COMBINATION OF TUMORS NECROCIS FACTOR (TNF) ANTAGONISTS AND COX-2 INHIBITORS FOR THE TREATMENT OF INFLAMMATION

COMBINAISON D'ANTAGONISTES DU FACTEUR DE NECROSE DES TUMEURS (TNF) ET D'INHIBITEURS DE COX-2 POUR LE TRAITEMENT DES INFLAMMATIONS

English Abstract

The present invention provides combinations of a tumor necrosis factor
antagonizing agent and a cyclooxygenase-2 inhibiting agent for treating
inflammatory disease in a mammal.

French Abstract

L'invention concerne des combinaisons comprenant un agent antagoniste du facteur de nécrose des tumeurs et un agent inhibiteur de la cyclooxygénase-2, destinées au traitement des maladies inflammatoires chez les mammifères.

Claims

48
What is claimed is:
1. A method for treating an inflammatory disorder in a mammal in need
thereof, comprising administering to the mammal a tumor necrosis factor
antagonizing
agent and a selective cyclooxygenase-2 inhibiting agent, wherein the tumor
necrosis
factor antagonizing agent and the selective cyclooxygenase-2 inhibiting agent
together
comprise an inflammatory disorder effective amount of the agents.
2. The method of claim 1 wherein the tumor necrosis factor antagonizing
agent is a protein.
3. The method of claim 2 wherein the protein competitively binds to a cell
surface tumor necrosis factor receptor.
4. The method of claim 2 wherein the protein competitively binds to an
intracellular tumor necrosis factor receptor.
5. The method of claim 2 wherein the tumor necrosis factor antagonizing
agent is etanercept.
6. The method of claim 1 wherein the tumor necrosis factor antagonizing
agent is selected from the group consisting of 2-[(4,5-dimethoxy-2-methyl-3,6-
dioxo-
1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; lenercept; etanercept; BB-
2275;
PCM-4; SH-636; onercept; vinigrol; TBP-1; solimastat; MDL-201112; AGT-1; D-
609; 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-pyrrolidinone; CytoTAb®; and
Infliximab.
7. The method of claim 1 wherein the selective cyclooxygenase-2 inhibiting
agent is selected from compounds of Formula 1:

<IMG>
wherein
A is a 5- or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carboxcyclic rings, wherein A is optionally
substituted
with one or more radicals selected from the group consisting of alkyl, halo,
oxo, and
alkoxy;
R1 is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl,
wherein cyclohexyl, pyridinyl, or phenyl are optionally substituted with one
or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
R2 is selected from the group consisting of alkyl and amino;
R3 is a radical selected from the group consisting of 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-
arylamino, N-arylkylamino, N-alkyl-N-arylkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-
alkyl-
N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenylalkoxy,
phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-
phenylaminosulfonyl; and
R4 is selected from the group consisting of hydrido and halo;

50
or a pharmaceutically-acceptable salt thereof.
8. The method of claim 7 wherein A is selected from the group consisting of
thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl,
benzofuryl, indenyl,
benzithienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl,
benzindazolyl,
cyclopentenone, benzopyranopyrazolyl, phenyl, and pyridyl.
9. The method of 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 of claim 9 wherein A is substituted with one or more halo
radical.
11. The method of claim 10 wherein the halo is choro.
12. The method of claim 9 wherein A is substituted by one or more alkyl
radical.
13. The method of claim 12 wherein the alkyl is methyl.
14. The method of claim 9 wherein A is substituted with one or more oxo
moiety.
15. The method of claim 9 wherein A is substituted with one or more alkoxy
radical.
16. The method of claim 7 wherein R1 is selected from the group consisting of
cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl is
optionally substituted with one or more radicals selected from C1-2 alkyl, C1-
2
haloalkyl, cyano, carboxyl, C1-2 alkoxycarbonyl, hydroxyl, C1-2 hydroxyalkyl,
C1-2
haloalkoxy, amino, C1-2 alkylamino, phenylamino, nitro, C1-2 alkoxy-C1-2-
alkyl, C1-2
alkylsulfinyl, C1-2 alkoxy, halo, alkoxy, and C1-2 alkylthio.

51
17. The method of claim 7 wherein R1 is selected from the group consisting of
pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or phenyl is
optionally
substituted with one or more radicals selected from the group consisting of
alkyl, halo,
and alkoxy.
18. The method of claim 17 wherein R1 is pyridyl.
19. The method of 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 the pyridyl is substituted with alkyl.
21. The method of claim 20 wherein alkyl is C1-2 alkyl.
22. The method of claim 21 wherein alkyl is methyl.
23. The method of claim 19 wherein the pyridyl is substituted with halo.
24. The method of claim 23 wherein the halo is chloro.
25. The method of claim 17 wherein R1 is cyclohexyl.
26. The method of claim 25 wherein the cyclohexyl is substituted with one or
more radicals selected from the group consisting of alkyl, halo, and alkoxy.
27. The method of claim 25 wherein the cyclohexyl is substituted with alkyl.
28. The method of claim 27 wherein the alkyl is C1-2 alkyl.
29. The method of claim 28 wherein the alkyl is methyl.

52
30. The method of claim 25 wherein the pyridyl is substituted with halo.
31. The method of claim 30 wherein the halo is chloro.
32. The method of claim 17 wherein R1 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 the 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 the phenyl is substituted with alkyl.
35. The method of claim 34 wherein the alkyl is C1-2 alkyl.
36. The method of claim 35 wherein the alkyl is methyl.
37. The method of claim 7 wherein R2 is alkyl or amino.
38. The method of claim 37 wherein the alkyl is C1-2 alkyl.
39. The method of claim 38 wherein the alkyl is methyl.
40. The method of claim 7 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, heteroaryl,
oxo, cyano,
carboxyl, cyano-C1-3-alkyl, heterocyclyloxy, C1-3 alkyloxy, alkylthio,
alkylcarbonyl,
cycloalkyl, phenyl, C1-3 haloalkyl, heterocyclo, cycloalkenyl, phenyl-C1-3-
alkyl,
heterocyclyl-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C1-3 hydroxyalkyl, C1-3
alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-
alkenyl, C1-3
alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-3
alkylaminocarbonyl, N-phenylaminocarbonyl, N-C1-3 alkyl-N-phenylaminocarbonyl,
C1-3 alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3 alkylamino, N-
arylamino,
N-arylkylamino, N-C1-3 alkyl-N-arylkylamino, N-C1-3 alkyl-N-arylamino, amino-
C1-3-

53
alkyl, C1-3 alkylaminoalkyl, N-phenylamino-C1-3-alkyl, N-phenyl-C1-3-
alkylaminoalkyl, N-C1-3 alkyl-N-phenyl-C1-3-alkylamino-C1-3-alkyl, N-C1-3
alkyl-N-
phenylamino-C1-3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C1-3-
alkylthio,
C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, aminosulfonyl, C1-3
alkylaminosulfonyl, N-
phenylaminosulfonyl, phenylsulfonyl, and N-C1-3 alkyl-N-phenylaminosulfonyl.
41. The method of claim 40 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, cyano, carboxyl, C1-2 alkyloxy, phenyl, C1-2
haloalkyl,
and C1-2 hydroxyalkyl.
42. The method of claim 7 wherein R4 is hydrido.
43. The method of claim 7 wherein R4 is halo.
44. The method of claim 43 wherein the halo is fluoro.
45. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide,
46. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
47. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-chloropyridine.
48. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide.
49. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.

54
50. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-
yl]benzenesulfonamide.
51. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide.
52. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(methyl-5-pyridinyl)pyridine.
53. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-cyclopenten-1-
one.
54. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
55. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide.
56. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide.
57. The method of claim 1 wherein the agents are administered in a sequential
manner.
58. The method of claim 1 wherein the agents are administered in a
substantially simultaneous manner.
59. The method of claim 1 wherein the tumor necrosis factor antagonizing
agent is administered parentally.

55
60. The method of claim 59 wherein the parental administration is by
intravenous injection, subcutaneous injection, intramuscular injection, or
intramedullary injection.
61. The method of claim 1 wherein the cyclooxygenase-2 inhibiting agent and
the tumor necrosis factor antagonizing agent are formulated in a single
composition.
62. The method of claim 1 wherein the cyclooxygenase-2 inhibiting agent and
the tumor necrosis factor antagonizing agent are each provided as a separate
component of a kit.
63. The method of claim 1 wherein the inflammatory disorder is selected from
the group consisting of rheumatoid arthritis, osteoarthritis, spondylarthropy,
ankylosing spondylitis, psoriatic arthritis, reactive arthritis, IBD related
arthritis,
undifferentiated spondyloarthropathy, Reider's syndrome, systemic lupus
erythematosus, Behcet's disease, eosinophilia fasciitis, eosinophila-myalgia
syndrome,
familial Mediterranean fever, hereditary angioedema, juvenile chronic
arthritis,
palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion
body
myositis, systemic sclerosis, atherosclerosis; sarcoidisis, Reynaud's
phenomenon,
Sjogren's syndrome, Still's disease, systemic rheumatoid vasculitis,
vasculitis,
Wegener's granulomatosis, Whipple's disease, and xerostomia.
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 for treating an inflammatory disorder in a mammal in need
thereof, comprising administering to the mammal a tumor necrosis factor
antagonizing

56
agent and a selective cyclooxygenase-2 inhibiting agent, wherein the agents
together
comprise an inflammatory disorder effective amount of the agents.
68. The method of claim 67 wherein the tumor necrosis factor antagonizing
agent 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 an
intracellular tumor necrosis factor receptor.
71. The method of claim 68 wherein the tumor necrosis factor antagonizing
agent is etanercept.
72. The method of claim 67 wherein the tumor necrosis factor antagonizing
agent is selected from the group consisting of 2-[(4,5-dimethoxy-2-methyl-3,6-
dioxo-
1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; etanercept; lenercept; BB-
2275;
PCM-4; SH-636; onercept; TBP-1; solimastat; MDL-201112; AGT-1; D-609; 4-[3-
(cyclopentyloxy)-4-methoxyphenyl]-pyrrolidinone; CytoTAb®; and Infliximab.
73. The method of claim 67 wherein the selective cyclooxygenase-2 inhibiting
agent is selected from compounds of Formula I:
<IMG>
wherein
A is a 5- or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carboxcyclic rings, wherein A is optionally
substituted

57
with one or more radicals selected from the group consisting of alkyl, halo,
oxo, and
alkoxy;
R1 is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl,
wherein cyclohexyl, pyridinyl, or phenyl are optionally substituted with one
or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
R2 is selected from the group consisting of alkyl and amino;
R3 is a radical selected from the group consisting of 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-
arylamino, N-arylkylamino, N-alkyl-N-arylkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-
alkyl-
N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenylalkoxy,
phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-
phenylaminosulfonyl; and
R4 is selected from the group consisting of hydrido and halo;
or a pharmaceutically-acceptable salt thereof.
74. The method of claim 73 wherein A is selected from the group consisting
of thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl,
benzofuryl,
indenyl, benzithienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl,
benzindazolyl, 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.

58
76. The method of claim 75 wherein A is substituted with halo.
77. The method of claim 76 wherein the halo is choro.
78. The method of claim 77 wherein A is substituted by alkyl.
79. The method of claim 78 wherein the alkyl is methyl.
80. The method of claim 75 wherein A is substituted with oxo.
81. The method of claim 75 wherein A is substituted with alkoxy.
82. The method of claim 73 wherein R1 is selected from the group consisting
of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl, pyridinyl, or phenyl
is
substituted with one or more radicals selected from C1-2 alkyl, C1-2
haloalkyl, cyano,
carboxyl, C1-2 alkoxycarbonyl, hydroxyl, C1-2 hydroxyalkyl, C1-2 haloalkoxy,
amino,
C1-2 alkylamino, phenylamino, nitro, C1-2 alkoxy-C1-2-alkyl, C1-2
alkylsulfinyl, C1-2
alkoxy, halo, alkoxy, and C1-2 alkylthio.
83. The method of claim 73 wherein R1 is selected from the group consisting
of pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or phenyl is
optionally
substituted with one or more radicals selected from the group consisting of
alkyl, halo,
and alkoxy.
84. The method of claim 83 wherein R1 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 the pyridyl is substituted with alkyl.

59
87. The method of claim 86 wherein alkyl is C1-2 alkyl.
88. The method of claim 87 wherein alkyl is methyl.
89. The method of claim 85 wherein the pyridyl is substituted with halo.
90. The method of claim 89 wherein the halo is chloro.
91. The method of claim 83 wherein R1 is cyclohexyl.
92. The method of claim 91 wherein the cyclohexyl is substituted with one or
more radicals selected from the group consisting of alkyl, halo, and alkoxy.
93. The method of claim 91 wherein the cyclohexyl is substituted with alkyl.
94. The method of claim 93 wherein the alkyl is C1-2 alkyl.
95. The method of claim 94 wherein the alkyl is methyl.
96. The method of claim 92 wherein the pyridyl is substituted with halo.
97. The method of claim 96 wherein the halo is chloro.
98. The method of claim 83 wherein R1 is phenyl.
99. The method of claim 98 wherein the 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 the phenyl is substituted with alkyl.
101. The method of claim 100 wherein the alkyl is C1-2 alkyl.

60
102. The method of claim 101 wherein the alkyl is methyl.
103. The method of claim 73 wherein R2 is alkyl or amino.
104. The method of claim 103 wherein the alkyl is C1-2 alkyl.
105. The method of claim 104 wherein the alkyl is methyl.
106. The method of claim 73 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, heteroaryl,
oxo, cyano,
carboxyl, cyano-C1-3-alkyl, heterocyclyloxy, C1-3 alkyloxy, alkylthio,
alkylcarbonyl,
cycloalkyl, phenyl, C1-3 haloalkyl, heterocyclo, cycloalkenyl, phenyl-C1-3-
alkyl,
heterocyclyl-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C1-3 hydroxyalkyl, C1-3
alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-
alkenyl, C1-3
alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-3
alkylaminocarbonyl, N-phenylaminocarbonyl, N-C1-3 alkyl-N-phenylaminocarbonyl,
C1-3 alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3 alkylamino, N-
arylamino,
N-arylkylamino, N-C1-3 alkyl-N-arylkylamino, N-C1-3 alkyl-N-arylamino, amino-
C1-3-
alkyl, Cl-3 alkylaminoalkyl, N-phenylamino-C1-3-alkyl, N-phenyl-C1-3-
alkylaminoalkyl, N-C1-3 alkyl-N-phenyl-C1-3-alkylamino-C1-3-alkyl, N-C1-3
alkyl-N-
phenylamino-C1-3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C1-3-
alkylthio,
C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, aminosulfonyl, C1-3
alkylaminosulfonyl, N-
phenylaminosulfonyl, phenylsulfonyl, and N-C1-3 alkyl-N-phenylaminosulfonyl.
107. The method of claim 106 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, cyano, carboxyl, C1-2 alkyloxy, phenyl, C1-2
haloalkyl,
and C1-2 hydroxyalkyl.
108. The method of claim 73 wherein R4 is hydrido.
109. The method of claim 73 wherein R4 is halo.

61
110. The method of claim 109 wherein the halo is fluoro.
111. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide,
112. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
113. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-
chloropyridine.
114. The method of claim 7 wherein the selective cyclooxygenase-2 inhibiting
agent is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide.
115. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
116. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-
yl]benzenesulfonamide.
117. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide.
118. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(methyl-5-
pyridinyl)pyridine.

62
119. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-
cyclopenten-
1-one.
120. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
121. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide.
122. The method of claim 73 wherein the selective cyclooxygenase-2
inhibiting agent is N-[[4-(5-methyl-3-phenylisoxazol-4-
yl]phenyl]sulfonyl]propanamide.
123. The method of claim 67 wherein the agents are administered in a
sequential manner.
124. The method of claim 67 wherein the agents are administered in a
substantially simultaneous manner.
125. The method of claim 67 wherein the tumor necrosis factor antagonizing
agent is administered parentally.
126. The method of claim 125 wherein the parental administration is by
intravenous injection, subcutaneous injection, intramuscular injection, or
intramedullary injection.
127. The method of claim 67 wherein the cyclooxygenase-2 inhibiting agent
and the tumor necrosis factor antagonizing agent are formulated in a single
composition.

63
128. The method of claim 67 wherein the cyclooxygenase-2 inhibiting agent
and the tumor necrosis factor antagonizing agent each are provided as a
separate
component of a kit.
129. The method of claim 67 wherein the inflammatory disorder is selected
from the group consisting of rheumatoid arthritis, osteoarthritis,
spondylarthropy,
ankylosing spondylitis, psoriatic arthritis, reactive arthritis, IBD related
arthritis,
undifferentiated spondyloarthropathy, Reider's syndrome, systemic lupus
erythematosus, Behcet's disease, eosinophilia fasciitis, eosinophila-myalgia
syndrome,
familial Mediterranean fever, hereditary angioedema, juvenile chronic
arthritis,
palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion
body
myositis, systemic sclerosis, atherosclerosis, sarcoidisis, Reynaud's
phenomenon,
Sjogren's syndrome, Still's disease, systemic rheumatoid vasculitis,
vasculitis,
Wegener's granulomatosis, Whipple's disease, and xerostomia.
130. The method of claim 129 wherein the inflammatory disorder is selected
from the group consisting of rheumatoid arthritis, and osteoarthritis.
131. The method of claim 130 wherein the inflammatory disorder is
rheumatoid arthritis.
132. A method of use of a composition in preparation of a medicament useful
in treating an inflammatory disorder in a mammal in need thereof, the
composition
comprising a tumor necrosis factor antagonizing agent and a cylcooxygenase-2
inhibitor, wherein the agents together comprise an inflammatory disorder
effective
amount of the agents.
133. The method of claim 132 wherein the tumor necrosis factor antagonizing
agent is a protein.
134. The method of claim 133 wherein the protein competitively binds to a
cell surface tumor necrosis factor receptor.

64
135. The method of claim 133 wherein the protein competitively binds to an
intracellular tumor necrosis factor receptor.
136. The method of claim 133 wherein the tumor necrosis factor antagonizing
agent is etanercept.
137. The method of claim 132 wherein the tumor necrosis factor antagonizing
agent is selected from the group consisting of 2-[(4,5-dimethoxy-2-methyl-3,6-
dioxo-
1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; etanercept; lenercept; BB-
2275;
PCM-4; SH-636; onercept; TBP-1; solimastat; MDL-201112; AGT-1; D-609; 4-[3-
(cyclopentyloxy)-4-methoxyphenyl]-pyrrolidinone; CytoTAb®; and Infliximab.
138. The method of claim 132 wherein the selective cyclooxygenase-2
inhibiting agent is selected from compounds of Formula 1:
<IMG>
wherein
A is a 5- or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carboxcyclic rings, wherein A is optionally
substituted
with one or more radicals selected from the group consisting of alkyl, halo,
oxo, and
alkoxy;
R1 is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl,
wherein cyclohexyl, pyridinyl, or phenyl are optionally substituted with one
or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
R2 is selected from the group consisting of alkyl and amino;

65
R3 is a radical selected from the group consisting of 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-
arylamino, N-arylkylamino, N-alkyl-N-arylkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-
alkyl-
N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenylalkoxy,
phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-
phenylaminosulfonyl; and
R4 is selected from the group consisting of hydrido and halo;
or a pharmaceutically-acceptable salt thereof.
139. The method of claim 138 wherein A is selected from the group consisting
of thienyl, oxazolyl, furyl, furanone, pyrrolyl, thiazolyl, imidazolyl,
benzofuryl,
indenyl, benzithienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl,
benzindazolyl, cyclopentenone, benzopyranopyrazolyl, phenyl, and pyridyl.
140. The method of claim 139 wherein A is substituted with one or more
radicals selected from the group consisting of alkyl, halo, oxo, and alkoxy.
141. The method of claim 140 wherein A is substituted with halo.
142. The method of claim 141 wherein the halo is choro.
143. The method of claim 141 wherein A is substituted by alkyl.
144. The method of claim 143 wherein the alkyl is methyl.

66
145. The method of claim 140 wherein A is substituted with oxo.
146. The method of claim 140 wherein A is substituted with alkoxy.
147. The method of claim 138 wherein R1 is selected from the group
consisting of cyclohexyl, pyridinyl, and phenyl, wherein cyclohexyl,
pyridinyl, or
phenyl is substituted with one or more radicals selected from C1-2 alkyl, C1-2
haloalkyl,
cyano, carboxyl, C1-2 alkoxycarbonyl, hydroxyl, C1-2 hydroxyalkyl, C1-2
haloalkoxy,
amino, C1-2 alkylamino, phenylamino, nitro, C1-2 alkoxy-C1-2-alkyl, C1-2
alkylsulfinyl,
C1-2 alkoxy, halo, alkoxy, and C1-2 alkylthio.
148. The method of claim 138 wherein R1 is selected from the group
consisting of pyridyl, cyclohexyl, and phenyl, wherein pyridyl, cyclohexyl, or
phenyl is
optionally substituted with one or more radicals selected from the group
consisting of
alkyl, halo, and alkoxy.
149. The method of claim 148 wherein R1 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. The method of claim 150 wherein the pyridyl is substituted with alkyl.
152. The method of claim 151 wherein alkyl is C1-2 alkyl.
153. The method of claim 152 wherein alkyl is methyl.
154. The method of claim 150 wherein the pyridyl is substituted with halo.
155. The method of claim 154 wherein the halo is chloro.

67
156. The method of claim 144 wherein R1 is cyclohexyl.
157. The method of claim 156 wherein the cyclohexyl is substituted with one
or more radicals selected from the group consisting of alkyl, halo, and
alkoxy.
158. The method of claim 156 wherein the cyclohexyl is substituted with
alkyl.
159. The method of claim 158 wherein the alkyl is C1-2 alkyl.
160. The method of claim 159 wherein the alkyl is methyl.
161. The method of claim 156 wherein the pyridyl is substituted with halo.
162. The method of claim 161 wherein the halo is chloro.
163. The method of claim 148 wherein R1 is phenyl.
164. The method of claim 163 wherein the phenyl is substituted with one or
more radicals selected from the group consisting of alkyl, halo, and alkoxy.
165. The method of claim 164 wherein the phenyl is substituted with alkyl.
166. The method of claim 165 wherein the alkyl is C1-2 alkyl.
167. The method of claim 166 wherein the alkyl is methyl.
168. The method of claim 138 wherein R2 is alkyl or amino.
169. The method of claim 168 wherein the alkyl is C1-2 alkyl.
170. The method of claim 169 wherein the alkyl is methyl.

68
171. The method of claim 138 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, heteroaryl,
oxo, cyano,
carboxyl, cyano-C1-3-alkyl, heterocyclyloxy, C1-3 alkyloxy, alkylthio,
alkylcarbonyl,
cycloalkyl, phenyl, C1-3 haloalkyl, heterocyclo, cycloalkenyl, phenyl-C1-3-
alkyl,
heterocyclyl-C-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C1-3 hydroxyalkyl, C1-3
alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-
alkenyl, C1-3
alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl,
alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C1-3-alkyl, C1-3
alkylanunocarbonyl, N-phenylaminocarbonyl, N-C1-3 alkyl-N-phenylaminocarbonyl,
C1-3 alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, C1-3 alkylamino, N-
arylamino,
N-arylkylamino, N-C1-3 alkyl-N-arylkylamino, N-C1-3 alkyl-N-arylamino, amino-
C1-3-
alkyl, C1-3 alkylaminoalkyl, N-phenylamino-C1-3-alkyl, N-phenyl-C1-3-
alkylaminoalkyl, N-C1-3 alkyl-N-phenyl-C1-3-alkylamino-C1-3-alkyl, N-C1-3
alkyl-N-
phenylamino-C1-3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C1-3-
alkylthio,
C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, aminosulfonyl, C1-3
alkylaminosulfonyl, N-
phenylaminosulfonyl, phenylsulfonyl, and N-C1-3 alkyl-N-phenylaminosulfonyl.
172. The method of claim 171 wherein R3 is a radical selected from the group
consisting of halo, C1-2 alkyl, cyano, carboxyl, C1-2 alkyloxy, phenyl, C1-2
haloalkyl,
and C1-2 hydroxyalkyl.
173. The method of claim 138 wherein R4 is hydrido.
174. The method of claim 138 wherein R4 is halo.
175. The method of claim 174 wherein the halo is fluoro.
176. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide,
177. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.

69
178. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-
chloropyridine.
179. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide.
180. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
181. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-
yl]benzenesulfonamide.
182. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide.
183. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(methyl-5-
pyridinyl)pyridine.
184. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 2-(3,5-difluorophenyl)-3-4-(methylsulfonyl)phenyl)-2-
cyclopenten-
1-one.
185. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone.
186. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide.

70
187. The method of claim 138 wherein the selective cyclooxygenase-2
inhibiting agent is N-[[4-(5-methyl-3-phenylisoxazol-4-
yl]phenyl]sulfonyl]propanamide.
188. The method of claim 132 wherein the agents are administered in a
sequential manner.
189. The method of claim 132 wherein the agents are administered in a
substantially simultaneous manner.
190. The method of claim 132 wherein the tumor necrosis factor antagonizing
agent is administered parentally.
191. The method of claim 190 wherein the parental administration is by
intravenous injection, subcutaneous injection, intramuscular injection, or
intramedullary injection.
192. The method of claim 132 wherein the cyclooxygenase-2 inhibiting agent
and the tumor necrosis factor antagonizing agent are formulated in a single
composition.
193. The method of claim 132 wherein the cyclooxygenase-2 inhibiting agent
and the tumor necrosis factor antagonizing agent each are provided as a
separate
component of a kit.
194. The method of claim 132 wherein the inflammatory disorder is selected
from the group consisting of rheumatoid arthritis, osteoarthritis,
spondylarthropy,
ankylosing spondylitis, psoriatic arthritis, reactive arthritis, IBD related
arthritis,
undifferentiated spondyloarthropathy, Reider's syndrome, systemic lupus
erythematosus, Behcet's disease, eosinophilia fasciitis, eosinophila-myalgia
syndrome,
familial Mediterranean fever, hereditary angioedema, juvenile chronic
arthritis,
palindromic rheumatism, idiopathic polymyositis, dermatomyositis, inclusion
body

71
myositis, systemic sclerosis, atherosclerosis, sarcoidisis, Reynaud's
phenomenon,
Sjogren's syndrome, Still's disease, systemic rheumatoid vasculitis,
vasculitis,
Wegener's granulomatosis, Whipple's disease, and xerostomia.
195. The method of claim 194 wherein the inflammatory disorder is selected
from the group consisting of rheumatoid arthritis, and osteoarthritis.
196. The method of claim 195 wherein the inflammatory disorder is
rheumatoid arthritis.
197. A pharmaceutical composition comprising an inflammatory disorder
effective amount of a tumor necrosis factor antagonizing agent and a
cylcooxygenase-
2 inhibitor.
198. The pharmaceutical composition of claim 197 wherein the tumor necrosis
factor antagonizing agent is a protein.
199. The pharmaceutical composition of claim 198 wherein the protein
competitively binds to a cell surface tumor necrosis factor receptor.
200. The pharmaceutical composition of claim 198 wherein the protein
competitively binds to an intracellular tumor necrosis factor receptor.
201. The pharmaceutical composition of claim 198 wherein the tumor necrosis
factor antagonizing agent is etanercept.
202. The pharmaceutical composition of claim 197 wherein the tumor necrosis
factor antagonizing agent is selected from the group consisting of 2-[(4,5-
dimethoxy-
2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid;
lenercept;
BB-2275; PCM-4; SH-636; onercept; TBP-1; etanercept; solimastat; MDL-201112;
AGT-1; D-609; 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-pyrrolidinone; CytoTAb R;
and Infliximab.

72
203. The pharmaceutical composition of claim 197 wherein the selective
cyclooxygenase-2 inhibiting agent is selected from compounds of Formula 1:
<IMG>
wherein
A is a 5- or 6-member ring substituent selected from partially unsaturated or
unsaturated heterocyclo and carboxcyclic rings, wherein A is optionally
substituted
with one or more radicals selected from the group consisting of alkyl, halo,
oxo, and
alkoxy;
R1 is selected from the group consisting of cyclohexyl, pyridinyl, and phenyl,
wherein cyclohexyl, pyridinyl, or phenyl are optionally substituted with one
or more
radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl,
hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, nitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
R2 is selected from the group consisting of alkyl and amino;
R3 is a radical selected from the group consisting of 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-
arylamino, N-arylkylamino, N-alkyl-N-arylkylamino, N-alkyl-N-arylamino,
aminoalkyl, alkylaminoalkyl, N-phenylaminoalkyl, N-phenylalkylaminoalkyl, N-
alkyl-
N-phenylalkylaminoalkyl, N-alkyl-N-phenylaminoalkyl, phenyloxy, phenylalkoxy,
phenylthio, phenylalkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,

73
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-
phenylaminosulfonyl; and
R4 is selected from the group consisting of hydrido and halo;
or a pharmaceutically-acceptable salt thereof.
204. The pharmaceutical composition of claim 203 wherein A is selected from
the group consisting of thienyl, oxazolyl, furyl, furanone, pyrrolyl,
thiazolyl,
imidazolyl, benzofuryl, indenyl, benzithienyl, isoxazolyl, pyrazolyl,
cyclopentenyl,
cyclopentadienyl, benzindazolyl, cyclopentenone, benzopyranopyrazolyl, phenyl,
and
pyridyl.
205. The pharmaceutical composition of claim 204 wherein A is substituted
with one or more radicals selected from the group consisting of alkyl, halo,
oxo, and
alkoxy.
206. The pharmaceutical composition of claim 205 wherein A is substituted
with halo.
207. The pharmaceutical composition of claim 206 wherein the halo is choro.
208. The pharmaceutical composition of claim 205 wherein A is substituted
by alkyl.
209. The pharmaceutical composition of claim 208 wherein the 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 substituted
with alkoxy.

74
212. The pharmaceutical composition of claim 203 wherein R1 is selected
from the group consisting of cyclohexyl, pyridinyl, and phenyl, wherein
cyclohexyl,
pyridinyl, or phenyl is substituted with one or more radicals selected from C1-
2 alkyl,
C1-2 haloalkyl, cyano, carboxyl, C1-2 alkoxycarbonyl, hydroxyl, C1-2
hydroxyalkyl, C1-2
haloalkoxy, amino, C1-2 alkylamino, phenylamino, nitro, C1-2 alkoxy-C1-2-
alkyl, C1-2
alkylsulfinyl, C1-2 alkoxy, halo, alkoxy, and C1-2 alkylthio.
213. The pharmaceutical composition of claim 203 wherein R1 is selected
from the group consisting of pyridyl, cyclohexyl, and phenyl, wherein pyridyl,
cyclohexyl, or phenyl is optionally substituted with one or more radicals
selected from
the group consisting of alkyl, halo, and alkoxy.
214. The pharmaceutical composition of claim 213 wherein R1 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 the pyridyl is
substituted with alkyl.
217. The pharmaceutical composition of claim 216 wherein alkyl is C1-2 alkyl.
218. The pharmaceutical composition of claim 217 wherein alkyl is methyl.
219. The pharmaceutical composition of claim 215 wherein the pyridyl is
substituted with halo.
220. The pharmaceutical composition of claim 219 wherein the halo is chloro.
221. The pharmaceutical composition of claim 213 wherein R1 is cyclohexyl.

75
222. The pharmaceutical composition of claim 221 wherein the cyclohexyl is
substituted with one or more radicals selected from the group consisting of
alkyl, halo,
and alkoxy.
223. The pharmaceutical composition of claim 221 wherein the cyclohexyl is
substituted with alkyl.
224. The pharmaceutical composition of claim 223 wherein the alkyl is C1-2
alkyl.
225. The pharmaceutical composition of claim 224 wherein the alkyl is
methyl.
226. The pharmaceutical composition of claim 221 wherein the pyridyl is
substituted with halo.
227. The pharmaceutical composition of claim 226 wherein the halo is chloro.
228. The pharmaceutical composition of claim 213 wherein R1 is phenyl.
229. The pharmaceutical composition of claim 228 wherein the phenyl is
substituted with one or more radicals selected from the group consisting of
alkyl, halo,
and alkoxy.
230. The pharmaceutical composition of claim 229 wherein the phenyl is
substituted with alkyl.
231. The pharmaceutical composition of claim 230 wherein the alkyl is C1-2
alkyl.
232. The pharmaceutical composition of claim 231 wherein the alkyl is
methyl.

76
233. The pharmaceutical composition of claim 203 wherein R2 is alkyl or
amino.
234. The pharmaceutical composition of claim 233 wherein the alkyl is C1-2
alkyl.
235. The pharmaceutical composition of claim 234 wherein the alkyl is
methyl.
236. The pharmaceutical composition of claim 203 wherein R3 is a radical
selected from the group consisting of halo, C1-2 alkyl, C2-3 alkenyl, C2-3
alkynyl, aryl,
heteroaryl, oxo, cyano, carboxyl, cyano-C1-3-alkyl, heterocyclyloxy, C1-3
alkyloxy,
alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C1-3 haloalkyl, heterocyclo,
cycloalkenyl,
phenyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C1-3
hydroxyalkyl,
C1-3 alkoxycarbonyl, phenylcarbonyl, phenyl-C1-3-alkylcarbonyl, phenyl-C2-3-
alkenyl,
C1-3 alkoxy-C1-3-alkyl, phenylthio-C1-3-alkyl, phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C1-
3-
alkyl, C1-3 alkylaminocarbonyl, N-phenylaminocarbonyl, N-C1-3 alkyl-N-
phenylaminocarbonyl, C1-3 alkylaminocarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl,
C1-3
alkylamino, N-arylamino, N-arylkylamino, N-C1-3 alkyl-N-arylkylamino, N-C1-3
alkyl-
N-arylamino, amino-C1-3-alkyl, C1-3 alkylaminoalkyl, N-phenylamino-C1-3-alkyl,
N-
phenyl-C1-3-alkylaminoalkyl, N-C1-3 alkyl-N-phenyl-C1-3-alkylamino-C1-3-alkyl,
N-C1-
3 alkyl-N-phenylamino-C1-3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-
C1-3-
alkylthio, C1-3 alkylsulfinyl, C1-3 alkylsulfonyl, aminosulfonyl, C1-3
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-C1-3 alkyl-N-
phenylaminosulfonyl.
237. The pharmaceutical composition of claim 236 wherein R3 is a radical
selected from the group consisting of halo, C1-2 alkyl, cyano, carboxyl, C1-2
alkyloxy,
phenyl, C1-2 haloalkyl, and C1-2 hydroxyalkyl.

77
238. The pharmaceutical composition of claim 203 wherein R4 is hydrido.
239. The pharmaceutical composition of claim 203 wherein R4 is halo.
240. The pharmaceutical composition of claim 239 wherein the halo is fluoro.
241. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide,
242. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-
2(5H)-
furanone.
243. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 2-(6-methylpyrid-3-yl)-3-(4-
methylsulfinylphenyl)-5-chloropyridine.
244. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-
1H-
pyrazol-1-yl]-benzenesulfonamide.
245. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-
2(5H)-
furanone.
246. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-[5-(4-chorophenyl)-3-(trifluoromethyl)-
1H-
pyrazole-1-yl]benzenesulfonamide.
247. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-
fluorobenzenesulfonamide.

78
248. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-
(methyl-5-pyridinyl)pyridine.
249. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 2-(3,5-difluorophenyl)-3-4-
(methylsulfonyl)phenyl)-2-cyclopenten-1-one.
250. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-(4-(methylsulfonyl)phenyl]-3-phenyl-
2(5H)-
furanone.
251. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is 4-[5-methyl-3-phenyl-isoxazol-4-
yl]benzenesulfonamide.
252. The pharmaceutical composition of claim 203 wherein the selective
cyclooxygenase-2 inhibiting agent is N-[[4-(5-methyl-3-phenylisoxazol-4-
yl]phenyl]sulfonyl]propanamide.
253. The pharmaceutical composition of claim 197 wherein the agents are
administered in a sequential manner.
254. The pharmaceutical composition of claim 197 wherein the agents are
administered in a substantially simultaneous manner.
255. The pharmaceutical composition of claim 197 wherein the tumor necrosis
factor antagonizing agent is administered parentally.
256. The pharmaceutical composition of claim 255 wherein the parental
administration is byintravenous injection, subcutaneous injection,
intramuscular
injection, or intramedullary injection.

79
257. The method of claim 197 wherein the cyclooxygenase-2 inhibiting agent
and the tumor necrosis factor antagonizing agent are formulated in a single
composition.
258. The pharmaceutical composition of claim 197 wherein the
cyclooxygenase-2 inhibiting agent and the tumor necrosis factor antagonizing
agent
each are provided as a separate component of a kit.
259. The pharmaceutical composition of claim 197 wherein the inflammatory
disorder is selected from the group consisting of rheumatoid arthritis,
osteoarthritis,
spondylarthropy, ankylosing spondylitis, psoriatic arthritis, reactive
arthritis, IBD
related arthritis, undifferentiated spondyloarthropathy, Reider's syndrome,
systemic
lupus erythematosus, Behcet's disease, eosinophilia fasciitis, eosinophila-
myalgia
syndrome, familial Mediterranean fever, hereditary angioedema, juvenile
chronic
arthritis, palindromic rheumatism, idiopathic polymyositis, dermatomyositis,
inclusion
body myositis, systemic sclerosis, sarcoidisis, Reynaud's phenomenon,
Sjogren's
syndrome, Still's disease, systemic rheumatoid vasculitis, systemic sclerosis,
vasculitis, Wegener's granulomatosis, Whipple's disease, and xerostomia.
260. The pharmaceutical composition of claim 259 wherein the inflammatory
disorder is selected from the group consisting of rheumatoid arthritis, and
osteoarthritis.
261. The pharmaceutical composition of claim 259 wherein the inflammatory
disorder is rheumatoid arthritis.
262. The pharmaceutical composition of claim 197 wherein the composition is
provided as a separate component of a kit.
263. The pharmaceutical composition of claim 197 wherein the composition is
administered orally.

80
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, a spray, an ointment, a cream or a suppository.
270. The pharmaceutical composition of claim 197 wherein the composition is
administered transdermally.
271. The pharmaceutical composition of claim 197 wherein the composition is
selected from the group consisting of a tablet, a capsule, a cachet, a
lozenge, a
dispensable powder, a granule, a solution, a suspension, an emulsion, and a
liquid.
272. The pharmaceutical composition of claim 197 wherein the selective
cyclooxygenase-2 inhibiting agent is present in an amount from about 0.1 mg to
about
10,000 mg.

Description

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
COMBINATION THERAPY FOR THE TREATMENT
OF INFLAMMATORY DISEASES
This application claims priority under 35 USC ~119(e) of United States
provisional application Serial No. 60/141,238, filed June 24, 1999.
Description
Field of the Invention
The present invention relates to methods for treating an inflammatory disease
in a mammal using a tumor necrosis factor antagonist and a selective
cyclooxygenase-
2 inhibitor.
Background of the Invention
Rheumatoid arthritis (RA) is estimated to occur in one to three percent of the
general population and is one of the most common causes of disability. There
is no
2 0 known cure for rheumatoid arthritis and current disease modifying
antirheumatic drugs
(DMARDs) fail to address the underlying cause of the disease. Current
rheumatoid
arthritis treatment consists predominantly of symptomatic relief by
administration of
non-steroidal anti-inflammatory drugs (NSAIDs). NSAID treatment is mainly
effective in the early stages of rheumatoid arthritis, and is unlikely to
produce
2 5 suppression of joint inflammation if the disease is present for more than
one year.
Gold, methotrexate, immunosuppressants and corticosteroids have been tried
with
limited success. In advanced cases of rheumatoid arthritis, the traditional
methods of
treatment have generally been aimed at avoiding toxicity.
Disease modifying antirheumatic drugs also play a predominant role in the
3 0 treatment of rheumatoid arthritis, but their toxicological profile limits
their application
and effectiveness in long-term therapy. For example, methotrexate (MTX) has
demonstrated long-term efficacy, but its toxicological profile, e.g.,
gastrointestinal
upset, mucosal ulcerations, renal impairment, pulmonary toxicity, is the most
common

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
reason cited among patients for treatment termination. The toxicity profile of
MTX
remains a major concern among physicians and prolonged treatment with MTX may
require invasive biopsy procedures in a patient to monitor hepatic function.
Another disease modifying antirheumatic drug, sulfasalazine, has been shown
to be more effective than hydroxychloroquine in the treatment of rheumatoid
arthritis,
but it is not as well tolerated, with 20% of patients terminating treatment
due to
adverse gastrointestinal side effects. Azathioprine, penicillamine and gold
compounds
have also been shown to be efficacious in treating rheumatoid arthritis, but
are not as
well tolerated as MTX, sulfasalazine or hydroxychloroquine. Cylcosporine has
shown
applicability in treating rheumatoid arthritis, but its renal toxicity has
limited its usage
to salvage therapy or in combination therapy with other disease modifying
antirheumatic drugs. Thus, treating rheumatoid arthritis with disease
modifying
antirheumatic drugs remains complicated by poor efficacy and the occurrence of
adverse side effects. Lack of predictability of these adverse reactions has
made regular
monitoring of a patients physiological condition mandatory where long term
therapy is
anticipated. Such monitoring include, for example, measuring blood count,
and/or
performing liver, kidney, urine or ophthalmologic tests.
Historically, treatment of the inflammatory actions was available through
the use of non-steroidal anti-inflammatory drugs (NSAIDs). This class of drugs
2 0 possesses anti-inflammatory, analgesic and anti-pyretic activity, and are
widely
used to treat chronic inflammatory states such as arthritis. However, common
NSAIDs that are active in reducing the PG-induced pain and swelling associated
with the inflammation process are also active in affecting the other PG-roles
which
is not associated with the inflammation process. Thus, use of high doses of
most
2 5 common NSAIDs can produce severe side effects, including life threatening
ulcers, that limit their therapeutic potential. An alternative to NSA>Ds is
the use
of corticosteroids, which have even more drastic side effects, especially when
long
term therapy is involved.
Prostaglandins (PGs) play a major role in the inflammation process and the
3 0 inhibition of prostaglandin production, especially production of PGG2,
PGH2 and
PGE2 has been a common target of anti-inflammatory drug discovery. Along with

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3
this role, PGs play a cytoprotective role in the gastrointestinal tract and
also on renal
function.
Previous NSAIDs have been found to prevent the production of PGs by
inhibiting enzymes in the human arachidonic acid/prostaglandin pathway,
including the enzyme cyclooxygenase (COX). The recent discovery of an
inducible enzyme associated with inflammation (named "cyclooxygenase-2" or
"COX-2" or "PGHS-2" or "prostaglandin G/H synthase II") provides a viable
target of inhibition which more effectively reduces inflammation and produces
fewer and less drastic side effects.
Compounds which selectively inhibit cyclooxygenase-2 have been described,
for example, in U.S. patents 5,380,738; 5,344,991; 5,393,790; 5,466,823;
5,434,178;
5,474,995 and 5,510,368; and WO documents WO 96/06840; WO 96/03388; WO
96/03387; WO 95/15316; WO 94/15932; WO 94/27980; WO 95/00501; WO
94/13635; WO 94/20480 and WO 94/26731.
Cytokines are signaling peptide molecules that modulate a wide variety of
cellular functions that includes inflammation. Cellular response occurs as a
result of
interaction between a particular cytokine and high-affinity cell-surface
receptors
specific for each cytokine. The receptor-binding event leads to the
transduction of a
signal across the cell membrane and the activation of intracellular
biochemical
2 0 pathways and gene translation or transcription events.
Tumor Necrosis Factor-alpha (TNF-a) is a cytokine produced primarily by
activated monocytes and macrophages. Excessive or unregulated tumor necrosis
factor production has been implicated in mediating a number of diseases.
Recent
studies indicate that tumor necrosis factor has a causative role in the
pathogenesis
2 5 of rheumatoid arthritis. Additional studies demonstrate that inhibition of
tumor
necrosis factor has broad application in the treatment of inflammation,
inflammatory bowel disease, multiple sclerosis and asthma.
Tumor necrosis factor has also been implicated in viral infections, such as
HIV, influenza virus, and herpes virus including herpes simplex virus type-1
3 0 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV),
varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6),
human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and
rhinotracheitis, among others.

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Interleukin-8 (IL-8) is another pro-inflammatory cytokine, which is
produced by mononuclear cells, fibroblasts, endothelial cells, and
keratinocytes,
and is associated with conditions including 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
reduction
of bone resorption.
Tumor necrosis factor receptor, 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. The inhibition of these cytokines is of benefit in
controlling, reducing
and alleviating many of these disease states. Modulation of cytokine response
is
achieved by blocking cytokine receptors with small molecules, altering the
cytokine to
reduce its affinity to its receptor, or by downregulating the expression of
cytokines.
Rau R. et al., (J. Rheumatol. (1998), 25(8), 1485-1492), describe a
combination of methotrexate (MTX) and parenteral gold or MTX and other disease
modifying antirheumatic drugs (DMARD) in the treatment of rheumatoid
arthritis.
Conagham P. and P. Brooks (Curr. Opin. Rheumatol. (1996), 8(3), 176-182),
describe methotrexate in combination therapy with intramuscular gold and other
DMARDs for the treatment of arthritis.
2 0 Furst D., (J. Rheumtol., Suppl. (1996) 44 (Rheumatoid Arthritis: The
Status
and Future of Combination Therapy), 86-90), reviews 16 references and
describes an
approach to rheumatoid arthritis disease modifying drug combination therapy.
Li E., (Curr. Opin, Rheumatol. (1998), 10(3), 159-168), describes certain
disease modifying antirheumatic drugs in combination therapy in patients
suffering
2 5 from rheumatoid arthritis.
Conagham P., et al., (Curr. Opin. Rheumatol. (1997) 9(3), 183-190), describes
MTX, sulfasalazine, and hydroxychloroquine in combination therapy for the
treatment
of rheumatoid arthritis.
O'Dell J., et al., (J. Rheumatol. Suppl. (1996), 44 (Rheumatoid Arthritis: The
3 0 Status and Future of Combination Therapy), 72-4), describe the single
agent therapy of
MTX, sulfasalazine or hydroxychloroquine and the combination of MTX,
sulfasalazine and hydroxychloroquine, and MTX in combination with either
sulfasalazine or hydroxychloroquine.

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s
Dijkmans B., et al., (J. Rheumatol. Suppl. (1996), 44, 23:61-63), describes a
2
phase study using a combination of cyclosporin A (CsA) (an inhibitor of
interleukin 2
(IL-2) and other cytokine production) with chloroquine for the treatment of
rheumatoid arthritis.
U.S. Patent No. 5,700,816 describes the treatment of inflammation and
inflammation-related disorders with a combination of a selective
cyclooxygenase-2
inhibitor and a leukotriene A4 hydrolase inhibitor.
U.S. Patent No. 5,859,041 describes a class of substituted imidazoles and its
use in preventing cytokine mediated disease by inhibiting cytokine activity.
U.S. Patent No. 5,772,992 describes compositions comprising a human
interleukin-3 variant or mutant protein and another colony stimulating factor,
cytokine,
lymphokine, interleukin, or hematopoietic growth factor.
U.S. Patent No. 5,864,036 describes a class of 1,4,5-substituted imidazole
compounds and their use in treating cytokine mediated diseases.
U.S. Patent No. 5,633,272 describes substituted isoxazoles used in co-therapy
for the treatment of inflammation, with conventional antiinflammatories.
U.S. Patent No. 5,512,544 describes tumor necrosis factor binding proteins
useful in the treatment of autoimmune disease and graft-versus-host reactions.
U.S. Patent No. 5,698,195 describes anti-tumor necrosis factor antibodies
2 0 useful in the treatment of, inter alia, chronic inflammatory diseases, and
autoimmune
disease.
WO document WO 91/03553, describes treating TNF-dependent inflammatory
disease, such as arthritis, by administrating tumor necrosis factor receptor
protein with
a interleukin-1 receptor and/or interleukin-2 receptor.
U.S. Patent No. 5,563,165 describes pyrazolyl benzenesulfonamide
compounds and their use in treating inflammation and inflammation-related
disorders.
US Patent No. 5,605,690 describes a method for treating TNF-dependent
inflammatory diseases in a mammal by administering a tumor necrosis factor
antagonist, and particularly pointing to a TNF-receptor.
3 0 WO document WO 98/06708, describes a crystalline form of 4-[5-methyl-3-
phenylosoxazol-4-yl]benzenesulfonamide in co-therapy with steroids, NSAIDs, 5-
lipooxygenase inhibitors, LTB4 receptor antagonists and LTA4 hydrolase
inhibitors,
used in treating cyclooxygenase-2 associated disorders, including
inflammation.

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U.S. Patent No. 5,633,273 describes the use of substituted isoxazoles in co-
therapy with steroids, NSAIDs, 5-lipooxygenase inhibitors, LTB4 receptor
antagonists
and LTA4 hydrolase inhibitors, for the treatment of inflammation and
inflammation
related disorders, such as arthritis.
U.S. Patent No. 5,869,471 describes the administration of NSAIDs and bone-
active phosphonates for the treatment of arthritis.
U.S. Patent No. 5,795,967 describes neutralizing antibodies directed against
tumor necrosis factor used to suppress inflammatory immune-potentiated events,
such
as suppressing transplantation immunity and treating autoimmune diseases.
U.S. Patent No. 5,306,732 describes vinigrol, a tumor necrosis factor
antagonist useful in the treatment of, inter alia, inflammation.
U.S. Patent No. 5,672,347 describes tumor necrosis factor antagonists useful
for treating inflammation, and in particular the use of neutralizing
antibodies directed
against tumor necrosis factor in mediating immune-potentiated inflammatory
events.
Description of the Invention
It has been found that the administration of a selective cyclooxygenase-2
inhibiting agent and a tumor necrosis factor antagonizing agent, for example,
2 0 etanercept (ENBREL~; Immunex Corp), not only results in reduction of
inflammation
in patients suffering from inflammatory disease, but also maintains and/or
increases
the range of motion of joints in patients suffering from arthritic disease.
The methods,
combinations and compositions of the present invention provide effective
therapy for
treating inflammatory and arthritic disorders, for example, rheumatoid
arthritis, with
2 5 reduced adverse side effects as compared to such methods known in the art.
The method comprises treating an inflammatory disorder in a mammal in need
thereof, by administering to the mammal a tumor necrosis factor antagonizing
agent
and a selective cyclooxygenase-2 inhibiting agent. Together the tumor necrosis
factor
antagonizing agent and the selective cyclooxygenase-2 inhibiting agent
comprise an
3 0 inflammatory disorder effective amount of the agents.
Tumor necrosis factor antagonizing agents useful in the present invention
include proteins, or biologically active equivalents thereof, that
competitively bind to a
cell surface tumor necrosis factor receptor or an intracellular tumor necrosis
factor

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receptor. In one embodiment of the present invention the tumor necrosis factor
antagonizing agent is etanercept, or a biologically active equivalent thereof
Other tumor necrosis factor antagonizing agents useful in the present
invention
include 2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-
undecanoic acid; lenercept; BB-2275; PCM-4; SH-636; onercept; TBP-1;
solimastat;
MDL-201112; AGT-1; vinigrol; D-609; 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-
pyrrolidinone; CytoTAb~; and Infliximab; or a biologically active equivalent
thereof.
A class of selective cyclooxygenase-2 inhibiting agents useful in the present
invention include compounds of Formula 1:
R'
4
R ~ AwRa
R2 ~
1.
wherein A is a 5- or 6-member ring substituent selected from partially
unsaturated or unsaturated heterocyclo and carboxcyclic rings, wherein A is
optionally
substituted with one or more radicals selected from alkyl, halo, oxo, and
alkoxy;
wherein R' is selected from cyclohexyl, pyridinyl, and phenyl, wherein
cyclohexyl, pyridinyl, or phenyl are optionally substituted with one or more
radicals
selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, phenylamino, vitro, alkoxyalkyl,
alkylsulfinyl, halo, alkoxy, and alkylthio;
2 0 wherein R2 is selected from alkyl and amino;
wherein R3 is a radical selected from 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,
2 5 phenylalkylcarbonyl, phenylalkenyl, alkoxyalkyl, phenylthioalkyl,
phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl,
alkylaminocarbonyl, N-phenylaminocarbonyl, N-alkyl-N-phenylaminocarbonyl,
alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-
arylkylamino, N-

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alkyl-N-arylkylamino, N-alkyl-N-arylamin~ aminoalkyl, alkylaminoalkyl, N-
phenylaminoalkyl, N-phenylalkylaminoalkyl, N-alkyl-N-phenylalkylaminoalkyl, N-
alkyl-N-phenylaminoalkyl, phenyloxy, phenylalkoxy, phenylthio,
phenylalkylthio,
alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-
phenylaminosulfonyl, phenylsulfonyl, and N-alkyl-N-phenylaminosulfonyl; and
wherein R4 is selected from hydrido and halo;
or a pharmaceutically-acceptable salt thereof.
The methods, combinations and compositions of the present invention can be
useful for the treatment or prevention of inflammatory and arthritic disorders
in a
mammal including, but not limited to, disorders such as:
rheumatoid arthritis (RA); osteoarthritis (OA); spondylarthropy; ankylosing
spondylitis; psoriatic arthritis; reactive arthritis; IBD related arthritis;
undifferentiated spondyloarthropathy; Reider's syndrome; systemic lupus
erythematosus; Behcet's disease; eosinophilia fasciitis; eosinophila-myalgia
syndrome; familial Mediterranean fever; hereditary angioedema; juvenile
chronic arthritis; palindromic rheumatism; idiopathic polymyositis;
dermatomyositis; inclusion body myositis; systemic sclerosis; atherosclerosis;
sarcoidisis; Reynaud's phenomenon; Sjogren's syndrome; Still's disease;
systemic rheumatoid vasculitis; vasculitis; Wegener's granulomatosis;
2 0 Whipple's disease; and xerostomia.
The present invention preferably includes compounds which selectively inhibit
cyclooxygenase-2 over cyclooxygenase-1. In one embodiment, the compounds have
a
selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1
inhibition of at
least 50, and in another embodiment have a selectivity ratio of at least 100.
Such
2 5 selectivity ratios may indicate an ability to reduce the incidence of
common NSAID-
induced side effects.
Within Formula 1 there is a subclass of compounds of particular interest
wherein A is selected from thienyl, oxazolyl, furyl, furanone, pyrrolyl,
thiazolyl,
imidazolyl, benzofuryl, indenyl, benzithienyl, isoxazolyl, pyrazolyl,
cyclopentenyl,
3 0 cyclopentadienyl, benzindazolyl, cyclopentenone, benzopyranopyrazolyl,
phenyl, and
pyridyl;
wherein R' is selected from cyclohexyl, pyridinyl, and phenyl, wherein
cyclohexyl, pyridinyl, or phenyl is substituted with one or more radicals
selected from

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C1_2 alkyl, C1_z haloalkyl, cyano, carboxyl, C1_Z alkoxycarbonyl, hydroxyl,
C~_2
hydroxyalkyl, C1_Z haloalkoxy, amino, C~_Z alkylamino, phenylamino, nitro,
C~_Z
alkoxy-C1_2-alkyl, C1_2 alkylsulfinyl, C1_2 alkoxy, halo, alkoxy, and C1_2
alkylthio;
wherein RZ is selected from alkyl and amino;
wherein R3 is a radical selected from halo, C~_2 alkyl, CZ_3 alkenyl, CZ_3
alkynyl,
aryl, heteroaryl, oxo, cyano, carboxyl, cyano-C1_3-alkyl, heterocyclyloxy,
C1_3
alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C1_3 haloalkyl,
heterocyclo,
cycloalkenyl, phenyl-C1_3-alkyl, heterocyclyl-C1_3-alkyl, C~_3 alkylthio-C1_3-
alkyl, C~_3
hydroxyalkyl, CI_3 alkoxycarbonyl, phenylcarbonyl, phenyl-C1_3-alkylcarbonyl,
phenyl-CZ_3-alkenyl, CI_3 alkoxy-Cl_3-alkyl, phenylthio-C1_3-alkyl,
phenylyloxyalkyl,
alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-
C1_3-
alkyl, C1_3 alkylaminocarbonyl, N-phenylaminocarbonyl, N-C~_3 alkyl-N-
phenylaminocarbonyl, C~_3 alkylaminocarbonyl-CI_3-alkyl, carboxy-C1_3-alkyl,
C~_3
alkylamino, N-arylamino, N-arylkylamino, N-C~_3 alkyl-N-arylkylamino, N-C~_3
alkyl-
N-arylamino, amino-C1_3-alkyl, C~_3 alkylaminoalkyl, N-phenylamino-C,_3-alkyl,
N-
phenyl-C1_3-alkylaminoalkyl, N-C~_3 alkyl-N-phenyl-C,_3-alkylamino-C~_3-alkyl,
N-C~_
3 alkyl-N-phenylamino-C1_3-alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-
CI_3-
alkylthio, C~_3 alkylsulfinyl, C1_3 alkylsulfonyl, aminosulfonyl, C~_3
alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl, and N-C1_3 alkyl-N-
2 0 phenylaminosulfonyl; and
wherein R4 is selected from hydrido and halo;
or a pharmaceutically-acceptable salt thereof.
Another class of compounds within Formula 1 of even more interest include
compounds wherein A is substituted with one or more radicals selected from
alkyl,
2 5 halo, oxo, and alkoxy;
wherein R' is selected from pyridyl, cyclohexyl, and phenyl, wherein pyridyl,
cyclohexyl, or phenyl is optionally substituted with one or more radicals
selected from
alkyl, halo, and alkoxy;
wherein RZ is C~_2 alkyl or amino;
3 0 wherein R3 is a radical selected from halo, C1_2 alkyl, cyano, carboxyl,
C1_Z
alkyloxy, phenyl, C1-2 haloalkyl, and C1_2 hydroxyalkyl; and
wherein R4 is selected from hydrido and fluoro;

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/0
or a pharmaceutically-acceptable salt thereof.
A family of specific compounds within Formula 1 of particular interest include
compounds and pharmaceutically-acceptable salts thereof, as follows:
Cl)
H2n
C2)
C3)
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;
C4)
H2N02S
_ CH3
N
CF3
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide;
C5)
4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone;
C6)

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4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
C7)
N-[[4-(5-methyl-3-phenylisoxazol-4y1]phenyl]sulfonyl]propanamide;
C8)
N H2
N'
F3
C
4-[5-(4-chorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-
yl]benzenesulfonamide;
C9)
CI
N
w
3-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2(3H)-oxazolone;
C 10)
H2N~
O~\O

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%;~
4-[3-(4-fluorophenyl)-2,3-dihydro-2-oxo-4-
oxazolyl]benzenesulfonamide;
C11)
H3C02
3-[4-(methylsulfonyl)phenyl]-2-phenyl-2-cyclopenten-1-one;
C12)
H2N~S
O~\O
4-(2-methyl-4-phenyl-5-oxazolyl)benzenesulfonamide;
C13)
F\
\ N
O
H3W S ~ /
O \O
3-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2(3H)-oxazolone;
C 14)
CH3
N~N
~ CF3
F
5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethy1)-
1H-pyrazole;
C15)

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~3
N H2
N~N
CF3
4-[5-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;
C 16)
H2N
4-[ 1-phenyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl]benzenesulfonamide;
C17)
N H2
N~N
CF3
w
F /
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide;
C18)
1-fluoro-4-[2-[4-(methylsulfonyl)phenyl]cyclopenten-1-yl]benzene;

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~ i,
C19)
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide;
C20)
CF3
N
\ ,N
N
,O
H CAS O
3
3-[ 1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1 H-imidazol-2-
yl]pyridine;
C21)
CF3
N
\ ,N
N
,O
S
1o H2N~ ~O
4-[2-(3-pyridinyll)-4-(trifluoromethyl)-1H-imidazol-1-
yl]benzenesulfonamide;

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C22)
H2N
C23)
1~~
4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide;
H2n
C24)
4-[3-(4-chlorophenyl)-2,3-dihydro-2-oxo-4-
oxazolyl]benzenesulfonamide;
H2N 2H
4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]benzenesulfonamide;
C25)
NH2
[ 1,1' :2', l"-terphenyl]-4-sulfonamide;

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C26)
CH3
OOS\
4-(methylsulfonyl)-1,1',2], l "-terphenyl;
C27)
NH2
OoS
\ N~
4-(2-phenyl-3-pyridinyl)benzenesulfonamide;
C28)
MeS
H2
w
\ /
C29)
H2N02S
_ OEt
N
CH3 ; and

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C30) 2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-chloropyridine.
Additional specific compounds of particular interest within Formula I include
each of the compounds and pharmaceutically-acceptable salts thereof as
follows:
4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide,
4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(SH)-furanone,
2-(6-methylpyrid-3-yl)-3-(4-methylsulfinylphenyl)-5-chloropyridine:
O~ /O
~~CH3
C1
H3
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-
benzenesulfonamide,
4-(4-(methylsulfonyl)phenyl]-3-phenyl-2(SH)-furanone,
4-[5-(4-chorophenyl)-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(SH)-furanone,
4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide, and
2 0 N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide.
Other selective cyclooxygenease-2 inhibiting agents useful in the present
invention include compounds such as:
C30)

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O
CI
~OH
O CF3
CI
C31)
HN-5~0
O
C32)
O
N
I ~ ~N~NH
CI
O
6-[[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-
pyridazinone;
C33)
NHS02CH3
w/
N02
N-(4-nitro-2-phenoxyphenyl)methanesulfonamide;
C34)
O
CI /
_OC2H5
O CF3
CI
C35)
NHS02CH3

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~ \~ H3C
\ ~CH3
F
\ O
F
3-(3,4-difluorophenoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-
2(SH)-furanone;
C36)
F
N-[6-[(2,4-difluorophenyl)thio]-2,3-dihydro-1-oxo-1H-inden-5-
yl]methanesulfonamide;
C37)
NHSO~CH.~
N02
N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide;
C38)
F
N-[6-(2,4-difluorophenoxy)-2,3-dihydro-1-oxo-1H-inden-5-
yl]methanesulfonamide;
NHSO~CHz F
NHSO~CHz F

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C39)
H2N
C40)
:,Z O
3-(4-chlorophenoxy)-4-[(methylsulfonyl)amino]benzenesulfonamide;
NHSOpCH3
O
F
H2N~SO0
C41 )
3-(4-fluorophenoxy)-4-[(methylsulfonyl)amino]benzenesulfonamide;
NHS02CH3 CH3
S N
NJ
H N~S~ O
2 O
3-[(1-methyl-1H-imidazol-2-yl)thio]-4 [(methylsulfonyl)
amino]benzenesulfonamide;
C42)
CH3
O ~S
O ~ / H3C CH3
O
\ O
O
5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-3-phenoxy-2(SH)-furanone;
C43)
NHS02CH3

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H3
N-[6-[(4-ethyl-2-thiazolyl)thio]-1,3-dihydro-1-oxo-5-
isobenzofuranyl]methanesulfonamide;
C44)
NHSO~CHz CI
H2N~S OO
3-[(2,4-dichlorophenyl)thio]-4-
[(methylsulfonyl)amino]benzenesulfonamide;
C45)
HN-~~ O
O
N-(2,3-dihydro-l,1-dioxido-6-phenoxy-1,2-benzisothiazol-5-
yl)methanesulfonamide;
C46)
O~ H
c
O~
H
N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-
yl]methanesulfonamide;
N HS02CH3

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
C47)
C48)
O
CI /
~O- Na+
O CF3
CI ; and
O
CI /
-NH2
O CF3
CI
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical
may be attached, for example, to an oxygen atom to form a hydroxyl radical or
two
hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-)
radical. Where used, either alone or within other terms such as "haloalkyl",
"alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", the term "alkyl" embraces
linear or
branched radicals having one to about twenty carbon atoms or, preferably, one
to
about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl"
radicals
having one to about ten carbon atoms. Most preferred are lower alkyl radicals
having
one to about six carbon atoms. Examples of such radicals include methyl,
ethyl, n-
propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ten-butyl, pentyl, iso-amyl,
hexyl and
the like. The term "alkenyl" embraces linear or branched radicals having at
least one
carbon-carbon double bond of two to about twenty carbon atoms or, preferably,
one to
about twelve carbon atoms. More preferred alkyl radicals are "lower alkenyl"
radicals
having two to about six carbon atoms. Examples of alkenyl radicals include
ethenyl,
propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkynyl"
denotes
2 0 linear or branched radicals having two to about twenty carbon atoms or,
preferably,
two to about twelve carbon atoms. More preferred alkynyl radicals are "lower
alkynyl"
radicals having two to about ten carbon atoms. Most preferred are lower
alkynyl
radicals having two to about six carbon atoms. Examples of such radicals
include
propargyl, butynyl, and the like. The terms "alkenyl", "lower alkenyl",
embrace
2 5 radicals having "cis" and "trans" orientations, or alternatively, "E" and
"Z"
orientations. The term "cycloalkyl" embraces saturated carbocyclic radicals
having

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
three to twelve carbon atoms. More preferred cycloalkyl radicals are "lower
cycloalkyl" radicals having three to about eight carbon atoms. Examples of
such
radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term
"cycloalkenyl" embraces partially unsaturated carbocyclic radicals having
three to
twelve carbon atoms. More preferred cycloalkenyl radicals are "lower
cycloalkenyl"
radicals having four to about eight carbon atoms. Examples of such radicals
include
cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" means halogens
such
as fluorine, chlorine, bromine or iodine. The term "haloalkyl" embraces
radicals
wherein any one or more of the alkyl carbon atoms is substituted with halo as
defined
above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl
radicals. A monohaloalkyl radical, for one example, may have either an iodo,
bromo,
chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals
may have
two or more of the same halo atoms or a combination of different halo
radicals.
"Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Examples of
haloalkyl
radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl,
dichloroethyl and dichloropropyl. The term "hydroxyalkyl" embraces linear or
branched alkyl radicals having one to about ten carbon atoms any one of which
may be
2 0 substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals
are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or
more
hydroxyl radicals. Examples of such radicals include hydroxymethyl,
hydroxyethyl,
hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and
"alkyloxy"
embrace linear or branched oxy-containing radicals each having alkyl portions
of one
2 5 to about ten carbon atoms. More preferred alkoxy radicals are "lower
alkoxy" radicals
having one to six carbon atoms. Examples of such radicals include methoxy,
ethoxy,
propoxy, butoxy and tent-butoxy. The term "alkoxyalkyl" embraces alkyl
radicals
having one or more alkoxy radicals attached to the alkyl radical, that is, to
form
monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals may be
further
3 0 substituted with one or more halo atoms, such as fluoro, chloro or bromo,
to provide
haloalkoxy radicals. More preferred haloalkoxy radicals are "lower haloalkoxy"
radicals having one to six carbon atoms and one or more halo radicals.
Examples of
such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or in
combination, means a carbocyclic aromatic system containing one, two or three
rings
wherein such rings may be attached together in a pendent manner or may be
fused.
The term "aryl" embraces aromatic radicals such as phenyl, naphthyl,
tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted
at a
substitutable position with one or more substituents selected independently
from alkyl,
alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,
aminocarbonylalkyl,
alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano,
carboxy,
aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term "heterocyclo"
embraces saturated, partially unsaturated and unsaturated heteroatom-
containing ring-
shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur
and
oxygen. Examples of saturated heterocyclo radicals include saturated 3 to 6-
membered heteromonocylic group containing 1 to 4 nitrogen atoms (e.g.
pyrrolidinyl,
imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen
atoms
(e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl,
etc.).
Examples of partially unsaturated heterocyclo radicals include
dihydrothiophene,
dihydropyran, dihydrofuran and dihydrothiazole. The term "heteroaryl" embraces
2 0 unsaturated heterocyclo radicals. Examples of unsaturated heterocyclo
radicals, also
termed "heteroaryl" radicals include unsaturated 3 to 6 membered
heteromonocyclic
group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl,
imidazolyl,
pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-
1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl,
2H-tetrazolyl,
2 5 etc.), etc.; unsaturated condensed heterocyclo group containing 1 to 5
nitrogen atoms,
for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl,
indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-
b]pyridazinyl, etc.),
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen
atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered
heteromonocyclic
3 0 group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3-
to 6-
membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen
atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-
oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclo
group

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
a-~
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,
benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,
thiazolyl,
thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-
thiadiazolyl, etc.) etc.;
unsaturated condensed heterocyclo group containing 1 to 2 sulfur atoms and 1
to 3
nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.
The term
also embraces radicals where heterocyclo radicals are fused with aryl
radicals.
Examples of such fused bicyclic radicals include benzofuran, benzothiophene,
and the
like. Said "heterocyclo group" may have 1 to 3 substituents such as alkyl,
hydroxyl,
halo, alkoxy, oxo, amino and alkylamino. The term "alkylthio" embraces
radicals
containing a linear or branched alkyl radical, of one to about ten carbon
atoms attached
to a divalent sulfur atom. More preferred alkylthio radicals are "lower
alkylthio"
radicals having alkyl radicals of one to six carbon atoms. Examples of such
lower
alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and
hexylthio. The
term "alkylthioalkyl" embraces radicals containing an alkylthio radical
attached
through the divalent sulfur atom to an alkyl radical of one to about ten
carbon atoms.
More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals
having alkyl
radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl
radicals
include methylthiomethyl. The term "alkylsulfinyl" embraces radicals
containing a
2 0 linear or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent -
S(=O)- radical. More preferred alkylsulfinyl radicals are "lower
alkylsulfinyl" radicals
having alkyl radicals of one to six carbon atoms. Examples of such lower
alkylsulfinyl
radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and
hexylsulfinyl. The
term "sulfonyl", whether used alone or linked to other terms such as
alkylsulfonyl,
2 5 denotes respectively divalent radicals -S02-. "Alkylsulfonyl" embraces
alkyl radicals
attached to a sulfonyl radical, where alkyl is defined as above. More
preferred
alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six
carbon
atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl,
ethylsulfonyl and propylsulfonyl. The "alkylsulfonyl" radicals may be further
3 0 substituted with one or more halo atoms, such as fluoro, chloro or bromo,
to provide
haloalkylsulfonyl radicals. The terms "sulfamyl", "aminosulfonyl" and
"sulfonamidyl"
denote NH202S-. The term "acyl" denotes a radical provided by the residue
after

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
vC
removal of hydroxyl from an organic acid. Examples of such acyl radicals
include
alkanoyl and amyl radicals. Examples of such lower alkanoyl radicals include
formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,
hexanoyl,
trifluoroacetyl. The term "carbonyl" or "oxo" whether used alone or with other
terms,
such as "alkoxycarbonyl", denotes -(C=O)-. The term carbonyl is also intended
to
encompass a hydrated carbonyl group -C(OH)2-. The term "aroyl" embraces aryl
radicals with a carbonyl radical as defined above. Examples of aroyl include
benzoyl,
naphthoyl, and the like and the aryl in said aroyl may be additionally
substituted. The
terms "carboxy" or "carboxyl", whether used alone or with other terms, such as
"carboxyalkyl", denotes -C02H. The term "carboxyalkyl" embraces alkyl radicals
substituted with a carboxy radical. More preferred are "lower carboxyalkyl"
which
embrace lower alkyl radicals as defined above, and may be additionally
substituted on
the alkyl radical with halo. Examples of such lower carboxyalkyl radicals
include
carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means
a
radical containing an alkoxy radical, as defined above, attached via an oxygen
atom to
a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with
alkyl
portions having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester)
radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms
"alkylcarbonyl",
2 0 "arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl, aryl
and aralkyl
radicals, as defined above, attached via an oxygen atom to a carbonyl radical.
Examples of such radicals include substituted or unsubstituted methylcarbonyl,
ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term "aralkyl" embraces
aryl-
substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl,
2 5 phenylethyl, and diphenylethyl. The aryl in said aralkyl may be
additionally
substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms
benzyl and
phenylmethyl are interchangeable. The term "heterocycloalkyl" embraces
saturated
and partially unsaturated heterocyclo-substituted alkyl radicals, such as
pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as
pyridylmethyl,
3 0 quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The
heteroaryl in said
heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy,
halkoalkyl and
haloalkoxy. The term "aralkoxy" embraces aralkyl radicals attached through an

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
oxygen atom to other radicals. The term "aralkoxyalkyl" embraces aralkoxy
radicals
attached through an oxygen atom to an alkyl radical. The term "aralkylthio"
embraces
aralkyl radicals attached to a sulfur atom. The term "aralkylthioalkyl"
embraces
aralkylthio radicals attached through a sulfur atom to an alkyl radical. 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" denotes amino groups which
have
been substituted with one or two alkyl radicals. Preferred are "lower N-
alkylamino"
radicals having alkyl portions having 1 to 6 carbon atoms. Suitable lower
alkylamino
may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-
dimethylamino, N,N-diethylamino or the like. The term "arylamino" denotes
amino
groups which have been substituted with one or two aryl radicals, such as N-
phenylamino. The "arylamino" radicals may be further substituted on the aryl
ring
portion of the radical. The term "aralkylamino" embraces aralkyl radicals
attached
through an nitrogen atom to other radicals. The terms "N-arylaminoalkyl" and
"N-
aryl-N-alkyl-aminoalkyl" denote amino groups which have been substituted with
one
aryl radical or one aryl and one alkyl radical, respectively, and having the
amino group
attached to an alkyl radical. Examples of such radicals include N-
phenylaminomethyl
and N-phenyl-N-methylaminomethyl. The term "aminocarbonyl" denotes an amide
2 0 group of the formula -C(=O)NH2. The term "alkylaminocarbonyl" denotes an
aminocarbonyl group which has been substituted with one or two alkyl radicals
on the
amino nitrogen atom. Preferred are "N-alkylaminocarbonyl" "N,N-
dialkylaminocarbonyl" radicals. More preferred are "lower N-
alkylaminocarbonyl"
"lower N,N-dialkylaminocarbonyl" radicals with lower alkyl portions as defined
2 5 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 an alkyl radical through a divalent oxygen
atom.
The term "arylthioalkyl" embraces radicals having an aryl radical attached to
an alkyl
radical through a divalent sulfur atom.
3 0 Suitable pharmaceutically-acceptable base addition salts of
compounds of the present invention include metallic ion salts and organic
ion salts. More preferred metallic ion salts include, but are not limited to
appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa)
salts

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
and other physiological acceptable metal ions. Such salts can be made from
the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and
zinc. Preferred organic salts can be made from tertiary amines and quaternary
ammonium salts, including in part, trimethylamine, diethylamine, N,N'-
dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the
above salts can be prepared by those skilled in the art by conventional means
from the corresponding compound of the present invention.
Also included in the combination of the invention are the isomeric
forms and tautomers of the described compounds and the pharmaceutically-
acceptable salts thereof. Illustrative pharmaceutically acceptable salts are
prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic,
malic, tartaric, citric, ascorbic, glucuronic, malefic, fumaric, pyruvic,
aspartic,
glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,
phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,
sulfanilic, cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric
and galacturonic acids.
The term "cyclooxygenase-2 inhibitor" or "COX-2 inhibitor" or
2 0 "cyclooxygenase-2 inhibiting agent" or "COX-2 inhibiting agent" embraces
compounds that selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
In one embodiment, the compounds have a selectivity ratio of
cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50,
and in another embodiment have a selectivity ratio of at least 100. Such
2 5 selectivity ratios may indicate an ability to reduce the incidence of
common
NSAID-induced side effects.
Nonlimiting examples of cyclooxygenase-2 inhibitors that may be used in the
present invention are identified in Table 1 below.
3 0 Table 1. Some Cyclooxygenase-2 Inhibitors

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
a~
Compound Trade Reference Dosage
Name
6-chloro-4-hydroxy-2- lornoxicam;CAS No.
methyl-N-2-pyridinyl-2H-Safem~ 70374-39-9
thieno[2,3-a]-1,2-thiazine-3-
carboxamide, 1,1-dioxide
1,5-biphenyl-3-substituted WO 97/13755
pyrazoles
radicicol WO 96/25928;
Kwon et al
(Cancer
Res(1992)
52
6296)
GB-
02283745
TP-72 Cancer Res.
1998584717
-723
1-(4-chlorobenzoyl)-3-[4-(4-A-183827.0
fluorophenyl )thiazol-2-
ylmethyl]-5-methoxy-2-
methy lindole
GR-253035 CAS Registry
No. 215522-
99-9
4-(4-cyclohexyl-2- JTE-522 CAS Registry
methyloxazol-5-yl)-2- Number:
fluorobenzenesulfonamide; 180200-68-4;
Benzenesulfonamide, JP 09052882
4-(4-
cyclohexyl-2-methyl-5-
oxazolyl)-2-fluoro-

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
', Compound Trade Reference Dosage
Name
5-chloro-3-(4-
(methylsulfonyl)phenyl)-2-
(methyl-5-pyridinyl)pyridine
2-(3,5-difluorophenyl)-3-4-
(methylsulfonyl)phenyl)-2-
cyclopenten-1-one
5-[4-(methylsulfonyl)-L-768277 CAS Registry
phenyl]-6-phenyl-
thiazolo[3,2-b][1,2,4]triazole No. 180696-
49-5
L-783003 CAS Registry
No. 215435-
69-1
4-(4-(methyl- MK-966; US 5968974 12.5-100 mg
po
sulfonyl)phenyl]-3-phenyl-Vioxx~;
2(SH)-furanone; rofecoxib
indomethacin-derived WO 96/37467-200 mg/kg/day
indolalkanoic acid 9
1-Methylsulfonyl-4-[1,1- WO 95/30656;
dimethyl-4-(4- WO 95/30652;
fluorophenyl)cyclopenta-2,4- WO 96/38418;
dien-3-yl]benzene WO 96/38442
4,4-dimethyl-2-phenyl-3-[4-
(methylsulfonyl)phenyl]cyclo
butenone
2-(4-methoxyphenyl)-4- EP 799823
methyl-1-(4-
sulfamoylphenyl)pyrrole
N-[5-(4- RWJ-63556
fluoro)phenoxy]thiophene-2-

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
Compound Trade Reference Dosage
Name
methanesulfonamide
5(E)-(3,5-di-tert-butyl-4-S-2474 EP 595546
hydroxy)benzylidene-2-ethyl-
1,2-isothiazolidine-1,1-
dioxide
3-formylamino-7- T-614 DE 3834204
methylsulfonylamino-6-
phenoxy-4H-1-benzopyran-4-
one
Benzenesulfonamide, celecoxib;US 5466823
4-(5-
(4-methylphenyl)-3- Celebrex~
(trifluoromethyl)-1H-pyrazol-
1_Yl)_
Benzenesulfonamide, valdecoxibCAS Registry
4-(5-
methyl-3-phenyl-4- Number:
isoxazolyl)- 181695-72-7;
Propanamide, N-[[4-(5-parecoxib CAS Registry
methyl-3-phenyl-4- Number:
isoxazolyl)phenyl]sulfonyl]- 198470-84-7;
US 5932598
meloxicam US 4233299 15-30 mg/day
nimesulideUS 3840597
1,5-biphenyl-3-substituted WO 97/13755
pyrazoles
radicicol WO 96/25928.
Kwon et al
(Cancer
Res(1992)
52
6296)
TP-72 Cancer Res

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
Compound Trade Reference Dosage
Name
1998 58 4
717
-723
1-(4-chlorobenzoyl)-3-[4-(4-A-183827.0
fluoro-phenyl )thiazol-2-
ylmethyl]-5-methoxy-2-
methy lindole
GR-253035
5-chloro-3-(4-
(methylsulfonyl)phenyl)-2-
(methyl-5-pyridinyl)-pyridine
2-(3,5-difluoro-phenyl)-3-4-
(methylsulfonyl)-phenyl)-2-
cyclopenten-1-one
CS 502 Sankyo
2-(6-methylpyrid-3-yl)-3-(4-MK-663; WO 98/03484;
L-
methylsulfinylphenyl)-5-791456 Bioorg. Med.
chloropyridine Chem. Lett.
1998, 8,
2777-
2782
The following individual references listed in Table No. 2 below, each hereby
incorporated by reference, describe various cyclooxygenase-2 inhibitors
suitable for
use in the present invention described herein, and processes for their
manufacture.
Table No. 2. Some Cyclooxygenase-2 Inhibitor References
WO 99/30721 WO 99/30729 US 5760068 WO 98/15528
WO 99/25695 WO 99/24404 WO 99/23087 FR 27/71005
EP 921119 FR 27/70131 WO 99/18960 WO 99/15505
WO 99/15503 WO 99/14205 WO 99/14195 WO 99/14194
WO 99/13799 GB 23/30833 US 5859036 WO 99/12930

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
WO 99/11605 WO 99/10332 WO 99/10331 WO 99/09988
I US 5869524 WO 99/05104 US 5859257 WO 98/47890
WO 98/47871 US 5830911 US 5824699 WO 98/45294
WO 98/43966 WO 98/41511 WO 98/41864 WO 98/41516
WO 98/37235 EP 86/3134 JP 10/175861 US 5776967
WO 98/29382 WO 98/25896 ZA 97/04806 EP 84/6,689
WO 98/21195 GB 23/19772 WO 98/11080 WO 98/06715
WO 98/06708 WO 98/07425 WO 98/04527 WO 98/03484
FR 27/51966 WO 97/38986 WO 97/46524 WO 97/44027
WO 97/34882 US 5681842 WO 97/37984 US 5686460
WO 97/36863 WO 97/40012 WO 97/36497 WO 97/29776
WO 97/29775 WO 97/29774 WO 97/28121 WO 97/28120
WO 97/27181 WO 95/11883 WO 97/14691 WO 97/13755
WO 97/13755 CA 21/80624 WO 97/11701 WO 96/41645
WO 96/41626 WO 96/41625 WO 96/38418 WO 96/37467
WO 96/37469 WO 96/36623 WO 96/36617 WO 96/31509
WO 96/25405 WO 96/24584 WO 96/23786 WO 96/19469
WO 96/16934 WO 96/13483 WO 96/03385 US 5510368
WO 96/09304 WO 96/06840 WO 96/06840 WO 96/03387
WO 95/21817 GB 22/83745 WO 94/27980 WO 94/26731
WO 94/20480 WO 94/13635 FR 27/70,131 US 5859036
WO 99/01131 WO 99/01455 WO 99/01452 WO 99/01130
WO 98/57966 WO 98/53814 WO 98/53818 WO 98/53817
WO 98/47890 US 5830911 US 5776967 WO 98/22101
DE 19/753463 WO 98/21195 WO 98/16227 US 5733909
WO 98/05639 WO 97/44028 WO 97/44027 WO 97/40012
WO 97/38986 US 5677318 WO 97/34882 WO 97/16435
WO 97/03678 WO 97/03667 WO 96/36623 WO 96/31509
WO 96/25928 WO 96/06840 WO 96/21667 WO 96/19469
US 5510368 WO 96/09304 GB 22/83745 WO 96/03392
WO 94/25431 WO 94/20480 WO 94/13635 JP 09052882

CA 02369145 2001-11-15
WO 01/00229 PCT/US00/16292
3 ~I
GB 22/94879 WO 95/15316 WO 95/15315 WO 96/03388
WO 96/24585 US 5344991 WO 95/00501 US 5968974
US 5945539 US 5994381
The celecoxib used in the therapeutic combinations of the present invention
can be prepared in the manner set forth in U.S. Patent No. 5,466,823.
The valdecoxib used in the therapeutic combinations of the present invention
can be prepared in the manner set forth in U.S. Patent No. 5,633,272.
The parecoxib used in the therapeutic combinations of the present invention
can be prepared in the manner set forth in U.S. Patent No. 5,932,598.
The rofecoxib used in the therapeutic combinations of the present invention
can be prepared in the manner set forth in U.S. Patent No. 5,968,974.
The Japan Tobacco JTE-522 used in the therapeutic combinations of the
present invention can be prepared in the manner set forth in JP 90/52,882.
The MK-663 used in the therapeutic combination of the present invention can
be prepared in the manner set forth in WO document WO 98/03484.
As used herein, the terms "tumor necrosis factor receptor" or "TNFR" refer to
proteins having amino acid sequences which are substantially similar to the
native
mammalian tumor necrosis factor receptor or tumor necrosis factor binding
protein
amino acid sequences, and which are capable of binding tumor necrosis factor
molecules and inhibiting tumor necrosis factor from binding to cell membrane
bound
tumor necrosis factor receptor. Two distinct types of tumor necrosis factor
receptor are
2 0 known to exist: Type I tumor necrosis factor receptor (TNFRI) and Type II
tumor
necrosis factor receptor (TNFRII). The mature full-length human TNFRI is a
glycoprotein having a molecular weight of about 75-80 kilodaltons (kDa). The
mature
full-length human TNFRII is a glycoprotein having a molecular weight of about
55-60
kilodaltons (kDa). The preferred tumor necrosis factor receptors of the
present
2 5 invention are soluble forms of TNFRI and TNFRII, as well as soluble tumor
necrosis
factor binding proteins. Soluble tumor necrosis factor receptor molecules
include, for
example, analogs or subunits of native proteins having at least 20 amino acids
and
which exhibit at least some biological activity in common with TNFRI, TNFRII
or
tumor necrosis factor binding proteins. Soluble tumor necrosis factor receptor

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3~'
constructs are devoid of a transmembrane region (and are secreted from the
cell) but
retain the ability to bind tumor necrosis factor. Various bioequivalent
protein and
amino acid analogs have an amino acid sequence corresponding to all or part of
the
extracellular region of a native tumor necrosis factor receptor, for example,
huTNFRI
DELTA 235, huTNFRI DELTA 185 and huTNFRI DELTA 163, and which are
biologically active in that they bind to tumor necrosis factor ligand.
Equivalent soluble
tumor necrosis factor receptors include polypeptides which vary from these
sequences
by one or more substitutions, deletions, or additions, and which retain the
ability to
bind tumor necrosis factor or inhibit tumor necrosis factor signal
transduction activity
via cell surface bound tumor necrosis factor receptor proteins.
The term "TNF antagonist" or "tumor necrosis factor antagonist" or "TNF
antagonizing agent" or tumor necrosis factor antagonizing agent" refers to,
for
example, soluble tumor necrosis factor receptor and tumor necrosis factor
binding
proteins that bind to tumor necrosis factor and prevent tumor necrosis factor
from
binding to cell membrane bound tumor necrosis factor receptors. Such proteins
competitively bind to cell surface receptors or intracellular tumor necrosis
factor
recognition sites displacing tumor necrosis factor or preventing tumor
necrosis factor
from binding to or interacting with the cells, therefore suppressing the
biological
activities caused by tumor necrosis factor. Tumor necrosis factor antagonizing
agents
2 0 that can be used in the present invention include, but not limited to
those described in
U.S. Patent No. 5,795,967, hereby incorporated by reference. Other examples of
tumor necrosis factor antagonists that may be used in the present invention
are
identified in Table 3 below.
2 5 Table 3. Tumor Necrosis Factor Antagonizing Agents
Compound Trade Reference Dosage
Name
etanercept;Immunex
ENBREL~ Corp; CAS
Registry
Number:
185243-69-0;
US 5,605,690;

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3~
Compound Trade Reference Dosage
Name
WO 91/03553
Undecanoic acid, 2-[(4,5- CAS Registry
dimethoxy-2-methyl-3,6- Number:
dioxo-1,4-cyclohexadien-1- 136164-66-4;
yl)methylene]- EP-00419905
lenercept;CAS Registry
Number:
RO-45-2081
156679-34-4;
EP-00417563
BB-2275 British Biotech
plc; CAS
Registry
No.
166798-78-3
PCM-4 Omega Phaem
Inc.
SH-636 Schering
AG
onercept Amgen Inc.
TBP-1 Serono SA;
EP-00398327
solimastat;British
BB-3644 Biotech,
plc;
WO-09633161
Hoechst
201112; Marion
Roussel,
Inc.;
CAS Registry
Number:
142130-73-2
Cyclopentanol,
3-(6-amino-
9H-purin-9-yl)-
(1R-cis)-
vinigrol US 5,306,732
CAS Registry
No. 111025-
83-3

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WO 01/00229 PCTNS00/16292
Compound Trade Reference Dosage
Name
AGT-1 Advanced
Biotherapy
Concepts,
Inc.
D-609 Tanabe
Research
Laboratories;
CAS Registry
Number:
83373-60-8
Carbonodithioi
c acid, O-
(octahydro-4,7-
methano-1H-
inden-5-yl)
ester,
potassium
salt
Pyrrolidinone, 4-[3- rolipram Schering
AG
(cyclopentyloxy)-4- CAS Registry
methoxyphenyl]- Number:
61413-54-5
2-
CytoTAb~ Protherics
Molecular
Design Ltd
Infliximab;Centocor,
Inc.;
CAS Registry
Avakine~; Number:
Remicade~ 170277-31-3
Immunoglobuli
n G (human-
mouse
monoclonal
cA2 heavy
chain anti-
human tumor
necrosis
factor)
disulfide
with
human-mouse
monoclonal
cA2li ht

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3g
Compound Trade Reference Dosage
Name
chain, dimer;
WO-09216553
In one embodiment, the tumor necrosis factor antagonist that may be used in
the present invention is etanercept (ENBREL~; Immunex Corp), or its
biologically
active equivalent. ENBREL~ is described in U.S. Patent No. 5,605,690 and is
hereby
incorporated by reference. ENBREL~ is a recombinant version of the soluble p75
Tumor Necrosis Factor receptor (TNFR) linked to the Fc portion of human IgGI.
It
inhibits tumor necrosis factor biological activity by acting as a competitive
inhibitor to
the binding of tumor necrosis factor to its cell receptors. For treatment of
arthritis or
inflammation, tumor necrosis factor is administered in systemic amounts
ranging from
about 0.1 mg/kg/week to about 100 mg/kg/week. In one embodiments of the
present
invention, tumor necrosis factor antagonist is administered in amounts ranging
from
about 0.5 mg/kg/week to about 50 mg/kg/week. For local intra-articular
administration, dosages preferably range from about 0.01 mg/kg to about 1.0
mg/kg
per injection. In another embodiment of the present invention the adult dose
of
ENBREL~ (entanercept) is 25 mg twice a day, as a subcutaneous injection.
"Biologically active," as used throughout the specification as a
characteristic of
tumor necrosis factor receptor antagonizing agent, means, for example, that a
particular molecule shares sufficient amino acid sequence similarity with the
embodiments of the present invention disclosed herein to be capable of binding
2 0 detectable quantities of tumor necrosis factor receptor, transmitting a
tumor necrosis
factor stimulus to a cell, for example, as a component of a hybrid receptor
construct, or
cross-reacting with anti-tumor necrosis factor receptor antibodies raised
against tumor
necrosis factor receptor from natural (i.e., nonrecombinant) sources. In one
embodiment of the present invention, the biologically active tumor necrosis
factor
2 5 receptor antagonizing agent within the scope of the present invention are
capable of
binding greater than 0.1 nmoles tumor necrosis factor per nmole receptor, and
in
another embodiment, are capable of binding greater than 0.5 nmole tumor
necrosis
factor per nmole receptor in standard binding assays (see U.S. Patent No.
5.605,690).

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3~
The phrase "combination therapy" (or "co-therapy") embraces the
administration of a cyclooxygenase-2 inhibiting agent and a tumor necrosis
factor
antagonizing agent as part of a specific treatment regimen intended to provide
a
beneficial effect from the co-action of these therapeutic agents. The
beneficial effect
of the combination includes, but is not limited to, pharmacokinetic or
pharmacodynamic co-action resulting from the combination of therapeutic
agents.
Administration of these therapeutic agents in combination typically is carried
out over
a defined time period (usually minutes, hours, days or weeks depending upon
the
combination selected). "Combination therapy" generally is not intended to
encompass
the administration of two or more of these therapeutic agents as part of
separate
monotherapy regimens that incidentally and arbitrarily result in the
combinations of
the present invention. "Combination therapy" is intended to embrace
administration
of these therapeutic agents in a sequential manner, that is, wherein each
therapeutic
agent is administered at a different time, as well as administration of these
therapeutic
agents, or at least two of the therapeutic agents, in a substantially
simultaneous
manner. Substantially simultaneous administration can be accomplished, for
example,
by administering to the subject a single capsule or intravenous injection
having a fixed
ratio of each therapeutic agent or in multiple, single capsules or intravenous
injections
for each of the therapeutic agents. Sequential or substantially simultaneous
2 0 administration of each therapeutic agent can be effected by any
appropriate route
including, but not limited to, oral routes, intravenous routes, intramuscular
routes, and
direct absorption through mucous membrane tissues. The therapeutic agents can
be
administered by the same route or by different routes. For example, a first
therapeutic
agent of the combination selected may be administered by intravenous injection
while
2 5 the other therapeutic agents of the combination may be administered
orally.
Alternatively, for example, all therapeutic agents may be administered orally
or all
therapeutic agents may be administered by intravenous injection. The sequence
in
which the therapeutic agents are administered is not narrowly critical.
The term "pharmaceutically acceptable" is used adjectivally herein to mean
3 0 that the modified noun is appropriate for use in a pharmaceutical product.
Pharmaceutically acceptable cations include metallic ions and organic ions.
More
preferred metallic ions include, but are not limited to appropriate alkali
metal salts,
alkaline earth metal salts and other physiological acceptable metal ions.
Exemplary

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~j v
ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc
in
their usual valences. Preferred organic ions include protonated tertiary
amines and
quaternary ammonium canons, including in part, trimethylamine, diethylamine,
N,N'-
dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
ethylenediamine,
meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically
acceptable acids include without limitation hydrochloric acid, hydrobromic
acid,
phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic
acid, tartaric
acid, malefic acid, malic acid, citric acid, isocitric acid, succinic acid,
lactic acid,
gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid,
propionic
acid, aspartic acid, glutamic acid, benzoic acid, and the like.
The term "treatment" refers to any process, action, application, therapy, or
the
like, wherein a mammal, including a human, is subject to medical aid with the
object
of improving the mammal's condition, directly or indirectly.
The phrase "therapeutically-effective" is intended to qualify the amount of
each agent that will achieve the goal of improvement in arthritic disease
severity and
the frequency of incidence over treatment of each agent by itself, while
avoiding
adverse side effects typically associated with alternative therapies.
A "therapeutic effect" relieves to some extent one or more of the symptoms of
an arthritic or inflammatory disorder. In reference to the treatment of
rheumatoid
arthritis, a therapeutic effect refers to one or more of the following: 1)
relieving or
reducing to some extent one or more of the symptoms associated with the
disorder, 2)
relieving or reducing to some extent gastrointestinal upset, 3) relieving or
reducing to
some extent mucosal ulcerations, 4) relieving or reducing to some extent renal
impairment, 5) relieving or reducing to some extent pulmonary toxicity, and/or
6)
2 5 relieving or reducing the side effects associated with the administration
of other
antiarthritic agents, such as disease modifying antirheumatic drugs.
Dosage levels of cyclooxygenase-2 inhibitors on the order of about 0.1 mg to
about 10,000 mg of the active ingredient compound are useful in the treatment
of the
above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The
3 0 amount of active ingredient that may be combined with other agents to
produce a
single dosage form will vary depending upon the host treated and the
particular mode
of administration.

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For therapeutic use, purified soluble tumor necrosis factor receptor
antagonizing agent is administered to a patient, preferably a human, for
treatment of an
inflammation disorder, for example arthritis. Thus, for example, soluble tumor
necrosis factor receptor antagonist compositions can be administered by
parental
administration, for example, intravenous injection, subcutaneous injection,
intramuscular injection, or intramedullary injection. Other routes of
administration for
tumor necrosis factor receptor antagonizing agents include, for example, intra-
articular, intraperitoneal or subcutaneous routes by bolus injection,
continuous
infusion, sustained release from implants, or other suitable techniques.
Typically, a
soluble tumor necrosis factor receptor therapeutic agent will be administered
in the
form of a composition comprising purified protein in conjunction with
physiologically
acceptable carriers, excipients or diluents. Such carriers will be nontoxic to
recipients
at the dosages and concentrations employed. Ordinarily, the preparation of
such
compositions entails combining the tumor necrosis factor receptor with
buffers,
antioxidants such as ascorbic acid, low molecular weight (less than about 10
residues)
polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose
or
dextrins, chelating agents such as EDTA, glutathione and other stabilizers and
excipients. Neutral buffered saline or saline mixed with nonspecific serum
albumin are
exemplary appropriate diluents. Preferably, product is formulated as a
lyophilizate
2 0 using appropriate excipient solutions (e.g., sucrose) as diluents.
Appropriate dosages
can be determined in trials. In accordance with appropriate industry
standards,
preservatives may also be added, such as benzyl alcohol. The amount and
frequency of
administration will depend, of course, on such factors as the nature and
severity of the
indication being treated, the desired response, the condition of the patient,
and so
2 5 forth.
For treatment of arthritis or an inflammatory disorder, tumor necrosis factor
receptor antagonizing agent is administered in systemic amounts ranging from
about
0.1 mg/kg/week to about 100 mg/kg/week. In one embodiment of the present
invention, tumor necrosis factor receptor antagonizing agent is administered
in
3 0 amounts ranging from about 0.5 mg/kg/week to about 50 mg/kg/week. For
local intra-
articular administration, dosages preferably range from about 0.01 mg/kg to
about 1.0
mg/kg per injection.

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It is understood, however, that a specific dose level for any particular
patient
will depend upon a variety of factors including the activity of the specific
compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate
of excretion, drug combination, and the severity of the particular disease
being treated
and form of administration.
Treatment dosages generally may be titrated to optimize safety and efficacy.
Typically, dosage-effect relationships from in vitro initially can provide
useful
guidance on the proper doses for patient administration. Studies in animal
models also
generally may be used for guidance regarding effective dosages for treatment
of
rheumatoid arthritis in accordance with the present invention. In terms of
treatment
protocols, it should be appreciated that the dosage to be administered will
depend on
several factors, including the particular agent that is administered, the
route
administered, the condition of the particular patient, etc. It will generally
be desirable
to administer the cyclooxygenase inhibitor either parenterally, intravenously,
or
subcutaneously. Other routes of administration are also contemplated,
including
intranasal and transdermal routes, and by inhalation. When administered, the
therapeutic composition for use in this invention is preferably in the form of
a
pyrogen-free, parenterally-acceptable aqueous solution. The preparation of
such a
parenterally-acceptable protein solution, having due regard to pH,
isotonicity, stability
2 0 and the like, is within the skill of the art. However, administration by
other routes is
contemplated where appropriate. Generally speaking, one will desire to
administer an
amount of the agent that is effective to achieve a serum level commensurate
with the
concentrations found to be effective in vitro. Thus, where an agent is found
to
demonstrate in vitro activity at, e.g., 10 uM, one will desire to administer
an amount
2 5 of the drug that is effective to provide about a 10 uM concentration in
vivo.
Determination of these parameters is well within the skill of the art.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions can be formulated according to the known art using suitable
dispersing or
wetting agents and suspending agents. The sterile injectable preparation can
also be a
3 0 sterile injectable solution or suspension in a nontoxic parenterally
acceptable diluent
or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that can be employed are water, Ringer's solution, and
isotonic
sodium chloride solution. In addition, sterile, fixed oils are conventionally
employed

CA 02369145 2001-11-15
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~! 3
as a solvent or suspending medium. For this purpose any bland fixed oil can be
employed including synthetic mono- or diglycerides. In addition, fatty acids
such as
oleic acid find use in the preparation of injectables. Dimethyl acetamide,
surfactants
including ionic and non-ionic detergents, polyethylene glycols can be used.
Mixtures
of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drugs can be prepared by mixing
the drugs with a suitable nonirritating excipient such as cocoa butter,
synthetic mono-
di- or triglycerides, fatty acids and polyethylene glycols that are sold at
ordinary
temperatures but liquid at the rectal temperature and will therefore melt in
the rectum
and release the drug.
Solid dosage forms for oral administration can include capsules, tablets,
pills,
powders, and granules. In such solid dosage forms, the compounds of this
invention
are ordinarily combined with one or more adjuvants appropriate to the
indicated route
of administration. If administered e~ r os, a contemplated aromatic sulfone
hydroximate inhibitor compound can be admixed with lactose, sucrose, starch
powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic
acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric
acids,
gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol,
and then tableted or encapsulated for convenient administration. Such capsules
or
2 0 tablets can contain a controlled-release formulation as can be provided in
a dispersion
of active compound in hydroxypropylmethyl cellulose. In the case of capsules,
tablets,
and pills, the dosage forms can also comprise buffering agents such as sodium
citrate,
magnesium or calcium carbonate or bicarbonate. Tablets and pills can
additionally be
prepared with enteric coatings.
2 5 For therapeutic purposes, formulations for parenteral administration can
be in
the form of aqueous or non-aqueous isotonic sterile injection solutions or
suspensions.
These solutions and suspensions can be prepared from sterile powders or
granules
having one or more of the carriers or diluents mentioned for use in the
formulations
for oral administration. A contemplated aromatic sulfone hydroximate inhibitor
3 0 compound can be dissolved in water, polyethylene glycol, propylene glycol,
ethanol,
corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or
various buffers. Other adjuvants and modes of administration are well and
widely
known in the pharmaceutical art.

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Liquid dosage forms for oral administration can include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, and elixirs containing
inert
diluents commonly used in the art, such as water. Such compositions can also
comprise adjuvants, such as wetting agents, emulsifying and suspending agents,
and
sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier
materials to produce a single dosage form varies depending upon the mammalian
host
treated and the particular mode of administration.
A combination of the present invention can be formulated as a pharmaceutical
composition. Such a composition can then be administered orally, parenterally,
by
inhalation spray, rectally, or topically in dosage unit formulations
containing
conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as
desired. Topical administration can also involve the use of transdermal
administration
such as transdermal patches or iontophoresis devices. The term parenteral as
used
herein includes subcutaneous injections, intravenous, intramuscular,
intrasternal
injection, or infusion techniques.
The above considerations regarding effective formulations and administration
procedures are well known in the art and are described in standard textbooks.
Drug
formulations are discussed in, for example, Hoover, John E., Remin tg 0n'5
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975,
hereby
incorporated by reference. Another discussion of drug formulations can be
found in
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel
Decker, New York, N.Y., 1980, hereby incorporated by reference.
2 5 BIOLOGICAL EVALUATION
A combination therapy of a cyclooxygenase-2 inhibitor and a tumor necrosis
factor antagonist for the treatment of an arthritic or inflammatory disorder
in a
mammal can be evaluated as described in the following tests.
Induction and assessment of collagen induced arthritis in mice
Arthritis is induced in 8-12 week old male DBA/1 mice by injection of 50 mg
of chick type II collagen (CII) in complete Freunds adjuvant (Sigma) on day 0
at the

CA 02369145 2001-11-15
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base of the tail as previously described [J. Stuart, Annual Rev. Immunol., 2,
199
(1984)]. Compounds are prepared as a suspension in 0.5% methylcellulose
(Sigma,
St. Louis, MO), 0.025% Tween 20 (Sigma). The cyclooxygenase-2 inhibitors and
the
tumor necrosis factor antagonist are administered alone or a cyclooxygenase-2
inhibitor and the tumor necrosis factor antagonist in combination. The
compounds are
administered in non-arthritic animals by gavage in a volume of 0.1 ml
beginning on
day 20 post collagen injection and continuing daily until final evaluation on
day 55.
Animals are boosted on day 21 with 50 mg of collagen (CII) in incomplete
Freunds
adjuvant. The animals are subsequently evaluated several times each week for
incidence and severity of arthritis until approximately day 56. Any animal
with paw
redness or swelling is counted as arthritic. Scoring of severity is carried
out using a
score of 0-3 for each paw (maximal score of 12/mouse) as previously described
[P.
Wooley, et al., Trans. Proc., 15, 180 (1983)]. The animals are measured for
incidence
of arthritis and severity in the animals where arthritis is observed. The
incidence of
arthritis is determined at a gross level by observing the swelling or redness
in the paw
or digits. Severity is measured with the following guidelines. Briefly,
animals
displaying four normal paws, i.e., no redness or swelling are scored 0. Any
redness or
swelling of digits or the paw is scored as 1. Gross swelling of the whole paw
or
deformity is scored as 2. Ankylosis of joints is scored as 3.
Histolog cal Examination of Paws
In order to verify the gross determination of a non-arthritic animal, a
histological examination is performed. Paws from animals sacrificed at the end
of the
experiment were removed, fixed and decalcified as previously described [R.
Jonsson,
J. Immunol. Methods, 88, 109 (1986)]. Samples are paraffin embedded,
sectioned, and
stained with hematoxylin and eosin by standard methods. Stained sections are
examined for cellular infiltrates, synovial hyperplasia, and bone and
cartilage erosion.
Rat Carra~eenan Foot Pad Edema Test
3 0 The carrageenan foot edema test is performed with materials, reagents and
procedures essentially as described by Winter et al., (Proc. Soc. Exp. Biol.
Med., 111,
544 (1962)). Male Sprague-Dawley rats are selected in each group so that the
average
body weight is as close as possible. Rats are fasted with free access to water
for over

CA 02369145 2001-11-15
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t~ ~
sixteen hours prior to the test. The rats are dosed orally (1 mL) with
compounds
suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or
with
vehicle alone. One hour later a subplantar injection of 0.1 mL of 1 % solution
of
carrageenan/sterile 0.9% saline is administered and the volume of the injected
foot is
measured with a displacement plethysmometer connected to a pressure transducer
with
a digital indicator. Three hours after the injection of the carrageenan, the
volume of
the foot is again measured. The average foot swelling in a group of drug-
treated
animals is compared with that of a group of placebo-treated animals and the
percentage inhibition of edema is determined (Otterness and Bliven, Laboratory
Models for Testing NSAIDs, in Non-steroidal Anti-Inflammatory DruQS, (J.
Lombardino, ed. 1985)).
Rat Carra~eenan-induced Analgesia Test
The analgesia test using rat carrageenan is performed with materials, reagents
and procedures essentially as described by Hargreaves, et al., Pain, 32, 77
(1988)).
Male Sprague-Dawley rats are treated as previously described for the
Carrageenan
Foot Pad Edema test. Three hours after the injection of the carrageenan, the
rats are
placed in a special plexiglass container with a transparent floor having a
high intensity
lamp as a radiant heat source, positionable under the floor. After an initial
twenty
2 0 minute period, thermal stimulation is begun on either the injected foot or
on the
contralateral uninfected foot. A photoelectric cell turns off the lamp and
timer when
light is interrupted by paw withdrawal. The time until the rat withdraws its
foot is
then measured. The withdrawal latency in seconds is determined for the control
and
drug-treated groups, and percent inhibition of the hyperalgesic foot
withdrawal
2 5 determined.
Besides being useful for human treatment, the method, combinations,
agents and compositions of the present invention are also useful for
treatment of mammals, including, but not limited to, horses, dogs, cats, rats,
3 0 mice, sheep, pigs, etc.
The present invention further includes kits comprising a cyclooxygenase-2
inhibitor and a tumor necrosis factor antagonist.

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Although this invention has been described with respect to specific
embodiments, the details of these embodiments are not to be construed as
limitations.