JP2003503360A - Combination therapy for the treatment of inflammatory diseases - Google Patents

Abstract

  (57) [Summary] The present invention provides a combination of a tumor necrosis factor antagonist and a cyclooxygenase-2 inhibitor for the treatment of an inflammatory disease in a mammal.

Description

Detailed Description of the Invention

This application is US provisional application 6 filed June 24, 1999 under 35UC § 119 (e).
Claim priority of 0 / 141,238.

TECHNICAL FIELD The present invention relates to methods of treating inflammatory diseases in mammals using tumor necrosis factor antagonists and selective cyclooxygenase-2 inhibitors.

BACKGROUND ART Rheumatoid arthritis is estimated to occur in 1 to 3% of the general population and is one of the most common causes of disability. There is no known cure for rheumatoid arthritis, and current disease-modifying antirheumatic drugs (DMARDs) do not approach the underlying cause of the disease. Current treatments for rheumatoid arthritis mainly consist of symptomatic remission by administration of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID treatment is effective primarily in early rheumatoid arthritis, and the presence of disease for more than a year is unlikely to result in suppression of joint inflammation. Gold, methotrexate, immunosuppressants and corticosteroids have been tried with limited success. In advanced cases of rheumatoid arthritis, treatment by traditional methods is generally aimed at avoiding toxicity.

Although disease modifying anti-rheumatic drugs also play a preferential role in the treatment of rheumatoid arthritis, their toxicological profile has limited their application and efficacy in long-term therapy. For example, methotrexate (MTX) has demonstrated long-term efficacy, but its toxicological profile, such as gastrointestinal upset, mucosal ulceration, renal injury, and respiratory toxicity, is the most common cause for patients to discontinue treatment. Is. The toxicity profile of MTX leaves doctors with great anxiety, and long-term treatment with MTX requires patients to undergo an invasive biopsy to monitor liver function.

[0005] Another disease-modifying anti-rheumatic drug, sulfasalazine, has been shown to be more effective than hydroxychloroquine in the treatment of rheumatoid arthritis, but is also not well tolerated.
Twenty percent of patients discontinue treatment due to adverse gastrointestinal side effects. Azathioprine,
Penicillamine and gold compounds also showed efficacy in treating rheumatoid arthritis, but MT
Not as tolerant as X, sulfasalazine or hydroxychloroquine. Although cyclosporine has shown applicability in the treatment of rheumatoid arthritis, its nephrotoxicity has limited its utility in life-saving therapy or in combination therapy with other disease-modifying anti-rheumatic drugs. That is, treatment of rheumatoid arthritis with disease modifying anti-rheumatic drugs remains complicated by poor efficacy and adverse side effects. The lack of predictability of these adverse effects forced regular monitoring of the patient's physiological status when long-term treatment was expected. Such monitoring includes, for example, measuring blood counts and / or performing liver, kidney, urine or ophthalmic tests.

Historically, treatment of inflammatory activity has been available through the use of nonsteroidal anti-inflammatory drugs (NSAIDs). This class of drugs has anti-inflammatory, analgesic and antipyretic activities and is widely used in the treatment of chronic inflammatory conditions such as arthritis. However, NSAIDs that are active in reducing PG-induced pain and swelling associated with inflammatory processes also commonly have activities that influence the role of other PGs that are not associated with inflammatory processes. Therefore, the use of most of the most common NSAIDs in high doses can result in serious side effects, including life-threatening ulcers, limiting their therapeutic potential. The use of corticosteroids as an alternative has more dramatic side effects if long-term treatment is involved.

Prostaglandins (PGs) play a major role in the inflammatory process, and the inhibition of prostaglandin production, especially PGG ₂ , PGH ₂ and PGE ₂ has been a general target for the discovery of anti-inflammatory drugs. . Together with this role, PG also plays a cytoprotective role on gastrointestinal and renal function.

The former NSAIDs are enzymes in the human arachidonic acid / prostaglandin pathway,
It has been found to prevent the production of PGs by inhibiting them, including cyclooxygenases (COX). Recent discoveries of inducible enzymes associated with inflammation (called "cyclooxygenase-2" or "COX-2" or "PGHS-2" or "prostaglandin G / H synthase II") reduce inflammation more effectively. Provide a visible target for inhibition that produces fewer or less dramatic side effects.

For compounds that selectively inhibit cyclooxygenase-2, for example, US Pat. Nos. 5,380,738; 5,344,991; 5,393,790; 5,466,823; 5,434,178, 5,4
74,995 and 5,510,368; and WO patents WO96 / 06840; WO96 / 03388; WO96 / 0
3387; WO95 / 15316; WO94 / 15932; WO94 / 27980; WO95 / 00501; WO94 / 13635; WO94 /
20480 and WO94 / 26731.

Cytokines are signaling peptide molecules that modify a wide range of cellular functions, including inflammation. Cellular responses occur as a result of interactions between specific cytokines and high affinity cell surface receptors specific for each cytokine. Receptor-binding events lead to transduction of signals across the cell membrane and activation of intracellular biochemical pathways as well as gene translation or transcription events.

Tumor necrosis factor-α (TNF-α) is a cytokine produced primarily by activated monocytes and macrophages. Excessive or irregular production of tumor necrosis factor has been interpreted as mediating many diseases. Recent studies have indicated that tumor necrosis factor has a causative role in the pathology of rheumatoid arthritis.
Subsequent studies have demonstrated that inhibition of tumor necrosis factor has wide application in the treatment of inflammation, non-specific inflammatory bowel disease, multiple sclerosis and asthma.

Tumor necrosis factor also affects viral infections such as HIV, influenza virus, and herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus. (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7),
It has been implicated in human herpesvirus-8 (HHV-8), herpesviruses including pseudorabies and rhinotracheitis.

Interleukin-8 (IL-8) is another pro-inflammatory cytokine produced by monocytes, fibroblasts, endothelial cells, keratinocytes and associated with conditions involving inflammation.

Interleukin-1 (IL-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 reduced bone resorption.

Tumor necrosis factor, IL-1 and IL-8, affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. Inhibition of these cytokines is beneficial in controlling, reducing and ameliorating many of these disease states. Modulation of the cytokine response is achieved by blockade of the cytokine receptor by small molecules, alteration of the cytokine that reduces the affinity of the cytokine for that receptor, or down-regulation of cytokine expression.

[0016] Rau, R et al. (J. Rheumatol. 1988, 25 (8): 1485-1492) reported methotrexate (MTX) and parenteral gold or MTX and other antirheumatic improving agents in the treatment of rheumatoid arthritis. (DMARD) combined use is described.

Conagham P. & P. Books (Curr. Opin. Rheumatol. 1996, 8 (3): 176-182) describe intramuscular gold and other DMARD and metrexate combination therapies for the treatment of arthritis. It has been described.

Furst D. (J. Rheumatol. Suppl. 1996, 44 (Rheumatoid Arthritis: The Sta
tus and Future of Common Therapy), 86-90) reviews 16 references and describes approaches to combination therapy of rheumatoid arthritis disease improving agents.

Li E. (Curr. Opin. Rheumatol. 1998, 10 (3): 159-168) describes certain disease-improving anti-rheumatic drugs in combination therapy for patients suffering from rheumatoid arthritis. ing.

[0020] Conagham P. et al. (Curr. Opin. Rheumatol. 1997, 9 (3): 183-190) describe the use of MTX, sulfasalazine and hydroxychloroquine in the combined therapy of rheumatoid arthritis.

O'Dell J. et al. (J. Rheumatol. Suppl. 1996, 44 (Rheumatoid Arthritis: The
Status and Future of Combination Therapy), 72-4) describes MTX, sulfasalazine or hydroxychloroquine monotherapy and MTX, sulfasalazine and hydroxychloroquine combination therapy, and MTX and either sulfasalazine or hydroxychloroquine combination therapy. ing.

Dijkmans B. et al. (J. Rheumatol. Suppl. 1996, 44, 23: 61-63) have reported cyclosporin A (CsA) (interleukin 2 (IL-2) and other cytokines) for the treatment of rheumatoid arthritis. It describes a two-phase study in which a production inhibitor) is used in combination with chloroquine.

US Pat. No. 5,700,816 describes the treatment of inflammation and inflammation-related disorders by the combination of selective cyclooxygenase-2 inhibitors with leukotriene A4 hydrolase inhibitors.

US Pat. No. 5,859,041 describes a class of substituted imidazoles and their use in the prevention of cytokine-mediated disorders by inhibiting cytokine activity.

US Pat. No. 5,772,992 describes compositions comprising human interleukin-3 mutant or mutein and other colony stimulating factors, cytokines, lymphokines, interleukins or hematopoietic cell growth factors.

US Pat. No. 5,864,036 describes a class of 1,4,5-substituted imidazole compounds and their use in the treatment of cytokine mediated diseases.

US Pat. No. 5,633,272 describes substituted isoxazoles for use with conventional anti-inflammatory agents in co-therapy for the treatment of inflammation.

US Pat. No. 5,512,544 describes tumor necrosis factor binding proteins useful in the treatment of autoimmune and graft-versus-host disease.

US Pat. No. 5,698,195 describes anti-tumor necrosis factor antibodies particularly useful in the treatment of chronic inflammatory and autoimmune diseases.

WO patent WO91 / 03553 describes tumor necrosis factor receptor protein interleukin-1.
TN by co-administration with receptors and / or interleukin-2 receptors
The treatment of F-dependent inflammatory diseases such as arthritis has been described.

US Pat. No. 5,563,165 describes pyrazolylbenzenesulfonamide compounds and their use in the treatment of inflammation and inflammation-related disorders.

US Pat. No. 5,605,690 describes the administration of tumor necrosis factor antagonists in a method for the treatment of TNF-dependent inflammatory diseases in mammals, notably the TNF-receptors.

WO patent WO98 / 06708 describes co-therapy with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB ₄ receptor antagonists and LTA ₄ hydrolase inhibitors used in the treatment of cyclooxygenase-2-related disorders including inflammation. The crystalline form of 4- [5-methyl-3-phenyloxazol-4-yl] benzenesulfonamide is described.

US Pat. No. 5,633,273 replaces in combination therapy with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB ₄ receptor antagonists and LTA ₄ hydrolase inhibitors for the treatment of inflammation and inflammation-related disorders such as arthritis. The use of isoxazole is described.

US Pat. No. 5,869,471 describes administration of NSAIDs and bone active phosphonates for the treatment of arthritis.

US Pat. No. 5,795,967 describes the neutralization of antibodies raised against tumor necrosis factor used to suppress inflammatory immunity-promoting events such as suppression of transplantation immunity and treatment of autoimmune diseases. Have been described.

US Pat. No. 5,306,732 describes a tumor necrosis factor antagonist, vinigrole, which is particularly useful in the treatment of inflammation.

US Pat. No. 5,672,347 describes tumor necrosis factor antagonists useful in the treatment of inflammation, and the use of antibodies raised against tumor necrosis factor in mediating immunostimulatory inflammatory events, particularly in neutralization. .

DISCLOSURE OF THE INVENTION Administration of selective cyclooxygenase-2 inhibitors and tumor necrosis factor antagonists such as etanercept (ENBREL®; Immunex Corp) in patients with inflammatory diseases. It has been found not only to result in reduced inflammation, but also to maintain and / or increase the range of motion of joints in patients suffering from joint disease. The methods, combinations and compositions of the present invention provide effective therapies for the treatment of inflammation and joint disorders such as rheumatoid arthritis, with reduced adverse side effects as compared to such methods known in the art. .

In this method, a tumor necrosis factor antagonist and a selective cyclooxygenase-2 inhibitor are administered to a mammal to treat an inflammatory disorder in a mammal in need thereof. The tumor necrosis factor antagonist and the selective cyclooxygenase-2 inhibitor together comprise an inflammatory disorder effective amount of those agents.

Tumor necrosis factor antagonists useful in the present invention include proteins that competitively bind to cell surface tumor necrosis factor receptors or intracellular tumor necrosis factor receptors or biologically active equivalents thereof. Included. In one embodiment of the invention, the tumor necrosis factor antagonist is etanercept or a biologically active equivalent thereof.

Other tumor necrosis factor antagonists useful in the present invention include 2-[(4,5-dimethoxy-2-methyl-3,
6-Dioxo-1,4-cyclohexadiene-1-yl) methylene] -undecanoic acid; Renercept; BB-2275; PCM-4; SH-636; Onercept; TBP-1; Solimastat; MDL
-201112; AGT-1; Vinigrole; D-609; 4- [3- (Cyclopentyloxy) -4-methoxyphenyl] -pyrrolidinone; CytoTAb®; and infliximab or biologically active equivalents thereof Is included.

[0043]   A class of selective cyclooxygenase-2 inhibitors useful in the present invention is Formula I:

[Chemical 5] Where A is a 5- or 6-membered ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxycyclo rings, and A is selected from the group consisting of alkyl, halo, oxo and alkoxy. Optionally substituted with one or more radicals, R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl;
Cyclohexyl, pyridinyl or phenyl consists of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio. Optionally substituted with one or more radicals selected from the group, R ² is selected from the group consisting of alkyl and amino, R ³ is halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
Oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl,
Haloalkyl, heterocyclo, cycloalkenyl, phenylalkyl, heterocyclylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, phenylcarbonyl, phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl, phenylyloxyalkyl,
Alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-aryl Amino, N-arylalkylamino, N-alkyl-N-arylalkylamino, N-alkyl-
N-arylamino, aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenyl Alkoxy, phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
R-is a radical selected from the group consisting of N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl, wherein R ⁴ is selected from the group consisting of hydride and halo, or their pharmaceuticals. Pharmaceutically acceptable salts are included.

The methods, combinations and compositions of the present invention can be used to treat or prevent inflammatory and joint disorders in mammals. These disorders include, but are not limited to, rheumatoid arthritis (RA), osteoarthritis (OA).
, Myelitis arthritis, ankylosing myelitis, psoriatic arthritis, reactive arthritis, IBD-related arthritis, undifferentiated myelitis, Ryder syndrome, systemic lupus erythematosus, Behcet's disease, eosinophilic fasciitis, eosinophilia Myalgia syndrome, familial Mediterranean fever, hereditary angioedema, juvenile chronic arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion body myositis, systemic sclerosis, atherosclerosis, sarcoidosis, raynaud Phenomenon, Sjogren's syndrome, Still's disease, systemic rheumatic vasculitis, vasculitis, Wegener's granulomatosis, Whipple's disease and xerostomia are included.

The present invention is preferably cyclooxygenase-1 or more than cyclooxygenase-2.
The compound which selectively inhibits is included. In one embodiment, the compound has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least
50, and in another embodiment has a selectivity of at least 100. Such selectivity ratios dictate the ability to reduce the incidence of common NSAID-induced side effects.

[0046]   Within Formula I, A is thienyl, oxazolyl, furyl, furanone, pyrrolyl, thia.
Zolyl, imidazolyl, benzofuryl, indenyl, benzothienyl (benzithi
enyl), isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl
, Benzoindazolyl, cyclopentenone, benzopyranopyrazolyl, phenyl
Selected from Le, and Pyridyl,   R¹Is selected from cyclohexyl, pyridinyl, and phenyl, and cyclohexene
Cyl for sil, pyridinyl, or phenyl_1-2Alkyl, C_1-2Haloalkyl, cyano
, Carboxyl, C_1-2Alkoxycarbonyl, hydroxyl, C_1-2Hydroxya
Rukiru, C_1-2Haloalkoxy, amino, C_1-2Alkylamino, phenylamino,
Nitro, C_1-2Alkoxy-C_1-2Alkyl, C_1-2Alkylsulfinyl, C_1-2Al
Coxy, halo, alkoxy, and C_1-21 or more than 2 selected from alkylthio
Replaced by the above radical,   R²Is selected from alkyl and amino,   R³Is halo, c_1-2Alkyl, C_2-3Alkenyl, C_2-3Alkynyl, aryl, het
Lower aryl, oxo, cyano, carboxyl, cyano-C_1-3Alkyl, hetero
Kuryloxy, C_1-3Alkyloxy, alkylthio, alkylcarbonyl, shiku
Lower alkyl, phenyl, C_1-3Haloalkyl, heterocyclo, cycloalkenyl,
Phenyl-C_1-3Alkyl, heterocyclyl-C_1-3Alkyl, C_1-3Alkylthio-C_{1- 3} Alkyl, C_1-3Hydroxyalkyl, C_1-3Alkoxycarbonyl, phenyl
Lubonyl, Phenyl-C_1-3Alkylcarbonyl, Phenyl-C_2-3Alkenyl, C_{1- 3} Alkoxy-C_1-3Alkyl, phenylthio-C_1-3Alkyl, phenylyloxy
Alkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylal
Kill, aminocarbonyl, aminocarbonyl-C_1-3Alkyl, C_1-3Alkylami
Nocarbonyl, N-phenylaminocarbonyl, N-C_1-3Alkyl-N-phenylami
Nocarbonyl, C_1-3Alkylaminocarbonyl-C_1-3Alkyl, carboxy-C_1-3 Alkyl, C_1-3Alkylamino, N-arylamino, N-arylalkylamino, N-
 C_1-3Alkyl-N-arylalkylamino, N-C_1-3Alkyl-N-arylamino, a
Mino-C_1-3Alkyl, C_1-3Alkylaminoalkyl, N-phenylamino-C_1-3A
Ruquil, N-phenyl-C_1-3Alkylaminoalkyl, N-C_1-3Alkyl-N-pheny
Le-C_1-3Alkylamino-C_1-3Alkyl, N-C_1-3Alkyl-N-phenylamino-C _1-3 Alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-
C_1-3Alkylthio, C_1-3Alkylsulfinyl, C_1-3Alkylsulfonyl, ami
Nosulfonyl, C_1-3Alkylaminosulfonyl, N-phenylaminosulfonyl,
Phenylsulfonyl, and N-C_1-3From alkyl-N-phenylaminosulfonyl
Is the radical of choice,   R^FourIs a compound of particular interest selected from hydride and halo or those
There are subclasses of pharmaceutically acceptable salts of

In another subclass of compounds within formula I of further interest, A is substituted with one or more radicals selected from alkyl, halo, oxo and alkoxy, R ¹ is pyridyl, Selected from cyclohexyl and phenyl, pyridyl, cyclohexyl or phenyl optionally substituted with one or more radicals selected from alkyl, halo and alkoxy, R ² is C _1-2 alkyl or amino, R ^{2 3} is a radical selected from halo, C _1-2 alkyl, cyano, carboxyl, C _1-2 alkyloxy, phenyl, C _1-2 haloalkyl, and C _1-2 hydroxyalkyl, R ⁴ is hydride and fluoro. Compounds selected from or pharmaceutically acceptable salts thereof are included.

A family of particular compounds within formula I of particular interest includes the following compounds and their pharmaceutically acceptable salts. C1)

[Chemical 6] 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide; C2) 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl ) Pyridine; C3) 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one; C4)

[Chemical 7] 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]-
Benzenesulfonamide; C5)

[Chemical 8] 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) -furanone; C6)

[Chemical 9] 4- (5-Methyl-3-phenylisoxazol-4-yl) benzenesulfonamide; C7) N-[[4- (5-Methyl-3-phenylisoxazol-4-yl) phenyl] sulfonyl] Propanamide; C8)

[Chemical 10] 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]-
Benzenesulfonamide; C9)

[Chemical 11] 3- (4-chlorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; C10)

[Chemical 12] 4- [3- (4-Fluorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; C11)

[Chemical 13] 3- [4- (Methylsulfonyl) phenyl] -2-phenyl-2-cyclopenten-1-one; C12)

[Chemical 14] 4- (2-Methyl-4-phenyl-5-oxazolyl) benzenesulfonamide; C13)

[Chemical 15] 3- (4-Fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -2 (3H) -oxazolone; C14)

[Chemical 16] 5- (4-fluorophenyl) -1- [4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; C15)

[Chemical 17] 4- [5-phenyl-3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; C16)

[Chemical 18] 4- [1-Phenyl-3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; C17)

[Chemical 19] 4- [5- (4-Fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]
Benzenesulfonamide; C18)

[Chemical 20] 1-Fluoro-4- [2- (4- (methylsulfonyl) phenyl) cyclopenten-1-yl] benzene; C19)

[Chemical 21] 4- [5- (4-chlorophenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide; C20)

[Chemical formula 22] 3- [1- [4- (Methylsulfonyl) phenyl] -4- (trifluoromethyl) -1H-imidazol-2-yl] pyridine; C21)

[Chemical formula 23] 4- [2- (3-pyridinyl) -4- (trifluoromethyl) -1H-imidazol-1-yl] benzenesulfonamide; C22)

[Chemical formula 24] 4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; C23)

[Chemical 25] 4- [3- (4-chlorophenyl) -2,3-dihydro-2-oxo-4-oxazolyl] benzenesulfonamide; C24)

[Chemical formula 26] 4- [5- (difluoromethyl) -3-phenylisoxazol-4-yl] benzenesulfonamide; C25)

[Chemical 27] [1, 1 ': 2', 1 "-terphenyl] -4-sulfonamide; C26)

[Chemical 28] 4- (Methylsulfonyl) -1, 1 ', 2], 1 "-terphenyl; C27)

[Chemical 29] 4- (2-phenyl-3-pyridinyl) benzenesulfonamide; C28)

[Chemical 30] C29)

[Chemical 31] C30) 2- (6-Methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine.

Further particular compounds of particular interest within Formula I are each compound 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-methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine:

[Chemical 32] 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl]-
Benzenesulfonamide, 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone, 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole- 1-yl) benzenesulfonamide, 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide, 5-chloro-3- (4- (methylsulfonyl) phenyl) -2- (Methyl-5-pyridinyl) pyridine, 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one, 4- [4- (methylsulfonyl) phenyl ] -3-Phenyl-2 (5H) -furanone, 4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide,
And N-[[4- (5-Methyl-3-phenylisoxazol-4-yl) phenyl] sulfonyl] propanamide.

Other selective cyclooxygenase-2 inhibitors useful in the present invention include the following compounds: C30)

[Chemical 33] C31)

[Chemical 34] C32)

[Chemical 35] 6-[[5- (4-chlorobenzoyl) -1,4-dimethyl-1H-pyrrol-2-yl] methyl] -3 (2
H) -Pyridazinone; C33)

[Chemical 36] N- (4-nitro-2-phenoxyphenyl) methanesulfonamide; C34)

[Chemical 37] C35)

[Chemical 38] 3- (3,4-Difluorophenoxy) -5,5-dimethyl-4- [4- (methylsulfonyl) phenyl] -2 (5H) -furanone; C36)

[Chemical Formula 39] N- [6-[(2,4-Difluorophenyl) thio] -2,3-dihydro-1-oxo-1H-indene-
5-yl] methanesulfonamide; C37)

[Chemical 40] N- [2- (cyclohexyloxy) -4-nitrophenyl] methanesulfonamide; C38)

[Chemical 41] N- [6- (2,4-Difluorophenoxy) -2,3-dihydro-1-oxo-1H-inden-5-yl] methanesulfonamide; C39)

[Chemical 42] 3- (4-chlorophenoxy) -4-[(methylsulfonyl) amino] benzenesulfonamide; C40)

[Chemical 43] 3- (4-Fluorophenoxy) -4-[(methylsulfonyl) amino] benzenesulfonamide; C41)

[Chemical 44] 3-[(1-Methyl-1H-imidazol-2-yl) thio] -4-[(methylsulfonyl) amino]
Benzenesulfonamide; C42)

[Chemical formula 45] 5,5-Dimethyl-4- [4- (methylsulfonyl) phenyl] -3-phenoxy-2 (5H) -furanone; C43)

[Chemical formula 46] N- [6-[(4-Ethyl-2-thiazolyl) thio] -1,3-dihydro-1-oxo-5-isobenzofuranyl] methanesulfonamide; C44)

[Chemical 47] 3-[(2,4-Dichlorophenyl) thio-4-[(methylsulfonyl) amino] benzenesulfonamide; C45)

[Chemical 48] N- (2,3-dihydro-1,1-dioxide-6-phenoxy-1,2-benzisothiazole-5
-Yl) methanesulfonamide; C46)

[Chemical 49] N- [3- (formylamino) -4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]
Methanesulfonamide; C47)

[Chemical 50] C48)

[Chemical 51]

The term “hydride” means a single hydrogen atom (H). The hydride radical can be attached, for example, to an oxygen atom to form a hydroxyl radical, and the two hydride radicals can be attached to a carbon atom to form a methylene (—CH ₂ —) radical. When used alone or in other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, the term “alkyl” refers to 1 to about 20 carbon atoms or Preferably 1 to about 12
Included are linear or branched radicals having 3 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having 1 to about 10 carbon atoms. Most preferred are lower alkyl radicals having 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term "alkenyl" embraces straight-chain or branched radicals having 2 to about 20 carbon atoms or preferably 2 to about 12 carbon atoms and at least one carbon-carbon double bond. . More preferred alkenyl radicals are "lower alkenyl" radicals having 2 to about 6 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkynyl" embraces straight-chain or branched radicals having 2 to about 20 carbon atoms or preferably 2 to about 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having 2 to about 10 carbon atoms. Most preferred are lower alkynyl radicals having 2 to about 6 carbon atoms. Examples of such radicals include propargyl, putinyl and the like. The terms "alkenyl", "lower alkenyl" include radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "cycloalkyl" includes saturated carbocyclic radicals having 3 to 12 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to about 8 carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkenyl" includes radicals of partially unsaturated carbocycles having 3 to 12 carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having 4 to about 8 carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" embraces radicals in which any one or more of the alkyl carbon atoms is replaced by a halogen as defined above. Especially included are monohaloalkyl, dihaloalkyl and polyhaloalkyl. Monohaloalkyl radicals have, for example, either iodine, bromine, chlorine or fluorine atoms within the radical. Dihalo and polyhaloalkyl radicals can have 2 or 3 or more of the same halo atoms or combinations of different halo radicals, "lower haloalkyl" embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, Dichloroethyl, and dichloropropyl are included. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having 1 to about 10 carbon atoms, any atom of which is substituted with one or more hydroxy radicals. More preferred hydroxy radicals are "lower hydroxyalkyl" having 1 to 6 carbon atoms and one or more hydroxy radicals.
It is a radical. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" each include straight or branched oxy-containing radicals where the alkyl portion has 1 to about 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" embraces alkyl radicals in which one or more alkoxy radicals are attached to an alkyl radical, ie, a monoalkoxyalkyl and dialkoxyalkyl radical. An "alkoxy" radical can also be substituted with one or more halo atoms such as fluoro, chloro or bromo to form a haloalkoxy radical. More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having 1 to 6 carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing 1, 2, or 3 rings, which rings may be attached or fused in a pendant fashion. . The term "aryl" includes phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aryl residue is also at the substituted position alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, It may be substituted with one or more substituents independently selected from aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term "heterocyclo" includes saturated, partially unsaturated and unsaturated heteroatom-containing cyclic radicals. In this case, the heteroatoms can be selected from nitrogen, sulfur and oxygen. Examples of the saturated heterocyclo radical include a saturated 3- to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); 1 or 2 oxygen atoms and a nitrogen atom. Saturated 3 to 6 membered heteromonocyclic group containing 1 to 3 (for example, morpholinyl etc.); Saturated 3 to 6 membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (Eg, thiazolidinyl and the like) are included. Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropyran and dihydrotuazole. The term "heteroaryl" includes unsaturated heterocycle radicals. Unsaturated heterocyclic radicals are also referred to as "heteroaryl" radicals, examples of which are unsaturated 3-6 membered heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, Pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
Triazolyl (eg, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H
-1,2,3-triazolyl etc.), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl etc.), etc .; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, Benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyrazinyl (for example, tetrazolo [1,5-b] pyridazinyl, etc.); unsaturated 3- to 6-membered heteromonocyclic group containing an oxygen atom , For example, pyranyl, furyl and the like; unsaturated 3- to 6-membered heteromonocyclic group containing a sulfur atom, such as thienyl and the like; 1-2 oxygen atoms and
Unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,5-oxadiazolyl and the like) and the like; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (for example, benzoxazolyl, benzooxadiazolyl and the like); 1 to Unsaturated 3 to 6 membered heteromonocyclic group containing 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl , 1,2,5-thiadiazolyl, etc.); unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzothiadiazolyl, etc.) and the like are included. To be done. The term also includes radicals where heterocycle radicals are fused with aryl radicals. Such fused bicyclic radicals include benzofuran, benzothiophene and the like. The above "heterocyclic group" means alkyl, hydroxyl, halo,
It may have 1 to 3 substituents such as alkoxy, oxo, amino and alkylamino. The term "alkylthio" embraces radicals including straight-chain or branched alkyl radicals of 1 to about 10 carbon atoms attached to a divalent sulfur atom. Further preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of 1 to 6 carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthioalkyl" includes 1 to about 10 divalent sulfur atoms.
Radicals containing an alkylthio radical attached to an alkyl radical of 4 carbon atoms are included. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" having alkyl radicals of 1 to 6 carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical of 1 to 10 carbon atoms attached to a divalent S (= O) -radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkyl radicals of 1 to 6 carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "sulfonyl", whether used alone or linked to other words, such as for example alkylsulfonyl, denotes each divalent radical --SO _2- . "
“Alkylsulfonyl” includes an alkyl radical attached to a sulfonyl radical, where alkyl is as defined above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl and propylsulfonyl. An “alkylsulfonyl” radical can be further substituted with one or more halo atoms such as fluoro, chloro or bromo to form a haloalkylsulfonyl radical. The terms "sulfamyl", "aminosulfonyl" and "sulfonylamidyl" are NH ₂ O ₂ S-
Means The term "acyl" is provided by the residue after removal of the hydroxyl from the organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkaloyl radicals include:
Formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl are included. "
The term "carbonyl" or "oxo", whether used alone or with other terms, such as "alkoxycarbonyl," means-(C = O)-. The term carbonyl is also intended to include the hydrated carbonyl group —C (OH) ₂ . The term "aroyl" includes aryl groups having a carbonyl as defined above. Examples of aroyl include benzoyl, naphthoyl, etc., and the aryl in the above aroyl may be further substituted. The term "carboxy" or "carboxyl", also means a -CO ₂ H, even when used as with other words for example "carboxyalkyl" used alone. The term "carboxyalkyl" embraces alkyl radicals substituted with carboxy radicals. “Lower carboxyalkyl” including lower alkyl radicals as described above is more preferable, and the alkyl radical may be further substituted with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical in which an alkoxy radical, as defined above, is attached to the carbonyl radical via an oxygen atom. More preferred are "lower alkoxycarbonyl" radicals in which the alkyl moiety has 1 to 6 carbon atoms. Examples of such lower alkoxycarbonyl (ester) radicals are substituted or unsubstituted methoxycarbonyl,
Included are ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" refer to an alkyl as defined above,
Aryl and aralkyl radicals include radicals linked to a carbonyl radical via an oxygen atom. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcyclocarbonyl and benzylcarbonyl. The term "aralkyl" includes aryl substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in the above aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are synonymous. The term "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 the above heteroaralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The term "aralkoxy" embraces aralkyl radicals which are attached to another radical via an oxygen atom. The term "aralkoxyalkyl" embraces aralkoxy radicals attached to the alkyl radical through an oxygen atom. The term "aralkylthio" includes aralkyl radicals attached to an alkyl radical via a sulfur atom. The term "aralkylthioalkyl" embraces aralkylthio radicals attached to the alkyl radical via a sulfur atom. The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl and the like. The term "alkylamino" is 1 or 2
Means an amino group substituted with 4 alkyl radicals. 1 alkyl part
“Lower N-alkylamino” radicals having ˜6 carbon atoms are preferred. Suitable lower alkylamino are mono- or dialkylamino such as N-methylamino,
Examples thereof include N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like. The term "arylamino" means an amino group substituted with 1 or 2 aryl radicals, for example N-phenylamino. An "arylamino" radical may be further substituted with the aryl ring portion of the radical. The term "aralkylamino" includes aralkyl radicals which are attached to another radical via a nitrogen atom. The terms "N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl" are substituted with one aryl radical or one aryl and one alkyl radical, respectively, and the amino group is an alkyl radical. Means an amino group attached to a radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term “aminocarbonyl” means an amide group of the formula —C (═O) NH ₂ . The term "alkylaminocarbonyl" means an aminocarbonyl group in which the amino nitrogen atom is replaced with one or two alkyl radicals. The "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" radicals are preferred. More preferred are "lower N-alkylaminocarbonyl" and "lower N, N-dialkylaminocarbonyl" radicals, in which case the lower alkyl moiety is as defined above. The term "alkylaminoalkyl" embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term "aryloxyalkyl" embraces radicals having an aryl radical attached to the alkyl radical via a divalent oxygen atom. The term "arylthioalkyl" embraces radicals having an aryl radical attached to the alkyl radical via a divalent sulfur atom.

Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metal ion salts and organic ion salts. Particularly preferred metal ion salts include, but are not limited to, suitable alkali metal (group Ia) salts, alkaline earth metal (II
Group a) salts and other physiologically acceptable metal ion salts are included. Such salts can be prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc ions. Preferred organic salts can be prepared from tertiary amine and quaternary ammonium salts. Some included within these are 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 from the corresponding compound of the invention in any conventional manner.

The combinations of the present invention also include isomeric forms and tautomers of the described compounds and pharmaceutically acceptable salts thereof. Exemplary pharmaceutically acceptable salts are
Formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranil Acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid). Prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, β-hydroxybutyric acid, galacturic acid and galacturonic acid .

The terms “cyclooxygenase-2 inhibitor” or “COX-2 inhibitor” or “cyclooxygenase-2 inhibitor” or “COX-2 inhibitor” selectively inhibit cyclooxygenase-2 over cyclooxygenase-1 Including compounds.
In one embodiment, the compounds have a cyclooxygenase-2 to cyclooxygenase-1 selectivity of at least 50, and in another embodiment a selectivity of at least 100. Such selectivity ratios dictate the ability to reduce the incidence of common NSAID-induced side effects.

Non-limiting examples of cyclooxygenase-2 inhibitors used in the present invention are shown in Table 1 below.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

The following individual references listed in Table 2 below are incorporated herein by reference:
These describe various cyclooxygenase-2 inhibitors suitable for use in the inventions described herein and methods for their preparation.

[Table 5]

[Table 6]

Celecoxib used in the therapeutic combination of the present invention can be prepared by the method described in US Pat. No. 5,466,823.

Valdecoxib used in the therapeutic combination of the present invention can be prepared by the method described in US Pat. No. 5,633,272.

Parecoxib used in the therapeutic combination of the present invention can be prepared by the method described in US Pat. No. 5,932,598.

The rofecoxib used in the therapeutic combination of the present invention can be prepared by the method described in US Pat. No. 5,968,974.

Japan Tabacco JTE-522 used in the therapeutic combination of the present invention is JP 90/52,
It can be produced by the method described in 882.

MK-663 used in the therapeutic combination of the present invention can be prepared by the method described in WO Patent WO98 / 03484.

As used herein, the term “tumor necrosis factor receptor” or “TNFR” refers to
Means a protein having an amino acid sequence substantially similar to that of a native mammalian tumor necrosis factor receptor or tumor necrosis factor binding protein, binding to tumor necrosis factor molecule and to cell membrane bound tumor necrosis factor receptor Can inhibit the binding of tumor necrosis factor. The existence of two different types of tumor necrosis factor receptor, type I tumor necrosis factor receptor (TNFRI) and type II tumor necrosis factor receptor (TNFRII), is known. Mature full-length human TNFRI is a glycoprotein with a molecular weight of approximately 75-80 kilodaltons (kDa). Mature full-length human TNFRII is a glycoprotein with a molecular weight of approximately 55-60 kilodaltons (kDa). Preferred tumor necrosis factor receptors of the present invention are soluble forms of TNFRI and TNRRII, and soluble tumor necrosis factor binding proteins. Soluble tumor necrosis factor receptor molecules include, for example, a native protein analog or sub-protein having at least 20 amino acids and exhibiting at least some biological activity in common with TNFRI, TNFRII or a tumor necrosis factor binding protein. Units are included. Soluble tumor necrosis factor receptor constructs lack the transmembrane region (secreted by the cell) but retain the ability to bind tumor necrosis factor. Various bioequivalent proteins and amino acid analogs are associated with native tumor necrosis factor receptors such as hu
It has amino acid sequences corresponding to all or part of the extracellular region of TNFRI DELTA 235, huTNFRI DELTA 185 and huTNFRI DELTA 163, which are biologically active in binding tumor necrosis factor ligands. Equivalent soluble tumor necrosis factor receptors are altered by these sequences and one or more substituents, deletions or additions to maintain the ability to bind tumor necrosis factor or to bind cell surface bound tumor necrosis. Included are polypeptides that inhibit tumor necrosis factor signaling activity via factor receptor proteins.

The term “TNF antagonist” or “tumor necrosis factor antagonist” or “TNF antagonist” or “tumor necrosis factor antagonist” binds, for example, to tumor necrosis factor,
By soluble tumor necrosis factor receptor and tumor necrosis factor binding protein which interferes with the binding of tumor necrosis factor to cell membrane bound tumor necrosis factor receptor. Such proteins bind to cell surface receptors or intracellular tumor necrosis factor recognition sites to replace tumor necrosis factor, or interfere with tumor necrosis factor binding to or interacting with cells, and thus tumor necrosis. Inhibits biological activity caused by factors. Tumor necrosis factor antagonists that can be used in the present invention are described in, but not limited to, US Pat. No. 5,795,967. This content is incorporated herein by reference. Other examples of tumor necrosis factor antagonists that can be used in the present invention are listed in Table 3 below.

[Table 7]

[Table 8]

In one embodiment, the tumor necrosis factor antagonist that can be used in the present invention is Etanercept (ENBREL ^™ ; Immunex Corp) or a biologically active equivalent thereof. EN
BREL ^™ is described in US Pat. No. 5,605,690. The contents of which are incorporated herein by reference. ENBREL ^™ is a recombinant version of soluble p75 tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. It inhibits tumor necrosis factor activity by acting as a competitive inhibitor of the binding of tumor necrosis factor to its cellular receptor. For treatment of arthritis or inflammation, tumor necrosis factor about 0.1 mg / kg / week to about
Systemic doses in the range of 100 mg / kg / week are administered. In one embodiment of the invention, a tumor necrosis factor antagonist is administered in an amount ranging from about 0.5 mg / kg / week to about 50 mg / kg / week. For local intra-articular administration, the dose is preferably about 0.01 mg / kg per injection
It is in the range of about 1.0 mg / kg. In another embodiment of the invention, the adult dose of ENBREL ^™ is 25 mg twice daily as a subcutaneous injection.

The term “biologically active” as used throughout this specification as a property of tumor necrosis factor antagonists refers to, for example, a particular molecule that binds a detectable amount of tumor necrosis factor receptor to the tumor. Transfer of tumor necrosis factor stimulation to cells with necrosis factor stimulation as a component of the hybrid receptor construct or anti-tumor excited to tumor necrosis factor receptor from a natural (ie, non-recombinant) source It is meant to form a sufficient amino acid sequence similar to the embodiments of the invention disclosed herein that is capable of cross-reacting with necrosis factor receptor antibodies. In an embodiment of the present invention, a biologically active tumor necrosis factor receptor antagonist within the scope of the present invention has a standard binding assay (see US Pat. No. 5,605,690) of 0.1 nmol or more tumors per 1 nmol receptor. Necrosis factor can bind,
In another embodiment, 0.5 nmol or more of tumor necrosis factor can bind to 1 nmol of receptor.

The phrase “combination therapy” (or “cotherapy”) refers to cyclooxygenase-2
It involves providing administration of the inhibitor and tumor necrosis factor antagonist as part of a specific dosing 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, the pharmacokinetic or pharmacokinetic co-action resulting from the combination of therapeutic agents. Combination administration of these therapeutic agents will usually be carried out within a predetermined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination therapy” generally is not intended to encompass administration of one or more of these therapeutic agents on a separate monotherapy basis to result in the combination of the present invention, either accidentally or necessarily. “Combination therapy” is intended to include sequential administration of these therapeutic agents, ie administration of each therapeutic agent at different times, as well as substantially simultaneous administration of at least two of these therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule or intravenous injection with a fixed ratio of each therapeutic agent, or multiple administration of a single capsule or intravenous injection of each therapeutic agent. . Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, the oral route, the intravenous route, the intramuscular route, and direct product absorption via mucosal tissue. , The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent of the selected combination may be administered by intravenous injection while the other therapeutic agent may be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered intravenously. The order of administration of the therapeutic agents is not critical.

The term “pharmaceutically acceptable” as used rhetorically herein means that the modified noun is suitable for use in a pharmaceutical product. Pharmaceutically acceptable cations include metal ions and organic ions. More preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Examples of ions are aluminum, calcium, lithium, magnesium, potassium,
Included are sodium and zinc, their normally charged ions. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations such as trimethylamine, diethylamine N, N'-dibenzylethylamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and Procaine is included. Examples of pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid. acid,
It includes isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid and the like.

The term “treatment” refers to any method, activity, application, treatment, etc., which is the subject of pharmaceutical assistance for the purpose of directly or indirectly improving the condition of mammals, including humans. .

The phrase “therapeutically effective” refers to an improvement in the severity and frequency of joint disease by treatment with each therapeutic agent alone, as well as an amount of the therapeutic agent that avoids the side effects normally associated with another treatment. It is the intention to show.

A “therapeutic effect” is to alleviate one or more symptoms of an articular or inflammatory disorder. Regarding the treatment of rheumatoid arthritis, the therapeutic effect means one or more of the following. That is, 1) relieving or reducing one or more symptoms associated with the disorder to some extent, 2) relieving or reducing the disorder of the gastrointestinal tract to some extent, 3) relieving or weakening mucosal ulcer to some extent, 4 ) Relieving or weakening renal damage to some extent, 5) Relieving or reducing pulmonary toxicity to some extent, and / or 6) Relieving or reducing side effects associated with administration of other anti-arthritic agents such as disease-improving anti-rheumatic drugs. That is.

Cyclooxygenase-2 inhibitors are useful in the treatment of the above conditions on the order of about 0.1 mg to about 10,000 mg of active ingredient compound, with preferred levels of about 0.1 mg to about 1,000 mg.
Is. The amount of active ingredient that is combined with other agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

For therapeutic use, for the treatment of inflammatory diseases such as arthritis, a purified soluble tumor necrosis factor receptor antagonist is administered to a patient, preferably a human. That is,
For example, the soluble tumor necrosis factor receptor antagonist composition can be administered parenterally, eg, by intravenous, subcutaneous, intramuscular, or intraspinal injection.
Other routes of administration of tumor necrosis factor receptor antagonists include, for example, bolus injection, continuous infusion, sustained release from implants or other suitable intra-articular, intraperitoneal or subcutaneous routes. Typically, the soluble tumor necrosis factor receptor therapeutic agent is administered in the form of a composition consisting of purified protein with a physiologically acceptable carrier, excipient or diluent. Such carriers are nontoxic to recipients at the dosages and concentrations employed. Generally, buffers, antioxidants such as ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates such as glucose, sucrose or dextrin are used to prepare such compositions.
Mixing of the tumor necrosis factor receptor with chelating agents such as EDTA, glutathione and other stabilizers and excipients is required. Neutral buffered saline or saline mixed with non-specific serum albumin are examples of suitable diluents. It is preferably formulated as a lyophilizate using a suitable excipient solution (eg sucrose) as a diluent. The appropriate dose can be determined by trial. Preservatives such as benzyl alcohol are added according to appropriate industry standards. The quantity and frequency administered will, of course, depend on such factors as the nature and severity of the indication to be treated, the desired response, the condition of the patient.

For the treatment of arthritis or inflammatory disorders, tumor necrosis factor receptor antagonist is about 0.1 mg /
An amount ranging from kg / week to about 100 mg / kg / week is administered systemically. In one embodiment of the invention, the tumor necrosis factor receptor antagonist is administered in an amount ranging from about 0.5 mg / kg / week to about 50 mg / kg / week. For topical intraarticular administration, preferred dosages range from about 0.01 mg / kg to about 1.0 mg / kg per injection.

However, the particular dose level for a particular patient will include activity, age, weight, general health, sex, diet, duration of administration, excretion rate of the particular compound used,
It should be understood that it will depend on various factors including the combination of agents, the severity of the particular disease treated and the mode of administration.

Treatment dosages will generally be determined to optimize safety and efficacy. In general, providing a dose-effect relationship initially in vitro is a useful guide for administering the appropriate dose to a patient. Testing in animal models is also commonly used for guidance on effective dosages for the treatment of rheumatoid arthritis according to the present invention. In terms of treatment protocol, the dose administered will depend on the particular drug administered, the route of administration,
It should be understood that it depends on several factors, including the particular patient's condition and the like. Cyclooxygenase inhibitors are generally preferably administered parenterally, intravenously or subcutaneously. Other routes of administration are also contemplated, including nasal and transdermal routes as well as inhalation. When administered, the therapeutic compositions used in the invention are preferably in the form of a pyrogen-free, parenterally acceptable aqueous solution. Regarding pH, of course,
The manufacture of such parenterally acceptable protein solutions that are isotonic and stable is well known to those skilled in the art. However, administration by other routes is also considered as appropriate. Generally speaking, it is desirable to administer an amount of an agent effective to achieve serum levels at concentrations found to be effective in vitro. Thus, for example, for a drug that has demonstrated in vitro activity at 10 μM, it is desirable to administer an amount of drug effective in vivo to provide a concentration of about 10 μM. Determination of these parameters is well known to those skilled in the art.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as 1,3-butanediol.
Among the acceptable vehicles and solvents that can be used are water, Rengel's solution, and isotonic sodium chloride solution. Furthermore, sterilized fixed oils are also convenient for use as solvents or suspension media. For this purpose any formulated non-volatile oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are also useful in preparing injectables. Dimethylacetamide, surfactants including ionic and nonionic, polyethylene glycol can also be used. Mixtures of solvents and wetting agents such as those mentioned above are also useful.

Suppositories for rectal administration of the drug are suitable non-irritating excipients for the drug, "solid at ambient temperature but liquid at rectal temperature" and thus melt in the rectum to release the drug. For example, it can be prepared by mixing the drug with cocoa butter, synthetic mono-, di- or triglycerides, fatty acids and polyethylene glycol.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the compound of the invention is typically mixed with one or more adjuvants appropriate to the indicated route of administration. For oral administration, contemplated aromatic sulfone hydroxymate inhibiting compounds are lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, oxides, phosphoric acid and sulfuric acid. Are mixed with sodium and calcium salts of, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or capsuled for convenient administration. Such capsules or tablets include controlled release formulations which provide the active compound as a dispersion in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the dosage form may also include buffering agents such as sodium citrate, carbonate or magnesium or calcium bicarbonate. Tablets and pills can additionally be enteric coated.

For therapeutic purposes, formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions are
It can be prepared from sterile powders or granules having one or more carriers or diluents as described above for use in the formulations for oral administration. The contemplated aromatic sulfone hydroxymate inhibitor compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, aqueous sodium chloride solution and / or various buffers. . Other adjuvants and modes of administration are well within the skill of the pharmaceutical arts,
Widely known.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Watched Adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents may also be added to such compositions.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the mammalian host treated and the particular mode of administration.

The combinations of the present invention can be formulated as pharmaceutical compositions. Such compositions are then orally, parenterally, by inhalation spray, in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and the desired vehicle. It can be administered rectally or topically. For topical administration,
For example, transdermal administration using transdermal patches or iontophoresis devices is included.
Parenteral terms as used herein include subcutaneous injection, intravenous, intramuscular, sternal muscle injection,
Or includes injection techniques.

The above considerations regarding effective formulations and dosing procedures are well known in the art and are described in standard texts. For drug formulations, for example, Hoov
er, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,
Waston, Pennsylvania; 1975. This is incorporated herein by reference. Other considerations regarding drug formulation include Liberman, HA & Lachman, L.
Edited, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980. This is incorporated herein by reference.

Biological Evaluation Combination therapy of cyclooxygenase-2 inhibitors and tumor necrosis factor antagonists for the treatment of articular and inflammatory disorders in mammals can be evaluated as described in the following studies. it can.

Induction and Evaluation of Collagen-Induced Arthritis in Mice As reported previously in male DBA / 1 mice aged 8-12 weeks (J. Stuart, Annual.
Rev. Immunol. 2: 199, 1984) 50 mg in complete Freund's adjuvant (Sigma)
Avian type II collagen (CII) is injected into the base of the tail on day 0 to induce arthritis.
Compound is 0.5% methylcellulose (Sigma, St. Louis, MO), 0.025% Tween 20
Prepare as a suspension in (Sigma). The cyclooxygenase-2 inhibitor and tumor necrosis factor antagonist are administered alone or in combination with the cyclooxygenase-2 inhibitor and tumor necrosis factor antagonist. Compounds are administered to non-arthritic animals by gavage in a volume of 0.1 ml daily starting 20 days after collagen injection and until the day of final evaluation at 55 days. Animals received 50 mg in incomplete Freund's adjuvant on day 21
Avian type II collagen (CII) is administered as a booster. Animals are then evaluated several times each week until day 56 for the incidence and severity of arthritis. Redness or swelling of the footpads is counted as arthritis. Severity scoring is performed as previously reported using a score of 0 to 3 (maximum score 12 / mouse) for each footpad (P. Wooley et al., Tr.
ans. Proc. 15: 180, 1983). The animals measure the incidence of arthritis, and the severity of arthritis is measured for the animals in which arthritis was observed. The incidence of arthritis is determined at the macroscopic level by observing swelling or redness of the foot or toes. Severity is measured according to the following guidelines. Briefly, 4 normal footpads with no redness or swelling are scored 0. Grade 1 if there is redness or swelling in either the toes or foot pads. If there is gross swelling or deformation of the entire footpad, it is rated 2. Joint stiffness is rated as 3.

Histological Examination of Footpads A histological examination is performed to confirm the gross assessment of non-arthritic animals.
At the end of the experiment, the footpads from the sacrificed animals are excised, fixed and decalcified as previously reported (R. Jonsson, J. Immunol. Methods 88: 109, 1986). Samples are embedded in paraffin, sectioned and stained with hematoxylin and eosin by standard methods. The stained sections are examined for cell infiltration, synovial fluid hyperplasia, and bone and cartilage erosion.

Rat Carrageenan Paw Edema Test The rat carrageenan paw edema test was performed by Winter et al. (Proc. Soc. Exp. Biol. Med. 111).
: 544, 1962) essentially by the materials, reagents and procedures described. Male Sprague-Dawley rats are selected so that the average weight of each group is as close as possible. Rats are fasted for 16 hours prior to testing with water ad libitum. 0.5 to rat
The compound or vehicle alone, suspended in a vehicle containing% methylcellulose and 0.025% surfactant, is administered orally (1 mL). One hour later, 0.1 mL of a 1% solution of carrageenan / sterile 0.9% saline was injected under the footpad, and the volume of the injected limb was
Measure with a displacement plethysmometer connected to a pressure transducer with a digital indicator. Limb volume is measured again 3 hours after carrageenan injection. Mean limb swelling in drug-treated animals was compared to that in placebo-treated animals to determine edema inhibition (Otterness & Bliven, Laboratory Models for Testing NS
AID, in Non-steroidal Anti-Inflammatory Drugs, J. Lombardino, 1985)
.

Rat Carrageenan-Induced Analgesic Test The analgesic test with rat carrageenan is performed with the materials, reagents and procedures essentially as described by Hargreaves et al. (Pain 32: 77, 1988). Male Sprague-Dawley rats previously described for the rat carrageenan footpad edema test are treated.
Three hours after carrageenan injection, the rats are placed in a special Plexiglas container with a transparent floor with a high-intensity lamp underneath as a source of irradiation heat. Initially, after a 20 minute period, thermal stimulation is initiated on either the injected limb or the contralateral uninjected limb. The photocell turns off the lamp and timer when the light is interrupted by the footpad avoidance. The time until the rat withdraws its paw is then measured. Latency to avoidance is measured in seconds in the control and drug treated groups to determine the percent inhibition of avoidance of hyperalgesic limbs.

In addition to being useful in the treatment of humans, the methods, combinations, agents and compositions of the present invention include, but are not limited to, mammals, horses, dogs, cats, rats, mice, sheep. It is also useful for treating pigs, pigs, etc.

The present invention further includes a kit consisting of a cyclooxygenase-2 inhibitor and a tumor necrosis factor antagonist.

Although the present invention has been described in terms of particular embodiments, the details of these embodiments are not intended to limit the invention.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/34 A61K 31/34 4C063 31/341 31/341 4C069 31/352 31/352 4C084 31/4015 31 / 4015 4C085 31/402 31/402 4C086 31/415 31/415 4C206 31/4164 31/4164 31/42 31/42 31/421 31/421 31/427 31/427 31/428 31/428 31/4418 31/4418 31/4439 31/4439 31/444 31/444 31/501 31/501 38/00 39/395 N 39/395 A61P 9/10 A61P 9/10 17/00 17/00 17/06 17 / 06 19/00 19/00 19/02 19/02 21/00 21/00 25/28 25/28 29/00 29/00 101 101 35/00 35/00 43/00 111 43/00 111 C07D 207 / 33 // C07D 207/33 213/34 213/34 213/61 213/61 231/12 F 231/12 261/08 261/08 263/32 263/32 275/06 275/06 307/58 307/58 311/58 311/58 401/04 401/04 405/06 405/06 417/12 417/12 A61K 37/02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL , SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG , BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, L U, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR , TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW F terms (reference) 4C033 AA03 AA04 AA12 AA20 4C037 JA04 4C055 AA01 BA02 BA08 BA27 BB04 BB17 CA01 CB02 A01C0 CB02 A01 CB15 CB02 A01 CB15 CB02 A01C0 AB01 AC01 AC02 AD01 AE03 BA03 BA07 BA10 BB01 BB04 BC01 4C062 FF05 FF53 4C063 AA01 BB01 BB08 CC25 CC28 CC76 DD04 DD12 DD62 EE01 4C069 AC07 4C084 AA02 AA20 BA08 MA23 MA52 MA31 MA31 MA21 MA23 MA23 MA28 MA13 MA17 MA22 MA13 MA17 MA22 MA13 MA17 MA22 MA13 MA17 MA22 MA13 MA17 MA22 MA13 MA28 MA21 MA23 MA13 MA17 MA22 MA13 MA17 MA22 MA23 MA13 MA17 MA23 MA13 MA65 MA66 NA14 ZA022 ZA362 ZA452 ZA892 ZA942 ZA962 ZB112 ZB152 ZB262 ZC202 4C085 AA13 BB11 CC21 EE01 EE03 GG02 GG03 GG04 GG06 GG08 4C086 AA01 BA03 BA08 BC04 BC08 BC17 BC36 BC38 BC41 BC67 BC69 BC80 BC82 BC84 GA02 GA07 GA08 GA10 MA02 MA04 MA13 MA17 MA22 MA23 MA28 MA31 MA35 MA37 MA4 1 MA43 MA52 MA55 MA56 MA63 MA65 MA66 NA14 ZA02 ZA36 ZA45 ZA89 ZA94 ZA96 ZB11 ZB15 ZB26 ZC20 4C206 AA01 CB21 DA11 JA01 JA13 KA01 MA02 MA04 MA33 MA37 MA42 MA43 MA45 ZA45 MA45 MA86 MA85 MA86 MA86 MA82 MA75 MA76 NA76 MA75 MA76 NA76 ZA94 ZA96 ZB11 ZB15 ZB26 ZC20

Claims (272)

[Claims] 1. A tumor necrosis factor antagonist and a selective cyclooxygenase-2 inhibitor, a tumor necrosis factor antagonist and a selective cyclooxygenase-2, to a mammal in need thereof in a method of treating an inflammatory disorder in a mammal. A method of administering both of the inhibitors so as to obtain a drug effective amount for inflammatory disorders. 2. The method according to claim 1, wherein the tumor necrosis factor antagonist is a protein. 3. The method according to claim 2, wherein the protein competitively binds to a cell surface tumor necrosis factor receptor. 4. The method according to claim 2, wherein the protein competitively binds to an intracellular tumor necrosis factor receptor. 5. The method according to claim 2, wherein the tumor necrosis factor antagonist is etanercept. 6. A tumor necrosis factor antagonist is 2-[(4,5-dimethoxy-2-methyl-3,6-
Dioxo-1,4-cyclohexadiene-1-yl) methylene] -undecanoic acid; Renercept; Etanercept; BB-2275; PCM-4; SH-636; Onercept; Vinigrole; TBP-1; Solimastat; MDL-201112; AGT -1; D-609; 4- [3- (cyclopentyloxy) -4-methoxyphenyl] -pyrrolidinone; CytoTAb (registered trademark); and the method according to claim 1, which is selected from the group consisting of infliximab. 7. A selective cyclooxygenase-2 inhibitor has the formula I: Where A is a 5- or 6-membered ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxycyclo rings, and A is selected from the group consisting of alkyl, halo, oxo and alkoxy. Optionally substituted with one or more radicals, R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl;
Cyclohexyl, pyridinyl, or phenyl is derived from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio. Optionally substituted with one or more selected radicals, R ² is selected from the group consisting of alkyl and amino, R ³ is halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
Oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl,
Haloalkyl, heterocyclo, cycloalkenyl, phenylalkyl, heterocyclylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, phenylcarbonyl, phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl, phenylyloxyalkyl,
Alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-aryl Amino, N-arylalkylamino, N-alkyl-N-arylalkylamino, N-alkyl-
N-arylamino, aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenyl Alkoxy, phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
R-is a radical selected from the group consisting of N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl, wherein R ⁴ is selected from the group consisting of hydride and halo, or their pharmaceuticals. A method according to claim 1 selected from pharmaceutically acceptable salts. 8. A is thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzoindazolyl, cyclopentenone, benzopyra. The method according to claim 7, which is selected from the group consisting of nopyrazolyl, phenyl, and pyridyl. 9. The method according to claim 8, wherein A is substituted with one or more radicals selected from the group consisting of alkyl, halo, oxo, and alkoxy. 10. The method according to claim 9, wherein A is substituted with one or more halo radicals. 11. The method of claim 10 wherein halo is chloro. 12. The method according to claim 9, wherein A is substituted with one or more alkyl radicals. 13. The method according to claim 12, wherein alkyl is methyl. 14. The method according to claim 9, wherein A is substituted with one or more oxo residues. 15. The method according to claim 9, wherein A is substituted with one or more alkoxy radicals. 16. R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is C _1-2 alkyl, C _1-2 haloalkyl, cyano, carboxyl, C _1-2 alkoxycarbonyl. , Hydroxyl, C _1-2 hydroxyalkyl, C _1-2 haloalkoxy, amino, C _1-2 alkylamino, phenylamino, nitro, C _1-2 alkoxy-C _1-2 alkyl, C _1-2 alkylsulfinyl, “C _1-2 alkoxy, halo, alkoxy, and C _1-2 alkylthio optionally substituted with one or more radicals” 7.
The method described. 17. R ¹ is selected from the group consisting of pyridyl, cyclohexyl, and phenyl, and pyridyl, cyclohexyl, or phenyl is any one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. The method according to claim 7, which is substituted with. 18. The method according to claim 17, wherein R ¹ is pyridyl. 19. The method according to claim 18, wherein pyridyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 20. The method of claim 19, wherein pyridyl is substituted with alkyl. 21. The method of claim 20, wherein the alkyl is C _1-2 alkyl. 22. The method of claim 21, wherein alkyl is methyl. 23. The method of claim 19, wherein pyridyl is substituted with halo. 24. The method of claim 23, wherein halo is chloro. 25. The method of claim 17, wherein R ¹ is cyclohexyl. 26. The "claim 25" wherein cyclohexyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
The method described. 27. A method according to claim 25, wherein cyclohexyl is substituted with alkyl.
The method described. 28. The method of claim 27, wherein alkyl is C _1-2 alkyl. 29. The method of claim 28, wherein alkyl is methyl. 30. The method of claim 25, wherein pyridyl is substituted with halo. 31. The method of claim 30, wherein halo is chloro. 32. The method of claim 17, wherein R ¹ is phenyl optionally substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 33. The method of claim 32, wherein phenyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 34. The method of claim 33, wherein phenyl is substituted with alkyl. 35. The method of claim 34, wherein alkyl is C _1-2 alkyl. 36. The method of claim 35, wherein alkyl is methyl. 37. The method of claim 7, wherein R ² is alkyl or amino. 38. The method of claim 37, wherein alkyl is C _1-2 alkyl. 39. The method of claim 38, wherein alkyl is methyl. 40. R³Is halo, c_1-2Alkyl, C_2-3Alkenyl, C_2-3Alkini
Ru, aryl, heteroaryl, oxo, cyano, carboxyl, cyano-C_1-3
Alkyl, heterocyclyloxy, C_1-3Alkyloxy, alkylthio, alk
Lecarbonyl, cycloalkyl, phenyl, C_1-3Haloalkyl, heterocyclo,
Cycloalkenyl, phenyl-C_1-3Alkyl, heterocyclyl-C_1-3Alkyl, C_{1 -3} Alkylthio-C_1-3Alkyl, C_1-3Hydroxyalkyl, C_1-3Alkoxycar
Bonyl, phenylcarbonyl, phenyl-C_1-3Alkylcarbonyl, Phenyl-C _2-3 Alkenyl, C_1-3Alkoxy-C_1-3Alkyl, phenylthio-C_1-3Alkyl
, Phenylyloxyalkyl, alkoxyphenylalkoxyalkyl, alco
Xycarbonylalkyl, aminocarbonyl, aminocarbonyl-C_1-3Alkyl
, C_1-3Alkylaminocarbonyl, N-phenylaminocarbonyl, N-C_1-3Al
Kill-N-phenylaminocarbonyl, C_1-3Alkylaminocarbonyl-C_1-3Archi
Le, carboxy-C_1-3Alkyl, C_1-3Alkylamino, N-arylamino, N-a
Reel Kiramino, N-C_1-3Alkyl-N-arylalkylamino, N-C_1-3Alkyl-
N-arylamino, amino-C_1-3Alkyl, C_1-3Alkylaminoalkyl, N-f
Phenylamino-C_1-3Alkyl, N-phenyl-C_1-3Alkylaminoalkyl, N-C _1-3 Alkyl-N-phenyl-C_1-3Alkylamino-C_1-3Alkyl, N-C_1-3Alkyl
-N-phenylamino-C_1-3Alkyl, phenyloxy, phenylalkoxy, fu
Phenylthio, phenyl-C_1-3Alkylthio, C_1-3Alkylsulfinyl, C_1-3A
Rukyisulfonyl, aminosulfonyl, C_1-3Alkylaminosulfonyl, N-fe
Nylaminosulfonyl, phenylsulfonyl, and N-C_1-3Alkyl-N-pheny
"Claim 7" which is a radical selected from the group consisting of luaminosulfonyl.
the method of. 41. R ³ is a radical selected from the group consisting of halo, C _1-2 alkyl, cyano, carboxyl, C _1-2 alkyloxy, phenyl, C _1-2 haloalkyl, and C _1-2 hydroxyalkyl. The method according to claim 40, wherein 42. The method according to claim 7, wherein R ⁴ is hydride. 43. The method of claim 7, wherein R ⁴ is halo. 44. The method of claim 43, wherein halo is fluoro. 45. The method of claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 46. The method according to claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 47. The method of claim 7, wherein the selective cyclooxygenase-2 inhibitor is 2- (6-methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine. . 48. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. 7 ”. 49. The method of claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) -furanone. 50. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. The method described. 51. The method of claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 52. A selective cyclooxygenase-2 inhibitor is 5-chloro-3- (4- (
The method according to claim 7, which is methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine. 53. The selective cyclooxygenase-2 inhibitor is 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one "Claim 7". The method described. 54. The method of claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 55. The method according to claim 7, wherein the selective cyclooxygenase-2 inhibitor is 4- [5-methyl-3-phenyl-isoxazol-4-yl] benzenesulfonamide. 56. A selective cyclooxygenase-2 inhibitor is N-[[4- (5-methyl-
The method according to claim 7, which is 3-phenylisoxazol-4-yl) phenyl] sulfonyl] propanamide. 57. The method of claim 1, wherein both agents are administered sequentially. 58. The method of claim 1, wherein both agents are administered substantially simultaneously. 59. The method of claim 1, wherein the tumor necrosis factor antagonist is administered parenterally. 60. The method according to claim 59, wherein the parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection or intraspinal injection. 61. The method of claim 1, wherein the selective cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are formulated in a single composition. 62. The method of claim 1, wherein the selective cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are each provided as separate components of the kit. 63. The inflammatory disorder is rheumatoid arthritis, osteoarthritis, spinal arthritis, ankylosing myelitis, psoriatic arthritis, reactive arthritis, IBD-related arthritis, undifferentiated myelitis, Ryder syndrome, systemic lupus erythematosus, Behcet's disease, eosinophilic fasciitis, eosinophilic polymyalgia syndrome, familial Mediterranean fever, hereditary angioedema, juvenile chronic arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion bodies Myositis, systemic sclerosis, atherosclerosis, sarcoidosis, Raynaud's phenomenon, Sjogren's syndrome, Still's disease, systemic rheumatic vasculitis, vasculitis, Wegener's granulomatosis, Whipple's disease and xerostomia “Claim 1
The method described. 64. The method of claim 63, wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis and osteoarthritis. 65. The method of claim 64, wherein the inflammatory disorder is rheumatoid arthritis. 66. The method of claim 64, wherein the inflammatory disorder is osteoarthritis. 67. A method of treating an inflammatory disorder in a mammal in need thereof, the method comprising administering to the mammal a tumor necrosis factor antagonist and a selective cyclooxygenase-2 inhibitor, both agents being both A method consisting of an effective amount against inflammatory disorders. 68. The method of claim 67, wherein the tumor necrosis factor antagonist is a protein. 69. The method of claim 68, wherein the protein competitively binds to a cell surface tumor necrosis factor receptor. 70. The method of claim 68, wherein the protein competitively binds to the tumor necrosis factor receptor inside the cell. 71. The tumor necrosis factor antagonist is etanercept.
The method described. 72. A tumor necrosis factor antagonist is 2-[(4,5-dimethoxy-2-methyl-3,
6-Dioxo-1,4-cyclohexadiene-1-yl) methylene] -undecanoic acid; ethanecept; renercept; BB-2275; PCM-4; SH-636; onercept; TBP-1; solymasat; MDL-201112; AGT -1; D-609; 4- [3- (cyclopentyloxy) -4-methoxyphenyl] -pyrrolidinone; CytoTAb (R); and the method of claim 67, selected from the group consisting of: and infliximab. 73. A selective cyclooxygenase-2 inhibitor has the formula I: Where A is a 5- or 6-membered ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxycyclo rings, and A is selected from the group consisting of alkyl, halo, oxo and alkoxy. Optionally substituted with one or more radicals, R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl;
Cyclohexyl, pyridinyl, or phenyl is derived from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio. Optionally substituted with one or more selected radicals, R ² is selected from the group consisting of alkyl and amino, R ³ is halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
Oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl,
Haloalkyl, heterocyclo, cycloalkenyl, phenylalkyl, heterocyclylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, phenylcarbonyl, phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl, phenylyloxyalkyl,
Alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-aryl Amino, N-arylalkylamino, N-alkyl-N-arylalkylamino, N-alkyl-
N-arylamino, aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenyl Alkoxy, phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
R-is a radical selected from the group consisting of N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl, wherein R ⁴ is selected from the group consisting of hydride and halo, or their pharmaceuticals. 68. The method of claim 67 selected from pharmaceutically acceptable salts. 74. A is thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl,
The method of claim 73 selected from the group consisting of isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzoindazolyl, cyclopentenone, benzopyranopyrazolyl, phenyl, and pyridyl. 75. The method of claim 74, wherein A is substituted with one or more radicals selected from the group consisting of alkyl, halo, oxo, and alkoxy. 76. The method of claim 75, wherein A is substituted with halo. 77. The method of claim 76, wherein halo is chloro. 78. The method of claim 77, wherein A is substituted with alkyl. 79. The method of claim 78, wherein alkyl is methyl. 80. The method of claim 75, wherein A is substituted with oxo. 81. The method of claim 75, wherein A is alkoxy substituted. 82. R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is C _1-2 alkyl, C _1-2 haloalkyl, cyano, carboxyl, C _1-2 alkoxycarbonyl. , Hydroxyl, C _1-2 hydroxyalkyl, C _1-2 haloalkoxy, amino, C _1-2 alkylamino, phenylamino, nitro, C _1-2 alkoxy-C _1-2 alkyl, C _1-2 alkylsulfinyl, 74. The method of claim 73, wherein the method is substituted with one or more radicals selected from C _1-2 alkoxy, halo, alkoxy, and C _1-2 alkylthio. 83. R ¹ is selected from the group consisting of pyridyl, cyclohexyl, and phenyl, and pyridyl, cyclohexyl, or phenyl is any one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. The method of claim 73 substituted with. 84. The method of claim 83, wherein R ¹ is pyridyl. 85. The method of claim 84, wherein pyridyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 86. The method of claim 85, wherein pyridyl is substituted with alkyl. 87. The method of claim 86, wherein alkyl is C _1-2 alkyl. 88. The method of claim 87, wherein alkyl is methyl. 89. The method of claim 85, wherein pyridyl is substituted with halo. 90. The method of claim 89, wherein halo is chloro. 91. The method of claim 83, wherein R ¹ is cyclohexyl. 92. The "claim 91" wherein cyclohexyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
The method described. 93. The method of claim 91, wherein cyclohexyl is substituted with alkyl.
The method described. 94. The method of claim 93, wherein alkyl is C _1-2 alkyl. 95. The method of claim 94, wherein alkyl is methyl. 96. The method of claim 92, wherein pyridyl is substituted with halo. 97. The method of claim 96, wherein halo is chloro. 98. The method of claim 83, wherein R ¹ is phenyl. 99. The method of claim 98, wherein phenyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 100. The method of claim 99, wherein phenyl is substituted with alkyl. 101. The method of claim 100, wherein alkyl is C _1-2 alkyl. 102. The method of claim 101, wherein alkyl is methyl. 103. The method of claim 73, wherein R ² is alkyl or amino. 104. The method of claim 103, wherein alkyl is C _1-2 alkyl. 105. The method of claim 104, wherein alkyl is methyl. Wherein 106] R ³ is halo, C _1-2 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heteroaryl, oxo, cyano, carboxyl, cyano -C _1-3 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 _1-3 alkylthio-C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 alkylcarbonyl, phenyl-
C _2-3 alkenyl, C _1-3 alkoxy-C _1-3 alkyl, phenylthio-C _1-3 alkyl, phenylyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 Alkyl, C _1-3 alkylaminocarbonyl, N-phenylaminocarbonyl, N-C _1-3 alkyl-N-phenylaminocarbonyl, C _1-3 alkylaminocarbonyl-C _1-3 alkyl, carboxy-C _1-3 Alkyl, C _1-3 alkylamino, N-arylamino, N-
Arylalkylamino, N-C _1-3 alkyl-N-arylalkylamino, N-C _1-3 alkyl-N-arylamino, amino-C _1-3 alkyl, C _1-3 alkylaminoalkyl, N-
Phenylamino-C _1-3 alkyl, N-Phenyl-C _1-3 alkylaminoalkyl, N-
C _1-3 alkyl-N-phenyl-C _1-3 alkylamino-C _1-3 alkyl, N-C _1-3 alkyl-N-phenylamino-C _1-3 alkyl, phenyloxy, phenylalkoxy,
Phenylthio, phenyl-C _1-3 alkylthio, C _1-3 alkylsulfinyl, C _1-3
A radical selected from the group consisting of alkylsulfonyl, aminosulfonyl, C _1-3 alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-C _1-3 alkyl-N-phenylaminosulfonyl. 73 "
The method described. 107. R ³ is a radical selected from the group consisting of halo, C _1-2 alkyl, cyano, carboxyl, C _1-2 alkyloxy, phenyl, C _1-2 haloalkyl, and C _1-2 hydroxyalkyl. The method of claim 106, wherein 108. The method of claim 73, wherein R ⁴ is hydride. 109. The method of claim 73, wherein R ⁴ is halo. 110. The method of claim 109, wherein halo is fluoro. 111. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 112. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 113. The selective cyclooxygenase-2 inhibitor is 2- (6-methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine.
A method according to claim 73. 114. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. 73 ”. 115. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) -furanone. 116. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. The method described. 117. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 118. A selective cyclooxygenase-2 inhibitor is 5-chloro-3- (4-
The method according to claim 73, which is (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine. 119. The claim 73 wherein the selective cyclooxygenase-2 inhibitor is 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one. The method described. 120. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 121. A selective cyclooxygenase-2 inhibitor is 4- [5-methyl-3-
Phenyl-isoxazol-4-yl] benzenesulfonamide.
The method described. 122. The method of claim 73, wherein the selective cyclooxygenase-2 inhibitor is N-[[4- (5-methyl-3-phenylisoxazol-4-yl) phenyl] sulfonyl] propanamide. Method. 123. The method of claim 67, wherein both agents are administered sequentially. 124. The method of claim 67, wherein both agents are administered substantially simultaneously. 125. The tumor necrosis factor antagonist is administered parenterally.
7 ”. 126. The method according to claim 125, wherein the parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection or intraspinal injection. 127. The method of claim 67, wherein the selective cyclooxygenase-2 inhibitor and tumor necrosis factor antagonist are formulated in a single composition. 128. The method of claim 67, wherein the selective cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are each provided as separate components of the kit. 129. The inflammatory disorder is rheumatoid arthritis, osteoarthritis, spinal arthritis, ankylosing myelitis, psoriatic arthritis, reactive arthritis, IBD-related arthritis, undifferentiated myelitis, Ryder syndrome, systemic lupus erythematosus, Behcet's disease, eosinophilic fasciitis, eosinophilic polymyalgia syndrome, familial Mediterranean fever, hereditary angioedema, juvenile chronic arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion bodies Myositis, systemic sclerosis, atherosclerosis, sarcoidosis, Raynaud's phenomenon, Sjogren's syndrome, Still's disease, systemic rheumatic vasculitis, vasculitis, Wegener's granulomatosis, Whipple's disease and xerostomia The method of claim 67, selected from 130. The method of claim 129, wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis and osteoarthritis. 131. The claim 130, wherein the inflammatory disorder is rheumatoid arthritis.
The method described. 132. A method of using the composition in the manufacture of a medicament useful in the treatment of an inflammatory disorder in a mammal in need thereof, the composition comprising a tumor necrosis factor antagonist and a cyclooxygenase-2 inhibitor. , Both drugs consist of effective amounts against inflammatory disorders. 133. The tumor necrosis factor antagonist is a protein.
The method described. 134. The method of claim 133, wherein the protein competitively binds to a cell surface tumor necrosis factor receptor. 135. The method according to claim 133, wherein the protein competitively binds to a tumor necrosis factor receptor inside a cell. 136. The tumor necrosis factor antagonist is etanercept.
33 ”. 137. A tumor necrosis factor antagonist is 2-[(4,5-dimethoxy-2-methyl-
3,6-Dioxo-1,4-cyclohexadiene-1-yl) methylene] -undecanoic acid; Etanercept; Renercept; BB-2275; PCM-4; SH-636; Onercept; TBP-1;
Solimastat; MDL-201112; AGT-1; D-609; 4- [3- (cyclopentyloxy) -4-
132. The method of claim 132, selected from the group consisting of methoxyphenyl] -pyrrolidinone; CytoTAb®; and infliximab. 138. A selective cyclooxygenase-2 inhibitor has the formula I: Where A is a 5- or 6-membered ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxycyclo rings, and A is selected from the group consisting of alkyl, halo, oxo and alkoxy. Optionally substituted with one or more radicals, R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl;
Cyclohexyl, pyridinyl, or phenyl is derived from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio. Optionally substituted with one or more selected radicals, R ² is selected from the group consisting of alkyl and amino, R ³ is halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
Oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl,
Haloalkyl, heterocyclo, cycloalkenyl, phenylalkyl, heterocyclylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, phenylcarbonyl, phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl, phenylyloxyalkyl,
Alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-aryl Amino, N-arylalkylamino, N-alkyl-N-arylalkylamino, N-alkyl-
N-arylamino, aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenyl Alkoxy, phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
R-is a radical selected from the group consisting of N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl, wherein R ⁴ is selected from the group consisting of hydride and halo, or their pharmaceuticals 138. The method of claim 132, wherein the method is selected from pharmaceutically acceptable salts. 139. A is thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzoindazolyl, cyclopentenone, benzopyran 138. The method of claim 138 selected from the group consisting of nopyrazolyl, phenyl, and pyridyl. 140. A claim 139, wherein A is substituted with one or more radicals selected from the group consisting of alkyl, halo, oxo, and alkoxy.
The method described. 141. The method of claim 140, wherein A is substituted with halo. 142. The method of claim 141, wherein halo is chloro. 143. A'wherein A is substituted by alkyl.
The method described. 144. The method of claim 143, wherein alkyl is methyl. 145. The method of claim 140, wherein A is substituted with oxo. 146. The method of claim 140, wherein A is alkoxy substituted. 147. R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is C _1-2 alkyl, C _1-2 haloalkyl, cyano, carboxyl, C _1-2 alkoxycarbonyl. ,
Hydroxyl, C _1-2 hydroxyalkyl, C _1-2 haloalkoxy, amino, C _1-2 alkylamino, phenylamino, nitro, C _1-2 alkoxy-C _1-2 alkyl, C _1-2
139. A compound of claim 138, which is substituted with one or more radicals selected from alkylsulfinyl, C _1-2 alkoxy, halo, alkoxy, and C _1-2 alkylthio.
The method described. 148. R ¹ is selected from the group consisting of pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or phenyl is alkyl,
139. The method of claim 138, optionally substituted with one or more radicals selected from the group consisting of halo and alkoxy. 149. The method of claim 148, wherein R ¹ is pyridyl. 150. The method of claim 149, wherein pyridyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 151. Pyridyl is substituted with alkyl. "Claim 150."
The method described. 152. The method of claim 151, wherein alkyl is C _1-2 alkyl. 153. The method of claim 152 wherein alkyl is methyl. 154. The method of claim 150, wherein pyridyl is substituted with halo. 155. The method of claim 154, wherein halo is chloro. 156. The method of claim 144, wherein R ¹ is cyclohexyl. 157. Cyclohexyl substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
The method described in 6). 158. Cyclohexyl substituted with alkyl
56 ”. 159. The method of claim 158, wherein alkyl is C _1-2 alkyl. 160. The method of claim 159, wherein alkyl is methyl. 161. The method of claim 156, wherein pyridyl is substituted with halo. 162. The method of claim 161, wherein halo is chloro. 163. The method of claim 148, wherein R ¹ is phenyl. 164. Phenyl substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
The method described. 165. The compound of claim 164, wherein phenyl is substituted with alkyl.
The method described. 166. The method of claim 165, wherein alkyl is C _1-2 alkyl. 167. The method of claim 166, wherein alkyl is methyl. 168. The method of claim 138, wherein R ² is alkyl or amino. 169. The method of claim 168, wherein alkyl is C _1-2 alkyl. 170. The method of claim 169, wherein alkyl is methyl. Wherein 171] R ³ is halo, C _1-2 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heteroaryl, oxo, cyano, carboxyl, cyano -C _1-3 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 _1-3 alkylthio-C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 alkylcarbonyl, phenyl-
C _2-3 alkenyl, C _1-3 alkoxy-C _1-3 alkyl, phenylthio-C _1-3 alkyl, phenylyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 Alkyl, C _1-3 alkylaminocarbonyl, N-phenylaminocarbonyl, N-C _1-3 alkyl-N-phenylaminocarbonyl, C _1-3 alkylaminocarbonyl-C _1-3 alkyl, carboxy-C _1-3 Alkyl, C _1-3 alkylamino, N-arylamino, N-
Arylalkylamino, N-C _1-3 alkyl-N-arylalkylamino, N-C _1-3 alkyl-N-arylamino, amino-C _1-3 alkyl, C _1-3 alkylaminoalkyl, N-
Phenylamino-C _1-3 alkyl, N-Phenyl-C _1-3 alkylaminoalkyl, N-
C _1-3 alkyl-N-phenyl-C _1-3 alkylamino-C _1-3 alkyl, N-C _1-3 alkyl-N-phenylamino-C _1-3 alkyl, phenyloxy, phenylalkoxy,
Phenylthio, phenyl-C _1-3 alkylthio, C _1-3 alkylsulfinyl, C _1-3
A radical selected from the group consisting of alkylsulfonyl, aminosulfonyl, C _1-3 alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-C _1-3 alkyl-N-phenylaminosulfonyl. 138
The method described. 172. R ³ is a radical selected from the group consisting of halo, C _1-2 alkyl, cyano, carboxyl, C _1-2 alkyloxy, phenyl, C _1-2 haloalkyl, and C _1-2 hydroxyalkyl. The method of claim 171 which is 173. The method of claim 138, wherein R ⁴ is hydride. 174. The method of claim 138 wherein R ⁴ is halo. 175. The method of claim 174, wherein halo is fluoro. 176. The method of claim 138, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 177. The method of claim 138, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 178. The selective cyclooxygenase-2 inhibitor is 2- (6-methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine.
138. The method of claim 138. 179. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. 138 ". 180. The method of claim 138, wherein the selective cyclooxygenase-2 inhibitor is 4- (4- (methylsulfonyl) phenyl) -3-phenyl-2 (5H) -furanone. 181. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. The method described. 182. The method of claim 138, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 183. A selective cyclooxygenase-2 inhibitor is 5-chloro-3- (4-
The method of claim 138, which is (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine. 184. The claim 138, wherein the selective cyclooxygenase-2 inhibitor is 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one. The method described. 185. The method of claim 138, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 186. A selective cyclooxygenase-2 inhibitor is 4- [5-methyl-3-
Phenyl-isoxazol-4-yl] benzenesulfonamide.
8 ”. 187. The "claim 138" according to claim 138, wherein the selective cyclooxygenase-2 inhibitor is N-[[4- (5-methyl-3-phenylisoxazol-4-yl) phenyl] sulfonyl] propanamide. Method. 188. The method of claim 132, wherein both agents are administered sequentially. 189. The method of claim 132, wherein both agents are administered substantially simultaneously. 190. The tumor necrosis factor antagonist is administered parenterally.
32 ”. 191. The method of claim 190, wherein the parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection or intraspinal injection. 192. The method of claim 132, wherein the selective cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are formulated in a single composition. 193. The method of claim 132, wherein the selective cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are each provided as separate components of the kit. 194. The inflammatory disorder is rheumatoid arthritis, osteoarthritis, spinal arthritis, ankylosing myelitis, psoriatic arthritis, reactive arthritis, IBD-related arthritis, undifferentiated myelitis, Ryder syndrome, systemic lupus erythematosus, Behcet's disease, eosinophilic fasciitis, eosinophilic polymyalgia syndrome, familial Mediterranean fever, hereditary angioedema, juvenile chronic arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion bodies Myositis, systemic sclerosis, atherosclerosis, sarcoidosis, Raynaud's phenomenon, Sjogren's syndrome, Still's disease, systemic rheumatic vasculitis, vasculitis, Wegener's granulomatosis, Whipple's disease and xerostomia 132. The method of claim 132, further selected. 195. The method of claim 194, wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis and osteoarthritis. 196. The claim 195, wherein the inflammatory disorder is rheumatoid arthritis.
The method described. 197. A pharmaceutical composition comprising an effective amount of a tumor necrosis factor antagonist and a cyclooxygenase-2 inhibitor against inflammatory disorders. 198. The tumor necrosis factor antagonist is a protein.
The pharmaceutical composition described in. 199. The pharmaceutical composition according to claim 198, wherein the protein competitively binds to the tumor necrosis factor receptor on the cell surface. 200. The pharmaceutical composition according to claim 198, wherein the protein competitively binds to the tumor necrosis factor receptor inside the cell. 201. The tumor necrosis factor antagonist is etanercept.
98 ”, a pharmaceutical composition. 202. A tumor necrosis factor antagonist is 2-[(4,5-dimethoxy-2-methyl-
3,6-dioxo-1,4-cyclohexadiene-1-yl) methylene] -undecanoic acid; Renercept; BB-2275; PCM-4; SH-636; Onercept; TBP-1; Etanercept,
Solimastat; MDL-201112; AGT-1; D-609; 4- [3- (cyclopentyloxy) -4-
197. A pharmaceutical composition according to claim 197 selected from the group consisting of methoxyphenyl] -pyrrolidinone; CytoTAb®; and infliximab. 203. A selective cyclooxygenase-2 inhibitor has the formula I: Where A is a 5- or 6-membered ring substituent selected from partially unsaturated or unsaturated heterocyclo and carboxycyclo rings, and A is selected from the group consisting of alkyl, halo, oxo and alkoxy. Optionally substituted with one or more radicals, R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl;
Cyclohexyl, pyridinyl, or phenyl is derived from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio. Optionally substituted with one or more radicals selected from the group consisting of, R ² is selected from the group consisting of alkyl and amino, R ³ is halo, alkyl, alkenyl, alkynyl, aryl, heteroaryl,
Oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl,
Haloalkyl, heterocyclo, cycloalkenyl, phenylalkyl, heterocyclylalkyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, phenylcarbonyl, phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl, phenylyloxyalkyl,
Alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-aryl Amino, N-arylalkylamino, N-alkyl-N-arylalkylamino, N-alkyl-
N-arylamino, aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenyl Alkoxy, phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl,
N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl, R ⁴ is selected from the group consisting of hydride and halo) or a pharmaceutically acceptable compound thereof. The pharmaceutical composition according to claim 197, selected from the following salts: 204. A is thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzoindazolyl, cyclopentenone, benzopyra. 203. The pharmaceutical composition of claim 203, selected from the group consisting of nopyrazolyl, phenyl, and pyridyl. 205. A is substituted with one or more radicals selected from the group consisting of alkyl, halo, oxo, and alkoxy.
The described pharmaceutical composition. 206. The pharmaceutical composition of claim 205, wherein A is substituted with halo. 207. The pharmaceutical composition of claim 206, wherein halo is chloro. 208. A claim 205 in which A is substituted by alkyl
The described pharmaceutical composition. 209. The pharmaceutical composition of claim 208, wherein alkyl is methyl. 210. The pharmaceutical composition of claim 205, wherein A is substituted with oxo. 211. The pharmaceutical composition of claim 205, wherein A is alkoxy substituted. 212. R ¹ is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is C _1-2 alkyl, C _1-2 haloalkyl, cyano, carboxyl, C _1-2 alkoxycarbonyl. ,
Hydroxyl, C _1-2 hydroxyalkyl, C _1-2 haloalkoxy, amino, C _1-2 alkylamino, phenylamino, nitro, C _1-2 alkoxy-C _1-2 alkyl, C _1-2
207. A compound of claim 203, which is substituted with one or more radicals selected from alkylsulfinyl, C _1-2 alkoxy, halo, alkoxy, and C _1-2 alkylthio.
The pharmaceutical composition described in. 213. R ¹ is selected from the group consisting of pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or phenyl is alkyl,
203. The pharmaceutical composition according to claim 203, optionally substituted with one or more radicals selected from the group consisting of halo and alkoxy. 214. The pharmaceutical composition according to claim 213, wherein R ¹ is pyridyl. 215. The pharmaceutical composition of claim 214, wherein pyridyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy. 216. The pharmaceutical composition of claim 215, wherein pyridyl is substituted with alkyl. 217. The pharmaceutical composition according to claim 216, wherein alkyl is C _1-2 alkyl. 218. The pharmaceutical composition of claim 217, wherein alkyl is methyl. 219. The pharmaceutical composition of claim 215, wherein pyridyl is substituted with halo. 220. The pharmaceutical composition of claim 219, wherein halo is chloro. 221. The pharmaceutical composition according to claim 213, wherein R ¹ is cyclohexyl. 222. Cyclohexyl substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
1) The pharmaceutical composition according to 1. 223. Cyclohexyl substituted with alkyl
21. The pharmaceutical composition according to 21. 224. The pharmaceutical composition according to claim 223, wherein alkyl is C _1-2 alkyl. 225. The pharmaceutical composition of claim 224, wherein alkyl is methyl. 226. The pharmaceutical composition of claim 221, wherein pyridyl is substituted with halo. 227. The pharmaceutical composition of claim 226, wherein halo is chloro. 228. The pharmaceutical composition according to claim 213, wherein R ¹ is phenyl. 229. Phenyl is substituted with one or more radicals selected from the group consisting of alkyl, halo, and alkoxy.
The described pharmaceutical composition. 230. The method of claim 229, wherein phenyl is substituted with alkyl.
The described pharmaceutical composition. 231. The pharmaceutical composition of claim 230, wherein alkyl is C _1-2 alkyl. 232. The pharmaceutical composition according to claim 231, wherein alkyl is methyl. 233. The pharmaceutical composition of claim 203, wherein R ² is alkyl or amino. 234. The pharmaceutical composition according to claim 233, wherein alkyl is C _1-2 alkyl. 235. The pharmaceutical composition of claim 234, wherein alkyl is methyl. Wherein 236] R ³ is halo, C _1-2 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, aryl, heteroaryl, oxo, cyano, carboxyl, cyano -C _1-3 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 _1-3 alkylthio-C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 alkylcarbonyl, phenyl-
C _2-3 alkenyl, C _1-3 alkoxy-C _1-3 alkyl, phenylthio-C _1-3 alkyl, phenylyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 Alkyl, C _1-3 alkylaminocarbonyl, N-phenylaminocarbonyl, N-C _1-3 alkyl-N-phenylaminocarbonyl, C _1-3 alkylaminocarbonyl-C _1-3 alkyl, carboxy-C _1-3 Alkyl, C _1-3 alkylamino, N-arylamino, N-
Arylalkylamino, N-C _1-3 alkyl-N-arylalkylamino, N-C _1-3 alkyl-N-arylamino, amino-C _1-3 alkyl, C _1-3 alkylaminoalkyl, N-
Phenylamino-C _1-3 alkyl, N-Phenyl-C _1-3 alkylaminoalkyl, N-
C _1-3 alkyl-N-phenyl-C _1-3 alkylamino-C _1-3 alkyl, N-C _1-3 alkyl-N-phenylamino-C _1-3 alkyl, phenyloxy, phenylalkoxy,
Phenylthio, phenyl-C _1-3 alkylthio, C _1-3 alkylsulfinyl, C _1-3
A radical selected from the group consisting of alkylsulfonyl, aminosulfonyl, C _1-3 alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-C _1-3 alkyl-N-phenylaminosulfonyl. 203
The pharmaceutical composition described in. 237. R ³ is a radical selected from the group consisting of halo, C _1-2 alkyl, cyano, carboxyl, C _1-2 alkyloxy, phenyl, C _1-2 haloalkyl, and C _1-2 hydroxyalkyl. The pharmaceutical composition according to claim 236, which is: 238. The pharmaceutical composition according to claim 203, wherein R ⁴ is hydride. 239. The pharmaceutical composition of claim 203, wherein R ⁴ is halo. 240. The pharmaceutical composition of claim 239, wherein halo is fluoro. 241. The pharmaceutical composition according to claim 203, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 242. The pharmaceutical composition according to claim 203, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 243. The selective cyclooxygenase-2 inhibitor is 2- (6-methylpyridin-3-yl) -3- (4-methylsulfinylphenyl) -5-chloropyridine.
The pharmaceutical composition according to claim 203. 244. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. 203. The pharmaceutical composition according to item 203. 245. The pharmaceutical composition according to claim 203, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 246. The selective cyclooxygenase-2 inhibitor is 4- [5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] -benzenesulfonamide. The pharmaceutical composition described in. 247. The pharmaceutical composition according to claim 203, wherein the selective cyclooxygenase-2 inhibitor is 4- (4-cyclohexyl-2-methyloxazol-5-yl) -2-fluorobenzenesulfonamide. 248. A selective cyclooxygenase-2 inhibitor is 5-chloro-3- (4-
The pharmaceutical composition according to claim 203, which is (methylsulfonyl) phenyl) -2- (methyl-5-pyridinyl) pyridine. 249. The selective cyclooxygenase-2 inhibitor is 2- (3,5-difluorophenyl) -3- (4- (methylsulfonyl) phenyl) -2-cyclopenten-1-one "Claim 203". The described pharmaceutical composition. 250. The pharmaceutical composition according to claim 203, wherein the selective cyclooxygenase-2 inhibitor is 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone. 251. A selective cyclooxygenase-2 inhibitor is 4- [5-methyl-3-
A phenyl-isoxazol-4-yl] benzenesulfonamide according to claim 20.
3) The pharmaceutical composition according to item 3. 252. The method of claim 203, wherein the selective cyclooxygenase-2 inhibitor is N-[[4- (5-methyl-3-phenylisoxazol-4-yl) phenyl] sulfonyl] propanamide. Pharmaceutical composition. 253. The pharmaceutical composition according to claim 197, wherein both drugs are administered successively. 254. The pharmaceutical composition according to claim 197, wherein both agents are administered substantially simultaneously. 255. A tumor necrosis factor antagonist is administered parenterally
97 ”, the pharmaceutical composition. 256. The pharmaceutical composition according to claim 255, which is administered parenterally by intravenous injection, subcutaneous injection, intramuscular injection or intraspinal injection. 257. The pharmaceutical composition of claim 197, wherein the cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist are formulated in a single composition. 258. The pharmaceutical composition according to claim 197, wherein each of the cyclooxygenase-2 inhibitor and the tumor necrosis factor antagonist is provided as a separate component of the kit. 259. The inflammatory disorder is rheumatoid arthritis, osteoarthritis, spinal arthritis, ankylosing myelitis, psoriatic arthritis, reactive arthritis, IBD-related arthritis, undifferentiated myelitis, Ryder syndrome, systemic lupus erythematosus, Behcet's disease, eosinophilic fasciitis, eosinophilic polymyalgia syndrome, familial Mediterranean fever, hereditary angioedema, juvenile chronic arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion bodies Myositis, systemic sclerosis, atherosclerosis, sarcoidosis, Raynaud's phenomenon, Sjogren's syndrome, Still's disease, systemic rheumatic vasculitis, vasculitis, Wegener's granulomatosis, Whipple's disease and xerostomia The pharmaceutical composition according to claim 197, selected from: 260. The pharmaceutical composition according to claim 259, wherein the inflammatory disorder is selected from the group consisting of rheumatoid arthritis and osteoarthritis. 261. The claim 259, wherein the inflammatory disorder is rheumatoid arthritis
The described pharmaceutical composition. 262. The pharmaceutical composition of claim 197, wherein the composition is provided as a separate component of the kit. 263. The pharmaceutical composition of claim 197, wherein the composition is administered orally. 264. The pharmaceutical composition of claim 197, wherein the composition is administered intravascularly. 265. The pharmaceutical composition of claim 197, wherein the composition is administered intraperitoneally. 266. The pharmaceutical composition of claim 197, wherein the composition is administered subcutaneously. 267. The pharmaceutical composition of claim 197, wherein the composition is administered topically. 268. The pharmaceutical composition of claim 197, wherein the composition is administered parenterally. 269. The pharmaceutical composition of claim 197, wherein the composition is administered as a gel, spray, ointment, cream or suppository. 270. The pharmaceutical composition of claim 197, wherein the composition is administered transdermally. 271. The composition is selected from the group consisting of tablets, capsules, cashews, lozenges, dispersible powders, granules, solutions, suspensions, emulsions and liquids.
197. The pharmaceutical composition according to claim 197. 272. The selective cyclooxygenase-2 inhibitor is from about 0.1 mg to about 10.
The pharmaceutical composition according to claim 197, present in an amount of 1,000 mg.