EP1189628A1 - Kombination von tumornekrosefaktor (tnf) antagonisten und von cox-2 inhibitoren für die behandlung der entzündung - Google Patents

Kombination von tumornekrosefaktor (tnf) antagonisten und von cox-2 inhibitoren für die behandlung der entzündung

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Publication number
EP1189628A1
EP1189628A1 EP00944668A EP00944668A EP1189628A1 EP 1189628 A1 EP1189628 A1 EP 1189628A1 EP 00944668 A EP00944668 A EP 00944668A EP 00944668 A EP00944668 A EP 00944668A EP 1189628 A1 EP1189628 A1 EP 1189628A1
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Prior art keywords
alkyl
phenyl
halo
pharmaceutical composition
group
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EP00944668A
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French (fr)
Inventor
J. Timothy Keane
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Pharmacia LLC
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Pharmacia LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods for treating an inflammatory disease in a mammal using a tumor necrosis factor antagonist and a selective cyclooxygenase- 2 inhibitor.
  • RA Rheumatoid arthritis
  • DMARDs current disease modifying antirheumatic drugs
  • Current rheumatoid arthritis treatment consists predominantly of symptomatic relief by administration of non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAID treatment is mainly effective in the early stages of rheumatoid arthritis, and is unlikely to produce suppression of joint inflammation if the disease is present for more than one year.
  • MTX methotrexate
  • MTX methotrexate
  • MTX has demonstrated long-term efficacy, but its toxicological profile, e.g., gastrointestinal upset, mucosal ulcerations, renal impairment, pulmonary toxicity, is the most common reason cited among patients for treatment termination.
  • the toxicity profile of MTX remains a major concern among physicians and prolonged treatment with MTX may require invasive biopsy procedures in a patient to monitor hepatic function.
  • Another disease modifying antirheumatic drug, sulfasalazine has been shown to be more effective than hydroxychloroquine in the treatment of rheumatoid arthritis, but it is not as well tolerated, with 20% of patients terminating treatment due to adverse gastrointestinal side effects.
  • Azathioprine, penicillamine and gold compounds have also been shown to be efficacious in treating rheumatoid arthritis, but are not as well tolerated as MTX, sulfasalazine or hydroxychloroquine.
  • Cylcosporine has shown applicability in treating rheumatoid arthritis, but its renal toxicity has limited its usage to salvage therapy or in combination therapy with other disease modifying antirheumatic drugs.
  • treating rheumatoid arthritis with disease modifying antirheumatic drugs remains complicated by poor efficacy and the occurrence of adverse side effects. Lack of predictability of these adverse reactions has made regular monitoring of a patients physiological condition mandatory where long term therapy is anticipated. Such monitoring include, for example, measuring blood count, and/or performing liver, kidney, urine or ophthalmologic tests.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • This class of drugs possesses anti-inflammatory, analgesic and anti-pyretic activity, and are widely used to treat chronic inflammatory states such as arthritis.
  • common NSAIDs that are active in reducing the PG-induced pain and swelling associated with the inflammation process are also active in affecting the other PG-roles which is not associated with the inflammation process.
  • use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential.
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and
  • PGE2 has been a common target of anti-inflammatory drug discovery. Along with this role, PGs play a cytoprotective role in the gastrointestinal tract and also on renal function.
  • COX-2 or "PGHS-2” or “prostaglandin G/H synthase II" provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
  • Compounds which selectively inhibit cyclooxygenase-2 have been described, for example, in U.S.
  • Cytokines are signaling peptide molecules that modulate a wide variety of cellular functions that includes inflammation. Cellular response occurs as a result of interaction between a particular cytokine and high-affinity cell-surface receptors specific for each cytokine. The receptor-binding event leads to the transduction of a signal across the cell membrane and the activation of intracellular biochemical pathways and gene translation or transcription events.
  • Tumor Necrosis Factor-alpha is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated tumor necrosis factor production has been implicated in mediating a number of diseases. Recent studies indicate that tumor necrosis factor has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of tumor necrosis factor has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
  • Tumor necrosis factor has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Ban virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
  • Interleukin-8 (IL-8) is another pro-i ⁇ nflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
  • Interleukin-1 is produced by activated monocytes and macrophages and is also involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
  • Tumor necrosis factor receptor, IL-1 and LL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions.
  • the inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
  • Modulation of cytokine response is achieved by blocking cytokine receptors with small molecules, altering the cytokine to reduce its affinity to its receptor, or by downregulating the expression of cytokines.
  • U.S. Patent No. 5,859,041 describes a class of substituted imidazoles and its use in preventing cytokine mediated disease by inhibiting cytokine activity.
  • U.S. Patent No. 5,772,992 describes compositions comprising a human interleukin-3 variant or mutant protein and another colony stimulating factor, cytokine, lymphokine, interleukin, or hematopoietic growth factor.
  • U.S. Patent No. 5,864,036 describes a class of 1,4,5 -substituted imidazole compounds and their use in treating cytokine mediated diseases.
  • U.S. Patent No. 5,633,272 describes substituted isoxazoles used in co-therapy for the treatment of inflammation, with conventional antiinflammatories.
  • U.S. Patent No. 5,512,544 describes tumor necrosis factor binding proteins useful in the treatment of autoimmune disease and graft-versus-host reactions.
  • U.S. Patent No. 5,698,195 describes anti-tumor necrosis factor antibodies useful in the treatment of, inter alia, chronic inflammatory diseases, and autoimmune disease.
  • WO document WO 91/03553 describes treating TNF-dependent inflammatory disease, such as arthritis, by administrating tumor necrosis factor receptor protein with a interleukin- 1 receptor and/or interleukin-2 receptor.
  • U.S. Patent No. 5,563,165 describes pyrazolyl benzenesulfonamide compounds and their use in treating inflammation and inflammation-related disorders.
  • US Patent No. 5,605,690 describes a method for treating TNF-dependent inflammatory diseases in a mammal by administering a tumor necrosis factor antagonist, and particularly pointing to a TNF-receptor.
  • WO document WO 98/06708 describes a crystalline form of 4-[5-methyl-3- phenylosoxazol-4-yl]benzenesulfonamide in co-therapy with steroids, NSAIDs, 5- lipooxygenase inhibitors, LTB 4 receptor antagonists and LTA hydrolase inhibitors, used in treating cyclooxygenase-2 associated disorders, including inflammation.
  • NSAIDs 5- lipooxygenase inhibitors
  • LTB 4 receptor antagonists LTA hydrolase inhibitors
  • U.S. Patent No. 5,633,273 describes the use of substituted isoxazoles in co- therapy with steroids, NSAIDs, 5-lipooxygenase inhibitors, LTB receptor antagonists and LTA 4 hydrolase inhibitors, for the treatment of inflammation and inflammation related disorders, such as arthritis.
  • U.S. Patent No. 5,869,471 describes the administration of NSAIDs and bone- active phosphonates for the treatment of arthritis.
  • U.S. Patent No. 5,795,967 describes neutralizing antibodies directed against tumor necrosis factor used to suppress inflammatory immune-potentiated events, such as suppressing transplantation immunity and treating autoimmune diseases.
  • U.S. Patent No. 5,306,732 describes vinigrol, a tumor necrosis factor antagonist useful in the treatment of, inter alia, inflammation.
  • U.S. Patent No. 5,672,347 describes tumor necrosis factor antagonists useful for treating inflammation, and in particular the use of neutralizing antibodies directed against tumor necrosis factor in mediating immune-potentiated inflammatory events.
  • a selective cyclooxygenase-2 inhibiting agent and a tumor necrosis factor antagonizing agent for example, etanercept (ENBREL®; Immunex Corp)
  • ENBREL® tumor necrosis factor antagonizing agent
  • the methods, combinations and compositions of the present invention provide effective therapy for treating inflammatory and arthritic disorders, for example, rheumatoid arthritis, with reduced adverse side effects as compared to such methods known in the art.
  • the method comprises treating an inflammatory disorder in a mammal in need thereof, by administering to the mammal a tumor necrosis factor antagonizing agent and a selective cyclooxygenase-2 inhibiting agent.
  • a tumor necrosis factor antagonizing agent and a selective cyclooxygenase-2 inhibiting agent comprise an inflammatory disorder effective amount of the agents.
  • Tumor necrosis factor antagonizing agents useful in the present invention include proteins, or biologically active equivalents thereof, that competitively bind to a cell surface tumor necrosis factor receptor or an intracellular tumor necrosis factor receptor.
  • the tumor necrosis factor antagonizing agent is etanercept, or a biologically active equivalent thereof
  • tumor necrosis factor antagonizing agents useful in the present invention include 2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-l,4-cyclohexadien-l-yl)methylene]- undecanoic acid; lenercept; BB-2275; PCM-4; SH-636; onercept; TBP-1; solimastat; MDL-201112; AGT-1; vinigrol; D-609; 4-[3-(cyclopentyloxy)-4-methoxyphenyl]- pyrrolidinone; CytoTAb®; and Infliximab; or a biologically active equivalent thereof.
  • a class of selective cyclooxygenase-2 inhibiting agents useful in the present invention include compounds of Formula 1 :
  • A is a 5- or 6-member ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxcyclic rings, wherein A is optionally substituted with one or more radicals selected from alkyl, halo, oxo, and alkoxy;
  • R 1 is selected from cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl are optionally substituted with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkyl sulf inyl, halo, alkoxy, and alkylthio; wherein R is selected from alkyl and amino; wherein R 3 is a radical selected from halo, alkyl
  • the methods, combinations and compositions of the present invention can be useful for the treatment or prevention of inflammatory and arthritic disorders in a mammal including, but not limited to, disorders such as: rheumatoid arthritis (RA); osteoarthritis (OA); spondylarthropy; ankylosing spondylitis; psoriatic arthritis; reactive arthritis; IBD related arthritis; undifferentiated spondyloarthropathy; Reider's syndrome; systemic lupus erythematosus; Behcet's disease; eosinophilia fasciitis; eosinophila-myalgia syndrome; familial Mediterranean fever; hereditary angioedema; juvenile chronic arthritis; palindromic rheumatism; idiopathic polymyositis; dermatomyositis; inclusion body myositis; systemic sclerosis; atherosclerosis; sarcoidisis; Reynaud's phenomenon; Sjo
  • the present invention preferably includes compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and in another embodiment have a selectivity ratio of at least 100.
  • selectivity ratios may indicate an ability to reduce the incidence of common NSALO- induced side effects.
  • A is selected from thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzithienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, cyclopentenone, benzopyranopyrazolyl, phenyl, and pyridyl; wherein R 1 is selected from cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is substituted with one or more radicals selected from C ⁇ - 2 alkyl, C 1-2 haloalkyl, cyano, carboxyl, C 1-2 alkoxycarbonyl, hydroxyl, C ]-2 hydroxyalkyl,
  • R 2 is selected from alkyl and amino; wherein R 3 is a radical selected from halo, C 1-2 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, heteroaryl, oxo, cyano, carboxyl, cyano-C ⁇ -3 -alkyl, heterocyclyloxy, C 1-3 alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C 1-3 haloalkyl, heterocyclo, cycloalkenyl, phenyl-C 1-3 -alkyl, heterocyclyl-C 1-3 -alkyl, C ⁇ -3 alkylthio;
  • alkylaminocarbonyl N-phenylaminocarbonyl, N-C ⁇ -3 alkyl-N- phenyl aminocarbonyl, C ⁇ -3 alkylaminocarbonyl-C ⁇ _ 3 -alkyl, carboxy-C ⁇ _ 3 -alkyl, C ⁇ -3 alkylamino, N-arylamino, N-arylkylamino, N-C ]-3 alkyl-N-arylkylamino, N-C ⁇ - 3 alkyl- N-arylamino, amino-C ⁇ -3 -alkyl, C ⁇ _ 3 alkylaminoalkyl, N-phenylamino-C ⁇ -3 -alkyl, N- phenyl-C ⁇ - 3 -alkylaminoalkyl, N-C ⁇ _ 3 alkyl-N-phenyl-C ⁇ - 3 -alkylamino-C ⁇ _ 3 -alkyl, N-Cj.
  • R 4 is selected from hydrido and halo; or a pharmaceutically-acceptable salt thereof.
  • Another class of compounds within Formula 1 of even more interest include compounds wherein A is substituted with one or more radicals selected from alkyl, halo, oxo, and alkoxy; wherein R 1 is selected from pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or phenyl is optionally substituted with one or more radicals selected from alkyl, halo, and alkoxy; wherein R is C ⁇ - 2 alkyl or amino; wherein R 3 is a radical selected from halo, C 1-2 alkyl, cyano, carboxyl, C 1-2 alkyloxy, phenyl, Cl-2 haloalkyl, and C 1-2 hydroxyalkyl; and wherein R is selected from hydrido and fluoro; or a pharmaceutically-acceptable salt thereof.
  • a family of specific compounds within Formula 1 of particular interest include compounds and pharmaceutically-acceptable salts thereof, as follows: Cl)
  • Additional specific compounds of particular interest within Formula I include each of the compounds and pharmaceutically-acceptable salts thereof as follows: 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide, 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone, 2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-chloropyridine:
  • selective cyclooxygenease-2 inhibiting agents useful in the present invention include compounds such as: C30)
  • hydro denotes a single hydrogen atom (H).
  • This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-) radical.
  • haloalkyl alkylsulfonyl
  • alkoxyalkyl alkoxyalkyl
  • hydroxyalkyl the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl” radicals having one to about ten carbon atoms.
  • alkyl radicals having one to about six carbon atoms.
  • examples of such radicals include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkenyl" radicals having two to about six carbon atoms.
  • alkenyl radicals examples include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkynyl denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
  • alkenyl "lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • cycloalkyl embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms.
  • More preferred cycloalkenyl radicals are "lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • halo means halogens such as fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
  • More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
  • the terms "alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
  • More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
  • the term "heterocyclo" embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring- shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclo radicals include saturated 3 to 6- membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.).
  • nitrogen atoms e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g. morpholinyl, etc.
  • heteroaryl embraces unsaturated heterocyclo radicals.
  • unsaturated heterocyclo radicals also termed “heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g.
  • unsaturated condensed heterocyclo group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example
  • benzoxazolyl, benzoxadiazolyl, etc. unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclo group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.
  • the term also embraces radicals where heterocyclo radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said "heterocyclo group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms.
  • alkylthioalkyl embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl.
  • alkylsulfinyl embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -
  • alkylsulfinyl radicals are "lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms.
  • lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methyl sulfonyl, ethylsulfonyl and propylsulfonyl. The "alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
  • halo atoms such as fluoro, chloro or bromo
  • sulfamyl denotes NH2O2S-.
  • acyl denotes a radical provided by the residue after A removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.
  • carbonyl is also intended to encompass a hydrated carbonyl group -C(OH)2-.
  • aroyl embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted.
  • carbboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO2H.
  • carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having 1 to 6 carbons.
  • alkoxycarbonyl (ester) radicals examples include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • alkylcarbonyl examples include radicals having alkyl, aryl and aralkyl radicals, as defined above, attached via an oxygen atom to a carbonyl radical.
  • radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl.
  • aralkyl embraces aryl- substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • benzyl and phenylmethyl are interchangeable.
  • heterocycloalkyl embraces saturated and partially unsaturated heterocyclo-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl.
  • the heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
  • alkyl embraces aralkoxy radicals attached through an oxygen atom to an alkyl radical.
  • aralkylthio embraces aralkyl radicals attached to a sulfur atom.
  • aralkylthioalkyl embraces aralkylthio radicals attached through a sulfur atom to an alkyl radical.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which have been substituted with one or two alkyl radicals.
  • lower N-alkylamino radicals having alkyl portions having 1 to 6 carbon atoms.
  • Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N- phenylamino.
  • the "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
  • aralkylamino embraces aralkyl radicals attached through an nitrogen atom to other radicals.
  • N-arylaminoalkyl and “N- aryl-N-alkyl-aminoalkyl” denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.
  • alkylaminocarbonyl denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom.
  • N-alkylaminocarbonyl "N,N- dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
  • alkylaminoalkyl embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
  • aryloxyalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent oxygen atom.
  • arylthioalkyl embraces radicals having an aryl radical attached to an alkyl radical through a divalent sulfur atom.
  • Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trimethylamine, diethylamine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.
  • isomeric forms and tautomers of the described compounds and the pharmaceutically- acceptable salts thereof are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and galacturonic acids.
  • the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and in another embodiment have a selectivity ratio of at least 100. Such selectivity ratios may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • Nonlimiting examples of cyclooxygenase-2 inhibitors that may be used in the present invention are identified in Table 1 below.
  • the celecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,466,823.
  • valdecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,633,272.
  • the parecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,932,598.
  • the rofecoxib used in the therapeutic combinations of the present invention can be prepared in the manner set forth in U.S. Patent No. 5,968,974.
  • the Japan Tobacco JTE-522 used in the therapeutic combinations of the present invention can be prepared in the manner set forth in JP 90/52,882.
  • the MK-663 used in the therapeutic combination of the present invention can be prepared in the manner set forth in WO document WO 98/03484.
  • tumor necrosis factor receptor or "TNFR” refer to proteins having amino acid sequences which are substantially similar to the native mammalian tumor necrosis factor receptor or tumor necrosis factor binding protein amino acid sequences, and which are capable of binding tumor necrosis factor molecules and inhibiting tumor necrosis factor from binding to cell membrane bound tumor necrosis factor receptor.
  • TNFRI tumor necrosis factor receptor
  • Type II tumor necrosis factor receptor TNFRII
  • the mature full-length human TNFRI is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kDa).
  • the mature full-length human TNFRII is a glycoprotein having a molecular weight of about 55-60 kilodaltons (kDa).
  • the preferred tumor necrosis factor receptors of the present invention are soluble forms of TNFRI and TNFRII, as well as soluble tumor necrosis factor binding proteins.
  • Soluble tumor necrosis factor receptor molecules include, for example, analogs or subunits of native proteins having at least 20 amino acids and which exhibit at least some biological activity in common with TNFRI, TNFRII or tumor necrosis factor binding proteins.
  • Soluble tumor necrosis factor receptor constructs are devoid of a transmembrane region (and are secreted from the cell) but retain the ability to bind tumor necrosis factor.
  • bioequivalent protein and amino acid analogs have an amino acid sequence corresponding to all or part of the extracellular region of a native tumor necrosis factor receptor, for example, huTNFRI DELTA 235, huTNFRI DELTA 185 and huTNFRI DELTA 163, and which are biologically active in that they bind to tumor necrosis factor ligand.
  • Equivalent soluble tumor necrosis factor receptors include polypeptides which vary from these sequences by one or more substitutions, deletions, or additions, and which retain the ability to bind tumor necrosis factor or inhibit tumor necrosis factor signal transduction activity via cell surface bound tumor necrosis factor receptor proteins.
  • tumor necrosis factor antagonist or “tumor necrosis factor antagonist” or “TNF antagonizing agent” or tumor necrosis factor antagonizing agent” refers to, for example, soluble tumor necrosis factor receptor and tumor necrosis factor binding proteins that bind to tumor necrosis factor and prevent tumor necrosis factor from binding to cell membrane bound tumor necrosis factor receptors. Such proteins competitively bind to cell surface receptors or intracellular tumor necrosis factor recognition sites displacing tumor necrosis factor or preventing tumor necrosis factor from binding to or interacting with the cells, therefore suppressing the biological activities caused by tumor necrosis factor.
  • Tumor necrosis factor antagonizing agents that can be used in the present invention include, but not limited to those described in U.S. Patent No. 5,795,967, hereby incorporated by reference. Other examples of tumor necrosis factor antagonists that may be used in the present invention are identified in Table 3 below.
  • the tumor necrosis factor antagonist that may be used in the present invention is etanercept (ENBREL®; Immunex Corp), or its biologically active equivalent.
  • ENBREL® is described in U.S. Patent No. 5,605,690 and is hereby incorporated by reference.
  • ENBREL® is a recombinant version of the soluble p75 Tumor Necrosis Factor receptor (TNFR) linked to the Fc portion of human IgGl. It inhibits tumor necrosis factor biological activity by acting as a competitive inhibitor to the binding of tumor necrosis factor to its cell receptors.
  • tumor necrosis factor is administered in systemic amounts ranging from about 0.1 mg/kg/week to about 100 mg/kg/week.
  • tumor necrosis factor antagonist is administered in amounts ranging from about 0.5 mg/kg/week to about 50 mg/kg/week.
  • dosages preferably range from about 0.01 mg/kg to about 1.0 mg kg per injection.
  • the adult dose of ENBREL® is 25 mg twice a day, as a subcutaneous injection.
  • Biologically active as used throughout the specification as a characteristic of tumor necrosis factor receptor antagonizing agent, means, for example, that a particular molecule shares sufficient amino acid sequence similarity with the embodiments of the present invention disclosed herein to be capable of binding detectable quantities of tumor necrosis factor receptor, transmitting a tumor necrosis factor stimulus to a cell, for example, as a component of a hybrid receptor construct, or cross-reacting with anti-tumor necrosis factor receptor antibodies raised against tumor necrosis factor receptor from natural (i.e., nonrecombinant) sources.
  • the biologically active tumor necrosis factor receptor antagonizing agent within the scope of the present invention are capable of binding greater than 0.1 nmoles tumor necrosis factor per nmole receptor, and in another embodiment, are capable of binding greater than 0.5 nmole tumor necrosis factor per nmole receptor in standard binding assays (see U.S. Patent No. 5.605,690).
  • the phrase "combination therapy" (or "co-therapy”) embraces the administration of a cyclooxygenase-2 inhibiting agent and a tumor necrosis factor antagonizing agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule or intravenous injection having a fixed ratio of each therapeutic agent or in multiple, single capsules or intravenous injections for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • pharmaceutically acceptable is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product.
  • Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
  • treatment refers to any process, action, application, therapy, or the like, wherein a mammal, including a human, is subject to medical aid with the object of improving the mammal's condition, directly or indirectly.
  • terapéuticaally-effective is intended to qualify the amount of each agent that will achieve the goal of improvement in arthritic disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • a "therapeutic effect” relieves to some extent one or more of the symptoms of an arthritic or inflammatory disorder.
  • a therapeutic effect refers to one or more of the following: 1) relieving or reducing to some extent one or more of the symptoms associated with the disorder, 2) relieving or reducing to some extent gastrointestinal upset, 3) relieving or reducing to some extent mucosal ulcerations, 4) relieving or reducing to some extent renal impairment, 5) relieving or reducing to some extent pulmonary toxicity, and/or 6) relieving or reducing the side effects associated with the administration of other antiarthritic agents, such as disease modifying antirheumatic drugs.
  • Dosage levels of cyclooxygenase-2 inhibitors on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg.
  • the amount of active ingredient that may be combined with other agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • purified soluble tumor necrosis factor receptor antagonizing agent is administered to a patient, preferably a human, for treatment of an inflammation disorder, for example arthritis.
  • soluble tumor necrosis factor receptor antagonist compositions can be administered by parental administration, for example, intravenous injection, subcutaneous injection, intramuscular injection, or intramedullary injection.
  • tumor necrosis factor receptor antagonizing agents include, for example, intra- articular, intraperitoneal or subcutaneous routes by bolus injection, continuous infusion, sustained release from implants, or other suitable techniques.
  • a soluble tumor necrosis factor receptor therapeutic agent will be administered in the form of a composition comprising purified protein in conjunction with physiologically acceptable carriers, excipients or diluents. Such carriers will be nontoxic to recipients at the dosages and concentrations employed.
  • compositions entails combining the tumor necrosis factor receptor with buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • antioxidants such as ascorbic acid
  • chelating agents such as EDTA, glutathione and other stabilizers
  • excipients Neutral buffered saline or saline mixed with nonspecific serum albumin are exemplary appropriate diluents.
  • product is formulated as a lyophilizate using appropriate excipient solutions (e.g., sucrose) as diluents. Appropriate dosages can be determined in trials.
  • preservatives may also be added, such as benzyl alcohol.
  • amount and frequency of administration will depend, of course, on such factors as the nature and severity of the indication being treated, the desired response, the condition of the patient, and so forth.
  • tumor necrosis factor receptor antagonizing agent is administered in systemic amounts ranging from about 0.1 mg/kg/week to about 100 mg kg/week. In one embodiment of the present invention, tumor necrosis factor receptor antagonizing agent is administered in amounts ranging from about 0.5 mg/kg/week to about 50 mg kg/week. For local intra- articular administration, dosages preferably range from about 0.01 mg/kg to about 1.0 mg/kg per injection.
  • a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration.
  • Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro initially can provide useful guidance on the proper doses for patient administration. Studies in animal models also generally may be used for guidance regarding effective dosages for treatment of rheumatoid arthritis in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. It will generally be desirable to administer the cyclooxygenase inhibitor either parenterally, intravenously, or subcutaneously. Other routes of administration are also contemplated, including intranasal and transdermal routes, and by inhalation.
  • the therapeutic composition for use in this invention is preferably in the form of a pyrogen-free, parenterally-acceptable aqueous solution.
  • a parenterally-acceptable protein solution having due regard to pH, isotonicity, stability and the like, is within the skill of the art.
  • administration by other routes is contemplated where appropriate.
  • one will desire to administer an amount of the agent that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro.
  • an agent is found to demonstrate in vitro activity at, e.g., 10 ⁇ M
  • one will desire to administer an amount of the drug that is effective to provide about a 10 ⁇ M concentration in vivo Determination of these parameters is well within the skill of the art.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed Y3 as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drugs can be prepared by mixing the drugs with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
  • formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • a contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • a combination of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
  • a combination therapy of a cyclooxygenase-2 inhibitor and a tumor necrosis factor antagonist for the treatment of an arthritic or inflammatory disorder in a mammal can be evaluated as described in the following tests.
  • the cyclooxygenase-2 inhibitors and the tumor necrosis factor antagonist are administered alone or a cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist in combination.
  • the compounds are administered in non-arthritic animals by gavage in a volume of 0.1 ml beginning on day 20 post collagen injection and continuing daily until final evaluation on day 55.
  • animals displaying four normal paws i.e., no redness or swelling are scored 0. Any redness or swelling of digits or the paw is scored as 1. Gross swelling of the whole paw or deformity is scored as 2. Ankylosis of joints is scored as 3.
  • Rat Carrageenan Foot Pad Edema Test The carrageenan foot edema test is performed with materials, reagents and procedures essentially as described by Winter et al., (Proc. Soc. Exp. Biol. Med.. Il l, 544 (1962)). Male Sprague-Dawley rats are selected in each group so that the average body weight is as close as possible. Rats are fasted with free access to water for over sixteen hours prior to the test. The rats are dosed orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone.
  • the analgesia test using rat carrageenan is performed with materials, reagents and procedures essentially as described by Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats are treated as previously described for the Carrageenan Foot Pad Edema test. Three hours after the injection of the carrageenan, the rats are placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant heat source, positionable under the floor. After an initial twenty minute period, thermal stimulation is begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turns off the lamp and timer when light is interrupted by paw withdrawal. The time until the rat withdraws its foot is then measured. The withdrawal latency in seconds is determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined.
  • the method, combinations, agents and compositions of the present invention are also useful for treatment of mammals, including, but not limited to, horses, dogs, cats, rats, mice, sheep, pigs, etc.
  • kits comprising a cyclooxygenase-2 inhibitor and a tumor necrosis factor antagonist.

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WO2001000229A1 (en) 2001-01-04

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