Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-09-17
2004-12-28
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233500, C514S253040, C514S253060, C514S301000, C514S314000, C544S060000, C544S128000, C544S127000, C544S362000, C544S363000, C546S115000, C546S176000
Reexamination Certificate
active
06835731
ABSTRACT:
TECHNICAL FIELD
This invention generally relates to novel compounds, pharmaceutical compositions and their use. This invention more specifically relates to novel heterocyclic compounds that bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
BACKGROUND OF THE INVENTION
Approximately 40 human chemokines have been described, that function, at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: P. Ponath,
Exp. Opin. Invest. Drugs
, 7:1-18, 1998; Baggiolini, M.,
Nature
392:565-568 (1998); Locati, et al.,
Annu. Rev. Med
. 50:425-440 (1999)). These
chemotactic
cytokines, or
chemokines
, constitute a family of proteins, approximately 8-10 kDa in size. Chemokines appear to share a common structural motif, that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the “CC” or &bgr;-chemokines and the “CXC” or &agr;-chemokines. The receptors of these chemokines are classified based upon the chemokine that constitutes the receptor's natural ligand. Receptors of the &bgr;-chemokines are designated “CCR” while those of the &agr;-chemokines are designated “CXCR”.
Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation (see
Chemokines in Disease
published by Humana Press (1999), Edited by C. Herbert; Murdoch, et al.,
Blood
95:3032-3043 (2000)). More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta, et al.,
J. Biol. Chem
., 7:4282-4287 (1998); Volin, et al.,
Biochem. Biophys Res. Commun
. 242:46-53 (1998)). Two specific chemokines have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
In most instances, HIV initially binds via its gp120 envelope protein to the CD4 receptor of the target cell. A conformational change appears to take place in gp120 which results in its subsequent binding to a chemokine receptor, such as CCR5 (Wyatt, et al.,
Science
, 280:1884-1888 (1998); Rizzuto, et al.,
Science
, 280:1949-1953 (1998); Berger, et al.,
Annu. Rev. Immunol
. 17:657-700 (1999)). HIV-1 isolates arising subsequently in the infection bind to the CXCR4 chemokine receptor.
Following the initial binding by HIV to CD4, virus-cell fusion results, which is mediated by members of the chemokine receptor family, with different members serving as fusion cofactors for macrophage-tropic (M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carroll, et al.,
Science
, 276:273-276 (1997); Feng, et al.,
Science
272:872-877 (1996); Bleul, et al.,
Nature
382:829-833 (1996); Oberlin, et al.,
Nature
382:833-835 (1996); Cocchi, et al.,
Science
270:1811-1815 (1995); Dragic, et al.,
Nature
381:667-673 (1996); Deng, et al.,
Nature
381:661-666 (1996); Alkhatib, et al.,
Science
272:1955-1958 (1996). During the course of infection within a patient, it appears that a majority of HIV particles shift from the M-tropic to the more pathogenic T-tropic viral phenotype (Blaak, et al.,
Proc. Natl. Acad. Sci
. 97:1269-1274 (2000); Miedema, et al.,
Immune. Rev
., 140:35 (1994); Simmonds, et al.,
J. Virol
. 70:8355-8360 (1996); Tersmette, et al.,
J. Virol
. 62:2026-2032 (1988); Connor, R. I., Ho, D. D.
J. Virol
. 68:4400-4408 (1994); Schuitemaker, et al.,
J. Virol
. 66:1354-1360 (1992)). The M-tropic viral phenotype correlates with the virus's ability to enter the cell following binding of the CCR5 receptor, while the T-tropic viral phenotype correlates with viral entry into the cell following binding and membrane fusion with the CXCR4 receptor. Clinical observations suggest that patients who possess genetic mutations in CCR5 appear resistant, or less susceptible to HIV infection (Liu, et al.,
Cell
86:367-377 (1996); Samson, et al.,
Nature
382:722-725 (1996); Michael, et al.,
Nature Med
. 3:338-340 (1997); Michael, et al.,
J. Virol
. 72:6040-6047 (1998); Obrien, et al.,
Lancet
349:1219 (1997); Zhang, et al.,
AIDS Res. Hum. Retroviruses
13:1357-1366 (1997); Rana, et al.,
J. Virol
. 71:3219-3227 (1997); Theodorou, et al.,
Lancet
349:1219-1220 (1997). Despite the number of chemokine receptors which have been reported to HIV mediate entry into cells, CCR5 and CXCR4 appear to be the only physiologically relevant coreceptors used by a wide variety of primary clinical HIV-1 strains (Zhang, et al.,
J. Virol
. 72:9307-9312 (1998); Zhang, et al.,
J. Virol
. 73:3443-3448 (1999); Simmonds, et al.,
J. Virol
. 72:8453-8457 (1988)). Fusion and entry of T-tropic viruses that use CXCR4 are inhibited by the natural CXC-chemokine stromal cell-derived factor-1, whereas fusion and entry of M-tropic viruses that use CCR5 are inhibited by the natural CC-chemokines namely, Regulated on Activation Normal T-cell Expressed and Secreted (RANTES) and Macrophage Inflammatory proteins (MIP-1 alpha and beta).
In addition to serving as a co-factor for HIV entry, the direct interaction of virus-associated gp120 with CXCR4 has been recently suggested as a possible cause of CD8
+
T-cell apoptosis and AIDS-related dementia via induction of neuronal cell apoptosis (Hesselgesser, et al.,
Curr. Biol
. 8:595-598 (1998); Hesselgesser, et al.,
Curr. Biol
. 7:112-121 (1997); Hesselgesser, et al., “Chemokines and Chemokine receptors in the Brain” in
Chemokines in Disease
published by Humana Press (1999), Edited by C. Herbert; Herbein, et al.,
Nature
395:189-194 (1998); Buttini, et al.,
Nature Med
. 4:441-446 (1998); Ohagen, et al.,
J. Virol
. 73:897-906 (1999); Biard-Piechaczyk, et al.,
Virology
268:329-344 (2000); Sanders, et al.,
J. Neuroscience Res
. 59:671-679 (2000); Bajetto, et al.,
J. Neurochem
. 73:2348-2357 (1999); Zheng, et al.,
J. Virol
. 73:8256-8267 (1999)).
However, the binding of chemokine receptors to their natural ligands appears to serve a more evolutionary and central role than only as mediators of HIV infection. The binding of the natural ligand, pre-B-cell growth-stimulating factor/stromal cell derived factor (PBSF/SDF-1) to the CXCR4 chemokine receptor provides an important signaling mechanism: CXCR4 or SDF-1 knock-out mice exhibit cerebellar, cardiac and gastrointestinal tract abnormalities and die in utero (Zou, et al.,
Nature
, 393:591-594 (1998); Tachibana, et al.,
Nature
, 393:591-594 (1998); Nagasawa, et al.,
Nature
382:635-638 (1996)). CXCR4-deficient mice also display hematopoietic defects (Nagasawa, et al.,
Nature
382:635-638 (1996)); the migration of CXCR4 expressing leukocytes and hematopoietic progenitors to SDF-1 appears to be important for maintaining B-cell lineage and localization of CD34
+
progenitor cells in bone marrow (Bleul, et al.,
J. Exp. Med
. 187:753-762 (1998); Viardot, et al.,
Ann. Hematol
. 77:195-197 (1998); Auiti, et al.,
J. Exp. Med
. 185:111-120 (1997); Peled, et al.,
Science
283:845-848 (1999); Qing, et al.,
Immunity
10:463-471 (1999); Lataillade, et al.,
Blood
95:756-768 (1999); Ishii, et al.,
J. Immunol
. 163:3612-3620 (1999); Maekawa, et al.,
Internal Medicine
39:90-100 (2000); Fedyk, et al.,
J. Leukocyte Biol
. 66:667-673 (1999); Peled, et al.,
Blood
95:3289-3296 (2000)).
The signal provided by SDF-1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth (See “
Chemokines and Cancer
” published by Humana Press (1999); Edited by B. J. Rollins; Arenburg, et al.,
J. Leukocyte Biol
. 62:554-562 (1997); Moore, et al.,
J. Invest. Med
. 46:113-120 (1998); Moore, et al.,
Trends cardiovasc. Med
. 8:51-58 (1998); Seghal, et al.,
J. Surg. Oncol
. 69:99-104 (1998)); the known angiogenic growth factors VEG-F a
Atsma Bem
Bogucki David
Bridger Gary
Crawford Jason
Dennis Christopher
AnorMED Inc.
Morrison & Foerster / LLP
Raymond Richard L.
Truong Tamthom N.
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