EP1682143A2 - Association de l'inhibiteur de hsp90 et de l'inhibiteur de la phophodiesterase destinee a traiter ou prevenir la neoplasie - Google Patents

Association de l'inhibiteur de hsp90 et de l'inhibiteur de la phophodiesterase destinee a traiter ou prevenir la neoplasie

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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)
English (en)
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/fr
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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

L'invention concerne une méthode de traitement ou de prévention de la néoplasie ou d'un trouble associé à la néoplasie chez un sujet. La méthode consiste à administrer au sujet une quantité efficace d'une combinaison associant un inhibiteur de Hsp90 et un inhibiteur de la phophodiestérase, et éventuellement un inhibiteur de Cox-2.
EP04817484A 2003-10-28 2004-10-28 Association de l'inhibiteur de hsp90 et de l'inhibiteur de la phophodiesterase destinee a traiter ou prevenir la neoplasie Withdrawn EP1682143A2 (fr)

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WO2005041879A3 (fr) 2005-10-06
CA2543503A1 (fr) 2005-05-12

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