WO2006091862A2 - Inhibiteurs des cytokines et utilisation therapeutique - Google Patents

Inhibiteurs des cytokines et utilisation therapeutique Download PDF

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WO2006091862A2
WO2006091862A2 PCT/US2006/006682 US2006006682W WO2006091862A2 WO 2006091862 A2 WO2006091862 A2 WO 2006091862A2 US 2006006682 W US2006006682 W US 2006006682W WO 2006091862 A2 WO2006091862 A2 WO 2006091862A2
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substituted
unsubstituted
alkyl
independently
phenyl
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PCT/US2006/006682
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WO2006091862A3 (fr
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Erik Boman
Susanna Conde Ceide
Russell Dahl
Justin Ernst
Jeffrey Kahl
Antonio Garrido Montalban
Zhinjun Wang
Christopher Larson
Eddine Saiah
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Kemia, Inc.
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Publication of WO2006091862A2 publication Critical patent/WO2006091862A2/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to low molecular weight compounds and compositions thereof, useful as cytokine inhibitors, and their preparation.
  • the invention further relates to methods of prevention and treatment of cytokine-mediated disorders, in particular inflammatory disorders, pain and cancer.
  • the invention also relates to pharmaceutical compositions and dosing regimens.
  • the invention relates to the use of cytokine inhibitors, optionally in conjunction with other therapies, for treatment of cancer, more particularly glioma, glioblastoma, osteosarcoma and bone metastases.
  • the present invention relates to methods of treating, modifying and managing pain, more particularly neuropathic pain, which comprise the administration of a cytokine inhibitor alone or in combination with known therapeutics.
  • Tumor necrosis factor- ⁇ TNF- a or TNFa
  • IL- 1 interleukin- 1
  • RA rheumatoid arthritis
  • IL-cds IL-I and TNF-cds believed to underlie the progression of many inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure, and psoriasis among others (Dinarello, CA. et al., Rev. Infect.
  • TNF- ⁇ also referred to as TNFa
  • IL-Ib interleukin- I ⁇
  • IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias [Treon, et al, Current Opinion in Hematology, 5, 42 (1998)]. Cytokines including IL- 1 , TNFa and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts [Bruserud, Leukemia Res. 20, 65 (1996)]. Clinical studies have linked TNFa production and/or signaling to a number of diseases including advanced cancer [MucWierzgon et al. J. Biol.
  • lymphoid malignancies [Levy et al. Crit. Rev. Immunol., 16, 31 (1996)] impaired wound healing in infection, inflammation, and cancer [Buck et al. Am. J. Pathol. 149, 195 (1996)], and myelodysplastic syndromes [Raza et al. Int. J. Hematol. 63, 265 (1996)].
  • cytokine inhibitors show potential in the treatment of malignancies .
  • Cytokines are also known to play a role in the production of pain, such as nociceptive pain, neuropathic pain, visceral pain, headaches, post-operative pain and the like.
  • nociceptive pain is elicited when noxious stimuli such as inflammatory chemical mediators are released following tissue injury, disease, or inflammation and are detected by normally functioning sensory receptors (nociceptors) at the site of injury [Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000)].
  • Nociceptors are distributed throughout the periphery of tissue and are sensitized by inflammatory mediators such as prostaglandin, substance P, bradykinin, histamine, and serotonin, as well as by intense, repeated, or prolonged noxious stimulation.
  • inflammatory mediators such as prostaglandin, substance P, bradykinin, histamine, and serotonin
  • cytokines and growth factors e.g., nerve growth factor
  • Sensitization of peripheral nociceptors plays an important role in clinical pain states such as hyperalgesia and allodynia.
  • Medications presently used during the treatment of pain in general include calcium channel blockers, muscle relaxants, nonnarcotic analgesics, opioid analgesics, and systemic corticosteroids.
  • patients rarely obtain complete pain relief.
  • cytokine- mediated diseases including inflammation, cancer and pain. While some cytokine protein therapeutics have been developed, they suffer from bioavailability and stability problems. In particular, there is a need for low molecular weight compounds that inhibit TNFa and/or IL-Ib production.
  • the present invention provides low molecular weight compounds and pharmaceutical compositions thereof.
  • compounds of the invention are useful as cytokine release inhibitory agents.
  • compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • the invention provides methods of preventing or treating disorders mediated by cytokines which comprise administering to a subject in need of such treatment a therapeutically effective amount of a compound as described herein.
  • cytokine-mediated disorders include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejections, pancreatitis, insulinitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome, gouty arthritis, Behcet's disease, spondylitis, endometriosis, and non-
  • Exemplary cytokine-mediated disorders also include acute or chronic pain, such as but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, algodystrophy, spondylarthritis, fibromyalgia, phantom limb pain, back pain, vertebral pain, post-surgery pain, herniated intervertebral disc-induced sciatica, cancer-related pain, vascular pain, visceral pain, childbirth-related pain, or HIV-related pain.
  • acute or chronic pain such as but not limited to neurological pain, neuropathies, polyneuropathies, diabetes-related polyneuropathies, trauma, migraine, tension and cluster headache, Horton's disease, varicose ulcers, neuralgias, musculoskeletal pain, osteo-traumatic pain, fractures, al
  • cytokine-mediated disorders are stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemia reperfusion, myocardial ischemia, restenosis, thrombosis, angiogenesis, Coronary Heart Disease, Coronary Artery Disease, acute coronary syndrome, Takayasu arteritis, cardiac failure such as heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvular disease or coronary artery bypass; hypercholesteremia, diseases or conditions related to blood coagulation or fibrinolysis, such as for example, acute venous thrombosis, pulmonary embolism, thrombosis during pregancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), clot formation from surgery, long bed rest or long periods of immobilization, venous thrombosis, fulminant meningococcemia, acute thrombotic strokes, acute coronary o
  • Cytokine-mediated disorders further include allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection and respiratory tract inflammation. Also included are psoriasis, eczema, atopic dermatitis, contact dermatitis, or acne.
  • cytokine-mediated disorders are Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral meningitis, bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olivopontocerebellar atrophy, AIDS dementia complex, MERRF syndrome, MELAS syndrome, Leber's disease, Wernicke's encephalopathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety, schizophrenia, aneurism, or epilepsy.
  • the cytokine-mediated disorders include bone resorption diseases, such as osteopetrosis, osteoporosis, or osteoarthritis. Also included are diabetes, systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia nervosa, or bulimia nervosa.
  • bone resorption diseases such as osteopetrosis, osteoporosis, or osteoarthritis.
  • diabetes systemic cachexia, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), obesity, anorexia nervosa, or bulimia nervosa.
  • the cytokine-mediated disease can be sepsis, HIV infection, hepatitis C virus (HCV) infection , malaria, infectious arthritis, leishmaniasis, Lyme disease, cancer, including but not limited to breast cancer, colon cancer, lung cancer, prostatic cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, or follicular lymphoma, Castleman's disease, or drug resistance.
  • HCV hepatitis C virus
  • the cytokine mediated disorder is a neutrophil-mediated disorder, such as, for example, bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis, hemodialysis, leukopheresis, granulocyte transfusion associated syndromes, or necrotizing enterocolitis.
  • ARDS adult respiratory distress syndrome
  • Combination therapy with cytokine inhibitors provides a beneficial therapeutic effect, particularly an additive or over-additive effect or an overall reduction of side effects of therapy.
  • a beneficial therapeutic effect is desirable in the treatment of cytokine-mediated disorders as described herein, and in particular in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis.
  • another aspect the of the invention provides methods of treating a cytokine-mediated disorder including administering one or more, typically one, of the ingredients (hereafter referred to as ingredient A) described herein together with one or more, typically one, cytokine inhibitor of the invention.
  • ingredient A typically one
  • a combination of any two or more ingredients A are administered with a cytokine inhibitor of the invention.
  • An additive or over-additive effect of the pharmaceutical combinations according to the invention provides for dose reduction, side-effect reduction and/or interval extension when compared to monotherapy with the individual compounds A or with the cytokine inhibitors.
  • the effects mentioned above are observed both when the two substances are administered simultaneously in a single formulation and when they are administered successively in separate formulations.
  • ingredient A being an injectable, especially a biological agent, other benefits of adding the cytokine inhibitor may be seen. For example, cost reduction by way of interval and/or dose reduction.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDS include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen,
  • Angiogenesis inhibitors may serve as ingredient A, such as VEGF inhibitors, taxol, pentoxyfylline and/or thalidomide.
  • Biological agents shall be understood to mean any natural or artificial/synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates, and the like. Therefore, ingredient A includes biological agents, such as etanercept, infliximab, alefacept, adalimumab, efalizumab, anakinra, IL-IRA, alpha-interferon, interferon beta 1-B, CTLA-4, and other antibodies or receptor constructs directed against TNFa, IL1-6, LFA-I, or C5.
  • biological agents such as etanercept, infliximab, alefacept, adalimumab, efalizumab, anakinra, IL-IRA, alpha-interferon, interferon beta 1-B, CTLA-4, and other antibodies or receptor constructs directed against TNFa, IL1-6, LFA-I, or C5.
  • ingredient A also within the scope of the invention for ingredient A are steroids, such as glucocorticoids, and vitamin D3 and analogs thereof (cholecalciferols), alone (the latter being used mostly for psoriasis) or in combination.
  • Steroids include budesonide, dexamethasone, fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide, mometasone and diflucortolone.
  • vitamin D3 derivatives are calcipotriol, tacalcitol, maxacalcitol, and tacalitol, the calciotropic hormones, lce,25-dihydroxyvitamin D3, and parathyroid hormone-related peptide.
  • cytokine inhibitors of the invention Many types of immunomodulatory, immunosuppressive or cytostatic drugs can be used in combination with the cytokine inhibitors of the invention.
  • exemplary agents include hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine, cyclophosphamide, macrolides, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E., 1999, Cutis 64(5):347-53); alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T,
  • agents or therapies which act on other targets or immune mediated products are suitable as the ingredient A.
  • agents or therapies which act on other targets or immune mediated products are suitable as the ingredient A.
  • PTKs protein tyrosine kinases
  • EGFR epidermal growth factor receptor
  • E-selectin inhibitors and therapies widely used for psoriasis such as anthralin, coal tar, phototherapies including ultraviolet B (UVB) or psoralen ultraviolet A (PUVA), photodynamic therapy and laser therapy.
  • UVB ultraviolet B
  • PUVA psoralen ultraviolet A
  • Retinoid therapy can also be used as ingredient A.
  • bexarotene, acitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapies are suitable additional ingredients.
  • Ingredients A useful in the invention further include small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-I or ICAM-I.
  • combinations comprising ingredient A and one or more cytokine inhibitors of the invention, typically in therapeutically effective amounts, for use as pharmaceutical compositions with anti-cytokine activity.
  • combinations comprising ingredient A and a cytokine inhibitor can be used for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine-mediated disease or condition.
  • the pharmaceutical preparations, containing as the active substance one or more compound combinations comprising ingredient A and the cytokine inhibitor further include the pharmaceutically acceptable derivatives thereof, and may be optionally combined with conventional excipients and/or carriers.
  • the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention may be administered in any conventional dosage form in any conventional manner, including any of the routes described herein.
  • routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial, by infusion, sublingual, transdermal, oral, topical and by inhalation.
  • Typical modes of administration are oral, topical or intravenous.
  • the pharmaceutical combinations of ingredient A and the cytokine inhibitor according to the invention may be administered separately, or in a combination formulation with other ingredients or adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, or provide like advantages.
  • Such combination therapies typically utilize lower dosages of the conventional therapeutics, and avoid the possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
  • Pharmaceutical combinations of ingredient A and the cytokine inhibitor may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition.
  • the ingredient A and/or the cytokine inhibitor may be used in the combination as a salt, solvate, tautomer and/or prodrug and as a single stereroisomer or mixtures of stereoisomers, including racemates.
  • the proportions in which the two components, ingredient A and the cytokine inhibitor, may be used in the combinations according to the invention are variable.
  • Ingredient A and the cytokine inhibitor are optionally present in the form of their solvates or hydrates.
  • the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on the particular ingredient A and the cytokine inhibitor, and are within the skill in the art.
  • UVB ultraviolet B
  • PUVA psoralens ultraviolet A
  • a typical combination for treating psoriasis is the cytokine inhibitor compound in combination with immunomodulatory and/or immunosuppresive drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti- CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll, DAB 389 , CTLA- 4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher E. M., 1998 Hospital Medicine, 59 No 7, and the obvious variants thereof.
  • immunomodulatory and/or immunosuppresive drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti- CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll,
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound with methotrexate (MTX). It is expected this combination will be effective because of the good tolerability of MTX in the short term and because of the acceptability if maintenance of remission is obtained with good quality of life.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound with cyclosporine, especially because of cyclosporine's efficiency for induction of remission.
  • Another embodiment of the invention comprises administration in the following sequence: induction with cytokine inhibitor and cyclosporine, followed by continuation with cytokine inhibitor after decrease of dosing and discontinuation of cyclosporine.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with retinoids.
  • Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, and this would be alleviated by continuation therapy with the cytokine inhibitor.
  • Yet another typical combination for treating psoriasis is the cytokine inhibitor compound, in combination with ingredients A selected from steroids, vitamin D analogs, retinoids and dithranol. In some such combination treatments, the steroids and retinoids can be administered topically.
  • a more typical combination for treating psoriasis is a cytokine inhibitor compound with vitamin D derivatives, most typically calcipotriol or tacalcitol.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with macrolides, most typically with ascomycin analogues, administered topically, and even more typically with those available orally such as pimecrolimus.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound in combination with cell adhesion molecules inhibitors, such as anti LFA3, or anti LFAl. This includes adhesion molecule blockage by recombinant fusion proteins like alefacept, anti LF A3 -IgCl, or by anti-CD 11 monoclonal antibodies, efalizumab, and the obvious variants thereof.
  • Cell adhesion molecules inhibitors appear to provide an acceptable response rate with limited tolerability problems.
  • Combination with a cytokine inhibitor could avoid the disadvantage of their injectable form, with CAM inhibitors being used intermittently.
  • Another embodiment of the invention comprises administration in the following sequence: induction with cytokine inhibitor and CAM inhibitors, followed by maintenance treatment with the cytokine inhibitor alone and retreatment with CAM inhibitors in case of significant relapse.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound with another anti-TNFa ingredient.
  • a typical embodiment is one wherein the other anti-TNFa ingredient is selected from infliximab or etanercept, typically infliximab.
  • Infliximab is believed to have a higher rate of response for induction of remission, which recently was suggested to be maintained on the long term.
  • topical or general antisense inhibitors of TNFa such as ICAM-I ISIS 2302 in combination with a cytokine inhibitor compound.
  • Another typical combination for treating psoriasis is the cytokine inhibitor compound with anti-CD4, anti-CD80 (IDEC-114 or ABX-IL8), DAB-IL-2, DAB 389 -IL-2, CTLA4-Ig, ILlO, the IL-2 receptor inhibitors such as daclizumab (anti-TAC), or basiliximab.
  • DMARDs Disease Modifying Antirheumatic Drugs
  • SAARDs Slow Acting Antirheumatic Drugs
  • a typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs, such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, lefmnomide, methotrexate, azathioprine or cyclophosphamide.
  • immunosuppressive immunomodulatory
  • cytostatic drugs such as, for example, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofm, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, si
  • cytokine inhibitor compound Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with angiogenesis inhibitors, such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha- interferon.
  • angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha- interferon.
  • cytokine inhibitor compound in combination with inhibitors of cell adhesion, such as inhibitors of LFA-I or inhibitors of ICAM-I.
  • a more typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with anti-TNF antibodies or TNF-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-I, IL-6, ICAM-I, C5, or IL-I receptor.
  • the cytokine inhibitor is combined with infliximab alone or infliximab and methotrexate.
  • Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound in combination with IL-I receptor antagonists, such as Kineret®.
  • cytokine inhibitor compound combined with NSAIDs, including acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate,
  • NSAIDs including acetaminophen, aspir
  • cytokine inhibitor compound Another typical combination for treating rheumatoid arthritis is the cytokine inhibitor compound combined with steroids, such as betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.
  • steroids such as betamethasone, dexamethasone, methylprednisolone, prednisolone, and deflazacort.
  • the following groups of drugs combined with the cytokine inhibitor may be effective: steroids such as budesonide, 5-AS A drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors.
  • steroids such as budesonide, 5-AS A drugs like mesalamine, immunosuppressants, biological agents and adhesion molecule inhibitors.
  • a typical combination for treating Crohn's disease is the cytokine inhibitor compound with one or more of the following: steroids including all those listed herein, 5-ASA drugs, methotrexate and azathioprine.
  • Another typical combination for treating Crohn's disease is the cytokine inhibitor compound combined with IL-I receptor antagonists, such as Kineret®.
  • cytokine inhibitor compound with anti-TNF antibodies or TNF- receptor antagonists, such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-I, IL-6, ICAM-I, or C5.
  • TNF- receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or biological agents directed against targets such as CD-4, LFA-I, IL-6, ICAM-I, or C5.
  • the cytokine inhibitor is administered with infliximab alone or combined with methotrexate.
  • cytokine inhibitor compound combined with IL-10, ISIS 2302 (anti ICAM 1), or Antegren (VCAM receptor antagonist).
  • the invention therefore also provides a method of anticoagulant and fibrinolytic therapy for a disease or condition relating to blood coagulation or fibrinolysis, comprising administering to a patient in need thereof a pharmaceutically effective amount of the cytokine inhibitor.
  • This administration may be of benefit given either prophylactically to patients at risk or therapeutically for patients who have developed complications related to these pathways.
  • Methods of treating a disorder relating to blood coagulation or fibrinolysis also include administering to a subject in need thereof a pharmaceutically effective amount of a cytokine inhibitor of the invention in combination with one or more anticoagulant or fibrinolytic agents.
  • the latter agents include recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulants, aspirin, dipyrimidamole, aggrennox, ticlopidine, clopidogrel (Plavix), abciximab, RheoPro, integrilin, aggrestat and the like.
  • tissue plasminogen activator rtPA
  • streptokinase SK
  • urokinase UK
  • proUK proUK
  • heparin heparin
  • enoxoparin dalteparin
  • coumarin anticoagulants aspirin, dipyrimidamole
  • aggrennox ticlopidine
  • abciximab abciximab
  • RheoPro integrilin
  • a method of treating a cancer which comprises administering to a mammal in need of such treatment a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • the method further comprises treating the mammal with surgery, radiation, cryotherapy, or one or more antiproliferative agents or a combination thereof.
  • the antiproliferative agent is an alkylating agent, platinum agent, antimetabolite, topoisomerase inhibitor, antitumor antibiotic, antimitotic agent, aromatase inhibitor, thymidylate synthase inhibitor, DNA antagonist, farnesyltransferase inhibitor, pump inhibitor, histone acetyltransferase inhibitor, metalloproteinase inhibitor, ribonucleoside reductase inhibitor, endothelin A receptor antagonist, retinoic acid receptor agonist, immunomodulator, hormonal or antihormonal agent, photodynamic agent, angiogenesis inhibitor, or a tyrosine kinase inhibitor.
  • the alkylating agent is busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, or chlorambucil.
  • platinum agents examples include spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.
  • the antimetabolite is azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2- chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irotulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine.
  • the topoisomerase inhibitor is amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR-3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-11), or topotecan.
  • the antitumor antibiotic is dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonaf ⁇ de.
  • antimitotic agents are colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner- Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (Eli Lilly), vinflunine (Fabre), hydravin (Prescient NeuroPharma), a
  • the aromatase inhibitor is aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.
  • the thymidylate synthase inhibitor is pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5, 10-methylenetetrahydro folate (BioKeys).
  • the DNA antagonist is trabectedin (PliarmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).
  • the farnesyltransferase inhibitor is arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • Examples of pump inhibitors are zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • Examples of histone acetyltransferase inhibitors include tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • the metalloproteinase inhibitor is neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
  • the ribonucleoside reductase inhibitor is gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
  • the endothelin A receptor antagonist is atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • the retinoic acid receptor agonist is fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD- 1550 (Ligand).
  • the immuno-modulator is an interferon, interferon a-2a (e.g., Roferon-A, Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CD 154 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP-25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Imrnuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • interferon a-2a
  • the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutaniide, or leuporelin.
  • the hormonal agent is an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methyl
  • the photodynamic agent is talaporfm (Light Sciences), Pd-bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
  • the angiogenesis inhibitor is neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Pfizer).
  • tyrosine kinase inhibitors include imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panitumumab (Abgenix), IMC-ICl 1 (Im
  • the anti-proliferative agent is melphalan, carmustine, cisplatin, 5- fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, or paclitaxel (Taxol ® ).
  • the cancer is osteosarcoma
  • epithelial cell-derived neoplasia epit
  • the cancer is acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gas
  • the cancer is leukemia, erythroblastoma, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non- hodgkin's lymphoma or follicular lymphoma. In some embodiments, the cancer is follicular lymphoma, acute myelogenous leukemia, multilple myeloma or non- hodgkin's lymphoma.
  • the cancer is brain cancer, glioma, glioblastoma, meningioma, astrocytoma, medulloblastoma, neuroblastoma or retinoblastoma. In some such embodiments, the cancer is glioma or glioblastoma. [0041] In yet other embodiments, the cancer is osteosarcoma, Kaposi's sarcoma, chondosarcoma, Ewing's sarcoma or myoblastoma. In some such embodiments, the cancer is osteosarcoma bone cancer.
  • the cancer is breast, lung, kidney or prostate cancer metastasis.
  • the neoplasm is bone metastasis.
  • a method of treating, modifying or managing pain which comprises administering to a patient in need of such treatment, modification or management, a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • a composition comprising a therapeutically effective amount of a cytokine inhibitor as described herein.
  • the composition further comprises an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, ⁇ - adrenergic receptor agonist, ⁇ -adrenergic receptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, NSAID, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, hyperbaric oxygen, ⁇ 2 ⁇ ligand, NMDA receptor antagonist, or a combination of any two or more thereof.
  • the antidepressant is nortriptyline, amitriptyline, imipramine, doxepin, clomipramine, fluoxetine, sertraline, nefazodone, venlafaxine, trazodone, or bupropion.
  • the anti-hypertensive is nifedipine, terazosin, prazosin, losartan, verapamil, telmisartan, fosinopril, bosentan, or olmesartan.
  • the anxiolytic is fluoxetine, paroxetine, sertraline, or venlafaxine.
  • Examples of calcium channel blockers include nifedipine, verapamil and clonidine.
  • the ⁇ -adrenergic receptor agonist is clonidine or midodrine.
  • the ⁇ -adrenergic receptor antagonist is terazosin, prazosin, or doxasozin.
  • the anesthetic is procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, or ropivacaine.
  • opioid analgesic include hydromorphone, oxycodone, morphine sulfate, meperidine, and fentanyl transdermal patch.
  • the NSAID is a COX-2 inhibitor, salicylic acid acetate, ⁇ buprofen, ketoprofen, naproxen sodium, ketorolac, diclofenac, indometacin, or acetaminophen.
  • the COX-2 inhibitor is rofecoxib, celecoxib, or valdecoxib.
  • the corticosteroid is prednisone, dexamethasone or hydrocortisone.
  • the anticonvulsant is carbamazepine, oxcarbazepine, gabapentin, pregabalin, phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, tiagabine, famotodine, phenobarbital, diphenylhydantoin, mephenytoin, ethotoin, mephobarbital, primidone, ethosuximide, methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide, acetazolamide, progabide, divalproex sodium, magnesium sulfate injection, metharbital, paramethadione, clobazam, sulthiame, dilantin, diphenylan, or L-5-hydroxytryptophan.
  • the NMDA receptor antagonist is dextromethorphan, dextrorphan, ketamine, memantine, amantadine, agmatine, aptiganel, gavestinel, selfotel, 7-chlorokynurate, remacemide, riluzole, pyrroloquinoline quinone or cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, hi others
  • the ⁇ 2 ⁇ ligand is gabapentin, pregabalin, [(lR,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(l-aminomethyl- cyclohexylmethyl)-4H-[l,2,4]-oxadiazol-5-one and C-[l-(lH-tetrazol-5-ylmethyl)- cycloheptylj-methylamine, (3S,4S)-(l
  • the composition further comprises acetylsalicylic acid, diclofenac, ibuprofen, indometacin, flufenamic acid, mefenamic acid, morphine, pethidine, methadone, fentanyl, buprenorphine, tramadol, gabapentin, pregabalin, carbamazepine, lamotrigin, topiramate, phenyloin, levitiracetam, procaine, lidocaine, mepivacaine, articaine, prilocaine, etidocaine, bupivacaine, ropivacaine, amitryptiline, paroxetine, citalopram, bupropione, duxoletine, ketamine, memantine, 2,3- benzodiazepines, or a combination of any two or more thereof.
  • the pain is acute pain, chronic pain, pain resulting from soft tissue and peripheral damage from acute trauma; neuropathic pain; post-stroke pain; pain from neuralgia, acute herpetic neuralgia, postherpetic neuralgia, occipital neuralgia, HIV related neuralgias, AIDS related neuralgias, trigeminal neuralgia, or segmental or intercostal neuralgia; pain associated with osteoarthritis or rheumatoid arthritis; musculo-skeletal pain; spinal pain, central nervous system pain; lower back pain, pain from sciatica, dental pain, myofascial pain syndromes, episiotomy pain, or gout pain; deep and visceral pain; muscle pain, eye pain, inflammatory pain, orofacial pain; abdominal pain, or gynecological pain; somatogenic pain; pain associated with nerve and root damage; pain associated with limb amputation, tic douloureux, neurom
  • the musculo-skeletal pain is pain associated with strains, sprains or broken bones.
  • the central nervous system pain is pain due to spinal cord or brain stem damage.
  • the deep and visceral pain is heart pain, hi others, the orofacial pain is odontalgia.
  • the gynecological pain is dysmenorrhoea, labor pain and pain associated with endometriosis, hi others, the pain associated with nerve and root damage, is pain associated with peripheral nerve disorders.
  • the peripheral nerve disorder is nerve entrapment or brachial plexus avulsions
  • the headache is migraine with aura, migraine without aura, vascular headaches, acute or chronic tension headache, sinus headache or cluster headache.
  • the chronic non-neuropathic pain is pain associated with HIV, arthralgia, vasculitis or fibromyalgia.
  • the complex regional pain syndrome is type I or type II.
  • the pain is nociceptive pain or neuropathic pain.
  • the nociceptive pain is associated with chemical or thermal burn, cut of the skin, contusion of the skin, osteoarthritis, rheumatoid arthritis, systemic lupus erthrematosis (SLE), or tendonitis, or is myofascial pain.
  • the neuropathic pain is post-stroke pain; complex regional pain syndrome; sympathetic maintained pain syndrome; pain associated with diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, fibromyalgia, chronic fatigue syndrome, radiculopathy, luetic neuropathy; spinal cord injury pain; pain related to cancer or metastases; phantom limb pain; or painful neuropathic condition induced by a drug.
  • the cancer is osteosarcoma, colorectal cancer, brain cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukemia; lymphoma; or angiogenesis including neoplasia.
  • the metastases are breast, lung, kidney or prostate cancer metastases.
  • Cytokine inhibitors useful in the methods of the invention are exemplified by Formulas IA, IB, IC and II and are described in U.S. application 10/939,324, filed 9/10/2004, and U.S. Application No. 60/656,196, filed February 24, 2005, which are each incorporated herein by reference in their entirety: Q
  • the cytokine inhibitors comprise: a targeting moiety comprising at least an amide group having an amide NH, the targeting moiety capable of forming one or more hydrogen bonds with a target protein, and wherein the targeting moiety is not a urea group; a pocket-expanding moiety directly attached to the targeting moiety, the pocket-expanding moiety comprising a planar moiety attached to a bulky non- planar hydrophobic moiety, said non-planar moiety forming hydrophobic interactions with a target protein; an orienting moiety comprising a planar hydrophobic moiety and attached to a different atom of the targeting moiety than the pocket-expanding moiety, said orienting moiety capable of forming a ⁇ - ⁇ or edge-to-face aromatic interaction with a target protein.
  • Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- ⁇ 3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen- 1 -yl]-2,5-dioxo-2,5-dihydro-pyrrol- 1 -yl ⁇ -phenyl)-amide;
  • 6-Hydroxy-nicotinic acid 3-[5-tert-butyl-2-methoxy-3-(propane-l-sulfonylatnino)- phenylcarbamoyl]-lH-indazol-5-yl ester;
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • isotopically labeled compounds are within the scope of the invention.
  • substituted refers to a functional group as defined below in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituted groups have 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include, but are not limited to: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; thiols; alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl sulfide groups; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; is
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n- ⁇ ropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like.
  • Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with any of the groups listed above, for example, methyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene brige, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms are located on adjacent carbon atoms, or 2 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 2 carbon atoms.
  • Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexyl, or tricyclic, such as, for example, adamantyl.
  • Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl, noradamantyl, bornyl, or norbomyl groups.
  • Substituted bridged cycloalkyl groups may be substituted one or more times with non- hydrogen and non-carbon groups as defined above.
  • Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain alkyl and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups.
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups.
  • Representative substituted aryl groups may be mono- substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms.
  • heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 10, 12, or 15 ring members.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups.
  • the phrase "heterocyclyl group” includes fused ring species including those comprising fused aromatic and non- aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l ,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • a heteroatom such as, but not limited to, quinuclidyl.
  • the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, tetrahydropyranyl, thiomorpholinyl, pyranyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl
  • Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various groups as defined above, including, but not limited to, alkyl, oxo, carbonyl, amino, alkoxy, cyano, and/or halo.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heteroaryl group includes 1, 2, 3, or 4 heteroatoms and has 5 to 20, 5 to 15, or 5 to 10 ring members.
  • the heteroaryl groups have 5, 6, 7, 8, or 9 ring members.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl (thienyl), benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • heteroaryl groups includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substituents are referred to as "substituted heteroaryl groups".
  • Representative substituted heteroaryl groups may be substituted one or more times with various groups as defined above, including, but not limited to, amino, oxo, alkoxy, alkyl, cyano, and/or halo.
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • carboxylate refers to a -COOH group.
  • carboxylic ester refers to -COOR 30 groups.
  • R 30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 31 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • Urethane groups include N- and 0-urethane groups, i.e., -
  • R 33 and R 34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • amine refers to -NHR 35 and -NR 36 R 37 groups, wherein R 35 , R 36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • sulfonamido includes S- and N-sulfonamide groups, i.e.,
  • R 38 and R 39 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • thiol refers to -SH groups
  • sulfides include -SR 40 groups
  • sulfoxides include -S(O)R 41
  • sulfones include -SO 2 R 42 groups
  • sulfonyls include -SO 2 OR 43 .
  • R 40 , R 41 , R 42 , and R 43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • urea refers to -NR 44 -C(O)-NR 45 R 46 groups.
  • R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 47 )NR 48 R 49 and -NR 47 C(NR 48 )R 49 groups, wherein R 47 , R 48 , and R 49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 50 C(NR 51 )NR 52 R 53 groups, wherein R 50 , R 51 , R 52 and R 53 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • R 54 , R 55 , R 56 and R 57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • imide refers to -C(O)NR 58 C(O)R 59 groups, wherein R 58 and R 59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 60 (NR 61 ) and -N(CR 60 R 61 ) groups, wherein R 60 and R 61 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that not both R 60 and R 61 are H simultaneously.
  • protected with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups.
  • Protecting groups are known to those skilled in the art , and can be added or removed using well- known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifiuoracetate.
  • a reagent such as, but not
  • N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloro acetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, A- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4- ⁇ icolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4- ⁇ icolyl thioether
  • substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals
  • carboxy protecting groups are Ci to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.
  • Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention.
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
  • organic acids e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, mal
  • the compound of the invention when it has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia, organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g. Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia e.g., organic amines (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e
  • prodrugs Certain compounds within the scope of the invention are derivatives referred to as prodrugs.
  • the expression "prodrug” denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 1985, 112, 309; Bodor, N., “Novel Approaches in Prodrug Design," Drugs of the Future 1981, 6, 165; and Bundgaard, H., “Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int
  • cancer refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites.
  • a neoplasm, or tumor is an abnormal, unregulated, and disorganized proliferation of cell growth.
  • a neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness and metastasis.
  • Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system.
  • Metastasis typically refers to the dissemination of tumor cells by lymphotics or blood vessels.
  • Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance. Bone tissues are one of the most favored sites of metastases of malignant tumors, occurring in about 30% of all the cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are particularly known to be likely to metastasize to bone.
  • Both benign and malignant tumors are classified according to the type of tissue in which they are found.
  • fibromas are neoplasms of fibrous connective tissue
  • melanomas are abnormal growths of pigment (melanin) cells.
  • Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas.
  • Malignant growths of connective tissue e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among the white blood cells.
  • nociceptive pain includes, but is not limited to, pain associated with chemical or thermal burns, cuts of the skin, contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.
  • neurode includes, but is not limited to, a functional disturbance or pathological change in the peripheral nervous system and is characterized clinically by sensory or motor neuron abnormalities.
  • the term mononeuropathy indicates that a single peripheral nerve is affected, while the term polyneuropathy indicates that several peripheral nerves are affected.
  • Deafferentation indicates a loss of the sensory input from a portion of the body, and can be caused by interruption of either peripheral sensory fibres or nerves from the central nervous system.
  • Neuropathic pain thus reflects injury or impairment of the nervous system, and is defined herein as pain initiated or caused by a primary lesion or dysfunction in the nervous system. In particular, neuropathic pain can be caused by injury or dysfunction of the peripheral nervous system.
  • the etiology of a neuropathy can be known or unknown.
  • Known etiologies include complications of a disease or toxic state such as diabetes (which is the most common metabolic disorder causing neuropathy), or irradiation, ischemia or vasculitis. It is understood that the methods of the invention can be used to treat chronic pain of these or other chronic neuropathies of known or unknown etiology.
  • neuropathic pain includes, but is not limited to, CRPS (Complex Regional Pain Syndrome) type I, CRPS type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer and metastases related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain, luetic neuropathy, and other painful neuropathic conditions such as those induced by drugs such as vincristine, velcade and thalidomide.
  • the neuropathic pain can result from a mononeuropathy, polyneuropathy, complex regional pain syndromes or dea
  • Visceral pain is conventionally viewed as a variant of somatic pain, but may differ in neurological mechanisms. Certain clinical characteristics are peculiar to visceral pain: (i) it is not evoked from all viscera and not always linked to visceral injury; (ii) it is often diffuse and poorly localized, due to the organization of visceral nociceptive pathways in the central nervous system (CNS), particularly the absence of a separate visceral sensory pathway and the low proportion of visceral afferent nerve fibers; (iii) it is sometimes referred to other nonvisceral structures; and (iv) it is
  • Headaches can be classified as primary and secondary headache disorders.
  • the pathophysiology of the two most common primary disorders i.e., migraine and tension-type headache, is complex and not fully understood.
  • nociceptive input to the CNS may be increased due to the activation and sensitization of peripheral nociceptors, and the barrage of nociceptive impulses results in the activation and sensitization of second- and third-order neurons in the CNS.
  • central sensitization plays a role in the initiation and maintenance of migraine and tension-type headache [Johnson, B. W. Pain Mechanisms: Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3 rd Ed., Mosby, Inc. St Louis, 2000)].
  • a "cytokine inhibitor" within the context of this invention is a compound which at a concentration of 10 ⁇ M inhibits induced cytokine release from a cell by about 50% or greater than 50%.
  • induction of TNFa release can be achieved by, but not limited to, treatment of a cell or cell line with lipopolysaccharide (LPS) or IL-Ib and is inhibited by compounds described herein.
  • LPS lipopolysaccharide
  • IL-Ib IL-Ib
  • Treating within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder (i.e., inflammation, cancer or pain).
  • successful treatment may include an alleviation of symptoms or halting the progression of the disease, as measured by a reduction in the growth rate of a tumor, a halt in the growth of the tumor, a reduction in the size of a tumor, partial or complete remission of the cancer, or increased survival rate or clinical benefit.
  • a "therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder or disease, or halts of further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder.
  • a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, pain symptoms, or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the pain symptoms.
  • a therapeutically effective amount of a cytokine inhibitor used in the present invention may vary depending upon the route of administration and dosage form. Effective amounts of invention compounds typically fall in the range of about 0.001 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 10 mg/kg/day. Typically, the compound or compounds used in the instant invention are selected to provide a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the ratio of doses between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies.
  • the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy.
  • the compounds of the invention can also be administered in conjunction with other anti-inflammatory agents, anticancer agents and other agents described herein.
  • the cytokine inhibitors disclosed herein can be used in the methods and compositions of the invention either alone or together with additional treatments or active ingredients or a combination thereof. Additional treatments comprise treatment by surgery, radiation, or cryotherapy, while treatment with additional active ingredients comprises the use of antiproliferative agents. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
  • Additional treatments comprise treatment by surgery, radiation, or cryotherapy
  • additional active ingredients comprises the use of antiproliferative agents.
  • Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
  • the specific amount of the additional active agent will depend on the specific agent used, the type of cancer being treated or managed, the severity and stage of the cancer, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the mammal.
  • the additional active ingredients that can be used in combination with the cytokine inhibitors of the present invention are used at dosages well known in the art.
  • inhibition in the context of neoplasia, cancer, tumor growth or tumor cell growth, may be assessed by delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition is referred to herein as prevention or chemoprevention.
  • prevention in the context of cancer includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or arresting or reversing the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.
  • antiproliferative agents includes agents that prevent the development, maturation, or spread of cells, by acting directly on the cell, e.g., by cytostatic or cytocidal effects, and not indirectly through mechanisms such as biological response modification.
  • antiproliferative agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be employed for treatment with compounds of the present invention for treatment of cancer by combination drug chemotherapy.
  • Exemplary antiproliferative agents can be categorized as alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, endothelin A receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal or antihormonal agents, photodynamic agents, angiogenesis inhibitors, tyrosine kinase inhibitors, and the like. Some antiproliferative agents operate through multiple or unknown mechanisms and can thus be classified into more than one category.
  • the alkylating agents are believed to act by alkylating and cross- linking guanine and possibly other bases in DNA, arresting cell division.
  • exemplary alkylating agents include nitrogen mustards, ethyleneimine compounds, alkyl sulfates, cisplatin, and various nitrosoureas.
  • a disadvantage with these compounds is that they not only attack malignant cells, but also other cells which are naturally dividing, such as those of bone marrow, skin, gastro-intestinal mucosa, and fetal tissue.
  • Suitable alkylating-type agents include, but are not limited to, busulfan, procarbazine, ifosfamide, altretamine, hexamethylmelamine, estramustine phosphate, thiotepa, mechlorethamine, dacarbazine, streptozocin, lomustine, temozolomide, cyclophosphamide, semustine, and chlorambucil.
  • Suitable platinum agents that may be used in the present invention include, but are not limited to spiroplatin, lobaplatin (Aeterna), tetraplatin, satraplatin (Johnson Matthey), ormaplatin, iproplatin, miriplatin (Sumitomo), nexplatin (AnorMED), polymer platinate (Access), oxaliplatin, or carboplatin.
  • Antimetabolites are typically reversible or irreversible enzyme inhibitors, or compounds that otherwise interfere with the replication, translation or transcription of nucleic acids.
  • Suitable antimetabolite agents include, but are not limited to azacytidine, trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision), 2-fluorodeoxy cytidine, irofulven (MGI Pharma), methotrexate, tomudex, ethynylcytidine (Taiho), fludarabine, gemcitabine, raltitrexed, or capecitabine.
  • azacytidine trimetrexate, floxuridine, deoxycoformycin, 2-chlorodeoxyadenosine, pentostatin, 6-mercaptopurine, hydroxyurea, 6-thioguanine, decitabine (SuperGen), cytarabine, clofarabine (Bioenvision
  • topoisomerase agents that may be used in the present invention include, but are not limited to amsacrine, exatecan mesylate (Daiichi), epirubicin, quinamed (ChemGenex), etoposide, gimatecan (Sigma-Tau), teniposide, mitoxantrone, diflomotecan (Beaufour-Ipsen), 7-ethyl-lO-hydroxy-camptothecin, dexrazoxanet (TopoTarget), elsamitrucin (Spectrum), pixantrone (Novuspharma), edotecarin (Merck & Co), becatecarin (Exelixis), karenitecin (BioNumerik), BBR- 3576 (Novuspharma), belotecan (Chong Kun Dang), rubitecan (SuperGen), irinotecan (CPT-I l), or topotecan.
  • amsacrine exatecan me
  • Suitable antibiotic-type antiproliferative agents include, but are not limited to dactinomycin (actinomycin D), azonafide, valrubicin, anthrapyrazole, daunorubicin (daunomycin), oxantrazole, therarubicin, losoxantrone, idarubicin, bleomycinic acid, rubidazone, sabarubicin (Menarini), plicamycinp, 13-deoxydoxorubicin hydrochloride (Gem Pharmaceuticals), porfiromycin, epirubicin, mitoxantrone (novantrone) or amonafide.
  • Suitable antimitotic antiproliferative agents include, but are not limited to colchicines, ABT-751 (Abbott), vinblastine, xyotax (Cell Therapeutics), vindesine, IDN 5109 (Bayer), dolastatin 10 (NCI), A 105972 (Abbott), rhizoxin (Fujisawa), A 204197 (Abbott), mivobulin (Warner-Lambert), synthadotin (BASF), cemadotin (BASF), indibulin (ASTAMedica), RPR 109881A (Aventis), TXD 258 (Aventis), combretastatin A4 (BMS), epothilone B (Novartis), isohomohalichondrin-B (PharmaMar), T 900607 (Tularik), ZD 6126 (AstraZeneca), batabulin(Tularik), cryptophycin 52 (El
  • Suitable aromatase inhibitors that may be used in the present invention include, but are not limited to aminoglutethimide, atamestane (BioMedicines), formestane, fadrozole, letrozole, exemestane, or anastrazole.
  • Suitable thymidylate synthase inhibitors include, but are not limited to, pemetrexed (Eli Lilly), nolatrexed (Eximias), ZD-9331 (BTG), doxifluridine (Nippon Roche), or 5,10- methylenetetrahydrofolate (BioKeys).
  • Suitable DNA antagonists that may be used in the present invention include, but are not limited to trabectedin (PharmaMar), edotreotide (Novartis), glufosfamide (Baxter International), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), or thymectacin (NewBiotics).
  • Suitable farnesyltransferase inhibitors include, but are not limited to arglabin (NuOncology Labs), tipifarnib (Johnson & Johnson), lonafarnib (Schering-Plough), perillyl alcohol (DOR BioPharma), or sorafenib (Bayer).
  • Suitable pump inhibitors that may be used in the present invention include, but are not limited to zosuquidar trihydrochloride (Eli Lilly), tariquidar (Xenova), biricodar dicitrate (Vertex), or MS-209 (Schering AG).
  • Suitable histone acetyltransferase inhibitors that may be used in the present invention include, but are not limited to tacedinaline (Pfizer), pivaloyloxymethyl butyrate (Titan), AP-CANC-03 and AP-CANC-04 (Aton Pharma), depsipeptide (Fujisawa), or MS-275 (Schering AG).
  • Suitable metalloproteinase inhibitors that may be used in the present invention include, but are not limited to neovastat (Aeterna Laboratories), metastat (CollaGenex), or marimastat (British Biotech).
  • Suitable ribonucleoside reductase inhibitors contemplated for use in the present invention include, but are not limited to, gallium maltolate (Titan), tezacitabine (Aventis), triapine (Vion), or didox (Molecules for Health).
  • Suitable endothelin A receptor antagonists that may be used in the present invention include, but are not limited to atrasentan (Abbott), bosentan (Roche), ambrisentan (BASF), sitaxsentan (Encysive), clazosentan (Roche), darusentan (Knoll), and ZD-4054 (AstraZeneca).
  • retinoic acid receptor agonists include compounds which are natural and synthetic analogues of retinol (Vitamin A). The retinoids bind to one or more retinoic acid receptors to initiate diverse processes such as reproduction, development, bone formation, cellular proliferation and differentiation, apoptosis, hematopoiesis, immune function and vision.
  • Suitable retinoic acid receptor agonists that may be used in the present invention include, but are not limited to fenretinide (Johnson & Johnson), alitretinoin (Ligand), tazarotene (Allergan), tetrinoin (Roche), isotretinoin (Roche), 13-cis-retinoic acid (UCSD), or LGD-1550 (Ligand).
  • Suitable immunomodulators that may be used in the present invention include, but are not limited to interferon, Roferon-A (Roche), dexosome therapy (Anosys), oncophage (Antigenics), pentrix (Australian Cancer Technology), GMK vaccine (Progenies), CDl 54 cell therapy (Tragen), adenocarcinoma vaccine (Biomira), transvax (Intercell), avicine (AVI BioPharma), norelin (Biostar), IRX-2 (Immuno-Rx), BLP -25 liposome vaccine (Biomira), PEP-005 (Peplin Biotech), multiganglioside vaccine (Progenies), synchrovax vaccine (CTL Immuno), ⁇ -alethine (Dovetail), melanoma vaccine (CTL Immuno), vasocare (Vasogen), rituximab (Genentech/Biogen pou), or p21 RAS vaccine (GemVax).
  • Suitable hormonal agents include, but are not limited to an estrogen, dexamethasone, a conjugated estrogen, prednisone, ethinyl estradiol, methylprednisolone, chlortrianisen, prednisolone, idenestrol, aminoglutethimide, hydroxyprogesterone caproate, leuprolide, medroxyprogesterone, octreotide, testosterone, mitotane, testosterone propionate, fluoxymesterone, methyltestosterone, 2-methoxyestradiol (EntreMed), diethylstilbestrol, arzoxifene (Eli Lilly), megestrol, tamoxifen, bicalutamide, toremofine, flutamide, goserelin, nilutamide, or leuporelin.
  • an estrogen dexamethasone
  • a conjugated estrogen prednisone
  • ethinyl estradiol
  • Suitable photodynamic agents that may be used in the present invention include, but are not limited to talaporfm (Light Sciences), Pd- bacteriopheophorbide (Yeda), theralux (Theratechnologies), lutetium texaphyrin (Pharmacyclics), motexafin, gadolinium (Pharmacyclics), or hypericin.
  • Suitable angio genesis inhibitors include, but are not limited to neovastat (AEterna Zentaris), ATN-224 (Attenuon), sorafenib (Bayer), thalidomide, bevacizumab (Genentech), ranibizumab (Genentech), benefin (Lane Labs), L-651582 (Merck & Co), vatalanib (Novartis), or sutent (Sugen).
  • Suitable tyrosine kinase inhibitors include, but are not limited to imatinib (Novartis), leflunomide (Sugen/Pharmacia), kahalide F (PharmaMar) iressa (AstraZeneca), lestaurtinib (Cephalon), erlotinib (Oncogene Science), canertinib (Pfizer), tandutinib (Millenium), squalamine (Genaera), midostaurin (Novartis), phenoxodiol, SU6668 (Pharmacia), cetuximab (ImClone), rhu-Mab (Genentech), ZD6474 (AstraZeneca), MDX-H210 (Medarex), vatalanib (Novartis), omnitarg (Genentech), lapatinib (GlaxoSmithKline), panit
  • Additional anti-proliferative agents which may be used in combination with cytokine inhibitors of the present invention include melphalan, carmustine, cisplatin, 5-fluorouracil, mitomycin C, adriamycin (doxorubicin), bleomycin, paclitaxel (Taxol ® ), and the like.
  • the cytokine inhibitors of the invention can be used together with additional active ingredients or agents.
  • the additional active agents are capable of relieving pain, inhibiting inflammatory reactions, providing a sedative effect or an antineuralgic effect, or ensuring patient comfort.
  • additional active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, antiinflammatories, cox-2 inhibitors, ⁇ - adrenergic receptor agonists or antagonists, ketamine, anesthetic agents, NMDA antagonists, ⁇ 2 ⁇ ligands, immunomodulatory agents, immunosuppressive agents, antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, other therapeutics known to relieve pain, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs or pharmacologically active metabolites thereof.
  • Opioids can be used to treat severe pain.
  • opioid analgesics include, but are not limited to, oxycodone (OxyContinTM), morphine sulfate (MS ContinTM, DuramorphTM, AstramorphTM), meperidine (DemerolTM), and fentanyl transdermal patch (DuragesicTM) and other known conventional medications [See, e.g., Physicians' Desk Reference, 594-595, 2851 and 2991 (57 th ed., 2003)].
  • Oxycodone (OxyContinTM) is a long-acting form of an opioid and may be used in initial and later stages of CRPS.
  • Morphine sulfate may be used for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate is sold in the United States under the trade name MS ContinTM, DuramorphTM, or AstramorphTM [See, e.g., Physicians' Desk Reference, 594-595 (57 th ed., 2003)].
  • Fentanyl transdermal patch (DuragesicTM) is a potent narcotic analgesic with much shorter half-life than morphine sulfate.
  • Meperidine (DemerolTM) and hydromorphone (DilaudidTM) may also be used for pain management [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Non-narcotic analgesics and antiinflammatories are preferably used for treatment of pain during pregnancy and breastfeeding.
  • Anti -inflammatories such as non-steroidal anti-inflammatory drugs (NSAIDs) and cox-2 inhibitors typically inhibit inflammatory reactions and pain by decreasing the activity of cyclo- oxygenase, which is responsible for prostaglandin synthesis.
  • NSAIDs may provide pain relief in the early stage of pain syndrome.
  • antiinflammatories include, but are not limited to, salicylic acid acetate (AspirinTM), ibuprofen (MotrinTM, AdvilTM), ketoprofen (OruvailTM), rofecoxib (VioxxTM), naproxen sodium (AnaproxTM, NaprelanTM, NaprosynTM), ketorolac (AcularTM), and other known conventional medications.
  • a specific cox-2 inhibitor is celecoxib (CelebrexTM) [See, e.g., Physicians' Desk Reference, 1990, 1910-1914 and 2891 (57 th ed., 2003); Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 511, 667 and 773 (23 rd ed., 2002)].
  • Antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. Some antidepressants also have sodium channel blocking ability to reduce the firing rate of injured peripheral afferent fibers.
  • antidepressants include, but are not limited to, nortriptyline (PamelorTM), amitriptyline (ElavilTM), imipramine (Tofranill), doxepin (SinequanTM), clomipramine (AnafranilTM), fluoxetine (ProzacTM), sertraline (ZoloftTM), nefazodone (SerzoneTM), venlafaxine (EffexorTM), trazodone (DesyrelTM), bupropion (WellbutrinTM) and other known conventional medications [See, e.g., Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57 th ed., 2003)].
  • Anticonvulsant drugs may also be used in embodiments of the invention.
  • anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (NeurontinTM), phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine [See, e.g., Physicians' Desk Reference, 2563 (57 th ed., 2003)].
  • Corticosteroids e.g., prednisone, dexamethasone or hydrocortisone
  • orally active class Ib anti-arrhythmic agents e.g., mexiletine
  • calcium channel blockers e.g., nifedipine
  • beta-blockers e.g., propranolol
  • ⁇ -blockers e.g., phenoxybenzamine
  • oc2-adrenergic agonists e.g., clonidine
  • cytokine inhibitor See, e.g., Physicians' Desk Reference, 1979, 2006 and 2190 (57 th ed., 2003)].
  • Administration of the cytokine inhibitors of the invention and the optional additional active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
  • a typical route of administration for cytokine inhibitors is oral.
  • Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference, 594-597 (57 th ed., 2003)].
  • the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
  • the specific amount of the additional active agent will depend on the specific agent used, the type of pain being treated or managed, the severity and stage of pain, and the amount(s) of cytokine inhibitors and any optional additional active agents concurrently administered to the patient.
  • Hydromorphone (DilaudidTM) is typically administered in an initial dose of about 2 mg orally, or about 1 mg intravenously to manage moderate to severe pain [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Morphine sulphate (DuramorphTM, AstramorphTM, MS ContinTM) is typically administered in an initial dose of about 2 mg IV/SC/IM, depending on whether a patient has already taken narcotic analgesics [See, e.g., Physicians' Desk Reference, 594-595 (57 th ed., 2003)].
  • Oxycodone is a long-acting form of an opioid and may be used in initial and later stages of pain syndrome.
  • Oxycodone (OxyContinTM) is usually administered in an amount of about 10-160 mg twice a day [See, e.g., Physicians' Desk Reference, 2851 (57 th ed., 2003)].
  • Meperidine (DemerolTM) is typically administered in an amount of about 50-150 mg PO/IV/IM/SC every 3-4 hours.
  • a typical pediatric dose of meperidine (DemerolTM) is 1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC every 3-4 hours [See, e.g., Physicians' Desk Reference, 2991 (57 th ed., 2003)].
  • Fentanyl transdermal patch (DuragesicTM) is available as a transdermal dosage form.
  • a typical adult dose is about 25 mcg/h (10 cm ), 50 mcg/h (20 cm 2 ), 75 mcg/h (75 cm 2 ), or 100 mcg/h (100 cm 2 ) [See, e.g., Physicians' Desk Reference, 1775 (57 th ed., 2003)].
  • Non-narcotic analgesics and antiinflammatories such as NSAIDs and cox-2 inhibitors may be used to treat patients suffering from mild to moderate pain.
  • Ibuprofen MotrinTM, AdvilTM
  • Naproxen sodium may also be used for relief of mild to moderate pain in an amount of about 275 mg thrice a day or about 550 mg twice a day [See, e.g., Physicians' Desk Reference, 1417,2193 and 2891 (57 th ed., 2003)].
  • Antidepressants e.g., nortriptyline (PamelorTM) may also be used in the practice of the invention to treat patients suffering from chronic and/or neuropathic pain.
  • the oral adult dose is typically in an amount of about 25-100 mg, and usually does not exceed 200 mg/d.
  • a typical pediatric dose is about 0.1 mg/kg PO as initial dose, increasing, as tolerated, up to about 0.5-2 mg/d.
  • Amitriptyline (EtrafonTM) is typically used for neuropathic pain in an adult dose of about 25-100 mg PO [See, e.g., Physicians' Desk Reference, 1417 and 2193 (57 th ed., 2003)].
  • Anticonvulsants such as gabapentin (NeurontinTM) may also be used to treat patients suffering from chronic and neuropathic pain.
  • gabapentin is orally administered in an amount of about 100-1,200 mg three times a day [See, e.g., Physicians' Desk Reference, 2563 (57 th ed., 2003)].
  • Carbamazepine (TegretolTM) is used to treat pain associated with true trigeminal neuralgia.
  • the oral adult dose is typically in an amount of about 100 mg twice a day as initial dose, increasing, as tolerated, up to about 2,400 mg/d [See, e.g., Physicians' Desk Reference, 2323-25 (57 th ed., 2003)].
  • the additional active agents can act additively or, more typically, synergistically with the cytokine inhibitor.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in the same pharmaceutical composition.
  • a cytokine inhibitor is administered concurrently with one or more second active agents in separate pharmaceutical compositions, hi still another example, a cytokine inhibitor is administered prior to or subsequent to administration of a second active agent.
  • the invention contemplates administration of a cytokine inhibitor and a second active agent by the same or different routes of administration, e.g., oral and parenteral.
  • the second active agent when a cytokine inhibitor is administered concurrently with a second active agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that elicits the adverse side effect.
  • cytokine inhibitors or combinations of cytokine inhibitors and additional active agents may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the dosage forms described below containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • Administration of the cytokine inhibitors and the additional active agents to a mammal can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
  • a typical route of administration for cytokine inhibitors described herein is oral.
  • Typical routes of administration for the additional active agents or ingredients of the invention are known to those of ordinary skill in the art [See, e.g., Physicians' Desk Reference (57 th ed., 2003)].
  • the cytokine inhibitor and the additional active agents are administrated simultaneously by coformulation.
  • the additional active agent can be administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally and once or twice daily in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg.
  • a cytokine inhibitor and an additional active agent are administered to a mammal, more typically a human, in a sequence and within a time interval such that the cytokine inhibitor can act together with the other agent to provide an increased benefit than if they were administered otherwise.
  • the additional active agents can be coadminstered by coformulation, administered at the same time or administered sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
  • the cytokine inhibitor and the additional active agent(s) exert their effects at times which overlap.
  • Each additional active agent can be administered separately, in any appropriate form and by any suitable route.
  • the cytokine inhibitor is administered before, concurrently or after administration of the additional active agent(s).
  • the cytokine inhibitor and the additional active agents are administered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
  • the cytokine inhibitor and the additional active agents are administered concurrently.
  • the cytokine inhibitor and the additional active agents are administered concurrently by coformulation.
  • the cytokine inhibitor and the additional active agents are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
  • the cytokine inhibitor and the optional additional active agent(s) are cyclically administered to a mammal. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, reduce the dose levels of the cytokine inhibitor and/or the optional active agent(s), and/or improve the efficacy of the treatment.
  • the cytokine inhibitor and the optional additional active agent(s) are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
  • One cycle can comprise the administration of a cytokine inhibitor and optionally the second active agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
  • Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
  • the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
  • the cytokine inhibitor described herein is administered in metronomic dosing regimens, either by continuous infusion or frequent administration without extended rest periods.
  • Such metronomic administration can involve dosing at constant intervals without rest periods.
  • the cytokine inhibitor is used at doses lower than other protocols such as daily dosing.
  • Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time. In typical examples, the use of lower doses can minimize toxic side effects and eliminate rest periods.
  • the cytokine inhibitor is delivered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months.
  • the scheduling of such dose regimens can be optimized by the skilled artisan.
  • Courses of treatment can be administered concurrently to a mammal, i.e., individual doses of the additional active agents are administered separately yet within a time interval such that the cytokine inhibitor can work together with the additional active agents.
  • one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
  • the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
  • compositions which may be prepared by mixing one or more cytokine inhibitory compounds as described herein, and optionally additional active ingredients, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat, or prevent a variety of disorders associated with excess cytokine production.
  • the compositions of the invention may be used to create
  • compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneally, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injections.
  • dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive.
  • Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri- glycerides.
  • the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above.
  • these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds used in the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum.
  • Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • Compounds used in the invention may be administered to the lungs by inhalation through the nose or mouth.
  • suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • Formulations for inhalation administration contain as excipients, for example, lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate.
  • Aqueous and nonaquous aerosols are typically used for delivery of inventive compounds by inhalation.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the compound together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • a nonaqueous suspension e.g., in a fluorocarbon propellant
  • Aerosols containing compounds for use according to the present invention are conveniently delivered using an inhaler, atomizer, pressurized pack or a nebulizer and a suitable propellant, e.g., without limitation, pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, nitrogen, air, or carbon dioxide.
  • a pressurized aerosol the dosage unit may be controlled by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Delivery of aerosols including compounds of the present invention using sonic nebulizers is advantageous because nebulizers minimize exposure of the agent to shear, which can result in degradation of the compound.
  • the pharmaceutical formulations and medicaments may be a spray, nasal drops or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds may be formulated in oily solutions or as a gel.
  • any suitable propellant may be used including compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • Dosage forms for the topical (including buccal and sublingual) or transdermal administration of compounds used in the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches.
  • the active component may be mixed under sterile conditions with a pharmaceutically-acceptable carrier or excipient, and with any preservatives, or buffers, which may be required.
  • Powders and sprays can be prepared, for example, with excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • the ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the inventive compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • the compounds used in this invention can be incorporated into various types of ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant).
  • the compounds are typically incorporated into topical ophthalmic formulations for delivery to the eye.
  • the compounds may be combined with one or more ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution.
  • Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonic aqueous buffer.
  • the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound.
  • the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac.
  • Gelling agents can also be used, including, but not limited to, gellan and xanthan gum.
  • sterile ophthalmic ointment formulations the compound of the invention is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations maybe prepared by suspending the invention compound in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations.
  • Preservatives and tonicity agents can be optionally incorporated.
  • Intrathecal administration via bolus dosage or constant infusion, allows the local administration of a compound to a region of the spinal cord, such as the dorsal horn regions, delivering the compound directly to the subarachnoid space containing the CSF (cerebrospinal fluid).
  • Central delivery to the spinal cord regions can also be performed by epidural injection to a region of the spinal cord exterior to the arachnoid membrane.
  • Enhancing permeation of the active compound through meningeal membranes may be achieved by using hypertonic dosing solutions that increase permeability of meningeal membranes, or by addition of permeation enhancers, such as, but not limited to, liposomal encapsulation, surfactants, or ion-pairing agents.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • the formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical formulations may also be formulated for controlled release or for slow release.
  • compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
  • cytokine inhibitors used in the instant invention are described below.
  • a first group of compounds are represented by Formula IA,
  • G is a C 3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O), C(S) or CH 2 ;
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C 6-10 aryl, -(Cj -3 alkyl)-(C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6-10 aryl), or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl), each of which is optionally substituted with one or more R 4 or R 5
  • each Z is independently F, Cl, -OR, -NR 2 , -SR, -NHCONHR, or -NHCOR;
  • L is a covalent bond or a saturated or unsaturated branched or unbranched Ci -10 carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(0) m ; and wherein L is optionally substituted with 1-2 oxo groups and one or of F, Cl, Br, or I;
  • each m is independently 0, 1 or 2;
  • Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C 1-6 alkoxy, Ci -6 alkyl-S(O) m , or phenyl- S (O) m , wherein the cycloalkyl, aryl, heterocyclyl, Ci -6 alkoxy, Ci -6 alkyl-S(O) ra , or phenyl-S(O) m is each optionally substituted with one or more R 27 ;
  • each R is independently hydrogen or substituted or unsubstituted Ci -6 alkyl; each R' is independently hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted (C 0-4 alkyl)-(C 6 . 10 aryl) or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 1 is independently F, Cl, Br, I, cyano, -C(O)R 5 -C(O)NR 2 , -C(O)OR, -OR, -NR'R', -SiR 3 , - S(O) m R, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing I 5 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • each R 2 , R 4 and R 5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1-6 alkyl, substituted or unsubstituted C 6-I0 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR' C(O)NR' R', - NR'C(S)NR'R ⁇ -NR 5 C(O)OR' or -SO 2 NR' 2 ;
  • each R" is independently substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 0-4 alkyl-C 6 . 10 aryl or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 3 is independently substituted or unsubstituted C 6-1O aryl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m , substituted or unsubstituted C 3-12 cycloalkyl, substituted or unsubstituted C 5-I2 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted straight or branched Ci -8 alkyl, R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )-, R 26 C( ⁇ CH 2 ) m N(R 21 )-, substituted or unsubstituted C 2-8 alkenyl, or substituted or unsubstituted C 2-8 alky
  • each R 6 is a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R 26 ;
  • each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(Co- 4 alkyl)amino, wherein the Co- 4 alkyl is optionally partially or folly halogenated;
  • R 20 is substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl, OR' or NR' 2 ;
  • R 21 is hydrogen or C 1-4 branched or unbranched alkyl optionally partially or fully halogenated
  • each R 22 , R 23 and R 24 is independently hydrogen, substituted or unsubstituted Ci -1 O alkyl, wherein the C 1-10 alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • each R 27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', -NR'R ⁇ -SiR' 3 , - S(O) m R ⁇ substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-1O alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-1O cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • the compound at a concentration of 10 ⁇ M inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
  • pyrazolyl pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzof ⁇ ranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3-only, benzodioxolyl, benzo[l,3]dioxol-2
  • pyrrolidinyl tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomo ⁇ holinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, or phthalimi
  • G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C 6-10 aryl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl.
  • Ar is indazolyl, phenyl, tetrahydronapthyl or naphthyl.
  • Ar is -(C 1-3 alkyl)-(C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6- i 0 aryl), or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl).
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -CZ 2 - and each Z is independently F, -OR or -CHR.
  • Y is -CF 2 -.
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CHOH-.
  • Y is -O- or -CH 2 -.
  • the C 6-10 aryl is phenyl or naphthyl, and/or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(C 1-3 alkyl)-(C 6-10 aryl).
  • one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(0) m .
  • L is a covalent bond, a C 1 -Cg alkoxy, -C(O)O-, -NH- or -O-.
  • R 27 is C 1-6 alkyl, C 1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C 1-3 alkyl)amino, mono- or di- (phenyl-d- 3 alkyl)amino, C 1-6 alkyl-S(O) m , phenyl-C 1-3 -alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy.
  • Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino. In others, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.
  • R 27 is -C(O)OR', -NR'R', substituted or unsubstituted straight or branched C 1-10 alkyl, substituted or unsubstituted C 7-2 O aralkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m .
  • Q is pyrimidinyl and R 27 is -NR'R' or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • Q is pyridinyl
  • R 27 is -NR'R', substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) n ,.
  • each R 1 is independently
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1-3 alkyl groups;
  • each R 1 is independently C 3-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3- io cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, cyano, Ci -3 alkoxy which is optionally partially or fully halogenated and NHiC(O) or mono- or di-(C
  • each R 2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR 5 or -SO 2 NR' 2 .
  • each R 2 is independently -NR 5 2 , -NO 2 , -C(O)NR 5 2 , - NR 5 SO 2 R 5 ', -NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR 5 or -SO 2 NR' 2 .
  • each R 3 is independently
  • a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocycle selected from cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclic ring is optionally, independently substituted with 1 to 3
  • Ci -3 alkyl groups C 1-4 alkyl or alkylene-phenyl-C(0)-Co- 4 alkyl or alkylene, Cj -4 alkyl or alkylene-C(O)-C 0- 4 alkyl or alkylene, C 1-4 alkyl or alkylene - ⁇ henyl-S(O) m -C 0-4 alkyl or alkylene;
  • R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • branched or unbranched alkyl optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or C 1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms; or
  • each R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 17 , R 19 , and R 25 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0-4 alkyl)amino, wherein the Co -4 alkyl is optionally partially or fully halogenated; each R 11 and R 16 is independently hydrogen or C 1-4 branched or unbranched alkyl optionally partially or folly halogenated; and
  • R 18 is independently hydrogen or C 1-4 branched or unbranched alkyl optionally independently substituted with oxo or R 25 .
  • each R 3 is independently phenyl, naphthyl, or heterocyclyl, each of which is optionally partially or folly halogenated and optionally substituted with 1-3 of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, foryl, tetrahydroforyl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzoforanyl, benzoxazolyl, benzoisooxazolyl, benzpyrazolyl, benzothioforanyl
  • each R 3 is independently phenyl, pyridazinyl or pyridyl, each of which is optionally partially or folly halogenated and optionally substituted with C 1-6 branched or unbranched alkyl which is optionally partially or folly halogenated, hydroxy, oxo, cyano, C 1 - 3 alkoxy optionally partially or folly halogenated, nitro, amino, mono- or di-(C 1-3 alkyl)amino; C 1-6 alkyl or C 1-6 alkoxy, each optionally partially or folly halogenated or optionally substituted with R 17 , amino, OR 18 , C 1-5 mono- or di-alkylamino optionally substituted with R 9 ; R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N
  • cytokine inhibitors of a first group of compounds having Formula IB are provided.
  • G is a C 3-10 carbocyclyl, 5-8 membered monocyclic heterocyclyl, or 8- 11 membered bicyclic heterocyclyl containing 1 or more heteroatoms selected from O, N or S; wherein G is substituted by one or more R 1 , R 2 or R 3 ;
  • X is C(O), C(S) or CH 2 ;
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C 6-10 aryl, -(C 1-3 alkyl)-(C 6 .io aryl), -(Y)-(C 0-3 alkyl)-(C 6- io aryl), or -(Y)-(C 0-3 alkyl)-(5- 10 member heteroaryl), each of which is optionally substituted with one or more R
  • each Z is independently F, Cl, -OR, -NR 2 , -SR, -NHCONHR, or -NHCOR;
  • L is a covalent bond or a saturated or unsaturated branched or uribranched C 1-1O carbon chain, wherein one or more methylene groups are optionally independently replaced by heteroatoms selected from O, NR or S(O) m ; and wherein L is optionally substituted with 1-2 oxo groups and one or more of F, Cl, Br, or I;
  • each m is independently 0, 1 or 2;
  • Q is hydrogen, -NR'R', cycloalkyl, aryl, heterocyclyl, C 1-6 alkoxy, Ci -6 alkyl-S(O) m , or phenyl-S(O) m , wherein the cycloalkyl, aryl, heterocyclyl, C 1-6 alkoxy, C 1-6 alkyl-S(O) m , or phenyl-S(O) m is each optionally substituted with one, or more R 27 ; provided that if R 4 and R 5 are absent, -L-Q is not -H;
  • each R is independently hydrogen or substituted or unsubstituted Cj -6 alkyl
  • each R' is independently hydrogen, substituted or unsubstituted C 1 - S alkyl, substituted or unsubstituted (Co -4 alkyl)-(C 6 . 1 o aryl) or substituted or unsubstituted (C 0-4 alkyl)-(5-10 member heterocyclyl);
  • each R 1 is independently F, Cl, Br, I, cyano, -C(O)R, -C(O)NR 2 , -C(O)OR, -OR, -NR'R', -SiR 3 , - S(O) 1n R, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-I0 alkenyl, substituted or unsubstituted C 2-10 alkynyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m ;
  • each R 2 , R 4 and R 5 is independently F, Cl, Br, I, cyano, substituted or unsubstituted straight or branched C 1-6 alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 member heteroaryl, -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR 5 C(O)NR 5 R', - NR 5 C(S)NR 5 R', -NR 5 C(O)OR' or -SO 2 NR' 2 ;
  • each R" is independently substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 0-4 alkyl-Ce-io aryl or substituted or unsubstituted (Co -4 alkyl)-(5-10 member heterocyclyl); each R 3 is independently substituted or unsubstituted C 6- Io ary.
  • heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m , substituted or unsubstituted C 3-I2 cycloalkyl, substituted or unsubstituted C 5-12 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted straight or branched C 1-8 alkyl, R 20 C(O)N(R 21 )-, R 22 O-, R 23 R 24 NC(O)-, R 26 (CH 2 ) m C(O)N(R 21 )-, R 26 C(O)(CH 2 ) m N(R 21 )-, substituted or unsubstituted C 2-8 alkenyl, or substituted or unsubstituted C 2-8 alkynyl, wherein one or more methylene groups of the Ci -8
  • each R 6 is a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with R ;
  • each R 26 is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono or di-(C 0-4 alkyl)amino, wherein the C 0-4 alkyl is optionally partially or fully halogenated;
  • R 20 is substituted or unsubstituted Q -1O alkyl, substituted or unsubstituted C 0-6 alkyl-phenyl, substituted or unsubstituted C 0-6 alkyl-heterocyclyl, OR' or NR' 2 ;
  • R 21 is hydrogen or C 1-4 branched or unbranched alkyl optionally partially or fully halogenated
  • each R , R and R is independently hydrogen, substituted or unsubstituted C 1-I0 alkyl, wherein the C MO alkyl is optionally interrupted by one or more O, N or S, substituted or unsubstituted Co -6 alkyl-phenyl, substituted or unsubstituted Co -6 alkyl-heterocyclyl; or R 23 and R 24 taken together optionally form a heterocyclic or heteroaryl ring;
  • each R 27 is independently F, Cl, Br, I, cyano, -C(O)R', -C(O)NR' 2 , -C(O)OR', -OR', -NR'R', -SiR' 3 , - S(O) 01 R', substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 2-10 alkenyl, substituted or unsubstituted C 2- Io alkynyl, substituted or unsubstituted C 3-1O cycloalkyl, substituted or unsubstituted C 5-8 cycloalkenyl, substituted or unsubstituted C 7-20 aralkyl, substituted or unsubstituted 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • the compound at a concentration of 10 ⁇ M inhibits induced TNFa-release from a cell by about 50% or greater than 50%.
  • pyrazolyl pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, 4H-benzo[l,4]oxazine-3-only, benzodioxolyl, benzo[l,3]dioxol-2- on
  • pyrrolidinyl tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, or benzofuran-3-one.
  • G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolonyl, benzo[l,4]oxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl,
  • G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomo ⁇ holinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl.
  • G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, or pyridinyl.
  • Ar is indazolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, piperidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C 6-10 aryl.
  • Ar is substituted with at least one R 4 or R 5 .
  • Ar is indazolyl, isoindolyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronapthyl, indanyl, indenyl, or imidazolyl.
  • Ar is indazolyl, phenyl, naphthyl, or tetrahydronaphthyl.
  • Ar is -(C 1-3 alkyl)- (C 6-10 aryl), -(Y)-(C 0-3 alkyl)-(C 6-10 aryl), Or -(Y)-(C 0-3 alkyl)-(5-10 member heteroaryl).
  • Ar is substituted with at least one R 4 or R 5 .
  • Y is -CHR or -CHZ- and Z is -OR.
  • Y is -CH 2 -.
  • the C 6-10 aryl is phenyl or naphthyl or the 5-10 member heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl, or quinazolinyl.
  • Ar is -(Cj -3 alkyl)-(C 6 .io aryl).
  • one or more methylene groups of L are independently replaced by hetero atoms selected from O, NR or S(O) n ,.
  • L is a covalent bond, a C 1 -C 9 alkoxy, - C(O)O-, -NH- or -O-.
  • Q is optionally substituted with R 27 .
  • the first group of compounds of Formula IB Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, ⁇ yrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2 5 3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5- b] ⁇ yridinyl, or imidazo[
  • R 27 is C 1-6 alkyl, C 1-6 alkoxy, hydroxy amino, substituted or unsubstituted 5-10 member heterocyclyl, mono- or di-(C 1-3 alkyl)amino, mono- or di- (phenyl-C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m , phenyl-d- 3 -alkoxy or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkyl or C 1-6 alkoxy.
  • Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinonyl, oxazepinyl, diazepinonyl, imidazolyl, pyridinyl or morpholino.
  • Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl.
  • R 27 is -C(O)OR, -NR'R', substituted or unsubstituted straight or branched C 1-I0 alkyl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted saturated or unsaturated 3- 11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m .
  • Q is pyrimidinyl and R 27 is -NR'R'or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(O) m .
  • Q is pyridinyl
  • R 27 is -NR'R' or substituted or unsubstituted Cj -6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S(0) m .
  • each R 1 is independently:
  • Ci -5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl; each of the aforementioned being optionally, partially or fully halogenated, Ci -6 branched or unbranched alkyl optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, hydroxy, cyano, C 1-3 alkoxy optionally partially or fo
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C 1-3 alkyl groups;
  • C 2 _ 6 branched or unbranched alkyl-C(O), C 2-6 branched or unbranched- S, C 2-6 branched or unbranched-S(O), C 2-6 branched or unbranched-S(O) 2 ;
  • each R 1 is independently C 3-1O branched or unbranched alkyl optionally partially or folly halogenated, and optionally substituted with one to three C 3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, foryl, isoxazolyl, or isothiazolyl; each of which is optionally substituted with 1 to 5 halogen, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, cyano, Cj -3 alkoxy which is optionally partially or fully halogenated and NH 2 C(O) or mono- or di-
  • each R 2 is independently -OR', -OR 6 , -C(O)R', -C(O)OR', -C(O)NR' 2 , -NR' 2 , -NO 2 , -S(O) 1n R", -NR 5 SO 2 R", -NR'C(0)NR'R ⁇ -NR'C(S)NR'R', -NR 5 C(O)OR' or -SO 2 NR' 2 .
  • R 2 is independently -NR' 2 , -NO 2 , -C(0)NR' 2 , -NR 5 SO 2 R", - NR 5 C(O)NR 5 R', -NR 5 C(S)NR 5 R 5 , -NR 5 C(O)OR' or -SO 2 NR' 2 .

Abstract

La présente invention concerne des composés de faible poids moléculaire et leurs compositions, utilisés comme inhibiteurs des cytokines, ainsi que leur préparation. L'invention concerne également des méthodes de prévention et de traitement des troubles médiés par les cytokines, en particulier les troubles inflammatoires, la douleur et le cancer. L'invention concerne également des compositions pharmaceutiques et des dosages posologiques. L'invention concerne en particulier l'utilisation des inhibiteurs des cytokines, éventuellement conjointement avec d'autres thérapies, dans le traitement du cancer, plus particulièrement du gliome, du glioblastome, de l'ostéosarcome et des métastases osseuses. La présente invention concerne, de plus, des méthodes de traitement, de modification et de gestion de la douleur, plus particulièrement des douleurs neuropathiques, consistant à administrer un inhibiteur des cytokines seul ou combiné à un traitement thérapeutique connu.
PCT/US2006/006682 2005-02-24 2006-02-23 Inhibiteurs des cytokines et utilisation therapeutique WO2006091862A2 (fr)

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Cited By (18)

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WO2008030931A2 (fr) * 2006-09-08 2008-03-13 Warsaw Orthopedic, Inc. Procédés de traitement d'une tendinite chez un sujet en utilisant un agent anti-cytokine
WO2009133834A1 (fr) * 2008-04-28 2009-11-05 塩野義製薬株式会社 Dérivé de cétoamide ayant une activité inhibitrice sur la lipase endothéliale
WO2011063076A1 (fr) * 2009-11-19 2011-05-26 Itherx Pharmaceuticals, Inc. Méthodes de traitement du virus de l'hépatite c avec des composés d'oxo-acétamide
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8501713B2 (en) 2007-08-03 2013-08-06 Summit Corporation Plc Drug combinations for the treatment of duchenne muscular dystrophy
US8518980B2 (en) 2006-02-10 2013-08-27 Summit Corporation Plc Treatment of Duchenne muscular dystrophy
US8815265B2 (en) 2010-06-30 2014-08-26 Avon Products, Inc. Cosmetic use of N-substituted sulfonyloxybenzylamines and related compounds
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
WO2016014436A1 (fr) * 2014-07-21 2016-01-28 ElectroCore, LLC Téléphone mobile pour stimuler le nerf trijumeau pour traiter des troubles
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2021145952A1 (fr) * 2020-01-13 2021-07-22 Astromedical Biotechnology, Ltd. Utilisation de kétamine dans le traitement de la cachexie
CN113950476A (zh) * 2019-05-30 2022-01-18 伦敦皇家学院 用于治疗神经性疼痛的经取代4-[5-(苯并呋喃-2-基)-1,2,4-噁二唑-3-基]苯甲酸化合物
WO2023068700A1 (fr) * 2021-10-20 2023-04-27 동국대학교 와이즈캠퍼스 산학협력단 Composition pour la prévention, le soulagement ou le traitement de l'agrégation plaquettaire, comprenant du durumamide a

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WO2005023761A2 (fr) * 2003-09-11 2005-03-17 Kemia, Inc. Inhibiteurs des cytokines

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8518980B2 (en) 2006-02-10 2013-08-27 Summit Corporation Plc Treatment of Duchenne muscular dystrophy
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
WO2008030931A3 (fr) * 2006-09-08 2008-04-24 Warsaw Orthopedic Inc Procédés de traitement d'une tendinite chez un sujet en utilisant un agent anti-cytokine
WO2008030931A2 (fr) * 2006-09-08 2008-03-13 Warsaw Orthopedic, Inc. Procédés de traitement d'une tendinite chez un sujet en utilisant un agent anti-cytokine
US8012955B2 (en) 2006-12-28 2011-09-06 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8697727B2 (en) 2006-12-28 2014-04-15 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US9181220B2 (en) 2006-12-28 2015-11-10 Rigel Pharmaceuticals, Inc. N-substituted-heterocycloalkyloxybenzamide compounds and methods of use
US8501713B2 (en) 2007-08-03 2013-08-06 Summit Corporation Plc Drug combinations for the treatment of duchenne muscular dystrophy
WO2009133834A1 (fr) * 2008-04-28 2009-11-05 塩野義製薬株式会社 Dérivé de cétoamide ayant une activité inhibitrice sur la lipase endothéliale
WO2011063076A1 (fr) * 2009-11-19 2011-05-26 Itherx Pharmaceuticals, Inc. Méthodes de traitement du virus de l'hépatite c avec des composés d'oxo-acétamide
US8815265B2 (en) 2010-06-30 2014-08-26 Avon Products, Inc. Cosmetic use of N-substituted sulfonyloxybenzylamines and related compounds
US9409860B2 (en) 2010-06-30 2016-08-09 Avon Products Inc. Cosmetic use of N-substituted sulfonyloxybenzylamines and related compounds
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
WO2016014436A1 (fr) * 2014-07-21 2016-01-28 ElectroCore, LLC Téléphone mobile pour stimuler le nerf trijumeau pour traiter des troubles
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
US10526286B2 (en) 2015-12-15 2020-01-07 Astrazeneca Ab Compounds
US10988445B2 (en) 2015-12-15 2021-04-27 Astrazeneca Ab Compounds
US11453644B1 (en) 2015-12-15 2022-09-27 Astrazeneca, Ab Compounds
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN113950476A (zh) * 2019-05-30 2022-01-18 伦敦皇家学院 用于治疗神经性疼痛的经取代4-[5-(苯并呋喃-2-基)-1,2,4-噁二唑-3-基]苯甲酸化合物
US11400060B2 (en) 2020-01-13 2022-08-02 Astromedical Biotechnology, Ltd. Use of ketamine in the treatment of cachexia
WO2021145952A1 (fr) * 2020-01-13 2021-07-22 Astromedical Biotechnology, Ltd. Utilisation de kétamine dans le traitement de la cachexie
WO2023068700A1 (fr) * 2021-10-20 2023-04-27 동국대학교 와이즈캠퍼스 산학협력단 Composition pour la prévention, le soulagement ou le traitement de l'agrégation plaquettaire, comprenant du durumamide a

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