Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-29
2003-01-14
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S451000, C514S453000, C514S454000, C514S455000, C549S385000
Reexamination Certificate
active
06506790
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to substituted benzo[1,2-b:5,4-b′]dipyran4-amines which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR5 now designated as CCR5 (
Nature Medicine
, 2: 1174-8, 1996). 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 TNF&agr;. 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 a topic 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 sirnilarities to the RANTES binding site observed on isolated T cells. Therefore, antagonism of RANTES' action on CCR5, as well as antagonism of other natural modulators of CCR5, should inhibit the recruitment of T cells into inflammatory lesions and provide a novel therapeutic approach for the treatment of a topic and autoimmune disorders.
Since T cells express CCR5, selective receptor modulators of CCR5, particularly antagonists, are likely to provide beneficial effects in diseases including, but not limited to, asthma and a topic disorders (for example, a topic dermatitis and allergies), rheumatoid arthritis, atherosclerosis, psoriasis, sarcoidosis and other fibrotic diseases, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Furtermore since CD8+ T cells have been implicated in COPD, CCR5 may play a role in their recruitment and therefore antagonists to CCR5 could provide potential therpeutic in the treatment of COPD. Also since CCR5 is a co-receptor for the entry of HIV into cells, selective receptor modulators may be useful in the treatment of HIV infection.
Surprisingly, it has now been discovered that a class of non-peptide compounds, in particular substituted benzo[1,2-b:5,4-b′]dipyran-4-amines of formula (I), function as CCR5 receptor modulators, and therefore, have utility in the treatment and prevention of disease states mediated by CCR5 receptor mechanisms.
SUMMARY OF THE INVENTION
In one aspect, the present invention is to a genus of novel compounds of formula (I), or pharmaceutically active salts thereof, said compounds which are also useful in treating the above-mentioned CCR5-mediated disease states:
wherein:
R
1
, R
2
, R
6
, and R
7
are independently hydrogen or C
1-6
alkyl;
R
3
is hydrogen or hydroxy;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, or aralkyl; or, NR
4
R
5
may form a heterocyclic ring having 5-, 6-, or 7-members, optionally containing one of oxygen, sulfur, or NR
8
;
R
8
is hydrogen, C
1-6
alkyl, or aralkyl;
X is hydrogen or one or more of C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
5-6
cycloalkenyl, aralkyl, aryl, CH
2
NR
9
R
10
, CH
2
OR
11
, COR
11
, CONR
9
R
10
, CO
2
R
11
, cyano, trifluoromethyl, NR
9
R
10
, NR
9
COR
11
, NR
9
CONR
9
R
10
NR
9
CO
2
R
12
, NR
9
SO
2
R
13
, nitro, hydroxy, C
1-6
alkoxy, OC(O)R
11
, OC(O)NR
9
R
10
, SR
14
, SOR
13
, SO
2
R
13
, SO
2
NR
9
R
10
or halogen;
R
9
and R
10
are independently hydrogen, C
1-6
allkyl, aralkyl or aryl; or NR
9
R
10
forms a heterocyclic ring having 5-, 6-, or 7-members, optionally containing one oxygen, sulfur, or NR
8
;
R
11
is hydrogen, C
1-6
alkyl, aralkyl, aryl, or trifluoromethyl;
R
12
is C
1-6
alkyl, aralkyl, aryl, or trifluoromethyl;
R
13
is C
1-6
alkyl, aralkyl, aryl, or trifluoromethyl;
R
14
is hydrogen, C
1-6
alkyl, aralkyl, aryl, or trifluoromethyl; and
is a single or a double bond.
In another aspect, the present invention is to a method of treating CCR5 mediated disease
Blaney Frank E.
Bondinell William E
Chan James A.
Delacroix-Muirheid C.
Jones Dwayne C.
Kinzig Charles M.
SmithKline Beecham Corporation
Stein-Fernandez Nora
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