Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-20
2003-04-15
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S353000, C544S356000
Reexamination Certificate
active
06548499
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel quinoxaline compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutical carrier, and to pharmaceutical methods of treatment. The compounds of the present invention are Interleukin-8 (IL-8) receptor antagonists. More particularly, the compounds of the present invention are useful in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as, for example, a chemokine-mediated disease selected from psoriasis, or atopic dermatitis, tumor growth and angiogenesis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases.
IL-8 is a 72 amino acid protein which is a member of the superfamily of leukocyte chemoattractant proteins which have been referred to as intercrines, C-X-C or C-C cytokines or, more recently as chemokines (Oppenheim J. J. et al., “Properties of the novel proinflammatory supergene “intercrine” cytokine family.”
Annu. Rev. Immunol
., 1991;9:617-648). Many members of the chemokine family appear to be involved in the inflammatory process and in the trafficking of leukocytes. The chemokine superfamily is composed of two branches: the &agr;- and the &bgr;-chemokines. The &agr;-chemokine branch includes IL-8, neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA/gro or GRO&agr;), and ENA-78, all of which have attracting and activating effects predominantly on neutrophils. This branch also includes PF4, &bgr;-thromboglobulin, and CTAPIII, which do not affect neutrophils.
IL-8 was originally identified by its ability to both attract and activate polymorphonuclear leukocytes (neutrophils) and has now been shown to be rapidly induced in a wide variety of cell and tissue types in response to pro-inflammatory cytokines such as IL-1b or TNF&agr;. Additionally, there is data demonstrating high systemic levels of IL-8 in certain neutrophil-mediated inflammatory diseases, suggesting the IL-8 and closely related factors may be the principal endogenous mediators of neutrophil activation. Many reports have been published regarding disorders in which high levels of IL-8 have been measured, and include rheumatoid arthritis, septic shock, asthma, cystic fibrosis, myocardial infarction, and psoriasis (Baggiolini et al.,
FEBS Lett
, 1992;307:97; Miller et al.,
Crit. Rev. Immunol
., 1992;12:17. Oppenhein et al.,
Annu. Rev. Immunol
, 1991;9:617; Seitz et al.,
J. Clin. Invest
., 1991;87:463; Miller et al.,
Am. Rev. Respir. Dis
., 1992;146:427; Donnely et al.,
Lancet
, 1993;341:643). Strong in vivo evidence indicating a central role of IL-8 in the pathology related to lung ischemia/reperfusion has recently been published (Sekido N., Mukaida N. et al., “Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8.” Nature, 1993;365(6447):654-7 Issn: 0028-0836). A monoclonal antibody to rabbit IL-8, capable of blocking the in vitro neutrophil chemotactic activity of IL-8, prevented tissue damage in the rabbit lung normally resulting from lung ischemia/reperfusion. More recently, another study has shown beneficial effects of an IL-8 neutralizing antibody in an endotoxin-induced pleurisy model in rabbit (Broaddus V. C., Boylan A. M. et al., “Neutralization of IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy,”
J. Immunol
., 1994;152(6):2960-2967). There were also reports indicating similar beneficial effects with IL-8 neutralizing antibodies in animal models of dermatitis, joint arthritis, and glomerulonephritis. Additionally, knockout mice have been generated in which the apparent mouse homologue of the IL-8R (closer to IL-8RB) was deleted by homologous recombination (Cacalano G., Lee J. et al., “Neutrophil and b cell expansion in mice that lack the murine IL-8 receptor homolog,”
Science
, 1994;265(5172):682-4 Issn: 0036-8075). Although these mice appear healthy, their neutrophils are greatly impaired, as compared to wild-type mice, in their ability to migrate to the peritoneum in response to intraperitoneal thioglycollate injection. All of these results suggest that IL-8 is an important mediator of neutrophil migration and activity in some inflammatory settings, and that a small molecule antagonist to the receptors for IL-8 should prove to be an effective treatment for some inflammatory pathologies and has the potential to be a broadly useful anti-inflammatory agent. Also, there have been reports that IL-8 is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies (Hebert et al.,
Cancer Invest
., 1993;11:743 and Richards et al.,
American Journal of Surgery
, 1997;174:507).
We have identified a series of quinoxalines that are IL-8 receptor antagonists and which can additionally be used in psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e. cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, allograft rejections, or allergic diseases.
SUMMARY OF THE INVENTION
Accordingly, a first aspect of the present invention is a compound of Formula I
wherein A is selected from the group consisting of:
wherein R
3
, R
3a
, and R
3b
are each independently the same or different and are hydrogen,
alkyl,
aryl-SO
2
—,
aryl,
heteroaryl,
—OR
4
wherein R
4
is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or
wherein
R
5
and R
6
are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, —(CH
2
)
m
—OH, or
R
5
and R
6
are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R
4
wherein R
4
is as defined above and m is an integer of 2 to 5,
wherein n is zero or an integer of 1 and R
7
and R
8
are
each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or
wherein R
5
and R
6
are as defined above or R
7
and R
8
taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or N—R
4
wherein R
4
and m are as defined above,
wherein R
7
, R
8
, and n are as defined above,
wherein R
7
, R
8
, and n are as defined above,
—(CH
2
)
n
—SO
2
OR
4
wherein R
4
and n are as defined above,
—(CH
2
)
n
—CO
2
R
4
wherein R
4
and n are as defined above,
—CH
2
OR
4
wherein R
4
is as defined above,
halogen,
CF
3
,
CBr
3
,
CCl
3
, or
NO
2
,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above,
wherein R
3
and R
3a
are as defined above, and
wherein o is an integer of 1 or 2, and R
9
is hydrogen or alkyl;
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
3
, R
3a
, and R
3b
are as defined above,
wherein R
14
is hydrogen, alkyl, aryl, or aralkyl, and R
3
and R
3a
are as defined abo
Carson Kenneth G.
Connor David Thomas
Li Jie Jack
Low Joseph Edwin
Luly Jay R.
DeConti, Jr. Guilio A.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Millennium Pharmaceuticals Inc.
Raymond Richard L.
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