminocarbonyl, phenylcarbonylamino-substituted pyrrolyl, carbonylamino-substituted pyridyl, Q-Q alkyl-substituted pyridyl, C ⁇ -C dialkylamino-substituted pyrimidyl, thiofuryl,
  • R unless joined with R or R in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, oxo, hydroxyl, halophenyl, halo (Q-Q) alkylphenyl, Q-Q alkylthio-substituted pyrimidyl, pyridyl, carboxyphenyl, nitrophenyl, aminosulfonylphenyl, Q-Q alkylsulfonylphenyl, Q-Q alkylsulfonylhalophenyl, Q-Q alkylaminosulfonylphenyl, Q-Q alkylsulfonylaminophenyl, Q-Q alkylaminocarbonyl, aminocarbonylphenyl, halohydroxyphenyl (Q-Q) alkylideneacetohydrazide, hydroxyl (Q-Q) alkoxyphenyl (Q-Q) alkyl
  • R ,212 is selected from the group consisting of H, halo and Q-Q alkoxy
  • R 213 is selected from the group consisting of H and halo
  • R 214 is selected from the group consisting of H and halo
  • R 215 is selected from the group consisting of H, halo and Q-Q alkoxy
  • R 216 is selected from the group consisting of H and Q-Q alkoxy; or a pharmaceutically acceptable salt or prodrug of such a compound.
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Q a is C or N; X a is C or N; Z a is Q N or O; M a is C orN; G a is selected from the group consisting of C, N, O and S; at least one of Q a , X a , Z a , M a , and G a is C; R 207 , unless joined with R 211 or R 208 in a ring system, is selected from the group consisting of H, methyl, ethyl, isopropyl, pentyl, phenyl, amino, aminohydroxythioacetamidyl-substituted purinyl, ethylacetateoxoaceto- hydrazide-substituted indolyl, chlorothienyl, thienyl, triazolpyridyl, pyridyl,
  • R 208 unless joined with R 207 or R 209 in a ring system, is selected from the group consisting of H, bromo, methyl, phenyl, amino, propylaminocarbonyl- propenenitrile-substituted imidazolyl, propylcyanopropenenitrile-substituted imidazolyl, dioxolyl-substituted benzene, pyridyl, difluoromethyl, trifluoromethyl, nitrophenyl, bromophenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, aminosulfonylphenyl, methylsulfonylphenyl, methoxyfluorophenyl, methylnitrilephenyl, methylsulfonylmethyl, methoxy- carboximidyl, methoxyhydroxyphenyl and methylthiophenyl;
  • R 207 and R 208 optionally join to form a ring system selected from the group consisting of:
  • T a and T are independently selected from the group consisting of C and S;
  • R 209 unless joined with R 208 or R 210 in a ring system, is selected from the group consisting of H, methyl, propyl, ' phenyl, diethyldiaminopentane-substituted pyridyl, oxohydrothienopentanamide oxodioxydiaminothiononyl-substituted imidazolyl, oxohydrothienopentanoylaminooxohexylaminohexanamidyl- methylamino-substituted imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, methylphenyl, difluoromethyl, trifluoromethyl, chlorophenyl, fluorophenyl, ethoxyphenyl, methoxycarbon
  • R 210 unless joined with R 209 or R 211 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, phenylcarbonyl- amino-substituted pyrrolyl, carbonylamino-substituted pyridyl, methylpyridyl, dimethylamino-substituted pyrimidyl, thiofuryl,
  • R 211 unless joined with R 210 or R 207 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, methylsulfonylhalo- phenyl, dimethylaminosulfonylphenyl, methylsulfonylaminophenyl, methyl- aminocarbonyl, aminocarbonylphenyl, bromodihydroxyphenylmethylidene- acetohydrazide, hydroxymethoxyphenylmethylideneacetohydrazide, methyl- carbonylphenyl, methoxyphenyl, trifluoromethoxyphenyl, methoxyetho
  • R 210 and R 211 optionally join to form a ring system selected from the group consisting of:
  • R 212 is selected from the group consisting of H, chloro, fluoro, and methoxy;
  • R 213 is selected from the group consisting of H and halo;
  • R 214 is selected from the group consisting of H and fluoro;
  • R 215 is selected from the group consisting of H, chloro, fluoro, and methoxy;
  • R 216 is selected from the group consisting of H and methoxy; or a pharmaceutically acceptable salt or prodrug of such a compound.
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Q a , X a , Z a and M a are independently selected from the group consisting of C and N, where at least one of Q , X a , Z a and M a is C; G a is N or S; 907 91 1 R , unless joined with R in a ring system, is selected from the group consisting of H, alkylaryl, substituted or unsubstituted heteroaryl, haloaryl- sulfinylacetohydrazide, haloarylaminocarbonylamino, haloarylalkanesulfanyl and arylalkylidenenitroaryl; 90R R is selected from the group consisting of H, halo, aryl, haloaryl, alkoxyaryl, substituted or unsubstituted heteroaryl and alkoxyhydroxyaryl; R 20
  • R 211 unless joined with R 207 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted heteroaryl, halohydroxyarylalkylidene- acetohydrazide, haloaryloxyacetohydrazide and hydroxyalkoxyaryl- alkylideneacetohydrazide; and R 207 and R 211 optionally join to form a ring system consisting of
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula (I), wherein: Q a , X a , Z a and M a are independently selected from the group consisting of C and N, where at least one of Q a , X a , Z a and M a is C; G a is N or S; 90 * 7 91 1 R , unless joined with R in a ring system, is selected from the group consisting of H, phenylethyl, triazolpyridyl, ethylacetateoxoindoleacetohydrazide, aminohydroxylpurinylthioacetamidyl, chlorophenylsulfinylacetohydrazide, chlorodimethoxyphenylaminocarbonylamino, chlorophenylethanonesulfanyl and phenylmethylidenenitrophen
  • Yl R unless joined with R in a ring system, is selected from the group consisting of H, methyl, phenyl, bromodihyrdoxyphenylmethylidene- acetohydrazide, bromophenoxyacetohydrazide and hydroxymethoxyphenyl- methylideneacetohydrazide; and 7 911 R and R optionally join to form a ring system consisting of
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula II, wherein: A', A", E a , J a and L a are independently selected from the group consisting of C and N; if either of E a or J a is N, then A', A" and L a are C; at least three of A', A", E a , J a and L a are C; R 217 is selected from the group consisting of H, Q-Q alkyl, halo, Q-Q alkylsulfonyl, aminosulfonyl, Q-Q alkoxy and Q-Q alkylthio; R 218 is selected from the group consisting of H, Q-Q alkyl and Q-Q alkoxy; 910 990 R , unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and Q-Q alkoxo; R 220 , unless joined in
  • the Hsp90 inhibitor comprises a compound having the structure shown in formula II, wherein: A', A", E a , J a and L a are independently selected from the group consisting of C and N; if either of E a or J is N, then A', A" and L a are C; at least three of A', A", E a , J a and L a are C; R 217 is selected from the group consisting of H, methyl, chloro, methylsulfonyl, aminosulfonyl, methoxy and methylthio; R 218 is selected from the group consisting of H, methyl and methoxy; 910 990 R , unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and ethoxo; R 220 , unless joined in a ring system with R 219 , is selected from the group consisting of H, oxo, carboxy
  • ring substituent groups that join to form additional ring structures adjacent the substituted ring can be described with reference to chemical formulas that show wavy lines cut through the ring to which the substituents are joined, rather than across the bond joining the substituent group to the ring. Accordingly, the partial ring that is shown is the ring to which the substituent groups are shown as being bonded in the general formula.
  • alkyl alone or in combination, means an alkyl radical, linear, cyclic or branched, which, unless otherwise noted, typically contains 1 to about 10 carbon atoms, and more typically 1 to about 6 carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
  • Cyclic alkyl (“cycloalkyl”) radicals contain 3 to about 7 carbon atoms, typically 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term "cycloalkyl” additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of benzothiepine.
  • Alkyl radicals can optionally be substituted with substituent groups as defined below. Examples of such substituted alkyl radicals include chloroethyl, hydroxyethyl, trifluoromethyl, cyanobutyl, aminopentyl, and the like.
  • alkenyl refers to an unsaturated, hydrocarbon radical, linear, cyclic or branched, that contains at least one double bond. Unless otherwise noted, such radicals typically contain 2 to about 6 carbon atoms, more typically 2 to 4 carbon atoms, for example 2 to 3 carbon atoms. Cyclic alkenyl (“cycloalkenyl”) radicals have 3 to about 10 carbon atoms, and include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Alkenyl radicals can optionally be substituted with substituent groups as defined below.
  • alkenyl radicals examples include propenyl, 2-chloropropenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, octen-1-yl, and the like.
  • 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 may be attached to a carbon atom to form a methylene (-CH 2 -) radical.
  • halo means a halogen group such as fluoro, chloro, bromo or iodo radicals.
  • haloalkyl describes alkyl radicals that is substituted with a halo group as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for example, can have either a bromo, chloro or fluoro group attached to the alkyl radical.
  • Dihalo radicals can have two or more of the same halo group or a combination of different halo groups, and polyhaloalkyl radicals can have more than two of the same halo group or a combination of different halo groups.
  • hydroxyalkyl describes a linear or branched alkyl radical having 1 to about 10 carbon atoms, any one of which can be substituted with one or more hydroxyl radicals.
  • 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.
  • alkoxyalkyl describes alkyl radicals having one or more alkoxy radicals attached thereto, to form for example a monoalkoxyalkyl or dialkoxyalkyl radical.
  • Alkoxy or alkoxyalkyl radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" or "haloalkoxyalkyl” radicals.
  • alkoxy and haloalkoxy radicals include methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl includes aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane and biphenyl.
  • heterocyclyl or “heterocyclic” means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by N, S, P, or O. This includes, for example, stractures such as
  • Z, Z 1 , Z 2 and Z 3 are Q S, P, O or N, with the proviso that at least one of Z, Z 1 , Z 2 and Z 3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom.
  • optional substituents are understood to be attached to Z, Z 1 , Z 2 or Z 3 only when the Z atom is C.
  • Heterocyclic radicals can be saturated, partially saturated or unsaturated heteroatom-containing ring- shaped radicals, where the heteroatoms are selected from N, S and O.
  • saturated heterocyclic radicals include piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.
  • heteroaryl radicals examples include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, quinolinyl, isoquinolinyl, benzothienyl, indolyl and tetrazolyl.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • alkylsulfonyl denotes the divalent radical -SO 2 -
  • alkylsulfonyl denotes an alkyl radical attached to a sulfonyl radical, where alkyl is defined as above.
  • arylsulfonyl denotes a sulfonyl radical substituted with an aryl radical.
  • sulfamyl or “sulfonamidyl”, whether alone or linked to other terms as in "N-alkylsulfamyl", “N-arylsulfamyl”, “N,N-dialkylsulfamyl” and “N-alkyl-N- arylsulfamyl”, denote a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 NH 2 ).
  • N-alkylsulfamyl and “N,N-dialkylsulfamyl” denote sulfamyl radicals substituted with 1 to 2 alkyl radicals or a cycloalkyl ring.
  • N-arylsulfamyl and “N-alkyl-N-arylsulfamyl” denote sulfamyl radicals substituted, respectively, with one aryl radical, or with one alkyl and one aryl radical.
  • carboxy or “carboxyl”, whether used alone or linked to other terms, as in “carboxy alkyl”, denote -CO 2 H.
  • carboxyalkyl denotes a carboxy radical as defined above, attached to an alkyl radical.
  • Alkylcarbonylalkyl denotes an alkyl radical substituted with an alkylcarbonyl radical.
  • alkoxycarbonylalkyl denotes a radical having alkoxycarbonyl, as defined above, attached to an alkyl radical.
  • amido when used by itself or linked to other terms as in “amidoalkyl", “N-monoalkylamido”, “N-monoarylamido”, “N,N-dialkylamido”, “N-alkyl-N-arylamido", “N-alkyl-N-hydroxyamido” and “N-alkyl-N-hydroxyamidoalkyl”, denotes a carbonyl radical substituted with an amino radical.
  • N-alkylamido and “N,N-dialkylamido” denote amido groups which have been substituted with one or two alkyl radicals, respectively.
  • N-monoarylamido and N-alkyl-N-arylamido denote amido radicals substituted, respectively, with one aryl radical, or with one alkyl and one aryl radical.
  • N-alkyl-N-hydroxyamido denotes an amido radical substituted with a hydroxyl radical and with an alkyl radical.
  • N-alkyl-N-hydroxyamidoalkyl denotes an alkyl radical substituted with an N-alkyl-N-hydroxyamido radical.
  • amidoalkyl denotes an alkyl radical substituted with one or more amido radicals.
  • aminoalkyl denotes an alkyl radical substituted with one or more amino radicals.
  • alkylaminoalkyl denotes an aminoalkyl radical having the nitrogen atom of the amino group substituted with an alkyl radical.
  • heterocycloalkyl denotes a heterocyclic-substituted alkyl radical such as pyridylmethyl or thienylmethyl.
  • aralkyl denotes an aryl-substituted alkyl radical such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl or diphenethyl.
  • benzyl and phenylmethyl are interchangeable.
  • alkylthio 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, (CH 3 -S-).
  • alkylthioalkyl denotes an alkylthio radical attached to an alkyl group, an example being methyl thiomethyl.
  • N-alkylamino and “N,N-dialkylamino” denote amino groups which have been substituted with one alkyl radical or with two alkyl radicals, respectively.
  • acyl whether used alone or within a term such as “acylamino”, denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
  • the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
  • oxo means a doubly-bonded oxygen
  • 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, alicyclic or heterocyclic group.
  • carbamoyl refers to a carbonyl group covalently bonded at the oxo carbon to an amino group.
  • hydroxamate refers to a carbonyl group covalently bonded at the oxo carbon to an amino group, wherein the amino group is in turn bonded to a hydroxyl group.
  • the present invention encompasses methods and compositions comprising
  • Hsp90 inhibiting compounds including, but not limited to, the following examples: 2-methyl-4-(4-nitrophenyl) 5-phenyl-l,3-oxazole; 4-[4-(4-fluorophenyl)- 1 ,3-thiazol-2-yl]benzoic acid; methyl 4-[4-(4-fluorophenyl)-l ,3-thiazol-2-yl]benzoate; 4- [4-(4-methoxyphenyl)- 1 ,3-thiazol-2-yl] -N-methylbenzamide; 4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]phenylamine; l-(4-nitrophenyl)-3-(trifluoromethyl)-lH-pyrazole; ethyl 4-(3,5-dimethyl-lH-pyrazol-l-yl)benzoate; 4-(3,5-dimethyl-lH-pyrazol-l-yl
  • the present invention encompasses methods and compositions comprising Hsp90 inhibiting compounds selected from the group consisting of 2-[(2-chlorophenyl)sulfinyl]-N-[4-(4-chlorophenyl)-l,3-thiazol-2-yl]acetamide; N-[5-(l-phenylethyl)-l,3-thiazol-2-yl]-4-(lH-pyrrol-l-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)-l-phenyl-lH-pyrazol-4-yl
  • the present invention encompasses methods and compositions comprising Hsp90 inhibiting compounds selected from the group consisting of (2E)-2-[4-(4-hydroxy-3-methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxyphenyl) amino]prop-2-enenitrile; 2-[(2-amino-6-hydroxy-7H-purin-8-yl)thio]-N-(4-phenyl-l,3-thiazol-2-yl) acetamide; N'-[(lE)-(2-hydroxy-4-methoxyphenyl)methylidene]-2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; and mixtures thereof.
  • Hsp90 inhibiting compounds selected from the group consisting of (2E)-2-[4-(4-hydroxy-3-methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxypheny
  • 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 neoplasia 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 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 Hsp90 inhibitor in combination with a PDE inhibitor, wherein the Hsp90 inhibitor is a dual Hsp90/Cox-2 inhibitor.
  • cyclooxygenase-2 inhibitor and "Cox-2 inhibitor”, which can be used interchangeably herein, denote compounds which inhibit the cyclooxygenase-2 enzyme (Cox-2) regardless of the degree of inhibition of the cyclooxygenase-1 enzyme (Cox-1), and include pharmaceutically acceptable racemates, enantiomers, tautomers, salts, esters and prodrags of those compounds.
  • a compound is considered a Cox-2 inhibitor although the compound inhibits Cox-2 to an equal, greater, or lesser degree than it inhibits Cox-1.
  • Cox-2 inhibitors herein therefore encompass many traditional non-selective NSAIDs (non-steroidal anti- inflammatory drags).
  • Suitable NSAIDs include ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone
  • Cox-2 inhibitors useful according to embodiments of the present invention are agents and compounds that selectively or preferentially inhibit Cox-2 to a greater degree than they inhibit Cox-1. Such agents and compounds are termed "Cox-2 selective inhibitors" herein.
  • selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IQo value for inhibition of Cox-1, divided by the corresponding IC 50 value for inhibition of Cox-2 (Cox-1 IQo/Cox- 2 IQo).
  • a Cox-2 selective inhibitor herein is thus any inhibitor for which Cox-1 IQo/Cox-2 IQo 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 100.
  • Cox-2 selective inhibitors useful in the present invention can have a Cox-2 IQo of less than about 1 ⁇ M, less than about 0.5 ⁇ M, or less than about 0.2 ⁇ M.
  • Cox-2 selective inhibitors useful in the present invention can have a Cox-1 IQo of greater than about 1 ⁇ M, for example greater than about 20 ⁇ M.
  • Cox-2 inhibitors exhibiting a high degree of selectivity for Cox-2 over Cox-1 inhibition can indicate ability to reduce incidence of common NSAID-induced side effects.
  • a Cox-2 selective inhibitor can be used in a form of a prodrag thereof.
  • a "prodrag” is a compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject.
  • a prodrag for a Cox-2 selective inhibitor is parecoxib, for example in a form of a salt such as parecoxib sodium, which is a therapeutically effective prodrag of the tricyclic Cox-2 selective inhibitor valdecoxib.
  • Cox-2 selective inhibitors is described in U.S. Patent No. 5,932,598, incorporated herein by reference.
  • the Cox-2 selective inhibitor is meloxicam or a pharmaceutically acceptable salt or prodrag thereof.
  • the Cox-2 selective inhibitor is RS 57067 (6-[[5-(4- chlorobenzoyl)- 1 ,4-dimethyl- lH-pyrrol-2-yl]methyl]-3 (2H)-pyridazinone) or a pharmaceutically acceptable salt or prodrag thereof.
  • the Cox-2 selective inhibitor is of the chromene or chroman structural class that is a substituted benzopyran or a substituted benzopyran analog, for example selected from the group consisting of substituted benzothiopyrans, dihydroquinolines and dihydronaphthalenes.
  • These compounds can have a stracture as shown in any of formulas (III), (IN), (V), (VI), (VII) and (VIII) below, and as illustrated in Table 4, and can be diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrags of such compounds.
  • Benzopyrans that can serve as a COX-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Patent No.
  • X 1 is selected from O, S, CR C R b and NR , where R ⁇ is selected from hydrido, Q-Q alkyl, (optionally substituted phenyl)-Q-Q alkyl, acyl and carboxy- Q-Q alkyl; and where each of R b and R c is independently selected from hydrido, Q-Q alkyl, phenyl-Q-Q alkyl, Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl; or where CR ⁇ R c forms a 3-6 membered cycloalkyl ring;
  • R 1 is selected from carboxyl, aminocarbonyl, Q-Q alkylsulfonylaminocarbonyl and Q-Q alkoxycarbonyl;
  • R 2 is selected from hydrido, phenyl, thienyl, Q-Q alkyl and Q-Q alkenyl;
  • R 3 is selected from Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl;
  • R 4 is one or more radicals independently selected from hydrido, halo, Q-Q alkyl, Q-Q alkenyl, Q-Q alkynyl, halo-Q-Q alkynyl, aryl-Q-Q alkyl, aryl-Q-Q alkynyl, aryl-Q-Q alkenyl, Q-Q alkoxy, methylenedioxy, Q-Q alkylthio, Q-Q alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Q-Q alkoxy-Q-Q alkyl, aryl-Q-Q alkyloxy, heteroaryl-Q-Q alkyloxy, aryl- Q-Q alkoxy-Q-Q alkyl, Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q haloalkylthio, Q-Q haloalkylsul
  • R 4 together with ring A forms a radical selected from naphthyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
  • Another class of benzopyran derivatives that can serve as the COX-2 selective inhibitor of the present invention includes a compound having the stracture of formula
  • X 2 is selected from O, S, CR C R b and ⁇ R ⁇ ; where R ⁇ is selected from hydrido, Q-Q alkyl, (optionally substituted phenyl)-Q-Q alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Q-Q alkyl; and where each of R b and R c is independently selected from hydrido, Q-Q alkyl, phenyl- Q-Q alkyl, Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl; or where CR c R ⁇ form a cyclopropyl ring; R 5 is selected from carboxyl, aminocarbonyl, Q-Q alkylsulfonylaminocarbonyl and Q-Q
  • X 3 is selected from the group consisting of O or S or NR a where R is alkyl; R 9 is selected from the group consisting of H and aryl; R 10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R 11 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and 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
  • X 4 is selected from O or S or NR ⁇ where R ⁇ is alkyl; R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; 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 R 15 is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl,
  • Formula (VII) is: wherein: X 5 is selected from the group consisting of O or S or NR b where R b is alkyl; R 16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R 17 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and R 18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy,
  • the COX-2 selective inhibitor can be a compound of Formula (VII), wherein: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; 17 R is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and i o R is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkyl- aminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosul
  • the COX-2 selective inhibitor can be a compound of Formula (VTI), wherein: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is carboxyl; 17 R is lower haloalkyl; and R 18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylamino- sulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or R together with ring A forms a naphth
  • the COX-2 selective inhibitor can be a compound of Formula (VII), wherein: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; 17 R is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl and trifluoromethyl; and 1 R R is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, me
  • the COX-2 selective inhibitor can be a compound of Formula (VII), wherein: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; R is selected from the group consisting trifluoromethyl and pentafluoroethyl; and R is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethyl- aminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2-
  • Another class of benzopyran derivatives that can serve as the COX-2 selective inhibitor of the present invention includes a compound having the structure of formula (VIII):
  • X r6 i ⁇ s selected from the group consisting of O and S;
  • R , 19 is lower haloalkyl;
  • R 20 is selected from the group consisting of hydrido and halo;
  • R 21 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkyl- aminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl;
  • R 22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy and aryl; and
  • R is selected from the group consisting of the group consisting of hydrido
  • the COX-2 selective inhibitor can be a compound of Formula (Vm), wherein: X 6 is selected from the group consisting of O and S; R 19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R 20 is selected from the group consisting of hydrido, chloro and fluoro; R 21 is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethyl- aminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylamino- sulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl and morpholinosulfonyl; R 22 is selected from the
  • the COX-2 selective inhibitor can be selected from the class of tricyclic COX-2 selective inhibitors represented by the general stracture of formula (IX):
  • Z 1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings
  • R 24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 24 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio
  • R 25 is selected from the group consisting of methyl and amino
  • R 26 is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyan
  • the COX-2 selective inhibitor of formula (DQ 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 prodrags thereof.
  • the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
  • Parecoxib can be used as a salt, for example parecoxib sodium.
  • COX-2 selective inhibitor is another tricyclic COX-2 selective inhibitor which can be advantageously employed.
  • specific compounds that are useful as the COX-2 selective inhibitor include, without limitation: 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(l,2-a) pyridine; 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; 5-(4-fluoiOphenyl)-l-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole; 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-l-phenyl-3-(trifluoromethyl) pyrazole; 4-(5-(4-chlorophenyl)-3-(4-
  • the Cox-2 selective inhibitor used in the present invention can be selected from the class of phenylacetic acid derivatives represented by the general structure of formula (X):
  • R > 27 is methyl, ethyl or propyl
  • R , 28 is chloro or fluoro
  • R > 29 is hydrogen, fluoro or methyl
  • R ,30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy
  • R is hydrogen, fluoro or methyl
  • R 32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl; provided that R 28 , R 29 , R 30 and R 31 are not all fluoro when R 27 is ethyl and R 30 is H; or an isomer, pharmaceutically acceptable salt, ester, or prodrag thereof.
  • a phenylacetic acid derivative Cox-2 selective inhibitor that is described in International Patent Publication No. WO 99/11605, incorporated by reference herein, is a compound that has the stracture shown in formula (X), wherein: R 27 is ethyl; R 28 and R 30 are chloro; R 29 and R 31 are hydrogen; and R 32 is methyl.
  • Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula (X), wherein: R 27 is propyl; R 28 and R 30 are chloro; R 29 and R 31 are methyl; and R 32 is ethyl.
  • Cox-2 selective inhibitor compounds that have a stracture similar to that shown in formula (X) are described in the patents individually cited below and incorporated herein by reference. [0157] U.S. Patent No. 6,310,099. [0158] U.S. Patent No. 6,291,523. [0159] U.S. Patent No. 5,958,978. [0160] Other Cox-2 selective inhibitors that can be used in the present invention have the general stracture shown in formula (XI), wherein the J group is a carbocycle or a heterocycle. Illustrative embodiments have the stracture:
  • X is O; J is 1-phenyl; R 33 is 2-NHSO 2 CH 3 ; R 34 is 4-NO 2 ; and there is no R 35 group (nimesulide); X is O; J is l-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-NHSO 2 CH 3 (flosulide); X is O; J is cyclohexyl; R 33 is 2-NHSO 2 CH 3 ; R 34 is 5-NO 2 ; and there is no R 35 group (NS-398 or N-(2-cyclohexyloxynitrophenyl)methanesulfonamide); X is S; J is l-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 3S is 6-N " SO 2 CH 3 -Na + (L-745337); X is S; J is thiophen-2-yl; R 33 is 4-F; there is no R 34 group; and
  • Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula (XII):
  • rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Q 1 , Q 2 , L 1 and L 2 is (a) an -S(O) n -R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having 1 to 6 carbon atoms, or (b) an -SO 2 NH 2 group, and is located in the para position; the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or Q 1 and
  • Cox-2 selective inhibitor in the present invention include N-(2-cyclohexyloxynitro- phenyl)methane sulfonamide and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3- furanylidene)methyl]benzenesulfonamide.
  • Cox-2 selective inhibitors that are useful in the present invention include darbufelone of Pfizer, CS-502 of Sankyo, LAS 34475 and LAS 34555 of Almirall
  • Compounds that can act as Cox-2 selective inhibitors include multibinding compounds containing from 2 to 10 ligands covalently attached 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 Cox-2 selective inhibitors include heterocyclic aromatic oxazole compounds as described in the patents individually cited below and incorporated herein by reference.
  • Z is an oxygen atom; one of R 40 and R 41 is a group of the formula
  • R >43 is lower alkyl, amino or lower alkylamino
  • R 44 , r R45 , R ,46 and R ,47 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R 44 , R 45 , R 46 and R 47 is not hydrogen
  • the other of R 40 and R 41 is an optionally substituted cycloalkyl, heterocyclyl or aryl
  • R is a lower alkyl or a halogenated lower alkyl, or a pharmaceutically acceptable salt thereof.
  • Cox-2 selective inhibitors useful herein include compounds described in the patents individually cited below and incorporated herein by reference. [0172] U.S. Patent No. 6,080,876. [0173] U.S. Patent No. 6,133,292. [0174] Such compounds are described by formula (XIV):
  • Z 3 is selected from the group consisting of (a) linear or branched Q -6 alkyl, (b) linear or branched Q. 6 alkoxy, (c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Q.
  • R 48 is selected from the group consisting of NH and CH 3
  • R 49 is selected from the group consisting of C 1-6 alkyl unsubstituted or substituted with C 3-6 cycloalkyl, and C 3-6 cycloalkyl
  • R 50 is selected from the group consisting of Q -6 alkyl unsubstituted or substituted with one, two or three fluoro atoms; and C 3-6 cycloalkyl; with the proviso that R 49 and R 50 are not the same.
  • Compounds that can act as Cox-2 selective inhibitors include pyridines described in the patents individually cited below and incorporated herein by reference. [0176] U.S. Patent No. 6, 369,275. [0177] U.S. Patent No. 6,127,545. [0178] U.S. Patent No. 6,130,334. [0179] U.S. Patent No. 6,204,387. [0180] U.S. Patent No. 6,071,936.
  • R 51 is selected from the group consisting of: CH 3 , NH 2) NHC(O)CF 3 and NHCH 3 ;
  • Z 4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), having substituents selected from the group consisting of hydrogen, halo, Q -6 alkoxy, C 1-6 alkylthio, CN, Q -6 alkyl, C 1-6 fluoroalkyl, N 3 , -CO 2 R 53 , hydroxy, -C(R 54 )(R 55 )-OH, -Q -6 alkyl-CO 2 -R 56 and C 1-6 fluoroalkoxy;
  • R >52 is selected from the group consisting of halo, Q -6 alkoxy, Q.
  • R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 and R 63 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; or R 54 and R 55 , R 58 and R 59 , or R 61 and R 62 , together with the atom to which they are attached, form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms.
  • diarylbenzopyran derivatives as described in U.S. Patent No. 6,340,694, incorporated herein by reference.
  • Such diarylbenzopyran derivatives have the general formula shown below in formula (XVI):
  • X is an oxygen atom or a sulfur atom
  • R 64 and R 65 identical to or different from each other, are independently hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, nitro, nitrile or carboxyl
  • R ,66 is a group of a formula S(O) n R ,68 where n is an integer of 0 to 2, R 68 is hydrogen, Q-Q lower alkyl, or a group of formula NR 69 R 70 wherein R 69 and R 70 , identical to or different from each other, are independently hydrogen or Q-Q lower alkyl group
  • R 67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyreolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Q-Q lower alkyl group, indanyl
  • R 71 through R 75 are independently hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, hydroxyalkyl, nitro, a group of formula S(O) n R 68 , a group of formula NR 69 R 70 , trifluoromethoxy, nitrile, carboxyl, acetyl or formyl, wherein n, R 68 , R 69 and R 70 have the same meaning as defined by R 66 above; and R 76 is hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, trifluoromethoxy, carboxyl or acetyl.
  • Compounds that can act as Cox-2 selective inhibitors include l-(4- sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines as described in U.S. Patent No. 6,376,519, incorporated herein by reference. Such compounds have the formula shown below in formula (XVII):
  • X is selected from the group consisting of Q-Q trihalomethyl, for example trifluoromethyl Q-Q alkyl; and an optionally substituted or di-substituted phenyl group of formula
  • R 77 and R 78 are independently selected from the group consisting of hydrogen, halogen (e.g., chlorine, fluorine or bromine), hydroxyl, nitro, Q-Q (e.g., Q-Q) alkyl, Q-Q (e.g., Q-Q) alkoxy, carboxy, Q-Q trihaloalkyl (e.g., trihalomethyl such as trifluoromethyl), and cyano; and Z 5 is selected from the group consisting of substituted and unsubstituted aryl.
  • Compounds that can act as Cox-2 selective inhibitors of the present invention include heterocycles as described in U.S. Patent No. 6,153,787, incorporated herein by reference.
  • X rl ⁇ O ⁇ . is fluoro or chloro.
  • Compounds that can act as Cox-2 selective inhibitors include 2,3,5- trisubstituted pyridines as described in U.S. Patent No. 6,046,217, incorporated herein by reference. Such compounds have the general formula shown below in formula (XX): or a pharmaceutically acceptable salt thereof, wherein: X 11 is selected from the group consisting of O, S and bond; n is O or 1; R 83 is selected from the group consisting of CH 3 , NH 2 and NHC(O)CF ; R 84 is selected from the group consisting of halo, C 1-6 alkoxy, Q -6 alkylthio, CN, C ⁇ .
  • R 85 to R 98 are independently chosen from the group consisting of hydrogen and Q, 6 alkyl; or R 85 and R 89 , or R 89 and R 90 , together with the atoms to which they are attached, form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms; or R and R 87 are joined to form a bond.
  • One exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein X is a bond.
  • Cox-2 selective inhibitor of formula (XX) is that wherein X is O.
  • Cox-2 selective inhibitor of formula (XX) is that wherein X is S.
  • Cox-2 selective inhibitor of formula (XX) is that wherein R 83 is CH 3 .
  • Cox-2 selective inhibitor of formula (XX) is that wherein R 84 is halo or C 1-6 fluoroalkyl.
  • Compounds that can act as Cox-2 selective 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):
  • R 108 is
  • R 113 is hydrogen, lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di(lower alkyl)amino or cyano; and R 111 and R 112 are independently halogen, cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carbalkoxy, trifluoromethoxy, acetamido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethyl- sulfonyl; R 109 is amino, mono or di(lower alkyl)amino
  • X 15 denotes oxygen, sulfur or NH
  • R 118 is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF 3 , cyano or alkoxy
  • R 119 and R 120 independently from one another, denote hydrogen, an optionally polyfluorized alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 ) n -X 16 ; or R 119 and R 120 , together with the N atom, denote a 3- to 7- membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl
  • Compounds that can act as Cox-2 selective inhibitors include 3-phenyl-4- (4(methylsulfonyl)phenyl)-2-(5H)-furanones as described in U.S. Patent 6,239,173. Such compounds have the formula shown below in formula (XXV):
  • R and R are each independently selected from the group consisting of hydrogen, CF 3 , CN, C 1-6 alkyl, -Q 5 , -O-Q 5 ; -S-Q 5 , and optionally C 1-3 alkyl- substituted -C 1-5 alkyl-Q 5 , -O-Q -5 alkyl-Q 5 , -S-Q -5 alkyl-Q 5 , -C 1-3 alkyl- O-Q -3 alkyl-Q 5 , -Q -3 alkyl-S-Q -3 alkyl-Q 5 , -Q -5 alkyl-O-Q 5 , -C 1-5 alkyl- S-Q 5 wherein the substituent resides on the alkyl;
  • R 129 , R 129' , R 130 , R 131 and R 132 are each independently selected from the group consisting of hydrogen and Q -6 alkyl; or R 129 and R 130 , or R 131 and R 132 , together with the carbon to which they are attached, form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; and
  • Compounds that can act as Cox-2 selective inhibitors include bicyclic carbonyl indole compounds as described in U.S. Patent No. 6,303,628. Such compounds have the formula shown below in formula (XXVI):
  • A is Q -6 alkylene or -NR 133
  • Z 9 is CH or N
  • Z 10 and Y 2 are independently selected from -CH 2 - O, S and -N-R , 1 1 33.
  • m is 1, 2 or 3
  • q and r are independently 0, 1 or 2
  • X 18 is independently selected from halogen, Q.
  • n is O, 1, 2, 3 or 4;
  • L 3 is oxygen or sulfur;
  • R , 133 is hydrogen or C 1-4 alkyl;
  • R , 134 is hydroxy, Q -6 alkyl, halo-substituted Q -6 alkyl, Q -6 alkoxy, halo- substituted Q -6 alkoxy, C 3- cycloalkoxy, Ci- 4 alkyl(C 3-7 cycloalkoxy), -NR R , C 1-4 alkylphenyl-O- or phenyl-O-, said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci- 4 alkyl, hydroxy, Q.
  • R 135 is Q -6 alkyl or halo-substituted C 1-6 alkyl; and R 136 and R 137 are independently selected from hydrogen, C 1-6 alkyl and halo- substituted Q -6 alkyl.
  • Compounds that can act as a Cox-2 selective inhibitors include benzimidazole compounds as described in U.S. Patent No. 6,310,079. Such compounds have the formula shown below in fonnula (XXVII):
  • a 10 is heteroaryl selected from (a) a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, and (b) a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
  • X 20 is independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, halo-substituted Q-Q alkyl, hydroxy-substituted Q-Q alkyl, (Q-Q alkoxy)Q-Q alkyl, halo-substituted Q-Q alkoxy, amino, N-(Q-Q alkyl)amino, N,N-
  • R 138 is selected from hydrogen; straight or branched Q-Q alkyl optionally substituted with one to three substituent(s) independently selected from halo, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; Q-Q cycloalkyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; Q-Q cycloalkenyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; phenyl optionally substituted with one
  • R 139 and R 140 are independently selected from hydrogen; halo; Q-Q alkyl; phenyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(C ⁇ -C 4 alkyl)amino; or R 138 and R 139 can form, together with the carbon atom to which they are attached, a Q-Q cycloalkyl ring; m is 0, 1, 2, 3, 4 or 5; and n is O, 1, 2, 3 or 4. [0201]
  • Compounds that can act as Cox-2 selective inhibitors include indole compounds that are described in U.S. Patent No. 6,300,363. Such compounds have the formula shown below in formula (XXVIII):
  • R 141 is hydrogen or C 1-6 alkyl optionally substituted with a substituent selected independently from hydroxy, OR 143 , nitro, amino, mono- or di-(C 1- alkyl)amino, CO 2 H, CO 2 (Q -4 alkyl), CONH 2 , CONH(Q -4 alkyl) and CON(Q -4 alkyl) 2 ;
  • R 142 is hydrogen; C 1-4 alkyl; C(O)R 145 where R 145 is selected from (a) Q -22 alkyl or C 2-22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from halo, hydroxy, OR 143 , S(O) m R 143 , nitro, amino, mono- or di-(Q- 4 alkyl)amino, NHSO 2 R 143 , CO 2 H, CO 2 (Q- 4 alkyl), CONH 2 , CONH(Q -4 alkyl), CON(Q -4 alkyl) 2 , OC(O)R 143 , thienyl, naphthyl and groups of the following formulae: (b) Q -22 alkyl or C 2- alkenyl, said alkyl or alkenyl being optionally substituted with 5 to 45 halogen atoms; (c) -Y 5 -C 3-7 cycloalkyl or
  • X is halo, Q- 4 alkyl, hydroxy, Q- 4 alkoxy, halo-substituted Q- 4 alkoxy, S(O) m R 143 , amino, mono- or di-(Q. 4 alkyl)amino, NHSO 2 R 143 , nitro, halosubstituted Q-4 alkyl, CN, CO 2 H, CO 2 (C alkyl), C ⁇ - 4 alkyl-OH, Q- 4 alkyl- OR 143 , CONH 2 , CONH(Q. 4 alkyl) or CON(Q -4 alkyl) 2 ;
  • R 143 is C 1-4 alkyl or halo-substituted C 1-4 alkyl; m is 0, 1 or 2; n is O, 1, 2 or 3; p is 1, 2, 3, 4 or 5; q is 2 or 3;
  • Z 11 is oxygen, sulfur or NR 144 ;
  • R 144 is hydrogen, C 1-6 alkyl, halo-substituted Q- 4 alkyl or -Y 5 -phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, Q.
  • X 23 and Y 6 are selected from hydrogen, halogen, alkyl, nitro, amino and other oxygen- and sulfur-containing functional groups such as hydroxy, methoxy and methylsulfonyl.
  • Compounds that can act as Cox-2 selective inhibitors include 2-aryloxy-4-aryl furan-2-ones as described in U.S. Patent No. 6,140,515. Such compounds have the formula shown below in formula (XXX):
  • R 146 is selected from the group consisting of SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 ;
  • R 147 is selected from the group consisting of OR 150 , mono- or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro;
  • R 150 is unsubstituted or mono- or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro;
  • R 148 is H or Ci-4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; and
  • R 149 is H and Ci- 4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; with the proviso that R 148 and R 149 are not the same.
  • Z 13 is C or N; when Z 13 is N, R 151 represents H or is absent, or is taken in conjunction with R 152 as described below; when Z is C, R represents H and R is a moiety which has the following characteristics: (a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration, (b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and (c) there exists an energetically stable configuration planar with ring A to within about 15 degrees; or R 151 and R 152 are taken in combination and represent a 5- or 6-membered aromatic or nonaromatic ring D fused to ring A, said ring D containing 0-3 heteroatoms selected from O, S and N; said ring D being lipophilic except for the
  • R 155 , R 156 , R 157 and R 158 are independently selected from the group consisting of hydrogen, Q- 5 alkyl, Q- 5 alkoxy, phenyl, halo, hydroxy, Q-5 alkylsulfonyl, Q- 5 alkylthio, trihalo-Q-5 alkyl, amino, nitro and 2-quinolinylmethoxy;
  • R 159 is hydrogen; Q- 5 alkyl; trihalo-Q- 5 alkyl; phenyl; substituted phenyl where the phenyl substituents are halogen, Q-5 alkoxy, trihalo-Q-5 alkyl or nitro; or heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen;
  • R 160 is hydrogen; Q.s alkyl; phenyl-Q- 5 alkyl; substituted phenyl-Q- 5 alkyl where the phenyl substituents are halogen,
  • Compounds that can act as Cox-2 selective inhibitors include 2-substituted imidazoles as described in U.S. Patent No. 6,040,320. Such compounds have the formula shown below in formula (XXXIII):
  • R is phenyl; heteroaryl containing 5 to 6 ring atoms; or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of Q- 5 alkyl, halogen, nitro, trifluoromethyl and nitrile;
  • R 1 is phenyl; heteroaryl containing 5 to 6 ring atoms; substituted heteroaryl wherein the substituents are independently selected from one or more members of the group consisting of Q- 5 alkyl and halogen; or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of Q.
  • R 166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl, Q- 5 alkoxycarbonyl, aryloxycarbonyl, aryl-Q- 5 alkyloxycarbonyl, aryl-Q- 5 alkyl, phthalimido-C 1-5 alkyl, amino-Q- 5 alkyl, diamino-Q- 5 alkyl, succinimido-Q -5 alkyl, Q- 5 alkylcarbonyl, arylcarbonyl, Q.
  • Compounds that can act as Cox-2 selective inhibitors include 1,3- and 2,3- diarylcycloalkano- and cycloalkenopyrazoles as described in U.S. Patent No. 6,083,969. Such compounds have the general formulas (XXX1N) and (XXXV) shown below:
  • R 168 and R 169 are independently selected from the group consisting of hydrogen, halogen, (Q-Q)alkyl, (Q-Q)alkoxy, nitro, amino, hydroxy, trifluoro, -S(Q-Q)alkyl, -SO(Q-Q)alkyl and -SO 2 (Q-Q)alkyl; and the fused moiety M is selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:
  • R 170 is selected from the group consisting of hydrogen, halogen, hydroxy and carbonyl
  • R is selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, (Q-Q)alkyl, (Q-Q)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxy, amino, (Q-Q)alkyl and (Q-Q)alkoxy; or R 170 and R 171 taken together form a moiety selected from the group consisting of -OCOCH 2 - -ONH(CH 3 )COCH 2 - -OCOCH.dbd. and -O-; and 1//oorr RR . 1 1 7 7 2 2 aa perennialn_nddj R ⁇ R, 1 1 7 7 3 3 ttaakken together form a moiety selected from the group consisting of -O- and
  • R , 174 is selected from the group consisting of hydrogen, OH, -OCOCH 3 , -COCH 3 and (Q-Q)alkyl; and R 175 is selected from the group consisting of hydrogen, OH, -OCOCH 3 , -COCH 3 , (C ⁇ -Qj)alkyl, -CONH 2 and -SO 2 CH 3 ; with the proviso that if M is a cyclohexyl group, then R 170 through R 173 may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drag forms thereof.
  • Compounds that can serve as Cox-2 selective inhibitors include esters derived from indolealkanols and amides derived from indolealkylamides as described in U.S. Patent No. 6,306,890. Such compounds have the general formula shown below in formula (XXXVI):
  • R , 176 is Q-Q alkyl, Q-Q branched alkyl, Q-Q cycloalkyl, Q-Q hydroxyalkyl, branched Q-Q hydroxyalkyl, hydroxy-substituted Q-Q aryl, primary, secondary or tertiary Q-Q alkylamino, primary, secondary or tertiary branched Q-Q alkylamino, primary, secondary or tertiary Q-Q arylamino, Q-Q alkylcarboxylic acid, branched Q-Q alkylcarboxylic acid, Q-Q alkylester, branched Q-Q alkylester, Q-Q aryl, Q-Q arylcarboxylic acid, Q-Q arylester, Q-Q aryl-substituted Q-Q alkyl, Q-Q heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-
  • X 26 is selected from the group consisting of O, S, -NR 185 , -NOR a and -NNR b R c ;
  • R 185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl;
  • R a , R b and R c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl;
  • R 181 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsul
  • R 186 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;
  • R 187 is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene;
  • R 188 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
  • R d and R e are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
  • R 182 , R 183 and R 184 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy
  • Z 14 is selected from the group consisting of:
  • X 27 is selected from the group consisting of S(O) 2 , S(O)(NR 191 ), S(O), Se(O) 2 , P(O)(OR 192 ) and P(O)(NR 193 R 194 );
  • X 28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen;
  • R 190 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH 2 and -NCHN(R 191 )R 192 ;
  • R 191 , R 192 , R 193 and R 194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193 and R 194 can be taken together, with the nitrogen to which they are attached, to
  • a 12 denotes oxygen, sulfur or NH
  • 901 R denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF 3 or alkoxy
  • D 5 denotes a group:
  • R 202 and R 203 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH 2 ) conflict-X 29 ; or R 202 and R 203 together with the N-atom denote a 3- to 7- membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH 2 ) n -X 29.
  • R ,202,' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 ) n -X 29.
  • X 29 denotes halogen, NO 2 , -OR 204 , -COR 204 , -CO 2 R 204 , -OCO 2 R 204 , -CN, -CONR 204 OR 205 , CONR ,20 ⁇ 4Trl>20 ⁇ 5 j , -SR 204 -S(O)R ,2 Z 0 U 4 4 , 20 -NR , ZU 4 4 Rr>2' 0 5 -NHC(O)R ,20 ⁇ 4 or -NHS(O) 2 R 204.
  • R 2 and R 205 independently of each other denote hydrogen, alkyl, aralkyl or aryl;
  • n is an integer from 0 to 6;
  • R 206 is CF 3 or a straight-chained or branched Q- 4 alkyl group optionally mono- or polysubstituted by halogen or alkoxy;
  • Cox-2 selective inhibitors useful in the subject methods and compositions can include compounds described in the patents individually cited below and incorporated herein by reference.
  • Cox-2 selective inhibitors useful in the present invention can be supplied by any source as long as the Cox-2 selective inhibitor is pharmaceutically acceptable.
  • Cox-2 selective inhibitors can be isolated and purified from natural sources or can be synthesized.
  • Cox-2 selective inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products.
  • Cox-2 inhibitors useful in the compositions and methods of the present invention can by synthesized, for example, according to the description in
  • Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention may be synthesized by the methods described in, for example, 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 set forth in U.S. Patent 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.
  • 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 set forth in Japanese Patent Publication No. JP
  • Patent Publication No. WO 95/00501 Patent Publication No. WO 95/00501.
  • Oxazoles can be prepared by the methods described in International Patent
  • Isoxazoles can be prepared by the methods described in International Patent
  • Imidazoles can be prepared by the methods described in International Patent
  • Cyclopentene Cox-2 inhibitors can be prepared by the methods described in
  • Patent Publication No. WO 95/00501 Patent Publication No. WO 95/00501.
  • Terphenyl compounds can be prepared by the methods described in
  • Thiazole compounds can be prepared by the methods described in
  • Pyridine compounds can be prepared by the methods described in
  • 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,
  • the Cox-2 selective inhibitor can be selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrags of any of them, and mixtures thereof.
  • the Cox-2 selective inhibitor comprises celecoxib.
  • the Cox-2 selective inhibitor comprises valdecoxib.
  • the Cox-2 selective inhibitor comprises parecoxib sodium.
  • an Hsp inhibitor with or without a Cox-2 inhibitor, is administered in combination with a PDE inhibitor.
  • the PDE inhibitor is a cGMP-specific PDE inhibitor.
  • cGMP-specific PDEs include PDE 5, PDE 6, and PDE 9. Any agent that inhibits one or more of these PDE isoenzymes can be used in the present invention.
  • cGMP-specific PDE inhibitors examples include, but are not limited to, exisulind, dipyridamole, MBCQ,
  • MMPX MY-5445, zaprinast, sildenafil, tadalafil, vardenafil, T-1032, A02131-1, GF248,
  • the cGMP-specific PDE inhibitor is selected from the group consisting of exisulind, sildenafil citrate, tadalafil, vardenafil and zaprinast. In an exemplary embodiment, the cGMP-specific PDE inhibitor is exisulind.
  • PC27879A (01506/1) Table 6: cGMP-specific phosphodiesterase (PDE) inhibitors
  • PC27879A (01506/1) Table 6: cGMP-specific phosphodiesterase (PDE) inhibitors
  • Hsp90 inhibitors and PDE inhibitors useful according to the present invention can be supplied by any source as long as they are pharmaceutically acceptable.
  • an Hsp90 inhibitor can be synthesized, for example, according to the description in Example 2
  • a PDE inhibitor can be synthesized, for example, according to the description in Example 4.
  • Hsp90 inhibitors and PDE inhibitors can also be isolated and purified from natural sources. Hsp90 inhibitors and PDE inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products.
  • a combination comprising a Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, is administered to a subject in need of such treatment according to standard routes of drug delivery that are well known to one of ordinary skill in the art.
  • any one, two or all three of the Hsp90 inhibitor, the PDE inhibitor and the optional Cox-2 inhibitor can optionally be supplied in the form of a pharmaceutically active salt, a prodrag, an isomer, a racemic mixture, or in any other chemical form or combination that, under physiological conditions, still provides for inhibition of their respective enzyme targets.
  • Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyravic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.
  • Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts.
  • Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts and other physiologically acceptable metal ions.
  • Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.
  • 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.
  • Pharmaceutical compositions can also include stabilizers, antioxidants, colorants and diluents.
  • Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective.
  • a Hsp90 inhibitor and a PDE inhibitor are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately.
  • a Cox-2 inhibitor is present in the combination, it can be administered together in a pharmaceutical carrier with either or both of the Hsp90 inhibitor and/or the PDE inhibitor, or separately from both.
  • the pharmaceutical compositions may be administered enterally and/or parenterally.
  • Oral intra-gastric
  • 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 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 can be at or near body temperature.
  • Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • Tablets can be uncoated or they can be coated by known techniques, for example to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions can be produced that contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be naturally-occurring 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 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbit
  • Aqueous suspensions can also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, 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, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by 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 exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
  • 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 can 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 sterile injectable aqueous or oleaginous suspensions.
  • Such suspensions can be formulated according to known art using suitable dispersing or wetting agents 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.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • omega-3 polyunsaturated fatty acids can find use in preparation of injectables.
  • 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 drag with a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at rectal temperature and will therefore, melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperature, but liquid at rectal temperature and will therefore, melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • buccal and sub-lingual administration including administration in the form of lozenges, pastilles or a chewable gum comprising the compounds set forth herein.
  • the compounds can be deposited in a flavored base, usually sucrose, and acacia 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 medicaments directly into and/or through a subject's skin.
  • Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.
  • Powders have the advantage of sticking to moist surfaces, and consequently, can remain active for longer periods. Therefore, powders are especially attractive for treating neoplasms in, for example, the otic canal. For much the same reason, creams are also effective pharmaceutically acceptable carriers.
  • compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers.
  • Viscosity-building agents include, for example, polyvinyl alcohol, polyvinyl pynolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition.
  • Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.
  • Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition.
  • cosolvents include polysorbates 20, 60 and 80, polyoxyethylene/polyoxypropylene surfactants (e.g.,
  • cosolvents are employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition.
  • 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.
  • the present invention encompasses a method of treating or preventing neoplasia or a neoplasia-related disorder 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, i.e., the total of said first and second amounts, is therapeutically effective for such treatment or prevention
  • the present invention also encompasses a method of preventing and treating neoplasia or a neoplasia-related disorder in a subject in need of such prevention and treatment, the method comprising administering a first amount of a 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.
  • the amount of the combination comprising an Hsp90 inhibitor and a PDE inhibitor and optionally a Cox-2 inhibitor required for use in the treatment or prevention of neoplasia and neoplasia-related disorders will vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, an appropriate daily dosage is described herein, although the limits that are identified as being preferred can be exceeded if expedient. The daily dosage can be administered as a single dosage or in divided dosages. [0283] The dosage level of an Hsp90 inhibitor will necessarily depend on the particular agent that is used.
  • an appropriate dosage level of an Hsp90 inhibitor is generally from about 0.0001 mg/kg to about 200 mg/kg subject body weight per day, administered in single or multiple doses. More typically, the dosage level is about 0.1 mg/kg to about 25 mg/kg per day.
  • the dosage level of a PDE inhibitor will likewise depend on the particular agent that is used. However, an appropriate dosage level of a PDE inhibitor is generally about 0.01 mg/kg to about 10 mg/kg per day. In larger mammals, for example humans, a typical indicated dose for the PDE inhibitor is about 1 mg to about 500 mg per day. [0285] 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 that is generally from about 0.01 mg/kg to about 140 mg/kg subject body weight per day, administered in single or multiple doses.
  • the dosage level is about 0.01 mg/kg to about 50 mg/kg per day, for example about 0.1 mg/kg to about 25 mg/kg per day, about 0.1 mg/kg to about 10 mg/kg per day, or about 0.5 mg/kg to about 10 mg/kg per day.
  • a typical indicated dose for the Cox-2 inhibitor is about 0.5 mg to about 7 g orally per day.
  • a compound can be administered on a regimen of several times per day, for example 1 to about 4 times per day, preferably once or twice per day.
  • the amount of the Cox-2 inhibitor that can be combined with carrier materials to produce a single dosage form varies depending upon the subject to be treated and the particular mode of administration.
  • a formulation intended for oral administration to humans can contain about 0.5 mg to about 7 g of active agent compounded optionally with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms for the Cox-2 inhibitor generally contain 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 effectiveness of a particular dosage of an Hsp90 inhibitor in combination with a PDE inhibitor and optionally 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.
  • the effectiveness of a particular dosage of a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, can be determined by staging the disorder at multiple points during a subject's treatment. For example, once a histologic diagnosis is made, staging (i.e., determination of the extent of disease) helps determine treatment decisions and prognosis. Clinical staging uses data from the patient's history, physical examination, and noninvasive studies. Pathologic staging requires tissue specimens.
  • Pathological staging is performed by obtaining a biopsy of the neoplasm or tumor.
  • a biopsy is performed by obtaining a tissue specimen of the tumor and examining the cells microscopically.
  • a bone marrow biopsy is especially useful in determining metastases from 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 to 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.
  • Elevation of serum chemistries and enzyme levels can also help staging. Elevation of liver enzymes (alkaline phosphatase, LDH and ALT) suggests presence of liver metastases. Elevated alkaline phosphatase and serum Ca may be the first evidence of bone metastases. Elevated acid phosphatase (tartrate inhibited) suggests extracapsular extension of prostate cancer. Fasting hypoglycemia may indicate an insulinoma, hepatocellular carcinoma, or retroperitoneal sarcoma.
  • Elevated BUN or creatinine levels may indicate an obstructive uropathy secondary to a pelvic mass, intrarenal obstruction from tubular precipitation of myeloma protein, or uric acid nephropathy from lymphoma or other cancers. Elevated uric acid levels often occur in myeloproliferative and lymphoproliferative disorders.
  • ⁇ -Fetoprotein may be elevated in hepatocellular carcinoma and testicular carcinomas, carcinoembryonic antigen-S in colon cancer, human chorionic gonadotropin in choriocarcinoma and testicular carcinoma, serum immunoglobulins in multiple myeloma, and DNA probes (bcr probe to identify the chromosome 22 change) in CML.
  • Tumors may synthesize proteins that produce no clinical symptoms, e.g., human chorionic gonadotropin, ⁇ -fetoprotein, carcinoembryonic antigen, CA 125, and CA 153. These protein products can be used as tumor markers in serial evaluation of patients for determining disease recunence or response to therapy. Thus, monitoring a subject for these tumor markers is indicative of progress of a neoplasia disorder. Such monitoring is also indicative of how well the methods, combinations and compositions of the present invention are treating or preventing a neoplasia disorder. Likewise, tumor marker monitoring is effective to determine appropriate dosages of a combination or composition of the present invention for treating neoplasia.
  • human chorionic gonadotropin e.g., human chorionic gonadotropin, ⁇ -fetoprotein, carcinoembryonic antigen, CA 125, and CA 153.
  • These protein products can be used as tumor markers in serial evaluation of patients for determining disease recunence or response
  • Imaging studies can detect metastases to brain, lung, spinal cord, or abdominal viscera, including the adrenal glands, retroperitoneal lymph nodes, liver, and spleen.
  • MRI with gadolinium is the procedure of choice for recognition and evaluation of brain tumors.
  • Ultrasonography can be used to study orbital, thyroid, cardiac, pericardial, hepatic, pancreatic, renal, and retroperitoneal areas. It may guide percutaneous biopsies and differentiate renal cell carcinoma from a benign renal cyst. Lymphangiography reveals enlarged pelvic and low lumbar lymph nodes and is useful in the clinical staging of patients with Hodgkin's disease, but it has generally been replaced by CT.
  • Liver-spleen scans can identify liver metastases and splenomegaly. Bone scans are sensitive in identifying metastases before they are evident on x-ray.
  • Gallium scans can help in staging lymphoid neoplasms.
  • Radiolabeled monoclonal antibodies e.g., to carcinoembryonic antigen, small cell lung cancer cells
  • provide important staging data in various neoplasms e.g., colon cancer, small cell lung cancer.
  • the term "subject" for purposes of treatment is one that is in need of the treatment of neoplasia or a neoplasia-related disorder.
  • the subject is one that is at risk for, or is predisposed to, developing neoplasia or a neoplasia-related disorder, including relapse of a previously occurring neoplasia or neoplasia-related disorder.
  • the phrase "subject in need of includes any subject that is suffering from or is predisposed to neoplasia or any neoplasia-related disorder described herein.
  • the phrase "subject in need of also includes any subject that requires a lower dose of conventional neoplasia treatment agents.
  • a “subject in need of includes any subject that requires a reduction in the side-effects of a conventional treatment agent.
  • a "subject in need of includes any subject that requires improved tolerability to any conventional treatment agent for a neoplasia disorder therapy.
  • the subject is an animal, typically a mammal, including humans, domestic and farm animals, zoo, sports and pet animals, such as dogs, horses, cats, cattle, etc.
  • the subject is most typically a human subject.
  • neoplasia disorders and neoplasia-related disorders including, but are not limited to, acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, AJJDS-related lymphoma, anal cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem 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,
  • Step 1 Preparation of l-(4-methylphenyl)-4,4,4-trifluorobutane-l,3-dione.
  • 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
  • Step 2 Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzenesulfonamide.
  • 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 Q 7 H 14 N 3 O 2 SF 3 ; Q 53.54; H, 3.70; N, 11.02.
  • the composition that was found by analysis was: Q 53.17; H, 3.81; N, 10.90.
  • Step 1 Preparation of l-bromo-2-(4-fluorophenyl)benzene
  • Step 2 Preparation of 2-(4-fluorophenyl)phenylboronic acid.
  • Step 3 Preparation of 4- [2-(4-fluorophenyl)phenyl]benzenesulf onamide.
  • 5 g (6.9 mmol) of 2-(4-fluorophenyl)phenylboronic acid from Step 2 was reacted with 2.5 g (10.4 mmol) of 4-bromobenzenesulfonamide (Lancaster) in toluene/ethanol at reflux in the presence of Pd° catalyst, e.g., tetrakis (terphenylphosphine)palladium(O), and 2M sodium carbonate.
  • Pd° catalyst e.g., tetrakis (terphenylphosphine)palladium(O), and 2M sodium carbonate.
  • the solution is made acidic by addition of 6M hydrochloric acid (to about pH 1 to 2), and heated to reflux for 30 minutes.
  • the solution is allowed to cool and basified with sodium hydroxide to a pH of about 13.0.
  • To the solution is added 0.01 mole of paramethylsulfinylbenzaldehyde and 2.0 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 yield 5-fluoro-2-methyl-l- (para-methylsulfinylbenzylidene)-indenyl-3 -acetic acid.
  • This example illustrates production of a combination comprising celecoxib, exisulind and 4- [2-(4-fluorophenyl)phenyl]benzenesulf onamide, and of a pharmaceutical composition containing the combination.
  • Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name Celebrex® from Pharmacia Corporation, Peapack, NJ.
  • Exisulind can be prepared as described in Example 4, or, alternatively, can be obtained under the trade name Aptosyn® from Cell Pathways, Inc., Horsham, PA.
  • a therapeutic composition of the present invention can be formed by intermixing 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.
  • each single dose unit contains about 200 mg of celecoxib and about 200 mg of 4-[2-(4- fluorophenyl)phenyl]benzenesulfonamide.
  • a solid carrier and other materials can be intermixed 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 about the same amount of the active ingredients as each of the single dose units of the liquid preparation described above.

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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 PHOPHODIESTERASE INHIBITOR FOR TREATING OR PREVENTING NEOPLASIA
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. provisional application Serial No. 60/515,021, filed on October 28, 2003, the disclosure of which in its entirety is incorporated by reference herein. FIELD OF THE F VENTION [0002] The present invention relates generally to drug combinations and methods of use thereof for prevention and/or treatment of neoplasia and neoplasia-related disorders, and more particularly to treating or preventing neoplasia and neoplasia-related disorders by administration of a combination of enzyme inhibitors to a subject. BACKGROUND OF THE INVENTION [0003] More than 1.2 million Americans develop cancer each year, making cancer the second leading cause of death in the United States. In 2000, cancer accounted for 23% of all deaths in the United States. U.S. Dept. of Health and Human Services, National Center for Health Statistics, National Vital Statistics Report. Vol. 50, No. 16 (2002). Consequently, novel treatment therapies are needed to counter the growing threat of cancer.
[0004] Cancer is a disorder arising from one or more genetic mutations that ultimately give rise to development of neoplasia. It is known that exposure of a cell to carcinogens, such as certain viruses, chemicals and radiation, can lead to DNA alteration that either inactivates a "suppressive" gene or activates an "oncogene".
[0005] "Suppressive" genes are growth regulatory genes, which upon mutation can no longer control cell growth. "Oncogenes" are initially normal genes (protooncogenes) that by mutation or altered context of expression become transforming genes. The protein products of transforming genes cause inappropriate cell growth. This occurs through activation of several intracellular signaling pathways, including the protein kinase C/mitogen-activated protein kinase (PKC/MAPK) pathway and the Ras/Raf/MEK 1/2/ERK Vz pathway. Transformed cells differ from normal cells in many ways, including cell morphology, cell-to-cell interactions, membrane content, cytoskeletal structure, protein secretion, gene expression and loss of apoptosis.
[0006] Oncogene transformed cells and cells that have lost suppressive gene regulation undergo uncontrolled proliferation, modified control of apoptosis, and initiation of angiogenesis. All three of these effects are characteristic for development of neoplasia and neoplasms.
[0007] Neoplasia is an abnormal, unregulated and disorganized proliferation of cell growth that is distinguished from normal cells by autonomous growth and somatic mutations. As neoplastic cells grow and divide they pass on their genetic mutations and proliferative characteristics to progeny cells. A neoplasm, or tumor, is an accumulation of neoplastic cells. A neoplasm can be benign or malignant.
[0008] Although several advances have been made in detection and therapy of cancer, no universally successful method for prevention or treatment is currently available. Cancer therapy currently relies on a combination of early diagnosis and aggressive treatment, which can include surgery, chemotherapy, radiation therapy and/or hormone therapy.
[0009] Surgery involves bulk removal of neoplasms. While surgery is sometimes effective in removing tumors located at certain sites, for example in the breast, colon or skin, it cannot be used in treatment of tumors located in other areas, such as the backbone, nor in treatment of disseminated neoplastic conditions such as leukemia. Moreover, surgical treatments are generally successful only if the cancer is detected at an early stage and before the cancer has metastasized to major organs, thus making surgery non- feasible.
[0010] Chemotherapy involves disruption of cell replication and/or cell metabolism. It is used most often in treatment of breast, lung and testicular cancer. The adverse effects of systemic chemotherapy used in treatment of neoplastic disease is problematic for patients undergoing cancer treatment. Of these adverse effects nausea and vomiting are the most common and severe side effects. Many of these chemotherapy-induced side effects, if severe, can lead to hospitalization, or require treatment with analgesics for management of pain. Likewise, radiation therapy is also not without such side effects as nausea, fatigue and fever. Of concern is that chemotherapy and radiation therapy-induced side effects significantly impact quality of life of the patient and may dramatically influence patient compliance with treatment. [0011] Novel cancer treatment strategies that eliminate the need for surgical intervention and reduce chemotherapy-induced side effects would, therefore, benefit many cancer sufferers.
[0012] Of particular interest is the finding that, among neoplastic cells, mRNA of the molecular chaperone 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 assists in protein refolding in cells exposed to environmental stress and is required for the conformational maturation of several important signaling proteins. Parsell & Lindquist (1993) Ann. Rev. Genet. 27, 437-496. [0013] Several of these signaling proteins are also required for the development of neoplasia. For example, Hsp90-associated "client" proteins that are associated with the growth and survival of neoplasia have been reported to include p53, HER-2, telomerase, V-Src, Bcr-Abl, Raf-1, Akt, ErbB2, and hypoxia-inducible factor 1 alpha (HTF-1 alpha). Blagosklonny et al. (2002) Leukemia 16(4), 455-462. Thus, Hsp90 is a molecular chaperone whose association is required for the stability and function of several mutated and over-expressed signaling proteins that promote the growth and/or survival of neoplastic cells. Neckers (2002) Trends Mol. Med. 8(4 Suppl), S55^S61. [0014] Inhibition of Hsp90 function results in selective degradation of important neoplastic signaling oncoproteins that are involved in cell proliferation, cell cycle regulation and apoptosis. Maloney et al. (2002) Expert Opin. Biol. Ther. 2(1), 3-24. Current Hsp90 inhibitors act by inhibiting Hsp90 ATPase activity and have shown promising activity against cancer. Neckers (2002) op. cit. Many of these Hsp90 inhibitors are naturally occurring 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 harmful side effects including, for example, hepatotoxicity, because of their inhibition of Hsp90 ATPase activity. Id.
[0015] Recent investigations into alternative therapeutic approaches to treatment of neoplasia have implicated inhibitors of cyclic GMP (cGMP) hydrolyzing enzymes called phophodiesterases ("PDEs"). Sulindac sulfone and its analog exisulind are inhibitors of cGMP-specific PDEs, and have been shown to induce apoptosis, or programmed cell death, in cancer cells. Rice et al. (2001) Cancer Res., 61, 1541-1547. [0016] PDEs constitute a large family of enzymes that catalyze hydrolysis of the intracellular second messengers, cyclic nucleotides (cAMP and cGMP), to their biologically inactive forms, 5'-AMP and 5'-GMP. In conjunction with adenylyl and guanylyl cyclases, PDEs are able to regulate cell signaling mechanisms that are mediated by cAMP and cGMP by reducing available intracellular pools. These second messengers play a critical role in transduction of extracellular signals to intracellular compartments. [0017] Eleven distinct classes of PDEs have been identified, each with 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 for the various PDE classes have been designed and synthesized. PDEs 5, 6, and 9 have been identified as having specific catalytic activity for cGMP, therefore the cGMP-specific PDE inhibitors targeting these particular isoenzymes result in accumulation of active cGMP in the cell. This leads to an increase in cGMP-dependent protein kinase (PKG) activity, an effector in many signal transduction pathways that can mediate apoptosis. Rice, et al. (2001), supra. [0018] Due to the high incidence and high mortality rate associated with cancer, a wealth of research is going on in this field. Of particular interest is the recent discovery that use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with 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 a regimen of NSAIDs such as, for example, aspirin and ibuprofen. Undesirably, however, some NSAIDs are known to cause gastrointestinal (Gl) bleeding or ulcers in patients undergoing consistent long term regimens of NS AID therapy. Henry et al. (1991) Lancet 337, 730.
[0019] A reduction of unwanted side effects of common NSAIDs was made possible by the discovery that two cyclooxygenases are involved in transformation of arachidonic acid as the first step in the prostaglandin synthesis pathway. These enzymes exist in two forms and have been termed cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2). Needleman et al. (1997) J. Rheumatol. 24, Suppl.49, 6-8.
[0020] Cox-1 is a constitutive enzyme responsible for 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 biosynthesis of prostaglandins in inflammatory cells. Inflammation causes induction of Cox-2, leading to release of prostanoids (prostaglandin E2), which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, inflammation and edema. Samad et al (2001) Nature 410(6827), 471-475.
[0021] Many common NSAIDs are now known to be inhibitors of both Cox-1 and Cox-2. Accordingly, when administered in 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-1.
[0022] Research into the area of arachidonic acid metabolism has resulted in the discovery of compounds that selectively inhibit the Cox-2 enzyme to a greater extent than they inhibit Cox-1. These Cox-2 selective inhibitors are believed to offer advantages that include the capacity to prevent or reduce inflammation while avoiding harmful side effects associated with the inhibition of Cox-1. Thus, Cox-2 selective inhibitors have shown great promise for use in therapies, especially in therapies that require maintenance administration, such as for pain and inflammation control.
[0023] Of particular importance for the present invention is that overexpression of Cox-2 has been documented in several premalignant and malignant tissues. Subbaramaiah & Dannenberg (2003) Trends Pharmacol. Sci. 24, 96-102. This increase in expression is thought to be a product of stimulation of PKC signaling, which stimulates activity of MAPK, enhancing transcription of Cox-2 by nuclear factors. Additionally, enhanced stability of Cox-2 mRNA transcripts in cancer cells due to augmented binding of the RNA-binding protein HuR, as well as activation of extracellular signal related kinase 1/2 (ERK 1/2) and p38, contributes to increased expression of Cox-2. Id. [0024] From the foregoing, it can be seen that a need exists for improved methods and therapeutic compositions to treat neoplasia and neoplasia-related disorders. It would also be useful to provide an improved method and composition for reducing the symptoms associated with neoplasia. Likewise, methods and compositions that improve patient outcomes following radiation and chemotherapy treatment regimens for neoplasms would also be desirable. Also, methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or neoplasia- related disorders are desirable. Finally, methods and compositions that improve the efficacy of treating neoplasia or a neoplasia-related disorder that is considered resistant or intractable to known methods of therapy alone would also be desirable. SUMMARY OF THE INVENTION [0025] Briefly, therefore, the present invention is directed to a combination comprising an Hsp90 inhibitor and a PDE inhibitor, in amounts effective when used in combination therapy for treatment or prevention of neoplasia or a neoplasia-related disorder.
[0026] In one embodiment 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, Z , Ma and Ga is C; R , unless joined with R or R 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, haloarylalkanonesulfanyl, arylalkylidenenitroaryl, alkoxyaryl, alkylthioaryl, alkylsulfonylaryl, haloalkoxy, alkoxypolyalkyl, carboxamidyl, carboxyalkyl, aminosulfonylaryl, alkoxycarbonyl, hydroxyaryl and halohydroxyaryl; R , unless joined with R or R 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, alkylnitrilearyl, alkylsulfonylalkyl, alkoxycarboximidyl, alkoxyhydroxyaryl and alkylthioaryl; R207 and R208 optionally join to form a ring system selected from the group consisting of:
and aryl, wherein T and Tb are independently selected from C and S; R209, unless joined with R208 or R210 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted or unsubstituted heteroaryl, alkylaryl, haloalkyl, haloaryl, alkoxyaryl, alkoxycarbonylaryl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonylaryl, alkoxyalkylaryl, alkylaminoaryl, alkylalkanethiol, alkoxyhaloaryl and aminosulfonylaryl; R208 and R209 optionally join 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 joined with R209 or R211 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, alkylaryl, alkylthio, alkoxyaryl, alkylaminoaryl, alkylthioaryl, haloalkyl, haloaryl, carboxyaryl, aminocarbonyl, substituted or unsubstituted heteroaryl, carboxyalkyl, alkoxyarylaminoalkene- nitrile, nitroarylalkeneamide, acetamidoaryl, acetamidoarylcyanoalkenyl- nitrile, carboxylalkoxy, alkylsulfonylaryl, haloalkylalkoxy, haloaryloxy, alkoxyhaloaryl, alkoxycarbonyl, alkylsulfonylhaloaryl, aminosulfonylaryl, thioaryl, aminocycloalkyl, alkoxycarbonylaryl, alkoxycarbonylaminocyclo- alkane and alkylcarboxyl; R209 and R210 optionally join to form a ring system selected from the group consisting of:
and aryl;
R , unless joined with R or R in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, hydroxyl, haloaryl, haloalkylaryl, substituted or unsubstituted heteroaryl, carboxyaryl, nitroaryl, aminosulfonylaryl, alkylsulfonylaryl, alkylsulfonylhaloaryl alkylaminosulfonylaryl, alkylsulfonyl- aminoaryl, alkylaminocarbonyl, aminocarbonylaryl, halohydroxyaryl- alkylideneacetohydrazide, hydroxyalkoxyarylalkylideneacetohydrazide, alkyl- carbonylaryl, alkoxyaryl, haloalkoxyaryl, alkoxyalkoxoaryl, alkoxycarbonylaryl, haloalkylcarbonylaryl, alcohol and haloaryloxyacetohydrazide;
R210 and R211 optionally join to form a ring system selected from the group consisting of:
oxoaryl and cycloalkyl; 907 911
R and R optionally join to form a ring system selected from the group consisting of: R212 is selected from the group consisting of H, halo and alkoxy; R213 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 prodrag of such a compound. [0027] In another embodiment the Hsp90 inhibitor comprises a compound having the stracture 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 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; R , unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and alkoxo; R220, unless joined in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, alkoxo, hydroxyalkyl, alkylnitrile, alkoxoaryl, haloalkoxo, and haloarylalkoxo; R219 and R220 optionally join to form a ring system consisting of a substituted or unsubstituted aryl ring; R221 and 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 prodrag of such a compound. [0028] In a further embodiment the Hsp90 inhibitor comprises a compound having the stracture selected from the group consisting of:"
(-)-enantiomer
or a pharmaceutically acceptable salt or prodrag of such a compound. [0029] Any Hsp90 inhibitor can be used in such a combination, including without limitation the Hsp90 inhibitors of any of the above-described embodiments. Any PDE inhibitor can be used in such a combination, including without limitation cGMP-selective PDE inhibitors.
[0030] There is further provided a method of treating or preventing neoplasia or a neoplasia-related disorder in a subject, the method comprising administering such a 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 coformulated in a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.
[0031] Optionally, a combination of the invention can further comprise a Cox-2 inhibitor, for example a Cox-2 selective inhibitor.
[0032] The present invention is also directed to a kit for the purpose of preventing or treating neoplasia in a subject that is in need of such prevention or treatment, the kit comprising a first dosage form that comprises an Hsp90 inhibitor in a first amount, 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 optional third amounts are effective when used in combination therapy for treating or preventing neoplasia or a neoplasia-related disorder.
[0033] Among several advantages found to be achieved by the present invention, therefore, may be noted the provision, in certain embodiments, of methods and compositions that are directed to preventing or treating neoplasia in a subject that is in need of such prevention or treatment, these methods comprising administering to the subject an Hsp90 inhibitor alone or in combination with a PDE inhibitor and optionally a Cox-2 inhibitor. Also provided in certain embodiments are improved methods and compositions for reducing the symptoms associated with neoplasia. Further, according to certain embodiments methods and compositions are provided that improve patient outcomes following radiation and chemotherapy treatment regimens for neoplasms. Still further, according to certain embodiments methods and compositions are provided that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or neoplasia-related disorders. Still further, according to certain embodiments methods and compositions are provided that improve the efficacy of treating neoplasia or a neoplasia-related disorder that is considered resistant or intractable to lαiown methods of therapy alone. DETAILED DESCRIPTION OF THE INVENTION [0034] It has been discovered that Hsp90 is a target for inhibition by the compounds listed and described by the tables and formulas herein. It has been demonstrated that the presence of these compounds, both in vitro and in vivo, result in disruption of the Hsp90- client protein complex. Hsp90 client protein complexes that are disrupted include, among others, those comprising as client proteins mutant p53, proliferating cell nuclear antigen (PCNA), Raf-1, and many other regulatory proteins that are important in tumorigenesis or neoplasm growth and proliferation. Such Hsp90 inhibiting compounds have a wide range of antitumor and anticancer activities.
[0035] Several of these compounds inhibit both Hsp90 and the Cox-2 enzyme. Thus, it has been discovered that in one embodiment of the present invention, certain compounds can act both as Hsp90 inhibitors and as Cox-2 inhibitors. The present invention encompasses such dual action compounds. These dual action compounds are referred to herein as "dual Hsp90/Cox-2 inhibitors" or "dual Hsp90/Cox-2 inhibiting compounds". Thus, in one embodiment, the present invention provides compounds that act both as a Cox-2 inhibitor and as an Hsp90 inhibitor.
[0036] The present invention encompasses a method for inhibiting the growth of neoplasia, including a malignant tumor or cancer, the method comprising exposing the neoplasia to an inhibitory or therapeutically effective amount or concentration of at least one of the Hsp90 inhibiting compounds disclosed herein, in combination with a PDE inhibitor.
[0037] The administration of a combination of an Hsp90 inhibitor as described herein with a PDE inhibitor is an unexpectedly effective therapy for prevention and treatment of neoplasia. Such administration is effective for preventing and treating the symptoms of neoplasia while reducing or avoiding the disadvantages and side effects associated with current treatment strategies.
[0038] In certain embodiments, the present invention provides methods and compositions that improve subject outcomes following radiation and chemotherapy treatment regimens for neoplasia. In certain embodiments, the present invention provides methods and compositions that reduce dosages or reduce unwanted side effects in conventional treatments for neoplasia or neoplasia-related disorders. In certain embodiments, the present invention provides methods and compositions that improve the efficacy of treating neoplasia or a neoplasia-related disorder that is considered resistant or intractable to known methods of therapy alone.
[0039] In certain embodiments, administration of an Hsp90 inhibitor in combination with a PDE inhibitor for prevention or treatment of neoplasia is unexpectedly superior to the use of either agent alone. Therefore, according to such embodiments, treatment or prevention of neoplasia can be accomplished by administering to a subject suffering from or needing prevention of a neoplasia a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor.
[0040] In certain embodiments, such a combination therapy is effective for lowering the dosages of conventional chemotherapy and radiotherapy treatments that are normally prescribed as a monotherapy. The administration of lower dosages of conventional treatment agents provides a reduction in side effects corresponding to such conventional agents.
[0041] Moreover, in certain embodiments, such a combination therapy demonstrates a synergistic efficacy for treating and preventing neoplasia, when the efficacy is greater than would be expected from simply combining the two therapies.
[0042] As used herein, the term "neoplasia" refers to new cell growth that results from a loss of responsiveness to normal growth controls, e.g., "neoplastic" cell growth. For purposes of the present invention, cancer is one subtype of neoplasia. As used herein, the term "neoplasia-related disorder" encompasses neoplasia, but also encompasses other cellular abnormalities, such as hyperplasia, metaplasia and dysplasia. The terms neoplasia, metaplasia, dysplasia and hyperplasia collectively refer generally to cells experiencing abnormal cell growth.
[0043] Both neoplasia and neoplasia-related disorders can involve a neoplasm or tumor, which can be benign, premalignant, metastatic or malignant. The present invention thus encompasses methods and compositions useful for treating or preventing benign, premalignant, metastatic and malignant neoplasias, and benign, premalignant, metastatic and malignant tumors. Tumors are generally known in the art to be formed from a mass of neoplastic cells. It is to be understood, however, that even one neoplastic cell is considered, for purposes of the present invention, to be a neoplasm or alternatively, neoplasia. [0044] The amount or dosage of a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor is one that provide a therapeutically effective amount of the combination therapy.
[0045] In one embodiment, the present invention provides a method for preventing a pathological condition or physiological disorder characterized by or associated with neoplasia in a subject that is in need of such prevention, the method comprising administering to the subject an Hsp90 inhibitor alone or in combination with a PDE inhibitor.
[0046] In any of the embodiments herein specifying presence of or administration of an Hsp90 inhibitor and a PDE inhibitor, it is understood that the combination can optionally further comprise a Cox-2 inhibitor.
[0047] As used herein, the term "prevention" refers to any reduction, no matter how slight, of a subject's predisposition or risk for developing a neoplasia or neoplasia-related disorder. For purposes of prevention herein, the subject is one that is at some degree of risk for, or is to some degree predisposed to, developing a neoplasia, a neoplasia-related disorder or a neoplasia-related complication.
[0048] As used herein, a subject that is "predisposed to" or "at risk for" developing neoplasia or a neoplasia-related disorder or condition includes any subject having an increased chance or statistical probability for such development. Such increased chance or probability can be due to various factors, including genetic predisposition, diet, age, exposure to neoplasia causing agents, physiological factors such as anatomical and biochemical abnormalities and certain autoimmune diseases, and the like. [0049] In another embodiment, the present invention provides a method for treating an existing pathological condition or physiological disorder characterized by or associated with neoplasia in a subject that is in need of such treatment, the method comprising administering to the subject an Hsp90 inhibitor in combination with a PDE inhibitor. [0050] The terms "treating" or "to treat" mean to alleviate symptoms, eliminate the causation of symptoms, either on a temporary or permanent basis, or to alter or slow the appearance of symptoms. The term "treatment" includes alleviation of, or elimination of causation of, symptoms associated with any of the diseases or disorders described herein. [0051] In still 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 that is in need of such prevention or treatment, the method comprising administering to the subject an Hsp90 inhibitor 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 three-way combination of an Hsp90 inhibitor, a PDE inhibitor and radiation therapy is administered to a subject in need thereof. In another embodiment a four-way combination of an Hsp90 inhibitor, a PDE inhibitor, a Cox-2 inhibitor and radiation therapy is administered to a subject in need thereof.
[0052] As used herein, the term "Hsp90 inhibitor" includes any compound that inhibits, disrupts or degrades activity of Hsp90 by disrupting an Hsp90-client protein complex or by interfering with 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 embodiments, such contact involves multiple and distinct contacts with residues in the Hsp90 protein. In further specific embodiments, such multiple and distinct contacts are with residues in the highly unusual, evolutionarily conserved nucleotide-binding pocket of the protein. In a specific embodiment, the nucleotide is ATP.
[0053] The compounds that are described above by formulas (I) and (II) include Hsp90 inhibitor compounds and certain analogs thereof, all of which are capable of disrupting an Hsp90-client protein complex. As a group, these compounds may be referred to herein as "Hsp90 inhibitors" or "Hsp90 inhibiting compounds". [0054] When it is said that a subject compound inhibits Hsp90, it is meant that Hsp90 activity is lower in the presence of the compound than it is under the same conditions in the absence of such compound. When it is said that an Hsp90 inhibitor has activity against Hsp90, it is meant that the Hsp90 inhibitor is capable of disrupting an Hsp90- client protein complex.
[0055] One method of expressing potency of a compound as an Hsp90 inhibitor is to measure the "IC50" value of the compound. The IC50 value of an Hsp90 inhibiting compound is the concentration of the compound that is required to decrease Hsp90 activity by one-half. Accordingly, a compound having a lower IC50 value is considered to be a more potent inhibitor than a compound having a higher IC5o value. [0056] It has been discovered that certain heterocycle-containing compounds, such as, but not limited to, pyrazole, pyrrole, imidazole, oxazole, pyrazole, thiazole, isoxazole, triazole, and furan compounds, and certain analogs of such compounds, can inhibit
Hsp90. Many of these compounds exhibit their inhibitory effect at low concentrations, having in vitro Hsp90 inhibition IC50 values of less than about 100 μM, some having IC50 values of less than about 50 μM, some having IC50 values of less than about 20 μM, and some even having IC50 values of less than about 2.5 μM.
[0057] In some embodiments, the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds of formula (I) listed in Table 1.
[0058] In other embodiments, the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds of formula (II) in Table 2.
[0059] In still other embodiments, the Hsp90 inhibitor or dual Hsp90/Cox-2 inhibitor is one of the compounds listed in Table 3.
PC27879A (01506/1)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
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PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
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PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I) Hsp90 Cox-2 Name R 209 RA R 211 Qa Xa 207 Za Ma R R 208 ICso inhib? 4-(3-methyl-5- phenyl-lH- aminosulfonyl pyrazol-1-yl) N N methyl phenyl yes phenyl benzenesulfon amide 2-[(3,5-dichloro phenoxy)methyl] - 4-(4-fluorophenyl) dichloro methylsulfonyl N fluorophenyl yes 5-[4-(methyl methoxy phenyl sulfonyl)phenyl] - 1,3-thiazole 1 - [4- (methy lsulf on yl)phenyl]-3-phen methylsulfonyl N N trifluoromethyl phenyl no yl-5-(trifluorometh phenyl yl)-lH-pyrazole 2-ethyl-l-(4- fluorophenyl)-5- methylsulfonyl [4-(methyl N ethyl fluorophenyl phenyl sulfonyl)phenyl] - lH-pyrrole 4-[4,5-dihydro-3- (trifluoromethyl)- aminosulfonyl lH-benz[g]indaz N N trifluoromethyl yes phenyl ol-l-yl]benzene sulfonamide
PC27879A (01506/1)
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PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1)
PC27879A (01506/1)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
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PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1) Table 1: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (I)
PC27879A (01506/1)
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PC27879A (01506/1) Table 2: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (II)
PC27879A (01506/1) Table 2: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (II)
PC27879A (01506/1) Table 2: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds of formula (II)
Table 3: Hsp90 inhibiting compounds and dual Hsp90/Cox-2 inhibiting compounds
[0060] In certain embodiments, the present invention provides a novel method for preventing or treating a pathological condition or physiological disorder characterized by or associated with neoplasia, including colorectal cancer, lung cancer, and breast cancer. [0061] It has been discovered that certain heterocycle compounds, such as, but not limited to, pyrazole, pyrrole, imidazole, oxazole, pyrazole, thiazole, isoxazole, triazole, and furan compounds, and analogs of such compounds, can inhibit the activity of Hsp90. Many of these compounds exhibit their inhibitory effect at low concentrations, having in vitro Hsp90 inhibition IC50 values of less than about 100 μM, some having IC50 values of less than about 50 μM, some having IC50 values of less than about 20 μM, and some having IC50 values of less than about 2.5 μM.
[0062] 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 joined with R208 or R211 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, amino, aminohydroxythioacetamidyl- substituted purinyl, Q-Q alkylacetateoxoaceto-hydrazide-substituted indolyl, halo-substituted thienyl, thienyl, triazolpyridyl, pyridyl, halo (Q-Q) alkyl, Q- C alkylphenyl, halophenyl, halophenyl-sulfinylacetohydrazide, halo (Q-Q) alkyl phenylaminocarbonylamino, halophenyl (Q-Q) alkanonesulfanyl, phenyl (Q-Q) alkylidenenitrophenyl, Q-Q alkoxyphenyl, Q-Q alkylthiophenyl, Q-Q alkylsulfonylphenyl, halo (Q-Q) alkoxy, Q-Q alkoxy (Q-Q) dialkyl, carboxamidyl, carboxyl (Q-Q) alkyl, aminosulfonylphenyl, C1-C4 alkoxycarbonyl, hydroxyphenyl and halohydroxyphenyl; R208, unless joined with R207 or R209 in a ring system, is selected from the group consisting of H, halo, Q-Q alkyl, phenyl, amino, C1-C alkylaminocarbonyl (C -C ) alkenenitrile-substituted imidazolyl, Q-Q alkylcyano (C2-C ) alkenenitrile-substituted imidazolyl, dioxolyl-substituted benzene, pyridyl, halo (Q-Q) alkyl, nitrophenyl, halophenyl, Q-Q alkoxyphenyl, aminosulfonylphenyl, Q-Q alkylsulfonylphenyl, Q-Q alkoxyhalophenyl, Q-Q alkylnitrilephenyl, Q-Q alkylsulfonyl (Q-Q) alkyl, Q-Q alkoxycarboximidyl, C1-C4 alkoxyhydroxyphenyl, and C1-C4 alkylthiophenyl; R207 and R208 optionally join to form a ring system selected from the group consisting of:
and aryl, wherein Ta and T are independently selected from the group consisting of C and S; R209, unless joined with R208 or R210 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, Q-Q dialkylamino (Q-Q) alkane- substituted pyridyl, oxohydrothieno (Q-Q) alkanamide oxooxyaminothio (Q-Q0) alkyl-substituted imidazolyl, oxohydrothieno (Q-Q) alkanoylaminooxo (Q-Q) alkylamino (Q-Q) alkanamidyl (Q-Q) alkylamino-substituted imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, Q-Q alkylphenyl, halo (Q-Q) alkyl, halophenyl, Q-Q alkoxyphenyl, Q-Q alkoxycarbonylphenyl, carboxyl, aminocarbonyl, Q-Q alkylaminocarbonyl, Q-Q alkylsulfonylphenyl, Q-Q alkoxy (Q-Q) alkylphenyl, Q-Q alkylaminophenyl, Q-Q alkyl (Q-Q) alkanethiol, Q-Q alkoxyhalophenyl and aminosulfonylphenyl; R and R optionally join 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; R ,210 , unless joined with R , 209 or R ,211 in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, oxo, Q-Q alkylphenyl, Q-Q alkylthio, Q-Q alkoxyphenyl, Q-Q alkylaminophenyl, Q-Q alkylthiophenyl, halo (Q-Q) alkyl, halophenyl, carboxyphenyl, aminocarbonyl, phenylcarbonylamino-substituted pyrrolyl, carbonylamino-substituted pyridyl, Q-Q alkyl-substituted pyridyl, Cι-C dialkylamino-substituted pyrimidyl, thiofuryl, chromenone, pyrimidyl, pyridyl, carboxy (Q-Q) alkyl, Q-Q alkoxyphenylamino (Q-Q) alkenenitrile, nitrophenyl (Cι-C ) alkeneamide, acetamidophenyl, acetamidophenylcyano (Q-Q) alkenylnitrile, carboxyl (Q- C ) alkoxy, Cι-C alkylsulfonylphenyl, halo (Q-Q) alkyl (Q-Q) alkoxy, halophenyloxy, Q-Q alkoxyhalophenyl, Q-Q alkoxycarbonyl, Q-Q alkylsulfonylhalophenyl, aminosulfonylphenyl, thiophenyl, amino (Q-Q) cycloalkyl, Q-Q alkoxycarbonylphenyl, Q-Q alkoxycarbonylamino (C!-C7) cycloalkane, and Q-Q alkylcarboxyl; R209 and R210 optionally join to form a ring system selected from the group consisting of:
and aryl; 91 1 91 π 9JT7 i
R , unless joined with R or R in a ring system, is selected from the group consisting of H, Q-Q alkyl, phenyl, oxo, hydroxyl, halophenyl, halo (Q-Q) alkylphenyl, Q-Q alkylthio-substituted pyrimidyl, pyridyl, carboxyphenyl, nitrophenyl, aminosulfonylphenyl, Q-Q alkylsulfonylphenyl, Q-Q alkylsulfonylhalophenyl, Q-Q alkylaminosulfonylphenyl, Q-Q alkylsulfonylaminophenyl, Q-Q alkylaminocarbonyl, aminocarbonylphenyl, halohydroxyphenyl (Q-Q) alkylideneacetohydrazide, hydroxyl (Q-Q) alkoxyphenyl (Q-Q) alkylideneacetohydrazide, Q-Q alkylcarbonylphenyl, Q-Q alkoxyphenyl, halo (Q-Q) alkoxyphenyl, Q-Q alkoxy (Q-Q) alkoxophenyl, Q-Q alkoxycarbonylphenyl, halo (Q-Q) alkylcarbonyl- phenyl, Q-Q alcohol and halophenyloxyacetohydrazide; R , 210 and R ,211 optionally join to form a ring system selected from the group consisting of:
oxoaryl and cycloalkyl; 9fY7 1 1 R 7 aanndd RR211 oopptionally join to form a ring system selected from the group consisting of:
R ,212 is selected from the group consisting of H, halo and Q-Q alkoxy; R213 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 Q-Q alkoxy; and R216 is selected from the group consisting of H and Q-Q alkoxy; or a pharmaceutically acceptable salt or prodrug of such a compound. [0063] 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 Q N or O; Ma is C orN; 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 joined with R211 or R208 in a ring system, is selected from the group consisting of H, methyl, ethyl, isopropyl, pentyl, phenyl, amino, aminohydroxythioacetamidyl-substituted purinyl, ethylacetateoxoaceto- hydrazide-substituted indolyl, chlorothienyl, thienyl, triazolpyridyl, pyridyl, trifluoromethyl, methylphenyl, bromophenyl, chlorophenyl, fluorophenyl, chlorophenylsulfinylacetohydrazide, chlorodimethoxyphenylaminocarbonyl- amino, chlorophenylethanonesulfanyl, phenylmethylidenenitrophenyl, methoxyphenyl, methylthiophenyl, ditert-butylthiophenyl, methylsulfonyl- phenyl, dichloromethoxy, methoxymethylpropyl, carboxamidyl, carboxyethyl, aminosulfonylphenyl, ethoxycarbonyl, hydroxyphenyl and dibromo- hydroxyphenyl;
R208, unless joined with R207 or R209 in a ring system, is selected from the group consisting of H, bromo, methyl, phenyl, amino, propylaminocarbonyl- propenenitrile-substituted imidazolyl, propylcyanopropenenitrile-substituted imidazolyl, dioxolyl-substituted benzene, pyridyl, difluoromethyl, trifluoromethyl, nitrophenyl, bromophenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, aminosulfonylphenyl, methylsulfonylphenyl, methoxyfluorophenyl, methylnitrilephenyl, methylsulfonylmethyl, methoxy- carboximidyl, methoxyhydroxyphenyl and methylthiophenyl;
R207 and R208 optionally join to form a ring system selected from the group consisting of:
and phenyl, wherein Ta and T are independently selected from the group consisting of C and S; R209, unless joined with R208 or R210 in a ring system, is selected from the group consisting of H, methyl, propyl, ' phenyl, diethyldiaminopentane-substituted pyridyl, oxohydrothienopentanamide oxodioxydiaminothiononyl-substituted imidazolyl, oxohydrothienopentanoylaminooxohexylaminohexanamidyl- methylamino-substituted imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, methylphenyl, difluoromethyl, trifluoromethyl, chlorophenyl, fluorophenyl, ethoxyphenyl, methoxycarbonylphenyl, carboxyl, aminocarbonyl, methyl- aminocarbonyl, dimethylaminocarbonyl, methylsulfonylphenyl, methoxy- methylphenyl, methyldiaminophenyl, methylethanethiol, methoxyfluoro- phenyl and aminosulfonylphenyl; R208 and R209 optionally join 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 joined with R209 or R211 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, phenylcarbonyl- amino-substituted pyrrolyl, carbonylamino-substituted pyridyl, methylpyridyl, dimethylamino-substituted pyrimidyl, thiofuryl, chromenone, pyrimidyl, pyridyl, carboxymethyl, methoxyphenylaminopropenenitrile, nitrophenyl- propeneamide, acetamidophenyl, acetamidophenylcyanoethenylnitrile, carboxylmethoxy, methylsulfonylphenyl, trifluoromethylmethoxy, chloro- phenyloxy, methoxyfluorophenyl, methoxycarbonyl, methylsulfonylfluoro- phenyl, aminosulfonylphenyl, thiophenyl, aminocyclohexyl, methoxycarbonylphenyl, methoxycarbonylaminocyclohexane and methylcarboxyl; R209 and R210 optionally join to form a ring system selected from the group consisting of:
and phenyl;
R211, unless joined 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, methylsulfonylhalo- phenyl, dimethylaminosulfonylphenyl, methylsulfonylaminophenyl, methyl- aminocarbonyl, aminocarbonylphenyl, bromodihydroxyphenylmethylidene- acetohydrazide, hydroxymethoxyphenylmethylideneacetohydrazide, methyl- carbonylphenyl, methoxyphenyl, trifluoromethoxyphenyl, methoxyethoxo- phenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, trifluoromethyl- carbonylphenyl, ethanol and bromophenyloxyacetohydrazide;
R210 and R211 optionally join to form a ring system selected from the group consisting of:
oxophenyl and cyclopentyl; 9fY7 91 1
R 7 aanndd RR211 oopptionally join to form a ring system selected from the group consisting of: R212 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 such a compound. [0064] 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 Q , Xa, Za and Ma is C; Ga is N or S; 907 91 1 R , unless joined with R in a ring system, is selected from the group consisting of H, alkylaryl, substituted or unsubstituted heteroaryl, haloaryl- sulfinylacetohydrazide, haloarylaminocarbonylamino, haloarylalkanesulfanyl and arylalkylidenenitroaryl; 90R R is selected from the group consisting of H, halo, aryl, haloaryl, alkoxyaryl, substituted or unsubstituted heteroaryl and alkoxyhydroxyaryl; R209, unless joined with R210 in a ring system, is selected from the group consisting of H, aryl, haloaryl, heteroaryl and alkoxyaryl; R210, unless joined with R209 in a ring system, is selected from the group consisting of H, aryl, substituted heteroaryl, alkoxyarylaminoalkenenitrile and nitroarylalkeneamide; R209 and R210 optionally join to form a ring system consisting of
R211, unless joined with R207 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted heteroaryl, halohydroxyarylalkylidene- acetohydrazide, haloaryloxyacetohydrazide and hydroxyalkoxyaryl- alkylideneacetohydrazide; and R207 and R211 optionally join to form a ring system consisting of
or a pharmaceutically acceptable salt or prodrag of such a compound. [0065] 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; 90*7 91 1 R , unless joined with R in a ring system, is selected from the group consisting of H, phenylethyl, triazolpyridyl, ethylacetateoxoindoleacetohydrazide, aminohydroxylpurinylthioacetamidyl, chlorophenylsulfinylacetohydrazide, chlorodimethoxyphenylaminocarbonylamino, chlorophenylethanonesulfanyl and phenylmethylidenenitrophenyl ; R208 is selected from the group consisting of H, bromo, phenyl, bromophenyl, dichlorophenyl, pyridyl, benzodioxolyl, imidazolepropylaminocarbonyl- propenenitrile and methoxyhydroxyphenyl; R209, unless joined with R210 in a ring system, is selected from the group consisting of H, phenyl, chlorophenyl, furyl and ethoxyphenyl; R210, unless joined with R209 in a ring system, is selected from the group consisting of H, phenyl, chromenone, pyrimidyl, pyridylcarbonylamino, dimethylaminopyrimidyl, pyrrolylphenylcarbonylamino, acetamidophenyl- cyanoethenylnitrile, methoxyphenylaminopropenenitrile and nitrophenyl- propeneamide; R209 and R210 optionally join to form a ring system consisting of
1 1 (Yl R , unless joined with R in a ring system, is selected from the group consisting of H, methyl, phenyl, bromodihyrdoxyphenylmethylidene- acetohydrazide, bromophenoxyacetohydrazide and hydroxymethoxyphenyl- methylideneacetohydrazide; and 7 911 R and R optionally join to form a ring system consisting of
or a pharmaceutically acceptable salt or prodrug of such a compound.
[0066] 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; 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, Q-Q alkyl, halo, Q-Q alkylsulfonyl, aminosulfonyl, Q-Q alkoxy and Q-Q alkylthio; R218 is selected from the group consisting of H, Q-Q alkyl and Q-Q alkoxy; 910 990 R , unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and Q-Q alkoxo; R220, unless joined in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, Q-Q alkoxo, hydroxy (Q-Q) alkyl, Q-Q alkylnitrile, Q-Q alkoxophenyl, halo (Q-Q) alkoxo and halophenyl (Q-Q) alkoxo; R219 and R220 optionally join to form a ring system selected from the group consisting of phenyl and halophenyl; 991 99* R and R are independently selected from the group consisting of H and Q-Q alkoxy; and R222 is selected from the group consisting of H, halo, Q-Q alkylsulfonyl, aminosulfonyl and Q-Q alkylamino; or a pharmaceutically acceptable salt or prodrag of such a compound. [0067] 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 J 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, methyl, chloro, methylsulfonyl, aminosulfonyl, methoxy and methylthio; R218 is selected from the group consisting of H, methyl and methoxy; 910 990 R , unless joined in a ring system with R , is selected from the group consisting of H, oxo, amino and ethoxo; R220, unless joined in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, ethoxo, propoxo, hydroxyethyl, methylnitrile, methoxophenyl, 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 prodrag of such a compound. [0068] In other embodiments, the Hsp90 inhibitor comprises a compound selected from the group consisting of:
fv v - CCHK '22
and mixtures thereof.
[0069] As shown above, ring substituent groups that join to form additional ring structures adjacent the substituted ring can be described with reference to chemical formulas that show wavy lines cut through the ring to which the substituents are joined, rather than across the bond joining the substituent group to the ring. Accordingly, the partial ring that is shown is the ring to which the substituent groups are shown as being bonded in the general formula.
[0070] As used herein, the term "alkyl", alone or in combination, means an alkyl radical, linear, cyclic or branched, which, unless otherwise noted, typically contains 1 to about 10 carbon atoms, and more typically 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Cyclic alkyl ("cycloalkyl") radicals contain 3 to about 7 carbon atoms, typically 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl ring has a carbon ring atom in common with the seven-membered heterocyclic ring of benzothiepine. [0071] Alkyl radicals can optionally be substituted with substituent groups as defined below. Examples of such substituted alkyl radicals include chloroethyl, hydroxyethyl, trifluoromethyl, cyanobutyl, aminopentyl, and the like.
[0072] The term "alkenyl" refers to an unsaturated, hydrocarbon radical, linear, cyclic or branched, that contains at least one double bond. Unless otherwise noted, such radicals typically contain 2 to about 6 carbon atoms, more typically 2 to 4 carbon atoms, for example 2 to 3 carbon atoms. Cyclic alkenyl ("cycloalkenyl") radicals have 3 to about 10 carbon atoms, and include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Alkenyl radicals can optionally be 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-l-yl, 3-methylbuten-l-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, octen-1-yl, and the like.
[0073] 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 may be attached to a carbon atom to form a methylene (-CH2-) radical. [0074] The term "halo" means a halogen group such as fluoro, chloro, bromo or iodo radicals. The term "haloalkyl" describes alkyl radicals that is substituted with a halo group as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, can have either a bromo, chloro or fluoro group attached to the alkyl radical. Dihalo radicals can have two or more of the same halo group or a combination of different halo groups, and polyhaloalkyl radicals can have more than two of the same halo group or a combination of different halo groups.
[0075] The term "hydroxyalkyl" describes a linear or branched alkyl radical having 1 to about 10 carbon atoms, any one of which can be substituted with one or more hydroxyl radicals.
[0076] 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. Alkoxy or alkoxyalkyl radicals can 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.
[0077] The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane and biphenyl.
[0078] The term "heterocyclyl" or "heterocyclic" means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by N, S, P, or O. This includes, for example, stractures such as
wherein Z, Z1, Z2 and Z3 are Q S, P, O or N, with the proviso that at least one of Z, Z1, Z2 and Z3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, optional substituents are understood to be attached to Z, Z1, Z2 or Z3 only when the Z atom is C. Heterocyclic radicals can be saturated, partially saturated or unsaturated heteroatom-containing ring- shaped radicals, where 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 termed "heteroaryl" radicals, include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, quinolinyl, isoquinolinyl, benzothienyl, indolyl and tetrazolyl. Also included are radicals where a heterocyclic ring is fused with an aryl ring. Examples of fused bicyclic radicals include benzofuran, benzothiophene, and the like. [0079] The term "sulfonyl", whether used alone or linked to other terms as in "alkylsulfonyl", denotes the divalent radical -SO2- "Alkylsulfonyl" denotes an alkyl radical attached to a sulfonyl radical, where alkyl is defined as above. The term "arylsulfonyl" denotes a sulfonyl radical substituted with an aryl radical. The terms "sulfamyl" or "sulfonamidyl", whether alone or linked to other terms as in "N-alkylsulfamyl", "N-arylsulfamyl", "N,N-dialkylsulfamyl" and "N-alkyl-N- arylsulfamyl", denote a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2). The terms "N-alkylsulfamyl" and "N,N-dialkylsulfamyl" denote sulfamyl radicals substituted 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 one aryl radical, or with one alkyl and one aryl radical. [0080] The terms "carboxy" or "carboxyl", whether used alone or linked to other terms, as in "carboxy alkyl", denote -CO2H. The term "carboxyalkyl" denotes a carboxy radical as defined above, attached to an alkyl radical.
[0081] The term "carbonyl", whether used alone or linked to other terms, as in "alkylcarbonyl", denotes -(C=O)-. The term "alkylcarbonyl" denotes a carbonyl radical substituted with an alkyl radical, for example CH3-(C=O)-. "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(=O)- or -(O=)C-OCH3. The term "alkoxycarbonylalkyl" denotes a radical having alkoxycarbonyl, as defined above, attached to an alkyl radical. Examples of such alkoxycarbonylalkyl radicals include (CH3)3CO-C(=O)(CH2)2- and -(CH2)2(=O)C-OCH3.
[0082] The term "amido" when used by itself or linked to other terms as in "amidoalkyl", "N-monoalkylamido", "N-monoarylamido", "N,N-dialkylamido", "N-alkyl-N-arylamido", "N-alkyl-N-hydroxyamido" and "N-alkyl-N-hydroxyamidoalkyl", denotes a carbonyl radical substituted with an amino radical. The terms "N-alkylamido" and "N,N-dialkylamido" denote amido groups which have been substituted with one or two alkyl radicals, respectively. The terms "N-monoarylamido" and "N-alkyl-N-arylamido" denote amido radicals substituted, respectively, with one aryl radical, or with one alkyl and one 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 -C(=NH)-NH2 radical. The term
"cyanoamidino" denotes a -C(=N-CN)-NH2 radical.
[0083] The term "heterocycloalkyl" denotes a heterocyclic-substituted alkyl radical such as pyridylmethyl or thienylmethyl.
[0084] The term "aralkyl" denotes an aryl-substituted alkyl radical such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl or diphenethyl. The terms benzyl and phenylmethyl are interchangeable.
[0085] The term "alkylthio" 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 containing a linear or branched alkyl radical of 1 to about 10 carbon atoms, attached to a divalent -S(=O)- group. The term "alkylthioalkyl" denotes an alkylthio radical attached to an alkyl group, an example being methyl thiomethyl.
[0086] The terms "N-alkylamino" and "N,N-dialkylamino" denote amino groups which have been substituted with one alkyl radical or with two alkyl radicals, respectively.
[0087] The term "acyl", whether used alone or within a term such as "acylamino", denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
The term "acylamino" denotes an amino radical substituted with an acyl group, an example being acetylamine (CH3C(=O)-NH-).
[0088] In either heterocyclyl or heteroaryl rings, the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
[0089] The term "oxo" means a doubly-bonded oxygen.
[0090] 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, alicyclic or heterocyclic group.
[0091] As used herein, the term "carbamoyl" refers to a carbonyl group covalently bonded at the oxo carbon to an amino group.
[0092] As used herein, the term "hydroxamate" refers to a carbonyl group covalently bonded at the oxo carbon to an amino group, wherein the amino group is in turn bonded to a hydroxyl group.
[0093] The term "oxime" means a radical comprising =NOH.
[0094] The present invention encompasses methods and compositions comprising
Hsp90 inhibiting compounds including, but not limited to, the following examples: 2-methyl-4-(4-nitrophenyl) 5-phenyl-l,3-oxazole; 4-[4-(4-fluorophenyl)- 1 ,3-thiazol-2-yl]benzoic acid; methyl 4-[4-(4-fluorophenyl)-l ,3-thiazol-2-yl]benzoate; 4- [4-(4-methoxyphenyl)- 1 ,3-thiazol-2-yl] -N-methylbenzamide; 4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]phenylamine; l-(4-nitrophenyl)-3-(trifluoromethyl)-lH-pyrazole; ethyl 4-(3,5-dimethyl-lH-pyrazol-l-yl)benzoate; 4-(3,5-dimethyl-lH-pyrazol-l-yl) benzenesulfonamide; 4-(4-methylphenyl)-2-phenyl-l,3-thiazole; 5-(4-chlorophenyl)-l-methyl-2-[4-(methylthio)phenyl]-3-thien-2-yl-lH-pyrrole; 3-(trifluoromethyl)-2H-benzo[h]pyrazolo[4,3-f]isoquinoline hydrochloride; 2H-benzo[h]pyrazolo[4,3-f]isoquinoline-3-carboxamide dehydrate; 2-[(2-chlorophenyl)sulfinyl]-N-[4-(4-chlorophenyl)-l,3-thiazol-2-yl]acetamide; N- [5-( 1 -phenylethyl)- 1 ,3-thiazol-2-yl] -4-( lH-pyrrol- 1 -yl)benzamide; N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-phenyl-l,3-thiazol-2-yl)urea; N'-[(4-bromophenoxy)acetyl]-2-(5-phenyl-2H-tetraazol-2-yl)acetohydrazide; (2E)-2-cyano-3-[3-(2-furyl)-l-phenyl-lH-pyrazol-4-yl]-N-[3-(lH-imidazol-l-yl) propyl]prop-2-enamide; (2E)-2-cyano-3-[3-(4-ethoxyphenyl)-l-phenyl-lH-pyrazol-4-yl]-N-[3-(lH-imid- azol-l-yl)propyl]prop-2-enamide; 3-bromo-2-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione; 3 - [4-(4-chlorophenyl)- 1 , 3 -thiazol-5-yl] -4H-chromen-4-one ; N-[4-(3,4-dichlorophenyl)-l,3-thiazol-2-yl]pyrimidin-2-amine hydrobromide; (2E)-2-[4-(4-hydroxy-3-methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxyphenyl) amino]prop-2-enenitrile; N'-[(lE)-(5-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-l,3-thiazol-2-yl)acetam- ide; (2E)-3-(4-nitrophenyl)-N-(4-pyridin-4-yl-l,3-thiazol-2-yl)prop-2-enamide; N'-[(lE)-(2-hydroxy-4-methoxyphenyl)methylidene]-2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; 2-(3 ,5-dimethyl- lH-pyrazol- 1 -yl)-6-methyl-4-pyrimidinethiol; N-[4-(4-bromophenyl)- 1 ,3-thiazol-2-yl]nicotinamide; N-(l,3-benzothiazol-2-yl)-7-oxo-l-phenyl-l,7-dihydropyrazolo[l,5a]pyrimidine- 6-carboxamide; 2-({5-[2,6-bis(dimethylamino)-4-pyrimidinyl]-4-methyl-4H-l,2,4-triazol-3-yl} sulf anyl)- 1 -(4-chlorophenyl)- 1 -ethanone; N-{(E)-[4-(l-methyl-lH-imidazol-2-yl)-3-nitrophenyl]methylidene}aniline; N-[4-({(E)-2-[4-(l,3-benzodioxol-5-yl)-l,3-thiazol-2-yl]-2-cyanoethenyl}amino) phenyl]acetamide; ethyl ((3Z)-2-oxo-3-{[(3-phenyl-lH-pyrazol-5-yl)carbonyl]hydrazono}-2,3- dihydro- lH-indol- 1 -yl)acetate; 5-[4-(4-chlorophenyl)-l,3-thiazol-2-yl]-2-(lH-l,2,4-triazol-l-yl)pyridine; 4-[2-(2-carboxyethyl)-5-(4-methoxyphenyl)-lH-pyrrol-l-yl]benzoic acid; 7-chloro-l-phenyl-4,5-dihydro-lH-benzo[g]indazole; 2-(4-fluorophenyl)-4,5-dihydro-2H-benzo[g]indazole; 4-(7-chloro-4,5-dihydro-lH-benzo[g]indazol-l-yl)benzoic acid; 4-(7-chloro-4,5-dihydro-2H-benzo g]indazol-2-yl)benzoic acid; 7-chloro-l-phenyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxylic acid; l,3-diphenyl-l,4,5,6-tetrahydro-7H-indazol-7-one; 2-(4-methoxyphenyl)-5-methyl-l-(4-nitrophenyl)-lH-pyrrole; l-[4-[2-(4-fluorophenyl)-5-methyl-lH-pyrrol-l-yl]phenyl]ethanone; methyl {4-[2-(4-fluorophenyl)-5-methyl-lH-pyrrol-l-yl]phenyl}acetate; ({(lS,3R)-3-[(3,5-ditert-butylphenyl)thio]cyclopentyl}oxy)acetic acid; 6-fluoro- 10- (methylsulf onyl)dibenzo [b ,f] thieno [3 ,4-d] oxepine ; 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-l,3-thiazole; 1 -(methylsulf onyl)-4-(2-phenylcyclopent- 1 -en- 1 -yl)benzene; 5-(4-fluorophenyl)-3-methyl-l-[4-(methylsulfonyl)phenyl]-lH-l,2,4-triazole; 2-(2-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-phenyl-l,3-thiazole; 4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide;
4-(3-methyl-5-phenyl-lH-pyrazol-l-yl)benzenesulfonamide;
2-[(3,5-dichlorophenoxy)methyl]-4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]-l,3-thiazole; l-[4-(methylsulfonyl)phenyl]-3-phenyl-5-(trifluoromethyl)-lH-pyrazole; 2-ethyl-l-(4-flurophenyl)-5-[4-(methylsulfonyl)phenyl]-lH-pyrrole; 4-[4,5-dihydro-3-(trifluoromethyl)-lH-benz[g]indazol-l-yl]benzenesulfonamide; l-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-5-pentyl-lH-pyrrole; l-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-4,5-dihydro-lH-benzo[g] indazole; 5-(4-fluorophenyl)- 1 - [4-(methylsulf onyl)phenyl] - 1 H-pyrazole ; l-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-lH-pyrazole-3-carboxylic acid; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]-N,N-dimethyl benzenesulfonamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4- [5 -(4-chlorophenyl)- 1 H-pyrazol- 1 -yljbenzenesulf onamide ; 4-[5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene sulfonamide; 5-(4-fluorophenyl)-l-(4-nitrophenyl)-lH-pyrazole-3-carboxamide; N-[4-[5-(4-fluoroρhenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl]methane sulfonamide; 5-(4-chlorophenyl)-l-(4-nitrophenyl)-3-(trifluoromethyl)-lH-pyrazole; methyl- 1 - [4-(aminosulfonyl)phenyl] -5-(4-methylphenyl)- lH-pyrazole-3- carboxylate; 4-[5-(4-butoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[3-(difluoromethyl)-5-(2-methoxy-2-methylpropyl)-lH-pyrazol-l-yl]benzene- sulfonamide; 4- [5-(4-fluorophenyl)-4-propyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]benzene- sulfonamide; (5Z)-5-(2,2,2-trifluoro-l-hydroxyethylidene)-6,7-dihydro-l-benzothiophen-4(5H)- one; 4-[5-(3,5-dimethoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene- sulfonamide; methyl 4-[5-(5-chlorothien-2-yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzoate; methyl 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzoate; 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)- IH-pyrazol- l-yl]-N-methyl benzamide; methyl 4-[7-methoxy-3-(trifluoromethyl)-4,5-dihydro-lH-benzo [g]indazol-l-yl] benzoate; l-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N,N-dimethyl-lH-pyrazole-3- carboxamide; 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-lH-imidazole; l-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-N-methyl-lH-pyrazole-3- carboxamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzamide; 4- [7-methoxy-3-(trifluoromethyl)-4,5-dihydro- lH-benzo [g]indazol- 1 -yl] benzamide; 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-lH-pyrazol-l-yl]benzamide; 4-(3,5-diphenyl-lH-pyrazol-l-yl)benzenesulfonamide; l-[4-(methylsulfonyl)phenyl]-3-phenylimidazo[5,l-a]isoquinoline; 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-lH- imidazole; 3-(3-fluoro-4-methoxyphenyl)-2-[4-(methylsulfonyl)phenyl]-l-benzofuran; l-[4-(aminosulfonyl)phenyl]-l,4-dihydrothiochromeno[4,3-c]pyrazole-3- carboxamide; 3-(3-fluorophenyl)-l-[4-(methylsulfonyl)phenyl]imidazo[5,l-a]isoquinoline; 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-thien-3-yl-lH-imidazole; 2-(4-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-lH- imidazole; 5-(4-fluorophenyl)-2-(4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-lH- imidazole; 3-{4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-lH-imidazol-2-yl}pyridine; l,4-bis[4-(methylsulfonyl)phenyl]-2-(4-chlorophenyl)-lH-imidazole; 2,5-bis(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-l,3-oxazole; 4-[2-(4-chlorophenyl)-l-[4-(methylsulfonyl)phenyl]-lH-imidazol-4-yl] benzonitrile; 5-(4-fluorophenyl)-2-isopropyl-4-[4-(methylsulfonyl)phenyl]-lH-imidazole; 4- [3-(4-methylphenyl)-5-(trifluoromethyl)- IH-pyrazol- 1 -yl]benzenesulf onamide; 2-(trifluoromethyl)pyrazolo[l,5-f]phenanthridine-9-sulfonamide; 4-[3,5-bis(4-chlorophenyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[7-fluoro-3-(trifluoromethyl)isothiochromeno[4,3-c]pyrazol-l(5H)-yl]benzene- sulfonamide; 4-(4-methoxy-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)- lH-imidazole; 7-fluoro-l,5-dihydro-l-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)[2]benzo- thiopyrano[4,3-c]pyrazole; 4-(4-fluorophenyl)-l-methyl-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)- lH-imidazole; 2-(4-chlorophenyl)-4-[(methylsulfonyl)methyl]-l-[4-(methylsulfonyl)phenyl]-lH- imidazole; N,N-dimethyl-4-[4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-lH-imidazol- 5-yl]benzenamine; 2-(4-chlorophenyl)-N-methoxy-N-methyl- 1 - [4-(methylsulfonyl)phenyl] - 1H- imidazole-4-carboxamide; 3-[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-lH-imidazol-2-yl]pyridine; 4-(5-amino-3-phenyl-lH-pyrazol-l-yl)benzenesulfonamide; {4-(4-fluorophenyl)-2-[4-(methylthio)phenyl]-l,3-thiazol-5-yl}acetic acid; 2,2,2-trifluoro- 1 - [4- [5-(4-fluorophenyl)-3-(trifluoromethyl)- IH-pyrazol- 1 -yl] phenyl] ethanone; l-(4-chlorophenyl)-3-methyl-5-phenyl-lH-pyrazole; 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol-l-yl]benzenesulfonamide; {3-[4-(methylsulfonyl)phenyl]-4-phenylisoxazol-5-yl}acetic acid; 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; methyl-3-(4-chlorophenyl)-l-(4-methoxyphenyl)-lH-pyrazole-5-carboxylate; 4-[2-(methylthio)-4-phenyl-l,3-oxazol-5-yl]benzenesulfonamide; 4-[4-phenyl-2-(2,2,2-trifluoroethoxy)-l,3-oxazol-5-yl]benzenesulfonamide; 4-[2-(3-chlorophenoxy)-4-phenyl-l,3-oxazol-5-yl]benzenesulfonamide; {3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl}acetic acid; - [ 1 - [4-(methylsulfonyl)phenyl] -4-(trifluoromethyl)- lH-imidazol-2-yl]pyridine; -[5-(4-methylphenyl)-lH-l,2,4-triazol-l-yl]benzenesulfonamide; -[5-(4-chlorophenyl)-2-methyl-l,3-thiazol-4-yl]benzenesulfonamide; -[4-(4-chlorophenyl)-2-methyl-l,3-thiazol-5-yl]benzenesulfonamide; -[4-phenyl-5-(trifluoromethyl)isoxazol-3-yl]benzenesulfonamide and 4-[3- phenyl-5-(trifluoromethyl)isoxazol-4-yl]benzenesulfonamide (1:1); -[2-(2-chlorophenyl)-4-(3-fluoro-4-methoxyphenyl)-l,3-thiazol-5-yl]benzene- sulfonamide; 5-(3-fluoro-4-methoxyphenyl)-2-methyl-4-[4-(methylsulfonyl)phenyl]-l,3- thiazole; 2-[4-(methylthio)phenyl]-3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole; -[5-(3-chloro-4-fluorophenyl)-2-(trifluoromethyl)-l,3-oxazol-4-yl]benzene- sulf onamide; -[4-(methylsulfinyl)phenyl]-3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[l,2-a] imidazole; 3-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-lH-pyrazole; -(2-methyl-5 -phenyl- 1 ,3-oxazol-4-yl)pyridine; -(2-methyl-5-phenyl-l,3-thiazol-4-yl)pyridine; -[2-(4-chlorophenyl)-5-phenyl-l,3-oxazol-4-yl]pyridine; -[2-(4-methoxyphenyl)-5-phenyl-l,3-thiazol-4-yl]pyridine; 5-phenyl-4-pyridin-4-yl- 1 ,3-thiazol-2-amine; -methyl-3-[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-lH-imidazol-2-yl] pyridine; -(2-phenyl- lH-imidazol- 1 -yl)benzenesulf onamide; -[2-(4-methylpyridin-3-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulfonamide; -(5-methyl-4-phenyl-l,3-oxazol-2-yl)benzenesulfonamide; -(2-oxo-4-phenyl-2,5-dihydrofuran-3-yl)benzenesulfonamide; -(3-methyl-4-phenyl-lH-pyrazol-5-yl)pyridine; - [ 1 -phenyl-4-(trifluoromethyl)- 1 H-imidazol-2-yl] pyridine ; 4-{5-[4-(methylsulfonyl)phenyl]-lH-imidazol-l-yl}pyridine; 6-(5-amino-2-propoxyphenyl)-l,3-dimethyl-l,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one; 5-(4-fluorophenyl)-3-methyl-4-[4-(methylsulfonyl)phenyl]isoxazole; ethyl (lS,2R,3R)-l-phenyl-3-pyridin-4-yl-2,3-dihydro-lH-indene-2-carboxylate; 4-[5-methyl-3-(4-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4-[3-(4-chlorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4-[l-(4-fluorophenyl)-5-methyl-lH-pyrazol-3-yl]pyridine; 2-(4-fluorophenyl)-3-pyridin-4-ylindan-l-ol;
4- { 5-(4-fluorophenyl)-2- [4-(methylsulfinyl)phenyl] - lH-imidazol-4-yl } pyridine; 3-[l-phenyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]benzenesulfonamide; 3-methyl-lH-benzo[h]pyrazolo[4,3-f]isoquinolin-l-ium chloride; 2,6-dibromo-4-[5-(4-fluorophenyl)-4-pyridin-4-yl-lH-imidazol-2-yl]phenol; 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-lH-imidazol-2-yl]phenol; 3-(4-fluorophenyl)-4-pyridin-4-ylfuran-2(5H)-one; 4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine;
4-{4-(4-fluorophenyl)-2-[4-(methylthio)phenyl]-lH-imidazol-5-yl}pyridine; 4-[5-tert-butyl-2-(4-fluorophenyl)-lH-pyrrol-3-yl]pyridine; 4-[4-(4-fluorophenyl)-l-methyl-lH-pyrazol-3-yl]pyridine; l-methyl-3-phenyl-4-pyridin-4-yl- 1 ,5-dihydro-2H-pyrrol-2-one; 4-(4-fluorophenyl)-5-pyridin-4-yl-l,3-thiazol-2-amine dihydrobromide; 4-(4-fluorophenyl)-5-pyridin-4-yl-l,3-oxazol-2-amine; 4-(2-oxo-4-phenyl-2,3-dihydro-l,3-oxazol-5-yl)benzenesulfonamide; 4-(2-phenyl- 1 H-imidazol- 1 -yl)pyridine ;
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]benzenecarboximidamide; N~ 1 ~,N~ 1 ~-diethyl-N~4~- { 4-[3-(4-fluorophenyl)- lH-pyrazol-4-yl]pyridin-2- yl }pentane- 1 ,4-di amine; methyl 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate; 4-[5-(4-chlorophenyl)isoxazol-4-yl]pyridine;
4-[5-(benzyloxy)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-(4-chlorophenyl)-5-pyridin-4-yl-l,3-thiazol-2-amine dihydrobromide; 2-{4-[3-(4-chlorophenyl)-4-pyrimidin-4-yl-lH-pyrazol-5-yl]piperidin-l-yl}-2- oxoethanol dihydrochloride hydrate; 5-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-l-[3-(trifluoromethyl) phenyl] - IH-pyrazole; 5-[3-fluoro-4-(methylsulfonyl)phenyl]-l-[4-(trifluoromethoxy)phenyl]-3- (trifluoromethyl)- 1 H-pyrazole ; 3-(difluoromethyl)-5-[3-fluoro-4-(methylsulfonyl)phenyl]-l-(4-fluorophenyl)-lH- pyrazole; 4-[l-(4-chlorophenyl)-3-methyl-lH-pyrazol-5-yl]benzenesulfonamide; 4-amino-2,3'-bithiophene-5-carboxamide;
4-[l-(4-chlorophenyl)-5-methyl-lH-pyrazol-3-yl]benzenesulfonamide; 4-[l-(4-chlorophenyl)-3-phenyl-lH-pyrazol-4-yl]benzenesulfonamide; 4-[l-(4-chlorophenyl)-5-phenyl-lH-pyrazol-4-yl]benzenesulf onamide; 3-(4-methoxyphenyl)-l-[4-(methylsulfonyl)phenyl]imidazo[5,l-a]isoquinoline; 2H-benzo[h]pyrazolo[4,3-f]isoquinolin-2-ium chloride; 2-methyl-2H-benzo[h]pyrazolo[4,3-f]isoquinoline; S-{[l-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-lH-pyrazol-3-yl]methyl} ethanethioate; 5-[(3aR,4R,6aS)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl]-N-{13-[l-[4- (aminosulfonyl)phenyl]-5-(4-chlorophenyl)-lH-pyrazol-3-yl]-10-oxo-3,6- dioxa-12-thia-9-azatridec-l-yl}pentanamide; 6-({5-[(3aR,4R,6aS)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl]pentanoyl} amino)-N-[6-( { [ 1 - [4-(aminosulf onyl)phenyl] -5-(4-chlorophenyl)- lH-pyrazol- 3-yl]methyl } amino)-6-oxohexyl]hexanamide; 7-fluoro-2H-benzo[h]pyrazolo[4,3-f]isoquinoline hydrochloride; 2-phenyl-2H-benzo[h]pyrazolo[4,3-f]isoquinolin-6-ium chloride; 2H-benzo[h]pyrazolo[4,3-f]quinoline; 2H-benzo[f]pyrazolo[3,4-h]isoquinoline;
2-(2-hydroxyethyl)-2H-benzo[h]pyrazolo[4,3-f]isoquinolin-6-ium chloride; benzo[h]isoxazolo[4,3-f]isoquinolin-6-ium 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]isoquinoline;
9,10-dimethoxy-2H-benzo[h]pyrazolo[4,3-f]isoquinoline hydrochloride;
3-ethyl-2H-benzo[h]pyrazolo[4,3-f]isoquinoline; ethyl 2H-benzo[h]pyrazolo[4,3-f]isoquinoline-3-carboxylate;
1 ,3-dimethyl-6-(2-propoxyphenyl)- 1 ,5-dihydro-4H-pyrazolo [3 ,4-d]pyrimidin-4- one; l-fluoro-4-{ (Z)-2-[4-(methylsulfonyl)phenyl]ethenyl }benzene; 4-fluoro-N-[4-(methylsulfonyl)phenyl]benzarnide; N-(4-fluorophenyl)-4-(methylsulfonyl)benzamide; N-(4-fluorophenyl)-imino-4-(methylsulfonyl)benzenemethanamine; 4-chloro-imino-N-[4-(methylsulfonyl)phenyl]benzenemethan amine; 4-[2-(4-fluorophenyl)phenyl]benzenesulfonamide; 4',5'-difluoro-4"-methoxy-3"-methyl-l,r:2',r'-terphenyl-4-sulfonamide; 4',5'-difluoro-2'-(5-methylpyridin-2-yl)- 1 , 1 '-biphenyl-4-sulf onamide; (3E)-4-[4-(methylsulfonyl)phenyl]-3-phenylbut-3-en-2-ol; 4-[(lE)-3-oxo-2-phenylbut-l-enyl]benzenesulfonamide; 4-[(lE)-3-oxo-2-phenylpent-l-enyl] benzenesulfonamide; (2E)-3-[4-(aminosulfonyl)phenyl]-2-(4-fluorophenyl)prop-2-enoic acid; 4-[(E)-2-cyano-2-phenylethenyl]benzenesulfonamide; 4-[(lE)-3-oxo-2,3-diphenylprop-l-enyl] benzenesulfonamide; (3E)-3 -phenyl-4-pyridin-4-ylbut-3 -en-2-one ; (2E)-l,2-diphenyl-3-pyridin-4-ylprop-2-en-l-one; 4-[(lE)-4,4,4-trifluoro-3-oxo-2-phenylbut-l-enyl]benzenesulf onamide; (3E)- 1 , 1 , l-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)-l-(4-fluorophenyl)-3-phenyl-2-pyridin-4-ylprop-2-en-l-one; (3E)-4-[4-(dimethylamino)phenyl]-3-pyridin-4-ylbut-3-en-2-one; 2-[4-(3,5-dimethylphenoxy)-3,5-diiodophenyl]acetic acid; ({ (lS,3R)-3-[(3,5-ditert-butylphenyl)thio]cyclopentyl }oxy)acetic acid; l-[cyclobutylidene(4-fluorophenyl)methyl]-4-(methylsulfonyl)benzene; 4-({[(4-chlorophenyl)amino]carbonyl}amino)benzenesulfonamide; 4-[(E)-(2-oxo-3,4-dihydronaphthalen-l(2H)-ylidene)methyl]benzenesulfonamide; 2-(5-amino-2-propoxyphenyl)-8-methoxyquinazolin-4(3H)-one; ethyl (lS,2R,3R)-l-phenyl-3-pyridin-4-yl-2,3-dihydro-lH-indene-2-carboxylate; 6,8-dichloro-2S-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid; benzo [h]pyrido [4,3 -f] quinazolin-2-aminium chloride ; and mixtures thereof.
[0095] The present invention encompasses methods and compositions comprising Hsp90 inhibiting compounds selected from the group consisting of 2-[(2-chlorophenyl)sulfinyl]-N-[4-(4-chlorophenyl)-l,3-thiazol-2-yl]acetamide; N-[5-(l-phenylethyl)-l,3-thiazol-2-yl]-4-(lH-pyrrol-l-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)-l-phenyl-lH-pyrazol-4-yl]-N-[3-(lH-imidazol-l-yl) propyl]prop-2-enamide; (2E)-2-cyano-3-[3-(4-ethoxyphenyl)-l-phenyl-lH-pyrazol-4-yl]-N-[3-(lH- imidazol-l-yl)propyl]prop-2-enamide; 3-bromo-2-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione; 3-[4-(4-chlorophenyl)-l,3-thiazol-5-yl]-4H-chromen-4-one; N-[4-(3,4-dichlorophenyl)-l,3-thiazol-2-yl]pyrimidin-2-amine hydrobiOmide; (2E)-2-[4-(4-hydroxy-3-methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxyphenyl) amino]prop-2-enenitrile; N'-[(lE)-(5-bromo-2,4-dihydroxyphenyl)methylidene]2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; 2-[(2-amino-6-hydiOxy-7H-purin-8-yl)thio]-N-(4-phenyl-l,3-thiazol-2-yl) acetamide; (2E)-3-(4-nitrophenyl)-N-(4-pyridin-4-yl-l,3-thiazol-2-yl)prop-2-enamide; N'-[(lE)-(2-hydroxy-4-methoxyphenyl)methylidene]-2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; N-[4-(4-bromophenyl)-l,3-thiazol-2-yl]nicotinamide; N-(l,3-benzothiazol-2-yl)-7-oxo-l-phenyl-l,7-dihydropyrazolo[l,5a]ρyrimidine- 6-carboxamide; N-{(E)-[4-(l-methyl-lH-imidazol-2-yl)-3-nitrophenyl]methylidene}aniline; N-[4-({(E)-2-[4-(l,3-benzodioxol-5-yl)-l,3-thiazol-2-yl]-2-cyanoethenyl}amino) phenyl] acetamide; ethyl ((3Z)-2-oxo-3-{[(3-phenyl-lH-pyrazol-5-yl)carbonyl]hydrazono}-2,3- dihydro- lH-indol- l-yl)acetate; 5- [4-(4-chlorophenyl)- 1 , 3 -thiazol- 1 -yl)pyridine ; and mixtures thereof.
[0096] The present invention encompasses methods and compositions comprising Hsp90 inhibiting compounds selected from the group consisting of (2E)-2-[4-(4-hydroxy-3-methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxyphenyl) amino]prop-2-enenitrile; 2-[(2-amino-6-hydroxy-7H-purin-8-yl)thio]-N-(4-phenyl-l,3-thiazol-2-yl) acetamide; N'-[(lE)-(2-hydroxy-4-methoxyphenyl)methylidene]-2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; and mixtures thereof.
[0097] Many of the Hsp90 inhibiting compounds described above can be synthesized by one of skill in the art according to methods disclosed in the patents individually cited below and incorporated herein by reference. [0098] U.S. Patent No. 5,466,823. [0100] U.S. Patent No. 5,504,215. [0101] U.S. Patent No. 5,508,426. [0102] U.S. Patent No. 5,510,496. [0103] U.S. Patent No. 5,719,163. [0104] U.S. Patent No. 5,756,529. [0105] U.S. Patent No. 5,760,068. [0106] U.S. Patent No. 5,859,257. [0107] U.S. Patent No. 5,935,598. [0108] U.S. Patent No. 5,985,902. [0109] U.S. Patent No. 6,028,072. [0110] U.S. Patent No. 6,090,834. [0111] U.S. Patent No. 6,156,781. [0112] U.S. Patent No. 6,413,960. [0113] U.S. Patent No. 6,492,411. [0114] U.S. Patent No. 6,586,603.
[0115] 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 neoplasia 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.
[0116] Therapeutic combinations comprising an Hsp90 inhibitor, a PDE inhibitor and a Cox-2 inhibitor are also encompassed by the present invention. Pharmaceutical compositions comprising an Hsp90 inhibitor, a PDE inhibitor and a Cox-2 inhibitor and a pharmaceutically acceptable carrier are also encompassed by the present invention. [0117] 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 Hsp90 inhibitor in combination with a PDE inhibitor, wherein the Hsp90 inhibitor is a dual Hsp90/Cox-2 inhibitor.
[0118] The terms "cyclooxygenase-2 inhibitor" and "Cox-2 inhibitor", which can be used interchangeably herein, denote compounds which inhibit the cyclooxygenase-2 enzyme (Cox-2) regardless of the degree of inhibition of the cyclooxygenase-1 enzyme (Cox-1), and include pharmaceutically acceptable racemates, enantiomers, tautomers, salts, esters and prodrags of those compounds. Thus, for purposes of the present invention, a compound is considered a Cox-2 inhibitor although the compound inhibits Cox-2 to an equal, greater, or lesser degree than it inhibits Cox-1. Cox-2 inhibitors herein therefore encompass many traditional non-selective NSAIDs (non-steroidal anti- inflammatory drags).
[0119] Suitable NSAIDs include ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctafenine, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, choline magnesium trisalicylate, salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam, 2-fluoro-a-methyl[l,l'- biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester (See Wenk et al. (2002) Europ. J. Pharmacol. 453, 319-324, incorporated herein by reference) and mixtures thereof. [0120] Particular NSAIDs of interest include ibuprofen, naproxen, sulindac, ketoprofen, fenoprofen, tiaprofenic acid, suprofen, etodolac, carprofen, ketorolac, piprofen, indoprofen, salicylic acid, flurbiprofen and mixtures thereof. [0121] Further Cox-2 inhibitors useful according to embodiments of the present invention are agents and compounds that selectively or preferentially inhibit Cox-2 to a greater degree than they inhibit Cox-1. Such agents and compounds are termed "Cox-2 selective inhibitors" herein.
[0122] In practice, in a test for selectivity of a Cox-2 selective inhibitor, the observed selectivity varies depending upon the conditions under which the test is performed and on the compound being tested. However, for the present purpose, selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IQo value for inhibition of Cox-1, divided by the corresponding IC50 value for inhibition of Cox-2 (Cox-1 IQo/Cox- 2 IQo). A Cox-2 selective inhibitor herein is thus any inhibitor for which Cox-1 IQo/Cox-2 IQo 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 100.
[0123] The term "IQo" with respect to a Cox-2 inhibitor refers to the concentration of a compound that is required to produce 50% inhibition of activity of Cox-1 or Cox-2. In various embodiments, Cox-2 selective inhibitors useful in the present invention can have a Cox-2 IQo of less than about 1 μM, less than about 0.5 μM, or less than about 0.2 μM. Cox-2 selective inhibitors useful in the present invention can have a Cox-1 IQo of greater than about 1 μM, for example greater than about 20 μM. [0124] Cox-2 inhibitors exhibiting a high degree of selectivity for Cox-2 over Cox-1 inhibition can indicate ability to reduce incidence of common NSAID-induced side effects.
[0125] A Cox-2 selective inhibitor can be used in a form of a prodrag thereof. In the present context, a "prodrag" is a compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject. One example of a prodrag for a Cox-2 selective inhibitor is parecoxib, for example in a form of a salt such as parecoxib sodium, which is a therapeutically effective prodrag of the tricyclic Cox-2 selective inhibitor valdecoxib. A class of prodrags of
Cox-2 selective inhibitors is described in U.S. Patent No. 5,932,598, incorporated herein by reference.
[0126] In one embodiment the Cox-2 selective inhibitor is meloxicam or a pharmaceutically acceptable salt or prodrag thereof.
[0127] In another embodiment the Cox-2 selective inhibitor is RS 57067 (6-[[5-(4- chlorobenzoyl)- 1 ,4-dimethyl- lH-pyrrol-2-yl]methyl]-3 (2H)-pyridazinone) or a pharmaceutically acceptable salt or prodrag thereof.
[0128] In another embodiment the Cox-2 selective inhibitor is of the chromene or chroman structural class that is a substituted benzopyran or a substituted benzopyran analog, for example selected from the group consisting of substituted benzothiopyrans, dihydroquinolines and dihydronaphthalenes. These compounds can have a stracture as shown in any of formulas (III), (IN), (V), (VI), (VII) and (VIII) below, and as illustrated in Table 4, and can be diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrags of such compounds.
[0129] Benzopyrans that can serve as a COX-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Patent No.
6,271,253, incorporated herein by reference. One such class of compounds is defined by the general formula shown below in formula (III):
wherein: X1 is selected from O, S, CRC Rb and NR , where Rα is selected from hydrido, Q-Q alkyl, (optionally substituted phenyl)-Q-Q alkyl, acyl and carboxy- Q-Q alkyl; and where each of Rb and Rc is independently selected from hydrido, Q-Q alkyl, phenyl-Q-Q alkyl, Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl; or where CRδRc forms a 3-6 membered cycloalkyl ring;
R1 is selected from carboxyl, aminocarbonyl, Q-Q alkylsulfonylaminocarbonyl and Q-Q alkoxycarbonyl;
R2 is selected from hydrido, phenyl, thienyl, Q-Q alkyl and Q-Q alkenyl;
R3 is selected from Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl;
R4 is one or more radicals independently selected from hydrido, halo, Q-Q alkyl, Q-Q alkenyl, Q-Q alkynyl, halo-Q-Q alkynyl, aryl-Q-Q alkyl, aryl-Q-Q alkynyl, aryl-Q-Q alkenyl, Q-Q alkoxy, methylenedioxy, Q-Q alkylthio, Q-Q alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Q-Q alkoxy-Q-Q alkyl, aryl-Q-Q alkyloxy, heteroaryl-Q-Q alkyloxy, aryl- Q-Q alkoxy-Q-Q alkyl, Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q haloalkylthio, Q-Q haloalkylsulfinyl, Q-Q haloalkylsulfonyl, Q-Q haloalkyl-Q-Q hydroxyalkyl, Q-Q hydroxyalkyl, hydroxyimino-Q-Q alkyl, Q-Q alkylamino, arylamino, aryl-Q-Q alkylamino, heteroarylamino, heteroaryl~Q-Q alkylamino, nitro, cyano, amino, aminosulfonyl, Q-Q alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Q-Q alkylaminosulfonyl, heteroaryl-Q-Q alkylaminosulfonyl, heterocyclyl- sulfonyl, Q-Q alkylsulfonyl, aryl-Q-Q alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Q-Q alkylcarbonyl, heteroaryl- Q-Q alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Q-Q alkoxycarbonyl, formyl, Q-Q haloalkylcarbonyl and Q-Q alkylcarbonyl; and the A ring atoms A1, A2, A3 and A4 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 ring A forms a radical selected from naphthyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
[0130] Another class of benzopyran derivatives that can serve as the COX-2 selective inhibitor of the present invention includes a compound having the stracture of formula
(IV):
wherein: X2 is selected from O, S, CRC Rb and ΝRα; where Rα is selected from hydrido, Q-Q alkyl, (optionally substituted phenyl)-Q-Q alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-Q-Q alkyl; and where each of Rb and Rc is independently selected from hydrido, Q-Q alkyl, phenyl- Q-Q alkyl, Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl; or where CRcRύ form a cyclopropyl ring; R5 is selected from carboxyl, aminocarbonyl, Q-Q alkylsulfonylaminocarbonyl and Q-Q alkoxycarbonyl; R6 is selected from hydrido, phenyl, thienyl, Q-Q alkynyl and Q-Q alkenyl; R7 is selected from Q-Q perfluoroalkyl, chloro, Q-Q alkylthio, Q-Q alkoxy, nitro, cyano and cyano-Q-Q alkyl; R8 is one or more radicals independently selected from hydrido, halo, Q-Q alkyl, Q-Q alkenyl, Q-Q alkynyl, halo-Q-Q alkynyl, aryl-Q-Q alkyl, aryl-Q-Q alkynyl, aryl-Q-Q alkenyl, Q-Q alkoxy, methylenedioxy, Q-Q alkylthio, Q-Q alkylsulfinyl, -O(CF2) O- aryloxy, arylthio, arylsulfinyl, heteroaryloxy, Q-Q alkoxy-Q-Q alkyl, aryl-Q-Q alkyloxy, heteroaryl- Q-Q alkyloxy, aryl-Q-Q alkoxy-Q-Q alkyl, Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q haloalkylthio, Q-Q haloalkylsulfinyl, Q-Q haloalkylsulfonyl, Q-Q haloalkyl-Q-Q hydroxyalkyl, Q-Q hydroxyalkyl, hydroxyimino-Q-Q alkyl, Q-Q alkylamino, arylamino, aryl-Q-Q alkylamino, heteroarylamino, heteroaryl-Q-Q alkylamino, nitro, cyano, amino, aminosulfonyl, Q-Q alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Q-Q alkylaminosulfonyl, heteroaryl-Q-Q alkylaminosulfonyl, heterocyclylsulfonyl, Q-Q alkylsulfonyl, aryl-Q-Q alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-Q-Q alkylcarbonyl, heteroaryl-Q-Q alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, Q-Q alkoxycarbonyl, formyl, Q-Q haloalkylcarbonyl and Q-Q alkylcarbonyl; and the D ring atoms D1, D2, D3 and D4 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 ring D forms a radical selected from naphthyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
[0131] Other benzopyran COX-2 selective inhibitors useful in the practice of the present invention are described in U.S. Patent Nos. 6,034,256 and 6,077,850, 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 R 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 R12 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, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyaryl- carbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or R12 together with ring E forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof; and including diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrags thereof.
[0132] A related class of compounds useful as COX-2 selective inhibitors in the present invention is described by formulas (VI) and (VII):
wherein: X4 is selected from O or S or NRα where Rα is alkyl; R13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R14 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 R15 together with ring G forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [0133] Formula (VII) is: wherein: X5 is selected from the group consisting of O or S or NRb where Rb is alkyl; R16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; R17 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and R18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, aryl- aminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkyl- aminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl and alkylcarbonyl; or 1 R wherein R together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
[0134] The COX-2 selective 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; 17 R is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl; and i o R is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkyl- aminosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered-nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or R together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [0135] The COX-2 selective inhibitor can be a compound of Formula (VTI), wherein: X5 is selected from the group consisting of oxygen and sulfur; R16 is carboxyl; 17 R is lower haloalkyl; and R18 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 heteroarylalkylamino- sulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or R together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
[0136] The COX-2 selective 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; 17 R is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl and trifluoromethyl; and 1 R R is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethyl- amino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2- furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N- morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropyl- carbonyl, phenylacetyl and phenyl; or R18 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof. [0137] The COX-2 selective 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 is selected from the group consisting trifluoromethyl and pentafluoroethyl; and R is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethyl- aminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl, dimethyl- aminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl and phenyl; or R together with ring A forms a naphthyl radical; or an isomer or prodrag thereof.
[0138] Another class of benzopyran derivatives that can serve as the COX-2 selective inhibitor of the present invention includes a compound having the structure of formula (VIII):
wherein: X r6 i ■s selected from the group consisting of O and S; R , 19 is lower haloalkyl; R20is selected from the group consisting of hydrido and halo; R21 is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkyl- aminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6- membered nitrogen-containing heterocyclosulfonyl; R22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy and aryl; and R is selected from the group consisting of the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl; or an isomer or prodrag thereof. [0139] The COX-2 selective inhibitor can be a compound of Formula (Vm), 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; R21 is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethyl- aminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylamino- sulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl and morpholinosulfonyl; R22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert- butyl, chloro, methoxy, diethylamino and phenyl; and R23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy and phenyl; or an isomer or prodrag thereof. Table 4. Examples of chromene Cox-2 selective inhibitors
Table 4. Examples of chromene Cox-2 selective inhibitors
Table 4. Examples of chromene Cox-2 selective inhibitors
Table 4. Examples of chromene Cox-2 selective inhibitors
[0140] In other embodiments the COX-2 selective inhibitor can be selected from the class of tricyclic COX-2 selective inhibitors represented by the general stracture of formula (IX):
wherein: Z1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings; R24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R24 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; 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, alkoxy- aralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkyl- amino, 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, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl; and pharmaceutically acceptable salts and prodrags thereof.
[0141] The COX-2 selective inhibitor of formula (DQ 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 prodrags thereof.
[0142] Additional information about these COX-2 selective inhibitors can be found in patents individually cited below and incorporated herein by reference.
[0143] U.S. Patent No. 5,466,823.
[0144] U.S. Patent No. 5,840,924.
[0145] International Patent Publication No. WO 00/25779.
[0146] International Patent Publication No. WO 98/03484.
Table 5. Examples of tricyclic Cox-2 selective inhibitors
Table 5. Examples of tricyclic Cox-2 selective inhibitors
[0147] In certain embodiments of the invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
[0148] In one embodiment of the invention, parecoxib (see, e.g., U.S. Patent No.
5,932,598), which is a therapeutically effective prodrag of the tricyclic Cox-2 selective inhibitor valdecoxib, B-19 (see, e.g., U.S. Patent No. 5,633,272), may be advantageously employed as a source of a Cox-2 inhibitor.
[0149] Parecoxib can be used as a salt, for example parecoxib sodium.
[0150] In another embodiment of the invention, the compound ABT-963 having the formula:
previously described in International Patent Publication No. WO 00/24719, is another tricyclic COX-2 selective inhibitor which can be advantageously employed. [0151] Examples of specific compounds that are useful as the COX-2 selective inhibitor include, without limitation: 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(l,2-a) pyridine; 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; 5-(4-fluoiOphenyl)-l-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole; 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-l-phenyl-3-(trifluoromethyl) pyrazole; 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-lH-pyrazol-l-yl)benzene- sulf onamide; 4-(3,5-bis(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-phenyl-lH-pyrazol-l-yl)benzenesulfonamide; 4-(3 ,5-bis(4-methoxyphenyl)- 1 H-pyrazol- 1 -yl)benzenesulf onamide; 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-lH-pyrazol-l-yl) benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-lH-pyrazol-l-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-lH-pyrazol-l-yl)benzene- sulfonamide; 4-(4-chloro-3,5-diphenyl-lH-pyrazol-l-yl)benzenesulfonamide; 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[5-phenyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene- sulfonamide; 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-lH-pyrazol-l-yl]benzenesulf onamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene- sulfonamide; 4-[3-(difluoromethyl)-5-(4-methylphenyl)-lH-pyrazol-l-yl]benzenesulf onamide; 4-[3-(difluoromethyl)-5-phenyl-lH-pyrazol-l-yl]benzenesulfonamide; 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-lH-pyrazol-l-yl]benzene- sulfonamide; -[3-cyano-5-(4-fluoiOphenyl)-lH-pyrazol-l-yl]benzenesulfonamide;-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-lH-pyrazol-l-yl]benzene- sulf onamide;-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzene- sulfonamide;-[4-chloro-5-phenyl-lH-pyrazol-l-yl]benzenesulfonamide;-[5-(4-chlorophenyl)-3-(hydroxymethyl)-lH-pyrazol-l-yl]benzenesulf onamide;-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzenesulfonamide;-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene;-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl] benzenesulfonamide;-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5- ene;-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl) thiazole;-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole;-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(l-propylamino)thiazole;-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]thiazole;-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole; -methylsulfonyl-4- [ 1 , 1 -dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl] benzene;-[4-(4-fluorophenyl)-l,l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide; -(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene; -[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide; -(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3- carbonitrile; -bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile; -(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3- carbonitrile; -[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulf onamide; -[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sul onamide; -[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulf onamide; -[l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-lH-imidazol-2-yl]pyridine; -[l-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-lH-imidazol-2-yl]pyridine; -methyl-4-[l-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-lH-imidazol-2-yl] pyridine; -methyl-6-[l-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-lH-imidazol-2-yl] pyridine; -[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulf onamide; 2-(3,4-difluorophenyl)-l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-lH- imidazole; -[2-(4-methylphenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzenesulfonamide; 2-(4-chlorophenyl)-l-[4-(methylsulfonyl)phenyl]-4-methyl-lH-imidazole; 2-(4-chlorophenyl)-l-[4-(methylsulfonyl)phenyl]-4-phenyl-lH-imidazole; 2-(4-chlorophenyl)-4-(4-fluorophenyl)-l-[4-(methylsulfonyl)phenyl]-lH- imidazole; 2-(3-fluoro-4-methoxyphenyl)-l-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)- lH-imidazole; l-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-lH-imidazole; 2-(4-methylphenyl)- 1 -[4-(methylsulf onyl)phenyl] -4-trifluoromethyl- 1H- imidazole; 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulfonamide; 2-(3-fluoro-5-methylphenyl)-l-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)- lH-imidazole; 4-[2-(3-fluoiO-5-methylphenyl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulfonamide; 2-(3-methylphenyl)-l-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-lH- imidazole; 4-[2-(3-methylphenyl)-4-trifluoromethyl-lH-imidazol-l-yl]benzenesulfonamide; l-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-lH-imidazole; 4-[2-(3-chlorophenyl)-4-trifluoromethyl-lH-imidazol-l-yl]benzenesulf onamide; 4-[2-phenyl-4-trifluoromethyl-lH-imidazol-l-yl]benzenesulfonamide; 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-lH-imidazol-l-yl]benzene- sulfonamide; l-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)- IH- pyrazole; 4-[l-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-lH-pyrazol-3-yl]benzene- sulfonamide; N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)- lH-pyrazol-l-yl]acetamide; ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH- pyrazol- 1 -yl] acetate; 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-l-(2-phenylethyl)-lH-pyrazole; 4-(4-fluorophenyl)-3- [4-(methylsulf onyl)phenyl] - 1 -(2-phenylethyl)-5- (trifluoromethyl)pyrazole; l-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH- pyrazole; 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-lH-imidazole; 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-lH-imidazole; 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl) pyridine; 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl) pyridine; 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6- (trifluoromethyl)pyridine ; 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl) pyridine; 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide; l-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene; 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole; 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; l-[2-(4-fluorophenyl)cyclopenten-l-yl]-4-(methylsulfonyl)benzene; 1 - [2-(4-fluoro-2-methylphenyl)cyclopenten- 1 -yl] -4-(methylsulf onyl)benzene; l-[2-(4-chlorophenyl)cyclopenten-l-yl]-4-(methylsulfonyl)benzene; 1 -[2-(2,4-dichlorophenyl)cyclopenten- 1 -yl] -4-(methylsulfonyl)benzene; 1 - [2-(4-trifluoromethylphenyl)cyclopenten- 1 -yl]-4-(methylsulf onyl)benzene; l-[2-(4-methylthiophenyl)cyclopenten-l-yl]-4-(methylsulfonyl)benzene; l-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-l-yl]-4-(methylsulfonyl)benzene; 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-l-yl]benzenesulfonamide; l-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-l-yl]-4-(methylsulfonyl)benzene; 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-l-yl]benzenesulfonamide; 4-[2-(4-fluorophenyl)cyclopenten-l-yl]benzenesulfonamide; 4-[2-(4-chlorophenyl)cyclopenten-l-yl]benzenesulfonamide; 1 - [2-(4-methoxyphenyl)cyclopenten- 1 -yl] -4-(methylsulf onyl)benzene ; l-[2-(2,3-difluorophenyl)cyclopenten-l-yl]-4-(methylsulfonyl)benzene; 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-l-yl]benzenesulfonamide; l-[2-(3-chloro-4-methoxyphenyl)cyclopenten-l-yl]-4-(methylsulfonyl)benzene; 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-l-yl]benzenesulfonamide; 4-[2-(2-methylpyridin-5-yl)cyclopenten-l-yl]benzenesulfonamide; ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl) phenyl]oxazol-2-yl]-2- benzylacetate;-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid;-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole;-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole;-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzene- sulfonamide;-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-7-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-(l-methylethyl)-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-7- ( 1 , 1 -dimethylethyl)-2-trifluoromethyl-2H- 1 -benzopyran-3 -c arboxylic acid;-chloro-8-(l-methylethyl)-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;-( 1 , 1 -dimethylethyl)-2-trifluoromethyl-2H- 1 -benzopyran-3 -carboxylic acid;-bromo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-trifluoromethoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; ,7-dichloro-2-trifluoromethyl-2H- 1 -benzopyran-3 -carboxylic acid;-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;,8-dimethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;,8-bis(dimethylethyl)-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-(l-methylethyl)-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-7-ethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-8-ethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-7-phenyl-2-trifluoromethyl-2H- 1 -benzopyran-3-carboxylic acid;,7-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;,8-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-trifluoromethyl-3H-naptho[2,l-b]pyran-3-carboxylic acid;-chloro-8-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-6-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; -chloro-6-methoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-bromo-8-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-bromo-6-fluoro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-bromo-6-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-bromo-5-fluoro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-8-fluoro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-bromo-8-methoxy-2-trifluoromethyl-2H- 1 -benzopyran-3-carboxylic acid;-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3- carboxylic acid;-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-[(l,l-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3- carboxylic acid;-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-l-benzopyran-3- carboxylic acid;-methylsulfonyl-2-trifluoromethyl-2H-l -benzopyran-3 -carboxylic acid;-chloro-6-[ [(phenylmethyl)amino] sulfonyl] -2-trifluoromethyl-2H- 1 -benzopyran- 3-carboxylic acid;-phenylacetyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;,8-dibromo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-chloro-5,6-dimethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;,8-dichloro-(S)-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-benzylsulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;- [ [N-(2-furylmethyl)amino] sulfonyl] -2- trifluoromethyl-2H- 1 -benzopyran-3- carboxylic acid;- [ [N-(2-phenylethyl)amino] sulfonyl] -2-trifluoromethyl-2H- 1 -benzopyran-3- carboxylic acid;-iodo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;-(l,l-dimethylethyl)-2-pentafluoroethyl-2H-l-benzopyran-3-carboxylic acid; 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl-2(5H)-furanone; 6-chloro-2-trifluoromethyl-2H-l-benzothiopyran-3-carboxylic acid; 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide; 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-lH-pyrazol-l-yl]benzene- sulf onamide; 3-[l-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-lH-imidazol-2-yl]pyridine; 2-methyl-5 - [ 1 - [4-(methylsulf onyl)phenyl] -4-trifluoromethyl- 1 H-imidazol-2-yl] pyridine; 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl]benzene- sulfonamide; 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulf onamide; 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]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 prodrags thereof.
[0152] In a further embodiment of the invention, the Cox-2 selective inhibitor used in the present invention can be selected from the class of phenylacetic acid derivatives represented by the general structure of formula (X):
wherein: R > 27 is methyl, ethyl or propyl; R , 28 is chloro or fluoro; R >29 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; provided that R28, R29, R30 and R31 are not all fluoro when R27 is ethyl and R30 is H; or an isomer, pharmaceutically acceptable salt, ester, or prodrag thereof. [0153] A phenylacetic acid derivative Cox-2 selective inhibitor that is described in International Patent Publication No. WO 99/11605, incorporated by reference herein, is a compound that has the stracture shown in formula (X), wherein: R27 is ethyl; R28 and R30 are chloro; R29 and R31 are hydrogen; and R32 is methyl. [0154] Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in formula (X), wherein: R27 is propyl; R28 and R30 are chloro; R29 and R31 are methyl; and R32 is ethyl. [0155] Another phenylacetic acid derivative Cox-2 selective inhibitor, described in International Patent Publication No. WO 02/20090, incorporated by reference herein, is COX- 189, also known as lumiracoxib, having the stracture shown in formula (X), wherein: R27 is methyl; R 2R is fluoro; R32 is chloro; and R29, R30, and R31 are hydrogen. [0156] Cox-2 selective inhibitor compounds that have a stracture similar to that shown in formula (X) are described in the patents individually cited below and incorporated herein by reference. [0157] U.S. Patent No. 6,310,099. [0158] U.S. Patent No. 6,291,523. [0159] U.S. Patent No. 5,958,978. [0160] Other Cox-2 selective inhibitors that can be used in the present invention have the general stracture shown in formula (XI), wherein the J group is a carbocycle or a heterocycle. Illustrative embodiments have the stracture:
wherein: X is O; J is 1-phenyl; R33 is 2-NHSO2CH3; R34 is 4-NO2; and there is no R35 group (nimesulide); X is O; J is l-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R35 is 6-NHSO2CH3 (flosulide); X is O; J is cyclohexyl; R33 is 2-NHSO2CH3; R34 is 5-NO2; and there is no R35 group (NS-398 or N-(2-cyclohexyloxynitrophenyl)methanesulfonamide); X is S; J is l-oxo-inden-5-yl; R33 is 2-F; R34 is 4-F; and R3S is 6-N"SO2CH3-Na+ (L-745337); X is S; J is thiophen-2-yl; R33 is 4-F; there is no R34 group; and R35 is 5-NHSO2CH3 (RWJ-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-SO2CH3)QH4 (L-784512). [0161] Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Patent No. 6,180,651. Such diarylmethylidenefuran derivatives have the general formula shown below in formula (XII):
wherein: rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms; at least one of the substituents Q1, Q2, L1 and L2 is (a) an -S(O)n-R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms or a lower haloalkyl radical having 1 to 6 carbon atoms, or (b) an -SO2NH2 group, and is located in the para position; the others independently being a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms, or 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 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or R36 and R37, or R38 and R39 are an oxygen atom, or R and R , or R and R , together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms; or an isomer or prodrag thereof.
[0162] Particular compounds of this family of compounds, which can serve as the
Cox-2 selective inhibitor in the present invention, include N-(2-cyclohexyloxynitro- phenyl)methane sulfonamide and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3- furanylidene)methyl]benzenesulfonamide.
[0163] Cox-2 selective inhibitors that are useful in the present invention include darbufelone of Pfizer, CS-502 of Sankyo, LAS 34475 and LAS 34555 of Almirall
Profesfarma, S-33516 of Servier, SD-8381 of Pharmacia, described in U.S. Patent No.
6,034,256, BMS-347070 of Bristol Myers Squibb, described in U.S. Patent No.
6,180,651, MK-966 of Merck, L-783003 and L-748731 of Merck, T-614 of Toyama,
D-1367 of Chiroscience, CT3 of Atlantic Pharmaceutical, CGP-28238 of Novartis,
BF-389 of Biofor/Scherer, GR-253035 of Glaxo Wellcome, 6-dioxo-9H-purin-8-yl cinnamic acid of Glaxo Wellcome, and S-2474 of Shionogi.
[0164] Information about S-33516, mentioned above, can be found in Current Drags Headline News, at http://www.current-drags.com/NEWS/Inflaml.htm (2001), where it was reported that S-33516 has IQ0 values of 0.1 and 0.001 mM against Cox-1 and Cox-2 respectively.
[0165] Compounds that can act as Cox-2 selective inhibitors include multibinding compounds containing from 2 to 10 ligands covalently attached to one or more linkers, as described in U.S. Patent No. 6,395,724.
[0166] Compounds that can act as Cox-2 inhibitors include a conjugated linoleic acid as described in U.S. Patent No. 6,077,868.
[0167] Compounds that can act as Cox-2 selective inhibitors include heterocyclic aromatic oxazole compounds as described in the patents individually cited below and incorporated herein by reference.
[0168] U.S. Patent No. 5,994,381.
[0169] U.S. Patent No. 6,362,209.
[0170] Such heterocyclic aromatic oxazole compounds have the formula shown below in formula (XIII):
wherein: Z is an oxygen atom; one of R40 and R41 is a group of the formula
wherein R >43 is lower alkyl, amino or lower alkylamino; and R 44 , r R45 , R ,46 and R ,47 are the same or different and each is hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R44, R45, R46 and R47 is not hydrogen; the other of R40 and R41 is an optionally substituted cycloalkyl, heterocyclyl or aryl; and R is a lower alkyl or a halogenated lower alkyl, or a pharmaceutically acceptable salt thereof.
[0171] Cox-2 selective inhibitors useful herein include compounds described in the patents individually cited below and incorporated herein by reference. [0172] U.S. Patent No. 6,080,876. [0173] U.S. Patent No. 6,133,292. [0174] Such compounds are described by formula (XIV):
wherein: Z3 is selected from the group consisting of (a) linear or branched Q-6 alkyl, (b) linear or branched Q.6 alkoxy, (c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, Q.3 alkoxy, CN, C1-3 fluoroalkyl, Q-3 alkyl and -CO2 H; R48 is selected from the group consisting of NH and CH3, R49 is selected from the group consisting of C1-6 alkyl unsubstituted or substituted with C3-6 cycloalkyl, and C3-6 cycloalkyl; R50 is selected from the group consisting of Q-6 alkyl unsubstituted or substituted with one, two or three fluoro atoms; and C3-6 cycloalkyl; with the proviso that R49 and R50 are not the same. [0175] Compounds that can act as Cox-2 selective inhibitors include pyridines described in the patents individually cited below and incorporated herein by reference. [0176] U.S. Patent No. 6, 369,275. [0177] U.S. Patent No. 6,127,545. [0178] U.S. Patent No. 6,130,334. [0179] U.S. Patent No. 6,204,387. [0180] U.S. Patent No. 6,071,936.
[0181] U.S. Patent No. 6,001,843.
[0182] U.S. Patent No. 6,040,450.
[0183] Such compounds have the general formula described by formula (XV):
wherein: R51 is selected from the group consisting of: CH3, NH2) NHC(O)CF3 and NHCH3; Z4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), having substituents selected from the group consisting of hydrogen, halo, Q-6 alkoxy, C1-6 alkylthio, CN, Q-6 alkyl, C1-6 fluoroalkyl, N3, -CO2R53, hydroxy, -C(R54)(R55)-OH, -Q-6alkyl-CO2-R56 and C1-6 fluoroalkoxy; R >52 is selected from the group consisting of halo, Q-6 alkoxy, Q.6 alkylthio, CN, Q-6 alkyl, C1-6 fluoroalkyl, N3, -CO2R57, hydroxy, -C(R58)(R59) -OH, -Q.6alkyl-CO2-R60, Q-6 fluoroalkoxy, NO2, NR61R62 and NHCOR63; and R53, R54, R55, R56, R57, R58, R59, R60, R61, R62 and R63 are each independently selected from the group consisting of hydrogen and C1-6 alkyl; 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. [0184] Compounds that can act as Cox-2 selective inhibitors include diarylbenzopyran derivatives as described in U.S. Patent No. 6,340,694, incorporated herein by reference. Such diarylbenzopyran derivatives have the general formula shown below in formula (XVI):
wherein: X is an oxygen atom or a sulfur atom; R64 and R65, identical to or different from each other, are independently hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, nitro, nitrile or carboxyl; R ,66 is a group of a formula S(O)nR ,68 where n is an integer of 0 to 2, R 68 is hydrogen, Q-Q lower alkyl, or a group of formula NR69R70 wherein R69 and R70, identical to or different from each other, are independently hydrogen or Q-Q lower alkyl group; and R67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyreolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a Q-Q lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by one of the following stractures:
wherein: R71 through R75, identical to or different from one another, are independently hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, hydroxyalkyl, nitro, a group of formula S(O)nR68, a group of formula NR69R70, trifluoromethoxy, nitrile, carboxyl, acetyl or formyl, wherein n, R68, R69 and R70 have the same meaning as defined by R66 above; and R76 is hydrogen, halogen, Q-Q lower alkyl, trifluoromethyl, alkoxy, hydroxy, trifluoromethoxy, carboxyl or acetyl. [0185] Compounds that can act as Cox-2 selective inhibitors include l-(4- sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines as described in U.S. Patent No. 6,376,519, incorporated herein by reference. Such compounds have the formula shown below in formula (XVII):
wherein: X is selected from the group consisting of Q-Q trihalomethyl, for example trifluoromethyl Q-Q alkyl; and an optionally substituted or di-substituted phenyl group of formula
wherein R77 and R78 are independently selected from the group consisting of hydrogen, halogen (e.g., chlorine, fluorine or bromine), hydroxyl, nitro, Q-Q (e.g., Q-Q) alkyl, Q-Q (e.g., Q-Q) alkoxy, carboxy, Q-Q trihaloalkyl (e.g., trihalomethyl such as trifluoromethyl), and cyano; and Z5 is selected from the group consisting of substituted and unsubstituted aryl. [0186] Compounds that can act as Cox-2 selective inhibitors of the present invention include heterocycles as described in U.S. Patent No. 6,153,787, incorporated herein by reference. Such heterocycles have the general formulas shown below in formulas (XVIII) and (XIX): wherein: R79 is mono-, di- or tri-substituted C1-12 alkyl, unsubstituted or mono-, di- or tri- substituted linear or branched Q-io alkenyl, unsubstituted or mono-, di- or tri- substituted linear or branched C2-1o alkynyl, unsubstituted or mono-, di- or tri- substituted C3-12 cycloalkenyl, or unsubstituted or mono-, di- or tri-substituted Q-12 cycloalkynyl, wherein the substituents are chosen from the group consisting of halo (selected from F, CI, Br, and I), OH, CF3, Q-6 cycloalkyl, =O, dioxolane and CN; R80 is selected from the group consisting of: CH3, NH2, NHC(O)CF3 and NHCH3; R81 and R82 are independently chosen from the group consisting of hydrogen and C1-10 alkyl; or R and R together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms. [0187] Formula (XIX) is:
wherein X rlιOυ . is fluoro or chloro. [0188] Compounds that can act as Cox-2 selective inhibitors include 2,3,5- trisubstituted pyridines as described in U.S. Patent No. 6,046,217, incorporated herein by reference. Such 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 bond; n is O or 1; R83 is selected from the group consisting of CH3, NH2 and NHC(O)CF ; R84 is selected from the group consisting of halo, C1-6 alkoxy, Q-6 alkylthio, CN, Cι.6 alkyl, C1-6 fluoroalkyl, N3, -CO2R92, hydroxy, -C(R93)(R94)-OH, Q-6 alkyl-CO2-R95, Q-6 fluoroalkoxy, NO2, NR96R97 and NHCOR98; R85 to R98 are independently chosen from the group consisting of hydrogen and Q,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 R and R87 are joined to form a bond. [0189] One exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein X is a bond.
[0190] Another exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein X is O.
[0191] Another exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein X is S.
[0192] Another exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein R83 is CH3.
[0193] Another exemplary embodiment of the Cox-2 selective inhibitor of formula (XX) is that wherein R84 is halo or C1-6 fluoroalkyl.
[0194] Compounds that can act as Cox-2 selective inhibitors include diaryl bicyclic heterocycles as described in U.S. Patent No. 6,329,421. Such compounds have the general formula shown below in formula (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(O)- -CH2-CH2-C(O)-CH2-, -CH2-C(O)-CH2-CH2, -C(O)-CH2-CH2-CH2, (c) -CH2-CH2-C(O)-, -CH2-C(O)-CH2-, -C(O)- CH2-CH2- (d) -CH2-CH2-O-C(O)-, -CH2-O-C(O)-CH2-, -O-C(O)-CH2- CH2- (e) -CH2-CH2-C(O)-O-, -CH2-C(O)-OCH2-, -C(O)-O-CH2-CH2-, (f) -C(R105)2-O-C(O)-, -C(O)-O-C(R105)2-, -O-C(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- (1) -N=CH-N=CH-, (m) -CH=N-CH=N- (n) -S-CH=N-, (o) -S-N=CH-, (p) -N=N-NH- (q) -CH=N-S- and (r) -N=CH-S-; R99 is selected from the group consisting of S(O)2CH3, S(O) NH2, S(O)2NHCOCF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHCOCF3, P(O)(CH3)OH and P(O)(CH3)NH2; R100 is selected from the group consisting of (a) Q-6 alkyl, (b)C3-7 cycloalkyl, (c) mono- or di-substituted phenyl or naphthyl where the substituent is selected from the group consisting of hydrogen, halo including F, CI, Br and I, C1-6 alkoxy, C1-6 alkylthio, CN, CF3, Q-6 alkyl, N3, -CO2H, -CO2-C1-4 alkyl, -C(R103)(R104)-OH, -C(R103)(R104)-O-Q-4 alkyl and -Q-6 alkyl-CO2-R106; (d) mono- or di-substituted heteroaryl where the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2 or 3 additional N atoms; or a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3 or 4 additional N atoms; and said substituents are selected from the group consisting of hydrogen, halo including F, CI, Br and I, C1-6 alkoxy, C1-6 alkylthio, CN, CF3, C1-6 alkyl, N3, -CO2H, -CO2-Q-4 alkyl, -C(R103)(R104)- OH and -C(R , 110U3Λ)(R , 104- )-O-Q-4 alkyl; and (e) benzoheteroaryl which includes the benzo fused analogs of (d); R101 and R102 are substituents residing on any position of -A5=A6-A7=A8- and are selected independently from the group consisting of hydrogen, CF3, CN, C1-6 alkyl, Q4, CO2H, C(R103)(R104)OH, -O-Q4, -S-Q4, and optionally Q-3 alkyl substituted -Q-5 alkyl-Q3, -O-C1-5 alkyl-Q3, -S-Q-5 alkyl-Q3, -C1-3 alkyl- O-C1-3 alkyl-Q3, -Q-3 alkyl-S-Q-3 alkyl-Q3, -C1-5 alkyl-O-Q4 and -C1-5 alkyl-S-Q4, wherein the substituent resides on the alkyl chain; where Q3 is Q4, CO2H or C(R103)(R104)OH and Q4 is CO2-C1-4 alkyl, tetrazolyl-5-yl, or C(R103)(R104)O-Q-4 alkyl; R103, R104 and R105 are each independently selected from the group consisting of hydrogen and C1-6 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 R105 groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; R106 is hydrogen or C1-6 alkyl; R107 is hydrogen, Q-6 alkyl or aryl; and X7 is O, S, NR107, CO, C(R107)2, C(R107)(OH), -C(R107)=C(R107)-, -C(R107)=N- or -N=C(R107)-. [0195] Compounds that can act as Cox-2 selective 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):
wherein: R108 is
where p is 0 to 2; m is 0 to 4; n is 0 to 5; X13 is O, S, SO, SO2, CO, CHCN, CH2 or C=NR113 where R113 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 alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethyl- sulfonyl; R109 is amino, mono or di(lower alkyl)amino, acetamido, acetimido, ureido, formamido, formamido or guanidino; and R110 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein the lower alkyl, lower alkyl containing, lower alkoxy and lower alkanoyl groups contain from 1 to 3 carbon atoms. [0196] Compounds that can act as Cox-2 selective inhibitors include pyrazole derivatives as described in U.S. Patent 6,136,831. Such compounds have the formula shown below in formula (XXIII):
(XXIII) wherein: R , 114 i •s hydrogen or halogen; R115 and R116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or lower alkanoyloxy; R > H7 is lower haloalkyl or lower alkyl; X14 is sulfur, oxygen or NH; and Z6 is lower alkylthio, lower alkylsulfonyl or sulfamoyl; or a pharmaceutically acceptable salt thereof. [0197] Compounds that can act as Cox-2 selective inhibitors include substituted derivatives of benzosulfonamides as described in U.S. Patent 6,297,282. Such 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 by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF3, cyano or alkoxy; R119 and R120, independently from one another, denote hydrogen, an optionally polyfluorized alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)n-X16; or R119 and R120, together with the N atom, denote a 3- to 7- membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH2)n — X16; X16 denotes halogen, NO2, -OR121, -COR121, -CO2 R121, -OCO2 R121, -CN, -CONR121OR122, -CONR121R122, -SR121, -S(O)R121, -S(O)2R121, -NR121R122, -NHC(O)R121 or -NHS(O)2R121; n denotes a whole number from 0 to 6; R123 denotes a straight-chained or branched alkyl group with 1-10 C-atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy; R124 denotes halogen, hydroxy, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C-atoms, which can optionally be mono- or polysubstituted by halogen, NO2, -OR121, -COR121, -CO2R121, -OCO2R121, -CN, -CONR121OR122, -CONR121R122, -SR121, -S(O)R121, -S(O)2R121, -NR121R122, -NHC(O)R121, -NHS(O)2R121, or a polyfluoroalkyl group; 191 199 R and R , independently from one another, denote hydrogen, alkyl, aralkyl or aryl; and m denotes a whole number from 0 to 2; and pharmaceutically-acceptable salts thereof.
[0198] Compounds that can act as Cox-2 selective inhibitors include 3-phenyl-4- (4(methylsulfonyl)phenyl)-2-(5H)-furanones as described in U.S. Patent 6,239,173. Such compounds have the formula shown below in formula (XXV):
or pharmaceutically acceptable salts thereof, wherein: -X17-Y!-Z7-, when side b is a double bond, and sides a and c are single bonds, is selected from the group consisting of -CH2CH2CH2-, -C(O)CH2CH2- -CH2CH2C(O)-, -CR129(R12 ')-O-C(O)-, -C(O)-O-CR129(R129')-, -CH NR1 7-CH2- CR , 1l29y(πR 112/9y')-NR 1l27'-C(O)-, -CR128=CR128'-S- -S-CR128=CR128'- -S-N=CH-, -CH=N-S- -N=CR128-O-, -O-CR128=N- -N=CR128-NH- -N=CR128-S- -S-CR128=N- -C(O)-NR , 1l27'-CR , 112/9y /(Rr, provided R 1122 is not -S(O)2CH3, and -CH=CH-NR127- provided R125 is not -S(O)2CH3; -X17-Y1-Z7-, when sides a and c are double bonds and side b is a single bond, is selected from the group consisting of =CH-O-CH=, =CH-NR127-CH=, =N-S-CH=, =CH-S-N=, =N-O-CH=, =CH-O-N=, =N-S-N= and =N-O-N=; R125 is selected from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHC(O)CF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHC(O)CF3, P(O)(CH3)OH and P(O)(CH3)NH2; R126 is selected from the group consisting of (a) C1-6 alkyl; (b) Q, Q, Q, Q or Q cycloalkyl; (c) mono-, di- or tri-substituted phenyl or naphthyl, where the substituent is selected from the group consisting of hydrogen, halo, Q-6 alkoxy, C1-6 alkylthio, CN, CF3, C1-6 alkyl, N3, -CO2H, -CO2-Q-4 alkyl, -C(R129)(R130)-OH, -C(R129)(R130)-O-Q-4 alkyl, and -Q-6 alkyl-CO2-R129; (d) mono-, di- or tri-substituted heteroaryl wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O or N, and optionally 1, 2 or 3 additional N atoms, or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3 or 4 additional N atoms, where the substituents are selected from the group consisting of hydrogen, halo (including fluoro, chloro, bromo and iodo), Q-6 alkyl, C1-6 alkoxy, Q-6 alkylthio, CN, CF3, N3, -C(R129)(R130)-OH, and -C(R129)(R130)-O-Q-4 alkyl; and (e) benzoheteroaryl including the benzo-fused analogs of (d); R127 is selected from the group consisting of hydrogen, CF3, CN, Q-6 alkyl, hydroxy-Q-6 alkyl, -C(O)-Q-6 alkyl, optionally Q-3 alkyl-substituted -C1-5 alkyl-Q5, -Q-3 alkyl-O-Q-3 alkyl-Q5, -Q-3 alkyl-S-Q-3 alkyl-Q5, -Q-5 alkyl-O-Q and -C1-5 alkyl-S-Q5 where the substituent resides on the alkyl; and -Q5; 1 R 1 R1
R and R are each independently selected from the group consisting of hydrogen, CF3, CN, C1-6 alkyl, -Q5, -O-Q5; -S-Q5, and optionally C1-3 alkyl- substituted -C1-5 alkyl-Q5, -O-Q-5 alkyl-Q5, -S-Q-5 alkyl-Q5, -C1-3 alkyl- O-Q-3 alkyl-Q5, -Q-3 alkyl-S-Q-3 alkyl-Q5, -Q-5 alkyl-O-Q5, -C1-5 alkyl- S-Q5 wherein the substituent resides on the alkyl;
R129, R129', R130, R131 and R132 are each independently selected from the group consisting of hydrogen and Q-6 alkyl; or R129 and R130, or R131 and R132, together with the carbon to which they are attached, form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms; and
Q5 is CO2H, CO2-Q-4 alkyl, tetrazolyl-5-yl, C(R131)(R132)(OH) or C(R131)(R132)(O-Q-4 alkyl); provided that when -X^Y^Z7- is -S-CR128=CR128', then R128 and R128' are other than CF3. Compounds that can act as Cox-2 selective inhibitors include bicyclic carbonyl indole compounds as described in U.S. Patent No. 6,303,628. Such compounds have the formula shown below in formula (XXVI):
or pharmaceutically acceptable salts thereof, wherein: A is Q-6 alkylene or -NR 133 Z8 is C(=L3)R134 or SO2R135; Z9 is CH or N; Z10 and Y2 are independently selected from -CH2- O, S and -N-R , 1133. m is 1, 2 or 3; q and r are independently 0, 1 or 2; X18 is independently selected from halogen, Q.4 alkyl, halo-substituted Q-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted Q-4 alkoxy, Q-4 alkylthio, nitro, amino, mono- or di(Q-4 alkyl)amino and cyano; n is O, 1, 2, 3 or 4; L3 is oxygen or sulfur; R , 133 is hydrogen or C1-4 alkyl; R , 134 is hydroxy, Q-6 alkyl, halo-substituted Q-6 alkyl, Q-6 alkoxy, halo- substituted Q-6 alkoxy, C3- cycloalkoxy, Ci-4 alkyl(C3-7 cycloalkoxy), -NR R , C1-4 alkylphenyl-O- or phenyl-O-, said phenyl being optionally substituted with one to five substituents independently selected from halogen, Ci-4 alkyl, hydroxy, Q.4 alkoxy and nitro; R135 is Q-6 alkyl or halo-substituted C1-6 alkyl; and R136 and R137 are independently selected from hydrogen, C1-6 alkyl and halo- substituted Q-6 alkyl. [0200] Compounds that can act as a Cox-2 selective inhibitors include benzimidazole compounds as described in U.S. Patent No. 6,310,079. Such compounds have the formula shown below in fonnula (XXVII):
or a pharmaceutically acceptable salt thereof, wherein: A10 is heteroaryl selected from (a) a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, and (b) a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring; X20 is independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, halo-substituted Q-Q alkyl, hydroxy-substituted Q-Q alkyl, (Q-Q alkoxy)Q-Q alkyl, halo-substituted Q-Q alkoxy, amino, N-(Q-Q alkyl)amino, N,N-di(Q-Q alkyl)amino, [N-(Q-Q alkyl)arnino]Q-Q alkyl, [N,N-di(Q-Q alkyl)amino]Q-Q alkyl, N-(Q-Q alkanoyl)amino, N-(Q-Q aIkyι)(Q-Q alkanoyl)amino, N-[(Q-Q alkyl)sulfonyl] amino, N-[(halo- substituted Q-Q alkyl)sulfonyl] amino, Q-Q alkanoyl, carboxy, (Q-Q alkoxy)carbonyl, carbamoyl, [N-(Q-Q alkyl)amino]carbonyl, [N,N-di(Q-Q alkyl)amino]carbonyl, cyano, nitro, mercapto, (Q-Q alkyl)thio, (Q-Q alkyl)sulfinyl, (Q-Q alkyl)sulfonyl, aminosulfonyl, [N-(Q-Q alkyl)amino] sulfonyl and [N,N-di(Q-Q alkyl)amino]sulfonyl; 91 X is independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, halo-substituted Q-Q alkyl, hydroxy-substituted Q-Q alkyl, (Q-Q alkoxy)Q-Q alkyl, halo-substituted Q-Q alkoxy, amino, N-(Q-Q alkyl)amino, N,N-di(Q-Q alkyl)amino, [N-(Q-Q alkyl)amino]Q-Q alkyl, [N,N-di(Q-Q alkyl)amino]C1-C alkyl, N-(Q-C4 alkanoyl)amino, N-(Q-Q alkyl)-N-(Q-C4 alkanoyl)amino, N-[(Ci-C4 alkyl)sulfonyl] amino, ^[(halo- substituted Q-Q alkyl)sulfonyl]amino, Q-Q alkanoyl, carboxy, (Q-Q alkoxy)carbonyl, carbamoyl, [N-(Q-Q alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (Q-Q alkyl)thio, (Q-Q alkyl)sulfinyl, (Q-Q alkyl)sulfonyl, aminosulfonyl, [N- (C!-C4 alkyl)amino] sulfonyl and [N,N-di(Q-Q alkyl)amino]sulfonyl;
R138 is selected from hydrogen; straight or branched Q-Q alkyl optionally substituted with one to three substituent(s) independently selected from halo, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; Q-Q cycloalkyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; Q-Q cycloalkenyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Q-Q alkyl)amino; phenyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, halo-substituted Q-Q alkyl, hydroxy- substituted Q-Q alkyl, (Q-Q alkoxy)Q-Q alkyl, halo-substituted Q-Q alkoxy, amino, N-(Q-Q alkyl)amino, N,N-di(Q-Q alkyl)amino, [N-(Q-Q alkyl)amino]Q-Q alkyl, [N,N-di(Q-Q alkyl)amino]Q-Q alkyl, N-(Q-Q alkanoyl)amino, N-[Q-Q alkyl)(Ci-C4 alkanoyl)] amino, N-[(Q-Q alkyl)sulfonyl] amino, N- [(halo-substituted C1-C4 alkyl)sulfonyl]amino, Q-Q alkanoyl, carboxy, (Q-Q alkoxy)carbonyl, carbamoyl, [N-(C1-C alkyl)amino]carbonyl, [N,N-di(Q-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (Q-Q alkyl)thio, (Q-Q alkyl)sulfinyl, (C1-C alkyl)sulfonyl, aminosulfonyl, [N-(Q-Q alkyl)amino] sulfonyl and [N,N-di(Ci-C alkyl)amino]sulfonyl; and heteroaryl selected from (a) a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; and (b) a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; said heteroaryl being optionally substituted with one to three substituent(s) selected from X20;
R139 and R140 are independently selected from hydrogen; halo; Q-Q alkyl; phenyl optionally substituted with one to three substituent(s) independently selected from halo, Q-Q alkyl, hydroxy, Q-Q alkoxy, amino, N-(Q-Q alkyl)amino and N,N-di(Cι-C4 alkyl)amino; or R138 and R139 can form, together with the carbon atom to which they are attached, a Q-Q cycloalkyl ring; m is 0, 1, 2, 3, 4 or 5; and n is O, 1, 2, 3 or 4. [0201] Compounds that can act as Cox-2 selective inhibitors include indole compounds that are described in U.S. Patent No. 6,300,363. Such compounds have the formula shown below in formula (XXVIII):
(xxviπ) and pharmaceutically acceptable salts thereof, wherein: L 4 i •s oxygen or sulfur; Y3 is a direct bond or Q-4 alkylidene; Q6 is (a) C1-6 alkyl or halosubstituted C1-6 alkyl, said alkyl being optionally substituted with up to three substituents independently selected from hydroxy, Ci-4 alkoxy, amino and mono- or di-(Q.4 alkyl)amino; (b) C3-7 cycloalkyl optionally substituted with up to three substituents independently selected from hydroxy, Q.4 alkyl and C1-4 alkoxy; (c) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to four substituents independently selected from halo, Q.4 alkyl, halo-substituted Q-4 alkyl, hydroxy, C1- alkoxy, halo-substituted C1- alkoxy, S(O)mR143, SO2NH2, SO2N(Q.4 alkyl)2, amino, mono- or di-(Q- alkyl)amino, NHSO2R143, NHC(O)R143, CN, CO2H, CO2(Q-4 alkyl), Q-4 alkyl-OH, Q.4 alkyl-OR143, CONH2, CONH(Q.4 alkyl), CON(Q.4 alkyl)2 and -O-Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, C1- alkyl, CF3, hydroxy, OR143, S(O)mR143, amino, mono- or di-(Q-4 alkyl)amino and CN; (d) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substitutents independently selected from halo, Q-4 alkyl, halo-substituted Q-4 alkyl, hydroxy, Q. alkoxy, halo-substituted Q-4 alkoxy, Ci-4 alkyl-OH, S(O)mR143, SO NH2, SO2N(Q.4 alkyl)2, amino, mono- or di-(C1- alkyl)amino, NHSO2R143, NHC(O)R143, CN, CO2H, CO2(Q-4 alkyl), Q-4 alkyl-OR143, CONH2, CONH(C1-4 alkyl), CON(Q-4 alkyl)2, phenyl, and mono-, di- or tri- substituted phenyl wherein the substituent is independently selected from halo, CF3, Q-4 alkyl, hydroxy, Q-4 alkoxy, OCF3, SR143, SO2CH3, SO2NH2, amino, Q-4 alkylamino and NHSO2R143; or (e) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from halo, Ci-4 alkyl, halo-substituted Q.4 alkyl, hydroxy, Q.4 alkoxy, halosubstituted Q-4 alkoxy, Q-4 alkyl-OH, S(O)mR143, SO2NH2, SO2N(Q-4 alkyl)2, amino, mono- or di-(Q- alkyl)amino, NHSO2R143, NHC(O)R143, CN, CO2H, CO2(Q-4 alkyl), C1-4 alkyl-OR143, CONH2, CONH(Q-4 alkyl), CON(Q-4 alkyl)2, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF3, Ci-4 alkyl, hydroxy, Q.4 alkoxy, OCF3, SR143, SO2CH3, SO2NH2, amino, C1-4 alkylamino and NHSO2R143;
R141 is hydrogen or C1-6 alkyl optionally substituted with a substituent selected independently from hydroxy, OR143, nitro, amino, mono- or di-(C1- alkyl)amino, CO2H, CO2(Q-4 alkyl), CONH2, CONH(Q-4 alkyl) and CON(Q-4 alkyl)2;
R142 is hydrogen; C1-4 alkyl; C(O)R145 where R145 is selected from (a) Q-22 alkyl or C2-22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from halo, hydroxy, OR143, S(O)mR143, nitro, amino, mono- or di-(Q-4 alkyl)amino, NHSO2R143, CO2H, CO2(Q-4 alkyl), CONH2, CONH(Q-4 alkyl), CON(Q-4 alkyl)2, OC(O)R143, thienyl, naphthyl and groups of the following formulae: (b) Q-22 alkyl or C2- alkenyl, said alkyl or alkenyl being optionally substituted with 5 to 45 halogen atoms; (c) -Y5-C3-7 cycloalkyl or -Y5-Q- cycloalkenyl, said cycloalkyl or cycloalkenyl being optionally substituted with up to three substituent independently selected from Q.4 alkyl, hydroxy, OR143, S(O)mR143, amino, mono- or di-(Q.4 alkyl)amino, CONH2, CONH(Q.4 alkyl) and CON(Q_ alkyl) ; (d) phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with up to seven substituents independently selected from halo, Q-8 alkyl, Q-4 alkyl-OH, hydroxy, Q.8 alkoxy, halo-substituted Q-8 alkyl, halo-substituted Q-8 alkoxy, CN, nitro, S(O)mR143, SO2NH2, SO2NH(Q-4 alkyl), SO2N(Q-4 alkyl)2, amino, Q-4 alkylamino, di-(Ci-4 alkyl)amino, CONH2, CONH(Q.4 alkyl), CON(Q-4 alkyl)2, OC(O)R143, and phenyl optionally substituted with up to three substituents independently selected from halo, Q.4 alkyl, hydroxy, OCH3, CF3, OCF3, CN, nitro, amino, mono- or di-(Q.4 alkyl)amino, CO2H, CO2(C1- alkyl) and CONH2; (e) a monocyclic aromatic group of 5 atoms, said aromatic group having one heteroatom selected from O, S and N and optionally containing up to three N atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from halo, Q.4 alkyl, halo-substituted Q-4 alkyl, hydroxy, Q-4 alkoxy, halo-substituted Ci-4 alkoxy, Q-4 alkyl-OH, S(O)mR143, SO2NH2, SO2N(Q-4 alkyl)2, amino, mono- or di-(Q-4 alkyl)amino, NHSO2R143, NHC(O)R143, CN, CO2H, CO2(Q-4 alkyl), Q.4 alkyl-OR143, CONH2, CONH(Q-4 alkyl), CON(Q-4 alkyl)2, phenyl, and mono-, di- or tri-substituted phenyl wherein the substituent is independently selected from halo, CF3, C1- alkyl, hydroxy, Q-4 alkoxy, OCF3, SR143, SO2CH3, SO2NH2, amino, Q-4 alkylamino and NHSO2R143; (f) a monocyclic aromatic group of 6 atoms, said aromatic group having one heteroatom which is N and optionally containing up to three atoms in addition to said heteroatom, and said aromatic group being substituted with up to three substituents independently selected from halo, C1-4 alkyl, halo-substituted Q-4 alkyl, hydroxy, Q-4 alkoxy, halo-substituted Cμ alkoxy, Q-4 alkyl-OH, S(O)mR143, SO2NH2, SO2N(Q.4 alkyl)2, amino, mono- or di-(Q-4 alkyl)amino, NHSO2R143, NHC(O)R143, CN, CO2H, CO2(Q-4 alkyl), Q.4 alkyl-OR143, CONH2, CONH(Q-4 alkyl), CON(C1-4 alkyl)2, phenyl, and mono-, di- or tri- substituted phenyl wherein the substituent is independently selected from halo, CF3, Q-4 alkyl, hydroxy, Q-4 alkoxy, OCF3, SR143, SO2CH3, SO2NH2, amino, Ci-4 alkylamino and NHSO R143; or (g) a group of the following formula:
99
X is halo, Q-4 alkyl, hydroxy, Q-4 alkoxy, halo-substituted Q-4 alkoxy, S(O)mR143, amino, mono- or di-(Q.4 alkyl)amino, NHSO2 R143, nitro, halosubstituted Q-4 alkyl, CN, CO2 H, CO2 (C alkyl), Cι-4 alkyl-OH, Q-4 alkyl- OR143, CONH2, CONH(Q.4 alkyl) or CON(Q-4 alkyl)2;
R143 is C1-4 alkyl or halo-substituted C1-4 alkyl; m is 0, 1 or 2; n is O, 1, 2 or 3; p is 1, 2, 3, 4 or 5; q is 2 or 3;
Z11 is oxygen, sulfur or NR144; and
R144 is hydrogen, C1-6 alkyl, halo-substituted Q-4 alkyl or -Y5-phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, Q.4 alkyl, hydroxy, Cμ alkoxy, S(O)mR143, amino, mono- or di- (Q-4 alkyl)amino, CF3, OCF3, CN and nitro; O 2005/041879 with the proviso that a group of formula -Y5-Q is not methyl or ethyl when X22 is hydrogen, L 4* i ■s oxygen, R141 is hydrogen and R , 114"2 i. s acetyl. [0202] Compounds that can act as Cox-2 selective inhibitors include aryl phenylhydrazides as described in U.S. Patent No. 6,077,869. Such compounds have the formula shown below in formula (XXIX):
wherein X23 and Y6 are selected from hydrogen, halogen, alkyl, nitro, amino and other oxygen- and sulfur-containing functional groups such as hydroxy, methoxy and methylsulfonyl.
[0203] Compounds that can act as Cox-2 selective inhibitors include 2-aryloxy-4-aryl furan-2-ones as described in U.S. Patent No. 6,140,515. Such compounds have the formula shown below in formula (XXX):
or a pharmaceutically acceptable salt thereof, wherein: R146 is selected from the group consisting of SCH3, -S(O)2CH3 and -S(O)2NH2; R147 is selected from the group consisting of OR150, mono- or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro; R150 is unsubstituted or mono- or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and fluoro; R148 is H or Ci-4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; and R149 is H and Ci-4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br; with the proviso that R148 and R149 are not the same. [0204] Compounds that can act as Cox-2 selective inhibitors include bisaryl compounds as described in U.S. Patent No. 5,994,379. Such compounds have the formula shown below in fonnula (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 is taken in conjunction with R152 as described below; when Z is C, R represents H and R is a moiety which has the following characteristics: (a) it is a linear chain of 3-4 atoms containing 0-2 double bonds, which can adopt an energetically stable transoid configuration and if a double bond is present, the bond is in the trans configuration, (b) it is lipophilic except for the atom bonded directly to ring A, which is either lipophilic or non-lipophilic, and (c) there exists an energetically stable configuration planar with ring A to within about 15 degrees; or R151 and R152 are taken in combination and represent a 5- or 6-membered aromatic or nonaromatic ring D fused to ring A, said ring D containing 0-3 heteroatoms selected from O, S and N; said ring D being lipophilic except for the atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said ring D having available an energetically stable configuration planar with ring A to within about 15 degrees; said ring D further being substituted with one Ra group selected from the group consisting of Q-2 alkyl, -O-Q-2 alkyl, -NHQ-2 alkyl, -N(Q-2 alkyl)2, -C(O)Q-2 alkyl, -S-Q-2 alkyl and -C(S)Q-2 alkyl; Y7 represents N, CH or C-O-Q-3 alkyl, and when Z13 is N, Y7 can also represent a carbonyl group; R153 represents H, Br, CI or F; and R154 represents H or CH3. [0205] Compounds that can act as Cox-2 selective inhibitors include 1,5- diarylpyrazoles as described in U.S. Patent No. 6,028,202. Such compounds have the formula shown below in formula (XXXII):
(XXXII) wherein: R155, R156, R157 and R158 are independently selected from the group consisting of hydrogen, Q-5 alkyl, Q-5 alkoxy, phenyl, halo, hydroxy, Q-5 alkylsulfonyl, Q-5 alkylthio, trihalo-Q-5 alkyl, amino, nitro and 2-quinolinylmethoxy; R159 is hydrogen; Q-5 alkyl; trihalo-Q-5 alkyl; phenyl; substituted phenyl where the phenyl substituents are halogen, Q-5 alkoxy, trihalo-Q-5 alkyl or nitro; or heteroaryl of 5-7 ring members where at least one of the ring members is nitrogen, sulfur or oxygen; R160 is hydrogen; Q.s alkyl; phenyl-Q-5 alkyl; substituted phenyl-Q-5 alkyl where the phenyl substituents are halogen, Q-5 alkoxy, trihalo-Q-5 alkyl or nitro; Q-5 alkoxycarbonyl; phenoxycarbonyl; or substituted phenoxycarbonyl where the phenyl substituents are halogen, Q_5 alkoxy, trihalo-Q-5 alkyl or nitro; R161 is Q-io alkyl; substituted Q-io alkyl where the substituents are halogen, trihalo-Q.5 alkyl, Q-5 alkoxy, carboxy, Q-5 alkoxycarbonyl, amino, Q-5 alkylamino, di(Q-5 alkyl)amino, di(Q-5 alkyl)amino-Q-5 alkylamino, Q-5 alkylamino-Q-5 alkylamino or a heterocycle containing 4-8 ring atoms where one more of the ring atoms is nitrogen, oxygen or sulfur, said heterocycle being optionally substituted with Q-5 alkyl; phenyl; substituted phenyl where the phenyl substituents are one or more of Q-5 alkyl, halogen, Q-5 alkoxy, trihalo-Q-5 alkyl or nitro; heteroaryl having 5-7 ring atoms where one or more atoms are nitrogen, oxygen or sulfur; fused heteroaryl where one or more 5-7 membered aromatic rings are fused to the heteroaryl; or NR163R164 where R163 and R164 are independently selected from hydrogen and Q-5 alkyl, or R163 and R164 may be taken together with the depicted nitrogen to form a heteroaryl ring of 5-7 ring members where one or more of the ring members is nitrogen, sulfur or oxygen, said heteroaryl ring being optionally substituted with Q-5 alkyl; and R162 is hydrogen, Q-5 alkyl, nitro, amino or halogen; or pharmaceutically acceptable salts thereof.
[0206] Compounds that can act as Cox-2 selective inhibitors include 2-substituted imidazoles as described in U.S. Patent No. 6,040,320. Such compounds have the formula shown below in formula (XXXIII):
wherein: R is phenyl; heteroaryl containing 5 to 6 ring atoms; or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of Q-5 alkyl, halogen, nitro, trifluoromethyl and nitrile; R1 is phenyl; heteroaryl containing 5 to 6 ring atoms; substituted heteroaryl wherein the substituents are independently selected from one or more members of the group consisting of Q-5 alkyl and halogen; or substituted phenyl wherein the substituents are independently selected from one or members of the group consisting of Q.5 alkyl, halogen, nitro, trifluoromethyl and nitrile; R166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl, Q-5 alkoxycarbonyl, aryloxycarbonyl, aryl-Q-5 alkyloxycarbonyl, aryl-Q-5 alkyl, phthalimido-C1-5 alkyl, amino-Q-5 alkyl, diamino-Q-5 alkyl, succinimido-Q-5 alkyl, Q-5 alkylcarbonyl, arylcarbonyl, Q.5 alkylcarbonyl-C1-5 alkyl, aryloxycarbonyl- Q-5 alkyl, heteroaryl-Q-5 alkyl where the heteroaryl contains 5 to 6 ring atoms, or substituted aryl-Q-5 alkyl wherein the aryl substituents are independently selected fron ne or more members of the group consisting of Q-5 alkyl, Q-5 alkoxy, halogen, amino, Q-5 alkylamino and di(Q-5 alkyl)amino; and is (Aπ),-(CH165)g-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; hydroxy; halogen; vinyl; ethynyl; Q-5 alkyl; Q-7 cycloalkyl; Q-5 alkoxy; phenoxy; phenyl; aryl- Q-5 alkyl; amino; Q-5 alkylamino; nitrile; phthalimido; amido; phenylcarbonyl; Q-5 alkylaminocarbonyl; phenylaminocarbonyl; aryl-Q-5 alkylaminocarbonyl; Q.5 alkylthio; Q-5 alkylsulfonyl; phenylsulfonyl; substituted sulfonamido wherein the sulfonyl substituent is selected from the group consisting of Q.5 alkyl, phenyl, araQ-5 alkyl, thienyl, furanyl and naphthyl; substituted vinyl wherein the substituents are independently selected from one or 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 Q-5 alkyl wherein the substituents are selected from the group consisting of one or more Q-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 Q-5 alkyl, halogen and Q-5 alkoxy; substituted phenoxy wherein the phenyl substituents are independently selected from one or more members of the group consisting of Q-5 alkyl, halogen and Q-5 alkoxy; substituted Q-5 alkoxy wherein the alkyl substituent is selected from the group consisting of phthalimido and amino; substituted aryl-Q-5 alkyl wherein the alkyl substituent is hydroxyl; substituted aryl-Q-5 alkyl wherein the phenyl substituents are independently selected from one or more members of the group consisting of Q.5 alkyl, halogen and Q.5 alkoxy; substituted amido wherein the carbonyl substituent is selected from the group consisting of Q.5 alkyl, phenyl, arylQ-5 alkyl, thienyl, furanyl and naphthyl; substituted phenylcarbonyl wherein the phenyl substituents are independently selected from one or members of the group consisting of Q-5 alkyl, halogen and Q-5 alkoxy; substituted .5 alkylthio wherein the alkyl substituent is selected from the group consisting of hydroxy and phthalimido; substituted Q.5 alkylsulfonyl wherein 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 members of the group consisting of bromine, fluorine, chlorine, Q.5 alkoxy and trifluoromethyl; with the proviso that (a) if A11 is sulfur and X24 is other than hydrogen, Q-5 alkylaminocarbonyl, phenylaminocarbonyl, aryl-Q-5 alkylaminocarbonyl, Q-5 alkylsulfonyl or phenylsulfonyl, then q must be equal to or greater than 1; (b) if A11 is sulfur and q is 1, then X24 cannot be Q-2 alkyl; (c) if A11 is carbonyl and q is 0, then X24 cannot be vinyl, ethynyl, Q-5 alkylaminocarbonyl, phenylaminocarbonyl, aryl-Q-5 alkylaminocarbonyl, Q-5 alkylsulfonyl or phenylsulfonyl; (d) if A11 is carbonyl, q is 0 and X24 is H, then R 166 i •s no +t ( /e„Λ) i iff „ n i :s„ n 0 a „_nd-j q „ is„ Λ 0, * the„„n X V24 cannot be hydrogen; and pharmaceutically acceptable salts thereof.
[0207] Compounds that can act as Cox-2 selective inhibitors include 1,3- and 2,3- diarylcycloalkano- and cycloalkenopyrazoles as described in U.S. Patent No. 6,083,969. Such compounds have the general formulas (XXX1N) and (XXXV) shown below:
(XXXIV) (XXXV) wherein: R168 and R169 are independently selected from the group consisting of hydrogen, halogen, (Q-Q)alkyl, (Q-Q)alkoxy, nitro, amino, hydroxy, trifluoro, -S(Q-Q)alkyl, -SO(Q-Q)alkyl and -SO2(Q-Q)alkyl; and the fused moiety M is selected from the group consisting of an optionally substituted cyclohexyl and cycloheptyl group having the formulae:
wherein:
R170 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, (Q-Q)alkyl, (Q-Q)alkoxy, =NOH, -NR174R175, -OCH3, -OCH2CH3, -OSO2NHCO2CH3, =CHCO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CON(CH3)2, -CH2CO2NHCH3, -CHCHCO2CH2CH3, -OCON(CH3)OH, -C(COCH3)2, di(Ci-C6)alkyl and di(Ci -Q)alkoxy; and 17T
R is selected from the group consisting of hydrogen, halogen, hydroxy, carbonyl, amino, (Q-Q)alkyl, (Q-Q)alkoxy and optionally substituted carboxyphenyl, wherein substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxy, amino, (Q-Q)alkyl and (Q-Q)alkoxy; or R170 and R171 taken together form a moiety selected from the group consisting of -OCOCH2- -ONH(CH3)COCH2- -OCOCH.dbd. and -O-; and 1//oorr RR .117722 aa „n_nddj R τ R, 117733 ttaakken together form a moiety selected from the group consisting of -O- and
R , 174 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3 and (Q-Q)alkyl; and R175 is selected from the group consisting of hydrogen, OH, -OCOCH3, -COCH3, (Cι-Qj)alkyl, -CONH2 and -SO2CH3; with the proviso that if M is a cyclohexyl group, then R170 through R173 may not all be hydrogen; and pharmaceutically acceptable salts, esters and pro-drag forms thereof. [0208] Compounds that can serve as Cox-2 selective inhibitors include esters derived from indolealkanols and amides derived from indolealkylamides as described in U.S. Patent No. 6,306,890. Such compounds have the general formula shown below in formula (XXXVI):
(XXXVI) wherein: R , 176 is Q-Q alkyl, Q-Q branched alkyl, Q-Q cycloalkyl, Q-Q hydroxyalkyl, branched Q-Q hydroxyalkyl, hydroxy-substituted Q-Q aryl, primary, secondary or tertiary Q-Q alkylamino, primary, secondary or tertiary branched Q-Q alkylamino, primary, secondary or tertiary Q-Q arylamino, Q-Q alkylcarboxylic acid, branched Q-Q alkylcarboxylic acid, Q-Q alkylester, branched Q-Q alkylester, Q-Q aryl, Q-Q arylcarboxylic acid, Q-Q arylester, Q-Q aryl-substituted Q-Q alkyl, Q-Q heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted or aryl-substituted Q-Q heterocyclic alkyl or aryl with O, N or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro or iodo; R177 is halo, Q-Q alkyl, Q-Q branched alkyl, Q-Q cycloalkyl, Q-Q aryl, Q- Q aryl-substituted Q-Q alkyl, Q-Q alkoxy, Q-Q branched alkoxy, Q-Q aryloxy, or halo-substituted versions thereof, where halo is chloro, fluoro, bromo, or iodo; R178 is hydrogen, Q-Q alkyl or Q-Q branched alkyl; R179 is Q-Q alkyl, Q-Q aroyl, Q-Q aryl, Q-Q heterocyclic alkyl or aryl with O, N or S in the ring, Q-Q aryl-substituted Q-Q alkyl, alkyl-substituted or aryl-substituted Q-Q heterocyclic alkyl or aryl with O, N or S in the ring, alkyl-substituted Q-Q aroyl, or alkyl-substituted Q-Q aryl, or halosubstituted versions thereof where halo is chloro, bromo, or iodo; n is 1, 2, 3, or 4; and X25 is O, NH, or N-R180, where R180 is Q-Q alkyl or Q-Q branched alkyl. [0209] Compounds that can act as Cox-2 selective inhibitors include pyridazinone compounds as described in U.S. Patent No. 6,307,047. Such compounds have the formula (XXXVII):
(XXXVII) or a pharmaceutically acceptable salt, ester, or prodrag thereof, wherein: X26 is selected from the group consisting of O, S, -NR185, -NORa and -NNRb Rc; R185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, and heterocyclic alkyl; Ra, Rb and Rc are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R181 is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocyclic, heterocyclic alkoxy, heterocyclic alkyl, heterocyclic oxy, hydroxyalkyl, hydroxyiminoalkoxy, -(CH2)nC(O)R186, -CH2)nCH(OH)R186, -(CH2)nC(NORd)R186, -(CH2)nCH(NORd)R186, - (CH2)nCH(NRdRe)R186, /041879
-R187R188, -(CH2)nC≡CR188, -(CH2)n[CH(CXZ0 3)]m(CH2)pR1 -(CH2)n(CX26 2)m(CH2)pR188, and -(CH2)n(CHX26')m(CH2)mR188;
R186 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocyclic, 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, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
Rd and Re are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocyclic, 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, heterocyclic, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y8 and Z14, provided that one of R182, R183 or R184 must be Z14, and further provided that only one of R182, R183 or R184 is Z14;
Z14 is selected from the group consisting of:
X27 is selected from the group consisting of S(O)2, S(O)(NR191), S(O), Se(O)2, P(O)(OR192) and P(O)(NR193R194); X28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl and halogen; R190 is selected from the group consisting of alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH2 and -NCHN(R191)R192; R191, R192, R193 and R194 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 consisting of -OR195, -SR195, -C(R197)(R198)R195, -C(O)R195, -C(O)OR195, -N(R197)C(O)R195, -NC(R197)R195 and -N(R197)R195; R195 is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, hydroxyalkyl and NR199R200; and R197, R198, R199 and R200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocyclic and heterocyclic alkyl. [0210] Compounds that can act as Cox-2 selective inhibitors include benzosulfonamide derivatives as described in U.S. Patent No. 6,004,948. Such compounds have the formula (XXXVIII):
(xxxviπ) wherein: A 12 denotes oxygen, sulfur or NH; 901 R denotes a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted by halogen, alkyl, CF3 or alkoxy; D5 denotes a group:
R202 and R203 independently of each other denote hydrogen, an optionally polyfluorinated alkyl radical, an aralkyl, aryl or heteroaryl radical or a radical (CH2)„-X29; or R202 and R203 together with the N-atom denote a 3- to 7- membered, saturated, partially or totally unsaturated heterocycle with one or more heteroatoms N, O, or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group or a group (CH2)n-X 29. R ,202,' denotes hydrogen, an optionally polyfluorinated alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH2)n-X 29. X29 denotes halogen, NO2, -OR204, -COR204, -CO2R204, -OCO2R204, -CN, -CONR204OR205, CONR ,20υ4Trl>20υ5j, -SR 204 -S(O)R ,2Z0U44, 20 -NR ,ZU44Rr>2' 05 -NHC(O)R ,20υ4 or -NHS(O)2R 204. Z Λl5 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=O or >S(O)m; R2 and R205 independently of each other denote hydrogen, alkyl, aralkyl or aryl; n is an integer from 0 to 6; R206 is CF3 or a straight-chained or branched Q-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 CF ; and pharmaceutically acceptable salts thereof.
[0211] Cox-2 selective inhibitors useful in the subject methods and compositions can include compounds described in the patents individually cited below and incorporated herein by reference. [0212] U.S. Patent No. 6,169,188. [0213] U.S. Patent No. 6,020,343. [0214] U.S. Patent No. 5,981,576.
[0215] U.S. Patent No. 6,222,048.
[0216] U.S. Patent No. 6,057,319.
[0217] U.S. Patent No. 6,046,236.
[0218] U.S. Patent No. 6,002,014.
[0219] U.S. Patent No. 5,945,539.
[0220] U.S. Patent No. 6,359,182.
[0221] Cox-2 selective inhibitors useful in the present invention can be supplied by any source as long as the Cox-2 selective inhibitor is pharmaceutically acceptable. Cox-2 selective inhibitors can be isolated and purified from natural sources or can be synthesized. Cox-2 selective inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products.
[0222] Likewise, Cox-2 inhibitors useful in the compositions and methods of the present invention can by synthesized, for example, according to the description in
Example 1. Several Cox-2 inhibitors that are suitable for use with the compositions and methods of the present invention may be synthesized by the methods described in, for example, U.S. Patent No. 5,466,823 to Talley et al.
[0223] Valdecoxib useful in therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,633,272.
[0224] 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.
[0225] 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.
[0226] Japan Tobacco JTE-522 useful in therapeutic combinations of the present invention can be prepared in the manner set forth in Japanese Patent Publication No. JP
90/52882.
[0227] Pyrazoles can be prepared by methods described in International Patent
Publication No. WO 95/15316.
[0228] Pyrazoles can further be prepared by methods described in International Patent
Publication No. WO 95/15315.
[0229] Pyrazoles can also be prepared by methods described in International Patent
Publication No. WO 96/03385. [0230] Thiophene analogs can be prepared by methods described in International
Patent Publication No. WO 95/00501.
[0231] Preparation of thiophene analogs is also described in International Patent
Publication No. WO 94/15932.
[0232] Oxazoles can be prepared by the methods described in International Patent
Publication No. WO 95/00501.
[0233] Preparation of oxazoles is also described in International Patent Publication
No. WO 94/27980.
[0234] Isoxazoles can be prepared by the methods described in International Patent
Publication No. WO 96/25405.
[0235] Imidazoles can be prepared by the methods described in International Patent
Publication No. WO 96/03388.
[0236] Preparation of imidazoles is also described in International Patent Publication
No. WO 96/03387.
[0237] Cyclopentene Cox-2 inhibitors can be prepared by the methods described in
U.S. Patent No. 5,344,991.
[0238] Preparation of cyclopentane Cox-2 inhibitors is also described in International
Patent Publication No. WO 95/00501.
[0239] Terphenyl compounds can be prepared by the methods described in
International Patent Publication No. WO 96/16934.
[0240] Thiazole compounds can be prepared by the methods described in
International Patent Publication No. WO 96/03,392.
[0241] Pyridine compounds can be prepared by the methods described in
International Patent Publication No. WO 96/03392.
[0242] Preparation of pyridine compounds is also described in International Patent
Publication No. WO 96/24,585.
[0243] 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, prodrags of any of them, and mixtures thereof. [0244] More particularly, the Cox-2 selective inhibitor can be selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, prodrags of any of them, and mixtures thereof.
[0245] In one embodiment the Cox-2 selective inhibitor comprises celecoxib.
[0246] In another embodiment the Cox-2 selective inhibitor comprises valdecoxib.
[0247] In another embodiment the Cox-2 selective inhibitor comprises parecoxib sodium.
[0248] According to 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 one embodiment, the PDE inhibitor is a cGMP-specific PDE inhibitor.
[0249] cGMP-specific PDEs include PDE 5, PDE 6, and PDE 9. Any agent that inhibits one or more of these PDE isoenzymes can be used in the present invention.
Examples of 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, zaprinast, sildenafil, tadalafil, vardenafil, T-1032, A02131-1, GF248,
E-4021, sophoflavescenol, UK-122764, CP-131, CP-33, CP-165, CP-265, CP-132,
CP-461, CP-248, SCH 51866, imidazol[5,l-f]triazin-4(3H)-ones, 4-benzylamino-l- chloro-6-substituted phthalazines, fused pyrazolyl compounds, prenylated flavanol glycosides, pharmaceutically acceptable salts and prodrags thereof and combinations thereof.
[0250] In some embodiments, the cGMP-specific PDE inhibitor is selected from the group consisting of exisulind, sildenafil citrate, tadalafil, vardenafil and zaprinast. In an exemplary embodiment, the cGMP-specific PDE inhibitor is exisulind.
PC27879A (01506/1)
Table 6: cGMP-specific phosphodiesterase (PDE) inhibitors
PC27879A (01506/1) Table 6: cGMP-specific phosphodiesterase (PDE) inhibitors
PC27879A (01506/1) Table 6: cGMP-specific phosphodiesterase (PDE) inhibitors
[0251] Hsp90 inhibitors and PDE inhibitors useful according to the present invention can be supplied by any source as long as they are pharmaceutically acceptable. Likewise, 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 PDE inhibitors can also be isolated and purified from natural sources. Hsp90 inhibitors and PDE inhibitors should be of a quality and purity that is conventional in the trade for use in pharmaceutical products. [0252] In one embodiment of the present invention, a combination comprising a Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, is administered to a subject in need of such treatment according to standard routes of drug delivery that are well known to one of ordinary skill in the art.
[0253] Any one, two or all three of the Hsp90 inhibitor, the PDE inhibitor and the optional Cox-2 inhibitor can optionally be supplied in the form of a pharmaceutically active salt, a prodrag, an isomer, a racemic mixture, or in any other chemical form or combination that, under physiological conditions, still provides for inhibition of their respective enzyme targets.
[0254] Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyravic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.
[0255] Suitable pharmaceutically-acceptable base addition salts include metallic ion salts and organic ion salts. Metallic ion salts include, but are not limited to, appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts and other physiologically acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound.
[0256] 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. Pharmaceutical compositions can also include stabilizers, antioxidants, colorants and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective. In one embodiment, a Hsp90 inhibitor and a PDE inhibitor are administered to a subject together in one pharmaceutical carrier. In another embodiment, they are administered separately. Where a Cox-2 inhibitor is present in the combination, it can be administered together in a pharmaceutical carrier with either or both of the Hsp90 inhibitor and/or the PDE inhibitor, or separately from both. [0257] The pharmaceutical compositions may be administered enterally and/or parenterally. Oral (intra-gastric) 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. [0258] Parenteral administration includes 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 can be at or near body temperature. [0259] Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example, maize starch, or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. Tablets can be uncoated or they can be coated by known techniques, for example to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
[0260] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
[0261] Aqueous suspensions can be produced that 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 acacia; dispersing or wetting agents can be naturally-occurring 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 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
[0262] Aqueous suspensions can also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. [0263] Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. [0264] Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by addition of an antioxidant such as ascorbic acid. [0265] Dispersible powders and granules suitable for preparation of an aqueous suspension by 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 exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
[0266] 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 can also contain a demulcent, a preservative and flavoring and coloring agents.
[0267] 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 sterile injectable aqueous or oleaginous suspensions. Such suspensions can be formulated according to known art using suitable dispersing or wetting agents 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 acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, omega-3 polyunsaturated fatty acids can find use in preparation of injectables.
[0268] 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 drag with a suitable non-irritating excipient which is solid at ordinary temperature, but liquid at rectal temperature and will therefore, melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[0269] Also encompassed by the present invention is buccal and sub-lingual administration, including administration in the form of lozenges, pastilles or a chewable gum comprising the compounds set forth herein. The compounds can be deposited in a flavored base, usually sucrose, and acacia or tragacanth. [0270] Other methods for administration of the Hsp90 inhibitor and the PDE inhibitor, and optionally the Cox-2 inhibitor, include dermal patches that release the medicaments directly into and/or through a subject's skin.
[0271] Topical delivery systems are also encompassed by the present invention and include ointments, powders, sprays, creams, jellies, collyriums, solutions or suspensions.
[0272] Powders have the advantage of sticking to moist surfaces, and consequently, can remain active for longer periods. Therefore, powders are especially attractive for treating neoplasms in, for example, the otic canal. For much the same reason, creams are also effective pharmaceutically acceptable carriers.
[0273] Compositions of the present invention can optionally be supplemented with additional agents such as, for example, viscosity enhancers, preservatives, surfactants and penetration enhancers.
[0274] Viscosity-building agents include, for example, polyvinyl alcohol, polyvinyl pynolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition.
[0275] Preservatives are optionally employed to prevent microbial growth prior to or during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically, such preservatives are employed at a level of about 0.001% to about 1.0% by weight of a pharmaceutical composition.
[0276] Solubility of components of the present compositions can be enhanced by a surfactant or other appropriate cosolvent in the composition. Such cosolvents 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 cosolvents are employed at a level of about 0.01% to about 2% by weight of a pharmaceutical composition.
[0277] Pharmaceutically acceptable excipients and carriers encompass all the foregoing and the like. The above considerations concerning effective formulations and administration procedures are well known in the art and are described in standard textbooks. See, e.g., Remington: The Science and Practice of Pharmacy, 20th Edition, (Lippincott, Williams and Wilkins), 2000; Lieberman et al, ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al, ed., Handbook of Pharmaceutical Excipients (3rd Edition), American Pharmaceutical Association, Washington, 1999.
[0278] Where an Hsp90 inhibitor 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. [0279] Thus, the present invention encompasses a method of treating or preventing neoplasia or a neoplasia-related disorder 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, i.e., the total of said first and second amounts, is therapeutically effective for such treatment or prevention
[0280] The present invention also encompasses a method of preventing and treating neoplasia or a neoplasia-related disorder in a subject in need of such prevention and treatment, the method comprising administering a first amount of a 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. [0281] In determining an effective amount or dose, a number of 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 illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages can also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics. Ninth Edition (1996), Appendix π, pp. 1707-1711.
[0282] It will be appreciated that the amount of the combination comprising an Hsp90 inhibitor and a PDE inhibitor and optionally a Cox-2 inhibitor required for use in the treatment or prevention of neoplasia and neoplasia-related disorders will vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, an appropriate daily dosage is described herein, although the limits that are identified as being preferred can be exceeded if expedient. The daily dosage can be administered as a single dosage or in divided dosages. [0283] 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 from about 0.0001 mg/kg to about 200 mg/kg subject body weight per day, administered in single or multiple doses. More typically, the dosage level is about 0.1 mg/kg to about 25 mg/kg per day.
[0284] The dosage level of a PDE inhibitor will likewise depend on the particular agent that is used. However, an appropriate dosage level of a PDE inhibitor is generally about 0.01 mg/kg to about 10 mg/kg per day. In larger mammals, for example humans, a typical indicated dose for the PDE inhibitor is about 1 mg to about 500 mg per day. [0285] 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 that is generally from about 0.01 mg/kg to about 140 mg/kg subject body weight per day, administered in single or multiple doses. More typically, the dosage level is about 0.01 mg/kg to about 50 mg/kg per day, for example about 0.1 mg/kg to about 25 mg/kg per day, about 0.1 mg/kg to about 10 mg/kg per day, or about 0.5 mg/kg to about 10 mg/kg per day. [0286] In larger mammals, for example humans, a typical indicated dose for the Cox-2 inhibitor is about 0.5 mg to about 7 g orally per day. A compound can be administered on a regimen of several times per day, for example 1 to about 4 times per day, preferably once or twice per day.
[0287] The amount of the Cox-2 inhibitor that can be combined with carrier materials to produce a single dosage form varies depending upon the subject to be treated and the particular mode of administration. For example, a formulation intended for oral administration to humans can contain about 0.5 mg to about 7 g of active agent compounded optionally with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95 percent of the total composition. Dosage unit forms for the Cox-2 inhibitor generally contain 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. [0288] The exact dosage and regimen for administering a Hsp90 inhibitor in combination with a PDE inhibitor, and optionally with a Cox-2 inhibitor, will necessarily depend upon the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances. Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711.
[0289] The effectiveness of a particular dosage of an Hsp90 inhibitor in combination with a PDE inhibitor and optionally 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.
[0290] In one embodiment, the effectiveness of a particular dosage of a combination therapy comprising an Hsp90 inhibitor and a PDE inhibitor, and optionally a Cox-2 inhibitor, can be determined by staging the disorder at multiple points during a subject's treatment. For example, once a histologic diagnosis is made, staging (i.e., determination of the extent of disease) helps determine treatment decisions and prognosis. Clinical staging uses data from the patient's history, physical examination, and noninvasive studies. Pathologic staging requires tissue specimens.
[0291] Pathological staging is performed by obtaining a biopsy of the neoplasm or tumor. A biopsy is performed by obtaining a tissue specimen of the tumor and examining the cells microscopically. A bone marrow biopsy is especially useful in determining metastases from 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 to 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.
[0292] Determination of serum chemistries and enzyme levels can also help staging. Elevation of liver enzymes (alkaline phosphatase, LDH and ALT) suggests presence of liver metastases. Elevated alkaline phosphatase and serum Ca may be the first evidence of bone metastases. Elevated acid phosphatase (tartrate inhibited) suggests extracapsular extension of prostate cancer. Fasting hypoglycemia may indicate an insulinoma, hepatocellular carcinoma, or retroperitoneal sarcoma. Elevated BUN or creatinine levels may indicate an obstructive uropathy secondary to a pelvic mass, intrarenal obstruction from tubular precipitation of myeloma protein, or uric acid nephropathy from lymphoma or other cancers. Elevated uric acid levels often occur in myeloproliferative and lymphoproliferative disorders. α-Fetoprotein may be elevated in hepatocellular carcinoma and testicular carcinomas, carcinoembryonic antigen-S in colon cancer, human chorionic gonadotropin in choriocarcinoma and testicular carcinoma, serum immunoglobulins in multiple myeloma, and DNA probes (bcr probe to identify the chromosome 22 change) in CML.
[0293] Tumors may synthesize proteins that produce no clinical symptoms, e.g., human chorionic gonadotropin, α-fetoprotein, carcinoembryonic antigen, CA 125, and CA 153. These protein products can be used as tumor markers in serial evaluation of patients for determining disease recunence or response to therapy. Thus, monitoring a subject for these tumor markers is indicative of progress of a neoplasia disorder. Such monitoring is also indicative of how well the methods, combinations and compositions of the present invention are treating or preventing a neoplasia disorder. Likewise, tumor marker monitoring is effective to determine appropriate dosages of a combination or composition of the present invention for treating neoplasia.
[0294] Other techniques include mediastinoscopy, which is especially valuable in the staging of non-small cell lung cancer. If mediastinoscopy shows mediastinal lymph node involvement, then the subject would not usually benefit from a thoracotomy and lung resection. Imaging studies, especially CT and MRI, can detect metastases to brain, lung, spinal cord, or abdominal viscera, including the adrenal glands, retroperitoneal lymph nodes, liver, and spleen. MRI (with gadolinium) is the procedure of choice for recognition and evaluation of brain tumors.
[0295] Ultrasonography can be used to study orbital, thyroid, cardiac, pericardial, hepatic, pancreatic, renal, and retroperitoneal areas. It may guide percutaneous biopsies and differentiate renal cell carcinoma from a benign renal cyst. Lymphangiography reveals enlarged pelvic and low lumbar lymph nodes and is useful in the clinical staging of patients with Hodgkin's disease, but it has generally been replaced by CT. [0296] Liver-spleen scans can identify liver metastases and splenomegaly. Bone scans are sensitive in identifying metastases before they are evident on x-ray. Because a positive scan requires new bony formation (i.e., osteoblastic activity), this technique is useless in neoplasms that are purely lytic (e.g., multiple myeloma); routine bone x-rays are the study of choice in such diseases. Gallium scans can help in staging lymphoid neoplasms. Radiolabeled monoclonal antibodies (e.g., to carcinoembryonic antigen, small cell lung cancer cells) provide important staging data in various neoplasms (e.g., colon cancer, small cell lung cancer). See The Merck Manual of Diagnosis & Therapy, 17th edition (1999), Sec. 11, Chapter 84, Hematology and Oncology, Overview of Cancer.
[0297] As used herein, the term "subject" for purposes of treatment is one that is in need of the treatment of neoplasia or a neoplasia-related disorder. For purposes of prevention, the subject is one that is at risk for, or is predisposed to, developing neoplasia or a neoplasia-related disorder, including relapse of a previously occurring neoplasia or neoplasia-related disorder.
[0298] As used herein, the phrase "subject in need of includes any subject that is suffering from or is predisposed to neoplasia or any neoplasia-related disorder described herein. The phrase "subject in need of also includes any subject that requires a lower dose of conventional neoplasia treatment agents. In addition, a "subject in need of includes any subject that requires a reduction in the side-effects of a conventional treatment agent. Furthermore, a "subject in need of includes any subject that requires improved tolerability to any conventional treatment agent for a neoplasia disorder therapy.
[0299] The subject is an animal, typically a mammal, including humans, domestic and farm animals, zoo, sports and pet animals, such as dogs, horses, cats, cattle, etc. The subject is most typically a human subject.
[0300] The methods, combinations and compositions of the present invention can be used for treatment or prevention of several neoplasia disorders and neoplasia-related disorders including, but are not limited to, acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, AJJDS-related lymphoma, anal cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem 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, chorioid plexus papilloma and carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal cancer, epithelioid carcinoma, esophageal cancer, Ewing's sarcoma, extragonadal germ cell tumor, fibrolamellar carcinoma, focal nodular hyperplasia, gallbladder cancer, gastrinoma, germ cell tumors, gestational trophoblastic tumor, glioblastoma, glioma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, insulinoma, interepithelial squamous cell neoplasia, intraepithelial neoplasia, intraocular melanoma, invasive squamous cell carcinoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, large cell carcinoma, laryngeal cancer, leiomyosarcoma, lentigo maligna melanoma, leukemia-related disorders, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, malignant mesothelial tumors, malignant thymoma, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, merkel cell carcinoma, mesothelial carcinoma, metastatic carcinoma, mucoepidermoid carcinoma, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, non-Hodgkin's lymphoma, oat cell carcinoma, oligodendro glial 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 blastoma, prostate cancer, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, small intestine cancer, soft tissue carcinomas, somatostatin-secreting tumor, squamous cell carcinoma, submesothelial carcinoma, superficial spreading melanoma, thyroid cancer, undifferentiated carcinoma, urethral cancer, uterine sarcoma, uveal melanoma, vaginal cancer, verracous carcinoma, vipoma, vulvar cancer, Waldenstrom's macroglobulinemia, well differentiated carcinoma, and Wilm's tumor. EXAMPLES [0301] In the following examples, all percentages are given on a weight basis unless otherwise indicated.
Example 1
[0302] This example shows the preparation of celecoxib.
Step 1: Preparation of l-(4-methylphenyl)-4,4,4-trifluorobutane-l,3-dione. [0303] Following the disclosure provided in U.S. Patent No. 5,760,068, 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.
Step 2: Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzenesulfonamide.
[0304] To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absolute ethanol, 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine hydrochloride was added. The reaction was refluxed under argon for 24 hours. After cooling to room temperature and filtering, the reaction mixture was concentrated to afford 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 Q7H14N3O2SF3; Q 53.54; H, 3.70; N, 11.02. The composition that was found by analysis was: Q 53.17; H, 3.81; N, 10.90.
Example 2
[0305] This example demonstrates the production of 4-[2-(4-fluorophenyl)phenyl] benzenesulfonamide.
Step 1: Preparation of l-bromo-2-(4-fluorophenyl)benzene
[0306] Following the general procedure outlined in U.S. 5,739,166, under nitrogen, 1.2 g (1.0 mmol) of Pd(PPh3)4 was added 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 2M Na2CO3. 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 silica gel chromatography (Waters Prep-500A) with hexane gave 4.35 g (81%) of l-bromo-2-(4-fmorophenyl)benzene as a colorless oil: NMR (CDC13) .delta. 7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67 (d, J=8 Hz, 1H).
Step 2: Preparation of 2-(4-fluorophenyl)phenylboronic acid.
[0307] Following the general procedure outlined in Synthetic Scheme VIII in U.S. Patent No. 5,739,166, 4.35 g (17.3 mmol) of l-bromo-2-(4-fluorophenyl)benzene from Step 1 was converted to 2-(4-fluorophenyl)phenylboronic acid by (1) halogen-metal interchange in THP at -78°C to generate a conesponding organolithium reagent, (2) reaction of the organolithium species with trimethyl borate to give the conesponding methyl ester, and (3) hydrolysis with aqueous sodium hydroxide to provide 2-(4- fluorophenyl)phenylboronic acid: NMR (CDC13) .delta. 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, 1H).
Step 3: Preparation of 4- [2-(4-fluorophenyl)phenyl]benzenesulf onamide. [0308] Following the general procedure outlined in Synthetic Scheme IX in U.S. Patent No. 5,739,166, 5 g (6.9 mmol) of 2-(4-fluorophenyl)phenylboronic acid from Step 2 was reacted with 2.5 g (10.4 mmol) of 4-bromobenzenesulfonamide (Lancaster) in toluene/ethanol at reflux in the presence of Pd° catalyst, e.g., tetrakis (terphenylphosphine)palladium(O), and 2M sodium carbonate. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (3:7) and 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 (CDCl.sub.3)Δ4.83 (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). MS (El): m/e (rel intensity) 327 (75) 245 (100); HRMS calculated for Q8H14 FNO2S: 327.0729. Found: 327.0743. Analysis calculated for Q8Hi4 FNO2S: Q 66.04; H, 4.31; N, 4.28. Found: Q 65.86; H, 4.51; N, 4.34. Example 3
[0309] This example illustrates the preparation of 4-[5-(2,5-dichlorophenyl)-3-
(trifluoromethyl)- IH-pyrazol- l-yl]benzenesulf onamide, following the disclosure provided in U.S. Patent No. 5,516,907.
[0310] 2,5-Dichloroacetophenone (6.24 g, 33 mmol) is dissolved in 25 mL 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 mL, 42 mmol) is added. The mixture is heated at 60°C for 24 hours, cooled and the volume reduced by 50%. The mixture is poured into
100 mL of 10% HCI and extracted with four 75 mL portions of ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to afford the crade diketone as a brown gum (8.54 g, 30 mmol) which is used without further purification.
[0311] The crade 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 stined at reflux for 24 hours. The mixture is cooled, filtered and concentrated in vacuo to afford the crude pyrazole. Recrystallization from diethyl ether/hexane affords the pure pyrazole.
Example 5
[0312] This example illustrates the preparation of 5-fluoro-2-methyl-l-(para- methylsulfinylbenzylidene)-indenyl-3-acetic acid (sulindac sulfone, also known as exisulind), following the disclosure provided in U.S. Patent No. 3,998,875. [0313] A solution of 0.01 mole of 5-fluoro-2-methyl-indanone-3-acetic acid in 6 ml of isopropanol is made basic by addition of 2.5M sodium hydroxide (to about pH 9 to 10). To this solution is added 0.015 moles of sodium borohydride. The solution is stined at ambient temperature for 80 minutes and at 60°C for 45 minutes. The solution is made acidic by addition of 6M hydrochloric acid (to about pH 1 to 2), and heated to reflux for 30 minutes. The solution is allowed to cool and basified with sodium hydroxide to a pH of about 13.0. To the solution is added 0.01 mole of paramethylsulfinylbenzaldehyde and 2.0 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 yield 5-fluoro-2-methyl-l- (para-methylsulfinylbenzylidene)-indenyl-3 -acetic acid. Example 5
[0314] This example illustrates production of a combination comprising celecoxib, exisulind and 4- [2-(4-fluorophenyl)phenyl]benzenesulf onamide, and of a pharmaceutical composition containing the combination.
[0315] Celecoxib can be prepared as described in Example 1 or, alternatively, can be obtained under the trade name Celebrex® from Pharmacia Corporation, Peapack, NJ.
[0316] Exisulind can be prepared as described in Example 4, or, alternatively, can be obtained under the trade name Aptosyn® from Cell Pathways, Inc., Horsham, PA.
[0317] 4-[2-(4-Fluorophenol)phenyl]benzenesulfonamide can be prepared as described in Example 2.
[0318] A therapeutic composition of the present invention can be formed by intermixing 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. \
[0319] After mixing, the combination of celecoxib, exisulind and 4-[2-(4- fluorophenyl)phenyl]benzenesulfonamide forms a therapeutic composition that is sufficient for the production of about 1000 human single dose units. Each single dose unit contains about 200 mg of celecoxib and about 200 mg of 4-[2-(4- fluorophenyl)phenyl]benzenesulfonamide.
[0320] If desired, a solid carrier and other materials can be intermixed 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 about the same amount of the active ingredients as each of the single dose units of the liquid preparation described above.
[0321] All references cited in this specification are incorporated by reference into this specification in their entireties. Discussion of any references herein is intended merely to summarize assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.
[0322] In view of the above, it will be seen that several advantages of the invention are achieved and other advantageous results obtained. [0323] As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS:
1. A combination comprising an Hsp90 inhibitor and a PDE inhibitor in amounts effective when used in combination therapy for treatment or prevention of neoplasia or a neoplasia-related disorder.
2. The combination of Claim 1, wherein the Hsp90 inhibitor comprises (A) a compound having the formula (I):
wherein: Qa is C or N; Xa is C or N; Za is Q 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 Q\ Xa, Za, Ma and Ga is C; R207, unless joined 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, haloarylalkanonesulfanyl, arylalkylidenenitroaryl, alkoxyaryl, alkylthioaryl, alkylsulfonylaryl, haloalkoxy, alkoxypolyalkyl, carboxamidyl, carboxyalkyl, aminosulfonylaryl, alkoxycarbonyl, hydroxyaryl and halohydroxyaryl ; R208, unless joined 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, alkylnitrilearyl, alkylsulfonylalkyl, alkoxycarboximidyl, alkoxyhydroxyaryl and alkylthioaryl; 907 90S R and R optionally join 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 joined with R208 or R210 in a ring system, is selected from the group consisting of H, alkyl, aryl, substituted or unsubstituted heteroaryl, alkylaryl, haloalkyl, haloaryl, alkoxyaryl, alkoxycarbonylaryl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfonylaryl, alkoxyalkylaryl, alkylaminoaryl, alkylalkanethiol, alkoxyhaloaryl and aminosulfonylaryl; R208 and R209 optionally join 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 joined with R209 or R211 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, alkylaryl, alkylthio, alkoxyaryl, alkylaminoaryl, alkylthioaryl, haloalkyl, haloaryl, carboxyaryl, aminocarbonyl, substituted or unsubstituted heteroaryl, carboxyalkyl, alkoxyarylaminoalkene- nitrile, nitroarylalkeneamide, acetamidoaryl, acetamidoarylcyanoalkenyl- nitrile, carboxylalkoxy, alkylsulfonylaryl, haloalkylalkoxy, haloaryloxy, alkoxyhaloaryl, alkoxycarbonyl, alkylsulfonylhaloaryl, aminosulfonylaryl, thioaryl, aminocycloalkyl, alkoxycarbonylaryl, alkoxycarbonylaminocyclo- alkane and alkylcarboxyl; R209 and R210 optionally join to form a ring system selected from the group consisting of: /0418
and aryl;
R ,211 , unless joined with R ,210 or R ,207 in a ring system, is selected from the group consisting of H, alkyl, aryl, oxo, hydroxyl, haloaryl, haloalkylaryl, substituted or unsubstituted heteroaryl, carboxyaryl, nitroaryl, aminosulfonylaryl, alkylsulfonylaryl, alkylsulfonylhaloaryl alkylaminosulfonylaryl, alkylsulfonyl- aminoaryl, alkylaminocarbonyl, aminocarbonylaryl, halohydroxyaryl- alkylideneacetohydrazide, hydroxyalkoxyarylalkylideneacetohydrazide, alkyl- carbonylaryl, alkoxyaryl, haloalkoxyaryl, alkoxyalkoxoaryl, alkoxycarbonylaryl, haloalkylcarbonylaryl, alcohol and haloaryloxyacetohydrazide;
R210 and R211 optionally join to form a ring system selected from the group consisting of:
oxoaryl and cycloalkyl; 9Ω7 91 1
R 7 aanndd RR211 ooρpttiionally join to form a ring system selected from the group consisting of:
R ,212 is selected from the group consisting of H, halo and alkoxy; R213 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 is selected from the group consisting of H, and alkoxy; (B) a compound having the 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 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 joined in a ring system with R220, is selected from the group consisting of H, oxo, amino and alkoxo; R220, unless joined in a ring system with R219, is selected from the group consisting of H, oxo, carboxyl, alkoxo, hydroxyalkyl, alkylnitrile, alkoxoaryl, haloalkoxo, and haloarylalkoxo; 910 990
R and R optionally join to form a ring system consisting of a substituted or unsubstituted aryl ring; R221 and R223 are independently selected from the group consisting of H and alkoxy; and 999
R is selected from the group consisting of H, halo, alkylsulfonyl, aminosulfonyl and alkylamino; (C) a compound selected from the group consisting of:
I
(-)-enantiomer
and or a pharmaceutically acceptable salt or prodrag of any such compound.
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)-l,3-thiazol-2-yl]acetamide; N-[5-(l-phenylethyl)-l,3-thiazol-2-yl]- 4-(lH-pyrrol-l-yl)benzamide; N-(5-chloro-2,4-dimethoxyphenyl)-N'-(5-phenyl- l,3-thiazol-2-yl)urea; N'-[(4-bromophenoxy)acetyl]-2-(5-phenyl-2H-tetraazol-2- yl)acetohydrazide; (2E)-2-cyano-3-[3-(2-furyl)-l-phenyl-lH-pyrazol-4-yl]-N-[3- (lH-imidazol-l-yl)propyl]prop-2-enamide; (2E)-2-cyano-3-[3-(4-ethoxyphenyl)- l-phenyl-lH-pyrazol-4-yl]-N-[3-(lH-irm^azol-l-yl)propyl]prop-2-enamide; 3-bromo-2-(4-chlorophenyl)pyrazolo[l,5-a]pyrimidine-5,7(4H,6H)-dione; 3-[4- (4-chlorophenyl)- 1 ,3-thiazol-5-yl] -4H-chromen-4-one; N- [4-(3 ,4-dichlorophenyl)- 1 ,3-thiazol-2-yl]pyrimidin-2-amine hydrobromide; (2E)-2-[4-(4-hydroxy-3- methoxyphenyl)-l,3-thiazol-2-yl]-3-[(3-methoxyphenyl)amino]prop-2-enenitrile; O 2005/041879
N'-[(lE)-(5-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-ρhenyl-l,3- thiazol-2-yl)acetamide; (2E)-3-(4-nitrophenyl)-N-(4-pyridin-4-yl-l,3-thiazol-2- yl)prop-2-enamide; N'-[(lE)-(2-hydroxy-4-methoxyphenyl)methylidene]-2-(5- ρhenyl-2H-tetraazol-2-yl)acetohydrazide; N-[4-(4-bromophenyl)-l,3-thiazol-2- yljnicotinamide; N-(l,3-benzothiazol-2-yl)-7-oxo-l-phenyl-l,7-dihydropyrazolo [l,5a]pyrimidine-6-carboxamide; N-{(E)-[4-(l-methyl-lH-imidazol-2-yl)-3- nitrophenyljmethylidene} aniline; N-[4-({(E)-2-[4-(l,3-benzodioxol-5-yl)-l,3- thiazol-2-yl]-2-cyanoethenyl}amino)phenyl]acetamide; ethyl((3Z)-2-oxo-3-{[(3- phenyl-lH-pyrazol-5-yl)carbonyl]hydrazono}-2,3-dihydro-lH-indol-l-yl)acetate; 5-[4-(4-chlorophenyl)-l,
3-thiazol-l-yl)pyridine; and mixtures thereof.
4. The combination of Claim 1 wherein the Hsp90 inhibitor is 4-[2-(4-fluorophenyl) phenyljbenzenesulfonamide.
5. The combination of Claim 1 wherein the Hsp90 inhibitor provides an IQo for Hsp90 of less than about 100 μM.
6. The combination of Claim 1 wherein the Hsp90 inhibitor provides an IQo for Hsp90 of less than about 2.5 μM.
7. The combination of Claim 1 wherein the Hsp90 inhibitor is a dual Hsp90/Cox-2 inhibitor.
8. The combination of Claim 1 wherein the PDE inhibitor is a cGMP-specific PDE inhibitor.
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, sophoflavescenol, UK-122764, CP-131, CP-33, CP-165, CP-265, CP-132, CP-461, CP-248, SCH 51866, imidazol[5,l-f]triazin-4(3H)-ones, 4-benzylamino- l-chloro-6-substituted phthalazines, fused pyrazolyl compounds, prenylated flavanol glycosides, and pharmaceutically acceptable salts and prodrags 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 Cox-2 selective inhibitor.
13. The combination of Claim 12 wherein the Cox-2 selective inhibitor provides a Cox-1 IQo/Cox-2 IQo ratio of at least about 10.
14. The combination of Claim 12 wherein the Cox-2 selective inhibitor provides a Cox-1 IQo/Cox-2 IQo ratio of at least about 100.
15. The combination of Claim 12 wherein the Cox-2 selective inhibitor is a tricyclic compound, a substituted benzopyran derivative or a phenylacetic acid derivative.
16. The combination of Claim 12 wherein the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib and pharmaceutically acceptable salts thereof.
17. The combination of Claim 12 wherein the Cox-2 selective inhibitor is parecoxib sodium.
18. A method of treating or preventing neoplasia or a neoplasia-related disorder in a subject, the method comprising administering the combination of Claim 1 to the subject.
19. The method of Claim 18 wherein the Hsp90 inhibitor and the PDE inhibitor are administered sequentially.
20. The method of Claim 18 wherein the Hsp90 inhibitor and the PDE inhibitor are administered substantially simultaneously.
21. The method of Claim 18 wherein the neoplasia is selected from the group consisting of acral lentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, AJ-DS-related lymphoma, anal cancer, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem 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, chorioid plexus papilloma and carcinoma, clear cell carcinoma, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal cancer, epithelioid carcinoma, esophageal cancer, Ewing's sarcoma, extragonadal germ cell tumor, fibrolamellar carcinoma, focal nodular hyperplasia, gallbladder cancer, gastrinoma, germ cell tumors, gestational trophoblastic tumor, glioblastoma, glioma, glucagonoma, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, insulinoma, interepithelial squamous cell neoplasia, intraepithelial neoplasia, intraocular melanoma, invasive squamous cell carcinoma, islet cell carcinoma, Kaposi's sarcoma, kidney cancer, large cell carcinoma, laryngeal cancer, leiomyosarcoma, lentigo maligna melanoma, leukemia-related disorders, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, malignant mesothelial tumors, malignant thymoma, medulloblastoma, medulloepithelioma, melanoma, meningeal carcinoma, merkel cell carcinoma, mesothelial carcinoma, metastatic carcinoma, mucoepidermoid carcinoma, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroepithelial adenocarcinoma, nodular melanoma, non-Hodgkin's lymphoma, oat 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 blastoma, prostate cancer, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, small intestine cancer, soft tissue carcinomas, somatostatin-secreting tumor, squamous cell carcinoma, submesothelial carcinoma, superficial spreading melanoma, thyroid cancer, undifferentiated carcinoma, urethral cancer, uterine sarcoma, uveal melanoma, vaginal cancer, verrucous carcinoma, vipoma, vulvar cancer, Waldenstrom's macroglobulinemia, well different *** 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 that comprises an Hsp90 inhibitor in a first amount and a second dosage form that comprises a PDE inhibitor in a second amount; wherein said first and second amounts are effective when used in combination therapy for treating or preventing neoplasia or a neoplasia-related disorder.
25. A kit comprising a first dosage form that comprises an Hsp90 inhibitor in a first amount, a second dosage form that comprises a PDE inhibitor in a second amount, and a third dosage form that comprises a Cox-2 inhibitor in a third amount; wherein said first, second and third amounts are effective when used in combination therapy for treating or preventing neoplasia or a neoplasia-related disorder.
EP04817484A 2003-10-28 2004-10-28 Combinations comprising an hsp90 inhibitor and a phophodiesterase inhibitor for treating or preventing neoplasia Withdrawn EP1682143A2 (en)

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