Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-28
2003-05-13
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S459000, C546S276400, C544S124000, C544S106000, C544S111000, C544S114000
Reexamination Certificate
active
06562843
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel substituted 3-pyridyl-4-arylpyrroles and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.
BACKGROUND OF THE INVENTION
TNF-&agr; and p38-Related Disorders
Inflammatory cytokines such as TNF-&agr; are produced via the activity of kinases. Such kinases include the Cytokine Suppressive Antiinflammatory Drug-Binding Protein (CSBP)/p38 kinase, a Mitogen-Activated Protein (MAP) kinase family of serine-threonine protein kinases. Inflammatory cytokines play an important role in a number of inflammatory disorders (1), neurodegenerative disorders (10), and AIDS-related disorders (11-14). Although the precise mechanism of kinases such as p38 is unknown, p38 has been implicated in both the production of TNF-&agr; and the signaling responses associated with the TNF-&agr; receptor (6).
Arthritis is a prime example of an inflammatory disorder, and is thus the inflammatory disorder focused on most in this section. Arthritis affects millions of people and can strike at 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 disorder 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 disorder over a prolonged period of time. In addition, NSAID's merely treat the symptoms of disorder without affecting the underlying cause.
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 mechanism of action remains unknown. Monoclonal antibodies to TNF-&agr; and receptor antagonists to interleukin 1&bgr; (IL-1&bgr;) have been shown to reduce symptoms of rheumatoid arthritis in small-scale human clinical trials (2).
In addition to protein-based therapies, there are small molecule agents that inhibit the production of these cytokines and have demonstrated activity in animal rheumatoid arthritis models (3). Of these small molecule agents, SB 203580 has proven effective in reducing the production of TNF-&agr; and IL-1&bgr; in lipopolysaccharide (LPS)-stimulated human monocyte cell lines with IC
50
values of 50 to 100 nM (4).
In addition to in vitro testing results, 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 (5). SB 203580 reduces the production of inflammatory cytokines by inhibiting the activity of CSBP/p38 kinase at an IC
50
of 200 nM (6). Due to SB 203580's oral activity and potency in animal models, researchers have suggested that a compound with such an activity profile has potential as a viable treatment for rheumatoid arthritis (5).
Pyridylpyrroles and their analogs have also been prepared as cytokine inhibitors and glucagon antagonists (7), and specifically as inhibitors of IL-1&bgr;, TNF-&agr; and other cytokines. Arylpyrroles (8) and triarylpyrroles (9) have also been prepared as cytokine inhibitors.
The role of CSBP/p38 has been implicated recently in various neurodegenerative and AIDS-related disorders. With regard to neurodegenerative disorders, p38 has been shown to have a role in determining whether a cell survives or undergoes neuronal programmed cell death or apoptosis (10, 11).
Also related to AIDS, the Kaposi's sarcoma-associated herpesvirus HHV8 has been shown to encode a G protein-coupled receptor that activates p38. It has been proposed that this activation contributes to tumorigenesis and angiogenesis leading to Kaposi's sarcoma (12).
Associated with AIDS is the rapid activation of p38 induced by infection of a CCR5
+
human T cell line by SIV, suggesting that p38 may play a role in early viral infection (13). Additionally, p38 inhibitors have been shown to block HIV replication in vitro in a manner that may be TNF-&agr;-independent (14).
Absence of Clinically Effective Agents
In general, arthritis—particularly rheumatoid arthritis—and the host of other inflammatory and AIDS-related disorders all take a severe toll on those afflicted. There is a tremendous need for small molecule agents to treat these disorders. To date, however, no such agents have ever been identified and shown to be clinically effective in humans.
SUMMARY OF THE INVENTION
This invention provides a compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
(a) R
1
is selected from the group consisting of (i) hydrogen, (ii) C
1-5
alkyl, (iii) substituted or unsubstituted C
1-5
alkylamino, (iv) N-containing C
1-5
alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C
1-5
alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R
2
is selected from the group consisting of (i) hydrogen, (ii) (CH
2
)
3
OH, (iii) substituted or unsubstituted C
1-5
alkyl phenyl, and (iv) N-containing C
1-5
alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R
3
is one or more substituents independently selected from the group consisting of hydrogen, halogen, methoxy, nitro, trifluoromethyl, hydroxy, dimethylamino and methylsulfoxide; and
(d) X is either C or N.
This invention also provides a second compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
(a) R
1
is selected from the group consisting of (i) hydrogen, (ii) C
1-5
alkyl, (iii) substituted or unsubstituted C
1-5
alkylamino, (iv) N-containing C
1-5
alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole, (v) phenyl, (vi) phenyl independently substituted with one or more of C
1-5
alkyl, amino, substituted amino, nitro, nitrile and sulfone, and (vii) pyridine;
(b) R
2
is selected from the group consisting of (i) hydrogen, (ii) (CH
2
)
3
OH, (iii) substituted or unsubstituted C
1-5
alkyl phenyl, and (iv) N-containing C
1-5
alkyl heterocycle selected from thiazolidine, piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine, thiazine, pyrrole and imidazole;
(c) R
4
is a substituted or unsubstituted heterocycle selected from pyridine, pyrimidine, furan or thiophene; and,
(d) X is either C or N.
This invention further provides a pharmaceutical composition comprising one of the instant compounds and a pharmaceutically acceptable carrier.
This invention still further provides a method of treating a subject having a disorder ameliorated by reducing TNF-&agr; production and/or p38 activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
Finally, this invention provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides novel substituted 3-pyridyl-4-arylpyrroles. These compounds have surprising usefulness in treating disorders ameliorated by a reduction in TNF-&agr; production and/or p38 activity, and are therefore useful for treating inflammatory disorders such as rheumatoid arthritis, as well as AIDS-related disorders.
Specifically, this invention provides a first compound having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
(a) R
1
is selected from the group consis
Desai Rita
Ortho-McNeil Pharmaceutical , Inc.
Rotman Alan L.
LandOfFree
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