Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-03
2003-02-18
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S315100
Reexamination Certificate
active
06521655
ABSTRACT:
This invention relates to a series of substituted imidazoles, pharmaceutical compositions containing them and intermediates used in their manufacture. The compounds of the invention inhibit the production of a number of inflammatory cytokines, particularly, TNF-&agr;, and IL-1&bgr;. Compounds of this invention are useful in the treatment of diseases associated with overproduction of inflammatory cytokines, such as rheumatoid arthritis, inflammatory bowel disease, septic shock, osteoporosis, and osteoarth ritis.
BACKGROUND OF THE INVENTION
The inflammatory cytokines, IL-1&bgr; and TNF-&agr; play an important role in a number of inflammatory diseases such as rheumatoid arthritis. C. Dinarello et al,. Inflammatory cytokines: Interleukin-1 and Tumor Necrosis Factor as Effector Molecules in Autoimmune Diseases
Curr. Opin. Immunol.
1991, 3, 941-48. Arthritis is an inflammatory disease which affects millions of people and can strike at any joint of the human body. Its symptoms range from mild pain and inflammation in affected joints, to severe and debilitating pain and inflammation. Although the disease is associated mainly with aging adults, it is not restricted to adults. The most common arthritis therapy involves the use of nonsteroidal antiinflammatory drugs (NSAID) to alleviate the symptoms. However, despite their widespread use, many individuals cannot tolerate the doses necessary to treat the disease over a prolonged period of time. In addition, NSAIDs merely treat the symptoms of disease without affecting the underlying cause. Other drugs, such as methotrexate, gold salts, D-pencillamine, and prednisone are often used when patients fail to respond to NSAIDS. These drugs also have significant toxicities and their mechanism of action remain unknown.
Receptor antagonists to IL-1&bgr; and monoclonal antibodies to TNF-&agr; have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials. In addition to protein based therapies, there are small molecule agents which inhibit the production of these cytokines and have demonstrated activity in animal arthritis models. J. C. Boehm et al., 1-Substituted 4-Aryl-5-pyridinylimidazoles: A New Class of Cytokine Suppressive Drugs With Low 5-Lipoxygenase and Cyclooxygenase Inhibitory Potency,
J. Med. Chem.,
1996, 39, 3929-37. Of these small molecule agents, SB 203580 has proved effective in reducing the production of TNF-&agr; and IL-1 in LPS stimulated human monocyte cell lines with IC
50
values of 50 to 100 nM. J. Adams et al., Imidazole Derivatives And Their Use as Cytokine Inhibitor, International Patent application WO 93/14081, Jul. 23, 1993. In addition to this in vitro test, SB 203580 inhibits the production of the inflammatory cytokines in rats and mice at IC
50
values of 15 to 25 mg/kg. A. M. Badger, et al, Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function,
The Journal of Pharmacology and Experimental Therapeutics,
1996, 279, 1453-61. Although human data is currently unavailable for SB 203580, monoclonal antibodies to TNF-&agr; have proved efficacious in the treatment of rheumatoid arthritis. M. J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor &agr;,
Arthritis Rheum.
1993 36, 1681-90. Due to SB 203580's oral activity and potency in animal models, researchers have suggested that a compound with this profile has potential as a viable treatment for rheumatoid arthritis. A. M. Badger, et al. Pharmacological Profile of SB 203580, A Selective Inhibitor of Cytokine Suppressive Binding Protein/p38 Kinase, in Animal Models of Arthritis, Bone Resorption, Endotoxin Shock and Immune Function,
The Journal of Pharmacology and Experimental Therapeutics,
1996, 279, 1453-61.
SB 203580 and other small molecule agents reduce the production of inflammatory cytokines by inhibiting the activity of a serine/threonin kinase p38 (note other researchers refer to this enzyme as CSBP), at an IC
50
of 200 nM. D. Griswold et al., Pharmacology of Cytokine Suppressive Anti-inflammatory Drug Binding Protein (CSPB), A Novel Stress-Induced Kinase,
Pharmacology Communications,
1996, 7, 323-29. Although the precise mechanism of this kinase is unknown, it has been implicated in both the production of TNF-&agr; and the signaling responses associated with the TNF-&agr; receptor.
SUMMARY OF THE INVENTION
The novel compounds of this invention inhibit the in vitro activity of p-38 in the nanomolar range. In addition, the compounds inhibit the in vitro secretion of TNF-&agr; and IL-1&bgr; in the nanomolar range. Animal models demonstrate the inhibition of LPS induced TNF-&agr;, as well as the inhibition of rheumatoid arthritis. With this range of activity the compounds of the invention are useful in the treatment of a variety of cytokine related disorders including: rheumatoid arthritis, inflammatory bowel disease, septic shock osteoporosis, osteoarthritis, neuropathic pain, HIV replication, HIV dementia, viral myocarditis, insulin-dependent diabetes, non-insulin dependent diabetes, periodontal disease, restenosis, alopecia areta, T-cell depletion in HIV infection or AIDS, psoriasis, actue pancreatitis, allograft rejection, allergic inflammation in the lung, atherosclerosis, mutiple sclerosis, cachexia, alzheimer's disease, stroke, Crohn's disease, inflammatory bowel disease, ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre Syndrome, and systemic lupus erythematosus.
The invention relates to compounds of the Formula I
wherein:
R
1
is phenyl, substituted phenyl (where the substituents are selected from the group consisting of C
1-5
alkyl, halogen, nitro, trifluoromethyl, and nitrile), or heteroaryl where the heteroaryl contains 5 to 6 ring atoms;
R
2
is phenyl, substituted phenyl (where the substituents are selected from the group consisting of C
1-5
alkyl, halogen, nitro, trifluoromethyl, and nitrile), heteroaryl where the heteroaryl contains 5 to 6 ring atoms and is optionally C
1-4
alkyl substituted;
R
3
is hydrogen, SEM, C
1-5
alkoxycarbonyl, aryloxycarbonyl, arylC
1-5
alkyloxycarbonyl, arylC
1-5
alkyl, substituted arylC
1-5
alkyl (where the aryl substituents are independently selected from one or more members of the group consisting of C
1-5
alkyl, C
1-5
alkoxy, halogen, amino, C
1-5
alkylamino, and diC
1-5
alkylamino), phthalimidoC
1-5
alkyl, aminoC
1-5
alkyl, diaminoC
1-5
alkyl, succinimidoC
1-5
alkyl, C
1-5
alkylcarbonyl, arylcarbonyl, C
1-5
alkylcarbonylC
1-5
alkyl, aryloxycarbonylC
1-5
alkyl, heteroarylC
1-5
alkyl where the heteroaryl contains 5 to 6 ring atoms;
R
4
is —(A)—(CH
2
)
q
—X where:
A is vinylene, ethynylene or
where
R
5
is selected from the group consisting of hydrogen, C
1-5
alkyl, phenyl and phenylC
1-5
alkyl;
q is 0-9;
X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl (where one or more substituents are selected from the group consisting of fluorine, bromine, chlorine and iodine), ethynyl, substituted ethynyl (where the substituents are selected from one or more of the group consisting of fluorine, bromine chlorine and iodine), C
1-5
alkyl, substituted C
1-5
alkyl (where the alkyl substituents are selected from the group consisting of one or more C
1-5
alkoxy trihaloalkyl, phthalimido and amino), C
3-7
cycloalkyl, C
1-5
alkoxy, substituted C
1-5
alkoxy (where the alkyl substituents are selected from the group consisting of phthalimido and amino), phthalimidooxy, phenoxy, substituted phenoxy (where the phenyl substituents are selected from the group consisting of C
1-5
alkyl, halogen and C
1-5
alkoxy), phenyl, substituted phenyl (where the phenyl substituents are selected from the group consisting of C
1-5
alkyl, halogen and C
1-5
alkoxy), arylC
1-5
alkyl, substituted arylC
1-5
alkyl (where the aryl substituents are selected from the group consisting of C
1-5
alkyl, halogen and C
1-5
alkoxy)
Beers Scott A.
Malloy Elizabeth A.
Wachter Michael P.
Wu Wei
Fan Jane
Harbour John W.
Ortho-McNeil Pharmaceutical , Inc.
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