Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-25
2002-10-22
Fan, Jane (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S256000
Reexamination Certificate
active
06469174
ABSTRACT:
Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
FIELD OF THE INVENTION
This invention relates to substituted pyrrolobenzimidazoles, and related pharmaceutical compositions and methods for treating inflammatory diseases. The compounds of the invention inhibit the production of cytokines, particularly TNF-&agr; and IL-1, which mediate inflammatory responses.
BACKGROUND OF THE INVENTION
The inflammatory cytokines IL-1 and TNF-&agr; play an important role in a number of inflammatory diseases. (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.) Rheumatoid arthritis is a prime example of such inflammatory diseases, and is thus the inflammatory disease focused on most in this section.
Rheumatoid arthritis is an inflammatory disease which affects millions of people and can affect any joint in 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 rheumatoid arthritis therapy involves the use of nonsteroidal anti-inflammatory drugs (NSAID's) to alleviate symptoms. However, despite the widespread use of NSAID's, many individuals cannot tolerate the doses necessary to treat the disease over a prolonged period of time. In addition, NSAID's merely treat the symptoms of disease without affecting the underlying cause(s). Other drugs, such as methotrexate, gold salts, D-penicillamine and prednisone are often used when patients fail to respond to NSAID's. These drugs also have significant toxicities and their mechanisms of action remain unknown.
Receptor antagonists to IL-1 and monoclonal antibodies to TNF-&agr; have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials. (M. J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor &agr;,
Arthritis Rheum.
1993 36, 1681-90.)
In addition to protein-based therapies, there are small molecule agents which inhibit the production of these cytokines and have demonstrated activity in animal rheumatoid 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 proven 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, 1993.)
In addition to this in vitro behavior, SB 203580 has been shown to inhibit the production of 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.)
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 molecules reduce the production of inflammatory cytokines by inhibiting the activity of a serine/threonine kinase, p38 (also referred to in the art as “CSBP”), at an IC
50
of 200 &mgr;m. (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.
Rheumatoid arthritis, and the host of other inflammatory disorders, take a severe toll on those afflicted. There is thus a tremendous need for small molecule anti-inflammatory agents. To date, however, no such agent—including SB 203580—has ever been shown to be anti-inflammatory in human clinical trials.
SUMMARY OF THE INVENTION
This invention provides a compound having the structure
or a pharmaceutically acceptable salt thereof, wherein:
(a) R
1
, R
2
and R
3
are independently selected from the group consisting of (i) hydrogen, (ii) C
1-5
alkyl, (iii) C
1-5
alkylamino, (iv) diC
1-5
alkylamino, (v) a phenyl substituted with one or more of hydrogen, halogen, C
1-5
alkyl, and trihaloC
1-5
alkyl, and (vi) a phenylC
1-5
alkyl substituted with one or more of hydrogen, halogen, C
1-5
alkyl, and trihaloC
1-5
alkyl;
(b) rings 1 and 2 are each independently substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C
1-5
alkyl, and trihaloC
1-5
, alkyl;
(c) A and B are independently nitrogen or carbon, at least one of A and B being nitrogen;
(d) D and E are nitrogen, with the proviso that (i) a double bond exists between the non-aryl carbon and either D or E, (ii) R
2
is absent if the double bond exists between the non-aryl carbon and D, and (iii) R
3
is absent if the double bond exists between the non-aryl carbon and E; and
(e) the compound is neither 1,6-dihydro-7-(4-pyridyl)-8-(4-fluorophenyl)-2-phenylmethyl-pyrrolo[3,2-e]benzimidazole, nor 3,6-dihydro-8-(4-fluorophenyl)-3-(3-phenylpropyl)-7-(4-pyridyl)-pyrrolo[3,2-e]benzimidazole.
This invention also provides a pharmaceutical composition comprising the instant compound, and a pharmaceutically acceptable carrier. This invention further provides a method of treating a subject having an inflammatory disease, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
Finally, this invention provides a method of making the instant compound, which comprises the step of contacting a first compound having the structure
with a second compound having the structure
under conditions permitting a Fischer indolization between the first and second compounds.
REFERENCES:
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.
M.J. Elliot et al., Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor &agr;,Arthritis Rheum.1993 36, 1681-90.
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.
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, and Immune Function,The Journal of Pharmacology and Experimental Therapeutics, 1996, 279, 1453-61.
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.
Gallagher, T.F. et al., Regulation of Stress-Induced Cytokine Production by Pyridinylimidazoles; Inhibition of CSBP Kinase,Bioorganic&Medicinal Chemistry, 1997, 5, 49-64.
Chetverikov, V.P. et al., Synthesis of 2-imidazo[4,5-e] indoles from 5-aminobenzimidazoles,Zhim. Geterotsiki. Soedin, 1980, 1, 74-8.
Dodd John H.
Henry James R.
Rupert Kenneth C.
Fan Jane
Ortho-McNeil Pharmaceutical , Inc.
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