Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-02
2001-06-05
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S103000, C546S106000
Reexamination Certificate
active
06242459
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to substituted bis-acridines and related compounds which are ligands, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (
Nature Medicine
1996, 2, 1174-8). In addition, this invention relates to the treatment and prevention of disease states mediated by CCR5.
BACKGROUND OF THE INVENTION
T cells are not only key regulators of the immune response to infectious agents but are believed critical for the initiation and maintenance of the inflammatory reaction in a variety of chronic diseases. Increased numbers or enhanced activation state of T cells, especially CD4+ T cells, have been demonstrated in the synovium of individuals with rheumatoid arthritis (M. J. Elliott and R. N. Maini,
Int. Arch. Allergy Immunol.
104: 112-1125, 1994), in the bronchial mucosa of asthmatics (C. J. Corrigan and A. B. Kay,
Immunol. Today
13: 501-506, 1992), in the lesions of multiple sclerosis (R. Martin and H. F. McFarland,
Crit. Rev. Clin. Lab. Sci.
32: 121-182, 1995), in psoriatic lesions (J. L. Jones, J. Berth-Jone, A. Fletcher and P. E. Hutchinson,
J. Pathol.
174: 77-82, 1994) and in the fatty streaks of atherosclerosis (R. Ross,
Annu. Rev. Physiol.
57: 791-804, 1995).
T cells, as well as other inflammatory cells, will migrate into tissues in response to the production of a variety chemotactic factors. Among these factors are a superfamily of 8-12 kDa proteins known as the chemokines. These proteins share structural features such as the presence of 3-4 conserved cysteine residues. RANTES, which stands for Regulated upon Activation Normal T cell Expressed and Secreted, is a 8 kDa protein member of CC branch of the chemokine family. These proteins recruit and activate immune and inflammatory cells through an interaction with G-protein coupled receptors. The CC branch is defined by the absence of an intervening amino acid residue between the first two cysteine residues and members of this family predominately elicit the migration of mononuclear cells, eosinophils and basophils (M. Baggiolini, B. Dewald, and B. Moser,
Adv. Immunol.
55:97-179, 1994; and J. J. Oppenheim, C. O. C. Zachariae, N. Mukaida, and K. Matsushima,
Annu. Rev. Immunol.
9: 617-648, 1991).
RANTES potently produces chemotaxis of T cells, basophils, eosinophils, monocytes and mast cells. RANTES was originally identified as gene product induced late after antigen activation of T-cells (T. J. Schall, J. Jongstra, B. J. Dyer, J. Jorgensen, et al.,
J. Immunol.
141:1018-1025, 1988), however, RANTES has been shown to be synthesized and secreted by a diverse group of cells that include epithelial and endothelial cells (C. Stellato, L. A. Beck, G. A. Gorgone, D. Proud, et al.,
J. Immunol.
155: 410-418, 1995; and A. Marfaing-Koka, O. Devergne, G. Gorgone, A. Portier, et al.,
J. Immunol.
154: 1870-1878, 1994), synovial fibroblasts (P. Rathanaswami, M. Hachicha, M. Sadick, T. J. Schall, et al.,
J. Biol. Chem.
268: 5834-5839, 1993) and dermal fibroblasts (M. Sticherling, M. Kupper, F. Koltrowitz, E. Bornscheuer, et al.,
J. Invest. Dermatol.
105: 585-591, 1995), mesangial cells (G. Wolf, S. Aberle, F. Thaiss, et al.,
Kidney Int.
44: 795-804, 1994) and platelets (Y. Koameyoshi, A. Dorschner, A. I. Mallet, E. Christophers, et al.,
J. Exp. Med.
176: 587-592, 1992). In these cells RANTES mRNA is rapidly upregulated in response to IL-1 or TNFa. Although RANTES mRNA is not usually detected in normal tissues (J. M. Pattison, P. J. Nelson, and A. M. Krensky,
Clin. Immunother.
4: 1-8, 1995), increased mRNA or protein has been found in diseases characterized by a mononuclear infiltrate. For example, RANTES mRNA was visualized using in situ hybridization in renal allografts undergoing rejection (J. M. Pattison, P. J. Nelson, and A. M. Krensky,
Clin. Immunother.
4: 1-8, 1995; and K. C. Nadeau, H. Azuma and N. I. Tilney,
Proc. Natl. Acad. USA
92: 8729-8733, 1995) in the skin of atopic dermatitis patients after exposure to antigen (S. Ying, L. Taborda-Barata, Q. Meng, M. Humbert, et al.,
J. Exp. Med.
181: 2153-2159, 1995), and in endothelial cells of coronary arteries undergoing accelerated atherosclerosis after cardiac transplant (J. M. Pattison, P. J. Nelson, and A. M. Krensky,
Clin. Immunother.
4: 1-8, 1995). Further, increased immunoreactive protein for RANTES has been detected in bronchoalveolar lavage fluid (R. Alam, J. York, M. Boyers, et al.,
Am. J. Resp. Crit. Care Med.
149: A951, 1994) and sputum from asthmatic individuals (C. M. Gelder, P. S. Thomas, D. H. Yates, I. M. Adcock, et al.,
Thorax
50: 1033-1037, 1995).
Several receptors have been identified that bind RANTES. In particular, CCR5, when expressed in either HEK 293 cells or CHO cells, binds RANTES. This receptor is expressed in T-cells and in monocytes and macrophages, immune/inflammatory cells which are important in the maintenance of a chronic inflammatory reaction. Pharmacological characterization of CCR5 indicates similarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural ligands of CCR5, should inhibit the recruitment of T cells into inflammatory lesions and provide a novel therapeutic approach for the treatment of atopic and autoimmune disorders.
Since T cells express CCR5, selective receptor ligands of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Also since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor ligands may be useful in the treatment of HIV infection.
A subset of compounds included in formula (I) have been reported to have intercalating activity (
J. Med. Chem.
1978, 21, 868-74;
Biochem. Pharmacol.
1977, 26, 275-8; and
J. Med. Chem.
1978, 21, 658-68), mutagenic activity (
Mutat. Res.
1990, 232, 337-43; and
Biochem. J.
1985, 226, 175-82), antitumor activity (
Biochem. Pharmacol.
1985, 34, 2123-8), antibacterial, antitubercular, and antileprotic activity (
Chem. Pharm. Bull.
1972, 20, 206-8), and anti-acetylcholinesterase activity (
Anal. Spectrosc. Libr.
1995, 6, 281-311).
Surprisingly, it has now been discovered that this class of non-peptide compounds, in particular substituted bis-acridines and related compounds of formula (I), function as CCR5 receptor ligands, agonists or antagonists, and therefore, have utility in the treatment of disease states wherein inhibition of CCR5 receptor mechanisms is indicated for prevention or therapeutic treatment.
SUMMARY OF THE INVENTION
In one aspect, the present invention is to a method of treating CCR5 mediated disease states, including, but not limited to, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, and HIV infection, all in mammals, preferably humans, comprising administering to such mammal in need thereof, an effective amount of a substituted bis-acridine or related compound of formula (I), or pharmaceutically active salts thereof:
wherein:
X are independently one or more of H, optionally substituted C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl, Ar-C
0-4
alkyl, CH
2
NR′
2
, CH
2
OR′, CN, COR′, CONR′
2
, CO
2
R′, CF
3
, N(R′)
2
, NR′COR′, NR′CONR′R′, NR′CO
2
R″, NR′SO
2
R″, NO
2
, OR′, S(O)
0-2
R″, S(O)
0-2
CF
3
, or halo;
R′ is H, optionally substituted C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl or Ar-C
0-4
alkyl;
R″ is C
1-6
alkyl, C
3-7
cycloalkyl-C
0-4
alkyl or Ar-C
0-4
alkyl;
D and D′ are independently CX or N;
V and V′ are independently C(R)
2
, NR
1
, O, or S(O)
0-2
;
R
1
are independ
Bondinell William E.
Fu Ku Thomas Wen
Reader Valerie A.
Huang Evelyn Mei
Kinzig Charles M.
SmithKline Beecham Corporation
Stein-Fernandez Nora
Venetianer Stephen
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