Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-08
2002-11-05
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S246000, C514S339000, C544S183000, C546S277100, C546S277700, C546S278700
Reexamination Certificate
active
06476028
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to substituted 3-(4-piperidinyl)indoles which are modulators, agonists or antagonists, of the CC chemokine receptor CC-CKR
5
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. Phvsiol
. 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 RANTE 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 modulators 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, receptor modulators 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, sarcoidosis and other fibrotic diseases, autoimmune diseases such as multiple sclerosis, and inflammatory bowel disease, all in mammals, preferably humans. Furthermore, 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 therapeutic in the treatment of COPD. Also since CCR5 is a co-receptor for the entry of HIV into cells, 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 3-(4-piperidinyl)indoles 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:
X is hydrogen or one or more of C
1-6
alkyl, CONRR′, trifluoromethyl, hydroxy, C
1-6
alkoxy, benzyloxy, C
1-6
alkylthio, or halo where R and R′ are independently hydrogen or C
1-6
alkyl;
R
1
is hydrogen or C
1-6
alkyl;
R
2
is hydrogen or C
1-6
alkyl;
the dotted line, . . . , indicates a single bond or a double bond;
R
3
is hydrogen or C
1-6
alkyl;
A is [C(R″)
2
]
m
CR″R
4
R
5
or [C(R″)
2
]
n
CR″=C R
4
R
5
where each R″ is independently hydrogen or C
1-6
alkyl;
m is 0-3;
n is 1-2
R
4
is phenyl, biphenyl, naphthyl, 1-benzotriazinyl, or 2-benzotriazinyl, optionally substituted with one or more of C
1-6
alkyl, cyano, trifluoromethyl, NR
6
R
7
, nitro, hydroxy, C
1-6
alkoxy, benzyloxy, C
1-6
alkylthio, or halo, where R
6
and R
7
are independently hydrogen or C
1-6
alkyl;
R
5
is R″ when m is 0; alternatively, R
5
is R″, phenyl or naphthyl when m is 1-3 or n is 1-2, wherein phenyl or naphthyl are optionally substituted with one or more of C
1-6
alkyl, cyano, trifluoromethyl, NR
6
R
7
, nitro, hydroxy, C
1-6
alkoxy, benzyloxy, C
1-6
alkylthio, or halo.
In another aspect, the present invention is to a method of treating CCR5 mediated disease states, including, but not limited to, COPD, asthma and atopic disorders (for example, atopic dermatitis and allergies), rheumatoid arthritis, sarcoidosis and other fibro
Bondinell William E.
Chan James
Dabbs Steven
Davies David T.
Porter Roderick A.
Covington Raymond
Kinzig Charles M.
Rotman Alan L.
SmithKline Beecham Corporation
Stein-Fernandez Nora
LandOfFree
Compounds and methods does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds and methods, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds and methods will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2961652